Normal tissue complication probability modelling of tissue fibrosis following breast radiotherapy

NASA Astrophysics Data System (ADS)

Alexander, M. A. R.; Brooks, W. A.; Blake, S. W.

2007-04-01

Cosmetic late effects of radiotherapy such as tissue fibrosis are increasingly regarded as being of importance. It is generally considered that the complication probability of a radiotherapy plan is dependent on the dose uniformity, and can be reduced by using better compensation to remove dose hotspots. This work aimed to model the effects of improved dose homogeneity on complication probability. The Lyman and relative seriality NTCP models were fitted to clinical fibrosis data for the breast collated from the literature. Breast outlines were obtained from a commercially available Rando phantom using the Osiris system. Multislice breast treatment plans were produced using a variety of compensation methods. Dose-volume histograms (DVHs) obtained for each treatment plan were reduced to simple numerical parameters using the equivalent uniform dose and effective volume DVH reduction methods. These parameters were input into the models to obtain complication probability predictions. The fitted model parameters were consistent with a parallel tissue architecture. Conventional clinical plans generally showed reducing complication probabilities with increasing compensation sophistication. Extremely homogenous plans representing idealized IMRT treatments showed increased complication probabilities compared to conventional planning methods, as a result of increased dose to areas receiving sub-prescription doses using conventional techniques.

NTCP modelling of lung toxicity after SBRT comparing the universal survival curve and the linear quadratic model for fractionation correction.

PubMed

Wennberg, Berit M; Baumann, Pia; Gagliardi, Giovanna; Nyman, Jan; Drugge, Ninni; Hoyer, Morten; Traberg, Anders; Nilsson, Kristina; Morhed, Elisabeth; Ekberg, Lars; Wittgren, Lena; Lund, Jo-Åsmund; Levin, Nina; Sederholm, Christer; Lewensohn, Rolf; Lax, Ingmar

2011-05-01

In SBRT of lung tumours no established relationship between dose-volume parameters and the incidence of lung toxicity is found. The aim of this study is to compare the LQ model and the universal survival curve (USC) to calculate biologically equivalent doses in SBRT to see if this will improve knowledge on this relationship. Toxicity data on radiation pneumonitis grade 2 or more (RP2+) from 57 patients were used, 10.5% were diagnosed with RP2+. The lung DVHs were corrected for fractionation (LQ and USC) and analysed with the Lyman- Kutcher-Burman (LKB) model. In the LQ-correction α/β = 3 Gy was used and the USC parameters used were: α/β = 3 Gy, D(0) = 1.0 Gy, [Formula: see text] = 10, α = 0.206 Gy(-1) and d(T) = 5.8 Gy. In order to understand the relative contribution of different dose levels to the calculated NTCP the concept of fractional NTCP was used. This might give an insight to the questions of whether "high doses to small volumes" or "low doses to large volumes" are most important for lung toxicity. NTCP analysis with the LKB-model using parameters m = 0.4, D(50) = 30 Gy resulted for the volume dependence parameter (n) with LQ correction n = 0.87 and with USC correction n = 0.71. Using parameters m = 0.3, D(50) = 20 Gy n = 0.93 with LQ correction and n = 0.83 with USC correction. In SBRT of lung tumours, NTCP modelling of lung toxicity comparing models (LQ,USC) for fractionation correction, shows that low dose contribute less and high dose more to the NTCP when using the USC-model. Comparing NTCP modelling of SBRT data and data from breast cancer, lung cancer and whole lung irradiation implies that the response of the lung is treatment specific. More data are however needed in order to have a more reliable modelling.

Assessing doses to terrestrial wildlife at a radioactive waste disposal site: inter-comparison of modelling approaches.

PubMed

Johansen, M P; Barnett, C L; Beresford, N A; Brown, J E; Černe, M; Howard, B J; Kamboj, S; Keum, D-K; Smodiš, B; Twining, J R; Vandenhove, H; Vives i Batlle, J; Wood, M D; Yu, C

2012-06-15

Radiological doses to terrestrial wildlife were examined in this model inter-comparison study that emphasised factors causing variability in dose estimation. The study participants used varying modelling approaches and information sources to estimate dose rates and tissue concentrations for a range of biota types exposed to soil contamination at a shallow radionuclide waste burial site in Australia. Results indicated that the dominant factor causing variation in dose rate estimates (up to three orders of magnitude on mean total dose rates) was the soil-to-organism transfer of radionuclides that included variation in transfer parameter values as well as transfer calculation methods. Additional variation was associated with other modelling factors including: how participants conceptualised and modelled the exposure configurations (two orders of magnitude); which progeny to include with the parent radionuclide (typically less than one order of magnitude); and dose calculation parameters, including radiation weighting factors and dose conversion coefficients (typically less than one order of magnitude). Probabilistic approaches to model parameterisation were used to encompass and describe variable model parameters and outcomes. The study confirms the need for continued evaluation of the underlying mechanisms governing soil-to-organism transfer of radionuclides to improve estimation of dose rates to terrestrial wildlife. The exposure pathways and configurations available in most current codes are limited when considering instances where organisms access subsurface contamination through rooting, burrowing, or using different localised waste areas as part of their habitual routines. Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.

Shape and Steepness of Toxicological Dose-Response Relationships of Continuous Endpoints

EPA Science Inventory

A re-analysis of a large number of historical dose-response data for continuous endpoints indicates that an exponential or a Hill model with four parameters both adequately describe toxicological dose-responses. The four parameters relate to the background response, the potency o...

Combining the LKB NTCP model with radiosensitivity parameters to characterize toxicity of radionuclides based on a multiclonogen kidney model: a theoretical assessment.

PubMed

Lin, Hui; Jing, Jia; Xu, Liangfeng; Wu, Dongsheng; Xu, Yuanying

2012-06-01

The Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP) model is often used to estimate the damage level to normal tissue. However, it does not manifestly involve the influence of radiosensitivity parameters. This work replaces the generalized mean equivalent uniform dose (gEUD) with the equivalent uniform dose (EUD) in the LKB model to investigate the effect of a variety of radiobiological parameters on the NTCP to characterize the toxicity of five types of radionuclides. The dose for 50 % complication probability (D (50)) is replaced by the corresponding EUD for 50 % complication probability (EUD(50)). The properties of a variety of radiobiological characteristics, such as biologically effective dose (BED), NTCP, and EUD, for five types of radioisotope ((131)I, (186)Re, (188)Re, (90)Y, and (67)Cu) are investigated by various radiosensitivity parameters such as intrinsic radiosensitivity α, alpha-beta ratio α/β, cell repair half-time, cell mean clonogen doubling time, etc. The high-energy beta emitters ((90)Y and (188)Re) have high initial dose rate and mean absorbed dose per injected activity in kidney, and their kidney toxicity should be of greater concern if they are excreted through kidneys. The radiobiological effect of (188)Re changes most sharply with the radiobiological parameters due to its high-energy electrons and very short physical half-life. The dose for a probability of 50% injury within 5y (D (50/5)) 28 Gy for whole-kidney irradiation should be adjusted according to different radionuclides and different radiosensitivity of individuals. The D (50/5) of individuals with low α/β or low α, or low biological clearance half-time, will be less than 28 Gy. The 50 % complication probability dose for (67)Cu and (188)Re could be 25 Gy and 22 Gy. The same mean absorbed dose generally corresponds to different degrees of damage for tissues of different radiosensitivity and different radionuclides. The influence of various radiobiological parameters should be taken into consideration in the NTCP model.

Rational Design of Glucose-Responsive Insulin Using Pharmacokinetic Modeling.

PubMed

Bakh, Naveed A; Bisker, Gili; Lee, Michael A; Gong, Xun; Strano, Michael S

2017-11-01

A glucose responsive insulin (GRI) is a therapeutic that modulates its potency, concentration, or dosing of insulin in relation to a patient's dynamic glucose concentration, thereby approximating aspects of a normally functioning pancreas. Current GRI design lacks a theoretical basis on which to base fundamental design parameters such as glucose reactivity, dissociation constant or potency, and in vivo efficacy. In this work, an approach to mathematically model the relevant parameter space for effective GRIs is induced, and design rules for linking GRI performance to therapeutic benefit are developed. Well-developed pharmacokinetic models of human glucose and insulin metabolism coupled to a kinetic model representation of a freely circulating GRI are used to determine the desired kinetic parameters and dosing for optimal glycemic control. The model examines a subcutaneous dose of GRI with kinetic parameters in an optimal range that results in successful glycemic control within prescribed constraints over a 24 h period. Additionally, it is demonstrated that the modeling approach can find GRI parameters that enable stable glucose levels that persist through a skipped meal. The results provide a framework for exploring the parameter space of GRIs, potentially without extensive, iterative in vivo animal testing. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Statistical methods for clinical verification of dose response parameters related to esophageal stricture and AVM obliteration from radiotherapy

NASA Astrophysics Data System (ADS)

Mavroidis, Panayiotis; Lind, Bengt K.; Theodorou, Kyriaki; Laurell, Göran; Fernberg, Jan-Olof; Lefkopoulos, Dimitrios; Kappas, Constantin; Brahme, Anders

2004-08-01

The purpose of this work is to provide some statistical methods for evaluating the predictive strength of radiobiological models and the validity of dose-response parameters for tumour control and normal tissue complications. This is accomplished by associating the expected complication rates, which are calculated using different models, with the clinical follow-up records. These methods are applied to 77 patients who received radiation treatment for head and neck cancer and 85 patients who were treated for arteriovenous malformation (AVM). The three-dimensional dose distribution delivered to esophagus and AVM nidus and the clinical follow-up results were available for each patient. Dose-response parameters derived by a maximum likelihood fitting were used as a reference to evaluate their compatibility with the examined treatment methodologies. The impact of the parameter uncertainties on the dose-response curves is demonstrated. The clinical utilization of the radiobiological parameters is illustrated. The radiobiological models (relative seriality and linear Poisson) and the reference parameters are validated to prove their suitability in reproducing the treatment outcome pattern of the patient material studied (through the probability of finding a worse fit, area under the ROC curve and khgr2 test). The analysis was carried out for the upper 5 cm of the esophagus (proximal esophagus) where all the strictures are formed, and the total volume of AVM. The estimated confidence intervals of the dose-response curves appear to have a significant supporting role on their clinical implementation and use.

Influence of dose calculation algorithms on the predicted dose distribution and NTCP values for NSCLC patients.

PubMed

Nielsen, Tine B; Wieslander, Elinore; Fogliata, Antonella; Nielsen, Morten; Hansen, Olfred; Brink, Carsten

2011-05-01

To investigate differences in calculated doses and normal tissue complication probability (NTCP) values between different dose algorithms. Six dose algorithms from four different treatment planning systems were investigated: Eclipse AAA, Oncentra MasterPlan Collapsed Cone and Pencil Beam, Pinnacle Collapsed Cone and XiO Multigrid Superposition, and Fast Fourier Transform Convolution. Twenty NSCLC patients treated in the period 2001-2006 at the same accelerator were included and the accelerator used for treatments were modeled in the different systems. The treatment plans were recalculated with the same number of monitor units and beam arrangements across the dose algorithms. Dose volume histograms of the GTV, PTV, combined lungs (excluding the GTV), and heart were exported and evaluated. NTCP values for heart and lungs were calculated using the relative seriality model and the LKB model, respectively. Furthermore, NTCP for the lungs were calculated from two different model parameter sets. Calculations and evaluations were performed both including and excluding density corrections. There are found statistical significant differences between the calculated dose to heart, lung, and targets across the algorithms. Mean lung dose and V20 are not very sensitive to change between the investigated dose calculation algorithms. However, the different dose levels for the PTV averaged over the patient population are varying up to 11%. The predicted NTCP values for pneumonitis vary between 0.20 and 0.24 or 0.35 and 0.48 across the investigated dose algorithms depending on the chosen model parameter set. The influence of the use of density correction in the dose calculation on the predicted NTCP values depends on the specific dose calculation algorithm and the model parameter set. For fixed values of these, the changes in NTCP can be up to 45%. Calculated NTCP values for pneumonitis are more sensitive to the choice of algorithm than mean lung dose and V20 which are also commonly used for plan evaluation. The NTCP values for heart complication are, in this study, not very sensitive to the choice of algorithm. Dose calculations based on density corrections result in quite different NTCP values than calculations without density corrections. It is therefore important when working with NTCP planning to use NTCP parameter values based on calculations and treatments similar to those for which the NTCP is of interest.

An Algorithm and R Program for Fitting and Simulation of Pharmacokinetic and Pharmacodynamic Data.

PubMed

Li, Jijie; Yan, Kewei; Hou, Lisha; Du, Xudong; Zhu, Ping; Zheng, Li; Zhu, Cairong

2017-06-01

Pharmacokinetic/pharmacodynamic link models are widely used in dose-finding studies. By applying such models, the results of initial pharmacokinetic/pharmacodynamic studies can be used to predict the potential therapeutic dose range. This knowledge can improve the design of later comparative large-scale clinical trials by reducing the number of participants and saving time and resources. However, the modeling process can be challenging, time consuming, and costly, even when using cutting-edge, powerful pharmacological software. Here, we provide a freely available R program for expediently analyzing pharmacokinetic/pharmacodynamic data, including data importation, parameter estimation, simulation, and model diagnostics. First, we explain the theory related to the establishment of the pharmacokinetic/pharmacodynamic link model. Subsequently, we present the algorithms used for parameter estimation and potential therapeutic dose computation. The implementation of the R program is illustrated by a clinical example. The software package is then validated by comparing the model parameters and the goodness-of-fit statistics generated by our R package with those generated by the widely used pharmacological software WinNonlin. The pharmacokinetic and pharmacodynamic parameters as well as the potential recommended therapeutic dose can be acquired with the R package. The validation process shows that the parameters estimated using our package are satisfactory. The R program developed and presented here provides pharmacokinetic researchers with a simple and easy-to-access tool for pharmacokinetic/pharmacodynamic analysis on personal computers.

Radiation dose reduction in computed tomography perfusion using spatial-temporal Bayesian methods

NASA Astrophysics Data System (ADS)

Fang, Ruogu; Raj, Ashish; Chen, Tsuhan; Sanelli, Pina C.

2012-03-01

In current computed tomography (CT) examinations, the associated X-ray radiation dose is of significant concern to patients and operators, especially CT perfusion (CTP) imaging that has higher radiation dose due to its cine scanning technique. A simple and cost-effective means to perform the examinations is to lower the milliampere-seconds (mAs) parameter as low as reasonably achievable in data acquisition. However, lowering the mAs parameter will unavoidably increase data noise and degrade CT perfusion maps greatly if no adequate noise control is applied during image reconstruction. To capture the essential dynamics of CT perfusion, a simple spatial-temporal Bayesian method that uses a piecewise parametric model of the residual function is used, and then the model parameters are estimated from a Bayesian formulation of prior smoothness constraints on perfusion parameters. From the fitted residual function, reliable CTP parameter maps are obtained from low dose CT data. The merit of this scheme exists in the combination of analytical piecewise residual function with Bayesian framework using a simpler prior spatial constrain for CT perfusion application. On a dataset of 22 patients, this dynamic spatial-temporal Bayesian model yielded an increase in signal-tonoise-ratio (SNR) of 78% and a decrease in mean-square-error (MSE) of 40% at low dose radiation of 43mA.

Modelling duodenum radiotherapy toxicity using cohort dose-volume-histogram data.

PubMed

Holyoake, Daniel L P; Aznar, Marianne; Mukherjee, Somnath; Partridge, Mike; Hawkins, Maria A

2017-06-01

Gastro-intestinal toxicity is dose-limiting in abdominal radiotherapy and correlated with duodenum dose-volume parameters. We aimed to derive updated NTCP model parameters using published data and prospective radiotherapy quality-assured cohort data. A systematic search identified publications providing duodenum dose-volume histogram (DVH) statistics for clinical studies of conventionally-fractionated radiotherapy. Values for the Lyman-Kutcher-Burman (LKB) NTCP model were derived through sum-squared-error minimisation and using leave-one-out cross-validation. Data were corrected for fraction size and weighted according to patient numbers, and the model refined using individual patient DVH data for two further cohorts from prospective clinical trials. Six studies with published DVH data were utilised, and with individual patient data included outcomes for 531 patients in total (median follow-up 16months). Observed gastro-intestinal toxicity rates ranged from 0% to 14% (median 8%). LKB parameter values for unconstrained fit to published data were: n=0.070, m=0.46, TD 50(1) [Gy]=183.8, while the values for the model incorporating the individual patient data were n=0.193, m=0.51, TD 50(1) [Gy]=299.1. LKB parameters derived using published data are shown to be consistent to those previously obtained using individual patient data, supporting a small volume-effect and dependence on exposure to high threshold dose. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Determination of MLC model parameters for Monaco using commercial diode arrays.

PubMed

Kinsella, Paul; Shields, Laura; McCavana, Patrick; McClean, Brendan; Langan, Brian

2016-07-08

Multileaf collimators (MLCs) need to be characterized accurately in treatment planning systems to facilitate accurate intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT). The aim of this study was to examine the use of MapCHECK 2 and ArcCHECK diode arrays for optimizing MLC parameters in Monaco X-ray voxel Monte Carlo (XVMC) dose calculation algorithm. A series of radiation test beams designed to evaluate MLC model parameters were delivered to MapCHECK 2, ArcCHECK, and EBT3 Gafchromic film for comparison. Initial comparison of the calculated and ArcCHECK-measured dose distributions revealed it was unclear how to change the MLC parameters to gain agreement. This ambiguity arose due to an insufficient sampling of the test field dose distributions and unexpected discrepancies in the open parts of some test fields. Consequently, the XVMC MLC parameters were optimized based on MapCHECK 2 measurements. Gafchromic EBT3 film was used to verify the accuracy of MapCHECK 2 measured dose distributions. It was found that adjustment of the MLC parameters from their default values resulted in improved global gamma analysis pass rates for MapCHECK 2 measurements versus calculated dose. The lowest pass rate of any MLC-modulated test beam improved from 68.5% to 93.5% with 3% and 2 mm gamma criteria. Given the close agreement of the optimized model to both MapCHECK 2 and film, the optimized model was used as a benchmark to highlight the relatively large discrepancies in some of the test field dose distributions found with ArcCHECK. Comparison between the optimized model-calculated dose and ArcCHECK-measured dose resulted in global gamma pass rates which ranged from 70.0%-97.9% for gamma criteria of 3% and 2 mm. The simple square fields yielded high pass rates. The lower gamma pass rates were attributed to the ArcCHECK overestimating the dose in-field for the rectangular test fields whose long axis was parallel to the long axis of the ArcCHECK. Considering ArcCHECK measurement issues and the lower gamma pass rates for the MLC-modulated test beams, it was concluded that MapCHECK 2 was a more suitable detector than ArcCHECK for the optimization process. © 2016 The Authors

Computational and human observer image quality evaluation of low dose, knowledge-based CT iterative reconstruction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Eck, Brendan L.; Fahmi, Rachid; Miao, Jun

2015-10-15

Purpose: Aims in this study are to (1) develop a computational model observer which reliably tracks the detectability of human observers in low dose computed tomography (CT) images reconstructed with knowledge-based iterative reconstruction (IMR™, Philips Healthcare) and filtered back projection (FBP) across a range of independent variables, (2) use the model to evaluate detectability trends across reconstructions and make predictions of human observer detectability, and (3) perform human observer studies based on model predictions to demonstrate applications of the model in CT imaging. Methods: Detectability (d′) was evaluated in phantom studies across a range of conditions. Images were generated usingmore » a numerical CT simulator. Trained observers performed 4-alternative forced choice (4-AFC) experiments across dose (1.3, 2.7, 4.0 mGy), pin size (4, 6, 8 mm), contrast (0.3%, 0.5%, 1.0%), and reconstruction (FBP, IMR), at fixed display window. A five-channel Laguerre–Gauss channelized Hotelling observer (CHO) was developed with internal noise added to the decision variable and/or to channel outputs, creating six different internal noise models. Semianalytic internal noise computation was tested against Monte Carlo and used to accelerate internal noise parameter optimization. Model parameters were estimated from all experiments at once using maximum likelihood on the probability correct, P{sub C}. Akaike information criterion (AIC) was used to compare models of different orders. The best model was selected according to AIC and used to predict detectability in blended FBP-IMR images, analyze trends in IMR detectability improvements, and predict dose savings with IMR. Predicted dose savings were compared against 4-AFC study results using physical CT phantom images. Results: Detection in IMR was greater than FBP in all tested conditions. The CHO with internal noise proportional to channel output standard deviations, Model-k4, showed the best trade-off between fit and model complexity according to AIC{sub c}. With parameters fixed, the model reasonably predicted detectability of human observers in blended FBP-IMR images. Semianalytic internal noise computation gave results equivalent to Monte Carlo, greatly speeding parameter estimation. Using Model-k4, the authors found an average detectability improvement of 2.7 ± 0.4 times that of FBP. IMR showed greater improvements in detectability with larger signals and relatively consistent improvements across signal contrast and x-ray dose. In the phantom tested, Model-k4 predicted an 82% dose reduction compared to FBP, verified with physical CT scans at 80% reduced dose. Conclusions: IMR improves detectability over FBP and may enable significant dose reductions. A channelized Hotelling observer with internal noise proportional to channel output standard deviation agreed well with human observers across a wide range of variables, even across reconstructions with drastically different image characteristics. Utility of the model observer was demonstrated by predicting the effect of image processing (blending), analyzing detectability improvements with IMR across dose, size, and contrast, and in guiding real CT scan dose reduction experiments. Such a model observer can be applied in optimizing parameters in advanced iterative reconstruction algorithms as well as guiding dose reduction protocols in physical CT experiments.« less

Physiologically based pharmacokinetic modeling of tea catechin mixture in rats and humans.

PubMed

Law, Francis C P; Yao, Meicun; Bi, Hui-Chang; Lam, Stephen

2017-06-01

Although green tea ( Camellia sinensis) (GT) contains a large number of polyphenolic compounds with anti-oxidative and anti-proliferative activities, little is known of the pharmacokinetics and tissue dose of tea catechins (TCs) as a chemical mixture in humans. The objectives of this study were to develop and validate a physiologically based pharmacokinetic (PBPK) model of tea catechin mixture (TCM) in rats and humans, and to predict an integrated or total concentration of TCM in the plasma of humans after consuming GT or Polyphenon E (PE). To this end, a PBPK model of epigallocatechin gallate (EGCg) consisting of 13 first-order, blood flow-limited tissue compartments was first developed in rats. The rat model was scaled up to humans by replacing its physiological parameters, pharmacokinetic parameters and tissue/blood partition coefficients (PCs) with human-specific values. Both rat and human EGCg models were then extrapolated to other TCs by substituting its physicochemical parameters, pharmacokinetic parameters, and PCs with catechin-specific values. Finally, a PBPK model of TCM was constructed by linking three rat (or human) tea catechin models together without including a description for pharmacokinetic interaction between the TCs. The mixture PBPK model accurately predicted the pharmacokinetic behaviors of three individual TCs in the plasma of rats and humans after GT or PE consumption. Model-predicted total TCM concentration in the plasma was linearly related to the dose consumed by humans. The mixture PBPK model is able to translate an external dose of TCM into internal target tissue doses for future safety assessment and dose-response analysis studies in humans. The modeling framework as described in this paper is also applicable to the bioactive chemical in other plant-based health products.

Predicting pneumonitis risk: a dosimetric alternative to mean lung dose.

PubMed

Tucker, Susan L; Mohan, Radhe; Liengsawangwong, Raweewan; Martel, Mary K; Liao, Zhongxing

2013-02-01

To determine whether the association between mean lung dose (MLD) and risk of severe (grade ≥3) radiation pneumonitis (RP) depends on the dose distribution pattern to normal lung among patients receiving 3-dimensional conformal radiation therapy for non-small-cell lung cancer. Three cohorts treated with different beam arrangements were identified. One cohort (2-field boost [2FB]) received 2 parallel-opposed (anteroposterior-posteroanterior) fields per fraction initially, followed by a sequential boost delivered using 2 oblique beams. The other 2 cohorts received 3 or 4 straight fields (3FS and 4FS, respectively), ie, all fields were irradiated every day. The incidence of severe RP was plotted against MLD in each cohort, and data were analyzed using the Lyman-Kutcher-Burman (LKB) model. The incidence of grade ≥3 RP rose more steeply as a function of MLD in the 2FB cohort (N=120) than in the 4FS cohort (N=138), with an intermediate slope for the 3FS group (N=99). The estimated volume parameter from the LKB model was n=0.41 (95% confidence interval, 0.15-1.0) and led to a significant improvement in fit (P=.05) compared to a fit with volume parameter fixed at n=1 (the MLD model). Unlike the MLD model, the LKB model with n=0.41 provided a consistent description of the risk of severe RP in all three cohorts (2FB, 3FS, 4FS) simultaneously. When predicting risk of grade ≥3 RP, the mean lung dose does not adequately take into account the effects of high doses. Instead, the effective dose, computed from the LKB model using volume parameter n=0.41, may provide a better dosimetric parameter for predicting RP risk. If confirmed, these findings support the conclusion that for the same MLD, high doses to small lung volumes ("a lot to a little") are worse than low doses to large volumes ("a little to a lot"). Copyright © 2013 Elsevier Inc. All rights reserved.

Hierarchical dose response of E. coli O157:H7 from human outbreaks incorporating heterogeneity in exposure.

PubMed

Teunis, P F M; Ogden, I D; Strachan, N J C

2008-06-01

The infectivity of pathogenic microorganisms is a key factor in the transmission of an infectious disease in a susceptible population. Microbial infectivity is generally estimated from dose-response studies in human volunteers. This can only be done with mildly pathogenic organisms. Here a hierarchical Beta-Poisson dose-response model is developed utilizing data from human outbreaks. On the lowest level each outbreak is modelled separately and these are then combined at a second level to produce a group dose-response relation. The distribution of foodborne pathogens often shows strong heterogeneity and this is incorporated by introducing an additional parameter to the dose-response model, accounting for the degree of overdispersion relative to Poisson distribution. It was found that heterogeneity considerably influences the shape of the dose-response relationship and increases uncertainty in predicted risk. This uncertainty is greater than previously reported surrogate and outbreak models using a single level of analysis. Monte Carlo parameter samples (alpha, beta of the Beta-Poisson model) can be readily incorporated in risk assessment models built using tools such as S-plus and @ Risk.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tucker, Susan L.; Liu, H. Helen; Wang, Shulian

Purpose: The aim of this study was to investigate the effect of radiation dose distribution in the lung on the risk of postoperative pulmonary complications among esophageal cancer patients. Methods and Materials: We analyzed data from 110 patients with esophageal cancer treated with concurrent chemoradiotherapy followed by surgery at our institution from 1998 to 2003. The endpoint for analysis was postsurgical pneumonia or acute respiratory distress syndrome. Dose-volume histograms (DVHs) and dose-mass histograms (DMHs) for the whole lung were used to fit normal-tissue complication probability (NTCP) models, and the quality of fits were compared using bootstrap analysis. Results: Normal-tissue complicationmore » probability modeling identified that the risk of postoperative pulmonary complications was most significantly associated with small absolute volumes of lung spared from doses {>=}5 Gy (VS5), that is, exposed to doses <5 Gy. However, bootstrap analysis found no significant difference between the quality of this model and fits based on other dosimetric parameters, including mean lung dose, effective dose, and relative volume of lung receiving {>=}5 Gy, probably because of correlations among these factors. The choice of DVH vs. DMH or the use of fractionation correction did not significantly affect the results of the NTCP modeling. The parameter values estimated for the Lyman NTCP model were as follows (with 95% confidence intervals in parentheses): n = 1.85 (0.04, {infinity}), m = 0.55 (0.22, 1.02), and D {sub 5} = 17.5 Gy (9.4 Gy, 102 Gy). Conclusions: In this cohort of esophageal cancer patients, several dosimetric parameters including mean lung dose, effective dose, and absolute volume of lung receiving <5 Gy provided similar descriptions of the risk of postoperative pulmonary complications as a function of Radiation dose distribution in the lung.« less

Validation and uncertainty analysis of a pre-treatment 2D dose prediction model

NASA Astrophysics Data System (ADS)

Baeza, Jose A.; Wolfs, Cecile J. A.; Nijsten, Sebastiaan M. J. J. G.; Verhaegen, Frank

2018-02-01

Independent verification of complex treatment delivery with megavolt photon beam radiotherapy (RT) has been effectively used to detect and prevent errors. This work presents the validation and uncertainty analysis of a model that predicts 2D portal dose images (PDIs) without a patient or phantom in the beam. The prediction model is based on an exponential point dose model with separable primary and secondary photon fluence components. The model includes a scatter kernel, off-axis ratio map, transmission values and penumbra kernels for beam-delimiting components. These parameters were derived through a model fitting procedure supplied with point dose and dose profile measurements of radiation fields. The model was validated against a treatment planning system (TPS; Eclipse) and radiochromic film measurements for complex clinical scenarios, including volumetric modulated arc therapy (VMAT). Confidence limits on fitted model parameters were calculated based on simulated measurements. A sensitivity analysis was performed to evaluate the effect of the parameter uncertainties on the model output. For the maximum uncertainty, the maximum deviating measurement sets were propagated through the fitting procedure and the model. The overall uncertainty was assessed using all simulated measurements. The validation of the prediction model against the TPS and the film showed a good agreement, with on average 90.8% and 90.5% of pixels passing a (2%,2 mm) global gamma analysis respectively, with a low dose threshold of 10%. The maximum and overall uncertainty of the model is dependent on the type of clinical plan used as input. The results can be used to study the robustness of the model. A model for predicting accurate 2D pre-treatment PDIs in complex RT scenarios can be used clinically and its uncertainties can be taken into account.

Dependency of EBT2 film calibration curve on postirradiation time

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chang, Liyun, E-mail: liyunc@isu.edu.tw; Ding, Hueisch-Jy; Ho, Sheng-Yow

2014-02-15

Purpose: The Ashland Inc. product EBT2 film model is a widely used quality assurance tool, especially for verification of 2-dimensional dose distributions. In general, the calibration film and the dose measurement film are irradiated, scanned, and calibrated at the same postirradiation time (PIT), 1-2 days after the films are irradiated. However, for a busy clinic or in some special situations, the PIT for the dose measurement film may be different from that of the calibration film. In this case, the measured dose will be incorrect. This paper proposed a film calibration method that includes the effect of PIT. Methods: Themore » dose versus film optical density was fitted to a power function with three parameters. One of these parameters was PIT dependent, while the other two were found to be almost constant with a standard deviation of the mean less than 4%. The PIT-dependent parameter was fitted to another power function of PIT. The EBT2 film model was calibrated using the PDD method with 14 different PITs ranging from 1 h to 2 months. Ten of the fourteen PITs were used for finding the fitting parameters, and the other four were used for testing the model. Results: The verification test shows that the differences between the delivered doses and the film doses calculated with this modeling were mainly within 2% for delivered doses above 60 cGy, and the total uncertainties were generally under 5%. The errors and total uncertainties of film dose calculation were independent of the PIT using the proposed calibration procedure. However, the fitting uncertainty increased with decreasing dose or PIT, but stayed below 1.3% for this study. Conclusions: The EBT2 film dose can be modeled as a function of PIT. For the ease of routine calibration, five PITs were suggested to be used. It is recommended that two PITs be located in the fast developing period (1∼6 h), one in 1 ∼ 2 days, one around a week, and one around a month.« less

Bayesian analysis of physiologically based toxicokinetic and toxicodynamic models.

PubMed

Hack, C Eric

2006-04-17

Physiologically based toxicokinetic (PBTK) and toxicodynamic (TD) models of bromate in animals and humans would improve our ability to accurately estimate the toxic doses in humans based on available animal studies. These mathematical models are often highly parameterized and must be calibrated in order for the model predictions of internal dose to adequately fit the experimentally measured doses. Highly parameterized models are difficult to calibrate and it is difficult to obtain accurate estimates of uncertainty or variability in model parameters with commonly used frequentist calibration methods, such as maximum likelihood estimation (MLE) or least squared error approaches. The Bayesian approach called Markov chain Monte Carlo (MCMC) analysis can be used to successfully calibrate these complex models. Prior knowledge about the biological system and associated model parameters is easily incorporated in this approach in the form of prior parameter distributions, and the distributions are refined or updated using experimental data to generate posterior distributions of parameter estimates. The goal of this paper is to give the non-mathematician a brief description of the Bayesian approach and Markov chain Monte Carlo analysis, how this technique is used in risk assessment, and the issues associated with this approach.

Study of the uncertainty in estimation of the exposure of non-human biota to ionising radiation.

PubMed

Avila, R; Beresford, N A; Agüero, A; Broed, R; Brown, J; Iospje, M; Robles, B; Suañez, A

2004-12-01

Uncertainty in estimations of the exposure of non-human biota to ionising radiation may arise from a number of sources including values of the model parameters, empirical data, measurement errors and biases in the sampling. The significance of the overall uncertainty of an exposure assessment will depend on how the estimated dose compares with reference doses used for risk characterisation. In this paper, we present the results of a study of the uncertainty in estimation of the exposure of non-human biota using some of the models and parameters recommended in the FASSET methodology. The study was carried out for semi-natural terrestrial, agricultural and marine ecosystems, and for four radionuclides (137Cs, 239Pu, 129I and 237Np). The parameters of the radionuclide transfer models showed the highest sensitivity and contributed the most to the uncertainty in the predictions of doses to biota. The most important ones were related to the bioavailability and mobility of radionuclides in the environment, for example soil-to-plant transfer factors, the bioaccumulation factors for marine biota and the gut uptake fraction for terrestrial mammals. In contrast, the dose conversion coefficients showed low sensitivity and contributed little to the overall uncertainty. Radiobiological effectiveness contributed to the overall uncertainty of the dose estimations for alpha emitters although to a lesser degree than a number of transfer model parameters.

An allometric pharmacokinetic/pharmacodynamics model for BI 893923, a novel IGF-1 receptor inhibitor.

PubMed

Titze, Melanie I; Schaaf, Otmar; Hofmann, Marco H; Sanderson, Michael P; Zahn, Stephan K; Quant, Jens; Lehr, Thorsten

2017-03-01

BI 893923 is a novel IGF1R/INSR inhibitor with promising anti-tumor efficacy. Dose-limiting hyperglycemia has been observed for other IGF1R/INSR inhibitors in clinical trials. To counterbalance anti-tumor efficacy with the risk of hyperglycemia and to determine the therapeutic window, we aimed to develop a translational pharmacokinetic/pharmacodynamics model for BI 893923. This aimed to translate pharmacokinetics and pharmacodynamics from animals to humans by an allometrically scaled semi-mechanistic model. Model development was based on a previously published PK/PD model for BI 893923 in mice (Titze et al., Cancer Chemother Pharmacol 77:1303-1314, 13). PK and blood glucose parameters were scaled by allometric principles using body weight as a scaling factor along with an estimation of the parameter exponents. Biomarker and tumor growth parameters were extrapolated from mouse to human using the body weight ratio as scaling factor. The allometric PK/PD model successfully described BI 893923 pharmacokinetics and blood glucose across mouse, rat, dog, minipig, and monkey. BI 893923 human exposure as well as blood glucose and tumor growth were predicted and compared for different dosing scenarios. A comprehensive risk-benefit analysis was conducted by determining the net clinical benefit for each schedule. An oral dose of 2750 mg BI 893923 divided in three evenly distributed doses was identified as the optimal human dosing regimen, predicting a tumor growth inhibition of 90.4% without associated hyperglycemia. Our model supported human therapeutic dose estimation by rationalizing the optimal efficacious dosing regimen with minimal undesired effects. This modeling approach may be useful for PK/PD scaling of other IGF1R/INSR inhibitors.

SU-E-T-430: Modeling MLC Leaf End in 2D for Sliding Window IMRT and Arc Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liang, X; Zhu, T

2014-06-01

Purpose: To develop a 2D geometric model for MLC accounting for leaf end dose leakage for dynamic IMRT and Rapidarc therapy. Methods: Leaf-end dose leakage is one of the problems for MLC dose calculation and modeling. Dosimetric leaf gap used to model the MLC and to count for leakage in dose calculation, but may not be accurate for smaller leaf gaps. We propose another geometric modeling method to compensate for the MLC round-shape leaf ends dose leakage, and improve the accuracy of dose calculation and dose verification. A triangular function is used to geometrically model the MLC leaf end leakagemore » in the leaf motion direction, and a step function is used in the perpendicular direction. Dose measurements with different leaf gap, different window width, and different window height were conducted, and the results were used to fit the analytical model to get the model parameters. Results: Analytical models have been obtained for stop-and-shoot and dynamic modes for MLC motion. Parameters a=0.4, lw'=5.0 mm for 6X and a=0.54, lw'=4.1 mm for 15x were obtained from the fitting process. The proposed MLC leaf end model improves the dose profile at the two ends of the sliding window opening. This improvement is especially significant for smaller sliding window openings, which are commonly used for highly modulated IMRT plans and arc therapy plans. Conclusion: This work models the MLC round leaf end shape and movement pattern for IMRT dose calculation. The theory, as well as the results in this work provides a useful tool for photon beam IMRT dose calculation and verification.« less

Episcleral eye plaque dosimetry comparison for the Eye Physics EP917 using Plaque Simulator and Monte Carlo simulation

PubMed Central

Amoush, Ahmad; Wilkinson, Douglas A.

2015-01-01

This work is a comparative study of the dosimetry calculated by Plaque Simulator, a treatment planning system for eye plaque brachytherapy, to the dosimetry calculated using Monte Carlo simulation for an Eye Physics model EP917 eye plaque. Monte Carlo (MC) simulation using MCNPX 2.7 was used to calculate the central axis dose in water for an EP917 eye plaque fully loaded with 17 IsoAid Advantage  125I seeds. In addition, the dosimetry parameters Λ, gL(r), and F(r,θ) were calculated for the IsoAid Advantage model IAI‐125  125I seed and benchmarked against published data. Bebig Plaque Simulator (PS) v5.74 was used to calculate the central axis dose based on the AAPM Updated Task Group 43 (TG‐43U1) dose formalism. The calculated central axis dose from MC and PS was then compared. When the MC dosimetry parameters for the IsoAid Advantage  125I seed were compared with the consensus values, Λ agreed with the consensus value to within 2.3%. However, much larger differences were found between MC calculated gL(r) and F(r,θ) and the consensus values. The differences between MC‐calculated dosimetry parameters are much smaller when compared with recently published data. The differences between the calculated central axis absolute dose from MC and PS ranged from 5% to 10% for distances between 1 and 12 mm from the outer scleral surface. When the dosimetry parameters for the  125I seed from this study were used in PS, the calculated absolute central axis dose differences were reduced by 2.3% from depths of 4 to 12 mm from the outer scleral surface. We conclude that PS adequately models the central dose profile of this plaque using its defaults for the IsoAid model IAI‐125 at distances of 1 to 7 mm from the outer scleral surface. However, improved dose accuracy can be obtained by using updated dosimetry parameters for the IsoAid model IAI‐125  125I seed. PACS number: 87.55.K‐ PMID:26699577

Extrapolation of the dna fragment-size distribution after high-dose irradiation to predict effects at low doses

NASA Technical Reports Server (NTRS)

Ponomarev, A. L.; Cucinotta, F. A.; Sachs, R. K.; Brenner, D. J.; Peterson, L. E.

2001-01-01

The patterns of DSBs induced in the genome are different for sparsely and densely ionizing radiations: In the former case, the patterns are well described by a random-breakage model; in the latter, a more sophisticated tool is needed. We used a Monte Carlo algorithm with a random-walk geometry of chromatin, and a track structure defined by the radial distribution of energy deposition from an incident ion, to fit the PFGE data for fragment-size distribution after high-dose irradiation. These fits determined the unknown parameters of the model, enabling the extrapolation of data for high-dose irradiation to the low doses that are relevant for NASA space radiation research. The randomly-located-clusters formalism was used to speed the simulations. It was shown that only one adjustable parameter, Q, the track efficiency parameter, was necessary to predict DNA fragment sizes for wide ranges of doses. This parameter was determined for a variety of radiations and LETs and was used to predict the DSB patterns at the HPRT locus of the human X chromosome after low-dose irradiation. It was found that high-LET radiation would be more likely than low-LET radiation to induce additional DSBs within the HPRT gene if this gene already contained one DSB.

Normal Tissue Complication Probability Modeling of Acute Hematologic Toxicity in Patients Treated With Intensity-Modulated Radiation Therapy for Squamous Cell Carcinoma of the Anal Canal

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bazan, Jose G.; Luxton, Gary; Mok, Edward C.

2012-11-01

Purpose: To identify dosimetric parameters that correlate with acute hematologic toxicity (HT) in patients with squamous cell carcinoma of the anal canal treated with definitive chemoradiotherapy (CRT). Methods and Materials: We analyzed 33 patients receiving CRT. Pelvic bone (PBM) was contoured for each patient and divided into subsites: ilium, lower pelvis (LP), and lumbosacral spine (LSS). The volume of each region receiving at least 5, 10, 15, 20, 30, and 40 Gy was calculated. Endpoints included grade {>=}3 HT (HT3+) and hematologic event (HE), defined as any grade {>=}2 HT with a modification in chemotherapy dose. Normal tissue complication probabilitymore » (NTCP) was evaluated with the Lyman-Kutcher-Burman (LKB) model. Logistic regression was used to test associations between HT and dosimetric/clinical parameters. Results: Nine patients experienced HT3+ and 15 patients experienced HE. Constrained optimization of the LKB model for HT3+ yielded the parameters m = 0.175, n = 1, and TD{sub 50} = 32 Gy. With this model, mean PBM doses of 25 Gy, 27.5 Gy, and 31 Gy result in a 10%, 20%, and 40% risk of HT3+, respectively. Compared with patients with mean PBM dose of <30 Gy, patients with mean PBM dose {>=}30 Gy had a 14-fold increase in the odds of developing HT3+ (p = 0.005). Several low-dose radiation parameters (i.e., PBM-V10) were associated with the development of HT3+ and HE. No association was found with the ilium, LP, or clinical factors. Conclusions: LKB modeling confirms the expectation that PBM acts like a parallel organ, implying that the mean dose to the organ is a useful predictor for toxicity. Low-dose radiation to the PBM was also associated with clinically significant HT. Keeping the mean PBM dose <22.5 Gy and <25 Gy is associated with a 5% and 10% risk of HT, respectively.« less

Preliminary calculation of solar cosmic ray dose to the female breast in space mission

NASA Technical Reports Server (NTRS)

Shavers, Mark; Poston, John W.; Atwell, William; Hardy, Alva C.; Wilson, John W.

1991-01-01

No regulatory dose limits are specifically assigned for the radiation exposure of female breasts during manned space flight. However, the relatively high radiosensitivity of the glandular tissue of the breasts and its potential exposure to solar flare protons on short- and long-term missions mandate a priori estimation of the associated risks. A model for estimating exposure within the breast is developed for use in future NASA missions. The female breast and torso geometry is represented by a simple interim model. A recently developed proton dose-buildup procedure is used for estimating doses. The model considers geomagnetic shielding, magnetic-storm conditions, spacecraft shielding, and body self-shielding. Inputs to the model include proton energy spectra, spacecraft orbital parameters, STS orbiter-shielding distribution at a given position, and a single parameter allowing for variation in breast size.

The effects of small field dosimetry on the biological models used in evaluating IMRT dose distributions

NASA Astrophysics Data System (ADS)

Cardarelli, Gene A.

The primary goal in radiation oncology is to deliver lethal radiation doses to tumors, while minimizing dose to normal tissue. IMRT has the capability to increase the dose to the targets and decrease the dose to normal tissue, increasing local control, decrease toxicity and allow for effective dose escalation. This advanced technology does present complex dose distributions that are not easily verified. Furthermore, the dose inhomogeneity caused by non-uniform dose distributions seen in IMRT treatments has caused the development of biological models attempting to characterize the dose-volume effect in the response of organized tissues to radiation. Dosimetry of small fields can be quite challenging when measuring dose distributions for high-energy X-ray beams used in IMRT. The proper modeling of these small field distributions is essential in reproducing accurate dose for IMRT. This evaluation was conducted to quantify the effects of small field dosimetry on IMRT plan dose distributions and the effects on four biological model parameters. The four biological models evaluated were: (1) the generalized Equivalent Uniform Dose (gEUD), (2) the Tumor Control Probability (TCP), (3) the Normal Tissue Complication Probability (NTCP) and (4) the Probability of uncomplicated Tumor Control (P+). These models are used to estimate local control, survival, complications and uncomplicated tumor control. This investigation compares three distinct small field dose algorithms. Dose algorithms were created using film, small ion chamber, and a combination of ion chamber measurements and small field fitting parameters. Due to the nature of uncertainties in small field dosimetry and the dependence of biological models on dose volume information, this examination quantifies the effects of small field dosimetry techniques on radiobiological models and recommends pathways to reduce the errors in using these models to evaluate IMRT dose distributions. This study demonstrates the importance of valid physical dose modeling prior to the use of biological modeling. The success of using biological function data, such as hypoxia, in clinical IMRT planning will greatly benefit from the results of this study.

Geometric parameter analysis to predetermine optimal radiosurgery technique for the treatment of arteriovenous malformation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mestrovic, Ante; Clark, Brenda G.; Department of Medical Physics, British Columbia Cancer Agency, Vancouver, British Columbia

2005-11-01

Purpose: To develop a method of predicting the values of dose distribution parameters of different radiosurgery techniques for treatment of arteriovenous malformation (AVM) based on internal geometric parameters. Methods and Materials: For each of 18 previously treated AVM patients, four treatment plans were created: circular collimator arcs, dynamic conformal arcs, fixed conformal fields, and intensity-modulated radiosurgery. An algorithm was developed to characterize the target and critical structure shape complexity and the position of the critical structures with respect to the target. Multiple regression was employed to establish the correlation between the internal geometric parameters and the dose distribution for differentmore » treatment techniques. The results from the model were applied to predict the dosimetric outcomes of different radiosurgery techniques and select the optimal radiosurgery technique for a number of AVM patients. Results: Several internal geometric parameters showing statistically significant correlation (p < 0.05) with the treatment planning results for each technique were identified. The target volume and the average minimum distance between the target and the critical structures were the most effective predictors for normal tissue dose distribution. The structure overlap volume with the target and the mean distance between the target and the critical structure were the most effective predictors for critical structure dose distribution. The predicted values of dose distribution parameters of different radiosurgery techniques were in close agreement with the original data. Conclusions: A statistical model has been described that successfully predicts the values of dose distribution parameters of different radiosurgery techniques and may be used to predetermine the optimal technique on a patient-to-patient basis.« less

Mechanistic simulation of normal-tissue damage in radiotherapy—implications for dose-volume analyses

NASA Astrophysics Data System (ADS)

Rutkowska, Eva; Baker, Colin; Nahum, Alan

2010-04-01

A radiobiologically based 3D model of normal tissue has been developed in which complications are generated when 'irradiated'. The aim is to provide insight into the connection between dose-distribution characteristics, different organ architectures and complication rates beyond that obtainable with simple DVH-based analytical NTCP models. In this model the organ consists of a large number of functional subunits (FSUs), populated by stem cells which are killed according to the LQ model. A complication is triggered if the density of FSUs in any 'critical functioning volume' (CFV) falls below some threshold. The (fractional) CFV determines the organ architecture and can be varied continuously from small (series-like behaviour) to large (parallel-like). A key feature of the model is its ability to account for the spatial dependence of dose distributions. Simulations were carried out to investigate correlations between dose-volume parameters and the incidence of 'complications' using different pseudo-clinical dose distributions. Correlations between dose-volume parameters and outcome depended on characteristics of the dose distributions and on organ architecture. As anticipated, the mean dose and V20 correlated most strongly with outcome for a parallel organ, and the maximum dose for a serial organ. Interestingly better correlation was obtained between the 3D computer model and the LKB model with dose distributions typical for serial organs than with those typical for parallel organs. This work links the results of dose-volume analyses to dataset characteristics typical for serial and parallel organs and it may help investigators interpret the results from clinical studies.

A generic biokinetic model for noble gases with application to radon.

PubMed

Leggett, Rich; Marsh, James; Gregoratto, Demetrio; Blanchardon, Eric

2013-06-01

To facilitate the estimation of radiation doses from intake of radionuclides, the International Commission on Radiological Protection (ICRP) publishes dose coefficients (dose per unit intake) based on reference biokinetic and dosimetric models. The ICRP generally has not provided biokinetic models or dose coefficients for intake of noble gases, but plans to provide such information for (222)Rn and other important radioisotopes of noble gases in a forthcoming series of reports on occupational intake of radionuclides (OIR). This paper proposes a generic biokinetic model framework for noble gases and develops parameter values for radon. The framework is tailored to applications in radiation protection and is consistent with a physiologically based biokinetic modelling scheme adopted for the OIR series. Parameter values for a noble gas are based largely on a blood flow model and physical laws governing transfer of a non-reactive and soluble gas between materials. Model predictions for radon are shown to be consistent with results of controlled studies of its biokinetics in human subjects.

Human Dose-Response Data for Francisella tularensis and a Dose- and Time-Dependent Mathematical Model of Early-Phase Fever Associated with Tularemia After Inhalation Exposure.

PubMed

McClellan, Gene; Coleman, Margaret; Crary, David; Thurman, Alec; Thran, Brandolyn

2018-04-25

Military health risk assessors, medical planners, operational planners, and defense system developers require knowledge of human responses to doses of biothreat agents to support force health protection and chemical, biological, radiological, nuclear (CBRN) defense missions. This article reviews extensive data from 118 human volunteers administered aerosols of the bacterial agent Francisella tularensis, strain Schu S4, which causes tularemia. The data set includes incidence of early-phase febrile illness following administration of well-characterized inhaled doses of F. tularensis. Supplemental data on human body temperature profiles over time available from de-identified case reports is also presented. A unified, logically consistent model of early-phase febrile illness is described as a lognormal dose-response function for febrile illness linked with a stochastic time profile of fever. Three parameters are estimated from the human data to describe the time profile: incubation period or onset time for fever; rise time of fever; and near-maximum body temperature. Inhaled dose-dependence and variability are characterized for each of the three parameters. These parameters enable a stochastic model for the response of an exposed population through incorporation of individual-by-individual variability by drawing random samples from the statistical distributions of these three parameters for each individual. This model provides risk assessors and medical decisionmakers reliable representations of the predicted health impacts of early-phase febrile illness for as long as one week after aerosol exposures of human populations to F. tularensis. © 2018 Society for Risk Analysis.

SU-E-T-122: Anisotropic Analytical Algorithm (AAA) Vs. Acuros XB (AXB) in Stereotactic Treatment Planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mynampati, D; Scripes, P Godoy; Kuo, H

2015-06-15

Purpose: To evaluate dosimetric differences between superposition beam model (AAA) and determinant photon transport solver (AXB) in lung SBRT and Cranial SRS dose computations. Methods: Ten Cranial SRS and ten Lung SBRT plans using Varian, AAA -11.0 were re-planned using Acuros -XB-11.0 with fixed MU. 6MV photon Beam model with HD120-MLC used for dose calculations. Four non-coplanar conformal arcs used to deliver 21Gy or 18Gy to SRS targets (0.4 to 6.2cc). 54Gy (3Fractions) or 50Gy (5Fractions) was planned for SBRT targets (7.3 to 13.9cc) using two VAMT non-coplanar arcs. Plan comparison parameters were dose to 1% PTV volume (D1), dosemore » to 99% PTV volume( D99), Target mean (Dmean), Conformity index (ratio of prescription isodose volume to PTV), Homogeneity Index [ (D2%-D98%)/Dmean] and R50 (ratio of 50% of prescription isodose volume to PTV). OAR parameters were Brain volume receiving 12Gy dose (V12Gy) and maximum dose (D0.03) to Brainstem for SRS. For lung SBRT, maximum dose to Heart and Cord, Mean lung dose (MLD) and volume of lung receiving 20Gy (V20Gy) were computed. PTV parameters compared by percentage difference between AXB and AAA parameters. OAR parameters and HI compared by absolute difference between two calculations. For analysis, paired t-test performed over the parameters. Results: Compared to AAA, AXB SRS plans have on average 3.2% lower D99, 6.5% lower CI and 3cc less Brain-V12. However, AXB SBRT plans have higher D1, R50 and Dmean by 3.15%, 1.63% and 2.5%. For SRS and SBRT, AXB plans have average HI 2 % and 4.4% higher than AAA plans. In both techniques, all other parameters vary within 1% or 1Gy. In both sets only two parameters have P>0.05. Conclusion: Even though t-test results signify difference between AXB and AAA plans, dose differences in dose estimations by both algorithms are clinically insignificant.« less

A Monte Carlo investigation of contaminant electrons due to a novel in vivo transmission detector.

PubMed

Asuni, G; Jensen, J M; McCurdy, B M C

2011-02-21

A novel transmission detector (IBA Dosimetry, Germany) developed as an IMRT quality assurance tool, intended for in vivo patient dose measurements, is studied here. The goal of this investigation is to use Monte Carlo techniques to characterize treatment beam parameters in the presence of the detector and to compare to those of a plastic block tray (a frequently used clinical device). Particular attention is paid to the impact of the detector on electron contamination model parameters of two commercial dose calculation algorithms. The linac head together with the COMPASS transmission detector (TRD) was modeled using BEAMnrc code. To understand the effect of the TRD on treatment beams, the contaminant electron fluence, energy spectra, and angular distributions at different SSDs were analyzed for open and non-open (i.e. TRD and block tray) fields. Contaminant electrons in the BEAMnrc simulations were separated according to where they were created. Calculation of surface dose and the evaluation of contributions from contaminant electrons were performed using the DOSXYZnrc user code. The effect of the TRD on contaminant electrons model parameters in Eclipse AAA and Pinnacle(3) dose calculation algorithms was investigated. Comparisons of the fluence of contaminant electrons produced in the non-open fields versus open field show that electrons created in the non-open fields increase at shorter SSD, but most of the electrons at shorter SSD are of low energy with large angular spread. These electrons are out-scattered or absorbed in air and contribute less to surface dose at larger SSD. Calculated surface doses with the block tray are higher than those with the TRD. Contribution of contaminant electrons to dose in the buildup region increases with increasing field size. The additional contribution of electrons to surface dose increases with field size for TRD and block tray. The introduction of the TRD results in a 12% and 15% increase in the Gaussian widths used in the contaminant electron source model of the Eclipse AAA dose algorithm. The off-axis coefficient in the Pinnacle(3) dose calculation algorithm decreases in the presence of TRD compared to without the device. The electron model parameters were modified to reflect the increase in electron contamination with the TRD, a necessary step for accurate beam modeling when using the device.

LETTER TO THE EDITOR: Clinical validation of the LKB model and parameter sets for predicting radiation-induced pneumonitis from breast cancer radiotherapy

NASA Astrophysics Data System (ADS)

Tsougos, Ioannis; Mavroidis, Panayiotis; Theodorou, Kyriaki; Rajala, J.; Pitkänen, M. A.; Holli, K.; Ojala, A. T.; Hyödynmaa, S.; Järvenpää, Ritva; Lind, Bengt K.; Kappas, Constantin

2006-02-01

The choice of the appropriate model and parameter set in determining the relation between the incidence of radiation pneumonitis and dose distribution in the lung is of great importance, especially in the case of breast radiotherapy where the observed incidence is fairly low. From our previous study based on 150 breast cancer patients, where the fits of dose-volume models to clinical data were estimated (Tsougos et al 2005 Evaluation of dose-response models and parameters predicting radiation induced pneumonitis using clinical data from breast cancer radiotherapy Phys. Med. Biol. 50 3535-54), one could get the impression that the relative seriality is significantly better than the LKB NTCP model. However, the estimation of the different NTCP models was based on their goodness-of-fit on clinical data, using various sets of published parameters from other groups, and this fact may provisionally justify the results. Hence, we sought to investigate further the LKB model, by applying different published parameter sets for the very same group of patients, in order to be able to compare the results. It was shown that, depending on the parameter set applied, the LKB model is able to predict the incidence of radiation pneumonitis with acceptable accuracy, especially when implemented on a sub-group of patients (120) receiving \\bar{\\bar{D}}|EUD higher than 8 Gy. In conclusion, the goodness-of-fit of a certain radiobiological model on a given clinical case is closely related to the selection of the proper scoring criteria and parameter set as well as to the compatibility of the clinical case from which the data were derived.

Verification of dosimetric accuracy on the TrueBeam STx: rounded leaf effect of the high definition MLC.

PubMed

Kielar, Kayla N; Mok, Ed; Hsu, Annie; Wang, Lei; Luxton, Gary

2012-10-01

The dosimetric leaf gap (DLG) in the Varian Eclipse treatment planning system is determined during commissioning and is used to model the effect of the rounded leaf-end of the multileaf collimator (MLC). This parameter attempts to model the physical difference between the radiation and light field and account for inherent leakage between leaf tips. With the increased use of single fraction high dose treatments requiring larger monitor units comes an enhanced concern in the accuracy of leakage calculations, as it accounts for much of the patient dose. This study serves to verify the dosimetric accuracy of the algorithm used to model the rounded leaf effect for the TrueBeam STx, and describes a methodology for determining best-practice parameter values, given the novel capabilities of the linear accelerator such as flattening filter free (FFF) treatments and a high definition MLC (HDMLC). During commissioning, the nominal MLC position was verified and the DLG parameter was determined using MLC-defined field sizes and moving gap tests, as is common in clinical testing. Treatment plans were created, and the DLG was optimized to achieve less than 1% difference between measured and calculated dose. The DLG value found was tested on treatment plans for all energies (6 MV, 10 MV, 15 MV, 6 MV FFF, 10 MV FFF) and modalities (3D conventional, IMRT, conformal arc, VMAT) available on the TrueBeam STx. The DLG parameter found during the initial MLC testing did not match the leaf gap modeling parameter that provided the most accurate dose delivery in clinical treatment plans. Using the physical leaf gap size as the DLG for the HDMLC can lead to 5% differences in measured and calculated doses. Separate optimization of the DLG parameter using end-to-end tests must be performed to ensure dosimetric accuracy in the modeling of the rounded leaf ends for the Eclipse treatment planning system. The difference in leaf gap modeling versus physical leaf gap dimensions is more pronounced in the more recent versions of Eclipse for both the HDMLC and the Millennium MLC. Once properly commissioned and tested using a methodology based on treatment plan verification, Eclipse is able to accurately model radiation dose delivered for SBRT treatments using the TrueBeam STx.

Analysis of variation in calibration curves for Kodak XV radiographic film using model-based parameters.

PubMed

Hsu, Shu-Hui; Kulasekere, Ravi; Roberson, Peter L

2010-08-05

Film calibration is time-consuming work when dose accuracy is essential while working in a range of photon scatter environments. This study uses the single-target single-hit model of film response to fit the calibration curves as a function of calibration method, processor condition, field size and depth. Kodak XV film was irradiated perpendicular to the beam axis in a solid water phantom. Standard calibration films (one dose point per film) were irradiated at 90 cm source-to-surface distance (SSD) for various doses (16-128 cGy), depths (0.2, 0.5, 1.5, 5, 10 cm) and field sizes (5 × 5, 10 × 10 and 20 × 20 cm²). The 8-field calibration method (eight dose points per film) was used as a reference for each experiment, taken at 95 cm SSD and 5 cm depth. The delivered doses were measured using an Attix parallel plate chamber for improved accuracy of dose estimation in the buildup region. Three fitting methods with one to three dose points per calibration curve were investigated for the field sizes of 5 × 5, 10 × 10 and 20 × 20 cm². The inter-day variation of model parameters (background, saturation and slope) were 1.8%, 5.7%, and 7.7% (1 σ) using the 8-field method. The saturation parameter ratio of standard to 8-field curves was 1.083 ± 0.005. The slope parameter ratio of standard to 8-field curves ranged from 0.99 to 1.05, depending on field size and depth. The slope parameter ratio decreases with increasing depth below 0.5 cm for the three field sizes. It increases with increasing depths above 0.5 cm. A calibration curve with one to three dose points fitted with the model is possible with 2% accuracy in film dosimetry for various irradiation conditions. The proposed fitting methods may reduce workload while providing energy dependence correction in radiographic film dosimetry. This study is limited to radiographic XV film with a Lumisys scanner.

LAND AND WATER USE CHARACTERISTICS AND HUMAN HEALTH INPUT PARAMETERS FOR USE IN ENVIRONMENTAL DOSIMETRY AND RISK ASSESSMENTS AT THE SAVANNAH RIVER SITE

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jannik, T.; Karapatakis, D.; Lee, P.

2010-08-06

Operations at the Savannah River Site (SRS) result in releases of small amounts of radioactive materials to the atmosphere and to the Savannah River. For regulatory compliance purposes, potential offsite radiological doses are estimated annually using computer models that follow U.S. Nuclear Regulatory Commission (NRC) Regulatory Guides. Within the regulatory guides, default values are provided for many of the dose model parameters but the use of site-specific values by the applicant is encouraged. A detailed survey of land and water use parameters was conducted in 1991 and is being updated here. These parameters include local characteristics of meat, milk andmore » vegetable production; river recreational activities; and meat, milk and vegetable consumption rates as well as other human usage parameters required in the SRS dosimetry models. In addition, the preferred elemental bioaccumulation factors and transfer factors to be used in human health exposure calculations at SRS are documented. Based on comparisons to the 2009 SRS environmental compliance doses, the following effects are expected in future SRS compliance dose calculations: (1) Aquatic all-pathway maximally exposed individual doses may go up about 10 percent due to changes in the aquatic bioaccumulation factors; (2) Aquatic all-pathway collective doses may go up about 5 percent due to changes in the aquatic bioaccumulation factors that offset the reduction in average individual water consumption rates; (3) Irrigation pathway doses to the maximally exposed individual may go up about 40 percent due to increases in the element-specific transfer factors; (4) Irrigation pathway collective doses may go down about 50 percent due to changes in food productivity and production within the 50-mile radius of SRS; (5) Air pathway doses to the maximally exposed individual may go down about 10 percent due to the changes in food productivity in the SRS area and to the changes in element-specific transfer factors; and (6) Air pathway collective doses may go down about 30 percent mainly due to the decrease in the inhalation rate assumed for the average individual.« less

A new formula for normal tissue complication probability (NTCP) as a function of equivalent uniform dose (EUD).

PubMed

Luxton, Gary; Keall, Paul J; King, Christopher R

2008-01-07

To facilitate the use of biological outcome modeling for treatment planning, an exponential function is introduced as a simpler equivalent to the Lyman formula for calculating normal tissue complication probability (NTCP). The single parameter of the exponential function is chosen to reproduce the Lyman calculation to within approximately 0.3%, and thus enable easy conversion of data contained in empirical fits of Lyman parameters for organs at risk (OARs). Organ parameters for the new formula are given in terms of Lyman model m and TD(50), and conversely m and TD(50) are expressed in terms of the parameters of the new equation. The role of the Lyman volume-effect parameter n is unchanged from its role in the Lyman model. For a non-homogeneously irradiated OAR, an equation relates d(ref), n, v(eff) and the Niemierko equivalent uniform dose (EUD), where d(ref) and v(eff) are the reference dose and effective fractional volume of the Kutcher-Burman reduction algorithm (i.e. the LKB model). It follows in the LKB model that uniform EUD irradiation of an OAR results in the same NTCP as the original non-homogeneous distribution. The NTCP equation is therefore represented as a function of EUD. The inverse equation expresses EUD as a function of NTCP and is used to generate a table of EUD versus normal tissue complication probability for the Emami-Burman parameter fits as well as for OAR parameter sets from more recent data.

Modeling the Risk of Radiation-Induced Acute Esophagitis for Combined Washington University and RTOG Trial 93-11 Lung Cancer Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, Ellen X.; Bradley, Jeffrey D.; El Naqa, Issam

2012-04-01

Purpose: To construct a maximally predictive model of the risk of severe acute esophagitis (AE) for patients who receive definitive radiation therapy (RT) for non-small-cell lung cancer. Methods and Materials: The dataset includes Washington University and RTOG 93-11 clinical trial data (events/patients: 120/374, WUSTL = 101/237, RTOG9311 = 19/137). Statistical model building was performed based on dosimetric and clinical parameters (patient age, sex, weight loss, pretreatment chemotherapy, concurrent chemotherapy, fraction size). A wide range of dose-volume parameters were extracted from dearchived treatment plans, including Dx, Vx, MOHx (mean of hottest x% volume), MOCx (mean of coldest x% volume), and gEUDmore » (generalized equivalent uniform dose) values. Results: The most significant single parameters for predicting acute esophagitis (RTOG Grade 2 or greater) were MOH85, mean esophagus dose (MED), and V30. A superior-inferior weighted dose-center position was derived but not found to be significant. Fraction size was found to be significant on univariate logistic analysis (Spearman R = 0.421, p < 0.00001) but not multivariate logistic modeling. Cross-validation model building was used to determine that an optimal model size needed only two parameters (MOH85 and concurrent chemotherapy, robustly selected on bootstrap model-rebuilding). Mean esophagus dose (MED) is preferred instead of MOH85, as it gives nearly the same statistical performance and is easier to compute. AE risk is given as a logistic function of (0.0688 Asterisk-Operator MED+1.50 Asterisk-Operator ConChemo-3.13), where MED is in Gy and ConChemo is either 1 (yes) if concurrent chemotherapy was given, or 0 (no). This model correlates to the observed risk of AE with a Spearman coefficient of 0.629 (p < 0.000001). Conclusions: Multivariate statistical model building with cross-validation suggests that a two-variable logistic model based on mean dose and the use of concurrent chemotherapy robustly predicts acute esophagitis risk in combined-data WUSTL and RTOG 93-11 trial datasets.« less

Methods for Probabilistic Radiological Dose Assessment at a High-Level Radioactive Waste Repository.

NASA Astrophysics Data System (ADS)

Maheras, Steven James

Methods were developed to assess and evaluate the uncertainty in offsite and onsite radiological dose at a high-level radioactive waste repository to show reasonable assurance that compliance with applicable regulatory requirements will be achieved. Uncertainty in offsite dose was assessed by employing a stochastic precode in conjunction with Monte Carlo simulation using an offsite radiological dose assessment code. Uncertainty in onsite dose was assessed by employing a discrete-event simulation model of repository operations in conjunction with an occupational radiological dose assessment model. Complementary cumulative distribution functions of offsite and onsite dose were used to illustrate reasonable assurance. Offsite dose analyses were performed for iodine -129, cesium-137, strontium-90, and plutonium-239. Complementary cumulative distribution functions of offsite dose were constructed; offsite dose was lognormally distributed with a two order of magnitude range. However, plutonium-239 results were not lognormally distributed and exhibited less than one order of magnitude range. Onsite dose analyses were performed for the preliminary inspection, receiving and handling, and the underground areas of the repository. Complementary cumulative distribution functions of onsite dose were constructed and exhibited less than one order of magnitude range. A preliminary sensitivity analysis of the receiving and handling areas was conducted using a regression metamodel. Sensitivity coefficients and partial correlation coefficients were used as measures of sensitivity. Model output was most sensitive to parameters related to cask handling operations. Model output showed little sensitivity to parameters related to cask inspections.

Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers.

PubMed

Gobburu, J V; Agersø, H; Jusko, W J; Ynddal, L

1999-09-01

To examine the pharmacokinetics (PK) and pharmacodynamics (PD) of ipamorelin, a growth hormone (GH) releasing peptide, in healthy volunteers. A trial was conducted with a dose escalation design comprising 5 different infusion rates (4.21, 14.02, 42.13, 84.27 and 140.45 nmol/kg over 15 minutes) with eight healthy male subjects at each dose level. Concentrations of ipamorelin and growth hormone were measured. The PK parameters showed dose-proportionality, with a short terminal half-life of 2 hours, a clearance of 0.078 L/h/kg and a volume of distribution at steady-state of 0.22 L/kg. The time course of GH stimulation by ipamorelin showed a single episode of GH release with a peak at 0.67 hours and an exponential decline to negligible GH concentration at all doses. The ipamorelin-GH concentration relationship was characterized using an indirect response model and population fitting. The model employed a zero-order GH release rate over a finite duration of time to describe the episodic release of GH. Ipamorelin induces the release of GH at all dose levels with the concentration (SC50) required for half-maximal GH stimulation of 214 nmol/L and a maximal GH production rate of 694 mIU/L/h. The inter-individual variability of the PD parameters was larger than that of the PK parameters. The proposed PK/PD model provides a useful characterization of ipamorelin disposition and GH responses across a range of doses.

The influence of Monte Carlo source parameters on detector design and dose perturbation in small field dosimetry

NASA Astrophysics Data System (ADS)

Charles, P. H.; Crowe, S. B.; Kairn, T.; Knight, R.; Hill, B.; Kenny, J.; Langton, C. M.; Trapp, J. V.

2014-03-01

To obtain accurate Monte Carlo simulations of small radiation fields, it is important model the initial source parameters (electron energy and spot size) accurately. However recent studies have shown that small field dosimetry correction factors are insensitive to these parameters. The aim of this work is to extend this concept to test if these parameters affect dose perturbations in general, which is important for detector design and calculating perturbation correction factors. The EGSnrc C++ user code cavity was used for all simulations. Varying amounts of air between 0 and 2 mm were deliberately introduced upstream to a diode and the dose perturbation caused by the air was quantified. These simulations were then repeated using a range of initial electron energies (5.5 to 7.0 MeV) and electron spot sizes (0.7 to 2.2 FWHM). The resultant dose perturbations were large. For example 2 mm of air caused a dose reduction of up to 31% when simulated with a 6 mm field size. However these values did not vary by more than 2 % when simulated across the full range of source parameters tested. If a detector is modified by the introduction of air, one can be confident that the response of the detector will be the same across all similar linear accelerators and the Monte Carlo modelling of each machine is not required.

A Characteristic Dose Model for Historical Internal Dose Reconstruction in the Framework of the IAEC Compensation Programme.

PubMed

Kravchik, T; Abraham, A; Israeli, M; Yahel, E

2017-04-25

A model was developed at the Nuclear Research Centre Negev (NRCN) to assess historical doses from internal exposures by a relatively fast and simple procedure. These assessments are needed in the framework of a compensation programme for the Israeli Atomic Energy Commission (IAEC) workers, which were diagnosed for cancer diseases. This compensation programme was recently recommended by a public committee to avoid lengthy court procedures. The developed model is based on the recorded doses from external exposures of all the workers at the NRCN, who were divided into groups representing their different working environments. Each group of workers was characterised by three parameters: working period, working areas and occupation. The model uses several conservative assumptions in order to calculate the doses to various body organs in certain years, which are relevant to the calculation of the probability of causation (POC). The POC value serves as a main parameter in the compensation programme. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Evaluation of gamma dose effect on PIN photodiode using analytical model

NASA Astrophysics Data System (ADS)

Jafari, H.; Feghhi, S. A. H.; Boorboor, S.

2018-03-01

The PIN silicon photodiodes are widely used in the applications which may be found in radiation environment such as space mission, medical imaging and non-destructive testing. Radiation-induced damage in these devices causes to degrade the photodiode parameters. In this work, we have used new approach to evaluate gamma dose effects on a commercial PIN photodiode (BPX65) based on an analytical model. In this approach, the NIEL parameter has been calculated for gamma rays from a 60Co source by GEANT4. The radiation damage mechanisms have been considered by solving numerically the Poisson and continuity equations with the appropriate boundary conditions, parameters and physical models. Defects caused by radiation in silicon have been formulated in terms of the damage coefficient for the minority carriers' lifetime. The gamma induced degradation parameters of the silicon PIN photodiode have been analyzed in detail and the results were compared with experimental measurements and as well as the results of ATLAS semiconductor simulator to verify and parameterize the analytical model calculations. The results showed reasonable agreement between them for BPX65 silicon photodiode irradiated by 60Co gamma source at total doses up to 5 kGy under different reverse voltages.

Evaluation of the influence of double and triple Gaussian proton kernel models on accuracy of dose calculations for spot scanning technique.

PubMed

Hirayama, Shusuke; Takayanagi, Taisuke; Fujii, Yusuke; Fujimoto, Rintaro; Fujitaka, Shinichiro; Umezawa, Masumi; Nagamine, Yoshihiko; Hosaka, Masahiro; Yasui, Keisuke; Omachi, Chihiro; Toshito, Toshiyuki

2016-03-01

The main purpose in this study was to present the results of beam modeling and how the authors systematically investigated the influence of double and triple Gaussian proton kernel models on the accuracy of dose calculations for spot scanning technique. The accuracy of calculations was important for treatment planning software (TPS) because the energy, spot position, and absolute dose had to be determined by TPS for the spot scanning technique. The dose distribution was calculated by convolving in-air fluence with the dose kernel. The dose kernel was the in-water 3D dose distribution of an infinitesimal pencil beam and consisted of an integral depth dose (IDD) and a lateral distribution. Accurate modeling of the low-dose region was important for spot scanning technique because the dose distribution was formed by cumulating hundreds or thousands of delivered beams. The authors employed a double Gaussian function as the in-air fluence model of an individual beam. Double and triple Gaussian kernel models were also prepared for comparison. The parameters of the kernel lateral model were derived by fitting a simulated in-water lateral dose profile induced by an infinitesimal proton beam, whose emittance was zero, at various depths using Monte Carlo (MC) simulation. The fitted parameters were interpolated as a function of depth in water and stored as a separate look-up table. These stored parameters for each energy and depth in water were acquired from the look-up table when incorporating them into the TPS. The modeling process for the in-air fluence and IDD was based on the method proposed in the literature. These were derived using MC simulation and measured data. The authors compared the measured and calculated absolute doses at the center of the spread-out Bragg peak (SOBP) under various volumetric irradiation conditions to systematically investigate the influence of the two types of kernel models on the dose calculations. The authors investigated the difference between double and triple Gaussian kernel models. The authors found that the difference between the two studied kernel models appeared at mid-depths and the accuracy of predicting the double Gaussian model deteriorated at the low-dose bump that appeared at mid-depths. When the authors employed the double Gaussian kernel model, the accuracy of calculations for the absolute dose at the center of the SOBP varied with irradiation conditions and the maximum difference was 3.4%. In contrast, the results obtained from calculations with the triple Gaussian kernel model indicated good agreement with the measurements within ±1.1%, regardless of the irradiation conditions. The difference between the results obtained with the two types of studied kernel models was distinct in the high energy region. The accuracy of calculations with the double Gaussian kernel model varied with the field size and SOBP width because the accuracy of prediction with the double Gaussian model was insufficient at the low-dose bump. The evaluation was only qualitative under limited volumetric irradiation conditions. Further accumulation of measured data would be needed to quantitatively comprehend what influence the double and triple Gaussian kernel models had on the accuracy of dose calculations.

The net fractional depth dose: a basis for a unified analytical description of FDD, TAR, TMR, and TPR.

PubMed

van de Geijn, J; Fraass, B A

1984-01-01

The net fractional depth dose (NFD) is defined as the fractional depth dose (FDD) corrected for inverse square law. Analysis of its behavior as a function of depth, field size, and source-surface distance has led to an analytical description with only seven model parameters related to straightforward physical properties. The determination of the characteristic parameter values requires only seven experimentally determined FDDs. The validity of the description has been tested for beam qualities ranging from 60Co gamma rays to 18-MV x rays, using published data from several different sources as well as locally measured data sets. The small number of model parameters is attractive for computer or hand-held calculator applications. The small amount of required measured data is important in view of practical data acquisition for implementation of a computer-based dose calculation system. The generating function allows easy and accurate generation of FDD, tissue-air ratio, tissue-maximum ratio, and tissue-phantom ratio tables.

Net fractional depth dose: a basis for a unified analytical description of FDD, TAR, TMR, and TPR

DOE Office of Scientific and Technical Information (OSTI.GOV)

van de Geijn, J.; Fraass, B.A.

The net fractional depth dose (NFD) is defined as the fractional depth dose (FDD) corrected for inverse square law. Analysis of its behavior as a function of depth, field size, and source-surface distance has led to an analytical description with only seven model parameters related to straightforward physical properties. The determination of the characteristic parameter values requires only seven experimentally determined FDDs. The validity of the description has been tested for beam qualities ranging from /sup 60/Co gamma rays to 18-MV x rays, using published data from several different sources as well as locally measured data sets. The small numbermore » of model parameters is attractive for computer or hand-held calculator applications. The small amount of required measured data is important in view of practical data acquisition for implementation of a computer-based dose calculation system. The generating function allows easy and accurate generation of FDD, tissue-air ratio, tissue-maximum ratio, and tissue-phantom ratio tables.« less

Beyond Gaussians: a study of single spot modeling for scanning proton dose calculation

PubMed Central

Li, Yupeng; Zhu, Ronald X.; Sahoo, Narayan; Anand, Aman; Zhang, Xiaodong

2013-01-01

Active spot scanning proton therapy is becoming increasingly adopted by proton therapy centers worldwide. Unlike passive-scattering proton therapy, active spot scanning proton therapy, especially intensity-modulated proton therapy, requires proper modeling of each scanning spot to ensure accurate computation of the total dose distribution contributed from a large number of spots. During commissioning of the spot scanning gantry at the Proton Therapy Center in Houston, it was observed that the long-range scattering protons in a medium may have been inadequately modeled for high-energy beams by a commercial treatment planning system, which could lead to incorrect prediction of field-size effects on dose output. In the present study, we developed a pencil-beam algorithm for scanning-proton dose calculation by focusing on properly modeling individual scanning spots. All modeling parameters required by the pencil-beam algorithm can be generated based solely on a few sets of measured data. We demonstrated that low-dose halos in single-spot profiles in the medium could be adequately modeled with the addition of a modified Cauchy-Lorentz distribution function to a double-Gaussian function. The field-size effects were accurately computed at all depths and field sizes for all energies, and good dose accuracy was also achieved for patient dose verification. The implementation of the proposed pencil beam algorithm also enabled us to study the importance of different modeling components and parameters at various beam energies. The results of this study may be helpful in improving dose calculation accuracy and simplifying beam commissioning and treatment planning processes for spot scanning proton therapy. PMID:22297324

Continuous Toxicological Dose-Response Relationships Are Pretty Homogeneous (Society for Risk Analysis Annual Meeting)

EPA Science Inventory

Dose-response relationships for a wide range of in vivo and in vitro continuous datasets are well-described by a four-parameter exponential or Hill model, based on a recent analysis of multiple historical dose-response datasets, mostly with more than five dose groups (Slob and Se...

Optimal clinical trial design based on a dichotomous Markov-chain mixed-effect sleep model.

PubMed

Steven Ernest, C; Nyberg, Joakim; Karlsson, Mats O; Hooker, Andrew C

2014-12-01

D-optimal designs for discrete-type responses have been derived using generalized linear mixed models, simulation based methods and analytical approximations for computing the fisher information matrix (FIM) of non-linear mixed effect models with homogeneous probabilities over time. In this work, D-optimal designs using an analytical approximation of the FIM for a dichotomous, non-homogeneous, Markov-chain phase advanced sleep non-linear mixed effect model was investigated. The non-linear mixed effect model consisted of transition probabilities of dichotomous sleep data estimated as logistic functions using piecewise linear functions. Theoretical linear and nonlinear dose effects were added to the transition probabilities to modify the probability of being in either sleep stage. D-optimal designs were computed by determining an analytical approximation the FIM for each Markov component (one where the previous state was awake and another where the previous state was asleep). Each Markov component FIM was weighted either equally or by the average probability of response being awake or asleep over the night and summed to derive the total FIM (FIM(total)). The reference designs were placebo, 0.1, 1-, 6-, 10- and 20-mg dosing for a 2- to 6-way crossover study in six dosing groups. Optimized design variables were dose and number of subjects in each dose group. The designs were validated using stochastic simulation/re-estimation (SSE). Contrary to expectations, the predicted parameter uncertainty obtained via FIM(total) was larger than the uncertainty in parameter estimates computed by SSE. Nevertheless, the D-optimal designs decreased the uncertainty of parameter estimates relative to the reference designs. Additionally, the improvement for the D-optimal designs were more pronounced using SSE than predicted via FIM(total). Through the use of an approximate analytic solution and weighting schemes, the FIM(total) for a non-homogeneous, dichotomous Markov-chain phase advanced sleep model was computed and provided more efficient trial designs and increased nonlinear mixed-effects modeling parameter precision.

SU-E-T-405: Evaluation of the Raystation Electron Monte Carlo Algorithm for Varian Linear Accelerators

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sansourekidou, P; Allen, C

2015-06-15

Purpose: To evaluate the Raystation v4.51 Electron Monte Carlo algorithm for Varian Trilogy, IX and 2100 series linear accelerators and commission for clinical use. Methods: Seventy two water and forty air scans were acquired with a water tank in the form of profiles and depth doses, as requested by vendor. Data was imported into Rayphysics beam modeling module. Energy spectrum was modeled using seven parameters. Contamination photons were modeled using five parameters. Source phase space was modeled using six parameters. Calculations were performed in clinical version 4.51 and percent depth dose curves and profiles were extracted to be compared tomore » water tank measurements. Sensitivity tests were performed for all parameters. Grid size and particle histories were evaluated per energy for statistical uncertainty performance. Results: Model accuracy for air profiles is poor in the shoulder and penumbra region. However, model accuracy for water scans is acceptable. All energies and cones are within 2%/2mm for 90% of the points evaluated. Source phase space parameters have a cumulative effect. To achieve distributions with satisfactory smoothness level a 0.1cm grid and 3,000,000 particle histories were used for commissioning calculations. Calculation time was approximately 3 hours per energy. Conclusion: Raystation electron Monte Carlo is acceptable for clinical use for the Varian accelerators listed. Results are inferior to Elekta Electron Monte Carlo modeling. Known issues were reported to Raysearch and will be resolved in upcoming releases. Auto-modeling is limited to open cone depth dose curves and needs expansion.« less

Disposition of smoked cannabis with high {Delta}{sup 9}-tetrahydrocannabinol content: A kinetic model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hunault, Claudine C., E-mail: claudine.hunault@rivm.n; Eijkeren, Jan C.H. van; Mensinga, Tjeert T.

Introduction: No model exists to describe the disposition and kinetics of inhaled cannabis containing a high THC dose. We aimed to develop a kinetic model providing estimates of the THC serum concentrations after smoking cannabis cigarettes containing high THC doses (up to 69 mg THC). Methods: Twenty-four male non-daily cannabis users smoked cannabis cigarettes containing 29.3 mg, 49.1 mg, and 69.4 mg THC. Blood samples were collected over a period of 0-8 h and serum THC concentrations were measured. A two-compartment open model was fitted on the individual observed data. Results: Large inter-individual variability was observed in the pharmacokinetic parameters.more » The median pharmacokinetic parameters generated by the model were C{sub max} = 175 ng/mL, T{sub max} = 14 min, and AUC{sub 0-8h} = 8150 ng x min/mL for the 69.4 mg THC dose. Median model results show an almost linear dose response relation for C{sub max}/Dose = 2.8 x 10{sup -6}/mL and AUC{sub 0-8h}/Dose = 136 x 10{sup -6} min/mL. However, for increasing dose level, there was a clear decreasing trend: C{sub max}/Dose = 3.4, 2.6 and 2.5 x 10{sup -6}/mL and AUC{sub 0-8h}/Dose = 157, 133 and 117 x 10{sup -6} min/mL for the 29.3, 49.1 and 69.4 mg dose, respectively. Within the restriction of 8 h of observation, the apparent terminal half life of THC was 150 min. Conclusion: The model offers insight into the pharmacokinetics of THC in recreational cannabis users smoking cannabis containing high doses of THC mixed with tobacco. The model is an objective method for providing serum THC concentrations up to 8 h after smoking cannabis with a high THC content (up to 23%).« less

Disposition of smoked cannabis with high Δ(9)-tetrahydrocannabinol content: a kinetic model.

PubMed

Hunault, Claudine C; van Eijkeren, Jan C H; Mensinga, Tjeert T; de Vries, Irma; Leenders, Marianne E C; Meulenbelt, Jan

2010-08-01

No model exists to describe the disposition and kinetics of inhaled cannabis containing a high THC dose. We aimed to develop a kinetic model providing estimates of the THC serum concentrations after smoking cannabis cigarettes containing high THC doses (up to 69mg THC). Twenty-four male non-daily cannabis users smoked cannabis cigarettes containing 29.3mg, 49.1mg, and 69.4mg THC. Blood samples were collected over a period of 0-8h and serum THC concentrations were measured. A two-compartment open model was fitted on the individual observed data. Large inter-individual variability was observed in the pharmacokinetic parameters. The median pharmacokinetic parameters generated by the model were Cmax=175ng/mL, Tmax=14min, and AUC0-8h=8150ng×min/mL for the 69.4mg THC dose. Median model results show an almost linear dose response relation for Cmax/Dose=2.8×10(-6)/mL and AUC0-8h/Dose=136×10(-6)min/mL. However, for increasing dose level, there was a clear decreasing trend: Cmax/Dose=3.4, 2.6 and 2.5×10(-6)/mL and AUC0-8h/Dose=157, 133 and 117×10(-6)min/mL for the 29.3, 49.1 and 69.4mg dose, respectively. Within the restriction of 8h of observation, the apparent terminal half life of THC was 150min. The model offers insight into the pharmacokinetics of THC in recreational cannabis users smoking cannabis containing high doses of THC mixed with tobacco. The model is an objective method for providing serum THC concentrations up to 8h after smoking cannabis with a high THC content (up to 23%). Copyright © 2010 Elsevier Inc. All rights reserved.

The use of TCP based EUD to rank and compare lung radiotherapy plans: in-silico study to evaluate the correlation between TCP with physical quality indices.

PubMed

Chaikh, Abdulhamid; Balosso, Jacques

2017-06-01

To apply the equivalent uniform dose (EUD) radiobiological model to estimate the tumor control probability (TCP) scores for treatment plans using different radiobiological parameter settings, and to evaluate the correlation between TCP and physical quality indices of the treatment plans. Ten radiotherapy treatment plans for lung cancer were generated. The dose distributions were calculated using anisotropic analytical algorithm (AAA). Dose parameters and quality indices derived from dose volume histograms (DVH) for target volumes were evaluated. The predicted TCP was computed using EUD model with tissue-specific parameter (a=-10). The assumed radiobiological parameter setting for adjuvant therapy [tumor dose to control 50% of the tumor (TCD 50 ) =36.5 Gy and γ 50 =0.72] and curative intent (TCD 50 =51.24 Gy and γ 50 =0.83) were used. The bootstrap method was used to estimate the 95% confidence interval (95% CI). The coefficients (ρ) from Spearman's rank test were calculated to assess the correlation between quality indices with TCP. Wilcoxon paired test was used to calculate P value. The 95% CI of TCP were 70.6-81.5 and 46.6-64.7, respectively, for adjuvant radiotherapy and curative intent. The TCP outcome showed a positive and good correlation with calculated dose to 95% of the target volume (D95%) and minimum dose (Dmin). Consistently, TCP correlate negatively with heterogeneity indices. This study confirms that more relevant and robust radiobiological parameters setting should be integrated according to cancer type. The positive correlation with quality indices gives chance to improve the clinical out-come by optimizing the treatment plans to maximize the Dmin and D95%. This attempt to increase the TCP should be carried out with the respect of dose constraints for organs at risks. However, the negative correlation with heterogeneity indices shows that the optimization of beam arrangements could be also useful. Attention should be paid to obtain an appropriate optimization of initial plans, when comparing and ranking radiotherapy plans using TCP models, to avoid over or underestimated for TCP outcome.

Physiologically based pharmacokinetic model for 6-mercpatopurine: exploring the role of genetic polymorphism in TPMT enzyme activity

PubMed Central

Ogungbenro, Kayode; Aarons, Leon

2015-01-01

Aims To extend the physiologically based pharmacokinetic (PBPK) model developed for 6-mercaptopurine to account for intracellular metabolism and to explore the role of genetic polymorphism in the TPMT enzyme on the pharmacokinetics of 6-mercaptopurine. Methods The developed PBPK model was extended for 6-mercaptopurine to account for intracellular metabolism and genetic polymorphism in TPMT activity. System and drug specific parameters were obtained from the literature or estimated using plasma or intracellular red blood cell concentrations of 6-mercaptopurine and its metabolites. Age-dependent changes in parameters were implemented for scaling, and variability was also introduced for simulation. The model was validated using published data. Results The model was extended successfully. Parameter estimation and model predictions were satisfactory. Prediction of intracellular red blood cell concentrations of 6-thioguanine nucleotide for different TPMT phenotypes (in a clinical study that compared conventional and individualized dosing) showed results that were consistent with observed values and reported incidence of haematopoietic toxicity. Following conventional dosing, the predicted mean concentrations for homozygous and heterozygous variants, respectively, were about 10 times and two times the levels for wild-type. However, following individualized dosing, the mean concentration was around the same level for the three phenotypes despite different doses. Conclusions The developed PBPK model has been extended for 6-mercaptopurine and can be used to predict plasma 6-mercaptopurine and tissue concentration of 6-mercaptopurine, 6-thioguanine nucleotide and 6-methylmercaptopurine ribonucleotide in adults and children. Predictions of reported data from clinical studies showed satisfactory results. The model may help to improve 6-mercaptopurine dosing, achieve better clinical outcome and reduce toxicity. PMID:25614061

A Model of Regularization Parameter Determination in Low-Dose X-Ray CT Reconstruction Based on Dictionary Learning.

PubMed

Zhang, Cheng; Zhang, Tao; Zheng, Jian; Li, Ming; Lu, Yanfei; You, Jiali; Guan, Yihui

2015-01-01

In recent years, X-ray computed tomography (CT) is becoming widely used to reveal patient's anatomical information. However, the side effect of radiation, relating to genetic or cancerous diseases, has caused great public concern. The problem is how to minimize radiation dose significantly while maintaining image quality. As a practical application of compressed sensing theory, one category of methods takes total variation (TV) minimization as the sparse constraint, which makes it possible and effective to get a reconstruction image of high quality in the undersampling situation. On the other hand, a preliminary attempt of low-dose CT reconstruction based on dictionary learning seems to be another effective choice. But some critical parameters, such as the regularization parameter, cannot be determined by detecting datasets. In this paper, we propose a reweighted objective function that contributes to a numerical calculation model of the regularization parameter. A number of experiments demonstrate that this strategy performs well with better reconstruction images and saving of a large amount of time.

Normal tissue complication probability modeling of radiation-induced hypothyroidism after head-and-neck radiation therapy.

PubMed

Bakhshandeh, Mohsen; Hashemi, Bijan; Mahdavi, Seied Rabi Mehdi; Nikoofar, Alireza; Vasheghani, Maryam; Kazemnejad, Anoshirvan

2013-02-01

To determine the dose-response relationship of the thyroid for radiation-induced hypothyroidism in head-and-neck radiation therapy, according to 6 normal tissue complication probability models, and to find the best-fit parameters of the models. Sixty-five patients treated with primary or postoperative radiation therapy for various cancers in the head-and-neck region were prospectively evaluated. Patient serum samples (tri-iodothyronine, thyroxine, thyroid-stimulating hormone [TSH], free tri-iodothyronine, and free thyroxine) were measured before and at regular time intervals until 1 year after the completion of radiation therapy. Dose-volume histograms (DVHs) of the patients' thyroid gland were derived from their computed tomography (CT)-based treatment planning data. Hypothyroidism was defined as increased TSH (subclinical hypothyroidism) or increased TSH in combination with decreased free thyroxine and thyroxine (clinical hypothyroidism). Thyroid DVHs were converted to 2 Gy/fraction equivalent doses using the linear-quadratic formula with α/β = 3 Gy. The evaluated models included the following: Lyman with the DVH reduced to the equivalent uniform dose (EUD), known as LEUD; Logit-EUD; mean dose; relative seriality; individual critical volume; and population critical volume models. The parameters of the models were obtained by fitting the patients' data using a maximum likelihood analysis method. The goodness of fit of the models was determined by the 2-sample Kolmogorov-Smirnov test. Ranking of the models was made according to Akaike's information criterion. Twenty-nine patients (44.6%) experienced hypothyroidism. None of the models was rejected according to the evaluation of the goodness of fit. The mean dose model was ranked as the best model on the basis of its Akaike's information criterion value. The D(50) estimated from the models was approximately 44 Gy. The implemented normal tissue complication probability models showed a parallel architecture for the thyroid. The mean dose model can be used as the best model to describe the dose-response relationship for hypothyroidism complication. Copyright © 2013 Elsevier Inc. All rights reserved.

Time-dependent dose-response relation for absence of vaginal elasticity after gynecological radiation therapy.

PubMed

Alevronta, Eleftheria; Åvall-Lundqvist, Elisabeth; Al-Abany, Massoud; Nyberg, Tommy; Lind, Helena; Waldenström, Ann-Charlotte; Olsson, Caroline; Dunberger, Gail; Bergmark, Karin; Steineck, Gunnar; Lind, Bengt K

2016-09-01

To investigate the dose-response relation between the dose to the vagina and the patient-reported symptom 'absence of vaginal elasticity' and how time to follow-up influences this relation. The study included 78 long-term gynecological cancer survivors treated between 1991 and 2003 with external beam radiation therapy. Of those, 24 experienced absence of vaginal elasticity. A normal tissue complication model is introduced that takes into account the influence of time to follow-up on the dose-response relation and the patient's age. The best estimates of the dose-response parameters were calculated using Probit, Probit-Relative Seriality (RS) and Probit-time models. Log likelihood (LL) values and the Akaike Information Criterion (AIC) were used to evaluate the model fit. The dose-response parameters for 'absence of vaginal elasticity' according to the Probit and Probit-time models with the 68% Confidence Intervals (CI) were: LL=-39.8, D 50 =49.7 (47.2-52.4) Gy, γ 50 =1.40 (1.12-1.70) and LL=-37.4, D 50 =46.9 (43.5-50.9) Gy, γ 50 =1.81 (1.17-2.51) respectively. The proposed model, which describes the influence of time to follow-up on the dose-response relation, fits our data best. Our data indicate that the steepness of the dose-response curve of the dose to the vagina and the symptom 'absence of vaginal elasticity' increases with time to follow-up, while D 50 decreases. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Assessing the reliability of dose coefficients for exposure to radioiodine by members of the public, accounting for dosimetric and risk model uncertainties.

PubMed

Puncher, M; Zhang, W; Harrison, J D; Wakeford, R

2017-06-26

Assessments of risk to a specific population group resulting from internal exposure to a particular radionuclide can be used to assess the reliability of the appropriate International Commission on Radiological Protection (ICRP) dose coefficients used as a radiation protection device for the specified exposure pathway. An estimate of the uncertainty on the associated risk is important for informing judgments on reliability; a derived uncertainty factor, UF, is an estimate of the 95% probable geometric difference between the best risk estimate and the nominal risk and is a useful tool for making this assessment. This paper describes the application of parameter uncertainty analysis to quantify uncertainties resulting from internal exposures to radioiodine by members of the public, specifically 1, 10 and 20-year old females from the population of England and Wales. Best estimates of thyroid cancer incidence risk (lifetime attributable risk) are calculated for ingestion or inhalation of 129 I and 131 I, accounting for uncertainties in biokinetic model and cancer risk model parameter values. These estimates are compared with the equivalent ICRP derived nominal age-, sex- and population-averaged estimates of excess thyroid cancer incidence to obtain UFs. Derived UF values for ingestion or inhalation of 131 I for 1 year, 10-year and 20-year olds are around 28, 12 and 6, respectively, when compared with ICRP Publication 103 nominal values, and 9, 7 and 14, respectively, when compared with ICRP Publication 60 values. Broadly similar results were obtained for 129 I. The uncertainties on risk estimates are largely determined by uncertainties on risk model parameters rather than uncertainties on biokinetic model parameters. An examination of the sensitivity of the results to the risk models and populations used in the calculations show variations in the central estimates of risk of a factor of around 2-3. It is assumed that the direct proportionality of excess thyroid cancer risk and dose observed at low to moderate acute doses and incorporated in the risk models also applies to very small doses received at very low dose rates; the uncertainty in this assumption is considerable, but largely unquantifiable. The UF values illustrate the need for an informed approach to the use of ICRP dose and risk coefficients.

Normal tissue complication probability (NTCP) parameters for breast fibrosis: pooled results from two randomised trials.

PubMed

Mukesh, Mukesh B; Harris, Emma; Collette, Sandra; Coles, Charlotte E; Bartelink, Harry; Wilkinson, Jenny; Evans, Philip M; Graham, Peter; Haviland, Jo; Poortmans, Philip; Yarnold, John; Jena, Raj

2013-08-01

The dose-volume effect of radiation therapy on breast tissue is poorly understood. We estimate NTCP parameters for breast fibrosis after external beam radiotherapy. We pooled individual patient data of 5856 patients from 2 trials including whole breast irradiation followed with or without a boost. A two-compartment dose volume histogram model was used with boost volume as the first compartment and the remaining breast volume as second compartment. Results from START-pilot trial (n=1410) were used to test the predicted models. 26.8% patients in the Cambridge trial (5 years) and 20.7% patients in the EORTC trial (10 years) developed moderate-severe breast fibrosis. The best fit NTCP parameters were BEUD3(50)=136.4 Gy, γ50=0.9 and n=0.011 for the Niemierko model and BEUD3(50)=132 Gy, m=0.35 and n=0.012 for the Lyman Kutcher Burman model. The observed rates of fibrosis in the START-pilot trial agreed well with the predicted rates. This large multi-centre pooled study suggests that the effect of volume parameter is small and the maximum RT dose is the most important parameter to influence breast fibrosis. A small value of volume parameter 'n' does not fit with the hypothesis that breast tissue is a parallel organ. However, this may reflect limitations in our current scoring system of fibrosis. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Real-time dose calculation and visualization for the proton therapy of ocular tumours

NASA Astrophysics Data System (ADS)

Pfeiffer, Karsten; Bendl, Rolf

2001-03-01

A new real-time dose calculation and visualization was developed as part of the new 3D treatment planning tool OCTOPUS for proton therapy of ocular tumours within a national research project together with the Hahn-Meitner Institut Berlin. The implementation resolves the common separation between parameter definition, dose calculation and evaluation and allows a direct examination of the expected dose distribution while adjusting the treatment parameters. The new tool allows the therapist to move the desired dose distribution under visual control in 3D to the appropriate place. The visualization of the resulting dose distribution as a 3D surface model, on any 2D slice or on the surface of specified ocular structures is done automatically when adapting parameters during the planning process. In addition, approximate dose volume histograms may be calculated with little extra time. The dose distribution is calculated and visualized in 200 ms with an accuracy of 6% for the 3D isodose surfaces and 8% for other objects. This paper discusses the advantages and limitations of this new approach.

The use and QA of biologically related models for treatment planning: short report of the TG-166 of the therapy physics committee of the AAPM.

PubMed

Allen Li, X; Alber, Markus; Deasy, Joseph O; Jackson, Andrew; Ken Jee, Kyung-Wook; Marks, Lawrence B; Martel, Mary K; Mayo, Charles; Moiseenko, Vitali; Nahum, Alan E; Niemierko, Andrzej; Semenenko, Vladimir A; Yorke, Ellen D

2012-03-01

Treatment planning tools that use biologically related models for plan optimization and/or evaluation are being introduced for clinical use. A variety of dose-response models and quantities along with a series of organ-specific model parameters are included in these tools. However, due to various limitations, such as the limitations of models and available model parameters, the incomplete understanding of dose responses, and the inadequate clinical data, the use of biologically based treatment planning system (BBTPS) represents a paradigm shift and can be potentially dangerous. There will be a steep learning curve for most planners. The purpose of this task group is to address some of these relevant issues before the use of BBTPS becomes widely spread. In this report, the authors (1) discuss strategies, limitations, conditions, and cautions for using biologically based models and parameters in clinical treatment planning; (2) demonstrate the practical use of the three most commonly used commercially available BBTPS and potential dosimetric differences between biologically model based and dose-volume based treatment plan optimization and evaluation; (3) identify the desirable features and future directions in developing BBTPS; and (4) provide general guidelines and methodology for the acceptance testing, commissioning, and routine quality assurance (QA) of BBTPS.

Computation of restoration of ligand response in the random kinetics of a prostate cancer cell signaling pathway.

PubMed

Dana, Saswati; Nakakuki, Takashi; Hatakeyama, Mariko; Kimura, Shuhei; Raha, Soumyendu

2011-01-01

Mutation and/or dysfunction of signaling proteins in the mitogen activated protein kinase (MAPK) signal transduction pathway are frequently observed in various kinds of human cancer. Consistent with this fact, in the present study, we experimentally observe that the epidermal growth factor (EGF) induced activation profile of MAP kinase signaling is not straightforward dose-dependent in the PC3 prostate cancer cells. To find out what parameters and reactions in the pathway are involved in this departure from the normal dose-dependency, a model-based pathway analysis is performed. The pathway is mathematically modeled with 28 rate equations yielding those many ordinary differential equations (ODE) with kinetic rate constants that have been reported to take random values in the existing literature. This has led to us treating the ODE model of the pathways kinetics as a random differential equations (RDE) system in which the parameters are random variables. We show that our RDE model captures the uncertainty in the kinetic rate constants as seen in the behavior of the experimental data and more importantly, upon simulation, exhibits the abnormal EGF dose-dependency of the activation profile of MAP kinase signaling in PC3 prostate cancer cells. The most likely set of values of the kinetic rate constants obtained from fitting the RDE model into the experimental data is then used in a direct transcription based dynamic optimization method for computing the changes needed in these kinetic rate constant values for the restoration of the normal EGF dose response. The last computation identifies the parameters, i.e., the kinetic rate constants in the RDE model, that are the most sensitive to the change in the EGF dose response behavior in the PC3 prostate cancer cells. The reactions in which these most sensitive parameters participate emerge as candidate drug targets on the signaling pathway. 2011 Elsevier Ireland Ltd. All rights reserved.

A virtual photon energy fluence model for Monte Carlo dose calculation.

PubMed

Fippel, Matthias; Haryanto, Freddy; Dohm, Oliver; Nüsslin, Fridtjof; Kriesen, Stephan

2003-03-01

The presented virtual energy fluence (VEF) model of the patient-independent part of the medical linear accelerator heads, consists of two Gaussian-shaped photon sources and one uniform electron source. The planar photon sources are located close to the bremsstrahlung target (primary source) and to the flattening filter (secondary source), respectively. The electron contamination source is located in the plane defining the lower end of the filter. The standard deviations or widths and the relative weights of each source are free parameters. Five other parameters correct for fluence variations, i.e., the horn or central depression effect. If these parameters and the field widths in the X and Y directions are given, the corresponding energy fluence distribution can be calculated analytically and compared to measured dose distributions in air. This provides a method of fitting the free parameters using the measurements for various square and rectangular fields and a fixed number of monitor units. The next step in generating the whole set of base data is to calculate monoenergetic central axis depth dose distributions in water which are used to derive the energy spectrum by deconvolving the measured depth dose curves. This spectrum is also corrected to take the off-axis softening into account. The VEF model is implemented together with geometry modules for the patient specific part of the treatment head (jaws, multileaf collimator) into the XVMC dose calculation engine. The implementation into other Monte Carlo codes is possible based on the information in this paper. Experiments are performed to verify the model by comparing measured and calculated dose distributions and output factors in water. It is demonstrated that open photon beams of linear accelerators from two different vendors are accurately simulated using the VEF model. The commissioning procedure of the VEF model is clinically feasible because it is based on standard measurements in air and water. It is also useful for IMRT applications because a full Monte Carlo simulation of the treatment head would be too time-consuming for many small fields.

Tumor control probability reduction in gated radiotherapy of non-small cell lung cancers: a feasibility study.

PubMed

Siochi, R Alfredo; Kim, Yusung; Bhatia, Sudershan

2014-10-16

We studied the feasibility of evaluating tumor control probability (TCP) reductions for tumor motion beyond planned gated radiotherapy margins. Tumor motion was determined from cone-beam CT projections acquired for patient setup, intrafraction respiratory traces, and 4D CTs for five non-small cell lung cancer (NSCLC) patients treated with gated radiotherapy. Tumors were subdivided into 1 mm sections whose positions and doses were determined for each beam-on time point. (The dose calculation model was verified with motion phantom measurements.) The calculated dose distributions were used to generate the treatment TCPs for each patient. The plan TCPs were calculated from the treatment planning dose distributions. The treatment TCPs were compared to the plan TCPs for various models and parameters. Calculated doses matched phantom measurements within 0.3% for up to 3 cm of motion. TCP reductions for excess motion greater than 5mm ranged from 1.7% to 11.9%, depending on model parameters, and were as high as 48.6% for model parameters that simulated an individual patient. Repeating the worst case motion for all fractions increased TCP reductions by a factor of 2 to 3, while hypofractionation decreased these reductions by as much as a factor of 3. Treatment motion exceeding gating margins by more than 5 mm can lead to considerable TCP reductions. Appropriate margins for excess motion are recommended, unless applying daily tumor motion verification and adjusting thegating window.

Optimal radiotherapy dose schedules under parametric uncertainty

NASA Astrophysics Data System (ADS)

Badri, Hamidreza; Watanabe, Yoichi; Leder, Kevin

2016-01-01

We consider the effects of parameter uncertainty on the optimal radiation schedule in the context of the linear-quadratic model. Our interest arises from the observation that if inter-patient variability in normal and tumor tissue radiosensitivity or sparing factor of the organs-at-risk (OAR) are not accounted for during radiation scheduling, the performance of the therapy may be strongly degraded or the OAR may receive a substantially larger dose than the allowable threshold. This paper proposes a stochastic radiation scheduling concept to incorporate inter-patient variability into the scheduling optimization problem. Our method is based on a probabilistic approach, where the model parameters are given by a set of random variables. Our probabilistic formulation ensures that our constraints are satisfied with a given probability, and that our objective function achieves a desired level with a stated probability. We used a variable transformation to reduce the resulting optimization problem to two dimensions. We showed that the optimal solution lies on the boundary of the feasible region and we implemented a branch and bound algorithm to find the global optimal solution. We demonstrated how the configuration of optimal schedules in the presence of uncertainty compares to optimal schedules in the absence of uncertainty (conventional schedule). We observed that in order to protect against the possibility of the model parameters falling into a region where the conventional schedule is no longer feasible, it is required to avoid extremal solutions, i.e. a single large dose or very large total dose delivered over a long period. Finally, we performed numerical experiments in the setting of head and neck tumors including several normal tissues to reveal the effect of parameter uncertainty on optimal schedules and to evaluate the sensitivity of the solutions to the choice of key model parameters.

Dose, image quality and spine modeling assessment of biplanar EOS micro-dose radiographs for the follow-up of in-brace adolescent idiopathic scoliosis patients.

PubMed

Morel, Baptiste; Moueddeb, Sonia; Blondiaux, Eleonore; Richard, Stephen; Bachy, Manon; Vialle, Raphael; Ducou Le Pointe, Hubert

2018-05-01

The aim of this study was to compare the radiation dose, image quality and 3D spine parameter measurements of EOS low-dose and micro-dose protocols for in-brace adolescent idiopathic scoliosis (AIS) patients. We prospectively included 25 consecutive patients (20 females, 5 males) followed for AIS and undergoing brace treatment. The mean age was 12 years (SD 2 years, range 8-15 years). For each patient, in-brace biplanar EOS radiographs were acquired in a standing position using both the conventional low-dose and micro-dose protocols. Dose area product (DAP) was systematically recorded. Diagnostic image quality was qualitatively assessed by two radiologists for visibility of anatomical structures. The reliability of 3D spine modeling between two operators was quantitatively evaluated for the most clinically relevant 3D radiological parameters using intraclass correlation coefficient (ICC). The mean DAP for the posteroanterior and lateral acquisitions was 300 ± 134 and 433 ± 181 mGy cm 2 for the low-dose radiographs, and 41 ± 19 and 81 ± 39 mGy cm 2 for micro-dose radiographs. Image quality was lower with the micro-dose protocol. The agreement was "good" to "very good" for all measured clinical parameters when comparing the low-dose and micro-dose protocols (ICC > 0.73). The micro-dose protocol substantially reduced the delivered dose (by a factor of 5-7 compared to the low-dose protocol) in braced children with AIS. Although image quality was reduced, the micro-dose protocol proved to be adapted to radiological follow-up, with adequate image quality and reliable clinical measurements. These slides can be retrieved under Electronic Supplementary Material.

Pharmacokinetics of plasma enfuvirtide after subcutaneous administration to patients with human immunodeficiency virus: Inverse Gaussian density absorption and 2-compartment disposition.

PubMed

Zhang, Xiaoping; Nieforth, Keith; Lang, Jean-Marie; Rouzier-Panis, Regine; Reynes, Jacques; Dorr, Albert; Kolis, Stanley; Stiles, Mark R; Kinchelow, Tosca; Patel, Indravadan H

2002-07-01

Enfuvirtide (T-20) is the first of a novel class of human immunodeficiency virus (HIV) drugs that block gp41-mediated viral fusion to host cells. The objectives of this study were to develop a structural pharmacokinetic model that would adequately characterize the absorption and disposition of enfuvirtide pharmacokinetics after both intravenous and subcutaneous administration and to evaluate the dose proportionality of enfuvirtide pharmacokinetic parameters at a subcutaneous dose higher than that currently used in phase III studies. Twelve patients with HIV infection received 4 single doses of enfuvirtide separated by a 1-week washout period in an open-label, randomized, 4-way crossover fashion. The doses studied were 90 mg (intravenous) and 45 mg, 90 mg, and 180 mg (subcutaneous). Serial blood samples were collected up to 48 hours after each dose. Plasma enfuvirtide concentrations were measured with use of a validated liquid chromatography-tandem mass spectrometry method. Enfuvirtide plasma concentration-time data after subcutaneous administration were well described by an inverse Gaussian density function-input model linked to a 2-compartment open distribution model with first-order elimination from the central compartment. The model-derived mean pharmacokinetic parameters (+/-SD) were volume of distribution of the central compartment (3.8 +/- 0.8 L), volume of distribution of the peripheral compartment (1.7 +/- 0.6 L), total clearance (1.44 +/- 0.30 L/h), intercompartmental distribution (2.3 +/- 1.1 L/h), bioavailability (89% +/- 11%), and mean absorption time (7.26 hours, 8.65 hours, and 9.79 hours for the 45-mg, 90-mg, and 180-mg dose groups, respectively). The terminal half-life increased from 3.46 to 4.35 hours for the subcutaneous dose range from 45 to 180 mg. An inverse Gaussian density function-input model linked to a 2-compartment open distribution model with first-order elimination from the central compartment was appropriate to describe complex absorption and disposition kinetics of enfuvirtide plasma concentration-time data after subcutaneous administration to patients with HIV infection. Enfuvirtide was nearly completely absorbed from subcutaneous depot, and pharmacokinetic parameters were linear up to a dose of 180 mg in this study.

Optimal Chemotherapy for Leukemia: A Model-Based Strategy for Individualized Treatment

PubMed Central

Jayachandran, Devaraj; Rundell, Ann E.; Hannemann, Robert E.; Vik, Terry A.; Ramkrishna, Doraiswami

2014-01-01

Acute Lymphoblastic Leukemia, commonly known as ALL, is a predominant form of cancer during childhood. With the advent of modern healthcare support, the 5-year survival rate has been impressive in the recent past. However, long-term ALL survivors embattle several treatment-related medical and socio-economic complications due to excessive and inordinate chemotherapy doses received during treatment. In this work, we present a model-based approach to personalize 6-Mercaptopurine (6-MP) treatment for childhood ALL with a provision for incorporating the pharmacogenomic variations among patients. Semi-mechanistic mathematical models were developed and validated for i) 6-MP metabolism, ii) red blood cell mean corpuscular volume (MCV) dynamics, a surrogate marker for treatment efficacy, and iii) leukopenia, a major side-effect. With the constraint of getting limited data from clinics, a global sensitivity analysis based model reduction technique was employed to reduce the parameter space arising from semi-mechanistic models. The reduced, sensitive parameters were used to individualize the average patient model to a specific patient so as to minimize the model uncertainty. Models fit the data well and mimic diverse behavior observed among patients with minimum parameters. The model was validated with real patient data obtained from literature and Riley Hospital for Children in Indianapolis. Patient models were used to optimize the dose for an individual patient through nonlinear model predictive control. The implementation of our approach in clinical practice is realizable with routinely measured complete blood counts (CBC) and a few additional metabolite measurements. The proposed approach promises to achieve model-based individualized treatment to a specific patient, as opposed to a standard-dose-for-all, and to prescribe an optimal dose for a desired outcome with minimum side-effects. PMID:25310465

Organ doses for reference adult male and female undergoing computed tomography estimated by Monte Carlo simulations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Choonsik; Kim, Kwang Pyo; Long, Daniel

2011-03-15

Purpose: To develop a computed tomography (CT) organ dose estimation method designed to readily provide organ doses in a reference adult male and female for different scan ranges to investigate the degree to which existing commercial programs can reasonably match organ doses defined in these more anatomically realistic adult hybrid phantomsMethods: The x-ray fan beam in the SOMATOM Sensation 16 multidetector CT scanner was simulated within the Monte Carlo radiation transport code MCNPX2.6. The simulated CT scanner model was validated through comparison with experimentally measured lateral free-in-air dose profiles and computed tomography dose index (CTDI) values. The reference adult malemore » and female hybrid phantoms were coupled with the established CT scanner model following arm removal to simulate clinical head and other body region scans. A set of organ dose matrices were calculated for a series of consecutive axial scans ranging from the top of the head to the bottom of the phantoms with a beam thickness of 10 mm and the tube potentials of 80, 100, and 120 kVp. The organ doses for head, chest, and abdomen/pelvis examinations were calculated based on the organ dose matrices and compared to those obtained from two commercial programs, CT-EXPO and CTDOSIMETRY. Organ dose calculations were repeated for an adult stylized phantom by using the same simulation method used for the adult hybrid phantom. Results: Comparisons of both lateral free-in-air dose profiles and CTDI values through experimental measurement with the Monte Carlo simulations showed good agreement to within 9%. Organ doses for head, chest, and abdomen/pelvis scans reported in the commercial programs exceeded those from the Monte Carlo calculations in both the hybrid and stylized phantoms in this study, sometimes by orders of magnitude. Conclusions: The organ dose estimation method and dose matrices established in this study readily provides organ doses for a reference adult male and female for different CT scan ranges and technical parameters. Organ doses from existing commercial programs do not reasonably match organ doses calculated for the hybrid phantoms due to differences in phantom anatomy, as well as differences in organ dose scaling parameters. The organ dose matrices developed in this study will be extended to cover different technical parameters, CT scanner models, and various age groups.« less

SU-E-T-459: Dosimetric Consequences of Rotated Elliptical Proton Spots in Modeling In-Air Proton Fluence for Calculating Doses in Water of Proton Pencil Beams

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matysiak, W; Yeung, D; Hsi, W

2014-06-01

Purpose: We present a study of dosimetric consequences on doses in water in modeling in-air proton fluence independently along principle axes for rotated elliptical spots. Methods: Phase-space parameters for modeling in-air fluence are the position sigma for the spatial distribution, the angle sigma for the angular distribution, and the correlation between position and angle distributions. Proton spots of the McLaren proton therapy system were measured at five locations near the isocenter for the energies of 180 MeV and 250 MeV. An elongated elliptical spot rotated with respect to the principle axes was observed for the 180 MeV, while a circular-likemore » spot was observed for the 250 MeV. In the first approach, the phase-space parameters were derived in the principle axes without rotation. In the second approach, the phase space parameters were derived in the reference frame with axes rotated to coincide with the major axes of the elliptical spot. Monte-Carlo simulations with derived phase-space parameters using both approaches to tally doses in water were performed and analyzed. Results: For the rotated elliptical 180 MeV spots, the position sigmas were 3.6 mm and 3.2 mm in principle axes, but were 4.3 mm and 2.0 mm when the reference frame was rotated. Measured spots fitted poorly the uncorrelated 2D Gaussian, but the quality of fit was significantly improved after the reference frame was rotated. As a Result, phase space parameters in the rotated frame were more appropriate for modeling in-air proton fluence of 180 MeV protons. Considerable differences were observed in Monte Carlo simulated dose distributions in water with phase-space parameters obtained with the two approaches. Conclusion: For rotated elliptical proton spots, phase-space parameters obtained in the rotated reference frame are better for modeling in-air proton fluence, and can be introduced into treatment planning systems.« less

Toward a general physiologically-based pharmacokinetic model for intravenously injected nanoparticles.

PubMed

Carlander, Ulrika; Li, Dingsheng; Jolliet, Olivier; Emond, Claude; Johanson, Gunnar

2016-01-01

To assess the potential toxicity of nanoparticles (NPs), information concerning their uptake and disposition (biokinetics) is essential. Experience with industrial chemicals and pharmaceutical drugs reveals that biokinetics can be described and predicted accurately by physiologically-based pharmacokinetic (PBPK) modeling. The nano PBPK models developed to date all concern a single type of NP. Our aim here was to extend a recent model for pegylated polyacrylamide NP in order to develop a more general PBPK model for nondegradable NPs injected intravenously into rats. The same model and physiological parameters were applied to pegylated polyacrylamide, uncoated polyacrylamide, gold, and titanium dioxide NPs, whereas NP-specific parameters were chosen on the basis of the best fit to the experimental time-courses of NP accumulation in various tissues. Our model describes the biokinetic behavior of all four types of NPs adequately, despite extensive differences in this behavior as well as in their physicochemical properties. In addition, this simulation demonstrated that the dose exerts a profound impact on the biokinetics, since saturation of the phagocytic cells at higher doses becomes a major limiting step. The fitted model parameters that were most dependent on NP type included the blood:tissue coefficients of permeability and the rate constant for phagocytic uptake. Since only four types of NPs with several differences in characteristics (dose, size, charge, shape, and surface properties) were used, the relationship between these characteristics and the NP-dependent model parameters could not be elucidated and more experimental data are required in this context. In this connection, intravenous biodistribution studies with associated PBPK analyses would provide the most insight.

Maxine: A spreadsheet for estimating dose from chronic atmospheric radioactive releases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jannik, Tim; Bell, Evaleigh; Dixon, Kenneth

MAXINE is an EXCEL© spreadsheet, which is used to estimate dose to individuals for routine and accidental atmospheric releases of radioactive materials. MAXINE does not contain an atmospheric dispersion model, but rather doses are estimated using air and ground concentrations as input. Minimal input is required to run the program and site specific parameters are used when possible. Complete code description, verification of models, and user’s manual have been included.

A photon source model based on particle transport in a parameterized accelerator structure for Monte Carlo dose calculations.

PubMed

Ishizawa, Yoshiki; Dobashi, Suguru; Kadoya, Noriyuki; Ito, Kengo; Chiba, Takahito; Takayama, Yoshiki; Sato, Kiyokazu; Takeda, Ken

2018-05-17

An accurate source model of a medical linear accelerator is essential for Monte Carlo (MC) dose calculations. This study aims to propose an analytical photon source model based on particle transport in parameterized accelerator structures, focusing on a more realistic determination of linac photon spectra compared to existing approaches. We designed the primary and secondary photon sources based on the photons attenuated and scattered by a parameterized flattening filter. The primary photons were derived by attenuating bremsstrahlung photons based on the path length in the filter. Conversely, the secondary photons were derived from the decrement of the primary photons in the attenuation process. This design facilitates these sources to share the free parameters of the filter shape and be related to each other through the photon interaction in the filter. We introduced two other parameters of the primary photon source to describe the particle fluence in penumbral regions. All the parameters are optimized based on calculated dose curves in water using the pencil-beam-based algorithm. To verify the modeling accuracy, we compared the proposed model with the phase space data (PSD) of the Varian TrueBeam 6 and 15 MV accelerators in terms of the beam characteristics and the dose distributions. The EGS5 Monte Carlo code was used to calculate the dose distributions associated with the optimized model and reference PSD in a homogeneous water phantom and a heterogeneous lung phantom. We calculated the percentage of points passing 1D and 2D gamma analysis with 1%/1 mm criteria for the dose curves and lateral dose distributions, respectively. The optimized model accurately reproduced the spectral curves of the reference PSD both on- and off-axis. The depth dose and lateral dose profiles of the optimized model also showed good agreement with those of the reference PSD. The passing rates of the 1D gamma analysis with 1%/1 mm criteria between the model and PSD were 100% for 4 × 4, 10 × 10, and 20 × 20 cm 2 fields at multiple depths. For the 2D dose distributions calculated in the heterogeneous lung phantom, the 2D gamma pass rate was 100% for 6 and 15 MV beams. The model optimization time was less than 4 min. The proposed source model optimization process accurately produces photon fluence spectra from a linac using valid physical properties, without detailed knowledge of the geometry of the linac head, and with minimal optimization time. © 2018 American Association of Physicists in Medicine.

Correlation between the Temperature Dependence of Intrsinsic Mr Parameters and Thermal Dose Measured by a Rapid Chemical Shift Imaging Technique

PubMed Central

Taylor, Brian A.; Elliott, Andrew M.; Hwang, Ken-Pin; Hazle, John D.; Stafford, R. Jason

2011-01-01

In order to investigate simultaneous MR temperature imaging and direct validation of tissue damage during thermal therapy, temperature-dependent signal changes in proton resonance frequency (PRF) shifts, R2* values, and T1-weighted amplitudes are measured from one technique in ex vivo tissue heated with a 980-nm laser at 1.5T and 3.0T. Using a multi-gradient echo acquisition and signal modeling with the Stieglitz-McBride algorithm, the temperature sensitivity coefficient (TSC) values of these parameters are measured in each tissue at high spatiotemporal resolutions (1.6×1.6×4mm3,≤5sec) at the range of 25-61 °C. Non-linear changes in MR parameters are examined and correlated with an Arrhenius rate dose model of thermal damage. Using logistic regression, the probability of changes in these parameters is calculated as a function of thermal dose to determine if changes correspond to thermal damage. Temperature calibrations demonstrate TSC values which are consistent with previous studies. Temperature sensitivity of R2* and, in some cases, T1-weighted amplitudes are statistically different before and after thermal damage occurred. Significant changes in the slopes of R2* as a function of temperature are observed. Logistic regression analysis shows that these changes could be accurately predicted using the Arrhenius rate dose model (Ω=1.01±0.03), thereby showing that the changes in R2* could be direct markers of protein denaturation. Overall, by using a chemical shift imaging technique with simultaneous temperature estimation, R2* mapping and T1-W imaging, it is shown that changes in the sensitivity of R2* and, to a lesser degree, T1-W amplitudes are measured in ex vivo tissue when thermal damage is expected to occur according to Arrhenius rate dose models. These changes could possibly be used for direct validation of thermal damage in contrast to model-based predictions. PMID:21721063

Guidelines for Use of the Approximate Beta-Poisson Dose-Response Model.

PubMed

Xie, Gang; Roiko, Anne; Stratton, Helen; Lemckert, Charles; Dunn, Peter K; Mengersen, Kerrie

2017-07-01

For dose-response analysis in quantitative microbial risk assessment (QMRA), the exact beta-Poisson model is a two-parameter mechanistic dose-response model with parameters α>0 and β>0, which involves the Kummer confluent hypergeometric function. Evaluation of a hypergeometric function is a computational challenge. Denoting PI(d) as the probability of infection at a given mean dose d, the widely used dose-response model PI(d)=1-(1+dβ)-α is an approximate formula for the exact beta-Poisson model. Notwithstanding the required conditions α<β and β>1, issues related to the validity and approximation accuracy of this approximate formula have remained largely ignored in practice, partly because these conditions are too general to provide clear guidance. Consequently, this study proposes a probability measure Pr(0 < r < 1 | α̂, β̂) as a validity measure (r is a random variable that follows a gamma distribution; α̂ and β̂ are the maximum likelihood estimates of α and β in the approximate model); and the constraint conditions β̂>(22α̂)0.50 for 0.02<α̂<2 as a rule of thumb to ensure an accurate approximation (e.g., Pr(0 < r < 1 | α̂, β̂) >0.99) . This validity measure and rule of thumb were validated by application to all the completed beta-Poisson models (related to 85 data sets) from the QMRA community portal (QMRA Wiki). The results showed that the higher the probability Pr(0 < r < 1 | α̂, β̂), the better the approximation. The results further showed that, among the total 85 models examined, 68 models were identified as valid approximate model applications, which all had a near perfect match to the corresponding exact beta-Poisson model dose-response curve. © 2016 Society for Risk Analysis.

The two-dimensional Monte Carlo: a new methodologic paradigm for dose reconstruction for epidemiological studies.

PubMed

Simon, Steven L; Hoffman, F Owen; Hofer, Eduard

2015-01-01

Retrospective dose estimation, particularly dose reconstruction that supports epidemiological investigations of health risk, relies on various strategies that include models of physical processes and exposure conditions with detail ranging from simple to complex. Quantification of dose uncertainty is an essential component of assessments for health risk studies since, as is well understood, it is impossible to retrospectively determine the true dose for each person. To address uncertainty in dose estimation, numerical simulation tools have become commonplace and there is now an increased understanding about the needs and what is required for models used to estimate cohort doses (in the absence of direct measurement) to evaluate dose response. It now appears that for dose-response algorithms to derive the best, unbiased estimate of health risk, we need to understand the type, magnitude and interrelationships of the uncertainties of model assumptions, parameters and input data used in the associated dose estimation models. Heretofore, uncertainty analysis of dose estimates did not always properly distinguish between categories of errors, e.g., uncertainty that is specific to each subject (i.e., unshared error), and uncertainty of doses from a lack of understanding and knowledge about parameter values that are shared to varying degrees by numbers of subsets of the cohort. While mathematical propagation of errors by Monte Carlo simulation methods has been used for years to estimate the uncertainty of an individual subject's dose, it was almost always conducted without consideration of dependencies between subjects. In retrospect, these types of simple analyses are not suitable for studies with complex dose models, particularly when important input data are missing or otherwise not available. The dose estimation strategy presented here is a simulation method that corrects the previous deficiencies of analytical or simple Monte Carlo error propagation methods and is termed, due to its capability to maintain separation between shared and unshared errors, the two-dimensional Monte Carlo (2DMC) procedure. Simply put, the 2DMC method simulates alternative, possibly true, sets (or vectors) of doses for an entire cohort rather than a single set that emerges when each individual's dose is estimated independently from other subjects. Moreover, estimated doses within each simulated vector maintain proper inter-relationships such that the estimated doses for members of a cohort subgroup that share common lifestyle attributes and sources of uncertainty are properly correlated. The 2DMC procedure simulates inter-individual variability of possibly true doses within each dose vector and captures the influence of uncertainty in the values of dosimetric parameters across multiple realizations of possibly true vectors of cohort doses. The primary characteristic of the 2DMC approach, as well as its strength, are defined by the proper separation between uncertainties shared by members of the entire cohort or members of defined cohort subsets, and uncertainties that are individual-specific and therefore unshared.

Impact of Gender on Pharmocokinetics of Intranasal Scopolamine

NASA Technical Reports Server (NTRS)

Putcha, L.; Lei, Wu.; S-L Chow, Diana

2013-01-01

Introduction: An intranasal gel dosage formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness (SMS), which is commonly experienced by astronauts during space missions. The bioavailability and pharmacokinetics (PK) were evaluated under IND guidelines. Since information is lacking on the effect of gender on the PK of Scopolamine, we examined gender differences in PK parameters of INSCOP at three dose levels of 0.1, 0.2 and 0.4 mg. Methods: Plasma scopolamine concentrations as a function of time data were collected from twelve normal healthy human subjects (6 male/6 female) who participated in a fully randomized double blind crossover study. The PK parameters were derived using WinNonlin. Covariate analysis of PK profiles was performed using NONMEN and statistically compared using a likelihood ratio test on the difference of objective function value (OFV). Statistical significance for covariate analysis was set at P<0.05(?OFV=3.84). Results: No significant difference in PK parameters between male and female subjects was observed with 0.1 and 0.2 mg doses. However, CL and Vd were significantly different between male and female subjects at the 0.4 mg dose. Results from population covariate modeling analysis indicate that a onecompartment PK model with first-order elimination rate offers best fit for describing INSCOP concentration-time profiles. The inclusion of sex as a covariate enhanced the model fitting (?OFV=-4.1) owing to the genderdependent CL and Vd differences after the 0.4 mg dose. Conclusion: Statistical modeling of scopolamine concentration-time data suggests gender-dependent pharmacokinetics of scopolamine at the high dose level of 0.4 mg. Clearance of the parent compound was significantly faster and the volume of distribution was significantly higher in males than in females, As a result, including gender as a covariate to the pharmacokinetic model of scopolamine offers the best fit for PK modeling of the drug at dose of 0.4 mg or higher.

Dosimetric Analysis of Radiation-induced Gastric Bleeding

DOE Office of Scientific and Technical Information (OSTI.GOV)

Feng, Mary, E-mail: maryfeng@umich.edu; Normolle, Daniel; Pan, Charlie C.

2012-09-01

Purpose: Radiation-induced gastric bleeding has been poorly understood. In this study, we described dosimetric predictors for gastric bleeding after fractionated radiation therapy. Methods and Materials: The records of 139 sequential patients treated with 3-dimensional conformal radiation therapy (3D-CRT) for intrahepatic malignancies were reviewed. Median follow-up was 7.4 months. The parameters of a Lyman normal tissue complication probability (NTCP) model for the occurrence of {>=}grade 3 gastric bleed, adjusted for cirrhosis, were fitted to the data. The principle of maximum likelihood was used to estimate parameters for NTCP models. Results: Sixteen of 116 evaluable patients (14%) developed gastric bleeds at amore » median time of 4.0 months (mean, 6.5 months; range, 2.1-28.3 months) following completion of RT. The median and mean maximum doses to the stomach were 61 and 63 Gy (range, 46-86 Gy), respectively, after biocorrection of each part of the 3D dose distributions to equivalent 2-Gy daily fractions. The Lyman NTCP model with parameters adjusted for cirrhosis predicted gastric bleed. Best-fit Lyman NTCP model parameters were n=0.10 and m=0.21 and with TD{sub 50} (normal) = 56 Gy and TD{sub 50} (cirrhosis) = 22 Gy. The low n value is consistent with the importance of maximum dose; a lower TD{sub 50} value for the cirrhosis patients points out their greater sensitivity. Conclusions: This study demonstrates that the Lyman NTCP model has utility for predicting gastric bleeding and that the presence of cirrhosis greatly increases this risk. These findings should facilitate the design of future clinical trials involving high-dose upper abdominal radiation.« less

Towards an integrative computational model for simulating tumor growth and response to radiation therapy

NASA Astrophysics Data System (ADS)

Marrero, Carlos Sosa; Aubert, Vivien; Ciferri, Nicolas; Hernández, Alfredo; de Crevoisier, Renaud; Acosta, Oscar

2017-11-01

Understanding the response to irradiation in cancer radiotherapy (RT) may help devising new strategies with improved tumor local control. Computational models may allow to unravel the underlying radiosensitive mechanisms intervening in the dose-response relationship. By using extensive simulations a wide range of parameters may be evaluated providing insights on tumor response thus generating useful data to plan modified treatments. We propose in this paper a computational model of tumor growth and radiation response which allows to simulate a whole RT protocol. Proliferation of tumor cells, cell life-cycle, oxygen diffusion, radiosensitivity, RT response and resorption of killed cells were implemented in a multiscale framework. The model was developed in C++, using the Multi-formalism Modeling and Simulation Library (M2SL). Radiosensitivity parameters extracted from literature enabled us to simulate in a regular grid (voxel-wise) a prostate cell tissue. Histopathological specimens with different aggressiveness levels extracted from patients after prostatectomy were used to initialize in silico simulations. Results on tumor growth exhibit a good agreement with data from in vitro studies. Moreover, standard fractionation of 2 Gy/fraction, with a total dose of 80 Gy as a real RT treatment was applied with varying radiosensitivity and oxygen diffusion parameters. As expected, the high influence of these parameters was observed by measuring the percentage of survival tumor cell after RT. This work paves the way to further models allowing to simulate increased doses in modified hypofractionated schemes and to develop new patient-specific combined therapies.

Dosimetric evaluation of intrafractional tumor motion by means of a robot driven phantom

DOE Office of Scientific and Technical Information (OSTI.GOV)

Richter, Anne; Wilbert, Juergen; Flentje, Michael

2011-10-15

Purpose: The aim of the work was to investigate the influence of intrafractional tumor motion to the accumulated (absorbed) dose. The accumulated dose was determined by means of calculations and measurements with a robot driven motion phantom. Methods: Different motion scenarios and compensation techniques were realized in a phantom study to investigate the influence of motion on image acquisition, dose calculation, and dose measurement. The influence of motion on the accumulated dose was calculated by employing two methods (a model based and a voxel based method). Results: Tumor motion resulted in a blurring of steep dose gradients and a reductionmore » of dose at the periphery of the target. A systematic variation of motion parameters allowed the determination of the main influence parameters on the accumulated dose. The key parameters with the greatest influence on dose were the mean amplitude and the pattern of motion. Investigations on necessary safety margins to compensate for dose reduction have shown that smaller safety margins are sufficient, if the developed concept with optimized margins (OPT concept) was used instead of the standard internal target volume (ITV) concept. Both calculation methods were a reasonable approximation of the measured dose with the voxel based method being in better agreement with the measurements. Conclusions: Further evaluation of available systems and algorithms for dose accumulation are needed to create guidelines for the verification of the accumulated dose.« less

COMPARISON OF ORGAN DOSES IN HUMAN PHANTOMS: VARIATIONS DUE TO BODY SIZE AND POSTURE.

PubMed

Feng, Xu; Xiang-Hong, Jia; Qian, Liu; Xue-Jun, Yu; Zhan-Chun, Pan; Chun-Xin, Yang

2017-04-20

Organ dose calculations performed using human phantoms can provide estimates of astronauts' health risks due to cosmic radiation. However, the characteristics of such phantoms strongly affect the estimation precision. To investigate organ dose variations with body size and posture in human phantoms, a non-uniform rational B-spline boundary surfaces model was constructed based on cryosection images. This model was used to establish four phantoms with different body size and posture parameters, whose organs parameters were changed simultaneously and which were voxelised with 4 × 4 × 4 mm3 resolution. Then, using Monte Carlo transport code, the organ doses caused by ≤500 MeV isotropic incident protons were calculated. The dose variations due to body size differences within a certain range were negligible, and the doses received in crouching and standing-up postures were similar. Therefore, a standard Chinese phantom could be established, and posture changes cannot effectively protect astronauts during solar particle events. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

A Model of Regularization Parameter Determination in Low-Dose X-Ray CT Reconstruction Based on Dictionary Learning

PubMed Central

Zhang, Cheng; Zhang, Tao; Li, Ming; Lu, Yanfei; You, Jiali; Guan, Yihui

2015-01-01

In recent years, X-ray computed tomography (CT) is becoming widely used to reveal patient's anatomical information. However, the side effect of radiation, relating to genetic or cancerous diseases, has caused great public concern. The problem is how to minimize radiation dose significantly while maintaining image quality. As a practical application of compressed sensing theory, one category of methods takes total variation (TV) minimization as the sparse constraint, which makes it possible and effective to get a reconstruction image of high quality in the undersampling situation. On the other hand, a preliminary attempt of low-dose CT reconstruction based on dictionary learning seems to be another effective choice. But some critical parameters, such as the regularization parameter, cannot be determined by detecting datasets. In this paper, we propose a reweighted objective function that contributes to a numerical calculation model of the regularization parameter. A number of experiments demonstrate that this strategy performs well with better reconstruction images and saving of a large amount of time. PMID:26550024

Do Intermediate Radiation Doses Contribute to Late Rectal Toxicity? An Analysis of Data From Radiation Therapy Oncology Group Protocol 94-06

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tucker, Susan L., E-mail: sltucker@mdanderson.org; Dong, Lei; Michalski, Jeff M.

2012-10-01

Purpose: To investigate whether the volumes of rectum exposed to intermediate doses, from 30 to 50 Gy, contribute to the risk of Grade {>=}2 late rectal toxicity among patients with prostate cancer receiving radiotherapy. Methods and Materials: Data from 1009 patients treated on Radiation Therapy Oncology Group protocol 94-06 were analyzed using three approaches. First, the contribution of intermediate doses to a previously published fit of the Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP) model was determined. Next, the extent to which intermediate doses provide additional risk information, after taking the LKB model into account, was investigated. Third, the proportionmore » of rectum receiving doses higher than a threshold, VDose, was computed for doses ranging from 5 to 85 Gy, and a multivariate Cox proportional hazards model was used to determine which of these parameters were significantly associated with time to Grade {>=}2 late rectal toxicity. Results: Doses <60 Gy had no detectable impact on the fit of the LKB model, as expected on the basis of the small estimate of the volume parameter (n = 0.077). Furthermore, there was no detectable difference in late rectal toxicity among cohorts with similar risk estimates from the LKB model but with different volumes of rectum exposed to intermediate doses. The multivariate Cox proportional hazards model selected V75 as the only value of VDose significantly associated with late rectal toxicity. Conclusions: There is no evidence from these data that intermediate doses influence the risk of Grade {>=}2 late rectal toxicity. Instead, the critical doses for this endpoint seem to be {>=}75 Gy. It is hypothesized that cases of Grade {>=}2 late rectal toxicity occurring among patients with V75 less than approximately 12% may be due to a 'background' level of risk, likely due mainly to biological factors.« less

TH-E-BRF-01: Exploiting Tumor Shrinkage in Split-Course Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Unkelbach, J; Craft, D; Hong, T

2014-06-15

Purpose: In split-course radiotherapy, a patient is treated in several stages separated by weeks or months. This regimen has been motivated by radiobiological considerations. However, using modern image-guidance, it also provides an approach to reduce normal tissue dose by exploiting tumor shrinkage. In this work, we consider the optimal design of split-course treatments, motivated by the clinical management of large liver tumors for which normal liver dose constraints prohibit the administration of an ablative radiation dose in a single treatment. Methods: We introduce a dynamic tumor model that incorporates three factors: radiation induced cell kill, tumor shrinkage, and tumor cellmore » repopulation. The design of splitcourse radiotherapy is formulated as a mathematical optimization problem in which the total dose to the liver is minimized, subject to delivering the prescribed dose to the tumor. Based on the model, we gain insight into the optimal administration of radiation over time, i.e. the optimal treatment gaps and dose levels. Results: We analyze treatments consisting of two stages in detail. The analysis confirms the intuition that the second stage should be delivered just before the tumor size reaches a minimum and repopulation overcompensates shrinking. Furthermore, it was found that, for a large range of model parameters, approximately one third of the dose should be delivered in the first stage. The projected benefit of split-course treatments in terms of liver sparing depends on model assumptions. However, the model predicts large liver dose reductions by more than a factor of two for plausible model parameters. Conclusion: The analysis of the tumor model suggests that substantial reduction in normal tissue dose can be achieved by exploiting tumor shrinkage via an optimal design of multi-stage treatments. This suggests taking a fresh look at split-course radiotherapy for selected disease sites where substantial tumor regression translates into reduced target volumes.« less

A Monte Carlo study of the impact of the choice of rectum volume definition on estimates of equivalent uniform doses and the volume parameter

NASA Astrophysics Data System (ADS)

Kvinnsland, Yngve; Muren, Ludvig Paul; Dahl, Olav

2004-08-01

Calculations of normal tissue complication probability (NTCP) values for the rectum are difficult because it is a hollow, non-rigid, organ. Finding the true cumulative dose distribution for a number of treatment fractions requires a CT scan before each treatment fraction. This is labour intensive, and several surrogate distributions have therefore been suggested, such as dose wall histograms, dose surface histograms and histograms for the solid rectum, with and without margins. In this study, a Monte Carlo method is used to investigate the relationships between the cumulative dose distributions based on all treatment fractions and the above-mentioned histograms that are based on one CT scan only, in terms of equivalent uniform dose. Furthermore, the effect of a specific choice of histogram on estimates of the volume parameter of the probit NTCP model was investigated. It was found that the solid rectum and the rectum wall histograms (without margins) gave equivalent uniform doses with an expected value close to the values calculated from the cumulative dose distributions in the rectum wall. With the number of patients available in this study the standard deviations of the estimates of the volume parameter were large, and it was not possible to decide which volume gave the best estimates of the volume parameter, but there were distinct differences in the mean values of the values obtained.

Important Physiological Parameters and Physical Activity Data for Evaluating Exposure Modeling Performance: a Synthesis

EPA Science Inventory

The purpose of this report is to develop a database of physiological parameters needed for understanding and evaluating performance of the APEX and SHEDS exposure/intake dose rate model used by the Environmental Protection Agency (EPA) as part of its regulatory activities. The A...

Grid Block Design Based on Monte Carlo Simulated Dosimetry, the Linear Quadratic and Hug–Kellerer Radiobiological Models

PubMed Central

Gholami, Somayeh; Nedaie, Hassan Ali; Longo, Francesco; Ay, Mohammad Reza; Dini, Sharifeh A.; Meigooni, Ali S.

2017-01-01

Purpose: The clinical efficacy of Grid therapy has been examined by several investigators. In this project, the hole diameter and hole spacing in Grid blocks were examined to determine the optimum parameters that give a therapeutic advantage. Methods: The evaluations were performed using Monte Carlo (MC) simulation and commonly used radiobiological models. The Geant4 MC code was used to simulate the dose distributions for 25 different Grid blocks with different hole diameters and center-to-center spacing. The therapeutic parameters of these blocks, namely, the therapeutic ratio (TR) and geometrical sparing factor (GSF) were calculated using two different radiobiological models, including the linear quadratic and Hug–Kellerer models. In addition, the ratio of the open to blocked area (ROTBA) is also used as a geometrical parameter for each block design. Comparisons of the TR, GSF, and ROTBA for all of the blocks were used to derive the parameters for an optimum Grid block with the maximum TR, minimum GSF, and optimal ROTBA. A sample of the optimum Grid block was fabricated at our institution. Dosimetric characteristics of this Grid block were measured using an ionization chamber in water phantom, Gafchromic film, and thermoluminescent dosimeters in Solid Water™ phantom materials. Results: The results of these investigations indicated that Grid blocks with hole diameters between 1.00 and 1.25 cm and spacing of 1.7 or 1.8 cm have optimal therapeutic parameters (TR > 1.3 and GSF~0.90). The measured dosimetric characteristics of the optimum Grid blocks including dose profiles, percentage depth dose, dose output factor (cGy/MU), and valley-to-peak ratio were in good agreement (±5%) with the simulated data. Conclusion: In summary, using MC-based dosimetry, two radiobiological models, and previously published clinical data, we have introduced a method to design a Grid block with optimum therapeutic response. The simulated data were reproduced by experimental data. PMID:29296035

Bayesian estimation of dose thresholds

NASA Technical Reports Server (NTRS)

Groer, P. G.; Carnes, B. A.

2003-01-01

An example is described of Bayesian estimation of radiation absorbed dose thresholds (subsequently simply referred to as dose thresholds) using a specific parametric model applied to a data set on mice exposed to 60Co gamma rays and fission neutrons. A Weibull based relative risk model with a dose threshold parameter was used to analyse, as an example, lung cancer mortality and determine the posterior density for the threshold dose after single exposures to 60Co gamma rays or fission neutrons from the JANUS reactor at Argonne National Laboratory. The data consisted of survival, censoring times and cause of death information for male B6CF1 unexposed and exposed mice. The 60Co gamma whole-body doses for the two exposed groups were 0.86 and 1.37 Gy. The neutron whole-body doses were 0.19 and 0.38 Gy. Marginal posterior densities for the dose thresholds for neutron and gamma radiation were calculated with numerical integration and found to have quite different shapes. The density of the threshold for 60Co is unimodal with a mode at about 0.50 Gy. The threshold density for fission neutrons declines monotonically from a maximum value at zero with increasing doses. The posterior densities for all other parameters were similar for the two radiation types.

Relative sensitivity of developmental and immune parameters in juvenile versus adult male rats after exposure to di(2-ethylhexyl) phthalate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tonk, Elisa C.M., E-mail: ilse.tonk@rivm.nl; Laboratory for Health Protection Research, National Institute for Public Health and the Environment; Verhoef, Aart

The developing immune system displays a relatively high sensitivity as compared to both general toxicity parameters and to the adult immune system. In this study we have performed such comparisons using di(2-ethylhexyl) phthalate (DEHP) as a model compound. DEHP is the most abundant phthalate in the environment and perinatal exposure to DEHP has been shown to disrupt male sexual differentiation. In addition, phthalate exposure has been associated with immune dysfunction as evidenced by effects on the expression of allergy. Male wistar rats were dosed with corn oil or DEHP by gavage from postnatal day (PND) 10–50 or PND 50–90 atmore » doses between 1 and 1000 mg/kg/day. Androgen-dependent organ weights showed effects at lower dose levels in juvenile versus adult animals. Immune parameters affected included TDAR parameters in both age groups, NK activity in juvenile animals and TNF-α production by adherent splenocytes in adult animals. Immune parameters were affected at lower dose levels compared to developmental parameters. Overall, more immune parameters were affected in juvenile animals compared to adult animals and effects were observed at lower dose levels. The results of this study show a relatively higher sensitivity of juvenile versus adult rats. Furthermore, they illustrate the relative sensitivity of the developing immune system in juvenile animals as compared to general toxicity and developmental parameters. This study therefore provides further argumentation for performing dedicated developmental immune toxicity testing as a default in regulatory toxicology. -- Highlights: ► In this study we evaluate the relative sensitivities for DEHP induced effects. ► Results of this study demonstrate the age-dependency of DEHP toxicity. ► Functional immune parameters were more sensitive than structural immune parameters. ► Immune parameters were affected at lower dose levels than developmental parameters. ► Findings demonstrate the susceptibility of the developing immune system for DEHP.« less

Normal Tissue Complication Probability Modeling of Radiation-Induced Hypothyroidism After Head-and-Neck Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bakhshandeh, Mohsen; Hashemi, Bijan, E-mail: bhashemi@modares.ac.ir; Mahdavi, Seied Rabi Mehdi

Purpose: To determine the dose-response relationship of the thyroid for radiation-induced hypothyroidism in head-and-neck radiation therapy, according to 6 normal tissue complication probability models, and to find the best-fit parameters of the models. Methods and Materials: Sixty-five patients treated with primary or postoperative radiation therapy for various cancers in the head-and-neck region were prospectively evaluated. Patient serum samples (tri-iodothyronine, thyroxine, thyroid-stimulating hormone [TSH], free tri-iodothyronine, and free thyroxine) were measured before and at regular time intervals until 1 year after the completion of radiation therapy. Dose-volume histograms (DVHs) of the patients' thyroid gland were derived from their computed tomography (CT)-basedmore » treatment planning data. Hypothyroidism was defined as increased TSH (subclinical hypothyroidism) or increased TSH in combination with decreased free thyroxine and thyroxine (clinical hypothyroidism). Thyroid DVHs were converted to 2 Gy/fraction equivalent doses using the linear-quadratic formula with {alpha}/{beta} = 3 Gy. The evaluated models included the following: Lyman with the DVH reduced to the equivalent uniform dose (EUD), known as LEUD; Logit-EUD; mean dose; relative seriality; individual critical volume; and population critical volume models. The parameters of the models were obtained by fitting the patients' data using a maximum likelihood analysis method. The goodness of fit of the models was determined by the 2-sample Kolmogorov-Smirnov test. Ranking of the models was made according to Akaike's information criterion. Results: Twenty-nine patients (44.6%) experienced hypothyroidism. None of the models was rejected according to the evaluation of the goodness of fit. The mean dose model was ranked as the best model on the basis of its Akaike's information criterion value. The D{sub 50} estimated from the models was approximately 44 Gy. Conclusions: The implemented normal tissue complication probability models showed a parallel architecture for the thyroid. The mean dose model can be used as the best model to describe the dose-response relationship for hypothyroidism complication.« less

Monte Carlo Determination of Dosimetric Parameters of a New (125)I Brachytherapy Source According to AAPM TG-43 (U1) Protocol.

PubMed

Baghani, Hamid Reza; Lohrabian, Vahid; Aghamiri, Mahmoud Reza; Robatjazi, Mostafa

2016-03-01

(125)I is one of the important sources frequently used in brachytherapy. Up to now, several different commercial models of this source type have been introduced to the clinical radiation oncology applications. Recently, a new source model, IrSeed-125, has been added to this list. The aim of the present study is to determine the dosimetric parameters of this new source model based on the recommendations of TG-43 (U1) protocol using Monte Carlo simulation. The dosimetric characteristics of Ir-125 including dose rate constant, radial dose function, 2D anisotropy function and 1D anisotropy function were determined inside liquid water using MCNPX code and compared to those of other commercially available iodine sources. The dose rate constant of this new source was found to be 0.983+0.015 cGyh-1U-1 that was in good agreement with the TLD measured data (0.965 cGyh-1U-1). The 1D anisotropy function at 3, 5, and 7 cm radial distances were obtained as 0.954, 0.953 and 0.959, respectively. The results of this study showed that the dosimetric characteristics of this new brachytherapy source are comparable with those of other commercially available sources. Furthermore, the simulated parameters were in accordance with the previously measured ones. Therefore, the Monte Carlo calculated dosimetric parameters could be employed to obtain the dose distribution around this new brachytherapy source based on TG-43 (U1) protocol.

The impact of variation in scaling factors on the estimation of ...

EPA Pesticide Factsheets

Many physiologically based pharmacokinetic (PBPK) models include values for metabolic rate parameters extrapolated from in vitro metabolism studies using scaling factors such as mg of microsomal protein per gram of liver (MPPGL) and liver mass (FVL). Variation in scaling factor values impacts metabolic rate parameter estimates (Vmax) and hence estimates of internal dose used in dose response analysis. The impacts of adult human variation in MPPGL and FVL on estimates of internal dose were assessed using a human PBPK model for BDCM for several internal dose metrics for two exposure scenarios (single 0.25 liter drink of water or 10 minute shower) under plausible (5 micrograms/L) and high level (20 micrograms/L) water concentrations. For both concentrations, all internal dose metrics were changed less than 5% for the showering scenario (combined inhalation and dermal exposure). In contrast, a 27-fold variation in area under the curve for BDCM in venous blood was observed at both oral exposure concentrations, whereas total amount of BDCM metabolized in liver was relatively unchanged. This analysis demonstrates that variability in the scaling factors used for in vitro to in vivo extrapolation (IVIVE) for metabolic rate parameters can have a significant route-dependent impact on estimates of internal dose under environmentally relevant exposure scenarios. This indicates the need to evaluate both uncertainty and variability for scaling factors used for IVIVE. Sca

Long-term bradycardia caused by atrioventricular block can remodel the canine heart to detect the histamine H1 blocker terfenadine-induced torsades de pointes arrhythmias.

PubMed

Takahara, Akira; Sugiyama, Atsushi; Ishida, Yuko; Satoh, Yoshioki; Wang, Kai; Nakamura, Yuji; Hashimoto, Keitaro

2006-03-01

Although a second-generation histamine H(1) blocker terfenadine induced torsades de pointes (TdP) arrhythmias in patients via the blockade of a rapid component of delayed rectifier K(+) current (I(Kr)), such action of terfenadine has not been detected in previous animal models. We analysed the potential of the canine persistent atrioventricular block heart, a new in vivo proarrhythmia model, to detect a torsadogenic effect of terfenadine of an oral dose of 3 or 30 mg kg(-1). The doses can provide therapeutic to supra-therapeutic plasma concentrations as an anti-histamine. In 2 weeks of bradycardiac heart model, there were no significant changes in any of the electrocardiogram parameters after the administration of both doses of terfenadine. In 4-6 weeks of bradycardiac heart model, the low dose of terfenadine hardly affected any of the electrocardiogram parameters except that it induced TdP in one out of six animals. The high dose significantly decreased the atrial rate and ventricular rate, prolonged the QT interval, and induced TdP in five out of six animals. Moreover, temporal variability of repolarization increased after the high-dose administration. These results suggest that long-term bradycardia caused by atrioventricular block can remodel the canine heart to detect terfenadine-induced TdP.

Improvement in latent variable indirect response modeling of multiple categorical clinical endpoints: application to modeling of guselkumab treatment effects in psoriatic patients.

PubMed

Hu, Chuanpu; Randazzo, Bruce; Sharma, Amarnath; Zhou, Honghui

2017-10-01

Exposure-response modeling plays an important role in optimizing dose and dosing regimens during clinical drug development. The modeling of multiple endpoints is made possible in part by recent progress in latent variable indirect response (IDR) modeling for ordered categorical endpoints. This manuscript aims to investigate the level of improvement achievable by jointly modeling two such endpoints in the latent variable IDR modeling framework through the sharing of model parameters. This is illustrated with an application to the exposure-response of guselkumab, a human IgG1 monoclonal antibody in clinical development that blocks IL-23. A Phase 2b study was conducted in 238 patients with psoriasis for which disease severity was assessed using Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA) scores. A latent variable Type I IDR model was developed to evaluate the therapeutic effect of guselkumab dosing on 75, 90 and 100% improvement of PASI scores from baseline and PGA scores, with placebo effect empirically modeled. The results showed that the joint model is able to describe the observed data better with fewer parameters compared with the common approach of separately modeling the endpoints.

Technical Review of SRS Dose Reconstrruction Methods Used By CDC

DOE Office of Scientific and Technical Information (OSTI.GOV)

Simpkins, Ali, A

2005-07-20

At the request of the Centers for Disease Control and Prevention (CDC), a subcontractor Advanced Technologies and Laboratories International, Inc.(ATL) issued a draft report estimating offsite dose as a result of Savannah River Site operations for the period 1954-1992 in support of Phase III of the SRS Dose Reconstruction Project. The doses reported by ATL differed than those previously estimated by Savannah River Site SRS dose modelers for a variety of reasons, but primarily because (1) ATL used different source terms, (2) ATL considered trespasser/poacher scenarios and (3) ATL did not consistently use site-specific parameters or correct usage parameters. Themore » receptors with the highest dose from atmospheric and liquid pathways were within about a factor of four greater than dose values previously reported by SRS. A complete set of technical comments have also been included.« less

Identification of Trends into Dose Calculations for Astronauts through Performing Sensitivity Analysis on Calculational Models Used by the Radiation Health Office

NASA Technical Reports Server (NTRS)

Adams, Thomas; VanBaalen, Mary

2009-01-01

The Radiation Health Office (RHO) determines each astronaut s cancer risk by using models to associate the amount of radiation dose that astronauts receive from spaceflight missions. The baryon transport codes (BRYNTRN), high charge (Z) and energy transport codes (HZETRN), and computer risk models are used to determine the effective dose received by astronauts in Low Earth orbit (LEO). This code uses an approximation of the Boltzman transport formula. The purpose of the project is to run this code for various International Space Station (ISS) flight parameters in order to gain a better understanding of how this code responds to different scenarios. The project will determine how variations in one set of parameters such as, the point of the solar cycle and altitude can affect the radiation exposure of astronauts during ISS missions. This project will benefit NASA by improving mission dosimetry.

[Pharmacokinetics study of amoxicillin sodium clavulanate potassium (10:1) injection in healthy volunteers].

PubMed

Miao, Jia; Nan, Feng; Shen, Qi; Qin, Yong-Ping; Wang, Ying; Yu, Qin; Zheng, Li; Liang, Mao-Zhi

2013-03-01

To study the pharmacokinetics of amoxicillin sodium clavulanate potassium (10:1) injection with different single doses intravenous infusion and one dose repeated intravenous injection in healthy volunteers for guiding the rational clinical regimen. Using infusion pump constantly intravenous dripping in 30 min, 4 mL blood samples were collected before and after the administration at 10 min, 20 min, 30 min, 45 min, and 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 10 h. The plasma concentrations of amoxicillin and clavulanate were detected by high performance liquid chromatography- mass spectrometry/mass spectrometry method. The pharmacokinetic parameters were calculated by DAS2.0.1 software. The dispositions of amoxicillin and clavulanate matched three or two compartment model with the weight coefficient 1/cc. To avoid the biases caused by compartment model fitting, the pharmacokinetic parameters were statistical moment parameters of non-compartment model. The peak concentrations, the areas under curve, the half-lifes and the clearances after single injections of 0. 55 g, 1.1 g and 2.2 g indicated that both amoxillin and clavulanate had linear dynamics characteristics. After 1.1 g single dose and multiple doses infusion, the pharmacokinetic parameters of amoxicillin and clavulanate were close respectively, and the trough concentrations before the 7th to 13th administration were lower than the detection limitation, which implied that the previous administration had cleared out before the next administration, and no accumulation happened after multiple doses. The amoxicillin sodium clavulanate potassium (10:1) injection possesses the linear kinetics. The dosage regimen of 1.1 g Q8h intravenous infusion could meet the needs of clinical therapy.

Comparison of computational to human observer detection for evaluation of CT low dose iterative reconstruction

NASA Astrophysics Data System (ADS)

Eck, Brendan; Fahmi, Rachid; Brown, Kevin M.; Raihani, Nilgoun; Wilson, David L.

2014-03-01

Model observers were created and compared to human observers for the detection of low contrast targets in computed tomography (CT) images reconstructed with an advanced, knowledge-based, iterative image reconstruction method for low x-ray dose imaging. A 5-channel Laguerre-Gauss Hotelling Observer (CHO) was used with internal noise added to the decision variable (DV) and/or channel outputs (CO). Models were defined by parameters: (k1) DV-noise with standard deviation (std) proportional to DV std; (k2) DV-noise with constant std; (k3) CO-noise with constant std across channels; and (k4) CO-noise in each channel with std proportional to CO variance. Four-alternative forced choice (4AFC) human observer studies were performed on sub-images extracted from phantom images with and without a "pin" target. Model parameters were estimated using maximum likelihood comparison to human probability correct (PC) data. PC in human and all model observers increased with dose, contrast, and size, and was much higher for advanced iterative reconstruction (IMR) as compared to filtered back projection (FBP). Detection in IMR was better than FPB at 1/3 dose, suggesting significant dose savings. Model(k1,k2,k3,k4) gave the best overall fit to humans across independent variables (dose, size, contrast, and reconstruction) at fixed display window. However Model(k1) performed better when considering model complexity using the Akaike information criterion. Model(k1) fit the extraordinary detectability difference between IMR and FBP, despite the different noise quality. It is anticipated that the model observer will predict results from iterative reconstruction methods having similar noise characteristics, enabling rapid comparison of methods.

Optimization of reaction parameters of radiation induced grafting of 1-vinylimidazole onto poly(ethylene-co-tetraflouroethene) using response surface method

NASA Astrophysics Data System (ADS)

Nasef, Mohamed Mahmoud; Aly, Amgad Ahmed; Saidi, Hamdani; Ahmad, Arshad

2011-11-01

Radiation induced grafting of 1-vinylimidazole (1-VIm) onto poly(ethylene-co-tetraflouroethene) (ETFE) was investigated. The grafting parameters such as absorbed dose, monomer concentration, grafting time and temperature were optimized using response surface method (RSM). The Box-Behnken module available in the design expert software was used to investigate the effect of reaction conditions (independent parameters) varied in four levels on the degree of grafting ( G%) (response parameter). The model yielded a polynomial equation that relates the linear, quadratic and interaction effects of the independent parameters to the response parameter. The analysis of variance (ANOVA) was used to evaluate the results of the model and detect the significant values for the independent parameters. The optimum parameters to achieve a maximum G% were found to be monomer concentration of 55 vol%, absorbed dose of 100 kGy, time in the range of 14-20 h and a temperature of 61 °C. Fourier transform infrared (FTIR), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were used to investigate the properties of the obtained films and provide evidence for grafting.

An accurate model for the computation of the dose of protons in water.

PubMed

Embriaco, A; Bellinzona, V E; Fontana, A; Rotondi, A

2017-06-01

The accurate and fast calculation of the dose in proton radiation therapy is an essential ingredient for successful treatments. We propose a novel approach with a minimal number of parameters. The approach is based on the exact calculation of the electromagnetic part of the interaction, namely the Molière theory of the multiple Coulomb scattering for the transversal 1D projection and the Bethe-Bloch formula for the longitudinal stopping power profile, including a gaussian energy straggling. To this e.m. contribution the nuclear proton-nucleus interaction is added with a simple two-parameter model. Then, the non gaussian lateral profile is used to calculate the radial dose distribution with a method that assumes the cylindrical symmetry of the distribution. The results, obtained with a fast C++ based computational code called MONET (MOdel of ioN dosE for Therapy), are in very good agreement with the FLUKA MC code, within a few percent in the worst case. This study provides a new tool for fast dose calculation or verification, possibly for clinical use. Copyright © 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Bayesian multimodel inference for dose-response studies

USGS Publications Warehouse

Link, W.A.; Albers, P.H.

2007-01-01

Statistical inference in dose?response studies is model-based: The analyst posits a mathematical model of the relation between exposure and response, estimates parameters of the model, and reports conclusions conditional on the model. Such analyses rarely include any accounting for the uncertainties associated with model selection. The Bayesian inferential system provides a convenient framework for model selection and multimodel inference. In this paper we briefly describe the Bayesian paradigm and Bayesian multimodel inference. We then present a family of models for multinomial dose?response data and apply Bayesian multimodel inferential methods to the analysis of data on the reproductive success of American kestrels (Falco sparveriuss) exposed to various sublethal dietary concentrations of methylmercury.

A diversity index for model space selection in the estimation of benchmark and infectious doses via model averaging.

PubMed

Kim, Steven B; Kodell, Ralph L; Moon, Hojin

2014-03-01

In chemical and microbial risk assessments, risk assessors fit dose-response models to high-dose data and extrapolate downward to risk levels in the range of 1-10%. Although multiple dose-response models may be able to fit the data adequately in the experimental range, the estimated effective dose (ED) corresponding to an extremely small risk can be substantially different from model to model. In this respect, model averaging (MA) provides more robustness than a single dose-response model in the point and interval estimation of an ED. In MA, accounting for both data uncertainty and model uncertainty is crucial, but addressing model uncertainty is not achieved simply by increasing the number of models in a model space. A plausible set of models for MA can be characterized by goodness of fit and diversity surrounding the truth. We propose a diversity index (DI) to balance between these two characteristics in model space selection. It addresses a collective property of a model space rather than individual performance of each model. Tuning parameters in the DI control the size of the model space for MA. © 2013 Society for Risk Analysis.

Inter-Individual Variability in High-Throughput Risk ...

EPA Pesticide Factsheets

We incorporate realistic human variability into an open-source high-throughput (HT) toxicokinetics (TK) modeling framework for use in a next-generation risk prioritization approach. Risk prioritization involves rapid triage of thousands of environmental chemicals, most which have little or no existing TK data. Chemicals are prioritized based on model estimates of hazard and exposure, to decide which chemicals should be first in line for further study. Hazard may be estimated with in vitro HT screening assays, e.g., U.S. EPA’s ToxCast program. Bioactive ToxCast concentrations can be extrapolated to doses that produce equivalent concentrations in body tissues using a reverse TK approach in which generic TK models are parameterized with 1) chemical-specific parameters derived from in vitro measurements and predicted from chemical structure; and 2) with physiological parameters for a virtual population. Here we draw physiological parameters from realistic estimates of distributions of demographic and anthropometric quantities in the modern U.S. population, based on the most recent CDC NHANES data. A Monte Carlo approach, accounting for the correlation structure in physiological parameters, is used to estimate ToxCast equivalent doses for the most sensitive portion of the population. To quantify risk, ToxCast equivalent doses are compared to estimates of exposure rates based on Bayesian inferences drawn from NHANES urinary analyte biomonitoring data. The inclusion

Gastrointestinal toxicity and its relation to dose distributions in the anorectal region of prostate cancer patients treated with radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Heemsbergen, Wilma D.; Hoogeman, Mischa S.; Hart, Guus A.M.

2005-03-15

Purpose: To study the correlations between the dose distributions in the anorectal region and late GI symptoms in patients treated for localized prostate carcinoma. Methods and materials: Data from a randomized study were analyzed. In this trial, patients were treated with either rectangular or conformal fields with a dose of 66 Gy. Data concerning GI symptoms were collected from questionnaires of 197 patients. The distributions of the anorectal region were projected on maps, and the dose parameters were calculated. The incidences of complaints were studied as a function of the dose-area parameters and clinical parameters, using a proportional hazard regressionmore » model. Finally, we tested a series of dose parameters originating from different parts of the anorectal region. Results: Analyzing the total region, only a statistically significant dose-area effect relation for bleeding was found (p < 0.01). Defining subareas, we found effect relations for bleeding, soiling, fecal incontinence, and mucus loss. For bleeding and mucus loss, the strongest correlation was found for the dose received by the upper 70-80% of the anorectal region (p < 0.01). For soiling and fecal incontinence, we found the strongest association with the dose to the lower 40-50% (p < 0.05). Conclusion: We found evidence that complaints originate from specific regions of the irradiated lower GI tract. Bleeding and mucus loss are probably related to irradiation of the upper part of the rectum. Soiling and fecal incontinence are more likely related to the dose to the anal canal and the lower part of the rectum.« less

Spiral computed tomography phase-space source model in the BEAMnrc/EGSnrc Monte Carlo system: implementation and validation.

PubMed

Kim, Sangroh; Yoshizumi, Terry T; Yin, Fang-Fang; Chetty, Indrin J

2013-04-21

Currently, the BEAMnrc/EGSnrc Monte Carlo (MC) system does not provide a spiral CT source model for the simulation of spiral CT scanning. We developed and validated a spiral CT phase-space source model in the BEAMnrc/EGSnrc system. The spiral phase-space source model was implemented in the DOSXYZnrc user code of the BEAMnrc/EGSnrc system by analyzing the geometry of spiral CT scan-scan range, initial angle, rotational direction, pitch, slice thickness, etc. Table movement was simulated by changing the coordinates of the isocenter as a function of beam angles. Some parameters such as pitch, slice thickness and translation per rotation were also incorporated into the model to make the new phase-space source model, designed specifically for spiral CT scan simulations. The source model was hard-coded by modifying the 'ISource = 8: Phase-Space Source Incident from Multiple Directions' in the srcxyznrc.mortran and dosxyznrc.mortran files in the DOSXYZnrc user code. In order to verify the implementation, spiral CT scans were simulated in a CT dose index phantom using the validated x-ray tube model of a commercial CT simulator for both the original multi-direction source (ISOURCE = 8) and the new phase-space source model in the DOSXYZnrc system. Then the acquired 2D and 3D dose distributions were analyzed with respect to the input parameters for various pitch values. In addition, surface-dose profiles were also measured for a patient CT scan protocol using radiochromic film and were compared with the MC simulations. The new phase-space source model was found to simulate the spiral CT scanning in a single simulation run accurately. It also produced the equivalent dose distribution of the ISOURCE = 8 model for the same CT scan parameters. The MC-simulated surface profiles were well matched to the film measurement overall within 10%. The new spiral CT phase-space source model was implemented in the BEAMnrc/EGSnrc system. This work will be beneficial in estimating the spiral CT scan dose in the BEAMnrc/EGSnrc system.

Spiral computed tomography phase-space source model in the BEAMnrc/EGSnrc Monte Carlo system: implementation and validation

NASA Astrophysics Data System (ADS)

Kim, Sangroh; Yoshizumi, Terry T.; Yin, Fang-Fang; Chetty, Indrin J.

2013-04-01

Currently, the BEAMnrc/EGSnrc Monte Carlo (MC) system does not provide a spiral CT source model for the simulation of spiral CT scanning. We developed and validated a spiral CT phase-space source model in the BEAMnrc/EGSnrc system. The spiral phase-space source model was implemented in the DOSXYZnrc user code of the BEAMnrc/EGSnrc system by analyzing the geometry of spiral CT scan—scan range, initial angle, rotational direction, pitch, slice thickness, etc. Table movement was simulated by changing the coordinates of the isocenter as a function of beam angles. Some parameters such as pitch, slice thickness and translation per rotation were also incorporated into the model to make the new phase-space source model, designed specifically for spiral CT scan simulations. The source model was hard-coded by modifying the ‘ISource = 8: Phase-Space Source Incident from Multiple Directions’ in the srcxyznrc.mortran and dosxyznrc.mortran files in the DOSXYZnrc user code. In order to verify the implementation, spiral CT scans were simulated in a CT dose index phantom using the validated x-ray tube model of a commercial CT simulator for both the original multi-direction source (ISOURCE = 8) and the new phase-space source model in the DOSXYZnrc system. Then the acquired 2D and 3D dose distributions were analyzed with respect to the input parameters for various pitch values. In addition, surface-dose profiles were also measured for a patient CT scan protocol using radiochromic film and were compared with the MC simulations. The new phase-space source model was found to simulate the spiral CT scanning in a single simulation run accurately. It also produced the equivalent dose distribution of the ISOURCE = 8 model for the same CT scan parameters. The MC-simulated surface profiles were well matched to the film measurement overall within 10%. The new spiral CT phase-space source model was implemented in the BEAMnrc/EGSnrc system. This work will be beneficial in estimating the spiral CT scan dose in the BEAMnrc/EGSnrc system.

Evaluation of dose response models and parameters predicting radiation induced pneumonitis using clinical data from breast cancer radiotherapy

NASA Astrophysics Data System (ADS)

Tsougos, Ioannis; Mavroidis, Panayiotis; Rajala, Juha; Theodorou, Kyriaki; Järvenpää, Ritva; Pitkänen, Maunu A.; Holli, Kaija; Ojala, Antti T.; Lind, Bengt K.; Hyödynmaa, Simo; Kappas, Constantin

2005-08-01

The purpose of this work is to evaluate the predictive strength of the relative seriality, parallel and LKB normal tissue complication probability (NTCP) models regarding the incidence of radiation pneumonitis, in a large group of patients following breast cancer radiotherapy, and furthermore, to illustrate statistical methods for examining whether certain published radiobiological parameters are compatible with a clinical treatment methodology and patient group characteristics. The study is based on 150 consecutive patients who received radiation therapy for breast cancer. For each patient, the 3D dose distribution delivered to lung and the clinical treatment outcome were available. Clinical symptoms and radiological findings, along with a patient questionnaire, were used to assess the manifestation of radiation-induced complications. Using this material, different methods of estimating the likelihood of radiation effects were evaluated. This was attempted by analysing patient data based on their full dose distributions and associating the calculated complication rates with the clinical follow-up records. Additionally, the need for an update of the criteria that are being used in the current clinical practice was also examined. The patient material was selected without any conscious bias regarding the radiotherapy treatment technique used. The treatment data of each patient were applied to the relative seriality, LKB and parallel NTCP models, using published parameter sets. Of the 150 patients, 15 experienced radiation-induced pneumonitis (grade 2) according to the radiation pneumonitis scoring criteria used. Of the NTCP models examined, the relative seriality model was able to predict the incidence of radiation pneumonitis with acceptable accuracy, although radiation pneumonitis was developed by only a few patients. In the case of modern breast radiotherapy, radiobiological modelling appears to be very sensitive to model and parameter selection giving clinically acceptable results in certain cases selectively (relative seriality model with Seppenwoolde et al (2003 Int. J. Radiat. Oncol. Biol. Phys. 55 724-35) and Gagliardi et al (2000 Int. J. Radiat. Oncol. Biol. Phys. 46 373-81) parameter sets). The use of published parameters should be considered as safe only after their examination using local clinical data. The variation of inter-patient radiosensitivity seems to play a significant role in the prediction of such low incidence rate complications. Scoring grades were combined to give stronger evidence of radiation pneumonitis since their differences could not be strictly associated with dose. This obviously reveals a weakness of the scoring related to this endpoint, and implies that the probability of radiation pneumonitis induction may be too low to be statistically analysed with high accuracy, at least with the latest advances of dose delivery in breast radiotherapy.

Normal Tissue Complication Probability (NTCP) modeling of late rectal bleeding following external beam radiotherapy for prostate cancer: A Test of the QUANTEC-recommended NTCP model.

PubMed

Liu, Mitchell; Moiseenko, Vitali; Agranovich, Alexander; Karvat, Anand; Kwan, Winkle; Saleh, Ziad H; Apte, Aditya A; Deasy, Joseph O

2010-10-01

Validating a predictive model for late rectal bleeding following external beam treatment for prostate cancer would enable safer treatments or dose escalation. We tested the normal tissue complication probability (NTCP) model recommended in the recent QUANTEC review (quantitative analysis of normal tissue effects in the clinic). One hundred and sixty one prostate cancer patients were treated with 3D conformal radiotherapy for prostate cancer at the British Columbia Cancer Agency in a prospective protocol. The total prescription dose for all patients was 74 Gy, delivered in 2 Gy/fraction. 159 3D treatment planning datasets were available for analysis. Rectal dose volume histograms were extracted and fitted to a Lyman-Kutcher-Burman NTCP model. Late rectal bleeding (>grade 2) was observed in 12/159 patients (7.5%). Multivariate logistic regression with dose-volume parameters (V50, V60, V70, etc.) was non-significant. Among clinical variables, only age was significant on a Kaplan-Meier log-rank test (p=0.007, with an optimal cut point of 77 years). Best-fit Lyman-Kutcher-Burman model parameters (with 95% confidence intervals) were: n = 0.068 (0.01, +infinity); m =0.14 (0.0, 0.86); and TD50 = 81 (27, 136) Gy. The peak values fall within the 95% QUANTEC confidence intervals. On this dataset, both models had only modest ability to predict complications: the best-fit model had a Spearman's rank correlation coefficient of rs = 0.099 (p = 0.11) and area under the receiver operating characteristic curve (AUC) of 0.62; the QUANTEC model had rs=0.096 (p= 0.11) and a corresponding AUC of 0.61. Although the QUANTEC model consistently predicted higher NTCP values, it could not be rejected according to the χ(2) test (p = 0.44). Observed complications, and best-fit parameter estimates, were consistent with the QUANTEC-preferred NTCP model. However, predictive power was low, at least partly because the rectal dose distribution characteristics do not vary greatly within this patient cohort.

CPU time optimization and precise adjustment of the Geant4 physics parameters for a VARIAN 2100 C/D gamma radiotherapy linear accelerator simulation using GAMOS.

PubMed

Arce, Pedro; Lagares, Juan Ignacio

2018-01-25

We have verified the GAMOS/Geant4 simulation model of a 6 MV VARIAN Clinac 2100 C/D linear accelerator by the procedure of adjusting the initial beam parameters to fit the percentage depth dose and cross-profile dose experimental data at different depths in a water phantom. Thanks to the use of a wide range of field sizes, from 2  ×  2 cm 2 to 40  ×  40 cm 2 , a small phantom voxel size and high statistics, fine precision in the determination of the beam parameters has been achieved. This precision has allowed us to make a thorough study of the different physics models and parameters that Geant4 offers. The three Geant4 electromagnetic physics sets of models, i.e. Standard, Livermore and Penelope, have been compared to the experiment, testing the four different models of angular bremsstrahlung distributions as well as the three available multiple-scattering models, and optimizing the most relevant Geant4 electromagnetic physics parameters. Before the fitting, a comprehensive CPU time optimization has been done, using several of the Geant4 efficiency improvement techniques plus a few more developed in GAMOS.

Probabilistic biosphere modeling for the long-term safety assessment of geological disposal facilities for radioactive waste using first- and second-order Monte Carlo simulation.

PubMed

Ciecior, Willy; Röhlig, Klaus-Jürgen; Kirchner, Gerald

2018-10-01

In the present paper, deterministic as well as first- and second-order probabilistic biosphere modeling approaches are compared. Furthermore, the sensitivity of the influence of the probability distribution function shape (empirical distribution functions and fitted lognormal probability functions) representing the aleatory uncertainty (also called variability) of a radioecological model parameter as well as the role of interacting parameters are studied. Differences in the shape of the output distributions for the biosphere dose conversion factor from first-order Monte Carlo uncertainty analysis using empirical and fitted lognormal distribution functions for input parameters suggest that a lognormal approximation is possibly not always an adequate representation of the aleatory uncertainty of a radioecological parameter. Concerning the comparison of the impact of aleatory and epistemic parameter uncertainty on the biosphere dose conversion factor, the latter here is described using uncertain moments (mean, variance) while the distribution itself represents the aleatory uncertainty of the parameter. From the results obtained, the solution space of second-order Monte Carlo simulation is much larger than that from first-order Monte Carlo simulation. Therefore, the influence of epistemic uncertainty of a radioecological parameter on the output result is much larger than that one caused by its aleatory uncertainty. Parameter interactions are only of significant influence in the upper percentiles of the distribution of results as well as only in the region of the upper percentiles of the model parameters. Copyright © 2018 Elsevier Ltd. All rights reserved.

The Effect of Ongoing Exposure Dynamics in Dose Response Relationships

PubMed Central

Pujol, Josep M.; Eisenberg, Joseph E.; Haas, Charles N.; Koopman, James S.

2009-01-01

Characterizing infectivity as a function of pathogen dose is integral to microbial risk assessment. Dose-response experiments usually administer doses to subjects at one time. Phenomenological models of the resulting data, such as the exponential and the Beta-Poisson models, ignore dose timing and assume independent risks from each pathogen. Real world exposure to pathogens, however, is a sequence of discrete events where concurrent or prior pathogen arrival affects the capacity of immune effectors to engage and kill newly arriving pathogens. We model immune effector and pathogen interactions during the period before infection becomes established in order to capture the dynamics generating dose timing effects. Model analysis reveals an inverse relationship between the time over which exposures accumulate and the risk of infection. Data from one time dose experiments will thus overestimate per pathogen infection risks of real world exposures. For instance, fitting our model to one time dosing data reveals a risk of 0.66 from 313 Cryptosporidium parvum pathogens. When the temporal exposure window is increased 100-fold using the same parameters fitted by our model to the one time dose data, the risk of infection is reduced to 0.09. Confirmation of this risk prediction requires data from experiments administering doses with different timings. Our model demonstrates that dose timing could markedly alter the risks generated by airborne versus fomite transmitted pathogens. PMID:19503605

Exposure reconstruction for the TCDD-exposed NIOSH cohort using a concentration- and age-dependent model of elimination.

PubMed

Aylward, Lesa L; Brunet, Robert C; Starr, Thomas B; Carrier, Gaétan; Delzell, Elizabeth; Cheng, Hong; Beall, Colleen

2005-08-01

Recent studies demonstrating a concentration dependence of elimination of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suggest that previous estimates of exposure for occupationally exposed cohorts may have underestimated actual exposure, resulting in a potential overestimate of the carcinogenic potency of TCDD in humans based on the mortality data for these cohorts. Using a database on U.S. chemical manufacturing workers potentially exposed to TCDD compiled by the National Institute for Occupational Safety and Health (NIOSH), we evaluated the impact of using a concentration- and age-dependent elimination model (CADM) (Aylward et al., 2005) on estimates of serum lipid area under the curve (AUC) for the NIOSH cohort. These data were used previously by Steenland et al. (2001) in combination with a first-order elimination model with an 8.7-year half-life to estimate cumulative serum lipid concentration (equivalent to AUC) for these workers for use in cancer dose-response assessment. Serum lipid TCDD measurements taken in 1988 for a subset of the cohort were combined with the NIOSH job exposure matrix and work histories to estimate dose rates per unit of exposure score. We evaluated the effect of choices in regression model (regression on untransformed vs. ln-transformed data and inclusion of a nonzero regression intercept) as well as the impact of choices of elimination models and parameters on estimated AUCs for the cohort. Central estimates for dose rate parameters derived from the serum-sampled subcohort were applied with the elimination models to time-specific exposure scores for the entire cohort to generate AUC estimates for all cohort members. Use of the CADM resulted in improved model fits to the serum sampling data compared to the first-order models. Dose rates varied by a factor of 50 among different combinations of elimination model, parameter sets, and regression models. Use of a CADM results in increases of up to five-fold in AUC estimates for the more highly exposed members of the cohort compared to estimates obtained using the first-order model with 8.7-year half-life. This degree of variation in the AUC estimates for this cohort would affect substantially the cancer potency estimates derived from the mortality data from this cohort. Such variability and uncertainty in the reconstructed serum lipid AUC estimates for this cohort, depending on elimination model, parameter set, and regression model, have not been described previously and are critical components in evaluating the dose-response data from the occupationally exposed populations.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Espinoza, I; Peschke, P; Karger, C

Purpose: In radiotherapy, it is important to predict the response of tumour to irradiation prior to the treatment. Mathematical modelling of tumour control probability (TCP) based on the dose distribution, medical imaging and other biological information may help to improve this prediction and to optimize the treatment plan. The aim of this work is to develop an image based 3D multiscale radiobiological model, which describes the growth and the response to radiotherapy of hypoxic tumors. Methods: The computer model is based on voxels, containing tumour, normal (including capillary) and dead cells. Killing of tumour cells due to irradiation is calculatedmore » by the Linear Quadratic Model (extended for hypoxia), and the proliferation and resorption of cells are modelled by exponential laws. The initial shape of the tumours is taken from CT images and the initial vascular and cell density information from PET and/or MR images. Including the fractionation regime and the physical dose distribution of the radiation treatment, the model simulates the spatial-temporal evolution of the tumor. Additionally, the dose distribution may be biologically optimized. Results: The model describes the appearance of hypoxia during tumour growth and the reoxygenation processes during radiotherapy. Among other parameters, the TCP is calculated for different dose distributions. The results are in accordance with published results. Conclusion: The simulation model may contribute to the understanding of the influence of biological parameters on tumor response during treatment, and specifically on TCP. It may be used to implement dose-painting approaches. Experimental and clinical validation is needed. This study is supported by a grant from the Ministry of Education of Chile, Programa Mece Educacion Superior (2)« less

Using spatial information about recurrence risk for robust optimization of dose-painting prescription functions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bender, Edward T.

Purpose: To develop a robust method for deriving dose-painting prescription functions using spatial information about the risk for disease recurrence. Methods: Spatial distributions of radiobiological model parameters are derived from distributions of recurrence risk after uniform irradiation. These model parameters are then used to derive optimal dose-painting prescription functions given a constant mean biologically effective dose. Results: An estimate for the optimal dose distribution can be derived based on spatial information about recurrence risk. Dose painting based on imaging markers that are moderately or poorly correlated with recurrence risk are predicted to potentially result in inferior disease control when comparedmore » the same mean biologically effective dose delivered uniformly. A robust optimization approach may partially mitigate this issue. Conclusions: The methods described here can be used to derive an estimate for a robust, patient-specific prescription function for use in dose painting. Two approximate scaling relationships were observed: First, the optimal choice for the maximum dose differential when using either a linear or two-compartment prescription function is proportional to R, where R is the Pearson correlation coefficient between a given imaging marker and recurrence risk after uniform irradiation. Second, the predicted maximum possible gain in tumor control probability for any robust optimization technique is nearly proportional to the square of R.« less

Assessment of hemoglobin responsiveness to epoetin alfa in patients on hemodialysis using a population pharmacokinetic pharmacodynamic model.

PubMed

Wu, Liviawati; Mould, Diane R; Perez Ruixo, Juan Jose; Doshi, Sameer

2015-10-01

A population pharmacokinetic pharmacodynamic (PK/PD) model describing the effect of epoetin alfa on hemoglobin (Hb) response in hemodialysis patients was developed. Epoetin alfa pharmacokinetics was described using a linear 2-compartment model. PK parameter estimates were similar to previously reported values. A maturation-structured cytokinetic model consisting of 5 compartments linked in a catenary fashion by first-order cell transfer rates following a zero-order input process described the Hb time course. The PD model described 2 subpopulations, one whose Hb response reflected epoetin alfa dosing and a second whose response was unrelated to epoetin alfa dosing. Parameter estimates from the PK/PD model were physiologically reasonable and consistent with published reports. Numerical and visual predictive checks using data from 2 studies were performed. The PK and PD of epoetin alfa were well described by the model. © 2015, The American College of Clinical Pharmacology.

The Dose-Volume Relationship of Small Bowel Irradiation and Acute Grade 3 Diarrhea During Chemoradiotherapy for Rectal Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Robertson, John M.; Lockman, David; Yan Di

Purpose: Previous work has found a highly significant relationship between the irradiated small-bowel volume and development of Grade 3 small-bowel toxicity in patients with rectal cancer. This study tested the previously defined parameters in a much larger group of patients. Methods and Materials: A total of 96 consecutive patients receiving pelvic radiation therapy for rectal cancer had treatment planning computed tomographic scans with small-bowel contrast that allowed the small bowel to be outlined with calculation of a small-bowel dose-volume histogram for the initial intended pelvic treatment to 45 Gy. Patients with at least one parameter above the previously determined dose-volumemore » parameters were considered high risk, whereas those with all parameters below these levels were low risk. The grade of diarrhea and presence of liquid stool was determined prospectively. Results: There was a highly significant association with small-bowel dose-volume and Grade 3 diarrhea (p {<=} 0.008). The high-risk and low-risk parameters were predictive with Grade 3 diarrhea in 16 of 51 high-risk patients and in 4 of 45 low-risk patients (p = 0.01). Patients who had undergone irradiation preoperatively had a lower incidence of Grade 3 diarrhea than those treated postoperatively (18% vs. 28%; p = 0.31); however, the predictive ability of the high-risk/low-risk parameters was better for preoperatively (p = 0.03) than for postoperatively treated patients (p = 0.15). Revised risk parameters were derived that improved the overall predictive ability (p = 0.004). Conclusions: The highly significant dose-volume relationship and validity of the high-risk and low-risk parameters were confirmed in a large group of patients. The risk parameters provided better modeling for the preoperative patients than for the postoperative patients.« less

Semimechanistic Bone Marrow Exhaustion Pharmacokinetic/Pharmacodynamic Model for Chemotherapy-Induced Cumulative Neutropenia.

PubMed

Henrich, Andrea; Joerger, Markus; Kraff, Stefanie; Jaehde, Ulrich; Huisinga, Wilhelm; Kloft, Charlotte; Parra-Guillen, Zinnia Patricia

2017-08-01

Paclitaxel is a commonly used cytotoxic anticancer drug with potentially life-threatening toxicity at therapeutic doses and high interindividual pharmacokinetic variability. Thus, drug and effect monitoring is indicated to control dose-limiting neutropenia. Joerger et al. (2016) developed a dose individualization algorithm based on a pharmacokinetic (PK)/pharmacodynamic (PD) model describing paclitaxel and neutrophil concentrations. Furthermore, the algorithm was prospectively compared in a clinical trial against standard dosing (Central European Society for Anticancer Drug Research Study of Paclitaxel Therapeutic Drug Monitoring; 365 patients, 720 cycles) but did not substantially improve neutropenia. This might be caused by misspecifications in the PK/PD model underlying the algorithm, especially without consideration of the observed cumulative pattern of neutropenia or the platinum-based combination therapy, both impacting neutropenia. This work aimed to externally evaluate the original PK/PD model for potential misspecifications and to refine the PK/PD model while considering the cumulative neutropenia pattern and the combination therapy. An underprediction was observed for the PK (658 samples), the PK parameters, and these parameters were re-estimated using the original estimates as prior information. Neutrophil concentrations (3274 samples) were overpredicted by the PK/PD model, especially for later treatment cycles when the cumulative pattern aggravated neutropenia. Three different modeling approaches (two from the literature and one newly developed) were investigated. The newly developed model, which implemented the bone marrow hypothesis semiphysiologically, was superior. This model further included an additive effect for toxicity of carboplatin combination therapy. Overall, a physiologically plausible PK/PD model was developed that can be used for dose adaptation simulations and prospective studies to further improve paclitaxel/carboplatin combination therapy. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Uncertainty of inhalation dose coefficients for representative physical and chemical forms of iodine-131

NASA Astrophysics Data System (ADS)

Harvey, Richard Paul, III

Releases of radioactive material have occurred at various Department of Energy (DOE) weapons facilities and facilities associated with the nuclear fuel cycle in the generation of electricity. Many different radionuclides have been released to the environment with resulting exposure of the population to these various sources of radioactivity. Radioiodine has been released from a number of these facilities and is a potential public health concern due to its physical and biological characteristics. Iodine exists as various isotopes, but our focus is on 131I due to its relatively long half-life, its prevalence in atmospheric releases and its contribution to offsite dose. The assumption of physical and chemical form is speculated to have a profound impact on the deposition of radioactive material within the respiratory tract. In the case of iodine, it has been shown that more than one type of physical and chemical form may be released to, or exist in, the environment; iodine can exist as a particle or as a gas. The gaseous species can be further segregated based on chemical form: elemental, inorganic, and organic iodides. Chemical compounds in each class are assumed to behave similarly with respect to biochemistry. Studies at Oak Ridge National Laboratories have demonstrated that 131I is released as a particulate, as well as in elemental, inorganic and organic chemical form. The internal dose estimate from 131I may be very different depending on the effect that chemical form has on fractional deposition, gas uptake, and clearance in the respiratory tract. There are many sources of uncertainty in the estimation of environmental dose including source term, airborne transport of radionuclides, and internal dosimetry. Knowledge of uncertainty in internal dosimetry is essential for estimating dose to members of the public and for determining total uncertainty in dose estimation. Important calculational steps in any lung model is regional estimation of deposition fractions and gas uptake of radionuclides in various regions of the lung. Variability in regional radionuclide deposition within lung compartments may significantly contribute to the overall uncertainty of the lung model. The uncertainty of lung deposition and biological clearance is dependent upon physiological and anatomical parameters of individuals as well as characteristic parameters of the particulate material. These parameters introduce uncertainty into internal dose estimates due to their inherent variability. Anatomical and physiological input parameters are age and gender dependent. This work has determined the uncertainty in internal dose estimates and the sensitive parameters involved in modeling particulate deposition and gas uptake of different physical and chemical forms of 131I with age and gender dependencies.

Modeling and optimization aspects of radiation induced grafting of 4-vinylpyridene onto partially fluorinated films

NASA Astrophysics Data System (ADS)

Nasef, Mohamed Mahmoud; Ahmad Ali, Amgad; Saidi, Hamdani; Ahmad, Arshad

2014-01-01

Modeling and optimization aspects of radiation induced grafting (RIG) of 4-vinylpyridine (4-VP) onto partially fluorinated polymers such as poly(ethylene-co-tetrafluoroethene) (ETFE) and poly(vinylidene fluoride) (PVDF) films were comparatively investigated using response surface method (RSM). The effects of independent parameters: absorbed dose, monomer concentration, grafting time and reaction temperature on the response, grafting yield (GY) were correlated through two quadratic models. The results of this work confirm that RSM is a reliable tool not only for optimization of the reaction parameters and prediction of GY in RIG processes, but also for the reduction of the number of the experiments, monomer consumption and absorbed dose leading to an improvement of the overall reaction cost.

Role of the parameters involved in the plan optimization based on the generalized equivalent uniform dose and radiobiological implications

NASA Astrophysics Data System (ADS)

Widesott, L.; Strigari, L.; Pressello, M. C.; Benassi, M.; Landoni, V.

2008-03-01

We investigated the role and the weight of the parameters involved in the intensity modulated radiation therapy (IMRT) optimization based on the generalized equivalent uniform dose (gEUD) method, for prostate and head-and-neck plans. We systematically varied the parameters (gEUDmax and weight) involved in the gEUD-based optimization of rectal wall and parotid glands. We found that the proper value of weight factor, still guaranteeing planning treatment volumes coverage, produced similar organs at risks dose-volume (DV) histograms for different gEUDmax with fixed a = 1. Most of all, we formulated a simple relation that links the reference gEUDmax and the associated weight factor. As secondary objective, we evaluated plans obtained with the gEUD-based optimization and ones based on DV criteria, using the normal tissue complication probability (NTCP) models. gEUD criteria seemed to improve sparing of rectum and parotid glands with respect to DV-based optimization: the mean dose, the V40 and V50 values to the rectal wall were decreased of about 10%, the mean dose to parotids decreased of about 20-30%. But more than the OARs sparing, we underlined the halving of the OARs optimization time with the implementation of the gEUD-based cost function. Using NTCP models we enhanced differences between the two optimization criteria for parotid glands, but no for rectum wall.

Retrospective use of PBPK modelling to understand a clinical drug-drug interaction between dextromethorphan and GSK1034702.

PubMed

Hobbs, Michael J; Bloomer, Jackie; Dear, Gordon

2017-08-01

1. In a clinical trial, a strong drug-drug interaction (DDI) was observed between dextromethorphan (DM, the object or victim drug) and GSK1034702 (the precipitant or perpetrator drug), following single and repeat doses. This study determined the inhibition parameters of GSK1034702 in vitro and applied PBPK modelling approaches to simulate the clinical observations and provide mechanistic hypotheses to understand the DDI. 2. In vitro assays were conducted to determine the inhibition parameters of human CYP2D6 by GSK1034702. PBPK models were populated with the in vitro parameters and DDI simulations conducted and compared to the observed data from a clinical study with DM and GSK1034702. 3. GSK1034702 was a potent direct and metabolism-dependent inhibitor of human CYP2D6, with inhibition parameters of: IC 50  =   1.6 μM, K inact  = 3.7 h -1 and K I  = 0.8 μM. Incorporating these data into PBPK models predicted a DDI after repeat, but not single, 5 mg doses of GSK1034702. 4. The DDI observed with repeat administration of GSK1034702 (5 mg) can be attributed to metabolism-dependent inhibition of CYP2D6. Further, in vitro data were generated and several potential mechanisms proposed to explain the interaction observed following a single dose of GSK1034702.

A simple method for low-contrast detectability, image quality and dose optimisation with CT iterative reconstruction algorithms and model observers.

PubMed

Bellesi, Luca; Wyttenbach, Rolf; Gaudino, Diego; Colleoni, Paolo; Pupillo, Francesco; Carrara, Mauro; Braghetti, Antonio; Puligheddu, Carla; Presilla, Stefano

2017-01-01

The aim of this work was to evaluate detection of low-contrast objects and image quality in computed tomography (CT) phantom images acquired at different tube loadings (i.e. mAs) and reconstructed with different algorithms, in order to find appropriate settings to reduce the dose to the patient without any image detriment. Images of supraslice low-contrast objects of a CT phantom were acquired using different mAs values. Images were reconstructed using filtered back projection (FBP), hybrid and iterative model-based methods. Image quality parameters were evaluated in terms of modulation transfer function; noise, and uniformity using two software resources. For the definition of low-contrast detectability, studies based on both human (i.e. four-alternative forced-choice test) and model observers were performed across the various images. Compared to FBP, image quality parameters were improved by using iterative reconstruction (IR) algorithms. In particular, IR model-based methods provided a 60% noise reduction and a 70% dose reduction, preserving image quality and low-contrast detectability for human radiological evaluation. According to the model observer, the diameters of the minimum detectable detail were around 2 mm (up to 100 mAs). Below 100 mAs, the model observer was unable to provide a result. IR methods improve CT protocol quality, providing a potential dose reduction while maintaining a good image detectability. Model observer can in principle be useful to assist human performance in CT low-contrast detection tasks and in dose optimisation.

Physiologically based pharmacokinetic modelling of methotrexate and 6-mercaptopurine in adults and children. Part 2: 6-mercaptopurine and its interaction with methotrexate.

PubMed

Ogungbenro, Kayode; Aarons, Leon

2014-04-01

6-mercaptopurine (6-MP) is a purine antimetabolite and prodrug that undergoes extensive intracellular metabolism to produce thionucleotides, active metabolites which have cytotoxic and immunosuppressive properties. Combination therapies involving 6-MP and methotrexate have shown remarkable results in the cure of childhood acute lymphoblastic leukaemia (ALL) in the last 30 years. 6-MP undergoes very extensive intestinal and hepatic metabolism following oral dosing due to the activity of xanthine oxidase leading to very low and highly variable bioavailability and methotrexate has been demonstrated as an inhibitor of xanthine oxidase. Despite the success recorded in the use of 6-MP in ALL, there is still lack of effect and life threatening toxicity in some patients due to variability in the pharmacokinetics of 6-MP. Also, dose adjustment during treatment is still based on toxicity. The aim of the current work was to develop a mechanistic model that can be used to simulate trial outcomes and help to improve dose individualisation and dosage regimen optimisation. A physiological based pharmacokinetic model was proposed for 6-MP, this model has compartments for stomach, gut lumen, enterocyte, gut tissue, spleen, liver vascular, liver tissue, kidney vascular, kidney tissue, skin, bone marrow, thymus, muscle, rest of body and red blood cells. The model was based on the assumption of the same elimination pathways in adults and children. Parameters of the model include physiological parameters and drug-specific parameter which were obtained from the literature or estimated using plasma and red blood cell concentration data. Age-dependent changes in parameters were implemented for scaling and variability was also introduced on the parameters for prediction. Inhibition of 6-MP first-pass effect by methotrexate was implemented to predict observed clinical interaction between the two drugs. The model was developed successfully and plasma and red blood cell concentrations were adequately predicted both in terms of mean prediction and variability. The predicted interaction between 6-MP and methotrexate was slightly lower than the reported clinical interaction between the two drugs. The model can be used to predict plasma and tissue concentration in adults and children following oral and intravenous dosing and may ultimately help to improve treatment outcome in childhood ALL patients.

Dose dependence of true stress parameters in irradiated bcc, fcc, and hcp metals

NASA Astrophysics Data System (ADS)

Byun, T. S.

2007-04-01

The dose dependence of true stress parameters has been investigated for nuclear structural materials: A533B pressure vessel steels, modified 9Cr-1Mo and 9Cr-2WVTa ferritic martensitic steels, 316 and 316LN stainless steels, and Zircaloy-4. After irradiation to significant doses, these alloys show radiation-induced strengthening and often experience prompt necking at yield followed by large necking deformation. In the present work, the critical true stresses for deformation and fracture events, such as yield stress (YS), plastic instability stress (PIS), and true fracture stress (FS), were obtained from uniaxial tensile tests or calculated using a linear strain-hardening model for necking deformation. At low dose levels where no significant embrittlement was detected, the true fracture stress was nearly independent of dose. The plastic instability stress was also independent of dose before the critical dose-to-prompt-necking at yield was reached. A few bcc alloys such as ferritic martensitic steels experienced significant embrittlement at doses above ∼1 dpa; and the true fracture stress decreased with dose. The materials fractured before yield at or above 10 dpa.

Calculation of Heavy Ion Inactivation and Mutation Rates in Radial Dose Model of Track Structure

NASA Technical Reports Server (NTRS)

Cucinotta, Francis A.; Wilson, John W.; Shavers, Mark R.; Katz, Robert

1997-01-01

In the track structure model, the inactivation cross section is found by summing an inactivation probability over all impact parameters from the ion to the sensitive sites within the cell nucleus. The inactivation probability is evaluated by using the dose response of the system to gamma rays and the radial dose of the ions and may be equal to unity at small impact parameters. We apply the track structure model to recent data with heavy ion beams irradiating biological samples of E. Coli, B. Subtilis spores, and Chinese hamster (V79) cells. Heavy ions have observed cross sections for inactivation that approach and sometimes exceed the geometric size of the cell nucleus. We show how the effects of inactivation may be taken into account in the evaluation of the mutation cross sections in the track structure model through correlation of sites for gene mutation and cell inactivation. The model is fit to available data for HPRT (hypoxanthine guanine phosphoribosyl transferase) mutations in V79 cells, and good agreement is found. Calculations show the high probability for mutation by relativistic ions due to the radial extension of ions track from delta rays. The effects of inactivation on mutation rates make it very unlikely that a single parameter such as LET (linear energy transfer) can be used to specify radiation quality for heavy ion bombardment.

WE-FG-202-12: Investigation of Longitudinal Salivary Gland DCE-MRI Changes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ger, R; Howell, R; Li, H

Purpose: To determine the correlation between dose and changes through treatment in dynamic contrast enhanced (DCE) MRI voxel parameters (Ktrans, kep, Ve, and Vp) within salivary glands of head and neck oropharyngeal squamous cell carcinoma (HNSCC) patients. Methods: 17 HNSCC patients treated with definitive radiation therapy completed DCE-MRI scans on a 3T scanner at pre-treatment, mid-treatment, and post-treatment time points. Mid-treatment and post-treatment DCE images were deformably registered to pre-treatment DCE images (Velocity software package). Pharmacokinetic analysis of the DCE images used a modified Tofts model to produce parameter maps with an arterial input function selected from each patient’s perivertebralmore » space on the image (NordicICE software package). In-house software was developed for voxel-by-voxel longitudinal analysis of the salivary glands within the registered images. The planning CT was rigidly registered to the pre-treatment DCE image to obtain dose values in each voxel. Voxels within the lower and upper dose quartiles for each gland were averaged for each patient, then an average of the patients’ means for the two quartiles were compared. Dose-relationships were also assessed by Spearman correlations between dose and voxel parameter changes for each patient’s gland. Results: Changes in parameters’ means between time points were observed, but inter-patient variability was high. Ve of the parotid was the only parameter that had a consistently significant longitudinal difference between dose quartiles. The highest Spearman correlation was Vp of the sublingual gland for the change in the pre-treatment to mid-treatment values with only a ρ=0.29. Conclusion: In this preliminary study, there was large inter-patient variability in the changes of DCE voxel parameters with no clear relationship with dose. Additional patients may reduce the uncertainties and allow for the determination of the existence of parameter and dose relationships.« less

Pharmacokinetic evaluation of avicularin using a model-based development approach.

PubMed

Buqui, Gabriela Amaral; Gouvea, Dayana Rubio; Sy, Sherwin K B; Voelkner, Alexander; Singh, Ravi S P; da Silva, Denise Brentan; Kimura, Elza; Derendorf, Hartmut; Lopes, Norberto Peporine; Diniz, Andrea

2015-03-01

The aim of this study was to use the pharmacokinetic information of avicularin in rats to project a dose for humans using allometric scaling. A highly sensitive and specific bioanalytical assay to determine avicularin concentrations in the plasma was developed and validated for UPLC-MS/MS. The plasma protein binding of avicularin in rat plasma determined by the ultrafiltration method was 64%. The pharmacokinetics of avicularin in nine rats was studied following an intravenous bolus administration of 1 mg/kg and was found to be best described by a two-compartment model using a nonlinear mixed effects modeling approach. The pharmacokinetic parameters were allometrically scaled by body weight and centered to the median rat weight of 0.23 kg, with the power coefficient fixed at 0.75 for clearance and 1 for volume parameters. Avicularin was rapidly eliminated from the systemic circulation within 1 h post-dose, and the avicularin pharmacokinetic was linear up to 5 mg/kg based on exposure comparison to literature data for a 5-mg/kg single dose in rats. Using allometric scaling and Monte Carlo simulation approaches, the rat doses of 1 and 5 mg/kg correspond to the human equivalent doses of 30 and 150 mg, respectively, to achieve comparable plasma avicularin concentrations in humans. Georg Thieme Verlag KG Stuttgart · New York.

Reconstruction of paediatric organ doses from axial CT scans performed in the 1990s - range of doses as input to uncertainty estimates.

PubMed

Olerud, Hilde M; Toft, Benthe; Flatabø, Silje; Jahnen, Andreas; Lee, Choonsik; Thierry-Chef, Isabelle

2016-09-01

To assess the range of doses in paediatric CT scans conducted in the 1990s in Norway as input to an international epidemiology study: the EPI-CT study, http://epi-ct.iarc.fr/ . National Cancer Institute dosimetry system for Computed Tomography (NCICT) program based on pre-calculated organ dose conversion coefficients was used to convert CT Dose Index to organ doses in paediatric CT in the 1990s. Protocols reported from local hospitals in a previous Norwegian CT survey were used as input, presuming these were used without optimization for paediatric patients. Large variations in doses between different scanner models and local scan parameter settings are demonstrated. Small children will receive a factor of 2-3 times higher doses compared with adults if the protocols are not optimized for them. For common CT examinations, the doses to the active bone marrow, breast tissue and brain may have exceeded 30 mGy, 60 mGy and 100 mGy respectively, for the youngest children in the 1990s. The doses children received from non-optimised CT examinations during the 1990s are of such magnitude that they may provide statistically significant effects in the EPI-CT study, but probably do not reflect current practice. • Some organ doses from paediatric CT in the 1990s may have exceeded 100 mGy. • Small children may have received doses 2-3 times higher compared with adults. • Different scanner models varied by a factor of 2-3 in dose to patients. • Different local scan parameter settings gave dose variations of a factor 2-3. • Modern CTs and age-adjusted protocols will give much lower paediatric doses.

Application of a computational decision model to examine acute drug effects on human risk taking.

PubMed

Lane, Scott D; Yechiam, Eldad; Busemeyer, Jerome R

2006-05-01

In 3 previous experiments, high doses of alcohol, marijuana, and alprazolam acutely increased risky decision making by adult humans in a 2-choice (risky vs. nonrisky) laboratory task. In this study, a computational modeling analysis known as the expectancy valence model (J. R. Busemeyer & J. C. Stout, 2002) was applied to individual-participant data from these studies, for the highest administered dose of all 3 drugs and corresponding placebo doses, to determine changes in decision-making processes that may be uniquely engendered by each drug. The model includes 3 parameters: responsiveness to rewards and losses (valence or motivation); the rate of updating expectancies about the value of risky alternatives (learning/memory); and the consistency with which trial-by-trial choices match expected outcomes (sensitivity). Parameter estimates revealed 3 key outcomes: Alcohol increased responsiveness to risky rewards and decreased responsiveness to risky losses (motivation) but did not alter expectancy updating (learning/memory); both marijuana and alprazolam produced increases in risk taking that were related to learning/memory but not motivation; and alcohol and marijuana (but not alprazolam) produced more random response patterns that were less consistently related to expected outcomes on the 2 choices. No significant main effects of gender or dose by gender interactions were obtained, but 2 dose by gender interactions approached significance. These outcomes underscore the utility of using a computational modeling approach to deconstruct decision-making processes and thus better understand drug effects on risky decision making in humans.

Quantitative prediction of repaglinide-rifampicin complex drug interactions using dynamic and static mechanistic models: delineating differential CYP3A4 induction and OATP1B1 inhibition potential of rifampicin.

PubMed

Varma, Manthena V S; Lin, Jian; Bi, Yi-An; Rotter, Charles J; Fahmi, Odette A; Lam, Justine L; El-Kattan, Ayman F; Goosen, Theunis C; Lai, Yurong

2013-05-01

Repaglinide is mainly metabolized by cytochrome P450 enzymes CYP2C8 and CYP3A4, and it is also a substrate to a hepatic uptake transporter, organic anion transporting polypeptide (OATP)1B1. The purpose of this study is to predict the dosing time-dependent pharmacokinetic interactions of repaglinide with rifampicin, using mechanistic models. In vitro hepatic transport of repaglinide, characterized using sandwich-cultured human hepatocytes, and intrinsic metabolic parameters were used to build a dynamic whole-body physiologically-based pharmacokinetic (PBPK) model. The PBPK model adequately described repaglinide plasma concentration-time profiles and successfully predicted area under the plasma concentration-time curve ratios of repaglinide (within ± 25% error), dosed (staggered 0-24 hours) after rifampicin treatment when primarily considering induction of CYP3A4 and reversible inhibition of OATP1B1 by rifampicin. Further, a static mechanistic "extended net-effect" model incorporating transport and metabolic disposition parameters of repaglinide and interaction potency of rifampicin was devised. Predictions based on the static model are similar to those observed in the clinic (average error ∼19%) and to those based on the PBPK model. Both the models suggested that the combined effect of increased gut extraction and decreased hepatic uptake caused minimal repaglinide systemic exposure change when repaglinide is dosed simultaneously or 1 hour after the rifampicin dose. On the other hand, isolated induction effect as a result of temporal separation of the two drugs translated to an approximate 5-fold reduction in repaglinide systemic exposure. In conclusion, both dynamic and static mechanistic models are instrumental in delineating the quantitative contribution of transport and metabolism in the dosing time-dependent repaglinide-rifampicin interactions.

Model-based iterative reconstruction in low-dose CT colonography-feasibility study in 65 patients for symptomatic investigation.

PubMed

Vardhanabhuti, Varut; James, Julia; Nensey, Rehaan; Hyde, Christopher; Roobottom, Carl

2015-05-01

To compare image quality on computed tomographic colonography (CTC) acquired at standard dose (STD) and low dose (LD) using filtered-back projection, adaptive statistical iterative reconstruction, and model-based iterative reconstruction (MBIR) techniques. A total of 65 symptomatic patients were prospectively enrolled for the study and underwent STD and LD CTC with filtered-back projection, adaptive statistical iterative reconstruction, and MBIR to allow direct per-patient comparison. Objective image noise, subjective image analyses, and polyp detection were assessed. Objective image noise analysis demonstrates significant noise reduction using MBIR technique (P < .05) despite being acquired at lower doses. Subjective image analyses were superior for LD MBIR in all parameters except visibility of extracolonic lesions (two-dimensional) and visibility of colonic wall (three-dimensional) where there were no significant differences. There was no significant difference in polyp detection rates (P > .05). Doses: LD (dose-length product, 257.7), STD (dose-length product, 483.6). LD MBIR CTC objectively shows improved image noise using parameters in our study. Subjectively, image quality is maintained. Polyp detection shows no significant difference but because of small numbers needs further validation. Average dose reduction of 47% can be achieved. This study confirms feasibility of using MBIR in this context of CTC in symptomatic population. Copyright © 2015 AUR. Published by Elsevier Inc. All rights reserved.

Modeling spray/puddle dissolution processes for deep-ultraviolet acid-hardened resists

NASA Astrophysics Data System (ADS)

Hutchinson, John M.; Das, Siddhartha; Qian, Qi-De; Gaw, Henry T.

1993-10-01

A study of the dissolution behavior of acid-hardened resists (AHR) was undertaken for spray and spray/puddle development processes. The Site Services DSM-100 end-point detection system is used to measure both spray and puddle dissolution data for a commercially available deep-ultraviolet AHR resist, Shipley SNR-248. The DSM allows in situ measurement of dissolution rate on the wafer chuck and hence allows parameter extraction for modeling spray and puddle processes. The dissolution data for spray and puddle processes was collected across a range of exposure dose and postexposure bake temperature. The development recipe was varied to decouple the contribution of the spray and puddle modes to the overall dissolution characteristics. The mechanisms involved in spray versus puddle dissolution and the impact of spray versus puddle dissolution on process performance metrics has been investigated. We used the effective-dose-modeling approach and the measurement capability of the DSM-100 and developed a lumped parameter model for acid-hardened resists that incorporates the effects of exposure, postexposure bake temperature and time, and development condition. The PARMEX photoresist-modeling program is used to determine parameters for the spray and for the puddle process. The lumped parameter AHR model developed showed good agreement with experimental data.

Population Pharmacokinetic/Pharmacodynamic Analysis of Alirocumab in Healthy Volunteers or Hypercholesterolemic Subjects Using an Indirect Response Model to Predict Low-Density Lipoprotein Cholesterol Lowering: Support for a Biologics License Application Submission: Part II.

PubMed

Nicolas, Xavier; Djebli, Nassim; Rauch, Clémence; Brunet, Aurélie; Hurbin, Fabrice; Martinez, Jean-Marie; Fabre, David

2018-05-03

Alirocumab, a human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly lowers low-density lipoprotein cholesterol levels. This analysis aimed to develop and qualify a population pharmacokinetic/pharmacodynamic model for alirocumab based on pooled data obtained from 13 phase I/II/III clinical trials. From a dataset of 2799 individuals (14,346 low-density lipoprotein-cholesterol values), individual pharmacokinetic parameters from the population pharmacokinetic model presented in Part I of this series were used to estimate alirocumab concentrations. As a second step, we then developed the current population pharmacokinetic/pharmacodynamic model using an indirect response model with a Hill coefficient, parameterized with increasing low-density lipoprotein cholesterol elimination, to relate alirocumab concentrations to low-density lipoprotein cholesterol values. The population pharmacokinetic/pharmacodynamic model allowed the characterization of the pharmacokinetic/pharmacodynamic properties of alirocumab in the target population and estimation of individual low-density lipoprotein cholesterol levels and derived pharmacodynamic parameters (the maximum decrease in low-density lipoprotein cholesterol values from baseline and the difference between baseline low-density lipoprotein cholesterol and the pre-dose value before the next alirocumab dose). Significant parameter-covariate relationships were retained in the model, with a total of ten covariates (sex, age, weight, free baseline PCSK9, total time-varying PCSK9, concomitant statin administration, total baseline PCSK9, co-administration of high-dose statins, disease status) included in the final population pharmacokinetic/pharmacodynamic model to explain between-subject variability. Nevertheless, the high number of covariates included in the model did not have a clinically meaningful impact on model-derived pharmacodynamic parameters. This model successfully allowed the characterization of the population pharmacokinetic/pharmacodynamic properties of alirocumab in its target population and the estimation of individual low-density lipoprotein cholesterol levels.

Comparison and Limitations of DVH-Based NTCP Models Derived From 3D-CRT and IMRT Data for Prediction of Gastrointestinal Toxicities in Prostate Cancer Patients by Using Propensity Score Matched Pair Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Troeller, Almut; Department of Radiotherapy and Radiation Oncology, Ludwig-Maximilians-Universität, Munich; Yan, Di, E-mail: dyan@beaumont.edu

2015-02-01

Purpose: This study compared normal tissue complication probability (NTCP) modeling of chronic gastrointestinal toxicities following prostate cancer treatment for 2 treatment modalities. Possible factors causing discrepancies in optimal NTCP model parameters between 3-dimensional conformal radiation therapy (3D-CRT) and intensity modulated RT (IMRT) were analyzed and discussed, including the impact of patient characteristics, image guidance, toxicity scoring bias, and NTCP model limitations. Methods and Materials: Rectal wall dose-volume histograms of 1115 patients treated for prostate cancer under an adaptive radiation therapy protocol were used to model gastrointestinal toxicity grade ≥2 (according to Common Terminology Criteria for Adverse Events). A total ofmore » 457 patients were treated with 3D-CRT and 658 with IMRT. 3D-CRT patients were matched to IMRT patients based on various patient characteristics, using a propensity score–based algorithm. Parameters of the Lyman equivalent uniform dose and cut-off dose logistic regression NTCP models were estimated for the 2 matched treatment modalities and the combined group. Results: After they were matched, the 3D-CRT and IMRT groups contained 275 and 550 patients with a large discrepancy of 28.7% versus 7.8% toxicities, respectively (P<.001). For both NTCP models, optimal parameters found for the 3D-CRT groups did not fit the IMRT patients well and vice versa. Models developed for the combined data overestimated NTCP for the IMRT patients and underestimated NTCP for the 3D-CRT group. Conclusions: Our analysis did not reveal a single definitive cause for discrepancies of model parameters between 3D-CRT and IMRT. Patient characteristics and bias in toxicity scoring, as well as image guidance alone, are unlikely causes of the large discrepancy of toxicities. Whether the cause was inherent to the specific NTCP models used in this study needs to be verified by future investigations. Because IMRT is increasingly used clinically, it is important that appropriate NTCP model parameters are determined for this treatment modality.« less

Comparison and limitations of DVH-based NTCP models derived from 3D-CRT and IMRT data for prediction of gastrointestinal toxicities in prostate cancer patients by using propensity score matched pair analysis.

PubMed

Troeller, Almut; Yan, Di; Marina, Ovidiu; Schulze, Derek; Alber, Markus; Parodi, Katia; Belka, Claus; Söhn, Matthias

2015-02-01

This study compared normal tissue complication probability (NTCP) modeling of chronic gastrointestinal toxicities following prostate cancer treatment for 2 treatment modalities. Possible factors causing discrepancies in optimal NTCP model parameters between 3-dimensional conformal radiation therapy (3D-CRT) and intensity modulated RT (IMRT) were analyzed and discussed, including the impact of patient characteristics, image guidance, toxicity scoring bias, and NTCP model limitations. Rectal wall dose-volume histograms of 1115 patients treated for prostate cancer under an adaptive radiation therapy protocol were used to model gastrointestinal toxicity grade ≥2 (according to Common Terminology Criteria for Adverse Events). A total of 457 patients were treated with 3D-CRT and 658 with IMRT. 3D-CRT patients were matched to IMRT patients based on various patient characteristics, using a propensity score-based algorithm. Parameters of the Lyman equivalent uniform dose and cut-off dose logistic regression NTCP models were estimated for the 2 matched treatment modalities and the combined group. After they were matched, the 3D-CRT and IMRT groups contained 275 and 550 patients with a large discrepancy of 28.7% versus 7.8% toxicities, respectively (P<.001). For both NTCP models, optimal parameters found for the 3D-CRT groups did not fit the IMRT patients well and vice versa. Models developed for the combined data overestimated NTCP for the IMRT patients and underestimated NTCP for the 3D-CRT group. Our analysis did not reveal a single definitive cause for discrepancies of model parameters between 3D-CRT and IMRT. Patient characteristics and bias in toxicity scoring, as well as image guidance alone, are unlikely causes of the large discrepancy of toxicities. Whether the cause was inherent to the specific NTCP models used in this study needs to be verified by future investigations. Because IMRT is increasingly used clinically, it is important that appropriate NTCP model parameters are determined for this treatment modality. Copyright © 2015 Elsevier Inc. All rights reserved.

Very low-dose adult whole-body tumor imaging with F-18 FDG PET/CT

NASA Astrophysics Data System (ADS)

Krol, Andrzej; Naveed, Muhammad; McGrath, Mary; Lisi, Michele; Lavalley, Cathy; Feiglin, David

2015-03-01

The aim of this study was to evaluate if effective radiation dose due to PET component in adult whole-body tumor imaging with time-of-flight F-18 FDG PET/CT could be significantly reduced. We retrospectively analyzed data for 10 patients with the body mass index ranging from 25 to 50. We simulated F-18 FDG dose reduction to 25% of the ACR recommended dose via reconstruction of simulated shorter acquisition time per bed position scans from the acquired list data. F-18 FDG whole-body scans were reconstructed using time-of-flight OSEM algorithm and advanced system modeling. Two groups of images were obtained: group A with a standard dose of F-18 FDG and standard reconstruction parameters and group B with simulated 25% dose and modified reconstruction parameters, respectively. Three nuclear medicine physicians blinded to the simulated activity independently reviewed the images and compared diagnostic quality of images. Based on the input from the physicians, we selected optimal modified reconstruction parameters for group B. In so obtained images, all the lesions observed in the group A were visible in the group B. The tumor SUV values were different in the group A, as compared to group B, respectively. However, no significant differences were reported in the final interpretation of the images from A and B groups. In conclusion, for a small number of patients, we have demonstrated that F-18 FDG dose reduction to 25% of the ACR recommended dose, accompanied by appropriate modification of the reconstruction parameters provided adequate diagnostic quality of PET images acquired on time-of-flight PET/CT.

Development of a Multicomponent Prediction Model for Acute Esophagitis in Lung Cancer Patients Receiving Chemoradiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

De Ruyck, Kim, E-mail: kim.deruyck@UGent.be; Sabbe, Nick; Oberije, Cary

2011-10-01

Purpose: To construct a model for the prediction of acute esophagitis in lung cancer patients receiving chemoradiotherapy by combining clinical data, treatment parameters, and genotyping profile. Patients and Methods: Data were available for 273 lung cancer patients treated with curative chemoradiotherapy. Clinical data included gender, age, World Health Organization performance score, nicotine use, diabetes, chronic disease, tumor type, tumor stage, lymph node stage, tumor location, and medical center. Treatment parameters included chemotherapy, surgery, radiotherapy technique, tumor dose, mean fractionation size, mean and maximal esophageal dose, and overall treatment time. A total of 332 genetic polymorphisms were considered in 112 candidatemore » genes. The predicting model was achieved by lasso logistic regression for predictor selection, followed by classic logistic regression for unbiased estimation of the coefficients. Performance of the model was expressed as the area under the curve of the receiver operating characteristic and as the false-negative rate in the optimal point on the receiver operating characteristic curve. Results: A total of 110 patients (40%) developed acute esophagitis Grade {>=}2 (Common Terminology Criteria for Adverse Events v3.0). The final model contained chemotherapy treatment, lymph node stage, mean esophageal dose, gender, overall treatment time, radiotherapy technique, rs2302535 (EGFR), rs16930129 (ENG), rs1131877 (TRAF3), and rs2230528 (ITGB2). The area under the curve was 0.87, and the false-negative rate was 16%. Conclusion: Prediction of acute esophagitis can be improved by combining clinical, treatment, and genetic factors. A multicomponent prediction model for acute esophagitis with a sensitivity of 84% was constructed with two clinical parameters, four treatment parameters, and four genetic polymorphisms.« less

Urinary symptoms following external beam radiotherapy of the prostate: Dose-symptom correlates with multiple-event and event-count models.

PubMed

Yahya, Noorazrul; Ebert, Martin A; Bulsara, Max; House, Michael J; Kennedy, Angel; Joseph, David J; Denham, James W

2015-11-01

This study aimed to compare urinary dose-symptom correlates after external beam radiotherapy of the prostate using commonly utilised peak-symptom models to multiple-event and event-count models which account for repeated events. Urinary symptoms (dysuria, haematuria, incontinence and frequency) from 754 participants from TROG 03.04-RADAR trial were analysed. Relative (R1-R75 Gy) and absolute (A60-A75Gy) bladder dose-surface area receiving more than a threshold dose and equivalent uniform dose using exponent a (range: a ∈[1 … 100]) were derived. The dose-symptom correlates were analysed using; peak-symptom (logistic), multiple-event (generalised estimating equation) and event-count (negative binomial regression) models. Stronger dose-symptom correlates were found for incontinence and frequency using multiple-event and/or event-count models. For dysuria and haematuria, similar or better relationships were found using peak-symptom models. Dysuria, haematuria and high grade (⩾ 2) incontinence were associated to high dose (R61-R71 Gy). Frequency and low grade (⩾ 1) incontinence were associated to low and intermediate dose-surface parameters (R13-R41Gy). Frequency showed a parallel behaviour (a=1) while dysuria, haematuria and incontinence showed a more serial behaviour (a=4 to a ⩾ 100). Relative dose-surface showed stronger dose-symptom associations. For certain endpoints, the multiple-event and event-count models provide stronger correlates over peak-symptom models. Accounting for multiple events may be advantageous for a more complete understanding of urinary dose-symptom relationships. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Low Dose Radiation Cancer Risks: Epidemiological and Toxicological Models

DOE Office of Scientific and Technical Information (OSTI.GOV)

David G. Hoel, PhD

2012-04-19

The basic purpose of this one year research grant was to extend the two stage clonal expansion model (TSCE) of carcinogenesis to exposures other than the usual single acute exposure. The two-stage clonal expansion model of carcinogenesis incorporates the biological process of carcinogenesis, which involves two mutations and the clonal proliferation of the intermediate cells, in a stochastic, mathematical way. The current TSCE model serves a general purpose of acute exposure models but requires numerical computation of both the survival and hazard functions. The primary objective of this research project was to develop the analytical expressions for the survival functionmore » and the hazard function of the occurrence of the first cancer cell for acute, continuous and multiple exposure cases within the framework of the piece-wise constant parameter two-stage clonal expansion model of carcinogenesis. For acute exposure and multiple exposures of acute series, it is either only allowed to have the first mutation rate vary with the dose, or to have all the parameters be dose dependent; for multiple exposures of continuous exposures, all the parameters are allowed to vary with the dose. With these analytical functions, it becomes easy to evaluate the risks of cancer and allows one to deal with the various exposure patterns in cancer risk assessment. A second objective was to apply the TSCE model with varing continuous exposures from the cancer studies of inhaled plutonium in beagle dogs. Using step functions to estimate the retention functions of the pulmonary exposure of plutonium the multiple exposure versions of the TSCE model was to be used to estimate the beagle dog lung cancer risks. The mathematical equations of the multiple exposure versions of the TSCE model were developed. A draft manuscript which is attached provides the results of this mathematical work. The application work using the beagle dog data from plutonium exposure has not been completed due to the fact that the research project did not continue beyond its first year.« less

Evaluation of GaAs low noise and power MMIC technologies to neutron, ionizing dose and dose rate effects

DOE Office of Scientific and Technical Information (OSTI.GOV)

Derewonko, H.; Bosella, A.; Pataut, G.

1996-06-01

An evaluation program of Thomson CSF-TCS GaAs low noise and power MMIC technologies to 1 MeV equivalent neutron fluence levels, up to 1 {times} 10{sup 15} n/cm{sup 2}, ionizing 1.17--1.33 MeV CO{sup 60} dose levels in excess of 200 Mrad(GaAs) and dose rate levels reaching 1.89 {times} 10{sup 11} rad(GaAs)/s is presented in terms of proper components and parameter choices, DC/RF electrical measurements and test methods under irradiation. Experimental results are explained together with drift analyses of electrical parameters that have determined threshold limits of component degradations. Modelling the effects of radiation on GaAs components relies on degradation analysis ofmore » active layer which appears to be the most sensitive factor. MMICs degradation under neutron fluence was simulated from irradiated FET data. Finally, based on sensitivity of technological parameters, rad-hard design including material, technology and MMIC design enhancement is discussed.« less

Estimating human-equivalent no observed adverse-effect levels for VOCs (volatile organic compounds) based on minimal knowledge of physiological parameters. Technical paper

DOE Office of Scientific and Technical Information (OSTI.GOV)

Overton, J.H.; Jarabek, A.M.

1989-01-01

The U.S. EPA advocates the assessment of health-effects data and calculation of inhaled reference doses as benchmark values for gauging systemic toxicity to inhaled gases. The assessment often requires an inter- or intra-species dose extrapolation from no observed adverse effect level (NOAEL) exposure concentrations in animals to human equivalent NOAEL exposure concentrations. To achieve this, a dosimetric extrapolation procedure was developed based on the form or type of equations that describe the uptake and disposition of inhaled volatile organic compounds (VOCs) in physiologically-based pharmacokinetic (PB-PK) models. The procedure assumes allometric scaling of most physiological parameters and that the value ofmore » the time-integrated human arterial-blood concentration must be limited to no more than to that of experimental animals. The scaling assumption replaces the need for most parameter values and allows the derivation of a simple formula for dose extrapolation of VOCs that gives equivalent or more-conservative exposure concentrations values than those that would be obtained using a PB-PK model in which scaling was assumed.« less

Total Ionizing Dose Influence on the Single Event Effect Sensitivity in Samsung 8Gb NAND Flash Memories

NASA Astrophysics Data System (ADS)

Edmonds, Larry D.; Irom, Farokh; Allen, Gregory R.

2017-08-01

A recent model provides risk estimates for the deprogramming of initially programmed floating gates via prompt charge loss produced by an ionizing radiation environment. The environment can be a mixture of electrons, protons, and heavy ions. The model requires several input parameters. This paper extends the model to include TID effects in the control circuitry by including one additional parameter. Parameters intended to produce conservative risk estimates for the Samsung 8 Gb SLC NAND flash memory are given, subject to some qualifications.

Model-Based Individualized Treatment of Chemotherapeutics: Bayesian Population Modeling and Dose Optimization

PubMed Central

Jayachandran, Devaraj; Laínez-Aguirre, José; Rundell, Ann; Vik, Terry; Hannemann, Robert; Reklaitis, Gintaras; Ramkrishna, Doraiswami

2015-01-01

6-Mercaptopurine (6-MP) is one of the key drugs in the treatment of many pediatric cancers, auto immune diseases and inflammatory bowel disease. 6-MP is a prodrug, converted to an active metabolite 6-thioguanine nucleotide (6-TGN) through enzymatic reaction involving thiopurine methyltransferase (TPMT). Pharmacogenomic variation observed in the TPMT enzyme produces a significant variation in drug response among the patient population. Despite 6-MP’s widespread use and observed variation in treatment response, efforts at quantitative optimization of dose regimens for individual patients are limited. In addition, research efforts devoted on pharmacogenomics to predict clinical responses are proving far from ideal. In this work, we present a Bayesian population modeling approach to develop a pharmacological model for 6-MP metabolism in humans. In the face of scarcity of data in clinical settings, a global sensitivity analysis based model reduction approach is used to minimize the parameter space. For accurate estimation of sensitive parameters, robust optimal experimental design based on D-optimality criteria was exploited. With the patient-specific model, a model predictive control algorithm is used to optimize the dose scheduling with the objective of maintaining the 6-TGN concentration within its therapeutic window. More importantly, for the first time, we show how the incorporation of information from different levels of biological chain-of response (i.e. gene expression-enzyme phenotype-drug phenotype) plays a critical role in determining the uncertainty in predicting therapeutic target. The model and the control approach can be utilized in the clinical setting to individualize 6-MP dosing based on the patient’s ability to metabolize the drug instead of the traditional standard-dose-for-all approach. PMID:26226448

Pharmacokinetic-Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance.

PubMed

Germovsek, Eva; Barker, Charlotte I S; Sharland, Mike; Standing, Joseph F

2018-04-19

Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies.

Four-factor prothrombin complex concentrate reverses apixaban-associated bleeding in a rabbit model of acute hemorrhage.

PubMed

Herzog, E; Kaspereit, F; Krege, W; Mueller-Cohrs, J; Doerr, B; Niebl, P; Dickneite, G

2015-12-01

Apixaban is a direct factor Xa inhibitor approved for the treatment and prevention of thromboembolic disease. There is a lack of data regarding its reversal in cases of acute bleeding or prior to emergency surgery that needs addressing. This study assessed whether a four-factor prothrombin complex concentrate (4F-PCC; Beriplex(®) /Kcentra(®) , CSL Behring) can effectively reverse apixaban-associated bleeding in an in vivo rabbit model and evaluated the correlations between in vivo hemostasis and in vitro coagulation parameters. For dose-finding purposes, anesthetized rabbits were treated with a single intravenous dose of apixaban (800-1600 μg kg(-1) ) and, following a standardized kidney incision, volume of blood loss and time to hemostasis were measured. In a subsequent study phase, anesthetized rabbits were treated with apixaban 1200 μg kg(-1) followed by 4F-PCC (6.25-100 IU kg(-1) ), and the effects on the same bleeding parameters were assessed. In parallel, coagulation parameters were monitored. Dose-dependent increases in time to hemostasis and total blood loss were observed post apixaban administration. Preincision treatment with 4F-PCC resulted in a statistically significant reversal in bleeding time (all doses) and volume (doses ≥ 12.5 IU kg(-1) ). Of the coagulation parameters measured, thrombin generation initiated using the RD reagent (phospholipids only) was the most sensitive to in vivo measures of 4F-PCC's hemostatic efficacy, although some correlations were also observed for prothrombin time and whole blood clotting time. In this rabbit model of acute hemorrhage, 4F-PCC showed potential for reversing the bleeding effects of apixaban. Clinical data in apixaban-treated patients are needed to confirm these results. © 2015 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

Comparison of three light doses in the photodynamic treatment of actinic keratosis using mathematical modeling

NASA Astrophysics Data System (ADS)

Vignion-Dewalle, Anne-Sophie; Betrouni, Nacim; Tylcz, Jean-Baptiste; Vermandel, Maximilien; Mortier, Laurent; Mordon, Serge

2015-05-01

Photodynamic therapy (PDT) is an emerging treatment modality for various diseases, especially for cancer therapy. Although high efficacy is demonstrated for PDT using standardized protocols in nonhyperkeratotic actinic keratoses, alternative light doses expected to increase efficiency, to reduce adverse effects or to expand the use of PDT, are still being evaluated and refined. We propose a comparison of the three most common light doses in the treatment of actinic keratosis with 5-aminolevulinic acid PDT through mathematical modeling. The proposed model is based on an iterative procedure that involves determination of the local fluence rate, updating of the local optical properties, and estimation of the local damage induced by the therapy. This model was applied on a simplified skin sample model including an actinic keratosis lesion, with three different light doses (red light dose, 37 J/cm2, 75 mW/cm2, 500 s blue light dose, 10 J/cm2, 10 mW/cm2, 1000 s and daylight dose, 9000 s). Results analysis shows that the three studied light doses, although all efficient, lead to variable local damage. Defining reference damage enables the nonoptimal parameters for the current light doses to be refined and the treatment to be more suitable.

A revised probabilistic estimate of the maternal methyl mercury intake dose corresponding to a measured cord blood mercury concentration.

PubMed

Stern, Alan H

2005-02-01

In 2001, the U.S. Environmental Protection Agency (EPA) adopted a revised reference dose (RfD) for methyl mercury (MeHg) of 0.1 microg/kg/day. The RfD is based on neurologic developmental effects measured in children associated with exposure in utero to MeHg from the maternal diet. The RfD derivation proceeded from a point of departure based on measured concentration of mercury in fetal cord blood (micrograms per liter). The RfD, however, is a maternal dose (micrograms per kilogram per day). Reconstruction of the maternal dose corresponding to this cord blood concentration, including the variability around this estimate, is a critical step in the RfD derivation. The dose reconstruction employed by the U.S. EPA using the one-compartment pharmacokinetic model contains two areas of significant uncertainty: It does not directly account for the influence of the ratio of cord blood: maternal blood Hg concentration, and it does not resolve uncertainty regarding the most appropriate central tendency estimates for pregnancy and third-trimester-specific model parameters. A probabilistic reassessment of this dose reconstruction was undertaken to address these areas of uncertainty and generally to reconsider the specification of model input parameters. On the basis of a thorough review of the literature and recalculation of the one-compartment model including sensitivity analyses, I estimated that the 95th and 99th percentiles (i.e., the lower 5th and 1st percentiles) of the maternal intake dose corresponding to a fetal cord blood Hg concentration of 58 microg/L are 0.3 and 0.2 microg/kg/day, respectively. For the 99th percentile, this is half the value previously estimated by the U.S. EPA.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sanchez-Nieto, Beatriz, E-mail: bsanchez@fis.puc.cl; Goset, Karen C.; Caviedes, Ivan

Purpose: To propose multivariate predictive models for changes in pulmonary function tests ({Delta}PFTs) with respect to preradiotherapy (pre-RT) values in patients undergoing RT for breast cancer and lymphoma. Methods and Materials: A prospective study was designed to measure {Delta}PFTs of patients undergoing RT. Sixty-six patients were included. Spirometry, lung capacity (measured by helium dilution), and diffusing capacity of carbon monoxide tests were used to measure lung function. Two lung definitions were considered: paired lung vs. irradiated lung (IL). Correlation analysis of dosimetric parameters (mean lung dose and the percentage of lung volume receiving more than a threshold dose) and {Delta}PFTsmore » was carried out to find the best dosimetric predictor. Chemotherapy, age, smoking, and the selected dose-volume parameter were considered as single and interaction terms in a multivariate analysis. Stability of results was checked by bootstrapping. Results: Both lung definitions proved to be similar. Modeling was carried out for IL. Acute and late damage showed the highest correlations with volumes irradiated above {approx}20 Gy (maximum R{sup 2} = 0.28) and {approx}40 Gy (maximum R{sup 2} = 0.21), respectively. RT alone induced a minor and transitory restrictive defect (p = 0.013). Doxorubicin-cyclophosphamide-paclitaxel (Taxol), when administered pre-RT, induced a late, large restrictive effect, independent of RT (p = 0.031). Bootstrap values confirmed the results. Conclusions: None of the dose-volume parameters was a perfect predictor of outcome. Thus, different predictor models for {Delta}PFTs were derived for the IL, which incorporated other nondosimetric parameters mainly through interaction terms. Late {Delta}PFTs seem to behave more serially than early ones. Large restrictive defects were demonstrated in patients pretreated with doxorubicin-cyclophosphamide-paclitaxel.« less

Chlorine truck attack consequences and mitigation.

PubMed

Barrett, Anthony Michael; Adams, Peter J

2011-08-01

We develop and apply an integrated modeling system to estimate fatalities from intentional release of 17 tons of chlorine from a tank truck in a generic urban area. A public response model specifies locations and actions of the populace. A chemical source term model predicts initial characteristics of the chlorine vapor and aerosol cloud. An atmospheric dispersion model predicts cloud spreading and movement. A building air exchange model simulates movement of chlorine from outdoors into buildings at each location. A dose-response model translates chlorine exposures into predicted fatalities. Important parameters outside defender control include wind speed, atmospheric stability class, amount of chlorine released, and dose-response model parameters. Without fast and effective defense response, with 2.5 m/sec wind and stability class F, we estimate approximately 4,000 (half within ∼10 minutes) to 30,000 fatalities (half within ∼20 minutes), depending on dose-response model. Although we assume 7% of the population was outdoors, they represent 60-90% of fatalities. Changing weather conditions result in approximately 50-90% lower total fatalities. Measures such as sheltering in place, evacuation, and use of security barriers and cryogenic storage can reduce fatalities, sometimes by 50% or more, depending on response speed and other factors. © 2011 Society for Risk Analysis.

The absorption and first-pass metabolism of [14C]-1,3-dinitrobenzene in the isolated vascularly perfused rat small intestine.

PubMed

Adams, P C; Rickert, D E

1996-11-01

We tested the hypothesis that the small intestine is capable of the first-pass, reductive metabolism of xenobiotics. A simplified version of the isolated vascularly perfused rat small intestine was developed to test this hypothesis with 1,3-dinitrobenzene (1,3-DNB) as a model xenobiotic. Both 3-nitroaniline (3-NA) and 3-nitroacetanilide (3-NAA) were formed and absorbed following intralumenal doses of 1,3-DNB (1.8 or 4.2 mumol) to isolated vascularly perfused rat small intestine. Dose, fasting, or antibiotic pretreatment had no effect on the absorption and metabolism of 1,3-DNB in this model system. The failure of antibiotic pretreatment to alter the metabolism of 1,3-DNA indicated that 1,3-DNB metabolism was mammalian rather than microfloral in origin. All data from experiments initiated with lumenal 1,3-DNB were fit to a pharmacokinetic model (model A). ANOVA analysis revealed that dose, fasting, or antibiotic pretreatment had no statistically significant effect on the model-dependent parameters. 3-NA (1.5 mumol) was administered to the lumen of isolated vascularly perfused rat small intestine to evaluate model A predictions for the absorption and metabolism of this metabolite. All data from experiments initiated with 3-NA were fit to a pharmacokinetic model (model B). Comparison of corresponding model-dependent pharmacokinetic parameters (i.e. those parameters which describe the same processes in models A and B) revealed quantitative differences. Evidence for significant quantitative differences in the pharmacokinetics or metabolism of formed versus preformed 3-NA in rat small intestine may require better definition of the rate constants used to describe tissue and lumenal processes or identification and incorporation of the remaining unidentified metabolites into the models.

A general model for stray dose calculation of static and intensity-modulated photon radiation.

PubMed

Hauri, Pascal; Hälg, Roger A; Besserer, Jürgen; Schneider, Uwe

2016-04-01

There is an increasing number of cancer survivors who are at risk of developing late effects caused by ionizing radiation such as induction of second tumors. Hence, the determination of out-of-field dose for a particular treatment plan in the patient's anatomy is of great importance. The purpose of this study was to analytically model the stray dose according to its three major components. For patient scatter, a mechanistic model was developed. For collimator scatter and head leakage, an empirical approach was used. The models utilize a nominal beam energy of 6 MeV to describe two linear accelerator types of a single vendor. The parameters of the models were adjusted using ionization chamber measurements registering total absorbed dose in simple geometries. Whole-body dose measurements using thermoluminescent dosimeters in an anthropomorphic phantom for static and intensity-modulated treatment plans were compared to the 3D out-of-field dose distributions calculated by a combined model. The absolute mean difference between the whole-body predicted and the measured out-of-field dose of four different plans was 11% with a maximum difference below 44%. Computation time of 36 000 dose points for one field was around 30 s. By combining the model-calculated stray dose with the treatment planning system dose, the whole-body dose distribution can be viewed in the treatment planning system. The results suggest that the model is accurate, fast and can be used for a wide range of treatment modalities to calculate the whole-body dose distribution for clinical analysis. For similar energy spectra, the mechanistic patient scatter model can be used independently of treatment machine or beam orientation.

Modeling gamma radiation dose in dwellings due to building materials.

PubMed

de Jong, Peter; van Dijk, Willem

2008-01-01

A model is presented that calculates the absorbed dose rate in air of gamma radiation emitted by building materials in a rectangular body construction. The basis for these calculations is formed by a fixed set of specific absorbed dose rates (the dose rate per Bq kg(-1) 238U, 232Th, and 40K), as determined for a standard geometry with the dimensions 4 x 5 x 2.8 m3. Using the computer codes Marmer and MicroShield, correction factors are assessed that quantify the influence of several room and material related parameters on the specific absorbed dose rates. The investigated parameters are the position in the construction; the thickness, density, and dimensions of the construction parts; the contribution from the outer leave; the presence of doors and windows; the attenuation by internal partition walls; the contribution from building materials present in adjacent rooms; and the effect of non-equilibrium due to 222Rn exhalation. To verify the precision, the proposed method is applied to three Dutch reference dwellings, i.e., a row house, a coupled house, and a gallery apartment. The averaged difference with MCNP calculations is found to be 4%.

A semi-mechanistic model of CP-690,550-induced reduction in neutrophil counts in patients with rheumatoid arthritis.

PubMed

Gupta, Pankaj; Friberg, Lena E; Karlsson, Mats O; Krishnaswami, Sriram; French, Jonathan

2010-06-01

CP-690,550, a selective inhibitor of the Janus kinase family, is being developed as an oral disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis (RA). A semi-mechanistic model was developed to characterize the time course of drug-induced absolute neutrophil count (ANC) reduction in a phase 2a study. Data from 264 RA patients receiving 6-week treatment (placebo, 5, 15, 30 mg bid) followed by a 6-week off-treatment period were analyzed. The model included a progenitor cell pool, a maturation chain comprising transit compartments, a circulation pool, and a feedback mechanism. The model was adequately described by system parameters (BASE(h), ktr(h), gamma, and k(circ)), disease effect parameters (DIS), and drug effect parameters (k(off) and k(D)). The disease manifested as an increase in baseline ANC and reduced maturation time due to increased demand from the inflammation site. The drug restored the perturbed system parameters to their normal values via an indirect mechanism. ANC reduction due to a direct myelosuppressive drug effect was not supported. The final model successfully described the dose- and time-dependent changes in ANC and predicted the incidence of neutropenia at different doses reasonably well.

Calculated and measured brachytherapy dosimetry parameters in water for the Xoft Axxent X-Ray Source: an electronic brachytherapy source.

PubMed

Rivard, Mark J; Davis, Stephen D; DeWerd, Larry A; Rusch, Thomas W; Axelrod, Steve

2006-11-01

A new x-ray source, the model S700 Axxent X-Ray Source (Source), has been developed by Xoft Inc. for electronic brachytherapy. Unlike brachytherapy sources containing radionuclides, this Source may be turned on and off at will and may be operated at variable currents and voltages to change the dose rate and penetration properties. The in-water dosimetry parameters for this electronic brachytherapy source have been determined from measurements and calculations at 40, 45, and 50 kV settings. Monte Carlo simulations of radiation transport utilized the MCNP5 code and the EPDL97-based mcplib04 cross-section library. Inter-tube consistency was assessed for 20 different Sources, measured with a PTW 34013 ionization chamber. As the Source is intended to be used for a maximum of ten treatment fractions, tube stability was also assessed. Photon spectra were measured using a high-purity germanium (HPGe) detector, and calculated using MCNP. Parameters used in the two-dimensional (2D) brachytherapy dosimetry formalism were determined. While the Source was characterized as a point due to the small anode size, < 1 mm, use of the one-dimensional (1D) brachytherapy dosimetry formalism is not recommended due to polar anisotropy. Consequently, 1D brachytherapy dosimetry parameters were not sought. Calculated point-source model radial dose functions at gP(5) were 0.20, 0.24, and 0.29 for the 40, 45, and 50 kV voltage settings, respectively. For 1

Dosimetric quality endpoints for low-dose-rate prostate brachytherapy using biological effective dose (bed) vs. conventional dose

DOE Office of Scientific and Technical Information (OSTI.GOV)

Singh, Rachana; Al-Hallaq, Hania; Pelizzari, Charles A.

2003-12-31

The purpose of this study was to compare conventional low-dose-rate prostate brachytherapy dosimetric quality parameters with their biological effective dose (BED) counterparts. To validate a model for transformation from conventional dose to BED, the postimplant plans of 31 prostate brachytherapy patients were evaluated using conventional dose-volume histogram (DVH) quality endpoints and analogous BED-DVH endpoints. Based on CT scans obtained 4 weeks after implantation, DVHs were computed and standard dosimetric endpoints V100 (volume receiving 100% of the prescribed dose), V150, V200, HI (1-[V150/V100]), and D90 (dose that 90% of the target volume received) were obtained for quality analysis. Using known andmore » reported transformations, dose grids were transformed to BED-early ({alpha}/{beta} = 10 Gy) and BED-late ({alpha}/{beta} = 3 Gy) grids, and the same dosimetric endpoints were analyzed. For conventional, BED-early and BED-late DVHs, no differences in V100 were seen (0.896, 0.893, and 0.894, respectively). However, V150 and V200 were significantly higher for both BED-early (0.582 and 0.316) and BED-late (0.595 and 0.337), compared with the conventional (0.539 and 0.255) DVHs. D90 was significantly lower for the BED-early (103.1 Gy) and BED-late transformations (106.9 Gy) as compared with the conventional (119.5 Gy) DVHs. The conventional prescription parameter V100 is the same for the corresponding BED-early and BED-late transformed DVHs. The toxicity parameters V150 and V200 are slightly higher using the BED transformations, suggesting that the BED doses are somewhat higher than predicted using conventional DVHs. The prescription/quality parameter D90 is slightly lower, implying that target coverage is lower than predicted using conventional DVHs. This methodology can be applied to analyze BED dosimetric endpoints to improve clinical outcome and reduce complications of prostate brachytherapy.« less

[Combined internal-external radiotherapy (CIERT) in a cell model].

PubMed

Oehme, Liane; Bartzsch, Thomas; Maucksch, Ute; Freudenberg, Robert; Wunderlich, Gerd; Kotzerke, Jörg

2018-06-01

Combined internal-external radiotherapy (CIERT) requires a unified assessment of biologic radiation effects in addition to the total dose. The concept of biological effective dose (BED) was evaluated in a cell model. The thyroid NIS-positive cell line FRTL-5 was irradiated with X-ray and the radiotracer Tc-99m pertechnetate either alone or in combination. The cellular uptake of the radionuclide during the incubation time of 24 h was controlled by the presence or absence of perchlorate. Dose calculation was performed based on measured uptake values. Cell specific radiobiologic parameters were derived from dose effect curves using the colony forming assay as biological endpoint. For the combination of the radiation qualities the sequence and time difference were varied. Cell survival was compared with the prediction of the BED model. The radiobiologic parameters from X-ray dose response were α = (0.22 ± 0.02) Gy -1 and β = (0.021 ± 0.001) Gy -2 . The half life for repair was (1.51 ± 0.21) h. These values could also explain the dose response curves for Tc-99m-irradiation with exponential decreasing dose rate. CIERT experiments showed no significant differences in cell survival regarding sequence and irradiation break. When the radionuclide uptake was not prevented the cell survival for the combination of X-ray and Tc-99m was lower than the prediction by BED calculations. The validity of the BED formalism for different dose rates and radiation qualities was verified. Supraaddive effects measured in the combination of X-ray and intracellular Tc-99m might be caused by Auger and conversion electrons, however further experiments are necessary. Schattauer GmbH.

A Monte Carlo approach to the microdosimetric kinetic model to account for dose rate time structure effects in ion beam therapy with application in treatment planning simulations.

PubMed

Manganaro, Lorenzo; Russo, Germano; Cirio, Roberto; Dalmasso, Federico; Giordanengo, Simona; Monaco, Vincenzo; Muraro, Silvia; Sacchi, Roberto; Vignati, Anna; Attili, Andrea

2017-04-01

Advanced ion beam therapeutic techniques, such as hypofractionation, respiratory gating, or laser-based pulsed beams, have dose rate time structures which are substantially different from those found in conventional approaches. The biological impact of the time structure is mediated through the β parameter in the linear quadratic (LQ) model. The aim of this study was to assess the impact of changes in the value of the β parameter on the treatment outcomes, also accounting for noninstantaneous intrafraction dose delivery or fractionation and comparing the effects of using different primary ions. An original formulation of the microdosimetric kinetic model (MKM) is used (named MCt-MKM), in which a Monte Carlo (MC) approach was introduced to account for the stochastic spatio-temporal correlations characteristic of the irradiations and the cellular repair kinetics. A modified version of the kinetic equations, validated on experimental cell survival in vitro data, was also introduced. The model, trained on the HSG cells, was used to evaluate the relative biological effectiveness (RBE) for treatments with acute and protracted fractions. Exemplary cases of prostate cancer irradiated with different ion beams were evaluated to assess the impact of the temporal effects. The LQ parameters for a range of cell lines (V79, HSG, and T1) and ion species (H, He, C, and Ne) were evaluated and compared with the experimental data available in the literature, with good results. Notably, in contrast to the original MKM formulation, the MCt-MKM explicitly predicts an ion and LET-dependent β compatible with observations. The data from a split-dose experiment were used to experimentally determine the value of the parameter related to the cellular repair kinetics. Concerning the clinical case considered, an RBE decrease was observed, depending on the dose, ion, and LET, exceeding up to 3% of the acute value in the case of a protraction in the delivery of 10 min. The intercomparison between different ions shows that the clinical optimality is strongly dependent on a complex interplay between the different physical and biological quantities considered. The present study provides a framework for exploiting the temporal effects of dose delivery. The results show the possibility of optimizing the treatment outcomes accounting for the correlation between the specific dose rate time structure and the spatial characteristic of the LET distribution, depending on the ion type used. © 2017 American Association of Physicists in Medicine.

Comparison of PDR brachytherapy and external beam radiation therapy in the case of breast cancer

NASA Astrophysics Data System (ADS)

Teymournia, L.; Berger, D.; Kauer-Dorner, D.; Poljanc, K.; Seitz, W.; Aiginger, H.; Kirisits, C.

2009-04-01

Pulsed dose rate brachytherapy (PDR) was compared to external beam radiation therapy (EBRT) in the case of breast cancer. The benefits were figured out by evaluation of dosimetric parameters and calculating the normal tissue complication probability (NTCP). PDR plans were set up for five randomly chosen left-sided breast cancer patients delivering a total dose of 50.4 Gy to the target (dose rate 0.8 Gy h-1). For EBRT five left-sided breast cancer patients were planned using 3D-conformal tangential photon beams with a prescribed total dose of 50 Gy (2 Gy/fraction) to the total breast volume. For plan ranking and NTCP calculation the physical dose was first converted into the biologically effective dose (BED) and then into the normalized total dose (NTD) using the linear quadratic model with an α/β ratio of 3 Gy. In PDR the relative effectiveness (RE) was calculated for each dose bin of the differential dose volume histogram to get the BED. NTCPs were calculated for the ipsilateral lung and the heart as contoured on CT slices based on the Lyman model and the Kutcher reduction scheme. Dosimetric parameters as Vth (percentage of the total volume exceeding a threshold dose) and Jackson's fdam (fraction of the organ damaged) were also used to figure out the benefits. The comparison of calculated NTCPs in PDR and EBRT showed no difference between these two modalities. All values were below 0.01%. fdam derived from EBRT was always higher (mean value 8.95% versus 1.21% for the lung). The mean V10 and V20 of the lung related to BED were 6.32% and 1.72% for PDR versus 11.72% and 9.59% for EBRT. When using dosimetric parameters as Vth and fdam, PDR was mostly superior to EBRT in respect of sparing normal tissues. NTCP calculation as a single method of modality ranking showed a lack of information, especially when normal tissue was exposed to low radiation doses.

SU-E-I-25: Determining Tube Current, Tube Voltage and Pitch Suitable for Low- Dose Lung Screening CT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Williams, K; Matthews, K

2014-06-01

Purpose: The quality of a computed tomography (CT) image and the dose delivered during its acquisition depend upon the acquisition parameters used. Tube current, tube voltage, and pitch are acquisition parameters that potentially affect image quality and dose. This study investigated physicians' abilities to characterize small, solid nodules in low-dose CT images for combinations of current, voltage and pitch, for three CT scanner models. Methods: Lung CT images was acquired of a Data Spectrum anthropomorphic torso phantom with various combinations of pitch, tube current, and tube voltage; this phantom was used because acrylic beads of various sizes could be placedmore » within the lung compartments to simulate nodules. The phantom was imaged on two 16-slice scanners and a 64-slice scanner. The acquisition parameters spanned a range of estimated CTDI levels; the CTDI estimates from the acquisition software were verified by measurement. Several experienced radiologists viewed the phantom lung CT images and noted nodule location, size and shape, as well as the acceptability of overall image quality. Results: Image quality for assessment of nodules was deemed unsatisfactory for all scanners at 80 kV (any tube current) and at 35 mA (any tube voltage). Tube current of 50 mA or more at 120 kV resulted in similar assessments from all three scanners. Physician-measured sphere diameters were closer to actual diameters for larger spheres, higher tube current, and higher kV. Pitch influenced size measurements less for larger spheres than for smaller spheres. CTDI was typically overestimated by the scanner software compared to measurement. Conclusion: Based on this survey of acquisition parameters, a low-dose CT protocol of 120 kV, 50 mA, and pitch of 1.4 is recommended to balance patient dose and acceptable image quality. For three models of scanners, this protocol resulted in estimated CTDIs from 2.9–3.6 mGy.« less

A kinematic model to estimate effective dose of radioactive substances in a human body

NASA Astrophysics Data System (ADS)

Sasaki, S.; Yamada, T.

2013-05-01

The great earthquake occurred in the north-east area in Japan in March 11, 2011. Facility system to control Fukushima Daiichi nuclear power station was completely destroyed by the following giant tsunami. From the damaged reactor containment vessels, an amount of radioactive substances had leaked and diffused in the vicinity of this station. Radiological internal exposure became a serious social issue both in Japan and all over the world. The present study provides an easily understandable, kinematic-based model to estimate the effective dose of radioactive substances in a human body by simplifying the complicated mechanism of metabolism. International Commission on Radiological Protection (ICRP) has developed a sophisticated model, which is well-known as a standard method to calculate the effective dose for radiological protection. However, owing to that ICRP method is fine, it is rather difficult for non-professional people of radiology to gasp the whole images of the movement and the influences of radioactive substances in a human body. Therefore, in the present paper we propose a newly-derived and easily-understandable model to estimate the effective dose. The present method is very similar with the traditional and conventional tank model in hydrology. Ingestion flux of radioactive substances corresponds to rain intensity and the storage of radioactive substances to the water storage in a basin in runoff analysis. The key of the present method is to estimate the energy radiated in the radioactive nuclear disintegration of an atom by using classical theory of β decay and special relativity for various kinds of radioactive atoms. The parameters used in this model are only physical half-time and biological half-time, and there are no operational parameters or coefficients to adjust our theoretical runoff to ICRP. Figure shows the time-varying effective dose with ingestion duration, and we can confirm the validity of our model. The time-varying effective dose with ingestion duration

Functional Data Analysis in NTCP Modeling: A New Method to Explore the Radiation Dose-Volume Effects

DOE Office of Scientific and Technical Information (OSTI.GOV)

Benadjaoud, Mohamed Amine, E-mail: mohamedamine.benadjaoud@gustaveroussy.fr; Université Paris sud, Le Kremlin-Bicêtre; Institut Gustave Roussy, Villejuif

2014-11-01

Purpose/Objective(s): To describe a novel method to explore radiation dose-volume effects. Functional data analysis is used to investigate the information contained in differential dose-volume histograms. The method is applied to the normal tissue complication probability modeling of rectal bleeding (RB) for patients irradiated in the prostatic bed by 3-dimensional conformal radiation therapy. Methods and Materials: Kernel density estimation was used to estimate the individual probability density functions from each of the 141 rectum differential dose-volume histograms. Functional principal component analysis was performed on the estimated probability density functions to explore the variation modes in the dose distribution. The functional principalmore » components were then tested for association with RB using logistic regression adapted to functional covariates (FLR). For comparison, 3 other normal tissue complication probability models were considered: the Lyman-Kutcher-Burman model, logistic model based on standard dosimetric parameters (LM), and logistic model based on multivariate principal component analysis (PCA). Results: The incidence rate of grade ≥2 RB was 14%. V{sub 65Gy} was the most predictive factor for the LM (P=.058). The best fit for the Lyman-Kutcher-Burman model was obtained with n=0.12, m = 0.17, and TD50 = 72.6 Gy. In PCA and FLR, the components that describe the interdependence between the relative volumes exposed at intermediate and high doses were the most correlated to the complication. The FLR parameter function leads to a better understanding of the volume effect by including the treatment specificity in the delivered mechanistic information. For RB grade ≥2, patients with advanced age are significantly at risk (odds ratio, 1.123; 95% confidence interval, 1.03-1.22), and the fits of the LM, PCA, and functional principal component analysis models are significantly improved by including this clinical factor. Conclusion: Functional data analysis provides an attractive method for flexibly estimating the dose-volume effect for normal tissues in external radiation therapy.« less

Fractional model for pharmacokinetics of high dose methotrexate in children with acute lymphoblastic leukaemia

NASA Astrophysics Data System (ADS)

Popović, Jovan K.; Spasić, Dragan T.; Tošić, Jela; Kolarović, Jovanka L.; Malti, Rachid; Mitić, Igor M.; Pilipović, Stevan; Atanacković, Teodor M.

2015-05-01

The aim of this study is to promote a model based on the fractional differential calculus related to the pharmacokinetic individualization of high dose methotrexate treatment in children with acute lymphoblastic leukaemia, especially in high risk patients. We applied two-compartment fractional model on 8 selected cases with the largest number (4-19) of measured concentrations, among 43 pediatric patients received 24-h methotrexate 2-5 g/m2 infusions. The plasma concentrations were determined by fluorescence polarization immunoassay. Our mathematical procedure, designed by combining Post's and Newton's method, was coded in Mathematica 8.0 and performed on Fujicu Celsius M470-2 PC. Experimental data show that most of the measured values of methotrexate were in decreasing order. However, in certain treatments local maximums were detected. On the other hand, integer order compartmental models do not give values which fit well with the observed data. By the use of our model, we obtained better results, since it gives more accurate behavior of the transmission, as well as the local maximums which were recognized in methotrexate monitoring. It follows from our method that an additional test with a small methotrexate dose can be suggested for the fractional system parameter identification and the prediction of a possible pattern with a full dose in the case of high risk patients. A special feature of the fractional model is that it can also recognize and better fit an observed non-monotonic behavior. A new parameter determination procedure can be successfully used.

TU-H-207A-08: Estimating Radiation Dose From Low-Dose Lung Cancer Screening CT Exams Using Tube Current Modulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hardy, A; Bostani, M; McMillan, K

Purpose: The purpose of this work is to estimate effective and lung doses from a low-dose lung cancer screening CT protocol using Tube Current Modulation (TCM) across patient models of different sizes. Methods: Monte Carlo simulation methods were used to estimate effective and lung doses from a low-dose lung cancer screening protocol for a 64-slice CT (Sensation 64, Siemens Healthcare) that used TCM. Scanning parameters were from the AAPM protocols. Ten GSF voxelized patient models were used and had all radiosensitive organs identified to facilitate estimating both organ and effective doses. Predicted TCM schemes for each patient model were generatedmore » using a validated method wherein tissue attenuation characteristics and scanner limitations were used to determine the TCM output as a function of table position and source angle. The water equivalent diameter (WED) was determined by estimating the attenuation at the center of the scan volume for each patient model. Monte Carlo simulations were performed using the unique TCM scheme for each patient model. Lung doses were tallied and effective doses were estimated using ICRP 103 tissue weighting factors. Effective and lung dose values were normalized by scanspecific 32 cm CTDIvol values based upon the average tube current across the entire simulated scan. Absolute and normalized doses were reported as a function of WED for each patient. Results: For all ten patients modeled, the effective dose using TCM protocols was below 1.5 mSv. Smaller sized patient models experienced lower absolute doses compared to larger sized patients. Normalized effective and lung doses showed some dependence on patient size (R2 = 0.77 and 0.78, respectively). Conclusion: Effective doses for a low-dose lung screening protocol using TCM were below 1.5 mSv for all patient models used in this study. Institutional research agreement, Siemens Healthcare; Past recipient, research grant support, Siemens Healthcare; Consultant, Toshiba America Medical Systems; Consultant, Samsung Electronics.« less

Evidence Theory Based Uncertainty Quantification in Radiological Risk due to Accidental Release of Radioactivity from a Nuclear Power Plant

NASA Astrophysics Data System (ADS)

Ingale, S. V.; Datta, D.

2010-10-01

Consequence of the accidental release of radioactivity from a nuclear power plant is assessed in terms of exposure or dose to the members of the public. Assessment of risk is routed through this dose computation. Dose computation basically depends on the basic dose assessment model and exposure pathways. One of the exposure pathways is the ingestion of contaminated food. The aim of the present paper is to compute the uncertainty associated with the risk to the members of the public due to the ingestion of contaminated food. The governing parameters of the ingestion dose assessment model being imprecise, we have approached evidence theory to compute the bound of the risk. The uncertainty is addressed by the belief and plausibility fuzzy measures.

SU-F-T-132: Variable RBE Models Predict Possible Underestimation of Vaginal Dose for Anal Cancer Patients Treated Using Single-Field Proton Treatments

DOE Office of Scientific and Technical Information (OSTI.GOV)

McNamara, A; Underwood, T; Wo, J

2016-06-15

Purpose: Anal cancer patients treated using a posterior proton beam may be at risk of vaginal wall injury due to the increased linear energy transfer (LET) and relative biological effectiveness (RBE) at the beam distal edge. We investigate the vaginal dose received. Methods: Five patients treated for anal cancer with proton pencil beam scanning were considered, all treated to a prescription dose of 54 Gy(RBE) over 28–30 fractions. Dose and LET distributions were calculated using the Monte Carlo simulation toolkit TOPAS. In addition to the standard assumption of a fixed RBE of 1.1, variable RBE was considered via the applicationmore » of published models. Dose volume histograms (DVHs) were extracted for the planning treatment volume (PTV) and vagina, the latter being used to calculate the vaginal normal tissue complication probability (NTCP). Results: Compared to the assumption of a fixed RBE of 1.1, the variable RBE model predicts a dose increase of approximately 3.3 ± 1.7 Gy at the end of beam range. NTCP parameters for the vagina are incomplete in the current literature, however, inferring value ranges from the existing data we use D{sub 50} = 50 Gy and LKB model parameters a=1–2 and m=0.2–0.4. We estimate the NTCP for the vagina to be 37–48% and 42–47% for the fixed and variable RBE cases, respectively. Additionally, a difference in the dose distribution was observed between the analytical calculation and Monte Carlo methods. We find that the target dose is overestimated on average by approximately 1–2%. Conclusion: For patients treated with posterior beams, the vaginal wall may coincide with the distal end of the proton beam and may receive a substantial increase in dose if variable RBE models are applied compared to using the current clinical standard of RBE equal to 1.1. This could potentially lead to underestimating toxicities when treating with protons.« less

Study on Coagulant Dosing Control System of Micro Vortex Water Treatment

NASA Astrophysics Data System (ADS)

Fengping, Hu; Qi, Fan; Wenjie, Hu; Xizhen, He; Hongling, Dai

2018-03-01

In view of the characteristics of nonlinearity, large time delay and multi disturbance in the process of coagulant dosing in water treatment, it is difficult to control the dosage of coagulant. According to the four indexes of raw water quality parameters (raw water flow, turbidity, pH value) and turbidity of sedimentation tank, the micro vortex coagulation dosing control model is constructed based on BP neural network and GA. The forecast results of BP neural network model are ideal, and after the optimization of GA, the prediction accuracy of the model is partly improved. The prediction error of the optimized network is ±0.5 mg/L, and has a better performance than non-optimized network.

Age and gender specific biokinetic model for strontium in humans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shagina, N. B.; Tolstykh, E. I.; Degteva, M. O.

A biokinetic model for strontium in humans is necessary for quantification of internal doses due to strontium radioisotopes. The ICRP-recommended biokinetic model for strontium has limitation for use in a population study, because it is not gender specific and does not cover all age ranges. The extensive Techa River data set on 90Sr in humans (tens of thousands of measurements) is a unique source of data on long-term strontium retention for men and women of all ages at intake. These, as well as published data, were used for evaluation of age- and gender-specific parameters for a new compartment biokinetic modelmore » for strontium (Sr-AGe model). The Sr-AGe model has similar structure as the ICRP model for the alkaline earth elements. The following parameters were mainly reevaluated: gastro-intestinal absorption and parameters related to the processes of bone formation and resorption defining calcium and strontium transfers in skeletal compartments. The Sr-AGe model satisfactorily describes available data sets on strontium retention for different kinds of intake (dietary and intravenous) at different ages (0–80 years old) and demonstrates good agreement with data sets for different ethnic groups. The Sr-AGe model can be used for dose assessment in epidemiological studies of general population exposed to ingested strontium radioisotopes.« less

Biological mechanisms of normal tissue damage: importance for the design of NTCP models.

PubMed

Trott, Klaus-Rüdiger; Doerr, Wolfgang; Facoetti, Angelica; Hopewell, John; Langendijk, Johannes; van Luijk, Peter; Ottolenghi, Andrea; Smyth, Vere

2012-10-01

The normal tissue complication probability (NTCP) models that are currently being proposed for estimation of risk of harm following radiotherapy are mainly based on simplified empirical models, consisting of dose distribution parameters, possibly combined with clinical or other treatment-related factors. These are fitted to data from retrospective or prospective clinical studies. Although these models sometimes provide useful guidance for clinical practice, their predictive power on individuals seems to be limited. This paper examines the radiobiological mechanisms underlying the most important complications induced by radiotherapy, with the aim of identifying the essential parameters and functional relationships needed for effective predictive NTCP models. The clinical features of the complications are identified and reduced as much as possible into component parts. In a second step, experimental and clinical data are considered in order to identify the gross anatomical structures involved, and which dose distributions lead to these complications. Finally, the pathogenic pathways and cellular and more specific anatomical parameters that have to be considered in this pathway are determined. This analysis is carried out for some of the most critical organs and sites in radiotherapy, i.e. spinal cord, lung, rectum, oropharynx and heart. Signs and symptoms of severe late normal tissue complications present a very variable picture in the different organs at risk. Only in rare instances is the entire organ the critical target which elicits the particular complication. Moreover, the biological mechanisms that are involved in the pathogenesis differ between the different complications, even in the same organ. Different mechanisms are likely to be related to different shapes of dose effect relationships and different relationships between dose per fraction, dose rate, and overall treatment time and effects. There is good reason to conclude that each type of late complication after radiotherapy depends on its own specific mechanism which is triggered by the radiation exposure of particular structures or sub-volumes of (or related to) the respective organ at risk. Hence each complication will need the development of an NTCP model designed to accommodate this structure. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

A modern Monte Carlo investigation of the TG-43 dosimetry parameters for an {sup 125}I seed already having AAPM consensus data

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aryal, Prakash; Molloy, Janelle A.; Rivard, Mark J., E-mail: mark.j.rivard@gmail.com

2014-02-15

Purpose: To investigate potential causes for differences in TG-43 brachytherapy dosimetry parameters in the existent literature for the model IAI-125A{sup 125}I seed and to propose new standard dosimetry parameters. Methods: The MCNP5 code was used for Monte Carlo (MC) simulations. Sensitivity of dose distributions, and subsequently TG-43 dosimetry parameters, was explored to reproduce historical methods upon which American Association of Physicists in Medicine (AAPM) consensus data are based. Twelve simulation conditions varying{sup 125}I coating thickness, coating mass density, photon interaction cross-section library, and photon emission spectrum were examined. Results: Varying{sup 125}I coating thickness, coating mass density, photon cross-section library, andmore » photon emission spectrum for the model IAI-125A seed changed the dose-rate constant by up to 0.9%, about 1%, about 3%, and 3%, respectively, in comparison to the proposed standard value of 0.922 cGy h{sup −1} U{sup −1}. The dose-rate constant values by Solberg et al. [“Dosimetric parameters of three new solid core {sup 125}I brachytherapy sources,” J. Appl. Clin. Med. Phys. 3, 119–134 (2002)], Meigooni et al. [“Experimental and theoretical determination of dosimetric characteristics of IsoAid ADVANTAGE™ {sup 125}I brachytherapy source,” Med. Phys. 29, 2152–2158 (2002)], and Taylor and Rogers [“An EGSnrc Monte Carlo-calculated database of TG-43 parameters,” Med. Phys. 35, 4228–4241 (2008)] for the model IAI-125A seed and Kennedy et al. [“Experimental and Monte Carlo determination of the TG-43 dosimetric parameters for the model 9011 THINSeed™ brachytherapy source,” Med. Phys. 37, 1681–1688 (2010)] for the model 6711 seed were +4.3% (0.962 cGy h{sup −1} U{sup −1}), +6.2% (0.98 cGy h{sup −1} U{sup −1}), +0.3% (0.925 cGy h{sup −1} U{sup −1}), and −0.2% (0.921 cGy h{sup −1} U{sup −1}), respectively, in comparison to the proposed standard value. Differences in the radial dose functions between the current study and both Solberg et al. and Meigooni et al. were <10% for r ≤ 5 cm, and increased for r > 5 cm with a maximum difference of 29% at r = 9 cm. In comparison to Taylor and Rogers, these differences were lower (maximum of 2% at r = 9 cm). For the similarly designed model 6711 {sup 125}I seed, differences did not exceed 0.5% for 0.5 ≤ r ≤ 10 cm. Radial dose function values varied by 1% as coating thickness and coating density were changed. Varying the cross-section library and source spectrum altered the radial dose function by 25% and 12%, respectively, but these differences occurred at r = 10 cm where the dose rates were very low. The 2D anisotropy function results were most similar to those of Solberg et al. and most different to those of Meigooni et al. The observed order of simulation condition variables from most to least important for influencing the 2D anisotropy function was spectrum, coating thickness, coating density, and cross-section library. Conclusions: Several MC radiation transport codes are available for calculation of the TG-43 dosimetry parameters for brachytherapy seeds. The physics models in these codes and their related cross-section libraries have been updated and improved since publication of the 2007 AAPM TG-43U1S1 report. Results using modern data indicated statistically significant differences in these dosimetry parameters in comparison to data recommended in the TG-43U1S1 report. Therefore, it seems that professional societies such as the AAPM should consider reevaluating the consensus data for this and others seeds and establishing a process of regular evaluations in which consensus data are based upon methods that remain state-of-the-art.« less

The occurrence of hormetic dose responses in the toxicological literature, the hormesis database: an overview

DOE Office of Scientific and Technical Information (OSTI.GOV)

Calabrese, Edward J.; Blain, Robyn

A relational retrieval database has been developed compiling toxicological studies assessing the occurrence of hormetic dose responses and their quantitative characteristics. This database permits an evaluation of these studies over numerous parameters, including study design and dose-response features and physical/chemical properties of the agents. The database contains approximately 5600 dose-response relationships satisfying evaluative criteria for hormesis across over approximately 900 agents from a broadly diversified spectrum of chemical classes and physical agents. The assessment reveals that hormetic dose-response relationships occur in males and females of numerous animal models in all principal age groups as well as across species displaying amore » broad range of differential susceptibilities to toxic agents. The biological models are extensive, including plants, viruses, bacteria, fungi, insects, fish, birds, rodents, and primates, including humans. The spectrum of endpoints displaying hormetic dose responses is also broad being inclusive of growth, longevity, numerous metabolic parameters, disease incidences (including cancer), various performance endpoints such as cognitive functions, immune responses among others. Quantitative features of the hormetic dose response reveal that the vast majority of cases display a maximum stimulatory response less than two-fold greater than the control while the width of the stimulatory response is typically less than 100-fold in dose range immediately contiguous with the toxicological NO(A)EL. The database also contains a quantitative evaluation component that differentiates among the various dose responses concerning the strength of the evidence supporting a hormetic conclusion based on study design features, magnitude of the stimulatory response, statistical significance, and reproducibility of findings.« less

The occurrence of hormetic dose responses in the toxicological literature, the hormesis database: an overview.

PubMed

Calabrese, Edward J; Blain, Robyn

2005-02-01

A relational retrieval database has been developed compiling toxicological studies assessing the occurrence of hormetic dose responses and their quantitative characteristics. This database permits an evaluation of these studies over numerous parameters, including study design and dose-response features and physical/chemical properties of the agents. The database contains approximately 5600 dose-response relationships satisfying evaluative criteria for hormesis across over approximately 900 agents from a broadly diversified spectrum of chemical classes and physical agents. The assessment reveals that hormetic dose-response relationships occur in males and females of numerous animal models in all principal age groups as well as across species displaying a broad range of differential susceptibilities to toxic agents. The biological models are extensive, including plants, viruses, bacteria, fungi, insects, fish, birds, rodents, and primates, including humans. The spectrum of endpoints displaying hormetic dose responses is also broad being inclusive of growth, longevity, numerous metabolic parameters, disease incidences (including cancer), various performance endpoints such as cognitive functions, immune responses among others. Quantitative features of the hormetic dose response reveal that the vast majority of cases display a maximum stimulatory response less than two-fold greater than the control while the width of the stimulatory response is typically less than 100-fold in dose range immediately contiguous with the toxicological NO(A)EL. The database also contains a quantitative evaluation component that differentiates among the various dose responses concerning the strength of the evidence supporting a hormetic conclusion based on study design features, magnitude of the stimulatory response, statistical significance, and reproducibility of findings.

Ladtap XL Version 2017: A Spreadsheet For Estimating Dose Resulting From Aqueous Releases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Minter, K.; Jannik, T.

LADTAP XL© is an EXCEL© spreadsheet used to estimate dose to offsite individuals and populations resulting from routine and accidental releases of radioactive materials to the Savannah River. LADTAP XL© contains two worksheets: LADTAP and IRRIDOSE. The LADTAP worksheet estimates dose for environmental pathways including external exposure resulting from recreational activities on the Savannah River and internal exposure resulting from ingestion of water, fish, and invertebrates originating from the Savannah River. IRRIDOSE estimates offsite dose to individuals and populations from irrigation of foodstuffs with contaminated water from the Savannah River. In 2004, a complete description of the LADTAP XL© codemore » and an associated user’s manual was documented in LADTAP XL©: A Spreadsheet for Estimating Dose Resulting from Aqueous Release (WSRC-TR-2004-00059) and revised input parameters, dose coefficients, and radionuclide decay constants were incorporated into LADTAP XL© Version 2013 (SRNL-STI-2011-00238). LADTAP XL© Version 2017 is a slight modification to Version 2013 with minor changes made for more user-friendly parameter inputs and organization, updates in the time conversion factors used within the dose calculations, and fixed an issue with the expected time build-up parameter referenced within the population shoreline dose calculations. This manual has been produced to update the code description, verification of the models, and provide an updated user’s manual. LADTAP XL© Version 2017 has been verified by Minter (2017) and is ready for use at the Savannah River Site (SRS).« less

Fitting NTCP models to bladder doses and acute urinary symptoms during post-prostatectomy radiotherapy.

PubMed

Mavroidis, Panayiotis; Pearlstein, Kevin A; Dooley, John; Sun, Jasmine; Saripalli, Srinivas; Das, Shiva K; Wang, Andrew Z; Chen, Ronald C

2018-02-02

To estimate the radiobiological parameters of three popular normal tissue complication probability (NTCP) models, which describe the dose-response relations of bladder regarding different acute urinary symptoms during post-prostatectomy radiotherapy (RT). To evaluate the goodness-of-fit and the correlation of those models with those symptoms. Ninety-three consecutive patients treated from 2010 to 2015 with post-prostatectomy image-guided intensity modulated radiotherapy (IMRT) were included in this study. Patient-reported urinary symptoms were collected pre-RT and weekly during treatment using the validated Prostate Cancer Symptom Indices (PCSI). The assessed symptoms were flow, dysuria, urgency, incontinence, frequency and nocturia using a Likert scale of 1 to 4 or 5. For this analysis, an increase by ≥2 levels in a symptom at any time during treatment compared to baseline was considered clinically significant. The dose volume histograms of the bladder were calculated. The Lyman-Kutcher-Burman (LKB), Relative Seriality (RS) and Logit NTCP models were used to fit the clinical data. The fitting of the different models was assessed through the area under the receiver operating characteristic curve (AUC), Akaike information criterion (AIC) and Odds Ratio methods. For the symptoms of urinary urgency, leakage, frequency and nocturia, the derived LKB model parameters were: 1) D 50  = 64.2Gy, m = 0.50, n = 1.0; 2) D 50  = 95.0Gy, m = 0.45, n = 0.50; 3) D 50  = 83.1Gy, m = 0.56, n = 1.00; and 4) D 50  = 85.4Gy, m = 0.60, n = 1.00, respectively. The AUC values for those symptoms were 0.66, 0.58, 0.64 and 0.64, respectively. The differences in AIC between the different models were less than 2 and ranged within 0.1 and 1.3. Different dose metrics were correlated with the symptoms of urgency, incontinence, frequency and nocturia. The symptoms of urinary flow and dysuria were poorly associated with dose. The values of the parameters of three NTCP models were determined for bladder regarding four acute urinary symptoms. All the models could fit the clinical data equally well. The NTCP predictions of urgency showed the best correlation with the patient reported outcomes.

Dose response explorer: an integrated open-source tool for exploring and modelling radiotherapy dose volume outcome relationships

NASA Astrophysics Data System (ADS)

El Naqa, I.; Suneja, G.; Lindsay, P. E.; Hope, A. J.; Alaly, J. R.; Vicic, M.; Bradley, J. D.; Apte, A.; Deasy, J. O.

2006-11-01

Radiotherapy treatment outcome models are a complicated function of treatment, clinical and biological factors. Our objective is to provide clinicians and scientists with an accurate, flexible and user-friendly software tool to explore radiotherapy outcomes data and build statistical tumour control or normal tissue complications models. The software tool, called the dose response explorer system (DREES), is based on Matlab, and uses a named-field structure array data type. DREES/Matlab in combination with another open-source tool (CERR) provides an environment for analysing treatment outcomes. DREES provides many radiotherapy outcome modelling features, including (1) fitting of analytical normal tissue complication probability (NTCP) and tumour control probability (TCP) models, (2) combined modelling of multiple dose-volume variables (e.g., mean dose, max dose, etc) and clinical factors (age, gender, stage, etc) using multi-term regression modelling, (3) manual or automated selection of logistic or actuarial model variables using bootstrap statistical resampling, (4) estimation of uncertainty in model parameters, (5) performance assessment of univariate and multivariate analyses using Spearman's rank correlation and chi-square statistics, boxplots, nomograms, Kaplan-Meier survival plots, and receiver operating characteristics curves, and (6) graphical capabilities to visualize NTCP or TCP prediction versus selected variable models using various plots. DREES provides clinical researchers with a tool customized for radiotherapy outcome modelling. DREES is freely distributed. We expect to continue developing DREES based on user feedback.

An update on modeling dose-response relationships: Accounting for correlated data structure and heterogeneous error variance in linear and nonlinear mixed models.

PubMed

Gonçalves, M A D; Bello, N M; Dritz, S S; Tokach, M D; DeRouchey, J M; Woodworth, J C; Goodband, R D

2016-05-01

Advanced methods for dose-response assessments are used to estimate the minimum concentrations of a nutrient that maximizes a given outcome of interest, thereby determining nutritional requirements for optimal performance. Contrary to standard modeling assumptions, experimental data often present a design structure that includes correlations between observations (i.e., blocking, nesting, etc.) as well as heterogeneity of error variances; either can mislead inference if disregarded. Our objective is to demonstrate practical implementation of linear and nonlinear mixed models for dose-response relationships accounting for correlated data structure and heterogeneous error variances. To illustrate, we modeled data from a randomized complete block design study to evaluate the standardized ileal digestible (SID) Trp:Lys ratio dose-response on G:F of nursery pigs. A base linear mixed model was fitted to explore the functional form of G:F relative to Trp:Lys ratios and assess model assumptions. Next, we fitted 3 competing dose-response mixed models to G:F, namely a quadratic polynomial (QP) model, a broken-line linear (BLL) ascending model, and a broken-line quadratic (BLQ) ascending model, all of which included heteroskedastic specifications, as dictated by the base model. The GLIMMIX procedure of SAS (version 9.4) was used to fit the base and QP models and the NLMIXED procedure was used to fit the BLL and BLQ models. We further illustrated the use of a grid search of initial parameter values to facilitate convergence and parameter estimation in nonlinear mixed models. Fit between competing dose-response models was compared using a maximum likelihood-based Bayesian information criterion (BIC). The QP, BLL, and BLQ models fitted on G:F of nursery pigs yielded BIC values of 353.7, 343.4, and 345.2, respectively, thus indicating a better fit of the BLL model. The BLL breakpoint estimate of the SID Trp:Lys ratio was 16.5% (95% confidence interval [16.1, 17.0]). Problems with the estimation process rendered results from the BLQ model questionable. Importantly, accounting for heterogeneous variance enhanced inferential precision as the breadth of the confidence interval for the mean breakpoint decreased by approximately 44%. In summary, the article illustrates the use of linear and nonlinear mixed models for dose-response relationships accounting for heterogeneous residual variances, discusses important diagnostics and their implications for inference, and provides practical recommendations for computational troubleshooting.

Minimal percentage of dose received by 90% of the urethra (%UD90) is the most significant predictor of PSA bounce in patients who underwent low-dose-rate brachytherapy (LDR-brachytherapy) for prostate cancer.

PubMed

Tanaka, Nobumichi; Asakawa, Isao; Fujimoto, Kiyohide; Anai, Satoshi; Hirayama, Akihide; Hasegawa, Masatoshi; Konishi, Noboru; Hirao, Yoshihiko

2012-09-14

To clarify the significant clinicopathological and postdosimetric parameters to predict PSA bounce in patients who underwent low-dose-rate brachytherapy (LDR-brachytherapy) for prostate cancer. We studied 200 consecutive patients who received LDR-brachytherapy between July 2004 and November 2008. Of them, 137 patients did not receive neoadjuvant or adjuvant androgen deprivation therapy. One hundred and forty-two patients were treated with LDR-brachytherapy alone, and 58 were treated with LDR-brachytherapy in combination with external beam radiation therapy. The cut-off value of PSA bounce was 0.1 ng/mL. The incidence, time, height, and duration of PSA bounce were investigated. Clinicopathological and postdosimetric parameters were evaluated to elucidate independent factors to predict PSA bounce in hormone-naïve patients who underwent LDR-brachytherapy alone. Fifty patients (25%) showed PSA bounce and 10 patients (5%) showed PSA failure. The median time, height, and duration of PSA bounce were 17 months, 0.29 ng/mL, and 7.0 months, respectively. In 103 hormone-naïve patients treated with LDR-brachytherapy alone, and univariate Cox proportional regression hazard model indicated that age and minimal percentage of the dose received by 30% and 90% of the urethra were independent predictors of PSA bounce. With a multivariate Cox proportional regression hazard model, minimal percentage of the dose received by 90% of the urethra was the most significant parameter of PSA bounce. Minimal percentage of the dose received by 90% of the urethra was the most significant predictor of PSA bounce in hormone-naïve patients treated with LDR-brachytherapy alone.

Land and Water Use Characteristics and Human Health Input Parameters for use in Environmental Dosimetry and Risk Assessments at the Savannah River Site. 2016 Update

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jannik, G. Tim; Hartman, Larry; Stagich, Brooke

Operations at the Savannah River Site (SRS) result in releases of small amounts of radioactive materials to the atmosphere and to the Savannah River. For regulatory compliance purposes, potential offsite radiological doses are estimated annually using computer models that follow U.S. Nuclear Regulatory Commission (NRC) regulatory guides. Within the regulatory guides, default values are provided for many of the dose model parameters, but the use of applicant site-specific values is encouraged. Detailed surveys of land-use and water-use parameters were conducted in 1991 and 2010. They are being updated in this report. These parameters include local characteristics of meat, milk andmore » vegetable production; river recreational activities; and meat, milk and vegetable consumption rates, as well as other human usage parameters required in the SRS dosimetry models. In addition, the preferred elemental bioaccumulation factors and transfer factors (to be used in human health exposure calculations at SRS) are documented. The intent of this report is to establish a standardized source for these parameters that is up to date with existing data, and that is maintained via review of future-issued national references (to evaluate the need for changes as new information is released). These reviews will continue to be added to this document by revision.« less

Land and Water Use Characteristics and Human Health Input Parameters for use in Environmental Dosimetry and Risk Assessments at the Savannah River Site 2017 Update

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jannik, T.; Stagich, B.

Operations at the Savannah River Site (SRS) result in releases of relatively small amounts of radioactive materials to the atmosphere and to the Savannah River. For regulatory compliance purposes, potential offsite radiological doses are estimated annually using computer models that follow U.S. Nuclear Regulatory Commission (NRC) regulatory guides. Within the regulatory guides, default values are provided for many of the dose model parameters, but the use of site-specific values is encouraged. Detailed surveys of land-use and water-use parameters were conducted in 1991, 2008, 2010, and 2016 and are being concurred with or updated in this report. These parameters include localmore » characteristics of meat, milk, and vegetable production; river recreational activities; and meat, milk, and vegetable consumption rates, as well as other human usage parameters required in the SRS dosimetry models. In addition, the preferred elemental bioaccumulation factors and transfer factors (to be used in human health exposure calculations at SRS) are documented. The intent of this report is to establish a standardized source for these parameters that is up to date with existing data, and that is maintained via review of future-issued national references (to evaluate the need for changes as new information is released). These reviews will continue to be added to this document by revision.« less

A systematic uncertainty analysis of an evaluative fate and exposure model.

PubMed

Hertwich, E G; McKone, T E; Pease, W S

2000-08-01

Multimedia fate and exposure models are widely used to regulate the release of toxic chemicals, to set cleanup standards for contaminated sites, and to evaluate emissions in life-cycle assessment. CalTOX, one of these models, is used to calculate the potential dose, an outcome that is combined with the toxicity of the chemical to determine the Human Toxicity Potential (HTP), used to aggregate and compare emissions. The comprehensive assessment of the uncertainty in the potential dose calculation in this article serves to provide the information necessary to evaluate the reliability of decisions based on the HTP A framework for uncertainty analysis in multimedia risk assessment is proposed and evaluated with four types of uncertainty. Parameter uncertainty is assessed through Monte Carlo analysis. The variability in landscape parameters is assessed through a comparison of potential dose calculations for different regions in the United States. Decision rule uncertainty is explored through a comparison of the HTP values under open and closed system boundaries. Model uncertainty is evaluated through two case studies, one using alternative formulations for calculating the plant concentration and the other testing the steady state assumption for wet deposition. This investigation shows that steady state conditions for the removal of chemicals from the atmosphere are not appropriate and result in an underestimate of the potential dose for 25% of the 336 chemicals evaluated.

Multivariate Normal Tissue Complication Probability Modeling of Heart Valve Dysfunction in Hodgkin Lymphoma Survivors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cella, Laura, E-mail: laura.cella@cnr.it; Department of Advanced Biomedical Sciences, Federico II University School of Medicine, Naples; Liuzzi, Raffaele

Purpose: To establish a multivariate normal tissue complication probability (NTCP) model for radiation-induced asymptomatic heart valvular defects (RVD). Methods and Materials: Fifty-six patients treated with sequential chemoradiation therapy for Hodgkin lymphoma (HL) were retrospectively reviewed for RVD events. Clinical information along with whole heart, cardiac chambers, and lung dose distribution parameters was collected, and the correlations to RVD were analyzed by means of Spearman's rank correlation coefficient (Rs). For the selection of the model order and parameters for NTCP modeling, a multivariate logistic regression method using resampling techniques (bootstrapping) was applied. Model performance was evaluated using the area under themore » receiver operating characteristic curve (AUC). Results: When we analyzed the whole heart, a 3-variable NTCP model including the maximum dose, whole heart volume, and lung volume was shown to be the optimal predictive model for RVD (Rs = 0.573, P<.001, AUC = 0.83). When we analyzed the cardiac chambers individually, for the left atrium and for the left ventricle, an NTCP model based on 3 variables including the percentage volume exceeding 30 Gy (V30), cardiac chamber volume, and lung volume was selected as the most predictive model (Rs = 0.539, P<.001, AUC = 0.83; and Rs = 0.557, P<.001, AUC = 0.82, respectively). The NTCP values increase as heart maximum dose or cardiac chambers V30 increase. They also increase with larger volumes of the heart or cardiac chambers and decrease when lung volume is larger. Conclusions: We propose logistic NTCP models for RVD considering not only heart irradiation dose but also the combined effects of lung and heart volumes. Our study establishes the statistical evidence of the indirect effect of lung size on radio-induced heart toxicity.« less

Quadrupedal rodent gait compensations in a low dose monoiodoacetate model of osteoarthritis.

PubMed

Lakes, Emily H; Allen, Kyle D

2018-06-01

Rodent gait analysis provides robust, quantitative results for preclinical musculoskeletal and neurological models. In prior work, surgical models of osteoarthritis have been found to result in a hind limb shuffle-stepping gait compensation, while a high dose monoiodoacetate (MIA, 3 mg) model resulted in a hind limb antalgic gait. However, it is unknown whether the antalgic gait caused by MIA is associated with severity of degeneration from the high dosage or the whole-joint degeneration associated with glycolysis inhibition. This study evaluates rodent gait changes resulting from a low dose, 1 mg unilateral intra-articular injection of MIA compared to saline injected and naïve rats. Spatiotemporal and dynamic gait parameters were collected from a total of 42 male Lewis rats spread across 3 time points: 1, 2, and 4 weeks post-injection. To provide a detailed analysis of this low dose MIA model, gait analysis was used to uniquely quantify both fore and hind limb gait parameters. Our data indicate that 1 mg of MIA caused relatively minor degeneration and a shuffle-step gait compensation, similar to the compensation observed in prior surgical models. These data from a 1 mg MIA model show a different gait compensation compared to a previously studied 3 mg model. This 1 mg MIA model resulted in gait compensations more similar to a previously studied surgical model of osteoarthritis. Additionally, this study provides detailed 4 limb analysis of rodent gait that includes spatiotemporal and dynamic data from the same gait trial. These data highlight the importance of measuring dynamic data in combination with spatiotemporal data, since compensatory gait patterns may not be captured by spatial, temporal, or dynamic characterizations alone. Copyright © 2018 Elsevier B.V. All rights reserved.

Extrapolation of Normal Tissue Complication Probability for Different Fractionations in Liver Irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tai An; Erickson, Beth; Li, X. Allen

2009-05-01

Purpose: The ability to predict normal tissue complication probability (NTCP) is essential for NTCP-based treatment planning. The purpose of this work is to estimate the Lyman NTCP model parameters for liver irradiation from published clinical data of different fractionation regimens. A new expression of normalized total dose (NTD) is proposed to convert NTCP data between different treatment schemes. Method and Materials: The NTCP data of radiation- induced liver disease (RILD) from external beam radiation therapy for primary liver cancer patients were selected for analysis. The data were collected from 4 institutions for tumor sizes in the range of of 8-10more » cm. The dose per fraction ranged from 1.5 Gy to 6 Gy. A modified linear-quadratic model with two components corresponding to radiosensitive and radioresistant cells in the normal liver tissue was proposed to understand the new NTD formalism. Results: There are five parameters in the model: TD{sub 50}, m, n, {alpha}/{beta} and f. With two parameters n and {alpha}/{beta} fixed to be 1.0 and 2.0 Gy, respectively, the extracted parameters from the fitting are TD{sub 50}(1) = 40.3 {+-} 8.4Gy, m =0.36 {+-} 0.09, f = 0.156 {+-} 0.074 Gy and TD{sub 50}(1) = 23.9 {+-} 5.3Gy, m = 0.41 {+-} 0.15, f = 0.0 {+-} 0.04 Gy for patients with liver cirrhosis scores of Child-Pugh A and Child-Pugh B, respectively. The fitting results showed that the liver cirrhosis score significantly affects fractional dose dependence of NTD. Conclusion: The Lyman parameters generated presently and the new form of NTD may be used to predict NTCP for treatment planning of innovative liver irradiation with different fractionations, such as hypofractioned stereotactic body radiation therapy.« less

MCNP-based computational model for the Leksell gamma knife.

PubMed

Trnka, Jiri; Novotny, Josef; Kluson, Jaroslav

2007-01-01

We have focused on the usage of MCNP code for calculation of Gamma Knife radiation field parameters with a homogenous polystyrene phantom. We have investigated several parameters of the Leksell Gamma Knife radiation field and compared the results with other studies based on EGS4 and PENELOPE code as well as the Leksell Gamma Knife treatment planning system Leksell GammaPlan (LGP). The current model describes all 201 radiation beams together and simulates all the sources in the same time. Within each beam, it considers the technical construction of the source, the source holder, collimator system, the spherical phantom, and surrounding material. We have calculated output factors for various sizes of scoring volumes, relative dose distributions along basic planes including linear dose profiles, integral doses in various volumes, and differential dose volume histograms. All the parameters have been calculated for each collimator size and for the isocentric configuration of the phantom. We have found the calculated output factors to be in agreement with other authors' works except the case of 4 mm collimator size, where averaging over the scoring volume and statistical uncertainties strongly influences the calculated results. In general, all the results are dependent on the choice of the scoring volume. The calculated linear dose profiles and relative dose distributions also match independent studies and the Leksell GammaPlan, but care must be taken about the fluctuations within the plateau, which can influence the normalization, and accuracy in determining the isocenter position, which is important for comparing different dose profiles. The calculated differential dose volume histograms and integral doses have been compared with data provided by the Leksell GammaPlan. The dose volume histograms are in good agreement as well as integral doses calculated in small calculation matrix volumes. However, deviations in integral doses up to 50% can be observed for large volumes such as for the total skull volume. The differences observed in treatment of scattered radiation between the MC method and the LGP may be important in this case. We have also studied the influence of differential direction sampling of primary photons and have found that, due to the anisotropic sampling, doses around the isocenter deviate from each other by up to 6%. With caution about the details of the calculation settings, it is possible to employ the MCNP Monte Carlo code for independent verification of the Leksell Gamma Knife radiation field properties.

Adaptive control of bivalirudin in the cardiac intensive care unit.

PubMed

Zhao, Qi; Edrich, Thomas; Paschalidis, Ioannis Ch

2015-02-01

Bivalirudin is a direct thrombin inhibitor used in the cardiac intensive care unit when heparin is contraindicated due to heparin-induced thrombocytopenia. Since it is not a commonly used drug, clinical experience with its dosing is sparse. In earlier work [1], we developed a dynamic system model that accurately predicts the effect of bivalirudin given dosage over time and patient physiological characteristics. This paper develops adaptive dosage controllers that regulate its effect to desired levels. To that end, and in the case that bivalirudin model parameters are available, we develop a Model Reference Control law. In the case that model parameters are unknown, an indirect Model Reference Adaptive Control scheme is applied to estimate model parameters first and then adapt the controller. Alternatively, direct Model Reference Adaptive Control is applied to adapt the controller directly without estimating model parameters first. Our algorithms are validated using actual patient data from a large hospital in the Boston area.

Sensitivity of predicted bioaerosol exposure from open windrow composting facilities to ADMS dispersion model parameters.

PubMed

Douglas, P; Tyrrel, S F; Kinnersley, R P; Whelan, M; Longhurst, P J; Walsh, K; Pollard, S J T; Drew, G H

2016-12-15

Bioaerosols are released in elevated quantities from composting facilities and are associated with negative health effects, although dose-response relationships are not well understood, and require improved exposure classification. Dispersion modelling has great potential to improve exposure classification, but has not yet been extensively used or validated in this context. We present a sensitivity analysis of the ADMS dispersion model specific to input parameter ranges relevant to bioaerosol emissions from open windrow composting. This analysis provides an aid for model calibration by prioritising parameter adjustment and targeting independent parameter estimation. Results showed that predicted exposure was most sensitive to the wet and dry deposition modules and the majority of parameters relating to emission source characteristics, including pollutant emission velocity, source geometry and source height. This research improves understanding of the accuracy of model input data required to provide more reliable exposure predictions. Copyright © 2016. Published by Elsevier Ltd.

Optimization of GATE and PHITS Monte Carlo code parameters for spot scanning proton beam based on simulation with FLUKA general-purpose code

NASA Astrophysics Data System (ADS)

Kurosu, Keita; Das, Indra J.; Moskvin, Vadim P.

2016-01-01

Spot scanning, owing to its superior dose-shaping capability, provides unsurpassed dose conformity, in particular for complex targets. However, the robustness of the delivered dose distribution and prescription has to be verified. Monte Carlo (MC) simulation has the potential to generate significant advantages for high-precise particle therapy, especially for medium containing inhomogeneities. However, the inherent choice of computational parameters in MC simulation codes of GATE, PHITS and FLUKA that is observed for uniform scanning proton beam needs to be evaluated. This means that the relationship between the effect of input parameters and the calculation results should be carefully scrutinized. The objective of this study was, therefore, to determine the optimal parameters for the spot scanning proton beam for both GATE and PHITS codes by using data from FLUKA simulation as a reference. The proton beam scanning system of the Indiana University Health Proton Therapy Center was modeled in FLUKA, and the geometry was subsequently and identically transferred to GATE and PHITS. Although the beam transport is managed by spot scanning system, the spot location is always set at the center of a water phantom of 600 × 600 × 300 mm3, which is placed after the treatment nozzle. The percentage depth dose (PDD) is computed along the central axis using 0.5 × 0.5 × 0.5 mm3 voxels in the water phantom. The PDDs and the proton ranges obtained with several computational parameters are then compared to those of FLUKA, and optimal parameters are determined from the accuracy of the proton range, suppressed dose deviation, and computational time minimization. Our results indicate that the optimized parameters are different from those for uniform scanning, suggesting that the gold standard for setting computational parameters for any proton therapy application cannot be determined consistently since the impact of setting parameters depends on the proton irradiation technique. We therefore conclude that customization parameters must be set with reference to the optimized parameters of the corresponding irradiation technique in order to render them useful for achieving artifact-free MC simulation for use in computational experiments and clinical treatments.

D-optimal experimental designs to test for departure from additivity in a fixed-ratio mixture ray.

PubMed

Coffey, Todd; Gennings, Chris; Simmons, Jane Ellen; Herr, David W

2005-12-01

Traditional factorial designs for evaluating interactions among chemicals in a mixture may be prohibitive when the number of chemicals is large. Using a mixture of chemicals with a fixed ratio (mixture ray) results in an economical design that allows estimation of additivity or nonadditive interaction for a mixture of interest. This methodology is extended easily to a mixture with a large number of chemicals. Optimal experimental conditions can be chosen that result in increased power to detect departures from additivity. Although these designs are used widely for linear models, optimal designs for nonlinear threshold models are less well known. In the present work, the use of D-optimal designs is demonstrated for nonlinear threshold models applied to a fixed-ratio mixture ray. For a fixed sample size, this design criterion selects the experimental doses and number of subjects per dose level that result in minimum variance of the model parameters and thus increased power to detect departures from additivity. An optimal design is illustrated for a 2:1 ratio (chlorpyrifos:carbaryl) mixture experiment. For this example, and in general, the optimal designs for the nonlinear threshold model depend on prior specification of the slope and dose threshold parameters. Use of a D-optimal criterion produces experimental designs with increased power, whereas standard nonoptimal designs with equally spaced dose groups may result in low power if the active range or threshold is missed.

Multiple-Objective Optimal Designs for Studying the Dose Response Function and Interesting Dose Levels

PubMed Central

Hyun, Seung Won; Wong, Weng Kee

2016-01-01

We construct an optimal design to simultaneously estimate three common interesting features in a dose-finding trial with possibly different emphasis on each feature. These features are (1) the shape of the dose-response curve, (2) the median effective dose and (3) the minimum effective dose level. A main difficulty of this task is that an optimal design for a single objective may not perform well for other objectives. There are optimal designs for dual objectives in the literature but we were unable to find optimal designs for 3 or more objectives to date with a concrete application. A reason for this is that the approach for finding a dual-objective optimal design does not work well for a 3 or more multiple-objective design problem. We propose a method for finding multiple-objective optimal designs that estimate the three features with user-specified higher efficiencies for the more important objectives. We use the flexible 4-parameter logistic model to illustrate the methodology but our approach is applicable to find multiple-objective optimal designs for other types of objectives and models. We also investigate robustness properties of multiple-objective optimal designs to mis-specification in the nominal parameter values and to a variation in the optimality criterion. We also provide computer code for generating tailor made multiple-objective optimal designs. PMID:26565557

Multiple-Objective Optimal Designs for Studying the Dose Response Function and Interesting Dose Levels.

PubMed

Hyun, Seung Won; Wong, Weng Kee

2015-11-01

We construct an optimal design to simultaneously estimate three common interesting features in a dose-finding trial with possibly different emphasis on each feature. These features are (1) the shape of the dose-response curve, (2) the median effective dose and (3) the minimum effective dose level. A main difficulty of this task is that an optimal design for a single objective may not perform well for other objectives. There are optimal designs for dual objectives in the literature but we were unable to find optimal designs for 3 or more objectives to date with a concrete application. A reason for this is that the approach for finding a dual-objective optimal design does not work well for a 3 or more multiple-objective design problem. We propose a method for finding multiple-objective optimal designs that estimate the three features with user-specified higher efficiencies for the more important objectives. We use the flexible 4-parameter logistic model to illustrate the methodology but our approach is applicable to find multiple-objective optimal designs for other types of objectives and models. We also investigate robustness properties of multiple-objective optimal designs to mis-specification in the nominal parameter values and to a variation in the optimality criterion. We also provide computer code for generating tailor made multiple-objective optimal designs.

Theory of Visual Attention (TVA) applied to mice in the 5-choice serial reaction time task.

PubMed

Fitzpatrick, C M; Caballero-Puntiverio, M; Gether, U; Habekost, T; Bundesen, C; Vangkilde, S; Woldbye, D P D; Andreasen, J T; Petersen, A

2017-03-01

The 5-choice serial reaction time task (5-CSRTT) is widely used to measure rodent attentional functions. In humans, many attention studies in healthy and clinical populations have used testing based on Bundesen's Theory of Visual Attention (TVA) to estimate visual processing speeds and other parameters of attentional capacity. We aimed to bridge these research fields by modifying the 5-CSRTT's design and by mathematically modelling data to derive attentional parameters analogous to human TVA-based measures. C57BL/6 mice were tested in two 1-h sessions on consecutive days with a version of the 5-CSRTT where stimulus duration (SD) probe length was varied based on information from previous TVA studies. Thereafter, a scopolamine hydrobromide (HBr; 0.125 or 0.25 mg/kg) pharmacological challenge was undertaken, using a Latin square design. Mean score values were modelled using a new three-parameter version of TVA to obtain estimates of visual processing speeds, visual thresholds and motor response baselines in each mouse. The parameter estimates for each animal were reliable across sessions, showing that the data were stable enough to support analysis on an individual level. Scopolamine HBr dose-dependently reduced 5-CSRTT attentional performance while also increasing reward collection latency at the highest dose. Upon TVA modelling, scopolamine HBr significantly reduced visual processing speed at both doses, while having less pronounced effects on visual thresholds and motor response baselines. This study shows for the first time how 5-CSRTT performance in mice can be mathematically modelled to yield estimates of attentional capacity that are directly comparable to estimates from human studies.

Population Pharmacokinetics of Intranasal Scopolamine

NASA Technical Reports Server (NTRS)

Wu, L.; Chow, D. S. L.; Putcha, L.

2013-01-01

Introduction: An intranasal gel dosage formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness (SMS).The bioavailability and pharmacokinetics (PK) was evaluated using data collected in Phase II IND protocols. We reported earlier statistically significant gender differences in PK parameters of INSCOP at a dose level of 0.4 mg. To identify covariates that influence PK parameters of INSCOP, we examined population covariates of INSCOP PK model for 0.4 mg dose. Methods: Plasma scopolamine concentrations versus time data were collected from 20 normal healthy human subjects (11 male/9 female) after a 0.4 mg dose. Phoenix NLME was employed for PK analysis of these data using gender, body weight and age as covariates for model selection. Model selection was based on a likelihood ratio test on the difference of criteria (-2LL). Statistical significance for base model building and individual covariate analysis was set at P less than 0.05{delta(-2LL)=3.84}. Results: A one-compartment pharmacokinetic model with first-order elimination best described INSCOP concentration ]time profiles. Inclusion of gender, body weight and age as covariates individually significantly reduced -2LL by the cut-off value of 3.84(P less than 0.05) when tested against the base model. After the forward stepwise selection and backward elimination steps, gender was selected to add to the final model which had significant influence on absorption rate constant (ka) and the volume of distribution (V) of INSCOP. Conclusion: A population pharmacokinetic model for INSCOP has been identified and gender was a significant contributing covariate for the final model. The volume of distribution and Ka were significantly higher in males than in females which confirm gender-dependent pharmacokinetics of scopolamine after administration of a 0.4 mg dose.

TH-C-18A-08: A Management Tool for CT Dose Monitoring, Analysis, and Protocol Review

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, J; Chan, F; Newman, B

2014-06-15

Purpose: To develop a customizable tool for enterprise-wide managing of CT protocols and analyzing radiation dose information of CT exams for a variety of quality control applications Methods: All clinical CT protocols implemented on the 11 CT scanners at our institution were extracted in digital format. The original protocols had been preset by our CT management team. A commercial CT dose tracking software (DoseWatch,GE healthcare,WI) was used to collect exam information (exam date, patient age etc.), scanning parameters, and radiation doses for all CT exams. We developed a Matlab-based program (MathWorks,MA) with graphic user interface which allows to analyze themore » scanning protocols with the actual dose estimates, and compare the data to national (ACR,AAPM) and internal reference values for CT quality control. Results: The CT protocol review portion of our tool allows the user to look up the scanning and image reconstruction parameters of any protocol on any of the installed CT systems among about 120 protocols per scanner. In the dose analysis tool, dose information of all CT exams (from 05/2013 to 02/2014) was stratified on a protocol level, and within a protocol down to series level, i.e. each individual exposure event. This allows numerical and graphical review of dose information of any combination of scanner models, protocols and series. The key functions of the tool include: statistics of CTDI, DLP and SSDE, dose monitoring using user-set CTDI/DLP/SSDE thresholds, look-up of any CT exam dose data, and CT protocol review. Conclusion: our inhouse CT management tool provides radiologists, technologists and administration a first-hand near real-time enterprise-wide knowledge on CT dose levels of different exam types. Medical physicists use this tool to manage CT protocols, compare and optimize dose levels across different scanner models. It provides technologists feedback on CT scanning operation, and knowledge on important dose baselines and thresholds.« less

Determination of the uncertainties in radiation doses from ingestion of strontium-90

NASA Astrophysics Data System (ADS)

Apostoaei, Andrei Iulian

Quantification of the uncertainties in the internal dosimetry is important because it can impact the outcome of dose reconstruction, risk assessment or epidemiological studies. This research focused on determination of the uncertainties in the dose factors from a single ingestion of 90Sr by adults, and analyzed the changes with age and the effect of gender. The uncertainties in the estimated dose factors are a factor of 6 for the bone surface, 5 for the red bone marrow, 2.5 for bladder and stomach, 2.2 for the small intestine, 2.1 for the upper large intestine and 2.7 for the lower large intestine. For the rest of the organs the uncertainty is a factor of 3. Only four parameters of the biokinetic model showed an age-dependency within the adult age group: the fractional transfers of strontium from plasma to cortical and trabecular bone, and the removal rates from the cortical and trabecular bone, respectively. When age-dependent biokinetic parameters were used, the estimated dose-factors are very close to the dose factors obtained using age-independent kinetics (within 40%). Thus, the dose factors based on age-independent parameters should suffice for most practical purposes. The dose factors and the associated uncertainties were also calculated as a function of age-at-exposure and attained age. These age dependent curves can be used for estimating doses from continuous intakes, or doses delivered over a limited portion of time. In addition to the committed dose, an expected dose is also estimated in this work. The expected dose is calculated using the dose rate weighted by the probability of surviving up to the age when the dose-rate is delivered. For exposure at young ages the expected dose and the committed dose are similar, but the committed dose decreases to zero when exposure occurs close to age 70, while the expected dose has elevated values pass age 70. No gender differences were found for bone surface, for red bone marrow, and the large intestine. The doses to the soft tissues for females are larger by 20% than the doses for males, because of the differences in the whole-body mass between males and females.

Derivation of the expressions for γ50 and D50 for different individual TCP and NTCP models

NASA Astrophysics Data System (ADS)

Stavreva, N.; Stavrev, P.; Warkentin, B.; Fallone, B. G.

2002-10-01

This paper presents a complete set of formulae for the position (D50) and the normalized slope (γ50) of the dose-response relationship based on the most commonly used radiobiological models for tumours as well as for normal tissues. The functional subunit response models (critical element and critical volume) are used in the derivation of the formulae for the normal tissue. Binomial statistics are used to describe the tumour control probability, the functional subunit response as well as the normal tissue complication probability. The formulae are derived for the single hit and linear quadratic models of cell kill in terms of the number of fractions and dose per fraction. It is shown that the functional subunit models predict very steep, almost step-like, normal tissue individual dose-response relationships. Furthermore, the formulae for the normalized gradient depend on the cellular parameters α and β when written in terms of number of fractions, but not when written in terms of dose per fraction.

Applicability of the linear-quadratic formalism for modeling local tumor control probability in high dose per fraction stereotactic body radiotherapy for early stage non-small cell lung cancer.

PubMed

Guckenberger, Matthias; Klement, Rainer Johannes; Allgäuer, Michael; Appold, Steffen; Dieckmann, Karin; Ernst, Iris; Ganswindt, Ute; Holy, Richard; Nestle, Ursula; Nevinny-Stickel, Meinhard; Semrau, Sabine; Sterzing, Florian; Wittig, Andrea; Andratschke, Nicolaus; Flentje, Michael

2013-10-01

To compare the linear-quadratic (LQ) and the LQ-L formalism (linear cell survival curve beyond a threshold dose dT) for modeling local tumor control probability (TCP) in stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC). This study is based on 395 patients from 13 German and Austrian centers treated with SBRT for stage I NSCLC. The median number of SBRT fractions was 3 (range 1-8) and median single fraction dose was 12.5 Gy (2.9-33 Gy); dose was prescribed to the median 65% PTV encompassing isodose (60-100%). Assuming an α/β-value of 10 Gy, we modeled TCP as a sigmoid-shaped function of the biologically effective dose (BED). Models were compared using maximum likelihood ratio tests as well as Bayes factors (BFs). There was strong evidence for a dose-response relationship in the total patient cohort (BFs>20), which was lacking in single-fraction SBRT (BFs<3). Using the PTV encompassing dose or maximum (isocentric) dose, our data indicated a LQ-L transition dose (dT) at 11 Gy (68% CI 8-14 Gy) or 22 Gy (14-42 Gy), respectively. However, the fit of the LQ-L models was not significantly better than a fit without the dT parameter (p=0.07, BF=2.1 and p=0.86, BF=0.8, respectively). Generally, isocentric doses resulted in much better dose-response relationships than PTV encompassing doses (BFs>20). Our data suggest accurate modeling of local tumor control in fractionated SBRT for stage I NSCLC with the traditional LQ formalism. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Pragmatic pharmacology: population pharmacokinetic analysis of fentanyl using remnant samples from children after cardiac surgery

PubMed Central

Van Driest, Sara L.; Marshall, Matthew D.; Hachey, Brian; Beck, Cole; Crum, Kim; Owen, Jill; Smith, Andrew H.; Kannankeril, Prince J.; Woodworth, Alison; Caprioli, Richard M.

2016-01-01

Aims One barrier contributing to the lack of pharmacokinetic (PK) data in paediatric populations is the need for serial sampling. Analysis of clinically obtained specimens and data may overcome this barrier. To add evidence for the feasibility of this approach, we sought to determine PK parameters for fentanyl in children after cardiac surgery using specimens and data generated in the course of clinical care, without collecting additional blood samples. Methods We measured fentanyl concentrations in plasma from leftover clinically‐obtained specimens in 130 paediatric cardiac surgery patients and successfully generated a PK dataset using drug dosing data extracted from electronic medical records. Using a population PK approach, we estimated PK parameters for this population, assessed model goodness‐of‐fit and internal model validation, and performed subset data analyses. Through simulation studies, we compared predicted fentanyl concentrations using model‐driven weight‐adjusted per kg vs. fixed per kg fentanyl dosing. Results Fentanyl clearance for a 6.4 kg child, the median weight in our cohort, is 5.7 l h–1 (2.2–9.2 l h–1), similar to values found in prior formal PK studies. Model assessment and subset analyses indicated the model adequately fit the data. Of the covariates studied, only weight significantly impacted fentanyl kinetics, but substantial inter‐individual variability remained. In simulation studies, model‐driven weight‐adjusted per kg fentanyl dosing led to more consistent therapeutic fentanyl concentrations than fixed per kg dosing. Conclusions We show here that population PK modelling using sparse remnant samples and electronic medical records data provides a powerful tool for assessment of drug kinetics and generation of individualized dosing regimens. PMID:26861166

Parameter uncertainty and variability in evaluative fate and exposure models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hertwich, E.G.; McKone, T.E.; Pease, W.S.

The human toxicity potential, a weighting scheme used to evaluate toxic emissions for life cycle assessment and toxics release inventories, is based on potential dose calculations and toxicity factors. This paper evaluates the variance in potential dose calculations that can be attributed to the uncertainty in chemical-specific input parameters as well as the variability in exposure factors and landscape parameters. A knowledge of the uncertainty allows us to assess the robustness of a decision based on the toxicity potential; a knowledge of the sources of uncertainty allows one to focus resources if the uncertainty is to be reduced. The potentialmore » does of 236 chemicals was assessed. The chemicals were grouped by dominant exposure route, and a Monte Carlo analysis was conducted for one representative chemical in each group. The variance is typically one to two orders of magnitude. For comparison, the point estimates in potential dose for 236 chemicals span ten orders of magnitude. Most of the variance in the potential dose is due to chemical-specific input parameters, especially half-lives, although exposure factors such as fish intake and the source of drinking water can be important for chemicals whose dominant exposure is through indirect routes. Landscape characteristics are generally of minor importance.« less

Unified approach for extrapolation and bridging of adult information in early-phase dose-finding paediatric studies.

PubMed

Petit, Caroline; Samson, Adeline; Morita, Satoshi; Ursino, Moreno; Guedj, Jérémie; Jullien, Vincent; Comets, Emmanuelle; Zohar, Sarah

2018-06-01

The number of trials conducted and the number of patients per trial are typically small in paediatric clinical studies. This is due to ethical constraints and the complexity of the medical process for treating children. While incorporating prior knowledge from adults may be extremely valuable, this must be done carefully. In this paper, we propose a unified method for designing and analysing dose-finding trials in paediatrics, while bridging information from adults. The dose-range is calculated under three extrapolation options, linear, allometry and maturation adjustment, using adult pharmacokinetic data. To do this, it is assumed that target exposures are the same in both populations. The working model and prior distribution parameters of the dose-toxicity and dose-efficacy relationships are obtained using early-phase adult toxicity and efficacy data at several dose levels. Priors are integrated into the dose-finding process through Bayesian model selection or adaptive priors. This calibrates the model to adjust for misspecification, if the adult and pediatric data are very different. We performed a simulation study which indicates that incorporating prior adult information in this way may improve dose selection in children.

Underestimation of Low-Dose Radiation in Treatment Planning of Intensity-Modulated Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jang, Si Young; Liu, H. Helen; Mohan, Radhe

2008-08-01

Purpose: To investigate potential dose calculation errors in the low-dose regions and identify causes of such errors for intensity-modulated radiotherapy (IMRT). Methods and Materials: The IMRT treatment plans of 23 patients with lung cancer and mesothelioma were reviewed. Of these patients, 15 had severe pulmonary complications after radiotherapy. Two commercial treatment-planning systems (TPSs) and a Monte Carlo system were used to calculate and compare dose distributions and dose-volume parameters of the target volumes and critical structures. The effect of tissue heterogeneity, multileaf collimator (MLC) modeling, beam modeling, and other factors that could contribute to the differences in IMRT dose calculationsmore » were analyzed. Results: In the commercial TPS-generated IMRT plans, dose calculation errors primarily occurred in the low-dose regions of IMRT plans (<50% of the radiation dose prescribed for the tumor). Although errors in the dose-volume histograms of the normal lung were small (<5%) above 10 Gy, underestimation of dose <10 Gy was found to be up to 25% in patients with mesothelioma or large target volumes. These errors were found to be caused by inadequate modeling of MLC transmission and leaf scatter in commercial TPSs. The degree of low-dose errors depends on the target volumes and the degree of intensity modulation. Conclusions: Secondary radiation from MLCs contributes a significant portion of low dose in IMRT plans. Dose underestimation could occur in conventional IMRT dose calculations if such low-dose radiation is not properly accounted for.« less

TH-C-BRD-04: Beam Modeling and Validation with Triple and Double Gaussian Dose Kernel for Spot Scanning Proton Beams

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hirayama, S; Takayanagi, T; Fujii, Y

2014-06-15

Purpose: To present the validity of our beam modeling with double and triple Gaussian dose kernels for spot scanning proton beams in Nagoya Proton Therapy Center. This study investigates the conformance between the measurements and calculation results in absolute dose with two types of beam kernel. Methods: A dose kernel is one of the important input data required for the treatment planning software. The dose kernel is the 3D dose distribution of an infinitesimal pencil beam of protons in water and consists of integral depth doses and lateral distributions. We have adopted double and triple Gaussian model as lateral distributionmore » in order to take account of the large angle scattering due to nuclear reaction by fitting simulated inwater lateral dose profile for needle proton beam at various depths. The fitted parameters were interpolated as a function of depth in water and were stored as a separate look-up table for the each beam energy. The process of beam modeling is based on the method of MDACC [X.R.Zhu 2013]. Results: From the comparison results between the absolute doses calculated by double Gaussian model and those measured at the center of SOBP, the difference is increased up to 3.5% in the high-energy region because the large angle scattering due to nuclear reaction is not sufficiently considered at intermediate depths in the double Gaussian model. In case of employing triple Gaussian dose kernels, the measured absolute dose at the center of SOBP agrees with calculation within ±1% regardless of the SOBP width and maximum range. Conclusion: We have demonstrated the beam modeling results of dose distribution employing double and triple Gaussian dose kernel. Treatment planning system with the triple Gaussian dose kernel has been successfully verified and applied to the patient treatment with a spot scanning technique in Nagoya Proton Therapy Center.« less

A revised dosimetric characterization of the model S700 electronic brachytherapy source containing an anode-centering plastic insert and other components not included in the 2006 model.

PubMed

Hiatt, Jessica R; Davis, Stephen D; Rivard, Mark J

2015-06-01

The model S700 Axxent electronic brachytherapy source by Xoft, Inc., was characterized by Rivard et al. in 2006. Since then, the source design was modified to include a new insert at the source tip. Current study objectives were to establish an accurate source model for simulation purposes, dosimetrically characterize the new source and obtain its TG-43 brachytherapy dosimetry parameters, and determine dose differences between the original simulation model and the current model S700 source design. Design information from measurements of dissected model S700 sources and from vendor-supplied CAD drawings was used to aid establishment of an updated Monte Carlo source model, which included the complex-shaped plastic source-centering insert intended to promote water flow for cooling the source anode. These data were used to create a model for subsequent radiation transport simulations in a water phantom. Compared to the 2006 simulation geometry, the influence of volume averaging close to the source was substantially reduced. A track-length estimator was used to evaluate collision kerma as a function of radial distance and polar angle for determination of TG-43 dosimetry parameters. Results for the 50 kV source were determined every 0.1 cm from 0.3 to 15 cm and every 1° from 0° to 180°. Photon spectra in water with 0.1 keV resolution were also obtained from 0.5 to 15 cm and polar angles from 0° to 165°. Simulations were run for 10(10) histories, resulting in statistical uncertainties on the transverse plane of 0.04% at r = 1 cm and 0.06% at r = 5 cm. The dose-rate distribution ratio for the model S700 source as compared to the 2006 model exceeded unity by more than 5% for roughly one quarter of the solid angle surrounding the source, i.e., θ ≥ 120°. The radial dose function diminished in a similar manner as for an (125)I seed, with values of 1.434, 0.636, 0.283, and 0.0975 at 0.5, 2, 5, and 10 cm, respectively. The radial dose function ratio between the current and the 2006 model had a minimum of 0.980 at 0.4 cm, close to the source sheath and for large distances approached 1.014. 2D anisotropy function ratios were close to unity for 50° ≤ θ ≤ 110°, but exceeded 5% for θ < 40° at close distances to the sheath and exceeded 15% for θ > 140°, even at large distances. Photon energy fluence of the updated model as compared to the 2006 model showed a decrease in output with increasing distance; this effect was pronounced at the lowest energies. A decrease in photon fluence with increase in polar angle was also observed and was attributed to the silver epoxy component. Changes in source design influenced the overall dose rate and distribution by more than 2% in several regions. This discrepancy is greater than the dose calculation acceptance criteria as recommended in the AAPM TG-56 report. The effect of the design change on the TG-43 parameters would likely not result in dose differences outside of patient applicators. Adoption of this new dataset is suggested for accurate depiction of model S700 source dose distributions.

A revised dosimetric characterization of the model S700 electronic brachytherapy source containing an anode-centering plastic insert and other components not included in the 2006 model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hiatt, Jessica R.; Davis, Stephen D.; Rivard, Mark J., E-mail: mark.j.rivard@gmail.com

2015-06-15

Purpose: The model S700 Axxent electronic brachytherapy source by Xoft, Inc., was characterized by Rivard et al. in 2006. Since then, the source design was modified to include a new insert at the source tip. Current study objectives were to establish an accurate source model for simulation purposes, dosimetrically characterize the new source and obtain its TG-43 brachytherapy dosimetry parameters, and determine dose differences between the original simulation model and the current model S700 source design. Methods: Design information from measurements of dissected model S700 sources and from vendor-supplied CAD drawings was used to aid establishment of an updated Montemore » Carlo source model, which included the complex-shaped plastic source-centering insert intended to promote water flow for cooling the source anode. These data were used to create a model for subsequent radiation transport simulations in a water phantom. Compared to the 2006 simulation geometry, the influence of volume averaging close to the source was substantially reduced. A track-length estimator was used to evaluate collision kerma as a function of radial distance and polar angle for determination of TG-43 dosimetry parameters. Results for the 50 kV source were determined every 0.1 cm from 0.3 to 15 cm and every 1° from 0° to 180°. Photon spectra in water with 0.1 keV resolution were also obtained from 0.5 to 15 cm and polar angles from 0° to 165°. Simulations were run for 10{sup 10} histories, resulting in statistical uncertainties on the transverse plane of 0.04% at r = 1 cm and 0.06% at r = 5 cm. Results: The dose-rate distribution ratio for the model S700 source as compared to the 2006 model exceeded unity by more than 5% for roughly one quarter of the solid angle surrounding the source, i.e., θ ≥ 120°. The radial dose function diminished in a similar manner as for an {sup 125}I seed, with values of 1.434, 0.636, 0.283, and 0.0975 at 0.5, 2, 5, and 10 cm, respectively. The radial dose function ratio between the current and the 2006 model had a minimum of 0.980 at 0.4 cm, close to the source sheath and for large distances approached 1.014. 2D anisotropy function ratios were close to unity for 50° ≤ θ ≤ 110°, but exceeded 5% for θ < 40° at close distances to the sheath and exceeded 15% for θ > 140°, even at large distances. Photon energy fluence of the updated model as compared to the 2006 model showed a decrease in output with increasing distance; this effect was pronounced at the lowest energies. A decrease in photon fluence with increase in polar angle was also observed and was attributed to the silver epoxy component. Conclusions: Changes in source design influenced the overall dose rate and distribution by more than 2% in several regions. This discrepancy is greater than the dose calculation acceptance criteria as recommended in the AAPM TG-56 report. The effect of the design change on the TG-43 parameters would likely not result in dose differences outside of patient applicators. Adoption of this new dataset is suggested for accurate depiction of model S700 source dose distributions.« less

Comparison of singlet oxygen threshold dose for PDT.

PubMed

Zhu, Timothy C; Liu, Baochang; Kim, Michele M; McMillan, Dayton; Liang, Xing; Finlay, Jarod C; Busch, Theresa M

2014-02-01

Macroscopic modeling of singlet oxygen ( 1 O 2 ) is of particular interest because it is the major cytotoxic agent causing biological effects for type II photosensitizers during PDT. We have developed a macroscopic model to calculate reacted singlet oxygen concentration ([1O2] rx for PDT. An in-vivo RIF tumor mouse model is used to correlate the necrosis depth to the calculation based on explicit PDT dosimetry of light fluence distribution, tissue optical properties, and photosensitizer concentrations. Inputs to the model include 4 photosensitizer specific photochemical parameters along with the apparent singlet oxygen threshold concentration. Photosensitizer specific model parameters are determined for several type II photosensitizers (Photofrin, BPD, and HPPH). The singlet oxygen threshold concentration is approximately 0.41 - 0.56 mM for all three photosensitizers studied, assuming that the fraction of singlet oxygen generated that interacts with the cell is ( f = 1). In comparison, value derived from other in-vivo mice studies is 0.4 mM for mTHPC. However, the singlet oxygen threshold doses were reported to be 7.9 and 12.1 mM for a multicell in-vitro EMT6/Ro spheroid model for mTHPC and Photofrin PDT, respectively. The sensitivity of threshold singlet oxygen dose for our experiment is examined. The possible influence of vascular vs. apoptotic cell killing mechanism on the singlet oxygen threshold dose is discussed using the BPD with different drug-light intervals 3 hrs vs. 15 min. The observed discrepancies between different experiments warrant further investigation to explain the cause of the difference.

Comparison of singlet oxygen threshold dose for PDT

PubMed Central

Zhu, Timothy C; Liu, Baochang; Kim, Michele M.; McMillan, Dayton; Liang, Xing; Finlay, Jarod C.; Busch, Theresa M.

2015-01-01

Macroscopic modeling of singlet oxygen (1O2) is of particular interest because it is the major cytotoxic agent causing biological effects for type II photosensitizers during PDT. We have developed a macroscopic model to calculate reacted singlet oxygen concentration ([1O2]rx for PDT. An in-vivo RIF tumor mouse model is used to correlate the necrosis depth to the calculation based on explicit PDT dosimetry of light fluence distribution, tissue optical properties, and photosensitizer concentrations. Inputs to the model include 4 photosensitizer specific photochemical parameters along with the apparent singlet oxygen threshold concentration. Photosensitizer specific model parameters are determined for several type II photosensitizers (Photofrin, BPD, and HPPH). The singlet oxygen threshold concentration is approximately 0.41 – 0.56 mM for all three photosensitizers studied, assuming that the fraction of singlet oxygen generated that interacts with the cell is (f = 1). In comparison, value derived from other in-vivo mice studies is 0.4 mM for mTHPC. However, the singlet oxygen threshold doses were reported to be 7.9 and 12.1 mM for a multicell in-vitro EMT6/Ro spheroid model for mTHPC and Photofrin PDT, respectively. The sensitivity of threshold singlet oxygen dose for our experiment is examined. The possible influence of vascular vs. apoptotic cell killing mechanism on the singlet oxygen threshold dose is discussed using the BPD with different drug-light intervals 3 hrs vs. 15 min. The observed discrepancies between different experiments warrant further investigation to explain the cause of the difference. PMID:25999651

The FLUKA Monte Carlo code coupled with the NIRS approach for clinical dose calculations in carbon ion therapy

NASA Astrophysics Data System (ADS)

Magro, G.; Dahle, T. J.; Molinelli, S.; Ciocca, M.; Fossati, P.; Ferrari, A.; Inaniwa, T.; Matsufuji, N.; Ytre-Hauge, K. S.; Mairani, A.

2017-05-01

Particle therapy facilities often require Monte Carlo (MC) simulations to overcome intrinsic limitations of analytical treatment planning systems (TPS) related to the description of the mixed radiation field and beam interaction with tissue inhomogeneities. Some of these uncertainties may affect the computation of effective dose distributions; therefore, particle therapy dedicated MC codes should provide both absorbed and biological doses. Two biophysical models are currently applied clinically in particle therapy: the local effect model (LEM) and the microdosimetric kinetic model (MKM). In this paper, we describe the coupling of the NIRS (National Institute for Radiological Sciences, Japan) clinical dose to the FLUKA MC code. We moved from the implementation of the model itself to its application in clinical cases, according to the NIRS approach, where a scaling factor is introduced to rescale the (carbon-equivalent) biological dose to a clinical dose level. A high level of agreement was found with published data by exploring a range of values for the MKM input parameters, while some differences were registered in forward recalculations of NIRS patient plans, mainly attributable to differences with the analytical TPS dose engine (taken as reference) in describing the mixed radiation field (lateral spread and fragmentation). We presented a tool which is being used at the Italian National Center for Oncological Hadrontherapy to support the comparison study between the NIRS clinical dose level and the LEM dose specification.

A Dosimetric Evaluation of The Eclipse and Pinnacle Treatment Planning Systems in Treatment of Vertebral Bodies Using IMRT and VMAT with Modeled and Commissioned Flattening Filter Free (FFF) Fields

NASA Astrophysics Data System (ADS)

Ajo, Ramzi, Jr.

Modern treatment planning systems (TPS's) utilize different algorithms in computing dose within the patient medium. The algorithms rely on properly modeled clinical setups in order to perform optimally. Aside from various parameters of the beam, modifiers, such as multileaf collimators (MLC's), must also be modeled properly. That could not be more true today, where dynamic delivery such as intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) are being increasingly utilized due to their ability to deliver higher dose precisely to the target while sparing more surrounding normal tissue. Two of the most popular TPS's, Pinnacle (Philips) and Eclipse (Varian), were compared, with special emphasis placed on parameterization of the dosimetric leaf gap (DLG) in Eclipse. The DLG is a parameter that accounts for Varian's rounded MLC leaf ends. While Pinnacle accounts for the rounded leaf end by modeling the MLC's, Eclipse uses a measured parameter. This study investigated whether a single value measured DLG is sufficient for dynamic delivery. Using five planning volumes for vertebral body SBRT treatments, each prescribed for 3000 cGy in 5 fractions, an array of 20 treatment plans was generated using varying energies of 6MV-FFF and 10MV-FFF. Treatment techniques consisted of 9-field Step-and-shoot IMRT, and dual-arc VMAT using patient specific optimization criteria in the Pinnacle TPS v9.8. Each plan was normalized to ensure coverage of 3000cGy to 95% of the target volume. The dose was computed in Pinnacle v9.8, with the Collapsed Cone Convolution Superposition algorithm and Eclipse v11, with the Acuros XB algorithm, using a dose grid resolution of 2 mm in both systems. Dose volume histograms (DVH's) were generated for a comparison of max and mean dose to the targets and spinal cord, as well as 95% coverage of the targets and the volume of the spinal cord receiving 14.5 Gy (V14.5). Patient specific quality assurance (PSQA) fields were generated and then delivered, using a Varian Edge linear accelerator, to a 4D QA phantom for a gamma analysis and distance to agreement (DTA) comparison. All Eclipse calculations were made for both measured and optimized DLG parameters. Calculated vs. measured point dose for the Pinnacle TPS had an average difference of 2.79 +/- 2.00%. Gamma analysis using a 3% and 3 mm DTA had 99/100 fields passing at > 95%. Using measured values of the DLG in Eclipse, calculated vs. measured point dose was -4.44 +/- 1.97%, and DTA had 33/110 fields passing at > 95%. After an optimization of the DLG in Eclipse, calculated vs. measured point dose had an average difference of 2.20 +/- 2.23%, and DTA with 95/110 fields passing at > 95%. This study looked at the performance of the Pinnacle and Eclipse TPS's, with special consideration given to the DLG parameterization used by Eclipse. The results support the idea that a single valued DLG is not sufficient for dynamic delivery. An optimization of the parameter is necessary to account for the high modulation of IMRT and VMAT techniques.

SU-E-T-627: Precision Modelling of the Leaf-Bank Rotation in Elekta’s Agility MLC: Is It Necessary?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vujicic, M; Belec, J; Heath, E

Purpose: To demonstrate the method used to determine the leaf bank rotation angle (LBROT) as a parameter for modeling the Elekta Agility multi-leaf collimator (MLC) for Monte Carlo simulations and to evaluate the clinical impact of LBROT. Methods: A detailed model of an Elekta Infinity linac including an Agility MLC was built using the EGSnrc/BEAMnrc Monte Carlo code. The Agility 160-leaf MLC is modelled using the MLCE component module which allows for leaf bank rotation using the parameter LBROT. A precise value of LBROT is obtained by comparing measured and simulated profiles of a specific field, which has leaves arrangedmore » in a repeated pattern such that one leaf is opened and the adjacent one is closed. Profile measurements from an Agility linac are taken with gafchromic film, and an ion chamber is used to set the absolute dose. The measurements are compared to Monte Carlo (MC) simulations and the LBROT is adjusted until a match is found. The clinical impact of LBROT is evaluated by observing how an MC dose calculation changes with LBROT. A clinical Stereotactic Body Radiation Treatment (SBRT) plan is calculated using BEAMnrc/DOSXYZnrc simulations with different input values for LBROT. Results: Using the method outlined above, the LBROT is determined to be 9±1 mrad. Differences as high as 4% are observed in a clinical SBRT plan between the extreme case (LBROT not modeled) and the nominal case. Conclusion: In small-field radiation therapy treatment planning, it is important to properly account for LBROT as an input parameter for MC dose calculations with the Agility MLC. More work is ongoing to elucidate the observed differences by determining the contributions from transmission dose, change in field size, and source occlusion, which are all dependent on LBROT. This work was supported by OCAIRO (Ontario Consortium of Adaptive Interventions in Radiation Oncology), funded by the Ontario Research Fund.« less

Sci—Fri PM: Dosimetry—04: Radiation out-of-field dose in the treatment of pediatric central nervous system malignancies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Taddei, P J; Tannous, J; Nabha, R

Children diagnosed with central nervous system (CNS) malignancies often receive radiotherapy, which can cause radiogenic late effects. In order to identify and reduce the risk of these late effects, we must understand the radiation doses that these children receive. Modern treatment planning systems accurately estimate the absorbed dose within the treatment fields but poorly estimate the dose outside them. The purpose of our study was to measure the out-of-field dose for children receiving localized radiotherapy for CNS cancer and apply an analytical model for estimating dose as a function of distance from the field edge. Radiation fields designed for amore » 12-year-old boy treated in our clinic were applied to an anthropomorphic phantom containing more than 200 thermoluminescent dosimeters. A double-Gaussian function of absorbed dose versus distance from the field edge (i.e., 50% isodose line) was applied, and parameters were allowed to vary and were fit to the model by minimizing the root mean square deviation, RMSD. The fitted model accurately predicted the dose from distances of 4 cm to 50 cm (RMSD = 0.54 cGy/Gy), but the model was not useful in estimating dose for distances less than 4 cm because of wide variation in measured dose, and the double-Gaussian model failed by systematically underestimating the dose beyond 50 cm. In conclusion, the double-Gaussian model may be applicable for points at distances from the field edge between 4 cm and 50 cm, where most children's radiosensitive tissues are located, but for points beyond 50 cm, an improvement should be investigated.« less

Radiotherapy Dose Fractionation under Parameter Uncertainty

NASA Astrophysics Data System (ADS)

Davison, Matt; Kim, Daero; Keller, Harald

2011-11-01

In radiotherapy, radiation is directed to damage a tumor while avoiding surrounding healthy tissue. Tradeoffs ensue because dose cannot be exactly shaped to the tumor. It is particularly important to ensure that sensitive biological structures near the tumor are not damaged more than a certain amount. Biological tissue is known to have a nonlinear response to incident radiation. The linear quadratic dose response model, which requires the specification of two clinically and experimentally observed response coefficients, is commonly used to model this effect. This model yields an optimization problem giving two different types of optimal dose sequences (fractionation schedules). Which fractionation schedule is preferred depends on the response coefficients. These coefficients are uncertainly known and may differ from patient to patient. Because of this not only the expected outcomes but also the uncertainty around these outcomes are important, and it might not be prudent to select the strategy with the best expected outcome.

SU-E-T-598: Parametric Equation for Quick and Reliable Estimate of Stray Neutron Doses in Proton Therapy and Application for Intracranial Tumor Treatments

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bonfrate, A; Farah, J; Sayah, R

2015-06-15

Purpose: Development of a parametric equation suitable for a daily use in routine clinic to provide estimates of stray neutron doses in proton therapy. Methods: Monte Carlo (MC) calculations using the UF-NCI 1-year-old phantom were exercised to determine the variation of stray neutron doses as a function of irradiation parameters while performing intracranial treatments. This was done by individually changing the proton beam energy, modulation width, collimator aperture and thickness, compensator thickness and the air gap size while their impact on neutron doses were put into a single equation. The variation of neutron doses with distance from the target volumemore » was also included in it. Then, a first step consisted in establishing the fitting coefficients by using 221 learning data which were neutron absorbed doses obtained with MC simulations while a second step consisted in validating the final equation. Results: The variation of stray neutron doses with irradiation parameters were fitted with linear, polynomial, etc. model while a power-law model was used to fit the variation of stray neutron doses with the distance from the target volume. The parametric equation fitted well MC simulations while establishing fitting coefficients as the discrepancies on the estimate of neutron absorbed doses were within 10%. The discrepancy can reach ∼25% for the bladder, the farthest organ from the target volume. Finally, the validation showed results in compliance with MC calculations since the discrepancies were also within 10% for head-and-neck and thoracic organs while they can reach ∼25%, again for pelvic organs. Conclusion: The parametric equation presents promising results and will be validated for other target sites as well as other facilities to go towards a universal method.« less

A NTCP approach for estimating the outcome in radioiodine treatment of hyperthyroidism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Strigari, L.; Sciuto, R.; Benassi, M.

2008-09-15

Radioiodine has been in use for over 60 years as a treatment for hyperthyroidism. Major changes in clinical practice have led to accurate dosimetry capable of avoiding the risks of adverse effects and the optimization of the treatment. The aim of this study was to test the capability of a radiobiological model, based on normal tissue complication probability (NTCP), to predict the outcome after oral therapeutic {sup 131}I administration. Following dosimetric study, 79 patients underwent treatment for hyperthyroidism using radioiodine and then 67 had at least a one-year follow up. The delivered dose was calculated using the MIRD formula, takingmore » into account the measured maximum uptake of administered iodine transferred to the thyroid, U0, and the effective clearance rate, T{sub eff} and target mass. The dose was converted to normalized total dose delivered at 2 Gy per fraction (NTD{sub 2}). Furthermore, the method to take into account the reduction of the mass of the gland during radioiodine therapy was also applied. The clinical outcome and dosimetric parameters were analyzed in order to study the dose-response relationship for hypothyroidism. The TD{sub 50} and m parameters of the NTCP model approach were then estimated using the likelihood method. The TD{sub 50}, expressed as NTD{sub 2}, resulted in 60 Gy (95% C.I.: 45-75 Gy) and 96 Gy (95% C.I.: 86-109 Gy) for patients affected by Graves or autonomous/multinodular disease, respectively. This supports the clinical evidence that Graves' disease should be characterized by more radiosensitive cells compared to autonomous nodules. The m parameter for all patients was 0.27 (95% C.I.: 0.22-0.36). These parameters were compared with those reported in the literature for hypothyroidism induced after external beam radiotherapy. The NTCP model correctly predicted the clinical outcome after the therapeutic administration of radioiodine in our series.« less

Simulating Space Radiation-Induced Breast Tumor Incidence Using Automata.

PubMed

Heuskin, A C; Osseiran, A I; Tang, J; Costes, S V

2016-07-01

Estimating cancer risk from space radiation has been an ongoing challenge for decades primarily because most of the reported epidemiological data on radiation-induced risks are derived from studies of atomic bomb survivors who were exposed to an acute dose of gamma rays instead of chronic high-LET cosmic radiation. In this study, we introduce a formalism using cellular automata to model the long-term effects of ionizing radiation in human breast for different radiation qualities. We first validated and tuned parameters for an automata-based two-stage clonal expansion model simulating the age dependence of spontaneous breast cancer incidence in an unexposed U.S. We then tested the impact of radiation perturbation in the model by modifying parameters to reflect both targeted and nontargeted radiation effects. Targeted effects (TE) reflect the immediate impact of radiation on a cell's DNA with classic end points being gene mutations and cell death. They are well known and are directly derived from experimental data. In contrast, nontargeted effects (NTE) are persistent and affect both damaged and undamaged cells, are nonlinear with dose and are not well characterized in the literature. In this study, we introduced TE in our model and compared predictions against epidemiologic data of the atomic bomb survivor cohort. TE alone are not sufficient for inducing enough cancer. NTE independent of dose and lasting ∼100 days postirradiation need to be added to accurately predict dose dependence of breast cancer induced by gamma rays. Finally, by integrating experimental relative biological effectiveness (RBE) for TE and keeping NTE (i.e., radiation-induced genomic instability) constant with dose and LET, the model predicts that RBE for breast cancer induced by cosmic radiation would be maximum at 220 keV/μm. This approach lays the groundwork for further investigation into the impact of chronic low-dose exposure, inter-individual variation and more complex space radiation scenarios.

Development and application of a complex numerical model and software for the computation of dose conversion factors for radon progenies.

PubMed

Farkas, Árpád; Balásházy, Imre

2015-04-01

A more exact determination of dose conversion factors associated with radon progeny inhalation was possible due to the advancements in epidemiological health risk estimates in the last years. The enhancement of computational power and the development of numerical techniques allow computing dose conversion factors with increasing reliability. The objective of this study was to develop an integrated model and software based on a self-developed airway deposition code, an own bronchial dosimetry model and the computational methods accepted by International Commission on Radiological Protection (ICRP) to calculate dose conversion coefficients for different exposure conditions. The model was tested by its application for exposure and breathing conditions characteristic of mines and homes. The dose conversion factors were 8 and 16 mSv WLM(-1) for homes and mines when applying a stochastic deposition model combined with the ICRP dosimetry model (named PM-A model), and 9 and 17 mSv WLM(-1) when applying the same deposition model combined with authors' bronchial dosimetry model and the ICRP bronchiolar and alveolar-interstitial dosimetry model (called PM-B model). User friendly software for the computation of dose conversion factors has also been developed. The software allows one to compute conversion factors for a large range of exposure and breathing parameters and to perform sensitivity analyses. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

US Transuranium and Uranium Registries case study on accidental exposure to uranium hexafluoride.

PubMed

Avtandilashvili, Maia; Puncher, Matthew; McComish, Stacey L; Tolmachev, Sergei Y

2015-03-01

The United States Transuranium and Uranium Registries' (USTUR) whole-body donor (Case 1031) was exposed to an acute inhalation of uranium hexafluoride (UF6) produced from an explosion at a uranium processing plant 65 years prior to his death. The USTUR measurements of tissue samples collected at the autopsy indicated long-term retention of inhaled slightly enriched uranium material (0.85% (235)U) in the deep lungs and thoracic lymph nodes. In the present study, the authors combined the tissue measurement results with historical bioassay data, and analysed them with International Commission on Radiological Protection (ICRP) respiratory tract models and the ICRP Publication 69 systemic model for uranium using maximum likelihood and Bayesian statistical methods. The purpose of the analysis was to estimate intakes and model parameter values that best describe the data, and evaluate their effect on dose assessment. The maximum likelihood analysis, which used the ICRP Publication 66 human respiratory tract model, resulted in a point estimate of 79 mg of uranium for the occupational intake composed of 86% soluble, type F material and 14% insoluble, type S material. For the Bayesian approach, the authors applied the Markov Chain Monte Carlo method, but this time used the revised human respiratory tract model, which is currently being used by ICRP to calculate new dose coefficients for workers. The Bayesian analysis estimated that the mean uranium intake was 160 mg, and calculated the case-specific lung dissolution parameters with their associated uncertainties. The parameters were consistent with the inhaled uranium material being predominantly soluble with a small but significant insoluble component. The 95% posterior range of the rapid dissolution fraction (the fraction of deposited material that is absorbed to blood rapidly) was 0.12 to 0.91 with a median of 0.37. The remaining fraction was absorbed slowly, with a 95% range of 0.000 22 d(-1) to 0.000 36 d(-1) and a median of 0.000 31 d(-1). The effective dose per unit intake calculated using the dissolution parameters derived from the maximum likelihood and the Bayesian analyses was higher than the current ICRP dose coefficient for type F uranium by a factor of 2 or 7, respectively; the higher value of the latter was due to use of the revised respiratory tract model. The dissolution parameter values obtained here may be more appropriate to use for radiation protection purposes when individuals are exposed to a UF6 mixture that contains an insoluble uranium component.

A modified microdosimetric kinetic model for relative biological effectiveness calculation

NASA Astrophysics Data System (ADS)

Chen, Yizheng; Li, Junli; Li, Chunyan; Qiu, Rui; Wu, Zhen

2018-01-01

In the heavy ion therapy, not only the distribution of physical absorbed dose, but also the relative biological effectiveness (RBE) weighted dose needs to be taken into account. The microdosimetric kinetic model (MKM) can predict the RBE value of heavy ions with saturation-corrected dose-mean specific energy, which has been used in clinical treatment planning at the National Institute of Radiological Sciences. In the theoretical assumption of the MKM, the yield of the primary lesion is independent of the radiation quality, while the experimental data shows that DNA double strand break (DSB) yield, considered as the main primary lesion, depends on the LET of the particle. Besides, the β parameter of the MKM is constant with LET resulting from this assumption, which also differs from the experimental conclusion. In this study, a modified MKM was developed, named MMKM. Based on the experimental DSB yield of mammalian cells under the irradiation of ions with different LETs, a RBEDSB (RBE for the induction of DSB)-LET curve was fitted as the correction factor to modify the primary lesion yield in the MKM, and the variation of the primary lesion yield with LET is considered in the MMKM. Compared with the present the MKM, not only the α parameter of the MMKM for mono-energetic ions agree with the experimental data, but also the β parameter varies with LET and the variation trend of the experimental result can be reproduced on the whole. Then a spread-out Bragg peaks (SOBP) distribution of physical dose was simulated with Geant4 Monte Carlo code, and the biological and clinical dose distributions were calculated, under the irradiation of carbon ions. The results show that the distribution of clinical dose calculated with the MMKM is closed to the distribution with the MKM in the SOBP, while the discrepancy before and after the SOBP are both within 10%. Moreover, the MKM might overestimate the clinical dose at the distal end of the SOBP more than 5% because of its constant β value, while a minimal value of β is calculated with the MMKM at this position. Besides, the discrepancy of the averaged cell survival fraction in the SOBP calculated with the two models is more than 15% at the high dose level. The MMKM may provide a reference for the accurate calculation of the RBE value in heavy ion therapy.

Radiation Dose-Response Model for Locally Advanced Rectal Cancer After Preoperative Chemoradiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Appelt, Ane L., E-mail: ane.lindegaard.appelt@slb.regionsyddanmark.dk; University of Southern Denmark, Odense; Ploen, John

2013-01-01

Purpose: Preoperative chemoradiation therapy (CRT) is part of the standard treatment of locally advanced rectal cancers. Tumor regression at the time of operation is desirable, but not much is known about the relationship between radiation dose and tumor regression. In the present study we estimated radiation dose-response curves for various grades of tumor regression after preoperative CRT. Methods and Materials: A total of 222 patients, treated with consistent chemotherapy and radiation therapy techniques, were considered for the analysis. Radiation therapy consisted of a combination of external-beam radiation therapy and brachytherapy. Response at the time of operation was evaluated from themore » histopathologic specimen and graded on a 5-point scale (TRG1-5). The probability of achieving complete, major, and partial response was analyzed by ordinal logistic regression, and the effect of including clinical parameters in the model was examined. The radiation dose-response relationship for a specific grade of histopathologic tumor regression was parameterized in terms of the dose required for 50% response, D{sub 50,i}, and the normalized dose-response gradient, {gamma}{sub 50,i}. Results: A highly significant dose-response relationship was found (P=.002). For complete response (TRG1), the dose-response parameters were D{sub 50,TRG1} = 92.0 Gy (95% confidence interval [CI] 79.3-144.9 Gy), {gamma}{sub 50,TRG1} = 0.982 (CI 0.533-1.429), and for major response (TRG1-2) D{sub 50,TRG1} and {sub 2} = 72.1 Gy (CI 65.3-94.0 Gy), {gamma}{sub 50,TRG1} and {sub 2} = 0.770 (CI 0.338-1.201). Tumor size and N category both had a significant effect on the dose-response relationships. Conclusions: This study demonstrated a significant dose-response relationship for tumor regression after preoperative CRT for locally advanced rectal cancer for tumor dose levels in the range of 50.4-70 Gy, which is higher than the dose range usually considered.« less

[Population pharmacokinetics applied to optimising cisplatin doses in cancer patients].

PubMed

Ramón-López, A; Escudero-Ortiz, V; Carbonell, V; Pérez-Ruixo, J J; Valenzuela, B

2012-01-01

To develop and internally validate a population pharmacokinetics model for cisplatin and assess its prediction capacity for personalising doses in cancer patients. Cisplatin plasma concentrations in forty-six cancer patients were used to determine the pharmacokinetic parameters of a two-compartment pharmacokinetic model implemented in NONMEN VI software. Pharmacokinetic parameter identification capacity was assessed using the parametric bootstrap method and the model was validated using the nonparametric bootstrap method and standardised visual and numerical predictive checks. The final model's prediction capacity was evaluated in terms of accuracy and precision during the first (a priori) and second (a posteriori) chemotherapy cycles. Mean population cisplatin clearance is 1.03 L/h with an interpatient variability of 78.0%. Estimated distribution volume at steady state was 48.3 L, with inter- and intrapatient variabilities of 31,3% and 11,7%, respectively. Internal validation confirmed that the population pharmacokinetics model is appropriate to describe changes over time in cisplatin plasma concentrations, as well as its variability in the study population. The accuracy and precision of a posteriori prediction of cisplatin concentrations improved by 21% and 54% compared to a priori prediction. The population pharmacokinetic model developed adequately described the changes in cisplatin plasma concentrations in cancer patients and can be used to optimise cisplatin dosing regimes accurately and precisely. Copyright © 2011 SEFH. Published by Elsevier Espana. All rights reserved.

Application of the DG-1199 methodology to the ESBWR and ABWR.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kalinich, Donald A.; Gauntt, Randall O.; Walton, Fotini

2010-09-01

Appendix A-5 of Draft Regulatory Guide DG-1199 'Alternative Radiological Source Term for Evaluating Design Basis Accidents at Nuclear Power Reactors' provides guidance - applicable to RADTRAD MSIV leakage models - for scaling containment aerosol concentration to the expected steam dome concentration in order to preserve the simplified use of the Accident Source Term (AST) in assessing containment performance under assumed design basis accident (DBA) conditions. In this study Economic and Safe Boiling Water Reactor (ESBWR) and Advanced Boiling Water Reactor (ABWR) RADTRAD models are developed using the DG-1199, Appendix A-5 guidance. The models were run using RADTRAD v3.03. Low Populationmore » Zone (LPZ), control room (CR), and worst-case 2-hr Exclusion Area Boundary (EAB) doses were calculated and compared to the relevant accident dose criteria in 10 CFR 50.67. For the ESBWR, the dose results were all lower than the MSIV leakage doses calculated by General Electric/Hitachi (GEH) in their licensing technical report. There are no comparable ABWR MSIV leakage doses, however, it should be noted that the ABWR doses are lower than the ESBWR doses. In addition, sensitivity cases were evaluated to ascertain the influence/importance of key input parameters/features of the models.« less

Retrospective population pharmacokinetic/pharmacodynamic analysis of pyridostigmine, a cholinesterase inhibitor, in Chinese males.

PubMed

Seng, Kok-Yong; Loke, Weng-Keong; Moochhala, Shabbir; Zhao, Bin; Lee, Jon-Deoon Edmund

2009-09-01

We have characterised the population pharmacokinetics-pharmacodynamics of pyridostigmine given as pyridostigmine bromide. Over three days 50 healthy Chinese male subjects each received seven doses of 30 mg pyridostigmine bromide orally (3 x 10 mg every 8 h). Plasma concentrations of pyridostigmine and red blood cell acetylcholinesterase (AChE) activity were determined at various times within the eight hours after the first and the seventh doses. The resulting pharmacokinetic data were fitted to a single compartment open model with first-order absorption and elimination. The pharmacodynamics were modelled using an inhibitory E(max) model. The potential influence of demographic and biological covariates on the model parameters was investigated. Nonlinear mixed effects modelling was performed using NONMEM. The apparent clearance and volume of distribution as well as absorption rate constant of plasma pyridostigmine were estimated to be 136 l/h, 130 l and 0.68 1/h, respectively. The maximum red blood cell AChE activity decrease (E(max)) and plasma pyridostigmine concentration producing 50% of this reduction (EC50) were estimated to be 9.32 AChE units per gram haemoglobin and 51.9 ng/ml, respectively. None of the tested covariates were found to be correlated with any of the model parameters. Dosing simulations suggested that 30 mg repeated every six hours might be needed to achieve steady-state trough percentage inhibition above the recommended 10% in healthy Chinese males. The pharmacokinetics and the effects of pyridostigmine on red blood cell AChE activity were described using a mixed effects model. For Chinese males, the dosing interval may have been shorter than that recommended for the Caucasian population. Additional studies are needed to confirm these findings.

USE OF A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL TO ESTIMATE ABSORBED CARBARYL DOSE IN CHILDREN AFTER TURF APPLICATION

EPA Science Inventory

A physiologically based pharmacokinetic (PBPK) model was developed to investigate exposure scenarios of children to carbaryl following turf application. Physiological, pharmacokinetic and pharmacodynamic parameters describing the fate and effects of carbaryl in rats were scaled ...

Modeling Zebrafish Developmental Toxicity using a Concurrent In vitro Assay Battery (SOT)

EPA Science Inventory

We describe the development of computational models that predict activity in a repeat-dose zebrafish embryo developmental toxicity assay using a combination of physico-chemical parameters and in vitro (human) assay measurements. The data set covered 986 chemicals including pestic...

Investigation of statistical iterative reconstruction for dedicated breast CT

PubMed Central

Makeev, Andrey; Glick, Stephen J.

2013-01-01

Purpose: Dedicated breast CT has great potential for improving the detection and diagnosis of breast cancer. Statistical iterative reconstruction (SIR) in dedicated breast CT is a promising alternative to traditional filtered backprojection (FBP). One of the difficulties in using SIR is the presence of free parameters in the algorithm that control the appearance of the resulting image. These parameters require tuning in order to achieve high quality reconstructions. In this study, the authors investigated the penalized maximum likelihood (PML) method with two commonly used types of roughness penalty functions: hyperbolic potential and anisotropic total variation (TV) norm. Reconstructed images were compared with images obtained using standard FBP. Optimal parameters for PML with the hyperbolic prior are reported for the task of detecting microcalcifications embedded in breast tissue. Methods: Computer simulations were used to acquire projections in a half-cone beam geometry. The modeled setup describes a realistic breast CT benchtop system, with an x-ray spectra produced by a point source and an a-Si, CsI:Tl flat-panel detector. A voxelized anthropomorphic breast phantom with 280 μm microcalcification spheres embedded in it was used to model attenuation properties of the uncompressed woman's breast in a pendant position. The reconstruction of 3D images was performed using the separable paraboloidal surrogates algorithm with ordered subsets. Task performance was assessed with the ideal observer detectability index to determine optimal PML parameters. Results: The authors' findings suggest that there is a preferred range of values of the roughness penalty weight and the edge preservation threshold in the penalized objective function with the hyperbolic potential, which resulted in low noise images with high contrast microcalcifications preserved. In terms of numerical observer detectability index, the PML method with optimal parameters yielded substantially improved performance (by a factor of greater than 10) compared to FBP. The hyperbolic prior was also observed to be superior to the TV norm. A few of the best-performing parameter pairs for the PML method also demonstrated superior performance for various radiation doses. In fact, using PML with certain parameter values results in better images, acquired using 2 mGy dose, than FBP-reconstructed images acquired using 6 mGy dose. Conclusions: A range of optimal free parameters for the PML algorithm with hyperbolic and TV norm-based potentials is presented for the microcalcification detection task, in dedicated breast CT. The reported values can be used as starting values of the free parameters, when SIR techniques are used for image reconstruction. Significant improvement in image quality can be achieved by using PML with optimal combination of parameters, as compared to FBP. Importantly, these results suggest improved detection of microcalcifications can be obtained by using PML with lower radiation dose to the patient, than using FBP with higher dose. PMID:23927318

Estimation of body surface area in the musk shrew ( Suncus murinus): a small animal for testing chemotherapy-induced emesis.

PubMed

Eiseman, Julie L; Sciullo, Michael; Wang, Hong; Beumer, Jan H; Horn, Charles C

2017-10-01

Several cancer chemotherapies cause nausea and vomiting, which can be dose-limiting. Musk shrews are used as preclinical models for chemotherapy-induced emesis and for antiemetic effectiveness. Unlike rats and mice, shrews possess a vomiting reflex and demonstrate an emetic profile similar to humans, including acute and delayed phases. As with most animals, dosing of shrews is based on body weight, while translation of such doses to clinically equivalent exposure requires doses based on body surface area. In the current study body surface area in musk shrews was directly assessed to determine the Meeh constant (K m ) conversion factor (female = 9.97, male = 9.10), allowing estimation of body surface area based on body weight. These parameters can be used to determine dosing strategies for shrew studies that model human drug exposures, particularly for investigating the emetic liability of cancer chemotherapeutic agents.

Population pharmacokinetics of gabapentin in healthy Korean subjects with influence of genetic polymorphisms of ABCB1.

PubMed

Tran, Phuong; Yoo, Hee-Doo; Ngo, Lien; Cho, Hea-Young; Lee, Yong-Bok

2017-12-01

The objective of this study was to perform population pharmacokinetic (PK) analysis of gabapentin in healthy Korean subjects and to investigate the possible effect of genetic polymorphisms (1236C > T, 2677G > T/A, and 3435C > T) of ABCB1 gene on PK parameters of gabapentin. Data were collected from bioequivalence studies, in which 173 subjects orally received three different doses of gabapentin (300, 400, and 800 mg). Only data from reference formulation were used. Population pharmacokinetics (PKs) of gabapentin was estimated using a nonlinear mixed-effects model (NONMEM). Gabapentin showed considerable inter-individual variability (from 5.2- to 8.7-fold) in PK parameters. Serum concentration of gabapentin was well fitted by a one-compartment model with first-order absorption and lag time. An inhibitory Emax model was applied to describe the effect of dose on bioavailability. The oral clearance was estimated to be 11.1 L/h. The volume of distribution was characterized as 81.0 L. The absorption rate constant was estimated at 0.860 h -1 , and the lag time was predicted at 0.311 h. Oral bioavailability was estimated to be 68.8% at dose of 300 mg, 62.7% at dose of 400 mg, and 47.1% at dose of 800 mg. The creatinine clearance significantly influenced on the oral clearance (P < 0.005) and ABCB1 2677G > T/A genotypes significantly influenced on the absorption rate constant (P < 0.05) of gabapentin. However, ABCB1 1236C > T and 3435C > T genotypes showed no significant effect on gabapentin PK parameters. The results of the present study indicate that the oral bioavailability of gabapentin is decreased when its dosage is increased. In addition, ABCB1 2677G > T/A polymorphism can explain the substantial inter-individual variability in the absorption of gabapentin.

Acute Esophagus Toxicity in Lung Cancer Patients After Intensity Modulated Radiation Therapy and Concurrent Chemotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kwint, Margriet; Uyterlinde, Wilma; Nijkamp, Jasper

2012-10-01

Purpose: The purpose of this study was to investigate the dose-effect relation between acute esophageal toxicity (AET) and the dose-volume parameters of the esophagus after intensity modulated radiation therapy (IMRT) and concurrent chemotherapy for patients with non-small cell lung cancer (NSCLC). Patients and Methods: One hundred thirty-nine patients with inoperable NSCLC treated with IMRT and concurrent chemotherapy were prospectively analyzed. The fractionation scheme was 66 Gy in 24 fractions. All patients received concurrently a daily dose of cisplatin (6 mg/m Superscript-Two ). Maximum AET was scored according to Common Toxicity Criteria 3.0. Dose-volume parameters V5 to V70, D{sub mean} andmore » D{sub max} of the esophagus were calculated. A logistic regression analysis was performed to analyze the dose-effect relation between these parameters and grade {>=}2 and grade {>=}3 AET. The outcome was compared with the clinically used esophagus V35 prediction model for grade {>=}2 after radical 3-dimensional conformal radiation therapy (3DCRT) treatment. Results: In our patient group, 9% did not experience AET, and 31% experienced grade 1 AET, 38% grade 2 AET, and 22% grade 3 AET. The incidence of grade 2 and grade 3 AET was not different from that in patients treated with CCRT using 3DCRT. The V50 turned out to be the most significant dosimetric predictor for grade {>=}3 AET (P=.012). The derived V50 model was shown to predict grade {>=}2 AET significantly better than the clinical V35 model (P<.001). Conclusions: For NSCLC patients treated with IMRT and concurrent chemotherapy, the V50 was identified as most accurate predictor of grade {>=}3 AET. There was no difference in the incidence of grade {>=}2 AET between 3DCRT and IMRT in patients treated with concurrent chemoradiation therapy.« less

Population pharmacokinetics of ϵ-aminocaproic acid in adolescents undergoing posterior spinal fusion surgery.

PubMed

Stricker, P A; Gastonguay, M R; Singh, D; Fiadjoe, J E; Sussman, E M; Pruitt, E Y; Goebel, T K; Zuppa, A F

2015-04-01

Despite demonstrated efficacy of ϵ-aminocaproic acid (EACA) in reducing blood loss in adolescents undergoing spinal fusion, there are no population-specific pharmacokinetic data to guide dosing. The aim of this study was to determine the pharmacokinetics of EACA in adolescents undergoing spinal fusion surgery and make dosing recommendations. Twenty children ages 12-17 years were enrolled, with 10 children in each of two groups based on diagnosis (idiopathic scoliosis or non-idiopathic scoliosis). Previously reported data from infants undergoing craniofacial surgery were included in the model to enable dosing recommendations over a wide range of weights, ages, and diagnoses. A population non-linear mixed effects modelling approach was used to characterize EACA pharmacokinetics. Population pharmacokinetic parameters were estimated using a two-compartment disposition model with allometrically scaled weight and an age effect on clearance. Pharmacokinetic parameters for the typical patient were a plasma clearance of 153 ml min(-1) 70 kg(-1) (6.32 ml min(-1) kg(-0.75)), intercompartmental clearance of 200 ml min(-1) 70 kg(-1) (8.26 ml min(-1) kg(-0.75)), central volume of distribution of 8.78 litre 70 kg(-1) (0.13 litre kg(-1)), and peripheral volume of distribution of 15.8 litre 70 kg(-1) (0.23 litre kg(-1)). Scoliosis aetiology did not have a clinically significant effect on drug pharmacokinetics. The following dosing schemes are recommended according to patient weight: weight <25 kg, 100 mg kg(-1) loading dose and 40 mg kg(-1) h(-1) infusion; weight ≤25 kg-<50 kg, 100 mg kg(-1) loading dose and 35 mg kg(-1) h(-1) infusion; and weight ≥50 kg, 100 mg kg(-1) loading dose and 30 mg kg(-1) h(-1) infusion. An efficacy trial employing this dosing strategy is warranted. NCT01408823. © The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Population pharmacokinetics of ϵ-aminocaproic acid in adolescents undergoing posterior spinal fusion surgery

PubMed Central

Stricker, P. A.; Gastonguay, M. R.; Singh, D.; Fiadjoe, J. E.; Sussman, E. M.; Pruitt, E. Y.; Goebel, T. K.; Zuppa, A. F.

2015-01-01

Background Despite demonstrated efficacy of ϵ-aminocaproic acid (EACA) in reducing blood loss in adolescents undergoing spinal fusion, there are no population-specific pharmacokinetic data to guide dosing. The aim of this study was to determine the pharmacokinetics of EACA in adolescents undergoing spinal fusion surgery and make dosing recommendations. Methods Twenty children ages 12–17 years were enrolled, with 10 children in each of two groups based on diagnosis (idiopathic scoliosis or non-idiopathic scoliosis). Previously reported data from infants undergoing craniofacial surgery were included in the model to enable dosing recommendations over a wide range of weights, ages, and diagnoses. A population non-linear mixed effects modelling approach was used to characterize EACA pharmacokinetics. Results Population pharmacokinetic parameters were estimated using a two-compartment disposition model with allometrically scaled weight and an age effect on clearance. Pharmacokinetic parameters for the typical patient were a plasma clearance of 153 ml min−1 70 kg−1 (6.32 ml min−1 kg−0.75), intercompartmental clearance of 200 ml min−1 70 kg−1 (8.26 ml min−1 kg−0.75), central volume of distribution of 8.78 litre 70 kg−1 (0.13 litre kg−1), and peripheral volume of distribution of 15.8 litre 70 kg−1 (0.23 litre kg−1). Scoliosis aetiology did not have a clinically significant effect on drug pharmacokinetics. Conclusions The following dosing schemes are recommended according to patient weight: weight <25 kg, 100 mg kg−1 loading dose and 40 mg kg−1 h−1 infusion; weight ≤25 kg–<50 kg, 100 mg kg−1 loading dose and 35 mg kg−1 h−1 infusion; and weight ≥50 kg, 100 mg kg−1 loading dose and 30 mg kg−1 h−1 infusion. An efficacy trial employing this dosing strategy is warranted. Clinical trial registration NCT01408823. PMID:25586726

Evaluation of Myrtus communis Linn. berries (common myrtle) in experimental ulcer models in rats.

PubMed

Sumbul, Sabiha; Ahmad, Mohd Aftab; Asif, Mohd; Saud, Ibne; Akhtar, Mohd

2010-11-01

The present study was conducted to investigate the protective effect of the dried berries of Myrtus communis L. in gastric ulcer against ethanol, indomethacin and pyloric ligation induced models in Wistar rats. Two doses of aqueous extracts of M. communis (AE( 1) and AE(2)) at the dose 105 and 175 mg/kg, respectively, and methanolic extracts (ME(1) and ME(2)) at the dose of 93 and 154 mg/kg, respectively, were administered orally to animals prior to the exposure of ulcerogens. The parameters taken to assess anti-ulcer activity were ulcer index, gastric juice volume, gastric pH, total acidity, gastric wall mucus and histopathological studies. Oral administration of AE(1) and AE(2) significantly reduced the ulcer index in all models of ulcers. Low dose of aqueous extract and high dose of methanolic extract of M. communis exhibited more significant effect in comparison to omeprazole (standard drug) in ethanol-induced ulcer model. Both the doses of aqueous and methanolic extracts also reduced the gastric juice volume, total acidity and increased the gastric pH and gastric wall mucus content in all the models of ulcers used in the present study. Histopathological examinations of gastric tissues of rats treated with the aqueous and methanolic extracts in indomethacin-induced ulcer exhibited significant ulcer-protective effect at both the dose levels.

Pharmacokinetic Interpretation of Cephradine Levels in Serum After Intravenous and Extravascular Administration in Humans

PubMed Central

Rattie, Elisabeth S.; Bernardo, Peter D.; Ravin, Louis J.

1976-01-01

Pharmacokinetic parameters were calculated from intravenous data based upon a two-compartment open model. These parameters were subsequently used to determine the absorption rates and bioavailability of cephradine administered intramuscularly and orally. The results indicate that cephradine obeys dose-independent kinetics and that biological availability is complete from all dosage forms. PMID:984770

A new dynamical atmospheric ionizing radiation (AIR) model for epidemiological studies

NASA Technical Reports Server (NTRS)

De Angelis, G.; Clem, J. M.; Goldhagen, P. E.; Wilson, J. W.

2003-01-01

A new Atmospheric Ionizing Radiation (AIR) model is currently being developed for use in radiation dose evaluation in epidemiological studies targeted to atmospheric flight personnel such as civilian airlines crewmembers. The model will allow computing values for biologically relevant parameters, e.g. dose equivalent and effective dose, for individual flights from 1945. Each flight is described by its actual three dimensional flight profile, i.e. geographic coordinates and altitudes varying with time. Solar modulated primary particles are filtered with a new analytical fully angular dependent geomagnetic cut off rigidity model, as a function of latitude, longitude, arrival direction, altitude and time. The particle transport results have been obtained with a technique based on the three-dimensional Monte Carlo transport code FLUKA, with a special procedure to deal with HZE particles. Particle fluxes are transformed into dose-related quantities and then integrated all along the flight path to obtain the overall flight dose. Preliminary validations of the particle transport technique using data from the AIR Project ER-2 flight campaign of measurements are encouraging. Future efforts will deal with modeling of the effects of the aircraft structure as well as inclusion of solar particle events. Published by Elsevier Ltd on behalf of COSPAR.

Design of experiments in medical physics: Application to the AAA beam model validation.

PubMed

Dufreneix, S; Legrand, C; Di Bartolo, C; Bremaud, M; Mesgouez, J; Tiplica, T; Autret, D

2017-09-01

The purpose of this study is to evaluate the usefulness of the design of experiments in the analysis of multiparametric problems related to the quality assurance in radiotherapy. The main motivation is to use this statistical method to optimize the quality assurance processes in the validation of beam models. Considering the Varian Eclipse system, eight parameters with several levels were selected: energy, MLC, depth, X, Y 1 and Y 2 jaw dimensions, wedge and wedge jaw. A Taguchi table was used to define 72 validation tests. Measurements were conducted in water using a CC04 on a TrueBeam STx, a TrueBeam Tx, a Trilogy and a 2300IX accelerator matched by the vendor. Dose was computed using the AAA algorithm. The same raw data was used for all accelerators during the beam modelling. The mean difference between computed and measured doses was 0.1±0.5% for all beams and all accelerators with a maximum difference of 2.4% (under the 3% tolerance level). For all beams, the measured doses were within 0.6% for all accelerators. The energy was found to be an influencing parameter but the deviations observed were smaller than 1% and not considered clinically significant. Designs of experiment can help define the optimal measurement set to validate a beam model. The proposed method can be used to identify the prognostic factors of dose accuracy. The beam models were validated for the 4 accelerators which were found dosimetrically equivalent even though the accelerator characteristics differ. Copyright © 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

A Kinetic Model for Calcium Dynamics in RAW 264.7 Cells: 1. Mechanisms, Parameters, and Subpopulational Variability

PubMed Central

Maurya, Mano Ram; Subramaniam, Shankar

2007-01-01

Calcium (Ca2+) is an important second messenger and has been the subject of numerous experimental measurements and mechanistic studies in intracellular signaling. Calcium profile can also serve as a useful cellular phenotype. Kinetic models of calcium dynamics provide quantitative insights into the calcium signaling networks. We report here the development of a complex kinetic model for calcium dynamics in RAW 264.7 cells stimulated by the C5a ligand. The model is developed using the vast number of measurements of in vivo calcium dynamics carried out in the Alliance for Cellular Signaling (AfCS) Laboratories. Ligand binding, phospholipase C-β (PLC-β) activation, inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) dynamics, and calcium exchange with mitochondria and extracellular matrix have all been incorporated into the model. The experimental data include data from both native and knockdown cell lines. Subpopulational variability in measurements is addressed by allowing nonkinetic parameters to vary across datasets. The model predicts temporal response of Ca2+ concentration for various doses of C5a under different initial conditions. The optimized parameters for IP3R dynamics are in agreement with the legacy data. Further, the half-maximal effect concentration of C5a and the predicted dose response are comparable to those seen in AfCS measurements. Sensitivity analysis shows that the model is robust to parametric perturbations. PMID:17483174

On the use of published radiobiological parameters and the evaluation of NTCP models regarding lung pneumonitis in clinical breast radiotherapy.

PubMed

Svolos, Patricia; Tsougos, Ioannis; Kyrgias, Georgios; Kappas, Constantine; Theodorou, Kiki

2011-04-01

In this study we sought to evaluate and accent the importance of radiobiological parameter selection and implementation to the normal tissue complication probability (NTCP) models. The relative seriality (RS) and the Lyman-Kutcher-Burman (LKB) models were studied. For each model, a minimum and maximum set of radiobiological parameter sets was selected from the overall published sets applied in literature and a theoretical mean parameter set was computed. In order to investigate the potential model weaknesses in NTCP estimation and to point out the correct use of model parameters, these sets were used as input to the RS and the LKB model, estimating radiation induced complications for a group of 36 breast cancer patients treated with radiotherapy. The clinical endpoint examined was Radiation Pneumonitis. Each model was represented by a certain dose-response range when the selected parameter sets were applied. Comparing the models with their ranges, a large area of coincidence was revealed. If the parameter uncertainties (standard deviation) are included in the models, their area of coincidence might be enlarged, constraining even greater their predictive ability. The selection of the proper radiobiological parameter set for a given clinical endpoint is crucial. Published parameter values are not definite but should be accompanied by uncertainties, and one should be very careful when applying them to the NTCP models. Correct selection and proper implementation of published parameters provides a quite accurate fit of the NTCP models to the considered endpoint.

Parametric study of irradiation effects on the ductile damage and flow stress behavior in ferritic-martensitic steels

NASA Astrophysics Data System (ADS)

Chakraborty, Pritam; Biner, S. Bulent

2015-10-01

Ferritic-martensitic steels are currently being considered as structural materials in fusion and Gen-IV nuclear reactors. These materials are expected to experience high dose radiation, which can increase their ductile to brittle transition temperature and susceptibility to failure during operation. Hence, to estimate the safe operational life of the reactors, precise evaluation of the ductile to brittle transition temperatures of ferritic-martensitic steels is necessary. Owing to the scarcity of irradiated samples, particularly at high dose levels, micro-mechanistic models are being employed to predict the shifts in the ductile to brittle transition temperatures. These models consider the ductile damage evolution, in the form of nucleation, growth and coalescence of voids; and the brittle fracture, in the form of probabilistic cleavage initiation, to estimate the influence of irradiation on the ductile to brittle transition temperature. However, the assessment of irradiation dependent material parameters is challenging and influences the accuracy of these models. In the present study, the effects of irradiation on the overall flow stress and ductile damage behavior of two ferritic-martensitic steels is parametrically investigated. The results indicate that the ductile damage model parameters are mostly insensitive to irradiation levels at higher dose levels though the resulting flow stress behavior varies significantly.

SU-F-T-344: Commissioning Constant Dose Rate VMAT in the Raystation Treatment Planning System for a Varian Clinac IX

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pursley, J; Gueorguiev, G; Prichard, H

Purpose: To demonstrate the commissioning of constant dose rate volumetric modulated arc therapy (VMAT) in the Raystation treatment planning system for a Varian Clinac iX with Exact couch. Methods: Constant dose rate (CDR) VMAT is an option in the Raystation treatment planning system, enabling VMAT delivery on Varian linacs without a RapidArc upgrade. Raystation 4.7 was used to commission CDR-VMAT for a Varian Clinac iX. Raystation arc model parameters were selected to match machine deliverability characteristics. A Varian Exact couch model was added to Raystation 4.7 and commissioned for use in VMAT optimization. CDR-VMAT commissioning checks were performed on themore » linac, including patient-specific QA measurements for 10 test patients using both the ArcCHECK from Sun Nuclear Corporation and COMPASS from IBA Dosimetry. Multi-criteria optimization (MCO) in Raystation was used for CDR-VMAT planning. Results: Raystation 4.7 generated clinically acceptable and deliverable CDR-VMAT plans for the Varian Clinac. VMAT plans were optimized including a model of the Exact couch with both rails in the out positions. CDR-VMAT plans generated with MCO in Raystation were dosimetrically comparable to Raystation MCO-generated IMRT plans. Patient-specific QA measurements with the ArcCHECK on the couch showed good agreement with the treatment planning system prediction. Patient-specific, structure-specific, multi-statistical parameter 3D QA measurements with gantry-mounted COMPASS also showed good agreement. Conclusion: Constant dose rate VMAT was successfully modeled in Raystation 4.7 for a Varian Clinac iX, and Raystation’s multicriteria optimization generated constant dose rate VMAT plans which were deliverable and dosimetrically comparable to IMRT plans.« less

WE-FG-202-09: Voxel-Level Analysis of Adverse Treatment Response in Pediatric Patients Treated for Ependymoma with Passive Scattering Proton Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peeler, C; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX; Mirkovic, D

2016-06-15

Purpose: We identified patients treated for ependymoma with passive scattering proton therapy who subsequently developed treatment-related imaging changes on MRI. We sought to determine if there is any spatial correlation between imaged response, dose, and LET. Methods: A group of 14 patients treated for ependymoma were identified as having post-treatment MR imaging changes observable as T2-FLAIR hyperintensity with or without enhancement on T1 post-contrast sequences. MR images were registered with treatment planning CT images and regions of treatment-related change contoured by a practicing radiation oncologist. The contoured regions were identified as response with voxels represented as 1 while voxels withinmore » the brain outside of the response region were represented as 0. An in-house Monte Carlo system was used to recalculate treatment plans to obtain dose and LET information. Voxels were binned according to LET values in 0.3 keV µm{sup −1} bins. Dose and corresponding response value (0 or 1) for each voxel for a given LET bin were then plotted and fit with the Lyman-Kutcher-Burman dose response model to determine TD{sub 50} and m parameters for each LET value. Response parameters from all patients were then collated, and linear fits of the data were performed. Results: The response parameters TD50 and m both show trends with LET. Outliers were observed due to low numbers of response voxels in some cases. TD{sub 50} values decreased with LET while m increased with LET. The former result would indicate that for higher LET values, the dose is more effective, which is consistent with relative biological effectiveness (RBE) models for proton therapy. Conclusion: A novel method of voxel-level analysis of image biomarker-based adverse patient treatment response in proton therapy according to dose and LET has been presented. Fitted TD{sub 50} values show a decreasing trend with LET supporting the typical models of proton RBE. Funding provided by NIH Program Project Grant 2U19CA021239-35.« less

SU-E-T-39: A Logistic Function-Based Model to Predict Organ-At-Risk (OAR) DVH in IMRT Treatment Planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, S; Zhang, H; Zhang, B

2015-06-15

Purpose: To investigate the feasibility of a logistic function-based model to predict organ-at-risk (OAR) DVH for IMRT planning. The predicted DVHs are compared to achieved DVHs by expert treatment planners. Methods: A logistic function is used to model the OAR dose-gradient function. This function describes the percentage of the prescription dose as a function of the normal distance to PTV surface. The slope of dose-gradient function is function of relative spatial orientation of the PTV and OARs. The OAR DVH is calculated using the OAR dose-gradient function assuming that the dose is same for voxels with same normal distance tomore » PTV. Ten previously planned prostate IMRT plans were selected to build the model, and the following plan parameters were calculated as possible features to the model: the PTV maximum/minimum dose, PTV volume, bladder/rectum volume in the radiation field, percentage of bladder/rectum overlapping with PTV, and the distance between the bladder/rectum centroid and PTV. The bladder/rectum dose-gradient function was modeled and applied on 10 additional test cases, and the predicted and achieved clinical bladder/rectum DVHs were compared: V70 (percentage of volume receiving 70Gy and above), V65, V60, V55, V50, V45, V40. Results: The following parameters were selected as model features: PTV volume, and distance of centroid of rectum/bladder to PTV. The model was tested with 10 additional patients. For bladder, the absolute difference (mean±standard deviation) between predicted and clinical DVHs is V70=−0.3±3.2, V65=−0.8±3.9, V60=1.5±4.3, V55=1.7±5.3, V50=−0.6±6.4, V45=0.6±6.5, and V40=0.9±5.7, the correlation coefficient is 0.96; for rectum, the difference is V70=1.5±3.8, V65=1.2±4.2, V60=−0.1±5.3, V55=1.0±6.6, V50=1.6±8.7, V45=1.9±9.8, and V40=1.5±10.1, and the correlation coefficient is 0.87. Conclusion: The OAR DVH can be accurately predicted using the OAR dose-gradient function in IMRT plans. This approach may be used as a quality control tool and aid less experienced planners determine benchmarks for plan quality.« less

Dosimetric characterization of the M−15 high‐dose‐rate Iridium−192 brachytherapy source using the AAPM and ESTRO formalism

PubMed Central

Thanh, Minh‐Tri Ho; Munro, John J.

2015-01-01

The Source Production & Equipment Co. (SPEC) model M−15 is a new Iridium−192 brachytherapy source model intended for use as a temporary high‐dose‐rate (HDR) brachytherapy source for the Nucletron microSelectron Classic afterloading system. The purpose of this study is to characterize this HDR source for clinical application by obtaining a complete set of Monte Carlo calculated dosimetric parameters for the M‐15, as recommended by AAPM and ESTRO, for isotopes with average energies greater than 50 keV. This was accomplished by using the MCNP6 Monte Carlo code to simulate the resulting source dosimetry at various points within a pseudoinfinite water phantom. These dosimetric values next were converted into the AAPM and ESTRO dosimetry parameters and the respective statistical uncertainty in each parameter also calculated and presented. The M−15 source was modeled in an MCNP6 Monte Carlo environment using the physical source specifications provided by the manufacturer. Iridium−192 photons were uniformly generated inside the iridium core of the model M−15 with photon and secondary electron transport replicated using photoatomic cross‐sectional tables supplied with MCNP6. Simulations were performed for both water and air/vacuum computer models with a total of 4×109 sources photon history for each simulation and the in‐air photon spectrum filtered to remove low‐energy photons below δ=10%keV. Dosimetric data, including D(r,θ),gL(r),F(r,θ),Φan(r), and φ¯an, and their statistical uncertainty were calculated from the output of an MCNP model consisting of an M−15 source placed at the center of a spherical water phantom of 100 cm diameter. The air kerma strength in free space, SK, and dose rate constant, Λ, also was computed from a MCNP model with M−15 Iridium−192 source, was centered at the origin of an evacuated phantom in which a critical volume containing air at STP was added 100 cm from the source center. The reference dose rate, D˙(r0,θ0)≡D˙(1cm,π/2), is found to be 4.038±0.064 cGy mCi−1 h−1. The air kerma strength, SK, is reported to be 3.632±0.086 cGy cm2 mCi−1 g−1, and the dose rate constant, Λ, is calculated to be 1.112±0.029 cGy h−1 U−1. The normalized dose rate, radial dose function, and anisotropy function with their uncertainties were computed and are represented in both tabular and graphical format in the report. A dosimetric study was performed of the new M−15 Iridium−192 HDR brachytherapy source using the MCNP6 radiation transport code. Dosimetric parameters, including the dose‐rate constant, radial dose function, and anisotropy function, were calculated in accordance with the updated AAPM and ESTRO dosimetric parameters for brachytherapy sources of average energy greater than 50 keV. These data therefore may be applied toward the development of a treatment planning program and for clinical use of the source. PACS numbers: 87.56.bg, 87.53.Jw PMID:26103489

Relation between lineal energy distribution and relative biological effectiveness for photon beams according to the microdosimetric kinetic model.

PubMed

Okamoto, Hiroyuki; Kanai, Tatsuaki; Kase, Yuki; Matsumoto, Yoshitaka; Furusawa, Yoshiya; Fujita, Yukio; Saitoh, Hidetoshi; Itami, Jun; Kohno, Toshiyuki

2011-01-01

Our cell survival data showed the obvious dependence of RBE on photon energy: The RBE value for 200 kV X-rays was approximately 10% greater than those for mega-voltage photon beams. In radiation therapy using mega-voltage photon beams, the photon energy distribution outside the field is different with that in the radiation field because of a large number of low energy scattering photons. Hence, the RBE values outside the field become greater. To evaluate the increase in RBE, the method of deriving the RBE using the Microdosimetric Kinetic model (MK model) was proposed in this study. The MK model has two kinds of the parameters, tissue-specific parameters and the dose-mean lineal energy derived from the lineal energy distributions measured with a Tissue-Equivalent Proportional Counter (TEPC). The lineal energy distributions with the same geometries of the cell irradiations for 200 kV X-rays, (60)Co γ-rays, and 6 MV X-rays were obtained with the TEPC and Monte Carlo code GEANT4. The measured lineal energy distribution for 200 kV X-rays was quite different from those for mega-voltage photon beams. The dose-mean lineal energy of 200 kV X-rays showed the greatest value, 4.51 keV/µm, comparing with 2.34 and 2.36 keV/µm for (60)Co γ-rays and 6 MV X-rays, respectively. By using the results of the TEPC and cell irradiations, the tissue-specific parameters in the MK model were determined. As a result, the RBE of the photon beams (y(D): 2~5 keV/µm) in arbitrary conditions can be derived by the measurements only or the calculations only of the dose-mean lineal energy.

SU-E-T-284: Revisiting Reference Dosimetry for the Model S700 Axxent 50 KV{sub p} Electronic Brachytherapy Source

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hiatt, JR; Rivard, MJ

2014-06-01

Purpose: The model S700 Axxent electronic brachytherapy source by Xoft was characterized in 2006 by Rivard et al. The source design was modified in 2006 to include a plastic centering insert at the source tip to more accurately position the anode. The objectives of the current study were to establish an accurate Monte Carlo source model for simulation purposes, to dosimetrically characterize the new source and obtain its TG-43 brachytherapy dosimetry parameters, and to determine dose differences between the source with and without the centering insert. Methods: Design information from dissected sources and vendor-supplied CAD drawings were used to devisemore » the source model for radiation transport simulations of dose distributions in a water phantom. Collision kerma was estimated as a function of radial distance, r, and polar angle, θ, for determination of reference TG-43 dosimetry parameters. Simulations were run for 10{sup 10} histories, resulting in statistical uncertainties on the transverse plane of 0.03% at r=1 cm and 0.08% at r=10 cm. Results: The dose rate distribution the transverse plane did not change beyond 2% between the 2006 model and the current study. While differences exceeding 15% were observed near the source distal tip, these diminished to within 2% for r>1.5 cm. Differences exceeding a factor of two were observed near θ=150° and in contact with the source, but diminished to within 20% at r=10 cm. Conclusions: Changes in source design influenced the overall dose rate and distribution by more than 2% over a third of the available solid angle external from the source. For clinical applications using balloons or applicators with tissue located within 5 cm from the source, dose differences exceeding 2% were observed only for θ>110°. This study carefully examined the current source geometry and presents a modern reference TG-43 dosimetry dataset for the model S700 source.« less

Tuning of Schottky barrier height of Al/n-Si by electron beam irradiation

NASA Astrophysics Data System (ADS)

Vali, Indudhar Panduranga; Shetty, Pramoda Kumara; Mahesha, M. G.; Petwal, V. C.; Dwivedi, Jishnu; Choudhary, R. J.

2017-06-01

The effect of electron beam irradiation (EBI) on Al/n-Si Schottky diode has been studied by I-V characterization at room temperature. The behavior of the metal-semiconductor (MS) interface is analyzed by means of variations in the MS contact parameters such as, Schottky barrier height (ΦB), ideality factor (n) and series resistance (Rs). These parameters were found to depend on the EBI dose having a fixed incident beam of energy 7.5 MeV. At different doses (500, 1000, 1500 kGy) of EBI, the Schottky contacts were prepared and extracted their contact parameters by applying thermionic emission and Cheung models. Remarkably, the tuning of ΦB was observed as a function of EBI dose. The improved n with increased ΦB is seen for all the EBI doses. As a consequence of which the thermionic emission is more favored. However, the competing transport mechanisms such as space charge limited emission, tunneling and tunneling through the trap states were ascribed due to n > 1. The analysis of XPS spectra have shown the presence of native oxide and increased radiation induced defect states. The thickness variation in the MS interface contributing to Schottky contact behavior is discussed. This study explains a new technique to tune Schottky contact parameters by metal deposition on the electron beam irradiated n-Si wafers.

Subantibiotic dose of azithromycin attenuates alveolar bone destruction and improves trabecular microarchitectures in a rat model of experimental periodontitis: A study using micro-computed tomography.

PubMed

Park, Hye-Shin; Lee, Yong Sun; Choi, Eun-Young; Choi, Jeom-Il; Choi, In Soon; Kim, Sung-Jo

2017-06-01

Azithromycin, a macrolide antibiotic, has anti-inflammatory and immunomodulatory activities apart from its antibacterial properties. In this study, we examined the efficacy of subantibiotic dose of azithromycin on ligature-induced periodontitis in rats using micro-computed tomography (micro-CT) imaging and bone parameter analysis. Male Sprague-Dawley rats were allocated to the following four groups: non-ligation (NL) group; ligation-only (L) group; ligation-plus-subantibiotic dose azithromycin (SA) group; and 4) ligation-plus-antibiotic dose azithromycin (AA) group. The rats from Groups L, SA and AA were subjected to periodontitis by placing a ligature around lower right first molar. Immediately after ligation, the rats in SA and AA groups received daily intraperitoneal injections of azithromycin at a dosage of 3.5 or 10mg/kg body weight, respectively. The ligatures were maintained for 2weeks at which time the rats had their mandibles hemisected for micro-CT analysis. Subantibiotic dose of azithromycin strongly suppressed reductions in alveolar bone height and bone volume fraction caused by experimental periodontitis. When subantibiotic dosage of azithromycin was administered to rats, ligature-induced alterations in microarchitectural parameters of trabecular bone were significantly reversed. Rats treated with subantibiotic dose of azithromycin presented no significant difference compared to rats with antibiotic dosage in all parameters. While further studies are necessary, subantibiotic dose of azithromycin could be utilized as a host modulator for the treatment of periodontitis. Copyright © 2017 Elsevier B.V. All rights reserved.

Three-Dimensional Radiobiologic Dosimetry: Application of Radiobiologic Modeling to Patient-Specific 3-Dimensional Imaging–Based Internal Dosimetry

PubMed Central

Prideaux, Andrew R.; Song, Hong; Hobbs, Robert F.; He, Bin; Frey, Eric C.; Ladenson, Paul W.; Wahl, Richard L.; Sgouros, George

2010-01-01

Phantom-based and patient-specific imaging-based dosimetry methodologies have traditionally yielded mean organ-absorbed doses or spatial dose distributions over tumors and normal organs. In this work, radiobiologic modeling is introduced to convert the spatial distribution of absorbed dose into biologically effective dose and equivalent uniform dose parameters. The methodology is illustrated using data from a thyroid cancer patient treated with radioiodine. Methods Three registered SPECT/CT scans were used to generate 3-dimensional images of radionuclide kinetics (clearance rate) and cumulated activity. The cumulated activity image and corresponding CT scan were provided as input into an EGSnrc-based Monte Carlo calculation: The cumulated activity image was used to define the distribution of decays, and an attenuation image derived from CT was used to define the corresponding spatial tissue density and composition distribution. The rate images were used to convert the spatial absorbed dose distribution to a biologically effective dose distribution, which was then used to estimate a single equivalent uniform dose for segmented volumes of interest. Equivalent uniform dose was also calculated from the absorbed dose distribution directly. Results We validate the method using simple models; compare the dose-volume histogram with a previously analyzed clinical case; and give the mean absorbed dose, mean biologically effective dose, and equivalent uniform dose for an illustrative case of a pediatric thyroid cancer patient with diffuse lung metastases. The mean absorbed dose, mean biologically effective dose, and equivalent uniform dose for the tumor were 57.7, 58.5, and 25.0 Gy, respectively. Corresponding values for normal lung tissue were 9.5, 9.8, and 8.3 Gy, respectively. Conclusion The analysis demonstrates the impact of radiobiologic modeling on response prediction. The 57% reduction in the equivalent dose value for the tumor reflects a high level of dose nonuniformity in the tumor and a corresponding reduced likelihood of achieving a tumor response. Such analyses are expected to be useful in treatment planning for radionuclide therapy. PMID:17504874

Safe uses of Hill's model: an exact comparison with the Adair-Klotz model

PubMed Central

2011-01-01

Background The Hill function and the related Hill model are used frequently to study processes in the living cell. There are very few studies investigating the situations in which the model can be safely used. For example, it has been shown, at the mean field level, that the dose response curve obtained from a Hill model agrees well with the dose response curves obtained from a more complicated Adair-Klotz model, provided that the parameters of the Adair-Klotz model describe strongly cooperative binding. However, it has not been established whether such findings can be extended to other properties and non-mean field (stochastic) versions of the same, or other, models. Results In this work a rather generic quantitative framework for approaching such a problem is suggested. The main idea is to focus on comparing the particle number distribution functions for Hill's and Adair-Klotz's models instead of investigating a particular property (e.g. the dose response curve). The approach is valid for any model that can be mathematically related to the Hill model. The Adair-Klotz model is used to illustrate the technique. One main and two auxiliary similarity measures were introduced to compare the distributions in a quantitative way. Both time dependent and the equilibrium properties of the similarity measures were studied. Conclusions A strongly cooperative Adair-Klotz model can be replaced by a suitable Hill model in such a way that any property computed from the two models, even the one describing stochastic features, is approximately the same. The quantitative analysis showed that boundaries of the regions in the parameter space where the models behave in the same way exhibit a rather rich structure. PMID:21521501

The prolonged gastrointestinal syndrome in rhesus macaques: the relationship between gastrointestinal, hematopoietic, and delayed multi-organ sequelae following acute, potentially lethal, partial-body irradiation.

PubMed

MacVittie, Thomas J; Bennett, Alexander; Booth, Catherine; Garofalo, Michael; Tudor, Gregory; Ward, Amanda; Shea-Donohue, Terez; Gelfond, Daniel; McFarland, Emylee; Jackson, William; Lu, Wei; Farese, Ann M

2012-10-01

The dose response relationship for the acute gastrointestinal syndrome following total-body irradiation prevents analysis of the full recovery and damage to the gastrointestinal system, since all animals succumb to the subsequent 100% lethal hematopoietic syndrome. A partial-body irradiation model with 5% bone marrow sparing was established to investigate the prolonged effects of high-dose radiation on the gastrointestinal system, as well as the concomitant hematopoietic syndrome and other multi-organ injury including the lung. Herein, cellular and clinical parameters link acute and delayed coincident sequelae to radiation dose and time course post-exposure. Male rhesus Macaca mulatta were exposed to partial-body irradiation with 5% bone marrow (tibiae, ankles, feet) sparing using 6 MV linear accelerator photons at a dose rate of 0.80 Gy min(-1) to midline tissue (thorax) doses in the exposure range of 9.0 to 12.5 Gy. Following irradiation, all animals were monitored for multiple organ-specific parameters for 180 d. Animals were administered medical management including administration of intravenous fluids, antiemetics, prophylactic antibiotics, blood transfusions, antidiarrheals, supplemental nutrition, and analgesics. The primary endpoint was survival at 15, 60, or 180 d post-exposure. Secondary endpoints included evaluation of dehydration, diarrhea, hematologic parameters, respiratory distress, histology of small and large intestine, lung radiographs, and mean survival time of decedents. Dose- and time-dependent mortality defined several organ-specific sequelae, with LD50/15 of 11.95 Gy, LD50/60 of 11.01 Gy, and LD50/180 of 9.73 Gy for respective acute gastrointestinal, combined hematopoietic and gastrointestinal, and multi-organ delayed injury to include the lung. This model allows analysis of concomitant multi-organ sequelae, thus providing a link between acute and delayed radiation effects. Specific and multi-organ medical countermeasures can be assessed for efficacy and interaction during the concomitant evolution of acute and delayed key organ-specific subsyndromes.

A rule of unity for human intestinal absorption 3: Application to pharmaceuticals.

PubMed

Patel, Raj B; Yalkowsky, Samuel H

2018-02-01

The rule of unity is based on a simple absorption parameter, Π, that can accurately predict whether or not an orally administered drug will be well absorbed or poorly absorbed. The intrinsic aqueous solubility and octanol-water partition coefficient, along with the drug dose are used to calculate Π. We show that a single delineator value for Π exist that can distinguish whether a drug is likely to be well absorbed (FA ≥ 0.5) or poorly absorbed (FA < 0.5) at any specified dose. The model is shown to give 82.5% correct predictions for over 938 pharmaceuticals. The maximum well-absorbed dose (i.e. the maximum dose that will be more than 50% absorbed) calculated using this model can be utilized as a guideline for drug design and synthesis. Copyright © 2017 John Wiley & Sons, Ltd.

Comparison of TG-43 and TG-186 in breast irradiation using a low energy electronic brachytherapy source.

PubMed

White, Shane A; Landry, Guillaume; Fonseca, Gabriel Paiva; Holt, Randy; Rusch, Thomas; Beaulieu, Luc; Verhaegen, Frank; Reniers, Brigitte

2014-06-01

The recently updated guidelines for dosimetry in brachytherapy in TG-186 have recommended the use of model-based dosimetry calculations as a replacement for TG-43. TG-186 highlights shortcomings in the water-based approach in TG-43, particularly for low energy brachytherapy sources. The Xoft Axxent is a low energy (<50 kV) brachytherapy system used in accelerated partial breast irradiation (APBI). Breast tissue is a heterogeneous tissue in terms of density and composition. Dosimetric calculations of seven APBI patients treated with Axxent were made using a model-based Monte Carlo platform for a number of tissue models and dose reporting methods and compared to TG-43 based plans. A model of the Axxent source, the S700, was created and validated against experimental data. CT scans of the patients were used to create realistic multi-tissue/heterogeneous models with breast tissue segmented using a published technique. Alternative water models were used to isolate the influence of tissue heterogeneity and backscatter on the dose distribution. Dose calculations were performed using Geant4 according to the original treatment parameters. The effect of the Axxent balloon applicator used in APBI which could not be modeled in the CT-based model, was modeled using a novel technique that utilizes CAD-based geometries. These techniques were validated experimentally. Results were calculated using two dose reporting methods, dose to water (Dw,m) and dose to medium (Dm,m), for the heterogeneous simulations. All results were compared against TG-43-based dose distributions and evaluated using dose ratio maps and DVH metrics. Changes in skin and PTV dose were highlighted. All simulated heterogeneous models showed a reduced dose to the DVH metrics that is dependent on the method of dose reporting and patient geometry. Based on a prescription dose of 34 Gy, the average D90 to PTV was reduced by between ~4% and ~40%, depending on the scoring method, compared to the TG-43 result. Peak skin dose is also reduced by 10%-15% due to the absence of backscatter not accounted for in TG-43. The balloon applicator also contributed to the reduced dose. Other ROIs showed a difference depending on the method of dose reporting. TG-186-based calculations produce results that are different from TG-43 for the Axxent source. The differences depend strongly on the method of dose reporting. This study highlights the importance of backscatter to peak skin dose. Tissue heterogeneities, applicator, and patient geometries demonstrate the need for a more robust dose calculation method for low energy brachytherapy sources.

Modeling intersubject variability of bronchial doses for inhaled radon progeny.

PubMed

Hofmann, Werner; Winkler-Heil, Renate; Hussain, Majid

2010-10-01

The main sources of intersubject variations considered in the present study were: (1) size and structure of nasal and oral passages, affecting extrathoracic deposition and, in further consequence, the fraction of the inhaled activity reaching the bronchial region; (2) size and asymmetric branching of the human bronchial airway system, leading to variations of diameters, lengths, branching angles, etc.; (3) respiratory parameters, such as tidal volume, and breathing frequency; (4) mucociliary clearance rates; and (5) thickness of the bronchial epithelium and depth of target cells, related to airway diameters. For the calculation of deposition fractions, retained surface activities, and bronchial doses, parameter values were randomly selected from their corresponding probability density functions, derived from experimental data, by applying Monte Carlo methods. Bronchial doses, expressed in mGy WLM-1, were computed for specific mining conditions, i.e., for defined size distributions, unattached fractions, and physical activities. Resulting bronchial dose distributions could be approximated by lognormal distributions. Geometric standard deviations illustrating intersubject variations ranged from about 2 in the trachea to about 7 in peripheral bronchiolar airways. The major sources of the intersubject variability of bronchial doses for inhaled radon progeny are the asymmetry and variability of the linear airway dimensions, the filtering efficiency of the nasal passages, and the thickness of the bronchial epithelium, while fluctuations of the respiratory parameters and mucociliary clearance rates seem to compensate each other.

Radionuclides in bats using a contaminated pond on the Nevada National Security Site, USA

DOE Office of Scientific and Technical Information (OSTI.GOV)

Warren, Ronald W.; Hall, Derek B.; Greger, Paul D.

In this study, perched groundwater percolating through radionuclide contamination in the E Tunnel Complex on the Nevada National Security Site, formerly the Nevada Test Site, emerges and is stored in a series of ponds making it available to wildlife, including bats. Since many bat species using the ponds are considered sensitive or protected/regulated and little information is available on dose to bats from radioactive water sources, bats were sampled to determine if the dose they were receiving exceeded the United States Department of Energy dose limit of 1.0E-3 Gy/day. Radionuclide concentrations in water, sediment, and flying insects were also measuredmore » as input parameters to the dose rate model and to examine trophic level relationships. The RESRAD-Biota model was used to calculate dose rates to bats using different screening levels. Efficacy of RESRAD-Biota and suggested improvements are discussed. Finally, dose to bats foraging and drinking at these ponds is well below the dose limit set to protect terrestrial biota populations.« less

Radionuclides in bats using a contaminated pond on the Nevada National Security Site, USA

DOE PAGES

Warren, Ronald W.; Hall, Derek B.; Greger, Paul D.

2014-01-03

In this study, perched groundwater percolating through radionuclide contamination in the E Tunnel Complex on the Nevada National Security Site, formerly the Nevada Test Site, emerges and is stored in a series of ponds making it available to wildlife, including bats. Since many bat species using the ponds are considered sensitive or protected/regulated and little information is available on dose to bats from radioactive water sources, bats were sampled to determine if the dose they were receiving exceeded the United States Department of Energy dose limit of 1.0E-3 Gy/day. Radionuclide concentrations in water, sediment, and flying insects were also measuredmore » as input parameters to the dose rate model and to examine trophic level relationships. The RESRAD-Biota model was used to calculate dose rates to bats using different screening levels. Efficacy of RESRAD-Biota and suggested improvements are discussed. Finally, dose to bats foraging and drinking at these ponds is well below the dose limit set to protect terrestrial biota populations.« less

Potential uncertainty reduction in model-averaged benchmark dose estimates informed by an additional dose study.

PubMed

Shao, Kan; Small, Mitchell J

2011-10-01

A methodology is presented for assessing the information value of an additional dosage experiment in existing bioassay studies. The analysis demonstrates the potential reduction in the uncertainty of toxicity metrics derived from expanded studies, providing insights for future studies. Bayesian methods are used to fit alternative dose-response models using Markov chain Monte Carlo (MCMC) simulation for parameter estimation and Bayesian model averaging (BMA) is used to compare and combine the alternative models. BMA predictions for benchmark dose (BMD) are developed, with uncertainty in these predictions used to derive the lower bound BMDL. The MCMC and BMA results provide a basis for a subsequent Monte Carlo analysis that backcasts the dosage where an additional test group would have been most beneficial in reducing the uncertainty in the BMD prediction, along with the magnitude of the expected uncertainty reduction. Uncertainty reductions are measured in terms of reduced interval widths of predicted BMD values and increases in BMDL values that occur as a result of this reduced uncertainty. The methodology is illustrated using two existing data sets for TCDD carcinogenicity, fitted with two alternative dose-response models (logistic and quantal-linear). The example shows that an additional dose at a relatively high value would have been most effective for reducing the uncertainty in BMA BMD estimates, with predicted reductions in the widths of uncertainty intervals of approximately 30%, and expected increases in BMDL values of 5-10%. The results demonstrate that dose selection for studies that subsequently inform dose-response models can benefit from consideration of how these models will be fit, combined, and interpreted. © 2011 Society for Risk Analysis.

Investigating the Effect of Ligand Amount and Injected Therapeutic Activity: A Simulation Study for 177Lu-Labeled PSMA-Targeting Peptides

PubMed Central

Schuchardt, Christiane; Kulkarni, Harshad R.; Shahinfar, Mostafa; Singh, Aviral; Glatting, Gerhard; Baum, Richard P.; Beer, Ambros J.

2016-01-01

In molecular radiotherapy with 177Lu-labeled prostate specific membrane antigen (PSMA) peptides, kidney and/or salivary glands doses limit the activity which can be administered. The aim of this work was to investigate the effect of the ligand amount and injected activity on the tumor-to-normal tissue biologically effective dose (BED) ratio for 177Lu-labeled PSMA peptides. For this retrospective study, a recently developed physiologically based pharmacokinetic model was adapted for PSMA targeting peptides. General physiological parameters were taken from the literature. Individual parameters were fitted to planar gamma camera measurements (177Lu-PSMA I&T) of five patients with metastasizing prostate cancer. Based on the estimated parameters, the pharmacokinetics of tumor, salivary glands, kidneys, total body and red marrow was simulated and time-integrated activity coefficients were calculated for different peptide amounts. Based on these simulations, the absorbed doses and BEDs for normal tissue and tumor were calculated for all activities leading to a maximal tolerable kidney BED of 10 Gy2.5/cycle, a maximal salivary gland absorbed dose of 7.5 Gy/cycle and a maximal red marrow BED of 0.25 Gy15/cycle. The fits yielded coefficients of determination > 0.85, acceptable relative standard errors and low parameter correlations. All estimated parameters were in a physiologically reasonable range. The amounts (for 25−29 nmol) and pertaining activities leading to a maximal tumor dose, considering the defined maximal tolerable doses to organs of risk, were calculated to be 272±253 nmol (452±420 μg) and 7.3±5.1 GBq. Using the actually injected amount (235±155 μg) and the same maximal tolerable doses, the potential improvement for the tumor BED was 1–3 fold. The results suggest that currently given amounts for therapy are in the appropriate order of magnitude for many lesions. However, for lesions with high binding site density or lower perfusion, optimizing the peptide amount and activity might improve the tumor-to-kidney and tumor-to-salivary glands BED ratio considerably. PMID:27611841

Investigating the Effect of Ligand Amount and Injected Therapeutic Activity: A Simulation Study for 177Lu-Labeled PSMA-Targeting Peptides.

PubMed

Kletting, Peter; Schuchardt, Christiane; Kulkarni, Harshad R; Shahinfar, Mostafa; Singh, Aviral; Glatting, Gerhard; Baum, Richard P; Beer, Ambros J

2016-01-01

In molecular radiotherapy with 177Lu-labeled prostate specific membrane antigen (PSMA) peptides, kidney and/or salivary glands doses limit the activity which can be administered. The aim of this work was to investigate the effect of the ligand amount and injected activity on the tumor-to-normal tissue biologically effective dose (BED) ratio for 177Lu-labeled PSMA peptides. For this retrospective study, a recently developed physiologically based pharmacokinetic model was adapted for PSMA targeting peptides. General physiological parameters were taken from the literature. Individual parameters were fitted to planar gamma camera measurements (177Lu-PSMA I&T) of five patients with metastasizing prostate cancer. Based on the estimated parameters, the pharmacokinetics of tumor, salivary glands, kidneys, total body and red marrow was simulated and time-integrated activity coefficients were calculated for different peptide amounts. Based on these simulations, the absorbed doses and BEDs for normal tissue and tumor were calculated for all activities leading to a maximal tolerable kidney BED of 10 Gy2.5/cycle, a maximal salivary gland absorbed dose of 7.5 Gy/cycle and a maximal red marrow BED of 0.25 Gy15/cycle. The fits yielded coefficients of determination > 0.85, acceptable relative standard errors and low parameter correlations. All estimated parameters were in a physiologically reasonable range. The amounts (for 25-29 nmol) and pertaining activities leading to a maximal tumor dose, considering the defined maximal tolerable doses to organs of risk, were calculated to be 272±253 nmol (452±420 μg) and 7.3±5.1 GBq. Using the actually injected amount (235±155 μg) and the same maximal tolerable doses, the potential improvement for the tumor BED was 1-3 fold. The results suggest that currently given amounts for therapy are in the appropriate order of magnitude for many lesions. However, for lesions with high binding site density or lower perfusion, optimizing the peptide amount and activity might improve the tumor-to-kidney and tumor-to-salivary glands BED ratio considerably.

Evaluation of Different Dose-Response Models for High Hydrostatic Pressure Inactivation of Microorganisms

PubMed Central

2017-01-01

Modeling of microbial inactivation by high hydrostatic pressure (HHP) requires a plot of the log microbial count or survival ratio versus time data under a constant pressure and temperature. However, at low pressure and temperature values, very long holding times are needed to obtain measurable inactivation. Since the time has a significant effect on the cost of HHP processing it may be reasonable to fix the time at an appropriate value and quantify the inactivation with respect to pressure. Such a plot is called dose-response curve and it may be more beneficial than the traditional inactivation modeling since short holding times with different pressure values can be selected and used for the modeling of HHP inactivation. For this purpose, 49 dose-response curves (with at least 4 log10 reduction and ≥5 data points including the atmospheric pressure value (P = 0.1 MPa), and with holding time ≤10 min) for HHP inactivation of microorganisms obtained from published studies were fitted with four different models, namely the Discrete model, Shoulder model, Fermi equation, and Weibull model, and the pressure value needed for 5 log10 (P5) inactivation was calculated for all the models above. The Shoulder model and Fermi equation produced exactly the same parameter and P5 values, while the Discrete model produced similar or sometimes the exact same parameter values as the Fermi equation. The Weibull model produced the worst fit (had the lowest adjusted determination coefficient (R2adj) and highest mean square error (MSE) values), while the Fermi equation had the best fit (the highest R2adj and lowest MSE values). Parameters of the models and also P5 values of each model can be useful for the further experimental design of HHP processing and also for the comparison of the pressure resistance of different microorganisms. Further experiments can be done to verify the P5 values at given conditions. The procedure given in this study can also be extended for enzyme inactivation by HHP. PMID:28880255

Objective assessment of gait in xylazine-induced ataxic horses.

PubMed

Nout-Lomas, Y S; Page, K M; Kang, H G; Aanstoos, M E; Greene, H M

2017-05-01

There is poor agreement between observers of equine neurological gait abnormalities using the modified Mayhew grading scale. To stimulate a dose-dependent ataxia in horses through xylazine administration and identify quantifiable relevant gait parameters. Balanced, randomised, 2-way crossover design. Eight horses were assessed before and after administration of xylazine (low dose and high dose). Gait analyses performed before and after xylazine administration included: 1) kinematic data collected on an equine high-speed treadmill (flat and 10% decline) and from accelerometers placed on head and sacrum; and 2) kinetic data collected on a force plate. All horses developed dose-dependent ataxia. Horses developed a dose-dependent increased stride time, stride length, and time of contact (P<0.0001), and a decreased stride frequency (P<0.0002) after administration of xylazine. Although pelvic acceleration increased in the mediolateral direction (P<0.05) in horses walked on the treadmill, this movement decreased when walking over ground after administration of xylazine (P<0.05). Furthermore, centre of pressure and path length indices changed significantly in horses following administration of xylazine (P<0.05). This study examined one breed of horse (Arabian), all of similar height and weight. Accelerometers were attached to skin, not bone; no correction was made for artefacts from skin displacement. The sedative drug effect is of certain duration, limiting the data collection period. Administration of xylazine induced a dose-dependent ataxia in horses and resulted in significant changes of gait parameters, pelvic accelerations, and stabilographic variables, some of which changed in a dose-dependent fashion. Some of the altered gait parameters in this model were probably a result of overall slowing down of the stride cycle secondary to the sedative effect. Continued efforts to discover and evaluate quantifiable gait parameters that are susceptible to change following development of clinical neurological disease in horses is warranted. © 2016 EVJ Ltd.

Patient-specific radiation dose and cancer risk for pediatric chest CT.

PubMed

Li, Xiang; Samei, Ehsan; Segars, W Paul; Sturgeon, Gregory M; Colsher, James G; Frush, Donald P

2011-06-01

To estimate patient-specific radiation dose and cancer risk for pediatric chest computed tomography (CT) and to evaluate factors affecting dose and risk, including patient size, patient age, and scanning parameters. The institutional review board approved this study and waived informed consent. This study was HIPAA compliant. The study included 30 patients (0-16 years old), for whom full-body computer models were recently created from clinical CT data. A validated Monte Carlo program was used to estimate organ dose from eight chest protocols, representing clinically relevant combinations of bow tie filter, collimation, pitch, and tube potential. Organ dose was used to calculate effective dose and risk index (an index of total cancer incidence risk). The dose and risk estimates before and after normalization by volume-weighted CT dose index (CTDI(vol)) or dose-length product (DLP) were correlated with patient size and age. The effect of each scanning parameter was studied. Organ dose normalized by tube current-time product or CTDI(vol) decreased exponentially with increasing average chest diameter. Effective dose normalized by tube current-time product or DLP decreased exponentially with increasing chest diameter. Chest diameter was a stronger predictor of dose than weight and total scan length. Risk index normalized by tube current-time product or DLP decreased exponentially with both chest diameter and age. When normalized by DLP, effective dose and risk index were independent of collimation, pitch, and tube potential (<10% variation). The correlations of dose and risk with patient size and age can be used to estimate patient-specific dose and risk. They can further guide the design and optimization of pediatric chest CT protocols. http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.11101900/-/DC1. RSNA, 2011

Dose specification and quality assurance of RTOG protocol 95-17; a cooperative group study of 192Ir breast implants as sole therapy

PubMed Central

Ibbott, Geoffrey S.; Hanson, W.F.; Martin, Elizabeth; Kuske, Robert R.; Arthur, Douglas; Rabinovitch, Rachel; White, Julia; Wilenzick, Raymond M.; Harris, Irene; Tailor, Ramesh C.

2007-01-01

Purpose RTOG protocol 95-17 was a phase I/II trial to evaluate multi-catheter brachytherapy as the sole method of adjuvant breast radiotherapy for stage I/II breast carcinoma following breast conserving surgery. Low or high dose rate sources were allowed. Dose prescription and treatment evaluation were based on recommendations in ICRU Report 58, and included the parameters mean central dose (MCD), average peripheral dose, dose homogeneity index (DHI), and the dimensions of the low and high dose regions. Methods and Materials Three levels of quality assurance were implemented: (1) Credentialing of institutions was required prior to entering patients onto the study. (2) Rapid review of each treatment plan was conducted prior to treatment, and (3) Retrospective review was performed by the Radiological Physics Center in conjunction with the study chairman and RTOG dosimetry staff. Results Credentialing focused on the accuracy of dose calculation algorithm and compliance with protocol guidelines. Rapid review was designed to identify and correct deviations from the protocol prior to treatment. The retrospective review involved recalculation of dosimetry parameters and review of dose distributions to evaluate the treatment. Specifying both central and peripheral doses resulted in uniform dose distributions, with a mean dose homogeneity index of 0.83 ±0.06. Conclusions Vigorous quality assurance resulted in a high-quality study with few deviations; only 4 of 100 patients were judged as minor variations from protocol and no patient was judged a major deviation. This study should be considered a model for quality assurance of future trials. PMID:18035213

A model to describe potential effects of chemotherapy on critical radiobiological treatments

NASA Astrophysics Data System (ADS)

Rodríguez-Pérez, D.; Desco, M. M.; Antoranz, J. C.

2016-08-01

Although chemo- and radiotherapy can annihilate tumors on their own. they are also used in coadjuvancy: improving local effects of radiotherapy using chemotherapy as a radiosensit.izer. The effects of radiotherapy are well described by current radiobiological models. The goal of this work is to describe a discrete radiotherapy model, that has been previously used describe high radiation dose response as well as unusual radio-responses of some types of tumors (e.g. prostate cancer), to obtain a model of chemo+radiotherapy that can describe how the outcome of their combination is a more efficient removal of the tumor. Our hypothesis is that, although both treatments haven different mechanisms, both affect similar key points of cell metabolism and regulation, that lead to cellular death. Hence, we will consider a discrete model where chemotherapy may affect a fraction of the same targets destroyed by radiotherapy. Although radiotherapy reaches all cells equally, chemotherapy diffuses through a tumor attaining lower concentration in its center and higher in its surface. With our simulations we study the enhanced effect of combined therapy treatment and how it depends on the tissue critical parameters (the parameters of the lion-extensive radiobiological model), the number of “targets” aimed at by chemotherapy, and the concentration and diffusion rate of the drug inside the tumor. The results show that an equivalent, cliemo-radio-dose can be computed that allows the prediction of the lower radiation dose that causes the same effect than a radio-only treatment.

Biological profiling and dose-response modeling tools ...

EPA Pesticide Factsheets

Through its ToxCast project, the U.S. EPA has developed a battery of in vitro high throughput screening (HTS) assays designed to assess the potential toxicity of environmental chemicals. At present, over 1800 chemicals have been tested in up to 600 assays, yielding a large number of concentration-response data sets. Standard processing of these data sets involves finding a best fitting mathematical model and set of model parameters that specify this model. The model parameters include quantities such as the half-maximal activity concentration (or “AC50”) that have biological significance and can be used to inform the efficacy or potency of a given chemical with respect to a given assay. All of this data is processed and stored in an online-accessible database and website: http://actor.epa.gov/dashboard2. Results from these in vitro assays are used in a multitude of ways. New pathways and targets can be identified and incorporated into new or existing adverse outcome pathways (AOPs). Pharmacokinetic models such as those implemented EPA’s HTTK R package can be used to translate an in vitro concentration into an in vivo dose; i.e., one can predict the oral equivalent dose that might be expected to activate a specific biological pathway. Such predicted values can then be compared with estimated actual human exposures prioritize chemicals for further testing.Any quantitative examination should be accompanied by estimation of uncertainty. We are developing met

Dose Titration Algorithm Tuning (DTAT) should supersede 'the' Maximum Tolerated Dose (MTD) in oncology dose-finding trials.

PubMed

Norris, David C

2017-01-01

Background . Absent adaptive, individualized dose-finding in early-phase oncology trials, subsequent 'confirmatory' Phase III trials risk suboptimal dosing, with resulting loss of statistical power and reduced probability of technical success for the investigational therapy. While progress has been made toward explicitly adaptive dose-finding and quantitative modeling of dose-response relationships, most such work continues to be organized around a concept of 'the' maximum tolerated dose (MTD). The purpose of this paper is to demonstrate concretely how the aim of early-phase trials might be conceived, not as 'dose-finding', but as dose titration algorithm (DTA) -finding. Methods. A Phase I dosing study is simulated, for a notional cytotoxic chemotherapy drug, with neutropenia constituting the critical dose-limiting toxicity. The drug's population pharmacokinetics and myelosuppression dynamics are simulated using published parameter estimates for docetaxel. The amenability of this model to linearization is explored empirically. The properties of a simple DTA targeting neutrophil nadir of 500 cells/mm 3 using a Newton-Raphson heuristic are explored through simulation in 25 simulated study subjects. Results. Individual-level myelosuppression dynamics in the simulation model approximately linearize under simple transformations of neutrophil concentration and drug dose. The simulated dose titration exhibits largely satisfactory convergence, with great variance in individualized optimal dosing. Some titration courses exhibit overshooting. Conclusions. The large inter-individual variability in simulated optimal dosing underscores the need to replace 'the' MTD with an individualized concept of MTD i . To illustrate this principle, the simplest possible DTA capable of realizing such a concept is demonstrated. Qualitative phenomena observed in this demonstration support discussion of the notion of tuning such algorithms. Although here illustrated specifically in relation to cytotoxic chemotherapy, the DTAT principle appears similarly applicable to Phase I studies of cancer immunotherapy and molecularly targeted agents.

A model for the relative biological effectiveness of protons: the tissue specific parameter α/β of photons is a predictor for the sensitivity to LET changes.

PubMed

Wedenberg, Minna; Lind, Bengt K; Hårdemark, Björn

2013-04-01

The biological effects of particles are often expressed in relation to that of photons through the concept of relative biological effectiveness, RBE. In proton radiotherapy, a constant RBE of 1.1 is usually assumed. However, there is experimental evidence that RBE depends on various factors. The aim of this study is to develop a model to predict the RBE based on linear energy transfer (LET), dose, and the tissue specific parameter α/β of the linear-quadratic model for the reference radiation. Moreover, the model should capture the basic features of the RBE using a minimum of assumptions, each supported by experimental data. The α and β parameters for protons were studied with respect to their dependence on LET. An RBE model was proposed where the dependence of LET is affected by the (α/β)phot ratio of photons. Published cell survival data with a range of well-defined LETs and cell types were selected for model evaluation rendering a total of 10 cell lines and 24 RBE values. A statistically significant relation was found between α for protons and LET. Moreover, the strength of that relation varied significantly with (α/β)phot. In contrast, no significant relation between β and LET was found. On the whole, the resulting RBE model provided a significantly improved fit (p-value < 0.01) to the experimental data compared to the standard constant RBE. By accounting for the α/β ratio of photons, clearer trends between RBE and LET of protons were found, and our results suggest that late responding tissues are more sensitive to LET changes than early responding tissues and most tumors. An advantage with the proposed RBE model in optimization and evaluation of treatment plans is that it only requires dose, LET, and (α/β)phot as input parameters. Hence, no proton specific biological parameters are needed.

LDR vs. HDR brachytherapy for localized prostate cancer: the view from radiobiological models.

PubMed

King, Christopher R

2002-01-01

Permanent LDR brachytherapy and temporary HDR brachytherapy are competitive techniques for clinically localized prostate radiotherapy. Although a randomized trial will likely never be conducted comparing these two forms of brachytherapy, a comparative radiobiological modeling analysis proves useful in understanding some of their intrinsic differences, several of which could be exploited to improve outcomes. Radiobiological models based upon the linear quadratic equations are presented for fractionated external beam, fractionated (192)Ir HDR brachytherapy, and (125)I and (103)Pd LDR brachytherapy. These models incorporate the dose heterogeneities present in brachytherapy based upon patient-derived dose volume histograms (DVH) as well as tumor doubling times and repair kinetics. Radiobiological parameters are normalized to correspond to three accepted clinical risk factors based upon T-stage, PSA, and Gleason score to compare models with clinical series. Tumor control probabilities (TCP) for LDR and HDR brachytherapy (as monotherapy or combined with external beam) are compared with clinical bNED survival rates. Predictions are made for dose escalation with HDR brachytherapy regimens. Model predictions for dose escalation with external beam agree with clinical data and validate the models and their underlying assumptions. Both LDR and HDR brachytherapy achieve superior tumor control when compared with external beam at conventional doses (<70 Gy), but similar to results from dose escalation series. LDR brachytherapy as boost achieves superior tumor control than when used as monotherapy. Stage for stage, both LDR and current HDR regimens achieve similar tumor control rates, in agreement with current clinical data. HDR monotherapy with large-dose fraction sizes might achieve superior tumor control compared with LDR, especially if prostate cancer possesses a high sensitivity to dose fractionation (i.e., if the alpha/beta ratio is low). Radiobiological models support the current clinical evidence for equivalent outcomes in localized prostate cancer with either LDR or HDR brachytherapy using current dose regimens. However, HDR brachytherapy dose escalation regimens might be able to achieve higher biologically effective doses of irradiation in comparison to LDR, and hence improved outcomes. This advantage over LDR would be amplified should prostate cancer possess a high sensitivity to dose fractionation (i.e., a low alpha/beta ratio) as the current evidence suggests.

SU-E-T-109: An Investigation of Including Variable Relative Biological Effectiveness in Intensity Modulated Proton Therapy Planning Optimization for Head and Neck Cancer Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cao, W; Zaghian, M; Lim, G

2015-06-15

Purpose: The current practice of considering the relative biological effectiveness (RBE) of protons in intensity modulated proton therapy (IMPT) planning is to use a generic RBE value of 1.1. However, RBE is indeed a variable depending on the dose per fraction, the linear energy transfer, tissue parameters, etc. In this study, we investigate the impact of using variable RBE based optimization (vRBE-OPT) on IMPT dose distributions compared by conventional fixed RBE based optimization (fRBE-OPT). Methods: Proton plans of three head and neck cancer patients were included for our study. In order to calculate variable RBE, tissue specific parameters were obtainedmore » from the literature and dose averaged LET values were calculated by Monte Carlo simulations. Biological effects were calculated using the linear quadratic model and they were utilized in the variable RBE based optimization. We used a Polak-Ribiere conjugate gradient algorithm to solve the model. In fixed RBE based optimization, we used conventional physical dose optimization to optimize doses weighted by 1.1. IMPT plans for each patient were optimized by both methods (vRBE-OPT and fRBE-OPT). Both variable and fixed RBE weighted dose distributions were calculated for both methods and compared by dosimetric measures. Results: The variable RBE weighted dose distributions were more homogenous within the targets, compared with the fixed RBE weighted dose distributions for the plans created by vRBE-OPT. We observed that there were noticeable deviations between variable and fixed RBE weighted dose distributions if the plan were optimized by fRBE-OPT. For organs at risk sparing, dose distributions from both methods were comparable. Conclusion: Biological dose based optimization rather than conventional physical dose based optimization in IMPT planning may bring benefit in improved tumor control when evaluating biologically equivalent dose, without sacrificing OAR sparing, for head and neck cancer patients. The research is supported in part by National Institutes of Health Grant No. 2U19CA021239-35.« less

Monte Carlo dose calculations of beta-emitting sources for intravascular brachytherapy: a comparison between EGS4, EGSnrc, and MCNP.

PubMed

Wang, R; Li, X A

2001-02-01

The dose parameters for the beta-particle emitting 90Sr/90Y source for intravascular brachytherapy (IVBT) have been calculated by different investigators. At a distant distance from the source, noticeable differences are seen in these parameters calculated using different Monte Carlo codes. The purpose of this work is to quantify as well as to understand these differences. We have compared a series of calculations using an EGS4, an EGSnrc, and the MCNP Monte Carlo codes. Data calculated and compared include the depth dose curve for a broad parallel beam of electrons, and radial dose distributions for point electron sources (monoenergetic or polyenergetic) and for a real 90Sr/90Y source. For the 90Sr/90Y source, the doses at the reference position (2 mm radial distance) calculated by the three code agree within 2%. However, the differences between the dose calculated by the three codes can be over 20% in the radial distance range interested in IVBT. The difference increases with radial distance from source, and reaches 30% at the tail of dose curve. These differences may be partially attributed to the different multiple scattering theories and Monte Carlo models for electron transport adopted in these three codes. Doses calculated by the EGSnrc code are more accurate than those by the EGS4. The two calculations agree within 5% for radial distance <6 mm.

Analytical model for out-of-field dose in photon craniospinal irradiation

NASA Astrophysics Data System (ADS)

Taddei, Phillip J.; Jalbout, Wassim; Howell, Rebecca M.; Khater, Nabil; Geara, Fady; Homann, Kenneth; Newhauser, Wayne D.

2013-11-01

The prediction of late effects after radiotherapy in organs outside a treatment field requires accurate estimations of out-of-field dose. However, out-of-field dose is not calculated accurately by commercial treatment planning systems (TPSs). The purpose of this study was to develop and test an analytical model for out-of-field dose during craniospinal irradiation (CSI) from photon beams produced by a linear accelerator. In two separate evaluations of the model, we measured absorbed dose for a 6 MV CSI using thermoluminescent dosimeters placed throughout an anthropomorphic phantom and fit the measured data to an analytical model of absorbed dose versus distance outside of the composite field edge. These measurements were performed in two separate clinics—the University of Texas MD Anderson Cancer Center (MD Anderson) and the American University of Beirut Medical Center (AUBMC)—using the same phantom but different linear accelerators and TPSs commissioned for patient treatments. The measurement at AUBMC also included in-field locations. Measured dose values were compared to those predicted by TPSs and parameters were fit to the model in each setting. In each clinic, 95% of the measured data were contained within a factor of 0.2 and one root mean square deviation of the model-based values. The root mean square deviations of the mathematical model were 0.91 cGy Gy-1 and 1.67 cGy Gy-1 in the MD Anderson and AUBMC clinics, respectively. The TPS predictions agreed poorly with measurements in regions of sharp dose gradient, e.g., near the field edge. At distances greater than 1 cm from the field edge, the TPS underestimated the dose by an average of 14% ± 24% and 44% ± 19% in the MD Anderson and AUBMC clinics, respectively. The in-field measured dose values of the measurement at AUBMC matched the dose values calculated by the TPS to within 2%. Dose algorithms in TPSs systematically underestimated the actual out-of-field dose. Therefore, it is important to use an improved model based on measurements when estimating out-of-field dose. The model proposed in this study performed well for this purpose in two clinics and may be applicable in other clinics with similar treatment field configurations.

Applying a Hypoxia-Incorporating TCP Model to Experimental Data on Rat Sarcoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ruggieri, Ruggero, E-mail: ruggieri.ruggero@gmail.com; Stavreva, Nadejda; Naccarato, Stefania

2012-08-01

Purpose: To verify whether a tumor control probability (TCP) model which mechanistically incorporates acute and chronic hypoxia is able to describe animal in vivo dose-response data, exhibiting tumor reoxygenation. Methods and Materials: The investigated TCP model accounts for tumor repopulation, reoxygenation of chronic hypoxia, and fluctuating oxygenation of acute hypoxia. Using the maximum likelihood method, the model is fitted to Fischer-Moulder data on Wag/Rij rats, inoculated with rat rhabdomyosarcoma BA1112, and irradiated in vivo using different fractionation schemes. This data set is chosen because two of the experimental dose-response curves exhibit an inverse dose behavior, which is interpreted as duemore » to reoxygenation. The tested TCP model is complex, and therefore, in vivo cell survival data on the same BA1112 cell line from Reinhold were added to Fischer-Moulder data and fitted simultaneously with a corresponding cell survival function. Results: The obtained fit to the combined Fischer-Moulder-Reinhold data was statistically acceptable. The best-fit values of the model parameters for which information exists were in the range of published values. The cell survival curves of well-oxygenated and hypoxic cells, computed using the best-fit values of the radiosensitivities and the initial number of clonogens, were in good agreement with the corresponding in vitro and in situ experiments of Reinhold. The best-fit values of most of the hypoxia-related parameters were used to recompute the TCP for non-small cell lung cancer patients as a function of the number of fractions, TCP(n). Conclusions: The investigated TCP model adequately describes animal in vivo data exhibiting tumor reoxygenation. The TCP(n) curve computed for non-small cell lung cancer patients with the best-fit values of most of the hypoxia-related parameters confirms previously obtained abrupt reduction in TCP for n < 10, thus warning against the adoption of severely hypofractionated schedules.« less

Basic PK/PD principles of drug effects in circular/proliferative systems for disease modelling.

PubMed

Jacqmin, Philippe; McFadyen, Lynn; Wade, Janet R

2010-04-01

Disease progression modelling can provide information about the time course and outcome of pharmacological intervention on the disease. The basic PK/PD principles of proliferative and circular systems within the context of modelling disease progression and the effect of treatment thereupon are illustrated with the goal to better understand/predict eventual clinical outcome. Circular/proliferative systems can be very complex. To facilitate the understanding of how a dosing regimen can be defined in such systems we have shown the derivation of a system parameter named the Reproduction Minimum Inhibitory Concentration (RMIC) which represents the critical concentration at which the system switches from growth to extinction. The RMIC depends on two parameters (RMIC = (R(0) - 1) x IC(50)): the basic reproductive ratio (R(0)) a fundamental parameter of the circular/proliferative system that represents the number of offspring produced by one replicating species during its lifespan, and the IC(50), the potency of the drug to inhibit the proliferation of the system. The RMIC is constant for a given system and a given drug and represents the lowest concentration that needs to be achieved for eradication of the system. When exposure is higher than the RMIC, success can be expected in the long term. Time varying inhibition of replicating species proliferation is a natural consequence of the time varying inhibitor drug concentrations and when combined with the dynamics of the circular/proliferative system makes it difficult to predict the eventual outcome. Time varying inhibition of proliferative/circular systems can be handled by calculating the equivalent effective constant concentration (ECC), the constant plasma concentration that would give rise to the average inhibition at steady state. When ECC is higher than the RMIC, eradication of the system can be expected. In addition, it is shown that scenarios that have the same steady state ECC whatever the dose, dosage schedule or PK parameters have also the same average R (0) in the presence of the inhibitor (i.e. R (0-INH)) and therefore lead to the same outcome. This allows predicting equivalent active doses and dosing schedules in circular and proliferative systems when the IC(50) and pharmacokinetic characteristics of the drugs are known. The results from the simulations performed demonstrate that, for a given system (defined by its RMIC), treatment success depends mainly on the pharmacokinetic characteristics of the drug and the dosing schedule.

Pharmacodynamics of a New Streptogramin, XRP 2868, in Murine Thigh and Lung Infection Models

PubMed Central

Andes, D.; Craig, W. A.

2006-01-01

XRP 2868 is a new streptogramin antibiotic with broad-spectrum activity against gram-positive cocci. We used the neutropenic murine thigh and lung infection models to characterize the time course of antimicrobial activity of XRP 2868 and determine which pharmacokinetic/pharmacodynamic (PK/PD) parameter and magnitude best correlated with efficacy. Serum levels following four two- to fourfold-escalating single-dose levels of XRP 2868 were measured by liquid chromatography mass spectrometry assay. In vivo postantibiotic effects (PAEs) were determined after doses of 2.5, 10, and 40 mg/kg. Mice had 106.8 to 108.4 CFU/thigh of strains of Streptococcus pneumoniae ATCC 10813 or Staphylococcus aureus ATCC 29213 at the start of therapy when treated for 24 h with 2.5 to 640 mg/kg/day of XRP 2868 fractionated for 3-, 6-, 12-, and 24-h dosing regimens. Nonlinear regression analysis was used to determine which PK/PD parameter best correlated with CFU/thigh at 24 h. Pharmacokinetic studies exhibited peak dose values of 0.03 to 0.07, area under the concentration-time curve (AUC) dose values of 0.02 to 0.07, and half-lives of 0.35 to 1.27 h. XRP 2868 produced in vivo PAEs of 0.5 to 3.4 h with S. pneumoniae strain ATCC 10813 and −1.5 to 10.7 h with S. aureus strain ATCC 29213. The 24-h AUC/MIC was the PK/PD parameter that best correlated with efficacy. In subsequent studies, we used the neutropenic murine thigh infection model to determine if the magnitude of the AUC/MIC needed for the efficacy of XRP 2868 varied among pathogens (including resistant strains). Mice had 106.1 to 107.8 CFU/thigh of four isolates of S. aureus (three methicillin-susceptible and one methicillin-resistant strain) and nine isolates of S. pneumoniae (one penicillin-susceptible, four penicillin-intermediate, and four penicillin-resistant strains) when treated for 24 h with 0.16 to 640 mg/kg of XRP 2868 every 6 h. A sigmoid dose-response model was used to estimate the doses (mg/kg/24 h) required to achieve a net bacteriostatic affect over 24 h. MICs ranged from 0.06 to 0.25 μg/ml. The 24-h AUC/MICs for each static dose (20.7 to 252 mg/kg/day) varied from 3 to 70. Mean 24-h AUC/MICs ± standard deviations (SDs) for S. pneumoniae and S. aureus isolates were 14 ± 10 and 31 ± 16, respectively. Beta-lactam and macrolide resistance did not alter the magnitude of AUC/MIC required for efficacy. PMID:16377693

Pharmacodynamics of a new streptogramin, XRP 2868, in murine thigh and lung infection models.

PubMed

Andes, D; Craig, W A

2006-01-01

XRP 2868 is a new streptogramin antibiotic with broad-spectrum activity against gram-positive cocci. We used the neutropenic murine thigh and lung infection models to characterize the time course of antimicrobial activity of XRP 2868 and determine which pharmacokinetic/pharmacodynamic (PK/PD) parameter and magnitude best correlated with efficacy. Serum levels following four two- to fourfold-escalating single-dose levels of XRP 2868 were measured by liquid chromatography mass spectrometry assay. In vivo postantibiotic effects (PAEs) were determined after doses of 2.5, 10, and 40 mg/kg. Mice had 10(6.8) to 10(8.4) CFU/thigh of strains of Streptococcus pneumoniae ATCC 10813 or Staphylococcus aureus ATCC 29213 at the start of therapy when treated for 24 h with 2.5 to 640 mg/kg/day of XRP 2868 fractionated for 3-, 6-, 12-, and 24-h dosing regimens. Nonlinear regression analysis was used to determine which PK/PD parameter best correlated with CFU/thigh at 24 h. Pharmacokinetic studies exhibited peak dose values of 0.03 to 0.07, area under the concentration-time curve (AUC) dose values of 0.02 to 0.07, and half-lives of 0.35 to 1.27 h. XRP 2868 produced in vivo PAEs of 0.5 to 3.4 h with S. pneumoniae strain ATCC 10813 and -1.5 to 10.7 h with S. aureus strain ATCC 29213. The 24-h AUC/MIC was the PK/PD parameter that best correlated with efficacy. In subsequent studies, we used the neutropenic murine thigh infection model to determine if the magnitude of the AUC/MIC needed for the efficacy of XRP 2868 varied among pathogens (including resistant strains). Mice had 10(6.1) to 10(7.8) CFU/thigh of four isolates of S. aureus (three methicillin-susceptible and one methicillin-resistant strain) and nine isolates of S. pneumoniae (one penicillin-susceptible, four penicillin-intermediate, and four penicillin-resistant strains) when treated for 24 h with 0.16 to 640 mg/kg of XRP 2868 every 6 h. A sigmoid dose-response model was used to estimate the doses (mg/kg/24 h) required to achieve a net bacteriostatic affect over 24 h. MICs ranged from 0.06 to 0.25 microg/ml. The 24-h AUC/MICs for each static dose (20.7 to 252 mg/kg/day) varied from 3 to 70. Mean 24-h AUC/MICs +/- standard deviations (SDs) for S. pneumoniae and S. aureus isolates were 14 +/- 10 and 31 +/- 16, respectively. Beta-lactam and macrolide resistance did not alter the magnitude of AUC/MIC required for efficacy.

A Monte Carlo model for mean glandular dose evaluation in spot compression mammography.

PubMed

Sarno, Antonio; Dance, David R; van Engen, Ruben E; Young, Kenneth C; Russo, Paolo; Di Lillo, Francesca; Mettivier, Giovanni; Bliznakova, Kristina; Fei, Baowei; Sechopoulos, Ioannis

2017-07-01

To characterize the dependence of normalized glandular dose (DgN) on various breast model and image acquisition parameters during spot compression mammography and other partial breast irradiation conditions, and evaluate alternative previously proposed dose-related metrics for this breast imaging modality. Using Monte Carlo simulations with both simple homogeneous breast models and patient-specific breasts, three different dose-related metrics for spot compression mammography were compared: the standard DgN, the normalized glandular dose to only the directly irradiated portion of the breast (DgNv), and the DgN obtained by the product of the DgN for full field irradiation and the ratio of the mid-height area of the irradiated breast to the entire breast area (DgN M ). How these metrics vary with field-of-view size, spot area thickness, x-ray energy, spot area and position, breast shape and size, and system geometry was characterized for the simple breast model and a comparison of the simple model results to those with patient-specific breasts was also performed. The DgN in spot compression mammography can vary considerably with breast area. However, the difference in breast thickness between the spot compressed area and the uncompressed area does not introduce a variation in DgN. As long as the spot compressed area is completely within the breast area and only the compressed breast portion is directly irradiated, its position and size does not introduce a variation in DgN for the homogeneous breast model. As expected, DgN is lower than DgNv for all partial breast irradiation areas, especially when considering spot compression areas within the clinically used range. DgN M underestimates DgN by 6.7% for a W/Rh spectrum at 28 kVp and for a 9 × 9 cm 2 compression paddle. As part of the development of a new breast dosimetry model, a task undertaken by the American Association of Physicists in Medicine and the European Federation of Organizations of Medical Physics, these results provide insight on how DgN and two alternative dose metrics behave with various image acquisition and model parameters. © 2017 American Association of Physicists in Medicine.

Limitations of current dosimetry for intracavitary accelerated partial breast irradiation with high dose rate iridium-192 and electronic brachytherapy sources

NASA Astrophysics Data System (ADS)

Raffi, Julie A.

Intracavitary accelerated partial breast irradiation (APBI) is a method of treating early stage breast cancer using a high dose rate (HDR) brachytherapy source positioned within the lumpectomy cavity. An expandable applicator stretches the surrounding tissue into a roughly spherical or elliptical shape and the dose is prescribed to 1 cm beyond the edge of the cavity. Currently, dosimetry for these treatments is most often performed using the American Association of Physicists in Medicine Task Group No. 43 (TG-43) formalism. The TG-43 dose-rate equation determines the dose delivered to a homogeneous water medium by scaling the measured source strength with standardized parameters that describe the radial and angular features of the dose distribution. Since TG-43 parameters for each source model are measured or calculated in a homogeneous water medium, the dosimetric effects of the patient's dimensions and composition are not accounted for. Therefore, the accuracy of TG-43 calculations for intracavitary APBI is limited by the presence of inhomogeneities in and around the target volume. Specifically, the breast is smaller than the phantoms used to determine TG-43 parameters and is surrounded by air, ribs, and lung tissue. Also, the composition of the breast tissue itself can affect the dose distribution. This dissertation is focused on investigating the limitations of TG-43 dosimetry for intracavitary APBI for two HDR brachytherapy sources: the VariSource TM VS2000 192Ir source and the AxxentRTM miniature x-ray source. The dose for various conditions was determined using thermoluminescent dosimeters (TLDs) and Monte Carlo (MC) calculations. Accurate measurements and calculations were achieved through the implementation of new measurement and simulation techniques and a novel breast phantom was developed to enable anthropomorphic phantom measurements. Measured and calculated doses for phantom and patient geometries were compared with TG-43 calculated doses to illustrate the limitations of TG-43 dosimetry for intracavitary APBI. TG-43 dose calculations overestimate the dose for regions approaching the lung and breast surface and underestimate the dose for regions in and beyond less-attenuating media such as lung tissue, and for lower energies, breast tissue as well.

Role of Radiation Dose in the Risk of Secondary Leukemia After a Solid Tumor in Childhood Treated Between 1980 and 1999

DOE Office of Scientific and Technical Information (OSTI.GOV)

Allard, Aurore; Haddy, Nadia; Le Deley, Marie-Cecile

2010-12-01

Purpose: The purpose of this study was to estimate the risk of secondary leukemia as a function of radiation dose, taking into account heterogeneous radiation dose distribution. Methods and Materials: We analyzed a case-control study that investigated the risk of secondary leukemia and myelodysplasia after a solid tumor in childhood; it included 61 patients with leukemia matched with 196 controls. Complete clinical, chemotherapy, and radiotherapy histories were recorded for each patient in the study. Average radiation dose to each of seven bone marrow components for each patient was incorporated into the models, and corresponding risks were summed up. Conditional maximummore » likelihood methods were used to estimate risk parameters. Results: Whatever the model, we failed to evidence a role for the radiation dose to active bone marrow in the risk of later leukemia, myelodysplasia, or myeloproliferative syndrome, when adjusting for epipodophyllotoxin and anthracycline doses. This result was confirmed when fitting models that included total dose of radiation delivered during radiotherapy, when fitting models taking into account dose per fraction, and when restricting the analysis to acute myeloid leukemia. Conclusions: In contrast to results found in similar studies that included children treated before the use of epipodophyllotoxins, this study failed to show a role for radiotherapy in the risk of secondary leukemia after childhood cancer in children treated between 1980 and 1999. This discrepancy was probably due to a competitive mechanism between these two carcinogens.« less

Field size dependent mapping of medical linear accelerator radiation leakage

NASA Astrophysics Data System (ADS)

Vũ Bezin, Jérémi; Veres, Attila; Lefkopoulos, Dimitri; Chavaudra, Jean; Deutsch, Eric; de Vathaire, Florent; Diallo, Ibrahima

2015-03-01

The purpose of this study was to investigate the suitability of a graphics library based model for the assessment of linear accelerator radiation leakage. Transmission through the shielding elements was evaluated using the build-up factor corrected exponential attenuation law and the contribution from the electron guide was estimated using the approximation of a linear isotropic radioactive source. Model parameters were estimated by a fitting series of thermoluminescent dosimeter leakage measurements, achieved up to 100 cm from the beam central axis along three directions. The distribution of leakage data at the patient plane reflected the architecture of the shielding elements. Thus, the maximum leakage dose was found under the collimator when only one jaw shielded the primary beam and was about 0.08% of the dose at isocentre. Overall, we observe that the main contributor to leakage dose according to our model was the electron beam guide. Concerning the discrepancies between the measurements used to calibrate the model and the calculations from the model, the average difference was about 7%. Finally, graphics library modelling is a readily and suitable way to estimate leakage dose distribution on a personal computer. Such data could be useful for dosimetric evaluations in late effect studies.

Influence of hyperforin on the morphology of internal organs and biochemical parameters, in experimental model in mice.

PubMed

Negreş, Simona; Scutari, Corina; Ionică, Floriana Elvira; Gonciar, Veaceslav; Velescu, Bruno Ştefan; Şeremet, Oana Cristina; Zanfirescu, Anca; Zbârcea, Cristina Elena; Ştefănescu, Emil; Ciobotaru, Emilia; ChiriŢă, Cornel

2016-01-01

Hyperforin (HY) is used to treat depression and skin irritation and has been shown a number of pharmacological activities. The literature does no cite data on changes that may occur in the body after HY intake (ethylene diammonium salt - EDS) in long-term administration. From this point of view, the present work is a key to determining the pharmacotoxicological profile of the HY-EDS, in long-term administration. In present research, the influence of toxic doses of HY-EDS was investigated on the biochemical serum parameters and the histopathological changes in internal organs on the experimental mice model. For acute toxicity determination, the HY-EDS was tested in doses of 2000-5000 mg÷kg, administered once per day orally. For subacute toxicity, the HY-EDS was tested in three groups of mice, in doses of 50, 75 and 100 mg÷kg÷day, administered once daily, for 28 consecutive days. As concern acute toxicity, a lethal effect has not occurred at any of the two tested doses and HY-EDS was classified as Class V toxic: median lethal dose (LD50) >5000 mg÷kg, p.o. After 14 days of follow-up in acute toxicity, the experimental results showed a statistically significant increase of aspartate transaminase (AST) and alanine transaminase (ALT), compared to the control group. There were no changes in creatinine and serum glucose compared to the control group. After the administration of repeated doses, it was observed an increase of serum transaminases and alkaline phosphatase. Histological examination revealed that the liver injuries were in an initial stage, making them reversible in case of HY-EDS treatment discontinuation. There was no evidence of kidney damage to any of the doses of HY-EDS.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Senova, Suhan; Service de Neurochirurgie, Centre Hospitalier Universitaire; Inserm, U955, Equipe 14, Université Paris Est, Faculté de médecine, Créteil

Purpose: To analyze the relationship between dosimetric characteristics and symptoms related to trigeminal neuropathy (TN) observed after radiosurgery (RS) for vestibular schwannomas (VS); to propose guidelines to optimize planification in VS RS regarding TN preservation; and to detail the mechanism of TN impairment after VS RS. Methods and Materials: One hundred seventy-nine patients treated between 2011 and 2013 for VS RS and without trigeminal impairment before RS were included in a retrospective study. Univariate and multivariate analyses were performed to determine predictors of TN among characteristics of the patients, the dosimetry, and the VS. Results: There were 20 Koos grade 1,more » 99 grade 2, 57 grade 3, and 3 grade 4. Fourteen patients (7.8%) presented a transitory or permanent TN. Between the patients with and without TN after VS RS, there was no significant difference regarding dosimetry or VS volume itself. Significant differences (univariate analysis P<.05, Mann-Whitney test) were found for parameters related to the cisternal portion of the trigeminal nerve: total integrated dose, maximum dose, mean dose, volume of the Vth nerve (Vol{sub v}), and volume of the Vth nerve receiving at least 11 Gy (Vol{sub Vcist>11Gy}), but also for maximal dose to the Vth nerve nucleus and intra-axial portion (Dose max{sub Vax}). After multivariate analysis, the best model predicting TN included Vol{sub Vcist>11Gy} (P=.0045), Dose max{sub Vax} (P=.0006), and Vol{sub v} (P=.0058). The negative predictive value of this model was 97%. Conclusions: The parameters Vol{sub Vcist>11Gy}, Dose max{sub Vax}, and Vol{sub v} should be checked when designing dosimetry for VS RS.« less

A survival model for fractionated radiotherapy with an application to prostate cancer

NASA Astrophysics Data System (ADS)

Zaider, Marco; Zelefsky, Michael J.; Hanin, Leonid G.; Tsodikov, Alexander D.; Yakovlev, Andrei Y.; Leibel, Steven A.

2001-10-01

This paper explores the applicability of a mechanistic survival model, based on the distribution of clonogens surviving a course of fractionated radiation therapy, to clinical data on patients with prostate cancer. The study was carried out using data on 1100 patients with clinically localized prostate cancer who were treated with three-dimensional conformal radiation therapy. The patients were stratified by radiation dose (group 1: <67.5 Gy; group 2: 67.5-72.5 Gy; group 3: 72.5-77.5 Gy; group 4: 77.5-87.5 Gy) and prognosis category (favourable, intermediate and unfavourable as defined by pre-treatment PSA and Gleason score). A relapse was recorded when tumour recurrence was diagnosed or when three successive prostate specific antigen (PSA) elevations were observed from a post-treatment nadir PSA level. PSA relapse-free survival was used as the primary end point. The model, which is based on an iterated Yule process, is specified in terms of three parameters: the mean number of tumour clonogens that survive the treatment, the mean of the progression time of post-treatment tumour development and its standard deviation. The model parameters were estimated by the maximum likelihood method. The fact that the proposed model provides an excellent description both of the survivor function and of the hazard rate is prima facie evidence of the validity of the model because closeness of the two survivor functions (empirical and model-based) does not generally imply closeness of the corresponding hazard rates. The estimated cure probabilities for the favourable group are 0.80, 0.74 and 0.87 (for dose groups 1-3, respectively); for the intermediate group: 0.25, 0.51, 0.58 and 0.78 (for dose groups 1-4, respectively) and for the unfavourable group: 0.0, 0.27, 0.33 and 0.64 (for dose groups 1-4, respectively). The distribution of progression time to tumour relapse was found to be independent of prognosis group but dependent on dose. As the dose increases the mean progression time decreases (41, 28.5, 26.2 and 14.7 months for dose groups 1-4, respectively). This analysis confirms that, in terms of cure rate, dose escalation has a significant positive effect only in the intermediate and unfavourable groups. It was found that progression time is inversely proportional to dose, which means that patients recurring in higher dose groups have shorter recurrence times, yet these groups have better survival, particularly long-term. The explanation for this seemingly illogical observation lies in the fact that less aggressive tumours, potentially recurring after a long period of time, are cured by higher doses and do not contribute to the recurrence pattern. As a result, patients in higher dose groups are less likely to recur; however, if they do, they tend to recur earlier. The estimated hazard rates for prostate cancer pass through a clear-cut maximum, thus revealing a time period with especially high values of instantaneous cancer-specific risk; the estimates appear to be nonproportional across dose strata.

SU-D-12A-06: A Comprehensive Parameter Analysis for Low Dose Cone-Beam CT Reconstruction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lu, W; Southern Medical University, Guangzhou; Yan, H

Purpose: There is always a parameter in compressive sensing based iterative reconstruction (IR) methods low dose cone-beam CT (CBCT), which controls the weight of regularization relative to data fidelity. A clear understanding of the relationship between image quality and parameter values is important. The purpose of this study is to investigate this subject based on experimental data and a representative advanced IR algorithm using Tight-frame (TF) regularization. Methods: Three data sets of a Catphan phantom acquired at low, regular and high dose levels are used. For each tests, 90 projections covering a 200-degree scan range are used for reconstruction. Threemore » different regions-of-interest (ROIs) of different contrasts are used to calculate contrast-to-noise ratios (CNR) for contrast evaluation. A single point structure is used to measure modulation transfer function (MTF) for spatial-resolution evaluation. Finally, we analyze CNRs and MTFs to study the relationship between image quality and parameter selections. Results: It was found that: 1) there is no universal optimal parameter. The optimal parameter value depends on specific task and dose level. 2) There is a clear trade-off between CNR and resolution. The parameter for the best CNR is always smaller than that for the best resolution. 3) Optimal parameters are also dose-specific. Data acquired under a high dose protocol require less regularization, yielding smaller optimal parameter values. 4) Comparing with conventional FDK images, TF-based CBCT images are better under a certain optimally selected parameters. The advantages are more obvious for low dose data. Conclusion: We have investigated the relationship between image quality and parameter values in the TF-based IR algorithm. Preliminary results indicate optimal parameters are specific to both the task types and dose levels, providing guidance for selecting parameters in advanced IR algorithms. This work is supported in part by NIH (1R01CA154747-01)« less

An analytical model of leakage neutron equivalent dose for passively-scattered proton radiotherapy and validation with measurements.

PubMed

Schneider, Christopher; Newhauser, Wayne; Farah, Jad

2015-05-18

Exposure to stray neutrons increases the risk of second cancer development after proton therapy. Previously reported analytical models of this exposure were difficult to configure and had not been investigated below 100 MeV proton energy. The purposes of this study were to test an analytical model of neutron equivalent dose per therapeutic absorbed dose  at 75 MeV and to improve the model by reducing the number of configuration parameters and making it continuous in proton energy from 100 to 250 MeV. To develop the analytical model, we used previously published H/D values in water from Monte Carlo simulations of a general-purpose beamline for proton energies from 100 to 250 MeV. We also configured and tested the model on in-air neutron equivalent doses measured for a 75 MeV ocular beamline. Predicted H/D values from the analytical model and Monte Carlo agreed well from 100 to 250 MeV (10% average difference). Predicted H/D values from the analytical model also agreed well with measurements at 75 MeV (15% average difference). The results indicate that analytical models can give fast, reliable calculations of neutron exposure after proton therapy. This ability is absent in treatment planning systems but vital to second cancer risk estimation.

Investigation of statistical iterative reconstruction for dedicated breast CT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Makeev, Andrey; Glick, Stephen J.

2013-08-15

Purpose: Dedicated breast CT has great potential for improving the detection and diagnosis of breast cancer. Statistical iterative reconstruction (SIR) in dedicated breast CT is a promising alternative to traditional filtered backprojection (FBP). One of the difficulties in using SIR is the presence of free parameters in the algorithm that control the appearance of the resulting image. These parameters require tuning in order to achieve high quality reconstructions. In this study, the authors investigated the penalized maximum likelihood (PML) method with two commonly used types of roughness penalty functions: hyperbolic potential and anisotropic total variation (TV) norm. Reconstructed images weremore » compared with images obtained using standard FBP. Optimal parameters for PML with the hyperbolic prior are reported for the task of detecting microcalcifications embedded in breast tissue.Methods: Computer simulations were used to acquire projections in a half-cone beam geometry. The modeled setup describes a realistic breast CT benchtop system, with an x-ray spectra produced by a point source and an a-Si, CsI:Tl flat-panel detector. A voxelized anthropomorphic breast phantom with 280 μm microcalcification spheres embedded in it was used to model attenuation properties of the uncompressed woman's breast in a pendant position. The reconstruction of 3D images was performed using the separable paraboloidal surrogates algorithm with ordered subsets. Task performance was assessed with the ideal observer detectability index to determine optimal PML parameters.Results: The authors' findings suggest that there is a preferred range of values of the roughness penalty weight and the edge preservation threshold in the penalized objective function with the hyperbolic potential, which resulted in low noise images with high contrast microcalcifications preserved. In terms of numerical observer detectability index, the PML method with optimal parameters yielded substantially improved performance (by a factor of greater than 10) compared to FBP. The hyperbolic prior was also observed to be superior to the TV norm. A few of the best-performing parameter pairs for the PML method also demonstrated superior performance for various radiation doses. In fact, using PML with certain parameter values results in better images, acquired using 2 mGy dose, than FBP-reconstructed images acquired using 6 mGy dose.Conclusions: A range of optimal free parameters for the PML algorithm with hyperbolic and TV norm-based potentials is presented for the microcalcification detection task, in dedicated breast CT. The reported values can be used as starting values of the free parameters, when SIR techniques are used for image reconstruction. Significant improvement in image quality can be achieved by using PML with optimal combination of parameters, as compared to FBP. Importantly, these results suggest improved detection of microcalcifications can be obtained by using PML with lower radiation dose to the patient, than using FBP with higher dose.« less

Photon iso-effective dose for cancer treatment with mixed field radiation based on dose-response assessment from human and an animal model: clinical application to boron neutron capture therapy for head and neck cancer

NASA Astrophysics Data System (ADS)

González, S. J.; Pozzi, E. C. C.; Monti Hughes, A.; Provenzano, L.; Koivunoro, H.; Carando, D. G.; Thorp, S. I.; Casal, M. R.; Bortolussi, S.; Trivillin, V. A.; Garabalino, M. A.; Curotto, P.; Heber, E. M.; Santa Cruz, G. A.; Kankaanranta, L.; Joensuu, H.; Schwint, A. E.

2017-10-01

Boron neutron capture therapy (BNCT) is a treatment modality that combines different radiation qualities. Since the severity of biological damage following irradiation depends on the radiation type, a quantity different from absorbed dose is required to explain the effects observed in the clinical BNCT in terms of outcome compared with conventional photon radiation therapy. A new approach for calculating photon iso-effective doses in BNCT was introduced previously. The present work extends this model to include information from dose-response assessments in animal models and humans. Parameters of the model were determined for tumour and precancerous tissue using dose-response curves obtained from BNCT and photon studies performed in the hamster cheek pouch in vivo models of oral cancer and/or pre-cancer, and from head and neck cancer radiotherapy data with photons. To this end, suitable expressions of the dose-limiting Normal Tissue Complication and Tumour Control Probabilities for the reference radiation and for the mixed field BNCT radiation were developed. Pearson’s correlation coefficients and p-values showed that TCP and NTCP models agreed with experimental data (with r  >  0.87 and p-values  >0.57). The photon iso-effective dose model was applied retrospectively to evaluate the dosimetry in tumours and mucosa for head and neck cancer patients treated with BNCT in Finland. Photon iso-effective doses in tumour were lower than those obtained with the standard RBE-weighted model (between 10% to 45%). The results also suggested that the probabilities of tumour control derived from photon iso-effective doses are more adequate to explain the clinical responses than those obtained with the RBE-weighted values. The dosimetry in the mucosa revealed that the photon iso-effective doses were about 30% to 50% higher than the corresponding RBE-weighted values. While the RBE-weighted doses are unable to predict mucosa toxicity, predictions based on the proposed model are compatible with the observed clinical outcome. The extension of the photon iso-effective dose model has allowed, for the first time, the determination of the photon iso-effective dose for unacceptable complications in the dose-limiting normal tissue. Finally, the formalism developed in this work to compute photon-equivalent doses can be applied to other therapies that combine mixed radiation fields, such as hadron therapy.

Photon iso-effective dose for cancer treatment with mixed field radiation based on dose-response assessment from human and an animal model: clinical application to boron neutron capture therapy for head and neck cancer.

PubMed

González, S J; Pozzi, E C C; Monti Hughes, A; Provenzano, L; Koivunoro, H; Carando, D G; Thorp, S I; Casal, M R; Bortolussi, S; Trivillin, V A; Garabalino, M A; Curotto, P; Heber, E M; Santa Cruz, G A; Kankaanranta, L; Joensuu, H; Schwint, A E

2017-10-03

Boron neutron capture therapy (BNCT) is a treatment modality that combines different radiation qualities. Since the severity of biological damage following irradiation depends on the radiation type, a quantity different from absorbed dose is required to explain the effects observed in the clinical BNCT in terms of outcome compared with conventional photon radiation therapy. A new approach for calculating photon iso-effective doses in BNCT was introduced previously. The present work extends this model to include information from dose-response assessments in animal models and humans. Parameters of the model were determined for tumour and precancerous tissue using dose-response curves obtained from BNCT and photon studies performed in the hamster cheek pouch in vivo models of oral cancer and/or pre-cancer, and from head and neck cancer radiotherapy data with photons. To this end, suitable expressions of the dose-limiting Normal Tissue Complication and Tumour Control Probabilities for the reference radiation and for the mixed field BNCT radiation were developed. Pearson's correlation coefficients and p-values showed that TCP and NTCP models agreed with experimental data (with r  >  0.87 and p-values  >0.57). The photon iso-effective dose model was applied retrospectively to evaluate the dosimetry in tumours and mucosa for head and neck cancer patients treated with BNCT in Finland. Photon iso-effective doses in tumour were lower than those obtained with the standard RBE-weighted model (between 10% to 45%). The results also suggested that the probabilities of tumour control derived from photon iso-effective doses are more adequate to explain the clinical responses than those obtained with the RBE-weighted values. The dosimetry in the mucosa revealed that the photon iso-effective doses were about 30% to 50% higher than the corresponding RBE-weighted values. While the RBE-weighted doses are unable to predict mucosa toxicity, predictions based on the proposed model are compatible with the observed clinical outcome. The extension of the photon iso-effective dose model has allowed, for the first time, the determination of the photon iso-effective dose for unacceptable complications in the dose-limiting normal tissue. Finally, the formalism developed in this work to compute photon-equivalent doses can be applied to other therapies that combine mixed radiation fields, such as hadron therapy.

Patient-specific Radiation Dose and Cancer Risk for Pediatric Chest CT

PubMed Central

Samei, Ehsan; Segars, W. Paul; Sturgeon, Gregory M.; Colsher, James G.; Frush, Donald P.

2011-01-01

Purpose: To estimate patient-specific radiation dose and cancer risk for pediatric chest computed tomography (CT) and to evaluate factors affecting dose and risk, including patient size, patient age, and scanning parameters. Materials and Methods: The institutional review board approved this study and waived informed consent. This study was HIPAA compliant. The study included 30 patients (0–16 years old), for whom full-body computer models were recently created from clinical CT data. A validated Monte Carlo program was used to estimate organ dose from eight chest protocols, representing clinically relevant combinations of bow tie filter, collimation, pitch, and tube potential. Organ dose was used to calculate effective dose and risk index (an index of total cancer incidence risk). The dose and risk estimates before and after normalization by volume-weighted CT dose index (CTDIvol) or dose–length product (DLP) were correlated with patient size and age. The effect of each scanning parameter was studied. Results: Organ dose normalized by tube current–time product or CTDIvol decreased exponentially with increasing average chest diameter. Effective dose normalized by tube current–time product or DLP decreased exponentially with increasing chest diameter. Chest diameter was a stronger predictor of dose than weight and total scan length. Risk index normalized by tube current–time product or DLP decreased exponentially with both chest diameter and age. When normalized by DLP, effective dose and risk index were independent of collimation, pitch, and tube potential (<10% variation). Conclusion: The correlations of dose and risk with patient size and age can be used to estimate patient-specific dose and risk. They can further guide the design and optimization of pediatric chest CT protocols. © RSNA, 2011 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.11101900/-/DC1 PMID:21467251

Reevaluation of the AAPM TG-43 brachytherapy dosimetry parameters for an 125I seed, and the influence of eye plaque design on dose distributions and dose-volume histograms

NASA Astrophysics Data System (ADS)

Aryal, Prakash

The TG-43 dosimetry parameters of the Advantage(TM) 125I model IAI-125A brachytherapy seed were studied. An investigation using modern MCNP radiation transport code with updated cross-section libraries was performed. Twelve different simulation conditions were studied for a single seed by varying the coating thickness, mass density, photon energy spectrum and cross-section library. The dose rate was found to be 6.3% lower at 1 cm in comparison to published results. New TG-43 dosimetry parameters are proposed. The dose distribution for a brachytherapy eye plaque, model EP917, was investigated, including the effects of collimation from high-Z slots. Dose distributions for 26 slot designs were determined using Monte Carlo methods and compared between the published literature, a clinical treatment planning system, and physical measurements. The dosimetric effect of the composition and mass density of the gold backing was shown to be less than 3%. Slot depth, width, and length changed the central axis (CAX) dose distributions by < 1% per 0.1 mm in design variation. Seed shifts in the slot towards the eye and shifts of the 125I-laden silver rod within the seed had the greatest impact on the CAX dose distribution, changing it by 14%, 9%, 4.3%, and 2.7% at 1, 2, 5, and 10 mm, respectively, from the inner scleral surface. The measured, full plaque slot geometry delivered 2.4% +/- 1.1% higher dose along the plaque's CAX than the geometry provided by the manufacturer and 2.2%+/-2.3% higher than Plaque Simulator(TM) (PS) treatment planning software (version 5.7.6). The D10 for the simulated tumor, inner sclera, and outer sclera for the measured slot plaque to manufacturer provided slot design was 9%, 10%, and 19% higher, respectively. In comparison to the measured plaque design, a theoretical plaque having narrow and deep slots delivered 30%, 37%, and 62% lower D 10 doses to the tumor, inner sclera, and outer sclera, respectively. CAX doses at --1, 0, 1, and 2 mm were also lower by a factor of 2.6, 1.72, 1.50, and 1.39, respectively. The study identified substantial sensitivity of the EP917 plaque dose distributions to slot design. KEYWORDS: Monte Carlo methods, dosimetry, 125I, TG-43, eye plaque brachytherapy.

An empirical model for parameters affecting energy consumption in boron removal from boron-containing wastewaters by electrocoagulation.

PubMed

Yilmaz, A Erdem; Boncukcuoğlu, Recep; Kocakerim, M Muhtar

2007-06-01

In this study, it was investigated parameters affecting energy consumption in boron removal from boron containing wastewaters prepared synthetically, via electrocoagulation method. The solution pH, initial boron concentration, dose of supporting electrolyte, current density and temperature of solution were selected as experimental parameters affecting energy consumption. The obtained experimental results showed that boron removal efficiency reached up to 99% under optimum conditions, in which solution pH was 8.0, current density 6.0 mA/cm(2), initial boron concentration 100mg/L and solution temperature 293 K. The current density was an important parameter affecting energy consumption too. High current density applied to electrocoagulation cell increased energy consumption. Increasing solution temperature caused to decrease energy consumption that high temperature decreased potential applied under constant current density. That increasing initial boron concentration and dose of supporting electrolyte caused to increase specific conductivity of solution decreased energy consumption. As a result, it was seen that energy consumption for boron removal via electrocoagulation method could be minimized at optimum conditions. An empirical model was predicted by statistically. Experimentally obtained values were fitted with values predicted from empirical model being as following; [formula in text]. Unfortunately, the conditions obtained for optimum boron removal were not the conditions obtained for minimum energy consumption. It was determined that support electrolyte must be used for increase boron removal and decrease electrical energy consumption.

SU-E-T-113: Dose Distribution Using Respiratory Signals and Machine Parameters During Treatment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Imae, T; Haga, A; Saotome, N

Purpose: Volumetric modulated arc therapy (VMAT) is a rotational intensity-modulated radiotherapy (IMRT) technique capable of acquiring projection images during treatment. Treatment plans for lung tumors using stereotactic body radiotherapy (SBRT) are calculated with planning computed tomography (CT) images only exhale phase. Purpose of this study is to evaluate dose distribution by reconstructing from only the data such as respiratory signals and machine parameters acquired during treatment. Methods: Phantom and three patients with lung tumor underwent CT scans for treatment planning. They were treated by VMAT while acquiring projection images to derive their respiratory signals and machine parameters including positions ofmore » multi leaf collimators, dose rates and integrated monitor units. The respiratory signals were divided into 4 and 10 phases and machine parameters were correlated with the divided respiratory signals based on the gantry angle. Dose distributions of each respiratory phase were calculated from plans which were reconstructed from the respiratory signals and the machine parameters during treatment. The doses at isocenter, maximum point and the centroid of target were evaluated. Results and Discussion: Dose distributions during treatment were calculated using the machine parameters and the respiratory signals detected from projection images. Maximum dose difference between plan and in treatment distribution was −1.8±0.4% at centroid of target and dose differences of evaluated points between 4 and 10 phases were no significant. Conclusion: The present method successfully evaluated dose distribution using respiratory signals and machine parameters during treatment. This method is feasible to verify the actual dose for moving target.« less

Site-Specific Reference Person Parameters and Derived Concentration Standards for the Savannah River Site

DOE PAGES

Stone, Daniel K.; Higley, Kathryn A.; Jannik, G. Timothy

2014-05-01

The U.S. Department of Energy Order 458.1 states that the compliance with the 1 mSv annual dose constraint to a member of the public may be demonstrated by calculating dose to the maximally exposed individual (MEI) or to a representative person. Historically, the MEI concept was used for dose compliance at the Savannah River Site (SRS) using adult dose coefficients and adult male usage parameters. For future compliance, SRS plans to use the representative person concept for dose estimates to members of the public. The representative person dose will be based on the reference person dose coefficients from the U.S.more » DOE Derived Concentration Technical Standard and on usage parameters specific to SRS for the reference and typical person. Usage parameters and dose coefficients were determined for inhalation, ingestion and external exposure pathways. The parameters for the representative person were used to calculate and tabulate SRS-specific derived concentration standards (DCSs) for the pathways not included in DOE-STD-1196-2011.« less

Population pharmacokinetics and exposure-response of osimertinib in patients with non-small cell lung cancer.

PubMed

Brown, Kathryn; Comisar, Craig; Witjes, Han; Maringwa, John; de Greef, Rik; Vishwanathan, Karthick; Cantarini, Mireille; Cox, Eugène

2017-06-01

To develop a population (pop) pharmacokinetic (PK) model for osimertinib (AZD9291) and its metabolite (AZ5104) and investigate the exposure-response relationships for selected efficacy and safety parameters. PK, safety and efficacy data were collected from two non-small cell lung cancer (NSCLC) patient studies (n = 748) and one healthy volunteer study (n = 32), after single or multiple once-daily dosing of 20-240 mg osimertinib. Nonlinear mixed effects modelling was used to characterise the popPK. Individual exposure values were used to investigate the relationship with response evaluation criteria in solid tumours (RECIST 1.1) efficacy parameters and key safety parameters (rash, diarrhoea, QTcF). A popPK model that adequately described osimertinib and its metabolite AZ5104 in a joint manner was developed. Body weight, serum albumin and ethnicity were identified as significant covariates on PK in the analysis, but were not found to have a clinically relevant impact on osimertinib exposure. No relationship was identified between exposure and efficacy over the dose range studied. A linear relationship was observed between exposure and the occurrence of rash or diarrhoea, and between concentration and QTcF, with a predicted mean (upper 90% confidence interval) increase of 14.2 (15.8) ms at the maximum concentration for an 80 mg once-daily dose at steady state. PopPK and exposure-response models were developed for osimertinib and AZ5104. There was no relationship between exposure and efficacy but a linear relationship between exposure and safety endpoints (rash, diarrhoea and QTcF) was observed. © 2016 The British Pharmacological Society.

Clinical implications in the use of the PBC algorithm versus the AAA by comparison of different NTCP models/parameters

PubMed Central

2013-01-01

Purpose Retrospective analysis of 3D clinical treatment plans to investigate qualitative, possible, clinical consequences of the use of PBC versus AAA. Methods The 3D dose distributions of 80 treatment plans at four different tumour sites, produced using PBC algorithm, were recalculated using AAA and the same number of monitor units provided by PBC and clinically delivered to each patient; the consequences of the difference on the dose-effect relations for normal tissue injury were studied by comparing different NTCP model/parameters extracted from a review of published studies. In this study the AAA dose calculation is considered as benchmark data. The paired Student t-test was used for statistical comparison of all results obtained from the use of the two algorithms. Results In the prostate plans, the AAA predicted lower NTCP value (NTCPAAA) for the risk of late rectal bleeding for each of the seven combinations of NTCP parameters, the maximum mean decrease was 2.2%. In the head-and-neck treatments, each combination of parameters used for the risk of xerostemia from irradiation of the parotid glands involved lower NTCPAAA, that varied from 12.8% (sd=3.0%) to 57.5% (sd=4.0%), while when the PBC algorithm was used the NTCPPBC’s ranging was from 15.2% (sd=2.7%) to 63.8% (sd=3.8%), according the combination of parameters used; the differences were statistically significant. Also NTCPAAA regarding the risk of radiation pneumonitis in the lung treatments was found to be lower than NTCPPBC for each of the eight sets of NTCP parameters; the maximum mean decrease was 4.5%. A mean increase of 4.3% was found when the NTCPAAA was calculated by the parameters evaluated from dose distribution calculated by a convolution-superposition (CS) algorithm. A markedly different pattern was observed for the risk relating to the development of pneumonitis following breast treatments: the AAA predicted higher NTCP value. The mean NTCPAAA varied from 0.2% (sd = 0.1%) to 2.1% (sd = 0.3%), while the mean NTCPPBC varied from 0.1% (sd = 0.0%) to 1.8% (sd = 0.2%) depending on the chosen parameters set. Conclusions When the original PBC treatment plans were recalculated using AAA with the same number of monitor units provided by PBC, the NTCPAAA was lower than the NTCPPBC, except for the breast treatments. The NTCP is strongly affected by the wide-ranging values of radiobiological parameters. PMID:23826854

Clinical implications in the use of the PBC algorithm versus the AAA by comparison of different NTCP models/parameters.

PubMed

Bufacchi, Antonella; Nardiello, Barbara; Capparella, Roberto; Begnozzi, Luisa

2013-07-04

Retrospective analysis of 3D clinical treatment plans to investigate qualitative, possible, clinical consequences of the use of PBC versus AAA. The 3D dose distributions of 80 treatment plans at four different tumour sites, produced using PBC algorithm, were recalculated using AAA and the same number of monitor units provided by PBC and clinically delivered to each patient; the consequences of the difference on the dose-effect relations for normal tissue injury were studied by comparing different NTCP model/parameters extracted from a review of published studies. In this study the AAA dose calculation is considered as benchmark data. The paired Student t-test was used for statistical comparison of all results obtained from the use of the two algorithms. In the prostate plans, the AAA predicted lower NTCP value (NTCPAAA) for the risk of late rectal bleeding for each of the seven combinations of NTCP parameters, the maximum mean decrease was 2.2%. In the head-and-neck treatments, each combination of parameters used for the risk of xerostemia from irradiation of the parotid glands involved lower NTCPAAA, that varied from 12.8% (sd=3.0%) to 57.5% (sd=4.0%), while when the PBC algorithm was used the NTCPPBC's ranging was from 15.2% (sd=2.7%) to 63.8% (sd=3.8%), according the combination of parameters used; the differences were statistically significant. Also NTCPAAA regarding the risk of radiation pneumonitis in the lung treatments was found to be lower than NTCPPBC for each of the eight sets of NTCP parameters; the maximum mean decrease was 4.5%. A mean increase of 4.3% was found when the NTCPAAA was calculated by the parameters evaluated from dose distribution calculated by a convolution-superposition (CS) algorithm. A markedly different pattern was observed for the risk relating to the development of pneumonitis following breast treatments: the AAA predicted higher NTCP value. The mean NTCPAAA varied from 0.2% (sd = 0.1%) to 2.1% (sd = 0.3%), while the mean NTCPPBC varied from 0.1% (sd = 0.0%) to 1.8% (sd = 0.2%) depending on the chosen parameters set. When the original PBC treatment plans were recalculated using AAA with the same number of monitor units provided by PBC, the NTCPAAA was lower than the NTCPPBC, except for the breast treatments. The NTCP is strongly affected by the wide-ranging values of radiobiological parameters.

Relative Biological Effectiveness of HZE Particles for Chromosomal Exchanges and Other Surrogate Cancer Risk Endpoints.

PubMed

Cacao, Eliedonna; Hada, Megumi; Saganti, Premkumar B; George, Kerry A; Cucinotta, Francis A

2016-01-01

The biological effects of high charge and energy (HZE) particle exposures are of interest in space radiation protection of astronauts and cosmonauts, and estimating secondary cancer risks for patients undergoing Hadron therapy for primary cancers. The large number of particles types and energies that makeup primary or secondary radiation in HZE particle exposures precludes tumor induction studies in animal models for all but a few particle types and energies, thus leading to the use of surrogate endpoints to investigate the details of the radiation quality dependence of relative biological effectiveness (RBE) factors. In this report we make detailed RBE predictions of the charge number and energy dependence of RBE's using a parametric track structure model to represent experimental results for the low dose response for chromosomal exchanges in normal human lymphocyte and fibroblast cells with comparison to published data for neoplastic transformation and gene mutation. RBE's are evaluated against acute doses of γ-rays for doses near 1 Gy. Models that assume linear or non-targeted effects at low dose are considered. Modest values of RBE (<10) are found for simple exchanges using a linear dose response model, however in the non-targeted effects model for fibroblast cells large RBE values (>10) are predicted at low doses <0.1 Gy. The radiation quality dependence of RBE's against the effects of acute doses γ-rays found for neoplastic transformation and gene mutation studies are similar to those found for simple exchanges if a linear response is assumed at low HZE particle doses. Comparisons of the resulting model parameters to those used in the NASA radiation quality factor function are discussed.

Effect of aminocaproic acid on clot strength and clot lysis of canine blood determined by use of an in vitro model of hyperfibrinolysis.

PubMed

Brown, Jamie C; Brainard, Benjamin M; Fletcher, Daniel J; Nie, Ben; Arnold, Robert D; Schmiedt, Chad W

2016-11-01

OBJECTIVE To determine pharmacodynamic and pharmacokinetic profiles of aminocaproic acid (ACA) by use of a thromboelastography (TEG)-based in vitro model of hyperfibrinolysis and high-performance liquid chromatography-mass spectrometry. ANIMALS 5 healthy adult dogs. PROCEDURES A single dose of injectable ACA (20, 50, or 100 mg/kg) or an ACA tablet (approximately 100 mg/kg) was administered orally. Blood samples were collected at 0, 15, 30, 45, 60, 90, 120, and 240 minutes after ACA administration for pharmacokinetic analysis. Samples were obtained at 0, 60, and 240 minutes for pharmacodynamic analysis by use of a TEG model of hyperfibrinolysis. RESULTS No adverse effects were detected. In the hyperfibrinolysis model, after all doses, a significantly higher TEG maximum amplitude (clot strength), compared with baseline, was detected at 60 and 240 minutes. Additionally, the percentage of fibrinolysis was reduced from the baseline value at 60 and 240 minutes, with the greatest reduction at 60 minutes. At 240 minutes, there was significantly less fibrinolysis for the 100 mg/kg dose than the 20 mg/kg dose. Maximum plasma ACA concentration was dose dependent. There was no significant difference in pharmacokinetic parameters between 100 mg/kg formulations. CONCLUSIONS AND CLINICAL RELEVANCE In an in vitro model of hyperfibrinolysis, ACA inhibited fibrinolysis at all doses tested. At 240 minutes after administration, the 100 mg/kg dose inhibited fibrinolysis more effectively than did the 20 mg/kg dose. Thus, ACA may be useful for in vivo prevention of fibrinolysis in dogs. IMPACT FOR HUMAN MEDICINE These data may improve research models of hyperfibrinolytic diseases.

Relative Biological Effectiveness of HZE Particles for Chromosomal Exchanges and Other Surrogate Cancer Risk Endpoints

DOE PAGES

Cacao, Eliedonna; Hada, Megumi; Saganti, Premkumar B.; ...

2016-04-25

The biological effects of high charge and energy (HZE) particle exposures are of interest in space radiation protection of astronauts and cosmonauts, and estimating secondary cancer risks for patients undergoing Hadron therapy for primary cancers. The large number of particles types and energies that makeup primary or secondary radiation in HZE particle exposures precludes tumor induction studies in animal models for all but a few particle types and energies, thus leading to the use of surrogate endpoints to investigate the details of the radiation quality dependence of relative biological effectiveness (RBE) factors. In this report we make detailed RBE predictionsmore » of the charge number and energy dependence of RBE’s using a parametric track structure model to represent experimental results for the low dose response for chromosomal exchanges in normal human lymphocyte and fibroblast cells with comparison to published data for neoplastic transformation and gene mutation. RBE’s are evaluated against acute doses of γ-rays for doses near 1 Gy. Models that assume linear or non-targeted effects at low dose are considered. Modest values of RBE (<10) are found for simple exchanges using a linear dose response model, however in the non-targeted effects model for fibroblast cells large RBE values (>10) are predicted at low doses <0.1 Gy. The radiation quality dependence of RBE’s against the effects of acute doses γ-rays found for neoplastic transformation and gene mutation studies are similar to those found for simple exchanges if a linear response is assumed at low HZE particle doses. Finally, we discuss comparisons of the resulting model parameters to those used in the NASA radiation quality factor function.« less

Relative Biological Effectiveness of HZE Particles for Chromosomal Exchanges and Other Surrogate Cancer Risk Endpoints

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cacao, Eliedonna; Hada, Megumi; Saganti, Premkumar B.

The biological effects of high charge and energy (HZE) particle exposures are of interest in space radiation protection of astronauts and cosmonauts, and estimating secondary cancer risks for patients undergoing Hadron therapy for primary cancers. The large number of particles types and energies that makeup primary or secondary radiation in HZE particle exposures precludes tumor induction studies in animal models for all but a few particle types and energies, thus leading to the use of surrogate endpoints to investigate the details of the radiation quality dependence of relative biological effectiveness (RBE) factors. In this report we make detailed RBE predictionsmore » of the charge number and energy dependence of RBE’s using a parametric track structure model to represent experimental results for the low dose response for chromosomal exchanges in normal human lymphocyte and fibroblast cells with comparison to published data for neoplastic transformation and gene mutation. RBE’s are evaluated against acute doses of γ-rays for doses near 1 Gy. Models that assume linear or non-targeted effects at low dose are considered. Modest values of RBE (<10) are found for simple exchanges using a linear dose response model, however in the non-targeted effects model for fibroblast cells large RBE values (>10) are predicted at low doses <0.1 Gy. The radiation quality dependence of RBE’s against the effects of acute doses γ-rays found for neoplastic transformation and gene mutation studies are similar to those found for simple exchanges if a linear response is assumed at low HZE particle doses. Finally, we discuss comparisons of the resulting model parameters to those used in the NASA radiation quality factor function.« less

Analysis of patient CT dose data using virtualdose

NASA Astrophysics Data System (ADS)

Bennett, Richard

X-ray computer tomography has many benefits to medical and research applications. Recently, over the last decade CT has had a large increase in usage in hospitals and medical diagnosis. In pediatric care, from 2000 to 2006, abdominal CT scans increased by 49 % and chest CT by 425 % in the emergency room (Broder 2007). Enormous amounts of effort have been performed across multiple academic and government groups to determine an accurate measure of organ dose to patients who undergo a CT scan due to the inherent risks with ionizing radiation. Considering these intrinsic risks, CT dose estimating software becomes a necessary tool that health care providers and radiologist must use to determine many metrics to base the risks versus rewards of having an x-ray CT scan. This thesis models the resultant organ dose as body mass increases for patients with all other related scan parameters fixed. In addition to this,this thesis compares a modern dose estimating software, VirtualDose CT to two other programs, CT-Expo and ImPACT CT. The comparison shows how the software's theoretical basis and the phantom they use to represent the human body affect the range of results in organ dose. CT-Expo and ImPACT CT dose estimating software uses a different model for anatomical representation of the organs in the human body and the results show how that approach dramatically changes the outcome. The results categorizes four datasets as compared to the three software types where the appropriate phantom was available. Modeling was done to simulate chest abdominal pelvis scans and whole body scans. Organ dose difference versus body mass index shows as body mass index (BMI) ranges from 23.5 kg/m 2 to 45 kg/m2 the amount of organ dose also trends a percent change from -4.58 to -176.19 %. Comparing organ dose difference with increasing x-ray tube potential from 120 kVp to 140 kVp the percent change in organ dose increases from 55 % to 65 % across all phantoms. In comparing VirtualDose to CT-Expo for organ dose difference versus age, male phantoms show percent difference of -19 % to 25 % for various organs minus bone surface and breast tissues results. Finally, for organ dose difference across all software for average adult phantom the results range from -45 % to 6 % in the comparison of ImPACT CT to VirtualDose and -27 % to 66 % for the comparison of CT-Expo to VirtualDose. In the comparison for increased BMI (done only in VirtualDose), results show that with all other parameters fixed, the organ dose goes down as BMI increases, which is due to the increase in adipose tissue and bulk of the patient model. The range of results when comparing all the three softwares have a wide range, in some cases greater than 150 %, it is evident that using a different anatomical basis for the human phantom and the theoretical basis for the dose estimation will cause fluctuation in the results. Therefore, choosing the software with the most accurate human phantom will provide a closer range to the true dose to the organ.

Impact of droplet evaporation rate on resulting in vitro performance parameters of pressurized metered dose inhalers.

PubMed

Sheth, Poonam; Grimes, Matthew R; Stein, Stephen W; Myrdal, Paul B

2017-08-07

Pressurized metered dose inhalers (pMDIs) are widely used for the treatment of pulmonary diseases. The overall efficiency of pMDI drug delivery may be defined by in vitro parameters such as the amount of drug that deposits on the model throat and the proportion of the emitted dose that has particles that are sufficiently small to deposit in the lung (i.e., fine particle fraction, FPF). The study presented examines product performance of ten solution pMDI formulations containing a variety of cosolvents with diverse chemical characteristics by cascade impaction with three inlets (USP induction port, Alberta Idealized Throat, and a large volume chamber). Through the data generated in support of this study, it was demonstrated that throat deposition, cascade impactor deposition, FPF, and mass median aerodynamic diameter of solution pMDIs depend on the concentration and vapor pressure of the cosolvent, and the selection of model throat. Theoretical droplet lifetimes were calculated for each formulation using a discrete two-stage evaporation process model and it was determined that the droplet lifetime is highly correlated to throat deposition and FPF indicating that evaporation kinetics significantly influences pMDI drug delivery. Copyright © 2017 Elsevier B.V. All rights reserved.

Radiation Parameters of High Dose Rate Iridium -192 Sources

NASA Astrophysics Data System (ADS)

Podgorsak, Matthew B.

A lack of physical data for high dose rate (HDR) Ir-192 sources has necessitated the use of basic radiation parameters measured with low dose rate (LDR) Ir-192 seeds and ribbons in HDR dosimetry calculations. A rigorous examination of the radiation parameters of several HDR Ir-192 sources has shown that this extension of physical data from LDR to HDR Ir-192 may be inaccurate. Uncertainty in any of the basic radiation parameters used in dosimetry calculations compromises the accuracy of the calculated dose distribution and the subsequent dose delivery. Dose errors of up to 0.3%, 6%, and 2% can result from the use of currently accepted values for the half-life, exposure rate constant, and dose buildup effect, respectively. Since an accuracy of 5% in the delivered dose is essential to prevent severe complications or tumor regrowth, the use of basic physical constants with uncertainties approaching 6% is unacceptable. A systematic evaluation of the pertinent radiation parameters contributes to a reduction in the overall uncertainty in HDR Ir-192 dose delivery. Moreover, the results of the studies described in this thesis contribute significantly to the establishment of standardized numerical values to be used in HDR Ir-192 dosimetry calculations.

Radiation Dose-Volume Effects in the Stomach and Small Bowel

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kavanagh, Brian D., E-mail: Brian.Kavanagh@ucdenver.ed; Pan, Charlie C.; Dawson, Laura A.

2010-03-01

Published data suggest that the risk of moderately severe (>=Grade 3) radiation-induced acute small-bowel toxicity can be predicted with a threshold model whereby for a given dose level, D, if the volume receiving that dose or greater (VD) exceeds a threshold quantity, the risk of toxicity escalates. Estimates of VD depend on the means of structure segmenting (e.g., V15 = 120 cc if individual bowel loops are outlined or V45 = 195 cc if entire peritoneal potential space of bowel is outlined). A similar predictive model of acute toxicity is not available for stomach. Late small-bowel/stomach toxicity is likely relatedmore » to maximum dose and/or volume threshold parameters qualitatively similar to those related to acute toxicity risk. Concurrent chemotherapy has been associated with a higher risk of acute toxicity, and a history of abdominal surgery has been associated with a higher risk of late toxicity.« less

Three-Dimensional Electron Beam Dose Calculations.

NASA Astrophysics Data System (ADS)

Shiu, Almon Sowchee

The MDAH pencil-beam algorithm developed by Hogstrom et al (1981) has been widely used in clinics for electron beam dose calculations for radiotherapy treatment planning. The primary objective of this research was to address several deficiencies of that algorithm and to develop an enhanced version. Two enhancements have been incorporated into the pencil-beam algorithm; one models fluence rather than planar fluence, and the other models the bremsstrahlung dose using measured beam data. Comparisons of the resulting calculated dose distributions with measured dose distributions for several test phantoms have been made. From these results it is concluded (1) that the fluence-based algorithm is more accurate to use for the dose calculation in an inhomogeneous slab phantom, and (2) the fluence-based calculation provides only a limited improvement to the accuracy the calculated dose in the region just downstream of the lateral edge of an inhomogeneity. The source of the latter inaccuracy is believed primarily due to assumptions made in the pencil beam's modeling of the complex phantom or patient geometry. A pencil-beam redefinition model was developed for the calculation of electron beam dose distributions in three dimensions. The primary aim of this redefinition model was to solve the dosimetry problem presented by deep inhomogeneities, which was the major deficiency of the enhanced version of the MDAH pencil-beam algorithm. The pencil-beam redefinition model is based on the theory of electron transport by redefining the pencil beams at each layer of the medium. The unique approach of this model is that all the physical parameters of a given pencil beam are characterized for multiple energy bins. Comparisons of the calculated dose distributions with measured dose distributions for a homogeneous water phantom and for phantoms with deep inhomogeneities have been made. From these results it is concluded that the redefinition algorithm is superior to the conventional, fluence-based, pencil-beam algorithm, especially in predicting the dose distribution downstream of a local inhomogeneity. The accuracy of this algorithm appears sufficient for clinical use, and the algorithm is structured for future expansion of the physical model if required for site specific treatment planning problems.

uSIMPK. An Excel for Windows-based simulation program for instruction of basic pharmacokinetics principles to pharmacy students.

PubMed

Brocks, Dion R

2015-07-01

Pharmacokinetics can be a challenging topic to teach due to the complex relationships inherent between physiological parameters, mathematical descriptors and equations, and their combined impact on shaping the blood fluid concentration vs. time curves of drugs. A computer program was developed within Microsoft Excel for Windows, designed to assist in the instruction of basic pharmacokinetics within an entry-to-practice pharmacy class environment. The program is composed of a series of spreadsheets (modules) linked by Visual Basic for Applications, intended to illustrate the relationships between pharmacokinetic and in some cases physiological parameters, doses and dose rates and the drug blood fluid concentration vs. time curves. Each module is accompanied by a simulation user's guide, prompting the user to change specific independent parameters and then observe the impact of the change(s) on the drug concentration vs. time curve and on other dependent parameters. "Slider" (or "scroll") bars can be selected to readily see the effects of repeated changes on the dependencies. Topics covered include one compartment single dose administration (iv bolus, oral, short infusion), intravenous infusion, repeated doses, renal and hepatic clearance, nonlinear elimination, two compartment model, plasma protein binding and the relationship between pharmacokinetics and drug effect. The program has been used in various forms in the classroom over a number of years, with positive ratings generally being received from students for its use in the classroom. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Nutritional support contributes to recuperation in a rat model of aplastic anemia by enhancing mitochondrial function.

PubMed

Yang, Guang; Zhao, Lifen; Liu, Bing; Shan, Yujia; Li, Yang; Zhou, Huimin; Jia, Li

2018-02-01

Acquired aplastic anemia (AA) is a hematopoietic stem cell disease that leads to hematopoietic disorder and peripheral blood pancytopenia. We investigated whether nutritional support is helpful to AA recovery. We established a rat model with AA. A nutrient mixture was administered to rats with AA through different dose gavage once per day for 55 d. Animals in this study were assigned to one of five groups: normal control (NC; group includes normal rats); AA (rats with AA); high dose (AA + nutritional mixture, 2266.95 mg/kg/d); medium dose (1511.3 mg/kg/d); and low dose (1057.91 mg/kg/d). The effects of nutrition administration on general status and mitochondrial function of rats with AA were evaluated. The nutrient mixture with which the rats were supplemented significantly improved weight, peripheral blood parameters, and histologic parameters of rats with AA in a dose-dependent manner. Furthermore, we observed that the number of mitochondria in the liver, spleen, kidney, and brain was increased after supplementation by transmission electron microscopy analysis. Nutrient administration also improved mitochondrial DNA content, adenosine triphosphate content, and membrane potential but inhibited oxidative stress, thus, repairing the mitochondrial dysfunction of the rats with AA. Taken together, nutrition supplements may contribute to the improvement of mitochondrial function and play an important role in the recuperation of rats with AA. Copyright © 2017 Elsevier Inc. All rights reserved.

SU-E-I-43: Pediatric CT Dose and Image Quality Optimization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stevens, G; Singh, R

2014-06-01

Purpose: To design an approach to optimize radiation dose and image quality for pediatric CT imaging, and to evaluate expected performance. Methods: A methodology was designed to quantify relative image quality as a function of CT image acquisition parameters. Image contrast and image noise were used to indicate expected conspicuity of objects, and a wide-cone system was used to minimize scan time for motion avoidance. A decision framework was designed to select acquisition parameters as a weighted combination of image quality and dose. Phantom tests were used to acquire images at multiple techniques to demonstrate expected contrast, noise and dose.more » Anthropomorphic phantoms with contrast inserts were imaged on a 160mm CT system with tube voltage capabilities as low as 70kVp. Previously acquired clinical images were used in conjunction with simulation tools to emulate images at different tube voltages and currents to assess human observer preferences. Results: Examination of image contrast, noise, dose and tube/generator capabilities indicates a clinical task and object-size dependent optimization. Phantom experiments confirm that system modeling can be used to achieve the desired image quality and noise performance. Observer studies indicate that clinical utilization of this optimization requires a modified approach to achieve the desired performance. Conclusion: This work indicates the potential to optimize radiation dose and image quality for pediatric CT imaging. In addition, the methodology can be used in an automated parameter selection feature that can suggest techniques given a limited number of user inputs. G Stevens and R Singh are employees of GE Healthcare.« less

egs_brachy: a versatile and fast Monte Carlo code for brachytherapy

NASA Astrophysics Data System (ADS)

Chamberland, Marc J. P.; Taylor, Randle E. P.; Rogers, D. W. O.; Thomson, Rowan M.

2016-12-01

egs_brachy is a versatile and fast Monte Carlo (MC) code for brachytherapy applications. It is based on the EGSnrc code system, enabling simulation of photons and electrons. Complex geometries are modelled using the EGSnrc C++ class library and egs_brachy includes a library of geometry models for many brachytherapy sources, in addition to eye plaques and applicators. Several simulation efficiency enhancing features are implemented in the code. egs_brachy is benchmarked by comparing TG-43 source parameters of three source models to previously published values. 3D dose distributions calculated with egs_brachy are also compared to ones obtained with the BrachyDose code. Well-defined simulations are used to characterize the effectiveness of many efficiency improving techniques, both as an indication of the usefulness of each technique and to find optimal strategies. Efficiencies and calculation times are characterized through single source simulations and simulations of idealized and typical treatments using various efficiency improving techniques. In general, egs_brachy shows agreement within uncertainties with previously published TG-43 source parameter values. 3D dose distributions from egs_brachy and BrachyDose agree at the sub-percent level. Efficiencies vary with radionuclide and source type, number of sources, phantom media, and voxel size. The combined effects of efficiency-improving techniques in egs_brachy lead to short calculation times: simulations approximating prostate and breast permanent implant (both with (2 mm)3 voxels) and eye plaque (with (1 mm)3 voxels) treatments take between 13 and 39 s, on a single 2.5 GHz Intel Xeon E5-2680 v3 processor core, to achieve 2% average statistical uncertainty on doses within the PTV. egs_brachy will be released as free and open source software to the research community.

The observed correlation between in vivo clinical pharmacokinetic parameters and in vitro potency of VEGFR-2 inhibitors. Can this be used as a prospective guide for the development of novel compounds?

PubMed

Benjamin, B; Sahu, M; Bhatnagar, U; Abhyankar, D; Srinivas, N R

2012-04-01

Literature data on the clinical pharmacokinetics of various VEGFR-2 inhibitors along with in vitro potency data were correlated and a linear relationship was established in spite of limited data set. In this work, a model set comprised of axitinib, recentin, sunitinib, pazopanib, and sorafenib were used. The in vitro potencies of the model set compounds were correlated with the published unbound plasma concentrations (Cmax, Cavg, Ctrough). The established linear regression (r2>0.90) equation was used to predict Cmax, Cavg, Ctrough of the 'prediction set' (motesanib, telatinib, CP547632, vatalanib, vandetanib) using in vitro potency and unbound protein free fraction. Cavg and Ctrough of prediction set were closely matched (0.2-1.8 fold of reported), demonstrating the usefulness of such predictions for tracking the target related modulation and/or efficacy signals within the clinically optimized population average. In case of Cmax where correlation was least anticipated, the predicted values were within 0.1-1.1 fold of those reported. Such predictions of appropriate parameters would provide rough estimates of whether or not therapeutically relevant dose(s) have been administered when clinical investigations of novel agents of this class are being performed. Therefore, it may aid in increasing clinical doses to a desired level if safety of the compound does not compromise such dose increases. In conclusion, the proposed model may prospectively guide the dosing strategies and would greatly aid the development of novel compounds in this class. © Georg Thieme Verlag KG Stuttgart · New York.

egs_brachy: a versatile and fast Monte Carlo code for brachytherapy.

PubMed

Chamberland, Marc J P; Taylor, Randle E P; Rogers, D W O; Thomson, Rowan M

2016-12-07

egs_brachy is a versatile and fast Monte Carlo (MC) code for brachytherapy applications. It is based on the EGSnrc code system, enabling simulation of photons and electrons. Complex geometries are modelled using the EGSnrc C++ class library and egs_brachy includes a library of geometry models for many brachytherapy sources, in addition to eye plaques and applicators. Several simulation efficiency enhancing features are implemented in the code. egs_brachy is benchmarked by comparing TG-43 source parameters of three source models to previously published values. 3D dose distributions calculated with egs_brachy are also compared to ones obtained with the BrachyDose code. Well-defined simulations are used to characterize the effectiveness of many efficiency improving techniques, both as an indication of the usefulness of each technique and to find optimal strategies. Efficiencies and calculation times are characterized through single source simulations and simulations of idealized and typical treatments using various efficiency improving techniques. In general, egs_brachy shows agreement within uncertainties with previously published TG-43 source parameter values. 3D dose distributions from egs_brachy and BrachyDose agree at the sub-percent level. Efficiencies vary with radionuclide and source type, number of sources, phantom media, and voxel size. The combined effects of efficiency-improving techniques in egs_brachy lead to short calculation times: simulations approximating prostate and breast permanent implant (both with (2 mm) 3 voxels) and eye plaque (with (1 mm) 3 voxels) treatments take between 13 and 39 s, on a single 2.5 GHz Intel Xeon E5-2680 v3 processor core, to achieve 2% average statistical uncertainty on doses within the PTV. egs_brachy will be released as free and open source software to the research community.

Metabolism and physiologically based pharmacokinetic modeling of flumioxazin in pregnant animals

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takaku, Tomoyuki, E-mail: takakut@sc.sumitomo-chem.co.jp; Nagahori, Hirohisa; Sogame, Yoshihisa

A physiologically based pharmacokinetic (PBPK) model was developed to predict the concentration of flumioxazin, in the blood and fetus of pregnant humans during a theoretical accidental intake (1000 mg/kg). The data on flumioxazin concentration in pregnant rats (30 mg/kg po) was used to develop the PBPK model in pregnant rats using physiological parameters and chemical specific parameters. The rat PBPK model developed was extrapolated to a human model. Liver microsomes of female rats and a mixed gender of humans were used for the in vitro metabolism study. To determine the % of flumioxazin absorbed after administration at a dose ofmore » 1000 mg/kg assuming maximum accidental intake, the biliary excretion study of [phenyl-U-{sup 14}C]flumioxazin was conducted in bile duct-cannulated female rats (Crl:CD (SD)) to collect and analyze the bile, urine, feces, gastrointestinal tract, and residual carcass. The % of flumioxazin absorbed at a dose of 1000 mg/kg in rats was low (12.3%) by summing up {sup 14}C of the urine, bile, and residual carcass. The pregnant human model that was developed demonstrated that the maximum flumioxazin concentration in the blood and fetus of a pregnant human at a dose of 1000 mg/kg po was 0.86 μg/mL and 0.68 μg/mL, respectively, which is much lower than K{sub m} (202.4 μg/mL). Because the metabolism was not saturated and the absorption rate was low at a dose of 1000 mg/kg, the calculated flumioxazin concentration in pregnant humans was thought to be relatively low, considering the flumioxazin concentration in pregnant rats at a dose of 30 mg/kg. For the safety assessment of flumioxazin, these results would be useful for further in vitro toxicology experiments. - Highlights: • A PBPK model of flumioxazin in pregnant humans was developed. • Simulated flumioxazin concentration in pregnant humans was relatively low. • The results would be useful for further in vitro toxicology experiments.« less

Pharmacokinetic Studies in Neonates: The Utility of an Opportunistic Sampling Design.

PubMed

Leroux, Stéphanie; Turner, Mark A; Guellec, Chantal Barin-Le; Hill, Helen; van den Anker, Johannes N; Kearns, Gregory L; Jacqz-Aigrain, Evelyne; Zhao, Wei

2015-12-01

The use of an opportunistic (also called scavenged) sampling strategy in a prospective pharmacokinetic study combined with population pharmacokinetic modelling has been proposed as an alternative strategy to conventional methods for accomplishing pharmacokinetic studies in neonates. However, the reliability of this approach in this particular paediatric population has not been evaluated. The objective of the present study was to evaluate the performance of an opportunistic sampling strategy for a population pharmacokinetic estimation, as well as dose prediction, and compare this strategy with a predetermined pharmacokinetic sampling approach. Three population pharmacokinetic models were derived for ciprofloxacin from opportunistic blood samples (SC model), predetermined (i.e. scheduled) samples (TR model) and all samples (full model used to previously characterize ciprofloxacin pharmacokinetics), using NONMEM software. The predictive performance of developed models was evaluated in an independent group of patients. Pharmacokinetic data from 60 newborns were obtained with a total of 430 samples available for analysis; 265 collected at predetermined times and 165 that were scavenged from those obtained as part of clinical care. All datasets were fit using a two-compartment model with first-order elimination. The SC model could identify the most significant covariates and provided reasonable estimates of population pharmacokinetic parameters (clearance and steady-state volume of distribution) compared with the TR and full models. Their predictive performances were further confirmed in an external validation by Bayesian estimation, and showed similar results. Monte Carlo simulation based on area under the concentration-time curve from zero to 24 h (AUC24)/minimum inhibitory concentration (MIC) using either the SC or the TR model gave similar dose prediction for ciprofloxacin. Blood samples scavenged in the course of caring for neonates can be used to estimate ciprofloxacin pharmacokinetic parameters and therapeutic dose requirements.

SU-E-T-562: Motion Tracking Optimization for Conformal Arc Radiotherapy Plans: A QUASAR Phantom Based Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Z; Wang, I; Yao, R

Purpose: This study is to use plan parameters optimization (Dose rate, collimator angle, couch angle, initial starting phase) to improve the performance of conformal arc radiotherapy plans with motion tracking by increasing the plan performance score (PPS). Methods: Two types of 3D conformal arc plans were created based on QUASAR respiratory motion phantom with spherical and cylindrical targets. Sinusoidal model was applied to the MLC leaves to generate motion tracking plans. A MATLAB program was developed to calculate PPS of each plan (ranges from 0–1) and optimize plan parameters. We first selected the dose rate for motion tracking plans andmore » then used simulated annealing algorithm to search for the combination of the other parameters that resulted in the plan of the maximal PPS. The optimized motion tracking plan was delivered by Varian Truebeam Linac. In-room cameras and stopwatch were used for starting phase selection and synchronization between phantom motion and plan delivery. Gaf-EBT2 dosimetry films were used to measure the dose delivered to the target in QUASAR phantom. Dose profiles and Truebeam trajectory log files were used for plan delivery performance evaluation. Results: For spherical target, the maximal PPS (PPSsph) of the optimized plan was 0.79: (Dose rate: 500MU/min, Collimator: 90°, Couch: +10°, starting phase: 0.83π). For cylindrical target, the maximal PPScyl was 0.75 (Dose rate: 300MU/min, Collimator: 87°, starting phase: 0.97π) with couch at 0°. Differences of dose profiles between motion tracking plans (with the maximal and the minimal PPS) and 3D conformal plans were as follows: PPSsph=0.79: %ΔFWHM: 8.9%, %Dmax: 3.1%; PPSsph=0.52: %ΔFWHM: 10.4%, %Dmax: 6.1%. PPScyl=0.75: %ΔFWHM: 4.7%, %Dmax: 3.6%; PPScyl=0.42: %ΔFWHM: 12.5%, %Dmax: 9.6%. Conclusion: By achieving high plan performance score through parameters optimization, we can improve target dose conformity of motion tracking plan by decreasing total MLC leaf travel distance and leaf speed.« less

Application of Adaptive DP-optimality to Design a Pilot Study for a Clotting Time Test for Enoxaparin.

PubMed

Gulati, Abhishek; Faed, James M; Isbister, Geoffrey K; Duffull, Stephen B

2015-10-01

Dosing of enoxaparin, like other anticoagulants, may result in bleeding following excessive doses and clot formation if the dose is too low. We recently showed that a factor Xa based clotting time test could potentially assess the effect of enoxaparin on the clotting system. However, the test did not perform well in subsequent individuals and effectiveness of an exogenous phospholipid, Actin FS, in reducing the variability in the clotting time was assessed. The aim of this work was to conduct an adaptive pilot study to determine the range of concentrations of Xa and Actin FS to take forward into a proof-of-concept study. A nonlinear parametric function was developed to describe the response surface over the factors of interest. An adaptive method was used to estimate the parameters using a D-optimal design criterion. In order to provide a reasonable probability of observing a success of the clotting time test, a P-optimal design criterion was incorporated using a loss function to describe the hybrid DP-optimality. The use of adaptive DP-optimality method resulted in an efficient estimation of model parameters using data from only 6 healthy volunteers. The use of response surface modelling identified a range of sets of Xa and Actin FS concentrations, any of which could be used for the proof-of-concept study. This study shows that parsimonious adaptive DP-optimal designs may provide both precise parameter estimates for response surface modelling as well as clinical confidence in the potential benefits of the study.

Stochastic dosimetry model for radon progeny in the rat lung.

PubMed

Winkler-HeiI, R; Hofmann, W; Hussain, M

2014-07-01

The stochastic dosimetry model presented here considers the distinctly asymmetric, stochastic branching pattern reported in morphometric measurements. This monopodial structure suggests that an airway diameter is a more appropriate morphometric parameter to classify bronchial dose distributions for inhaled radon progeny than the commonly assigned airway generation numbers. Bronchial doses were calculated for the typical exposure conditions reported for the Pacific Northwest National Laboratory rat inhalation studies, yielding an average bronchial dose of 7.75 mGy WLM(-1). If plotted as functions of airway generations, the resulting dose distributions are highest in the central bronchial airways, while significantly decreasing towards peripheral generations. However, if plotted as functions of airway diameters, doses are much more uniformly distributed among bronchial airways. The comparison between rat and human lungs indicates that dose conversion coefficients for the rat lung are higher than the corresponding values for the human lung by a factor of 1.34 for the experimental PNNL exposure conditions, and of 1.25 for typical human indoor conditions. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

A flexible Monte Carlo tool for patient or phantom specific calculations: comparison with preliminary validation measurements

NASA Astrophysics Data System (ADS)

Davidson, S.; Cui, J.; Followill, D.; Ibbott, G.; Deasy, J.

2008-02-01

The Dose Planning Method (DPM) is one of several 'fast' Monte Carlo (MC) computer codes designed to produce an accurate dose calculation for advanced clinical applications. We have developed a flexible machine modeling process and validation tests for open-field and IMRT calculations. To complement the DPM code, a practical and versatile source model has been developed, whose parameters are derived from a standard set of planning system commissioning measurements. The primary photon spectrum and the spectrum resulting from the flattening filter are modeled by a Fatigue function, cut-off by a multiplying Fermi function, which effectively regularizes the difficult energy spectrum determination process. Commonly-used functions are applied to represent the off-axis softening, increasing primary fluence with increasing angle ('the horn effect'), and electron contamination. The patient dependent aspect of the MC dose calculation utilizes the multi-leaf collimator (MLC) leaf sequence file exported from the treatment planning system DICOM output, coupled with the source model, to derive the particle transport. This model has been commissioned for Varian 2100C 6 MV and 18 MV photon beams using percent depth dose, dose profiles, and output factors. A 3-D conformal plan and an IMRT plan delivered to an anthropomorphic thorax phantom were used to benchmark the model. The calculated results were compared to Pinnacle v7.6c results and measurements made using radiochromic film and thermoluminescent detectors (TLD).

General equations for optimal selection of diagnostic image acquisition parameters in clinical X-ray imaging.

PubMed

Zheng, Xiaoming

2017-12-01

The purpose of this work was to examine the effects of relationship functions between diagnostic image quality and radiation dose on the governing equations for image acquisition parameter variations in X-ray imaging. Various equations were derived for the optimal selection of peak kilovoltage (kVp) and exposure parameter (milliAmpere second, mAs) in computed tomography (CT), computed radiography (CR), and direct digital radiography. Logistic, logarithmic, and linear functions were employed to establish the relationship between radiation dose and diagnostic image quality. The radiation dose to the patient, as a function of image acquisition parameters (kVp, mAs) and patient size (d), was used in radiation dose and image quality optimization. Both logistic and logarithmic functions resulted in the same governing equation for optimal selection of image acquisition parameters using a dose efficiency index. For image quality as a linear function of radiation dose, the same governing equation was derived from the linear relationship. The general equations should be used in guiding clinical X-ray imaging through optimal selection of image acquisition parameters. The radiation dose to the patient could be reduced from current levels in medical X-ray imaging.

Improvements to image quality using hybrid and model-based iterative reconstructions: a phantom study.

PubMed

Aurumskjöld, Marie-Louise; Ydström, Kristina; Tingberg, Anders; Söderberg, Marcus

2017-01-01

The number of computed tomography (CT) examinations is increasing and leading to an increase in total patient exposure. It is therefore important to optimize CT scan imaging conditions in order to reduce the radiation dose. The introduction of iterative reconstruction methods has enabled an improvement in image quality and a reduction in radiation dose. To investigate how image quality depends on reconstruction method and to discuss patient dose reduction resulting from the use of hybrid and model-based iterative reconstruction. An image quality phantom (Catphan® 600) and an anthropomorphic torso phantom were examined on a Philips Brilliance iCT. The image quality was evaluated in terms of CT numbers, noise, noise power spectra (NPS), contrast-to-noise ratio (CNR), low-contrast resolution, and spatial resolution for different scan parameters and dose levels. The images were reconstructed using filtered back projection (FBP) and different settings of hybrid (iDose 4 ) and model-based (IMR) iterative reconstruction methods. iDose 4 decreased the noise by 15-45% compared with FBP depending on the level of iDose 4 . The IMR reduced the noise even further, by 60-75% compared to FBP. The results are independent of dose. The NPS showed changes in the noise distribution for different reconstruction methods. The low-contrast resolution and CNR were improved with iDose 4 , and the improvement was even greater with IMR. There is great potential to reduce noise and thereby improve image quality by using hybrid or, in particular, model-based iterative reconstruction methods, or to lower radiation dose and maintain image quality. © The Foundation Acta Radiologica 2016.

Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection.

PubMed

Namour, Florence; Diderichsen, Paul Matthias; Cox, Eugène; Vayssière, Béatrice; Van der Aa, Annegret; Tasset, Chantal; Van't Klooster, Gerben

2015-08-01

Filgotinib (GLPG0634) is a selective inhibitor of Janus kinase 1 (JAK1) currently in development for the treatment of rheumatoid arthritis and Crohn's disease. While less selective JAK inhibitors have shown long-term efficacy in treating inflammatory conditions, this was accompanied by dose-limiting side effects. Here, we describe the pharmacokinetics of filgotinib and its active metabolite in healthy volunteers and the use of pharmacokinetic-pharmacodynamic modeling and simulation to support dose selection for phase IIB in patients with rheumatoid arthritis. Two trials were conducted in healthy male volunteers. In the first trial, filgotinib was administered as single doses from 10 mg up to multiple daily doses of 200 mg. In the second trial, daily doses of 300 and 450 mg for 10 days were evaluated. Non-compartmental analysis was used to determine individual pharmacokinetic parameters for filgotinib and its metabolite. The overall pharmacodynamic activity for the two moieties was assessed in whole blood using interleukin-6-induced phosphorylation of signal-transducer and activator of transcription 1 as a biomarker for JAK1 activity. These data were used to conduct non-linear mixed-effects modeling to investigate a pharmacokinetic/pharmacodynamic relationship. Modeling and simulation on the basis of early clinical data suggest that the pharmacokinetics of filgotinib are dose proportional up to 200 mg, in agreement with observed data, and support that both filgotinib and its metabolite contribute to its pharmacodynamic effects. Simulation of biomarker response supports that the maximum pharmacodynamic effect is reached at a daily dose of 200 mg filgotinib. Based on these results, a daily dose range up to 200 mg has been selected for phase IIB dose-finding studies in patients with rheumatoid arthritis.

TH-A-BRD-01: Radiation Biology for Radiation Therapy Physicists

DOE Office of Scientific and Technical Information (OSTI.GOV)

Orton, C; Borras, C; Carlson, D

Mechanisms by which radiation kills cells and ways cell damage can be repaired will be reviewed. The radiobiological parameters of dose, fractionation, delivery time, dose rate, and LET will be discussed. The linear-quadratic model for cell survival for high and low dose rate treatments and the effect of repopulation will be presented and discussed. The rationale for various radiotherapy techniques such as conventional fractionation, hyperfractionation, hypofractionation, and low and high dose rate brachytherapy, including permanent implants, will be presented. The radiobiological principles underlying radiation protection guidelines and the different radiation dosimetry terms used in radiation biology and in radiation protectionmore » will be reviewed. Human data on radiation induced cancer, including increases in the risk of second cancers following radiation therapy, as well as data on radiation induced tissue reactions, such as cardiovascular effects, for follow up times up to 20–40 years, published by ICRP, NCRP and BEIR Committees, will be examined. The latest risk estimates per unit dose will be presented. Their adoption in recent radiation protection standards and guidelines and their impact on patient and workers safety in radiotherapy will be discussed. Biologically-guided radiotherapy (BGRT) provides a systematic method to derive prescription doses that integrate patient-specific information about tumor and normal tissue biology. Treatment individualization based on patient-specific biology requires the identification of biological objective functions to facilitate the design and comparison of competing treatment modalities. Biological objectives provide a more direct approach to plan optimization instead of relying solely on dose-based surrogates and can incorporate factors that alter radiation response, such as DNA repair, tumor hypoxia, and relative biological effectiveness. We review concepts motivating biological objectives and provide examples of how they might be used to address clinically relevant problems. Underlying assumptions and limitations of existing models and their proper application will be discussed. This multidisciplinary educational session combines the fundamentals of radiobiology for radiation therapy and radiation protection with the practical application of biophysical models for treatment planning and evaluation. Learning Objectives: To understand fractionation in teletherapy and dose rate techniques in brachytherapy. To understand how the linear-quadratic models the effect of radiobiological parameters for radiotherapy. To understand the radiobiological basis of radiation protection standards applied to radiotherapy. To distinguish between stochastic effects and tissue reactions. To learn how to apply concepts of biological effective dose and RBE-weighted dose and to incorporate biological factors that alter radiation response. To discuss clinical strategies to increase therapeutic ratio, i.e., maximize local control while minimizing the risk of acute and late normal tissue effects.« less

Biological optimization of simultaneous boost on intra-prostatic lesions (DILs): sensitivity to TCP parameters.

PubMed

Azzeroni, R; Maggio, A; Fiorino, C; Mangili, P; Cozzarini, C; De Cobelli, F; Di Muzio, N G; Calandrino, R

2013-11-01

The aim of this investigation was to explore the potential of biological optimization in the case of simultaneous integrated boost on intra-prostatic dominant lesions (DIL) and evaluating the impact of TCP parameters uncertainty. Different combination of TCP parameters (TD50 and γ50 in the Poisson-like model), were considered for DILs and the prostate outside DILs (CTV) for 7 intermediate/high-risk prostate patients. The aim was to maximize TCP while constraining NTCPs below 5% for all organs at risk. TCP values were highly depending on the parameters used and ranged between 38.4% and 99.9%; the optimized median physical doses were in the range 94-116 Gy and 69-77 Gy for DIL and CTV respectively. TCP values were correlated with the overlap PTV-rectum and the minimum distance between rectum and DIL. In conclusion, biological optimization for selective dose escalation is feasible and suggests prescribed dose around 90-120 Gy to the DILs. The obtained result is critically depending on the assumptions concerning the higher radioresistence in the DILs. In case of very resistant clonogens into the DIL, it may be difficult to maximize TCP to acceptable levels without violating NTCP constraints. Copyright © 2012 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Analysis of uncertainties in Monte Carlo simulated organ dose for chest CT

NASA Astrophysics Data System (ADS)

Muryn, John S.; Morgan, Ashraf G.; Segars, W. P.; Liptak, Chris L.; Dong, Frank F.; Primak, Andrew N.; Li, Xiang

2015-03-01

In Monte Carlo simulation of organ dose for a chest CT scan, many input parameters are required (e.g., half-value layer of the x-ray energy spectrum, effective beam width, and anatomical coverage of the scan). The input parameter values are provided by the manufacturer, measured experimentally, or determined based on typical clinical practices. The goal of this study was to assess the uncertainties in Monte Carlo simulated organ dose as a result of using input parameter values that deviate from the truth (clinical reality). Organ dose from a chest CT scan was simulated for a standard-size female phantom using a set of reference input parameter values (treated as the truth). To emulate the situation in which the input parameter values used by the researcher may deviate from the truth, additional simulations were performed in which errors were purposefully introduced into the input parameter values, the effects of which on organ dose per CTDIvol were analyzed. Our study showed that when errors in half value layer were within ± 0.5 mm Al, the errors in organ dose per CTDIvol were less than 6%. Errors in effective beam width of up to 3 mm had negligible effect (< 2.5%) on organ dose. In contrast, when the assumed anatomical center of the patient deviated from the true anatomical center by 5 cm, organ dose errors of up to 20% were introduced. Lastly, when the assumed extra scan length was longer by 4 cm than the true value, dose errors of up to 160% were found. The results answer the important question: to what level of accuracy each input parameter needs to be determined in order to obtain accurate organ dose results.

Development of a golden beam data set for the commissioning of a proton double-scattering system in a pencil-beam dose calculation algorithm

DOE Office of Scientific and Technical Information (OSTI.GOV)

Slopsema, R. L., E-mail: rslopsema@floridaproton.org; Flampouri, S.; Yeung, D.

2014-09-15

Purpose: The purpose of this investigation is to determine if a single set of beam data, described by a minimal set of equations and fitting variables, can be used to commission different installations of a proton double-scattering system in a commercial pencil-beam dose calculation algorithm. Methods: The beam model parameters required to commission the pencil-beam dose calculation algorithm (virtual and effective SAD, effective source size, and pristine-peak energy spread) are determined for a commercial double-scattering system. These parameters are measured in a first room and parameterized as function of proton energy and nozzle settings by fitting four analytical equations tomore » the measured data. The combination of these equations and fitting values constitutes the golden beam data (GBD). To determine the variation in dose delivery between installations, the same dosimetric properties are measured in two additional rooms at the same facility, as well as in a single room at another facility. The difference between the room-specific measurements and the GBD is evaluated against tolerances that guarantee the 3D dose distribution in each of the rooms matches the GBD-based dose distribution within clinically reasonable limits. The pencil-beam treatment-planning algorithm is commissioned with the GBD. The three-dimensional dose distribution in water is evaluated in the four treatment rooms and compared to the treatment-planning calculated dose distribution. Results: The virtual and effective SAD measurements fall between 226 and 257 cm. The effective source size varies between 2.4 and 6.2 cm for the large-field options, and 1.0 and 2.0 cm for the small-field options. The pristine-peak energy spread decreases from 1.05% at the lowest range to 0.6% at the highest. The virtual SAD as well as the effective source size can be accurately described by a linear relationship as function of the inverse of the residual energy. An additional linear correction term as function of RM-step thickness is required for accurate parameterization of the effective SAD. The GBD energy spread is given by a linear function of the exponential of the beam energy. Except for a few outliers, the measured parameters match the GBD within the specified tolerances in all of the four rooms investigated. For a SOBP field with a range of 15 g/cm{sup 2} and an air gap of 25 cm, the maximum difference in the 80%–20% lateral penumbra between the GBD-commissioned treatment-planning system and measurements in any of the four rooms is 0.5 mm. Conclusions: The beam model parameters of the double-scattering system can be parameterized with a limited set of equations and parameters. This GBD closely matches the measured dosimetric properties in four different rooms.« less

A Monte Carlo study of macroscopic and microscopic dose descriptors for kilovoltage cellular dosimetry

NASA Astrophysics Data System (ADS)

Oliver, P. A. K.; Thomson, Rowan M.

2017-02-01

This work investigates how doses to cellular targets depend on cell morphology, as well as relations between cellular doses and doses to bulk tissues and water. Multicellular models of five healthy and cancerous soft tissues are developed based on typical values of cell compartment sizes, elemental compositions and number densities found in the literature. Cells are modelled as two concentric spheres with nucleus and cytoplasm compartments. Monte Carlo simulations are used to calculate the absorbed dose to the nucleus and cytoplasm for incident photon energies of 20-370 keV, relevant for brachytherapy, diagnostic radiology, and out-of-field radiation in higher-energy external beam radiotherapy. Simulations involving cell clusters, single cells and single nuclear cavities are carried out for cell radii between 5 and 10~μ m, and nuclear radii between 2 and 9~μ m. Seven nucleus and cytoplasm elemental compositions representative of animal cells are considered. The presence of a cytoplasm, extracellular matrix and surrounding cells can affect the nuclear dose by up to 13 % . Differences in cell and nucleus size can affect dose to the nucleus (cytoplasm) of the central cell in a cluster of 13 cells by up to 13 % (8 % ). Furthermore, the results of this study demonstrate that neither water nor bulk tissue are reliable substitutes for subcellular targets for incident photon energies  <50 keV: nuclear (cytoplasm) doses differ from dose-to-medium by up to 32 % (18 % ), and from dose-to-water by up to 21 % (8 % ). The largest differences between dose descriptors are seen for the lowest incident photon energies; differences are less than 3 % for energies ≥slant 90 keV. The sensitivity of results with regard to the parameters of the microscopic tissue structure model and cell model geometry, and the importance of the nucleus and cytoplasm as targets for radiation-induced cell death emphasize the importance of accurate models for cellular dosimetry studies.

A normal tissue dose response model of dynamic repair processes.

PubMed

Alber, Markus; Belka, Claus

2006-01-07

A model is presented for serial, critical element complication mechanisms for irradiated volumes from length scales of a few millimetres up to the entire organ. The central element of the model is the description of radiation complication as the failure of a dynamic repair process. The nature of the repair process is seen as reestablishing the structural organization of the tissue, rather than mere replenishment of lost cells. The interactions between the cells, such as migration, involved in the repair process are assumed to have finite ranges, which limits the repair capacity and is the defining property of a finite-sized reconstruction unit. Since the details of the repair processes are largely unknown, the development aims to make the most general assumptions about them. The model employs analogies and methods from thermodynamics and statistical physics. An explicit analytical form of the dose response of the reconstruction unit for total, partial and inhomogeneous irradiation is derived. The use of the model is demonstrated with data from animal spinal cord experiments and clinical data about heart, lung and rectum. The three-parameter model lends a new perspective to the equivalent uniform dose formalism and the established serial and parallel complication models. Its implications for dose optimization are discussed.

Differences between the nonselective adenosine receptor antagonists caffeine and theophylline in motor and mood effects: studies using medium to high doses in animal models.

PubMed

López-Cruz, Laura; Pardo, Marta; Salamone, John D; Correa, Mercè

2014-08-15

Caffeine and theophylline are methylxanthines that are broadly consumed, sometimes at high doses, and act as minor psychostimulants. Both are nonselective adenosine antagonists for A1 and A2A receptors, which are colocalized with dopamine D1 and D2 receptors in striatal areas. Adenosine antagonists generally have opposite actions to those of dopamine antagonists. Although the effects of caffeine are widely known, theophylline has been much less well characterized, especially at high doses. Adult male CD1 mice were used to study the effect of a broad range of doses (25.0, 50.0 or 100.0mg/kg) of caffeine and theophylline on measures of spontaneous locomotion and coordination, as well as the pattern of c-Fos immunoreactivity in brain areas rich in adenosine and dopamine receptors. In addition, we evaluated possible anxiety and stress effects of these doses. Caffeine, at these doses, impaired or suppressed locomotion in several paradigms. However, theophylline was less potent than caffeine at suppressing motor parameters, and even stimulated locomotion. Both drugs induced corticosterone release, however caffeine was more efficacious at intermediate doses. While caffeine showed an anxiogenic profile at all doses, theophylline only did so at the highest dose used (50mg/kg). Only theophylline increased c-Fos immunoreactivity in cortical areas. Theophylline has fewer disruptive effects than caffeine on motor parameters and produces less stress and anxiety effects. These results are relevant for understanding the potential side effects of methylxanthines when consumed at high doses. Copyright © 2014 Elsevier B.V. All rights reserved.

Technical aspects of the integration of three-dimensional treatment planning dose parameters (GEC-ESTRO Working Group) into pre-implant planning for LDR gynecological interstitial brachytherapy.

PubMed

Chi, A; Gao, M; Nguyen, N P; Albuquerque, K

2009-06-01

This study investigates the technical feasibility of pre-implant image-based treatment planning for LDR GYN interstitial brachytherapy(IB) based on the GEC-ESTRO guidelines. Initially, a virtual plan is generated based on the prescription dose and GEC-ESTRO defined OAR dose constraints with a pre-implant CT. After the actual implant, a regular diagnostic CT was obtained and fused with our pre-implant scan/initial treatment plan in our planning software. The Flexi-needle position changes, and treatment plan modifications were made if needed. Dose values were normalized to equivalent doses in 2 Gy fractions (LQED 2 Gy) derived from the linear-quadratic model with alpha/beta of 3 for late responding tissues and alpha/beta of 10 for early responding tissues. D(90) to the CTV, which was gross tumor (GTV) at the time of brachytherapy with a margin to count for microscopic disease, was 84.7 +/- 4.9% of the prescribed dose. The OAR doses were evaluated by D(2cc) (EBRT+IB). Mean D(2cc) values (LQED(2Gy)) for the rectum, bladder, sigmoid, and small bowel were the following: 63.7 +/- 8.4 Gy, 61.2 +/- 6.9 Gy, 48.0 +/- 3.5 Gy, and 49.9 +/- 4.2 Gy. This study confirms the feasibility of applying the GEC-ESTRO recommended dose parameters in pre-implant CT-based treatment planning in GYN IB. In the process, this pre-implant technique also demonstrates a good approximation of the target volume dose coverage, and doses to the OARs.

Population pharmacokinetic and pharmacogenetic analysis of 6-mercaptopurine in paediatric patients with acute lymphoblastic leukaemia

PubMed Central

Hawwa, Ahmed F; Collier, Paul S; Millership, Jeff S; McCarthy, Anthony; Dempsey, Sid; Cairns, Carole; McElnay, James C

2008-01-01

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECTThe cytotoxic effects of 6-mercaptopurine (6-MP) were found to be due to drug-derived intracellular metabolites (mainly 6-thioguanine nucleotides and to some extent 6-methylmercaptopurine nucleotides) rather than the drug itself.Current empirical dosing methods for oral 6-MP result in highly variable drug and metabolite concentrations and hence variability in treatment outcome. WHAT THIS STUDY ADDSThe first population pharmacokinetic model has been developed for 6-MP active metabolites in paediatric patients with acute lymphoblastic leukaemia and the potential demographic and genetically controlled factors that could lead to interpatient pharmacokinetic variability among this population have been assessed.The model shows a large reduction in interindividual variability of pharmacokinetic parameters when body surface area and thiopurine methyltransferase polymorphism are incorporated into the model as covariates.The developed model offers a more rational dosing approach for 6-MP than the traditional empirical method (based on body surface area) through combining it with pharmacogenetically guided dosing based on thiopurine methyltransferase genotype. AIMS To investigate the population pharmacokinetics of 6-mercaptopurine (6-MP) active metabolites in paediatric patients with acute lymphoblastic leukaemia (ALL) and examine the effects of various genetic polymorphisms on the disposition of these metabolites. METHODS Data were collected prospectively from 19 paediatric patients with ALL (n = 75 samples, 150 concentrations) who received 6-MP maintenance chemotherapy (titrated to a target dose of 75 mg m−2 day−1). All patients were genotyped for polymorphisms in three enzymes involved in 6-MP metabolism. Population pharmacokinetic analysis was performed with the nonlinear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance for the active metabolites. RESULTS The developed model revealed considerable interindividual variability (IIV) in the clearance of 6-MP active metabolites [6-thioguanine nucleotides (6-TGNs) and 6-methylmercaptopurine nucleotides (6-mMPNs)]. Body surface area explained a significant part of 6-TGNs clearance IIV when incorporated in the model (IIV reduced from 69.9 to 29.3%). The most influential covariate examined, however, was thiopurine methyltransferase (TPMT) genotype, which resulted in the greatest reduction in the model's objective function (P < 0.005) when incorporated as a covariate affecting the fractional metabolic transformation of 6-MP into 6-TGNs. The other genetic covariates tested were not statistically significant and therefore were not included in the final model. CONCLUSIONS The developed pharmacokinetic model (if successful at external validation) would offer a more rational dosing approach for 6-MP than the traditional empirical method since it combines the current practice of using body surface area in 6-MP dosing with a pharmacogenetically guided dosing based on TPMT genotype. PMID:18823306

Artificial neural network based gynaecological image-guided adaptive brachytherapy treatment planning correction of intra-fractional organs at risk dose variation.

PubMed

Jaberi, Ramin; Siavashpour, Zahra; Aghamiri, Mahmoud Reza; Kirisits, Christian; Ghaderi, Reza

2017-12-01

Intra-fractional organs at risk (OARs) deformations can lead to dose variation during image-guided adaptive brachytherapy (IGABT). The aim of this study was to modify the final accepted brachytherapy treatment plan to dosimetrically compensate for these intra-fractional organs-applicators position variations and, at the same time, fulfilling the dosimetric criteria. Thirty patients with locally advanced cervical cancer, after external beam radiotherapy (EBRT) of 45-50 Gy over five to six weeks with concomitant weekly chemotherapy, and qualified for intracavitary high-dose-rate (HDR) brachytherapy with tandem-ovoid applicators were selected for this study. Second computed tomography scan was done for each patient after finishing brachytherapy treatment with applicators in situ. Artificial neural networks (ANNs) based models were used to predict intra-fractional OARs dose-volume histogram parameters variations and propose a new final plan. A model was developed to estimate the intra-fractional organs dose variations during gynaecological intracavitary brachytherapy. Also, ANNs were used to modify the final brachytherapy treatment plan to compensate dosimetrically for changes in 'organs-applicators', while maintaining target dose at the original level. There are semi-automatic and fast responding models that can be used in the routine clinical workflow to reduce individually IGABT uncertainties. These models can be more validated by more patients' plans to be able to serve as a clinical tool.

"SABER": A new software tool for radiotherapy treatment plan evaluation.

PubMed

Zhao, Bo; Joiner, Michael C; Orton, Colin G; Burmeister, Jay

2010-11-01

Both spatial and biological information are necessary in order to perform true optimization of a treatment plan and for predicting clinical outcome. The goal of this work is to develop an enhanced treatment plan evaluation tool which incorporates biological parameters and retains spatial dose information. A software system is developed which provides biological plan evaluation with a novel combination of features. It incorporates hyper-radiosensitivity using the induced-repair model and applies the new concept of dose convolution filter (DCF) to simulate dose wash-out effects due to cell migration, bystander effect, and/or tissue motion during treatment. Further, the concept of spatial DVH (sDVH) is introduced to evaluate and potentially optimize the spatial dose distribution in the target volume. Finally, generalized equivalent uniform dose is derived from both the physical dose distribution (gEUD) and the distribution of equivalent dose in 2 Gy fractions (gEUD2) and the software provides three separate models for calculation of tumor control probability (TCP), normal tissue complication probability (NTCP), and probability of uncomplicated tumor control (P+). TCP, NTCP, and P+ are provided as a function of prescribed dose and multivariable TCP, NTCP, and P+ plots are provided to illustrate the dependence on individual parameters used to calculate these quantities. Ten plans from two clinical treatment sites are selected to test the three calculation models provided by this software. By retaining both spatial and biological information about the dose distribution, the software is able to distinguish features of radiotherapy treatment plans not discernible using commercial systems. Plans that have similar DVHs may have different spatial and biological characteristics and the application of novel tools such as sDVH and DCF within the software may substantially change the apparent plan quality or predicted plan metrics such as TCP and NTCP. For the cases examined, both the calculation method and the application of DCF can change the ranking order of competing plans. The voxel-by-voxel TCP model makes it feasible to incorporate spatial variations of clonogen densities (n), radiosensitivities (SF2), and fractionation sensitivities (alpha/beta) as those data become available. The new software incorporates both spatial and biological information into the treatment planning process. The application of multiple methods for the incorporation of biological and spatial information has demonstrated that the order of application of biological models can change the order of plan ranking. Thus, the results of plan evaluation and optimization are dependent not only on the models used but also on the order in which they are applied. This software can help the planner choose more biologically optimal treatment plans and potentially predict treatment outcome more accurately.

Analyzing the quality robustness of chemotherapy plans with respect to model uncertainties.

PubMed

Hoffmann, Anna; Scherrer, Alexander; Küfer, Karl-Heinz

2015-01-01

Mathematical models of chemotherapy planning problems contain various biomedical parameters, whose values are difficult to quantify and thus subject to some uncertainty. This uncertainty propagates into the therapy plans computed on these models, which poses the question of robustness to the expected therapy quality. This work introduces a combined approach for analyzing the quality robustness of plans in terms of dosing levels with respect to model uncertainties in chemotherapy planning. It uses concepts from multi-criteria decision making for studying parameters related to the balancing between the different therapy goals, and concepts from sensitivity analysis for the examination of parameters describing the underlying biomedical processes and their interplay. This approach allows for a profound assessment of a therapy plan, how stable its quality is with respect to parametric changes in the used mathematical model. Copyright © 2014 Elsevier Inc. All rights reserved.

SU-F-T-54: Determination of the AAPM TG-43 Brachytherapy Dosimetry Parameters for A New Titanium-Encapsulated Yb-169 Source by Monte Carlo Calculations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Reynoso, F; Washington University School of Medicine, St. Louis, MO; Munro, J

2016-06-15

Purpose: To determine the AAPM TG-43 brachytherapy dosimetry parameters of a new titanium-encapsulated Yb-169 source designed to maximize the dose enhancement during gold nanoparticle-aided radiation therapy (GNRT). Methods: An existing Monte Carlo (MC) model of the titanium-encapsulated Yb-169 source, which was described in the current investigators’ published MC optimization study, was modified based on the source manufacturer’s detailed specifications, resulting in an accurate model of the titanium-encapsulated Yb-169 source that was actually manufactured. MC calculations were then performed using the MCNP5 code system and the modified source model, in order to obtain a complete set of the AAPM TG-43 parametersmore » for the new Yb-169 source. Results: The MC-calculated dose rate constant for the new titanium-encapsulated Yb-169 source was 1.05 ± 0.03 cGy per hr U, indicating about 10% decrease from the values reported for the conventional stainless steel-encapsulated Yb-169 sources. The source anisotropy and radial dose function for the new source were found similar to those reported for the conventional Yb-169 sources. Conclusion: In this study, the AAPM TG-43 brachytherapy dosimetry parameters of a new titanium-encapsulated Yb-169 source were determined by MC calculations. The current results suggested that the use of titanium, instead of stainless steel, to encapsulate the Yb-169 core would not lead to any major change in the dosimetric characteristics of the Yb-169 source, while it would allow more low energy photons being transmitted through the source filter thereby leading to an increased dose enhancement during GNRT. Supported by DOD/PCRP grant W81XWH-12-1-0198 This investigation was supported by DOD/PCRP grant W81XWH-12-1- 0198.« less

Predictors of High-Grade Esophagitis after Definitive 3D Conformal Therapy, Intensity Modulated Radiation Therapy, or Proton Beam Therapy for Non-Small Cell Lung Cancer

PubMed Central

Gomez, Daniel R.; Tucker, Susan L.; Martel, Mary K.; Mohan, Radhe; Balter, Peter A.; Guerra, Jose Luis Lopez; Liu, Hongmei; Komaki, Ritsuko; Cox, James D.; Liao, Zhongxing

2014-01-01

Introduction We analyzed the ability of various patient- and treatment-related factors to predict radiation-induced esophagitis (RE) in patients with non-small cell lung cancer (NSCLC) treated with three-dimensional (3D) conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), or proton beam therapy (PBT). Methods and Materials Patients were treated for NSCLC with 3D-CRT, IMRT, or PBT at MD Anderson from 2000 to 2008 and had full dose-volume histogram (DVH) data available. The endpoint was severe (grade ≥3) RE. The Lyman-Kutcher-Burman (LKB) model was used to analyze RE as a function of the fractional esophageal DVH, with clinical variables included as dose-modifying factors. Results Overall, 652 patients were included: 405 treated with 3D-CRT, 139 with IMRT, and 108 with PBT; corresponding rates of grade ≥3 RE were 8%, 28%, and 6%, with a median time to onset of 42 days (range 11–93 days). A fit of the fractional-DVH LKB model demonstrated that the volume parameter n was significantly different (p=0.046) than 1, indicating that high doses to small volumes are more predictive than mean esophageal dose. The model fit was better for 3D-CRT and PBT than for IMRT. Including receipt of concurrent chemotherapy as a dose-modifying factor significantly improved the LKB model (p=0.005), and the model was further improved by including a variable representing treatment with >30 fractions. Examining individual types of chemotherapy agents revealed a trend toward receipt of concurrent taxanes and increased risk of RE (p=0.105). Conclusions The fractional dose (dose rate) and number of fractions (total dose) distinctly affect the risk of severe RE estimated using the LKB model, and concurrent chemotherapy improves the model fit. This risk of severe RE is underestimated by this model in patients receiving IMRT. PMID:22920974

WE-AB-207B-10: On Spinal Nerve Toxicity from Single-Session SAbR in Pigs and the Translation of Small Animal NTCP Models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hrycushko, B; Medin, P

Purpose: The incidence of peripheral neuropathy has risen with increased utilization of SAbR. There is no consensus regarding the dose-tolerance of the peripheral nervous system. In 2015, we commenced an investigation to test the hypotheses that single-session irradiation to the pig spinal nerves exhibit a similar dose-tolerance as that of the spinal cord and that a dose-length effect exists. This work evaluates the direct application of small animal NTCP models to both large animal spinal cord and preliminary peripheral nerve data. Methods: To date, 16 of 25 Yucatan minipigs have received single-session SAbR to a 1.5cm length and 4 ofmore » 25 have received irradiation to a 0.5cm length of left-sided C6-C8 spinal nerves. Toxicity related gait change has been observed in 13 animals (9 from the long length group and 4 from the short). This preliminary data is overlaid on several dose-response models which have been fit to rodent spinal cord tolerance experiments. Model parameters define a toxicity profile between a completely serial or parallel behaving organ. Adequacy of model application, including how length effects are handled, to published minipig spinal cord dose-response data and to preliminary peripheral nerve response data was evaluated through residual analysis. Results: No rodent-derived dose-response models were directly applicable to all pig data for the different lengths irradiated. Several models fit the long-length irradiated spinal cord data well, with the more serial-like models fitting best. Preliminary data on the short-length irradiation suggests no length effect exists, disproving our hypothesis. Conclusion: Direct application of small-animal NTCP models to pig data suggests dose-length effect predictions from small animal data may not translate clinically. However, the small animal models used have not considered dose heterogeneity and it is expected that including the low-to-mid dose levels in the penumbral region will improve this match. This work was funded by the Cancer Prevention Research Institute of Texas (CPRIT).« less

Usefulness of model-based iterative reconstruction in semi-automatic volumetry for ground-glass nodules at ultra-low-dose CT: a phantom study.

PubMed

Maruyama, Shuki; Fukushima, Yasuhiro; Miyamae, Yuta; Koizumi, Koji

2018-06-01

This study aimed to investigate the effects of parameter presets of the forward projected model-based iterative reconstruction solution (FIRST) on the accuracy of pulmonary nodule volume measurement. A torso phantom with simulated nodules [diameter: 5, 8, 10, and 12 mm; computed tomography (CT) density: - 630 HU] was scanned with a multi-detector CT at tube currents of 10 mA (ultra-low-dose: UL-dose) and 270 mA (standard-dose: Std-dose). Images were reconstructed with filtered back projection [FBP; standard (Std-FBP), ultra-low-dose (UL-FBP)], FIRST Lung (UL-Lung), and FIRST Body (UL-Body), and analyzed with a semi-automatic software. The error in the volume measurement was determined. The errors with UL-Lung and UL-Body were smaller than that with UL-FBP. The smallest error was 5.8% ± 0.3 for the 12-mm nodule with UL-Body (middle lung). Our results indicated that FIRST Body would be superior to FIRST Lung in terms of accuracy of nodule measurement with UL-dose CT.

Monte Carlo simulation of secondary neutron dose for scanning proton therapy using FLUKA

PubMed Central

Lee, Chaeyeong; Lee, Sangmin; Lee, Seung-Jae; Song, Hankyeol; Kim, Dae-Hyun; Cho, Sungkoo; Jo, Kwanghyun; Han, Youngyih; Chung, Yong Hyun

2017-01-01

Proton therapy is a rapidly progressing field for cancer treatment. Globally, many proton therapy facilities are being commissioned or under construction. Secondary neutrons are an important issue during the commissioning process of a proton therapy facility. The purpose of this study is to model and validate scanning nozzles of proton therapy at Samsung Medical Center (SMC) by Monte Carlo simulation for beam commissioning. After the commissioning, a secondary neutron ambient dose from proton scanning nozzle (Gantry 1) was simulated and measured. This simulation was performed to evaluate beam properties such as percent depth dose curve, Bragg peak, and distal fall-off, so that they could be verified with measured data. Using the validated beam nozzle, the secondary neutron ambient dose was simulated and then compared with the measured ambient dose from Gantry 1. We calculated secondary neutron dose at several different points. We demonstrated the validity modeling a proton scanning nozzle system to evaluate various parameters using FLUKA. The measured secondary neutron ambient dose showed a similar tendency with the simulation result. This work will increase the knowledge necessary for the development of radiation safety technology in medical particle accelerators. PMID:29045491

A nonlinear isobologram model with Box-Cox transformation to both sides for chemical mixtures.

PubMed

Chen, D G; Pounds, J G

1998-12-01

The linear logistical isobologram is a commonly used and powerful graphical and statistical tool for analyzing the combined effects of simple chemical mixtures. In this paper a nonlinear isobologram model is proposed to analyze the joint action of chemical mixtures for quantitative dose-response relationships. This nonlinear isobologram model incorporates two additional new parameters, Ymin and Ymax, to facilitate analysis of response data that are not constrained between 0 and 1, where parameters Ymin and Ymax represent the minimal and the maximal observed toxic response. This nonlinear isobologram model for binary mixtures can be expressed as [formula: see text] In addition, a Box-Cox transformation to both sides is introduced to improve the goodness of fit and to provide a more robust model for achieving homogeneity and normality of the residuals. Finally, a confidence band is proposed for selected isobols, e.g., the median effective dose, to facilitate graphical and statistical analysis of the isobologram. The versatility of this approach is demonstrated using published data describing the toxicity of the binary mixtures of citrinin and ochratoxin as well as a new experimental data from our laboratory for mixtures of mercury and cadmium.

A nonlinear isobologram model with Box-Cox transformation to both sides for chemical mixtures.

PubMed Central

Chen, D G; Pounds, J G

1998-01-01

The linear logistical isobologram is a commonly used and powerful graphical and statistical tool for analyzing the combined effects of simple chemical mixtures. In this paper a nonlinear isobologram model is proposed to analyze the joint action of chemical mixtures for quantitative dose-response relationships. This nonlinear isobologram model incorporates two additional new parameters, Ymin and Ymax, to facilitate analysis of response data that are not constrained between 0 and 1, where parameters Ymin and Ymax represent the minimal and the maximal observed toxic response. This nonlinear isobologram model for binary mixtures can be expressed as [formula: see text] In addition, a Box-Cox transformation to both sides is introduced to improve the goodness of fit and to provide a more robust model for achieving homogeneity and normality of the residuals. Finally, a confidence band is proposed for selected isobols, e.g., the median effective dose, to facilitate graphical and statistical analysis of the isobologram. The versatility of this approach is demonstrated using published data describing the toxicity of the binary mixtures of citrinin and ochratoxin as well as a new experimental data from our laboratory for mixtures of mercury and cadmium. PMID:9860894

Physiologically-Based Pharmacokinetic Modeling of Macitentan: Prediction of Drug-Drug Interactions.

PubMed

de Kanter, Ruben; Sidharta, Patricia N; Delahaye, Stéphane; Gnerre, Carmela; Segrestaa, Jerome; Buchmann, Stephan; Kohl, Christopher; Treiber, Alexander

2016-03-01

Macitentan is a novel dual endothelin receptor antagonist for the treatment of pulmonary arterial hypertension (PAH). It is metabolized by cytochrome P450 (CYP) enzymes, mainly CYP3A4, to its active metabolite ACT-132577. A physiological-based pharmacokinetic (PBPK) model was developed by combining observations from clinical studies and physicochemical parameters as well as absorption, distribution, metabolism and excretion parameters determined in vitro. The model predicted the observed pharmacokinetics of macitentan and its active metabolite ACT-132577 after single and multiple dosing. It performed well in recovering the observed effect of the CYP3A4 inhibitors ketoconazole and cyclosporine, and the CYP3A4 inducer rifampicin, as well as in predicting interactions with S-warfarin and sildenafil. The model was robust enough to allow prospective predictions of macitentan-drug combinations not studied, including an alternative dosing regimen of ketoconazole and nine other CYP3A4-interacting drugs. Among these were the HIV drugs ritonavir and saquinavir, which were included because HIV infection is a known risk factor for the development of PAH. This example of the application of PBPK modeling to predict drug-drug interactions was used to support the labeling of macitentan (Opsumit).

An age dependent model for radium metabolism in man.

PubMed

Johnson, J R

1983-01-01

The model developed by a Task Group of Committee 2 of ICRP to describe Alkaline Earth Metabolism in Adult Man (ICRP Publication 20) has been modified so that recycling is handled explicitly, and retention in mineral bone is represented by second compartments rather than by the product of a power function and an exponential. This model has been extended to include all ages from birth to adult man, and has been coupled with modified "ICRP" lung and G.I. tract models so that activity in organs can be calculated as functions of time during or after exposures. These activities, and age dependent "specific effective energy" factors, are then used to calculate age dependent dose rates, and dose commitments. This presentation describes this work, with emphasis on the model parameters and results obtained for radium.

SU-E-T-50: Automatic Validation of Megavoltage Beams Modeled for Clinical Use in Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Melchior, M; Salinas Aranda, F; 21st Century Oncology, Ft. Myers, FL

2014-06-01

Purpose: To automatically validate megavoltage beams modeled in XiO™ 4.50 (Elekta, Stockholm, Sweden) and Varian Eclipse™ Treatment Planning Systems (TPS) (Varian Associates, Palo Alto, CA, USA), reducing validation time before beam-on for clinical use. Methods: A software application that can automatically read and analyze DICOM RT Dose and W2CAD files was developed using MatLab integrated development environment.TPS calculated dose distributions, in DICOM RT Dose format, and dose values measured in different Varian Clinac beams, in W2CAD format, were compared. Experimental beam data used were those acquired for beam commissioning, collected on a water phantom with a 2D automatic beam scanningmore » system.Two methods were chosen to evaluate dose distributions fitting: gamma analysis and point tests described in Appendix E of IAEA TECDOC-1583. Depth dose curves and beam profiles were evaluated for both open and wedged beams. Tolerance parameters chosen for gamma analysis are 3% and 3 mm dose and distance, respectively.Absolute dose was measured independently at points proposed in Appendix E of TECDOC-1583 to validate software results. Results: TPS calculated depth dose distributions agree with measured beam data under fixed precision values at all depths analyzed. Measured beam dose profiles match TPS calculated doses with high accuracy in both open and wedged beams. Depth and profile dose distributions fitting analysis show gamma values < 1. Relative errors at points proposed in Appendix E of TECDOC-1583 meet therein recommended tolerances.Independent absolute dose measurements at points proposed in Appendix E of TECDOC-1583 confirm software results. Conclusion: Automatic validation of megavoltage beams modeled for their use in the clinic was accomplished. The software tool developed proved efficient, giving users a convenient and reliable environment to decide whether to accept or not a beam model for clinical use. Validation time before beam-on for clinical use was reduced to a few hours.« less

WAZA-ARI: computational dosimetry system for X-ray CT examinations II: development of web-based system.

PubMed

Ban, Nobuhiko; Takahashi, Fumiaki; Ono, Koji; Hasegawa, Takayuki; Yoshitake, Takayasu; Katsunuma, Yasushi; Sato, Kaoru; Endo, Akira; Kai, Michiaki

2011-07-01

A web-based dose computation system, WAZA-ARI, is being developed for patients undergoing X-ray CT examinations. The system is implemented in Java on a Linux server running Apache Tomcat. Users choose scanning options and input parameters via a web browser over the Internet. Dose coefficients, which were calculated in a Japanese adult male phantom (JM phantom) are called upon user request and are summed over the scan range specified by the user to estimate a normalised dose. Tissue doses are finally computed based on the radiographic exposure (mA s) and the pitch factor. While dose coefficients are currently available only for limited CT scanner models, the system has achieved a high degree of flexibility and scalability without the use of commercial software.

Blockade of the High-Affinity Interleukin-2 Receptors with Daclizumab High-Yield Process: Pharmacokinetic/Pharmacodynamic Analysis of Single- and Multiple-Dose Phase I Trials.

PubMed

Minocha, Mukul; Tran, Jonathan Q; Sheridan, James P; Othman, Ahmed A

2016-01-01

Daclizumab high-yield process (DAC HYP) is a humanized monoclonal antibody that selectively blocks the α-subunit (CD25) of the high-affinity interleukin-2 receptors, and has shown robust efficacy as a treatment for multiple sclerosis (MS). This work quantitatively characterized the relationship between DAC HYP serum concentrations and saturation of CD25 expressed on antigen-rich target T cells in blood. Serial pharmacokinetic and 968 CD25 measurements from three double-blind, randomized, placebo-controlled, phase I studies of DAC HYP (50-300 mg subcutaneous and 200-400 mg intravenous doses or placebo) in healthy volunteers (n = 95) were analyzed using nonlinear mixed-effects modeling. CD25 occupancy was determined using flow cytometry and a fluorescently-labeled DAC HYP-competing antibody. CD25 occupancy was described using a direct inhibitory sigmoidal maximum effect (E max) model (where DAC HYP fully inhibited CD25 labeling with competing antibody). Two IC50 (serum concentration corresponding to 50 % of maximal inhibition) parameters were used to describe rapid CD25 saturation at initiation of dosing and apparently slower desaturation during DAC HYP washout. Parameter estimates (95 % bootstrap confidence intervals) were: baseline CD25 labeling, 47 % (45-48); DAC HYP IC50(saturation), 0.023 µg/mL (0.005-0.073); IC50(desaturation) 0.86 µg/mL (0.74-0.98); Hill coefficient 5.6 (4.3-6.8). Based on the developed model, the 150 mg monthly subcutaneous regimen of DAC HYP in subjects with MS is predicted to saturate CD25 on target effector T cells within a few hours of dosing and maintain CD25 saturation during the entire dosing interval. Free CD25 levels return to baseline within 4-6 months of the last DAC HYP dose.

Pharmacokinetics, Microbial Response, and Pulmonary Outcomes of Multidose Intravenous Azithromycin in Preterm Infants at Risk for Ureaplasma Respiratory Colonization

PubMed Central

Merchan, L. Marcela; Hassan, Hazem E.; Terrin, Michael L.; Waites, Ken B.; Kaufman, David A.; Ambalavanan, Namasivayam; Donohue, Pamela; Dulkerian, Susan J.; Schelonka, Robert; Magder, Laurence S.; Shukla, Sagar; Eddington, Natalie D.

2014-01-01

The study objectives were to refine the population pharmacokinetics (PK) model, determine microbial clearance, and assess short-term pulmonary outcomes of multiple-dose azithromycin treatment in preterm infants at risk for Ureaplasma respiratory colonization. Fifteen subjects (7 of whom were Ureaplasma positive) received intravenous azithromycin at 20 mg/kg of body weight every 24 h for 3 doses. Azithromycin concentrations were determined in plasma samples obtained up to 168 h post-first dose by using a validated liquid chromatography-tandem mass spectrometry method. Respiratory samples were obtained predose and at three time points post-last dose for Ureaplasma culture, PCR, antibiotic susceptibility testing, and cytokine concentration determinations. Pharmacokinetic data from these 15 subjects as well as 25 additional subjects (who received either a single 10-mg/kg dose [n = 12] or a single 20-mg/kg dose [n = 13]) were analyzed by using a nonlinear mixed-effect population modeling (NONMEM) approach. Pulmonary outcomes were assessed at 36 weeks post-menstrual age and 6 months adjusted age. A 2-compartment model with all PK parameters allometrically scaled on body weight best described the azithromycin pharmacokinetics in preterm neonates. The population pharmacokinetics parameter estimates for clearance, central volume of distribution, intercompartmental clearance, and peripheral volume of distribution were 0.15 liters/h · kg0.75, 1.88 liters · kg, 1.79 liters/h · kg0.75, and 13 liters · kg, respectively. The estimated area under the concentration-time curve over 24 h (AUC24)/MIC90 value was ∼4 h. All posttreatment cultures were negative, and there were no drug-related adverse events. One Ureaplasma-positive infant died at 4 months of age, but no survivors were hospitalized for respiratory etiologies during the first 6 months (adjusted age). Thus, a 3-day course of 20 mg/kg/day intravenous azithromycin shows preliminary efficacy in eradicating Ureaplasma spp. from the preterm respiratory tract. PMID:25385115

Non-linear absorption pharmacokinetics of amoxicillin: consequences for dosing regimens and clinical breakpoints.

PubMed

de Velde, Femke; de Winter, Brenda C M; Koch, Birgit C P; van Gelder, Teun; Mouton, Johan W

2016-10-01

To describe the population pharmacokinetics of oral amoxicillin and to compare the PTA of current dosing regimens. Two groups, each with 14 healthy male volunteers, received oral amoxicillin/clavulanic acid tablets on two separate days 1 week apart. One group received 875/125 mg twice daily and 500/125 mg three times daily and the other group 500/125 mg twice daily and 250/125 mg three times daily. A total of 1428 amoxicillin blood samples were collected before and after administration. We analysed the concentration-time profiles using a non-compartmental pharmacokinetic method (PKSolver) and a population pharmacokinetic method (NONMEM). The PTA was computed using Monte Carlo simulations for several dosing regimens. AUC0-24 and Cmax increased non-linearly with dose. The final model included the following components: Savic's transit compartment model, Michaelis-Menten absorption, two distribution compartments and first-order elimination. The mean central volume of distribution was 27.7 L and mean clearance was 21.3 L/h. We included variability for the central volume of distribution (34.4%), clearance (25.8%), transit compartment model parameters and Michaelis-Menten absorption parameters. For 40% fT>MIC and >97.5% PTA, the breakpoints were 0.125 mg/L (500 mg twice daily), 0.25 mg/L (250 mg three times daily and 875 mg twice daily), 0.5 mg/L (500 mg three times daily) and 1 mg/L (750, 875 or 1000 mg three times daily and 500 mg four times daily). The amoxicillin absorption rate appears to be saturable. The PTAs of high-dose as well as twice-daily regimens are less favourable than regimens with lower doses and higher frequency. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

A nonhuman primate model of the hematopoietic acute radiation syndrome plus medical management.

PubMed

Farese, Ann M; Cohen, Melanie V; Katz, Barry P; Smith, Cassandra P; Jackson, William; Cohen, Daniel M; MacVittie, Thomas J

2012-10-01

The development of medical countermeasures against the hematopoietic subsyndrome of the acute radiation syndrome requires well characterized and validated animal models. The model must define the radiation dose- and time-dependent relationships for mortality and major signs of morbidity to include other organ damage that may contribute to morbidity and mortality. Herein, the authors define these parameters for a nonhuman primate exposed to total body radiation and administered medical management. A blinded, randomized study (n = 48 rhesus macaques) determined the lethal dose-response relationship using bilateral 6 MV linear accelerator photon radiation to doses in the range of 7.20 to 8.90 Gy at 0.80 Gy min(-1). Following irradiation, animals were monitored for complete bloodcounts, body weight, temperature, diarrhea, and hydration status for 60 d. Animals were administered medical management consisting of intravenous fluids, prophylactic antibiotics, blood transfusions, anti-diarrheals, analgesics, and nutrition. The primary endpoint was survival at 60 d post-irradiation; secondary endpoints included hematopoietic-related parameters, number of transfusions, incidence of documented infection, febrile neutropenia, severity of diarrhea, mean survival time of decedents, and tissue histology. The study defined an LD30/60 of 7.06 Gy, LD50/60 of 7.52 Gy, and an LD70/60 of 7.99 Gy with a relatively steep slope of 1.13 probits per linear dose. This study establishes a rhesus macaque model of the hematopoietic acute radiation syndrome and shows the marked effect of medical management on increased survival and overall mean survival time for decedents. Furthermore, following a nuclear terrorist event, medical management may be the only treatment administered at its optimal schedule.

Population Pharmacokinetics of Bevacizumab in Children with Osteosarcoma: Implications for Dosing

PubMed Central

Turner, David C.; Navid, Fariba; Daw, Najat C.; Mao, Shenghua; Wu, Jianrong; Santana, Victor M.; Neel, Michael; Rao, Bhaskar; Willert, Jennifer Reikes; Loeb, David M.; Harstead, K. Elaine; Throm, Stacy L.; Freeman, Burgess B.; Stewart, Clinton F.

2014-01-01

Purpose To describe sources of interindividual variability in bevacizumab disposition in pediatric patients and explore associations among bevacizumab pharmacokinetics and clinical wound healing outcomes. Experimental Design Prior to tumor resection, three doses of bevacizumab (15 mg/kg) were administered to patients (median age 12.2 years) enrolled on a multi-institutional osteosarcoma trial. Serial sampling for bevacizumab pharmacokinetics was obtained from 27 patients. A population pharmacokinetic model was fit to the data, and patient demographics and clinical chemistry values were systematically tested as predictive covariates on model parameters. Associations between bevacizumab exposure and wound healing status were evaluated by logistic regression. Results Bevacizumab concentration-time data were adequately described by a two-compartment model. Pharmacokinetic parameter estimates were similar to those previously reported in adults with a long median (range) terminal half-life of 12.2 days (8.6 to 32.4 days) and a volume of distribution indicating confinement primarily to the vascular space,49.1 mL/kg (27.1 to 68.3 mL/kg). Body composition was a key determinant of bevacizumab exposure as body mass index percentile was significantly (p<0.05) correlated to body-weight normalized clearance and volume of distribution. Furthermore, bevacizumab exposure prior to primary tumor resection was associated with increased risk of major wound healing complications after surgery (p<0.05). Conclusion A population pharmacokinetic model for bevacizumab was developed which demonstrated that variability in bevacizumab exposure using weight-based dosing is related to body composition. Bevacizumab dosage scaling using ideal body weight would provide an improved dosing approach in children by minimizing pharmacokinetic variability and reducing likelihood of major wound healing complications. PMID:24637635

Model-Based Approach to Predict Adherence to Protocol During Antiobesity Trials.

PubMed

Sharma, Vishnu D; Combes, François P; Vakilynejad, Majid; Lahu, Gezim; Lesko, Lawrence J; Trame, Mirjam N

2018-02-01

Development of antiobesity drugs is continuously challenged by high dropout rates during clinical trials. The objective was to develop a population pharmacodynamic model that describes the temporal changes in body weight, considering disease progression, lifestyle intervention, and drug effects. Markov modeling (MM) was applied for quantification and characterization of responder and nonresponder as key drivers of dropout rates, to ultimately support the clinical trial simulations and the outcome in terms of trial adherence. Subjects (n = 4591) from 6 Contrave ® trials were included in this analysis. An indirect-response model developed by van Wart et al was used as a starting point. Inclusion of drug effect was dose driven using a population dose- and time-dependent pharmacodynamic (DTPD) model. Additionally, a population-pharmacokinetic parameter- and data (PPPD)-driven model was developed using the final DTPD model structure and final parameter estimates from a previously developed population pharmacokinetic model based on available Contrave ® pharmacokinetic concentrations. Last, MM was developed to predict transition rate probabilities among responder, nonresponder, and dropout states driven by the pharmacodynamic effect resulting from the DTPD or PPPD model. Covariates included in the models and parameters were diabetes mellitus and race. The linked DTPD-MM and PPPD-MM was able to predict transition rates among responder, nonresponder, and dropout states well. The analysis concluded that body-weight change is an important factor influencing dropout rates, and the MM depicted that overall a DTPD model-driven approach provides a reasonable prediction of clinical trial outcome probabilities similar to a pharmacokinetic-driven approach. © 2017, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Prophylactic ranitidine treatment in critically ill children – a population pharmacokinetic study

PubMed Central

Hawwa, Ahmed F; Westwood, Paul M; Collier, Paul S; Millership, Jeffrey S; Yakkundi, Shirish; Thurley, Gillian; Shields, Mike D; Nunn, Anthony J; Halliday, Henry L; McElnay, James C

2013-01-01

Aims To characterize the population pharmacokinetics of ranitidine in critically ill children and to determine the influence of various clinical and demographic factors on its disposition. Methods Data were collected prospectively from 78 paediatric patients (n = 248 plasma samples) who received oral or intravenous ranitidine for prophylaxis against stress ulcers, gastrointestinal bleeding or the treatment of gastro-oesophageal reflux. Plasma samples were analysed using high-performance liquid chromatography, and the data were subjected to population pharmacokinetic analysis using nonlinear mixed-effects modelling. Results A one-compartment model best described the plasma concentration profile, with an exponential structure for interindividual errors and a proportional structure for intra-individual error. After backward stepwise elimination, the final model showed a significant decrease in objective function value (−12.618; P < 0.001) compared with the weight-corrected base model. Final parameter estimates for the population were 32.1 l h−1 for total clearance and 285 l for volume of distribution, both allometrically modelled for a 70 kg adult. Final estimates for absorption rate constant and bioavailability were 1.31 h−1 and 27.5%, respectively. No significant relationship was found between age and weight-corrected ranitidine pharmacokinetic parameters in the final model, with the covariate for cardiac failure or surgery being shown to reduce clearance significantly by a factor of 0.46. Conclusions Currently, ranitidine dose recommendations are based on children's weights. However, our findings suggest that a dosing scheme that takes into consideration both weight and cardiac failure/surgery would be more appropriate in order to avoid administration of higher or more frequent doses than necessary. PMID:23016949

New Insights to Compare and Choose TKTD Models for Survival Based on an Interlaboratory Study for Lymnaea stagnalis Exposed to Cd.

PubMed

Baudrot, Virgile; Preux, Sara; Ducrot, Virginie; Pave, Alain; Charles, Sandrine

2018-02-06

Toxicokinetic-toxicodynamic (TKTD) models, as the General Unified Threshold model of Survival (GUTS), provide a consistent process-based framework compared to classical dose-response models to analyze both time and concentration-dependent data sets. However, the extent to which GUTS models (Stochastic Death (SD) and Individual Tolerance (IT)) lead to a better fitting than classical dose-response model at a given target time (TT) has poorly been investigated. Our paper highlights that GUTS estimates are generally more conservative and have a reduced uncertainty through smaller credible intervals for the studied data sets than classical TT approaches. Also, GUTS models enable estimating any x% lethal concentration at any time (LC x,t ), and provide biological information on the internal processes occurring during the experiments. While both GUTS-SD and GUTS-IT models outcompete classical TT approaches, choosing one preferentially to the other is still challenging. Indeed, the estimates of survival rate over time and LC x,t are very close between both models, but our study also points out that the joint posterior distributions of SD model parameters are sometimes bimodal, while two parameters of the IT model seems strongly correlated. Therefore, the selection between these two models has to be supported by the experimental design and the biological objectives, and this paper provides some insights to drive this choice.

Joint feedback analysis modeling of nonesterified fatty acids in obese Zucker rats and normal Sprague-Dawley rats after different routes of administration of nicotinic acid.

PubMed

Tapani, Sofia; Almquist, Joachim; Leander, Jacob; Ahlström, Christine; Peletier, Lambertus A; Jirstrand, Mats; Gabrielsson, Johan

2014-08-01

Data were pooled from several studies on nicotinic acid (NiAc) intervention of fatty acid turnover in normal Sprague-Dawley and obese Zucker rats in order to perform a joint PKPD of data from more than 100 normal Sprague-Dawley and obese Zucker rats, exposed to several administration routes and rates. To describe the difference in pharmacodynamic parameters between obese and normal rats, we modified a previously published nonlinear mixed effects model describing tolerance and oscillatory rebound effects of NiAc on nonesterified fatty acids plasma concentrations. An important conclusion is that planning of experiments and dose scheduling cannot rely on pilot studies on normal animals alone. The obese rats have a less-pronounced concentration-response relationship and need higher doses to exhibit desired response. The relative level of fatty acid rebound after cessation of NiAc administration was also quantified in the two rat populations. Building joint normal-disease models with scaling parameter(s) to characterize the "degree of disease" can be a useful tool when designing informative experiments on diseased animals, particularly in the preclinical screen. Data were analyzed using nonlinear mixed effects modeling, for the optimization, we used an improved method for calculating the gradient than the usually adopted finite difference approximation. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

SU-F-J-178: A Computer Simulation Model Observer for Task-Based Image Quality Assessment in Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dolly, S; Mutic, S; Anastasio, M

Purpose: Traditionally, image quality in radiation therapy is assessed subjectively or by utilizing physically-based metrics. Some model observers exist for task-based medical image quality assessment, but almost exclusively for diagnostic imaging tasks. As opposed to disease diagnosis, the task for image observers in radiation therapy is to utilize the available images to design and deliver a radiation dose which maximizes patient disease control while minimizing normal tissue damage. The purpose of this study was to design and implement a new computer simulation model observer to enable task-based image quality assessment in radiation therapy. Methods: A modular computer simulation framework wasmore » developed to resemble the radiotherapy observer by simulating an end-to-end radiation therapy treatment. Given images and the ground-truth organ boundaries from a numerical phantom as inputs, the framework simulates an external beam radiation therapy treatment and quantifies patient treatment outcomes using the previously defined therapeutic operating characteristic (TOC) curve. As a preliminary demonstration, TOC curves were calculated for various CT acquisition and reconstruction parameters, with the goal of assessing and optimizing simulation CT image quality for radiation therapy. Sources of randomness and bias within the system were analyzed. Results: The relationship between CT imaging dose and patient treatment outcome was objectively quantified in terms of a singular value, the area under the TOC (AUTOC) curve. The AUTOC decreases more rapidly for low-dose imaging protocols. AUTOC variation introduced by the dose optimization algorithm was approximately 0.02%, at the 95% confidence interval. Conclusion: A model observer has been developed and implemented to assess image quality based on radiation therapy treatment efficacy. It enables objective determination of appropriate imaging parameter values (e.g. imaging dose). Framework flexibility allows for incorporation of additional modules to include any aspect of the treatment process, and therefore has great potential for both assessment and optimization within radiation therapy.« less

Insights into the mechanism of X-ray-induced disulfide-bond cleavage in lysozyme crystals based on EPR, optical absorption and X-ray diffraction studies.

PubMed

Sutton, Kristin A; Black, Paul J; Mercer, Kermit R; Garman, Elspeth F; Owen, Robin L; Snell, Edward H; Bernhard, William A

2013-12-01

Electron paramagnetic resonance (EPR) and online UV-visible absorption microspectrophotometry with X-ray crystallography have been used in a complementary manner to follow X-ray-induced disulfide-bond cleavage. Online UV-visible spectroscopy showed that upon X-irradiation, disulfide radicalization appeared to saturate at an absorbed dose of approximately 0.5-0.8 MGy, in contrast to the saturating dose of ∼0.2 MGy observed using EPR at much lower dose rates. The observations suggest that a multi-track model involving product formation owing to the interaction of two separate tracks is a valid model for radiation damage in protein crystals. The saturation levels are remarkably consistent given the widely different experimental parameters and the range of total absorbed doses studied. The results indicate that even at the lowest doses used for structural investigations disulfide bonds are already radicalized. Multi-track considerations offer the first step in a comprehensive model of radiation damage that could potentially lead to a combined computational and experimental approach to identifying when damage is likely to be present, to quantitate it and to provide the ability to recover the native unperturbed structure.

The acute gastrointestinal subsyndrome of the acute radiation syndrome: a rhesus macaque model.

PubMed

MacVittie, Thomas J; Farese, Ann M; Bennett, Alexander; Gelfond, Daniel; Shea-Donohue, Terez; Tudor, Gregory; Booth, Catherine; McFarland, Emylee; Jackson, William

2012-10-01

The development of medical countermeasures against the acute gastrointestinal subsyndrome of the acute radiation syndrome in humans requires well characterized and validated animal models. These models must adhere to the criteria of the U.S. Food and Drug Administration's Animal Rule and consider the natural history and clinical context of the human radiation response and treatment in the nuclear terrorist scenario. The models must define the radiation dose- and time-dependent relationships for mortality and major signs of morbidity, including concurrent damage in other organs, such as the bone marrow, that may contribute to the overall mortality and morbidity. There are no such models of the gastrointestinal syndrome in response to total-body irradiation in the nonhuman primate. Herein, these parameters are defined for the rhesus macaque exposed to potentially lethal doses of radiation and administered medical management. Rhesus macaques (n = 69) were exposed bilaterally to 6 MV linear accelerator-derived photon total body irradiation to midline tissue (thorax) doses ranging from 10.0 to 14.0 Gy at 0.80 Gy min(-1). Following irradiation, all animals were administered supportive care consisting of fluids, anti-emetics, anti-diarrheal medication, antibiotics, blood transfusions, analgesics, and nutrition. The primary endpoint was survival at 15 d post-irradiation. Secondary endpoints included indices of dehydration, diarrhea, weight loss, hematological parameters, cellular histology of the small and large intestine, and mean survival time of decedents. Mortality within the 15-d in vivo study defined the acute gastrointestinal syndrome and provided an LD30/15 of 10.76 Gy, LD50/15 of 11.33 Gy, and an LD70/15 of 11.90 Gy. Intestinal crypt and villus loss were dose- and time-dependent with an apparent nadir 7 d post-irradiation and recovery noted thereafter. Severe myelosuppression and thrombocytopenia were noted in all animals, requiring the administration of antibiotics and blood transfusions. The model defines the dose response relationship and time course of acute gastrointestinal syndrome-induced morbidity and mortality in the rhesus macaque.

Computer modeling of airway deposition distribution of Foster(®) NEXThaler(®) and Seretide(®) Diskus(®) dry powder combination drugs.

PubMed

Jókay, Ágnes; Farkas, Árpád; Füri, Péter; Horváth, Alpár; Tomisa, Gábor; Balásházy, Imre

2016-06-10

Asthma is a serious global health problem with rising prevalence and treatment costs. Due to the growing number of different types of inhalation devices and aerosol drugs, physicians often face difficulties in choosing the right medication for their patients. The main objectives of this study are (i) to elucidate the possibility and the advantages of the application of numerical modeling techniques in aerosol drug and device selection, and (ii) to demonstrate the possibility of the optimization of inhalation modes in asthma therapy with a numerical lung model by simulating patient-specific drug deposition distributions. In this study we measured inhalation parameter values of 25 healthy adult volunteers when using Foster(®) NEXThaler(®) and Seretide(®) Diskus(®). Relationships between emitted doses and patient-specific inhalation flow rates were established. Furthermore, individualized emitted particle size distributions were determined applying size distributions at measured flow rates. Based on the measured breathing parameter values, we calculated patient-specific drug deposition distributions for the active components (steroid and bronchodilator) of both drugs by the help of a validated aerosol lung deposition model adapted to therapeutic aerosols. Deposited dose fractions and deposition densities have been computed in the entire respiratory tract, in distinct anatomical regions of the airways and at the level of airway generations. We found that Foster(®) NEXThaler(®) deposits more efficiently in the lungs (average deposited steroid dose: 42.32±5.76% of the nominal emitted dose) than Seretide(®) Diskus(®) (average deposited steroid dose: 24.33±2.83% of the nominal emitted dose), but the variance of the deposition values of different individuals in the lung is significant. In addition, there are differences in the required minimal flow rates, therefore at certain patients Seretide(®) Diskus(®) or pMDIs could be a better choice. Our results show that validated computer deposition models could be useful tools in providing valuable deposition data and assisting health professionals in the personalized drug selection and delivery optimization. Patient-specific modeling could open a new horizon in the treatment of asthma towards a more effective personalized medicine in the future. Copyright © 2016 Elsevier B.V. All rights reserved.

Dose selection based on physiologically based pharmacokinetic (PBPK) approaches.

PubMed

Jones, Hannah M; Mayawala, Kapil; Poulin, Patrick

2013-04-01

Physiologically based pharmacokinetic (PBPK) models are built using differential equations to describe the physiology/anatomy of different biological systems. Readily available in vitro and in vivo preclinical data can be incorporated into these models to not only estimate pharmacokinetic (PK) parameters and plasma concentration-time profiles, but also to gain mechanistic insight into compound properties. They provide a mechanistic framework to understand and extrapolate PK and dose across in vitro and in vivo systems and across different species, populations and disease states. Using small molecule and large molecule examples from the literature and our own company, we have shown how PBPK techniques can be utilised for human PK and dose prediction. Such approaches have the potential to increase efficiency, reduce the need for animal studies, replace clinical trials and increase PK understanding. Given the mechanistic nature of these models, the future use of PBPK modelling in drug discovery and development is promising, however some limitations need to be addressed to realise its application and utility more broadly.

On use of the multistage dose-response model for assessing laboratory animal carcinogenicity

PubMed Central

Nitcheva, Daniella; Piegorsch, Walter W.; West, R. Webster

2007-01-01

We explore how well a statistical multistage model describes dose-response patterns in laboratory animal carcinogenicity experiments from a large database of quantal response data. The data are collected from the U.S. EPA’s publicly available IRIS data warehouse and examined statistically to determine how often higher-order values in the multistage predictor yield significant improvements in explanatory power over lower-order values. Our results suggest that the addition of a second-order parameter to the model only improves the fit about 20% of the time, while adding even higher-order terms apparently does not contribute to the fit at all, at least with the study designs we captured in the IRIS database. Also included is an examination of statistical tests for assessing significance of higher-order terms in a multistage dose-response model. It is noted that bootstrap testing methodology appears to offer greater stability for performing the hypothesis tests than a more-common, but possibly unstable, “Wald” test. PMID:17490794

Population modelling to describe pharmacokinetics of amiodarone in rats: relevance of plasma protein and tissue depot binding.

PubMed

Campos Moreno, Eduardo; Merino Sanjuán, Matilde; Merino, Virginia; Nácher, Amparo; Martín Algarra, Rafael V; Casabó, Vicente G

2007-02-01

The objective of this paper was to characterize the disposition phase of AM in rats, after different high doses and modalities of i.v. administration. Three fitting programs, WINNONLIN, ADAPT II and NONMEM were employed. The two-stage fitting methods led to different results, none of which can adequately explain amiodarone's behaviour, although a great amount of data per subject is available. The non-linear mixed effect modelling approach allows satisfactory estimation of population pharmacokinetic parameters, and their respective variability. The best model to define the AM pharmacokinetic profile is a two-compartment model, with saturable and dynamic plasma protein binding and linear tissular depot dynamic binding. These results indicate that peripheral tissues act as depots, causing an important fall in AM plasma levels in the first moment after dosing. Later, the return of the drug from these depots causes a slow increase in serum concentration whenever the dose is reduced.

The effects of 5HT3 receptor antagonist granisetron on inflammatory parameters and angiogenesis in the air-pouch model of inflammation.

PubMed

Maleki-Dizaji, Nasrin; Eteraf-Oskouei, Tahereh; Fakhrjou, Ashraf; Maljaie, Seyyed Hadi; Garjani, Alireza

2010-09-01

The antagonists of 5HT(3) receptors have shown impressive efficacy in rheumatoid arthritis, osteoarthritis or fibromyalgia. The mechanistic relationships between 5HT(3) receptors, angiogenesis and sequence of cytokine expression, and leukocyte recruitment during inflammation are not clear. We evaluate the effects of granisetron on inflammatory parameters and angiogenesis in rat air-pouch model. Male Wistar rats were anesthetized, and then 20 ml and 10 ml of sterile air were injected subcutaneously in the back on day 0 and day 3, respectively. On day 6, inflammation was induced by injection of 1 ml of carrageenan 1% into pouches. After 6 and 72 h, the rats were sacrificed; pouch fluid was collected in order to determine exudate volume, the number of accumulated cells and TNFalpha/PGE(2) concentration. Pouches were dissected out and weighed. Angiogenesis of granulomatous tissue was assayed using a hemoglobin kit. Leukocyte accumulation was dose-dependently inhibited by granisetron both at 6 and 72 h after induction of inflammation. All doses of granisetron decreased hemoglobin level in the whole granulation tissue in a bell-shaped manner. Vascular network formation was also inhibited by granisetron. Granisetron increased PGE(2) level at a lower dose (50 microg/pouch) but higher doses (100 and 200 microg/pouch) inhibited the release. At the same time, TNFalpha production was decreased by the lower dose and increased by higher doses of granisetron in a reciprocal fashion. Anti-inflammatory activities of 5HT(3) receptor antagonist, granisetron probably are mediated through modulation of TNFalpha/PGE(2) production and leukocyte infiltration. (c) 2010 Elsevier B.V. All rights reserved.

The linearized multistage model and the future of quantitative risk assessment.

PubMed

Crump, K S

1996-10-01

The linearized multistage (LMS) model has for over 15 years been the default dose-response model used by the U.S. Environmental Protection Agency (USEPA) and other federal and state regulatory agencies in the United States for calculating quantitative estimates of low-dose carcinogenic risks from animal data. The LMS model is in essence a flexible statistical model that can describe both linear and non-linear dose-response patterns, and that produces an upper confidence bound on the linear low-dose slope of the dose-response curve. Unlike its namesake, the Armitage-Doll multistage model, the parameters of the LMS do not correspond to actual physiological phenomena. Thus the LMS is 'biological' only to the extent that the true biological dose response is linear at low dose and that low-dose slope is reflected in the experimental data. If the true dose response is non-linear the LMS upper bound may overestimate the true risk by many orders of magnitude. However, competing low-dose extrapolation models, including those derived from 'biologically-based models' that are capable of incorporating additional biological information, have not shown evidence to date of being able to produce quantitative estimates of low-dose risks that are any more accurate than those obtained from the LMS model. Further, even if these attempts were successful, the extent to which more accurate estimates of low-dose risks in a test animal species would translate into improved estimates of human risk is questionable. Thus, it does not appear possible at present to develop a quantitative approach that would be generally applicable and that would offer significant improvements upon the crude bounding estimates of the type provided by the LMS model. Draft USEPA guidelines for cancer risk assessment incorporate an approach similar to the LMS for carcinogens having a linear mode of action. However, under these guidelines quantitative estimates of low-dose risks would not be developed for carcinogens having a non-linear mode of action; instead dose-response modelling would be used in the experimental range to calculate an LED10* (a statistical lower bound on the dose corresponding to a 10% increase in risk), and safety factors would be applied to the LED10* to determine acceptable exposure levels for humans. This approach is very similar to the one presently used by USEPA for non-carcinogens. Rather than using one approach for carcinogens believed to have a linear mode of action and a different approach for all other health effects, it is suggested herein that it would be more appropriate to use an approach conceptually similar to the 'LED10*-safety factor' approach for all health effects, and not to routinely develop quantitative risk estimates from animal data.

Generation of uniformly distributed dose points for anatomy-based three-dimensional dose optimization methods in brachytherapy.

PubMed

Lahanas, M; Baltas, D; Giannouli, S; Milickovic, N; Zamboglou, N

2000-05-01

We have studied the accuracy of statistical parameters of dose distributions in brachytherapy using actual clinical implants. These include the mean, minimum and maximum dose values and the variance of the dose distribution inside the PTV (planning target volume), and on the surface of the PTV. These properties have been studied as a function of the number of uniformly distributed sampling points. These parameters, or the variants of these parameters, are used directly or indirectly in optimization procedures or for a description of the dose distribution. The accurate determination of these parameters depends on the sampling point distribution from which they have been obtained. Some optimization methods ignore catheters and critical structures surrounded by the PTV or alternatively consider as surface dose points only those on the contour lines of the PTV. D(min) and D(max) are extreme dose values which are either on the PTV surface or within the PTV. They must be avoided for specification and optimization purposes in brachytherapy. Using D(mean) and the variance of D which we have shown to be stable parameters, achieves a more reliable description of the dose distribution on the PTV surface and within the PTV volume than does D(min) and D(max). Generation of dose points on the real surface of the PTV is obligatory and the consideration of catheter volumes results in a realistic description of anatomical dose distributions.

Dose-specific effects of transcutaneous electrical nerve stimulation (TENS) on experimental pain: a systematic review.

PubMed

Claydon, Leica S; Chesterton, Linda S; Barlas, Panos; Sim, Julius

2011-09-01

To determine the hypoalgesic effects of transcutaneous electrical nerve stimulation (TENS) parameter combinations on experimental models in healthy humans. Searches were performed using the electronic databases Ovid MEDLINE, CINAHL, AMED, and Web of Science (from inception to December 2009). Manual searches of journals and reference lists of retrieved trials were also performed. Randomized controlled trials (RCTs) were included in the review if they compared the hypoalgesic effect of TENS relative with placebo and control, using an experimental pain model in healthy human participants. Two reviewers independently selected the trials, assessed their methodologic quality and extracted data. Forty-three RCTs were eligible for inclusion. A best evidence synthesis revealed: Overall "conflicting" (inconsistent findings in multiple RCTs) evidence of TENS efficacy on experimental pain irrespective of TENS parameters used. Overall intense TENS has "moderate" evidence of efficacy (1 high-quality and 2 low-quality trials). Conventional TENS has overall conflicting evidence of efficacy, this is derived from "strong" evidence of efficacy (generally consistent findings in multiple high-quality RCTs) on pressure pain but strong evidence of inefficacy on other pain models. "Limited" evidence (positive findings from 1 RCT) of hypoalgesia exists for some novel parameters. Low-intensity, low-frequency, local TENS has strong evidence of inefficacy. Inappropriate TENS (using "barely perceptible" intensities) has moderate evidence of inefficacy. The level of hypoalgesic efficacy of TENS is clearly dependent on TENS parameter combination selection (defined in terms of intensity, frequency, and stimulation site) and experimental pain model. Future clinical RCTs may consider these TENS dose responses.

Statistical optimization of process parameters for the simultaneous adsorption of Cr(VI) and phenol onto Fe-treated tea waste biomass

NASA Astrophysics Data System (ADS)

Gupta, Ankur; Balomajumder, Chandrajit

2017-12-01

In this study, simultaneous removal of Cr(VI) and phenol from binary solution was carried out using Fe-treated tea waste biomass. The effect of process parameters such as adsorbent dose, pH, initial concentration of Cr(VI) (mg/L), and initial concentration of phenol (mg/L) was optimized. The analysis of variance of the quadratic model demonstrates that the experimental results are in good agreement with the predicted values. Based on experimental design at an initial concentration of 55 mg/L of Cr(VI), 27.50 mg/L of phenol, pH 2.0, 15 g/L adsorbent dose, 99.99% removal of Cr(VI), and phenol was achieved.

Macroscopic singlet oxygen model incorporating photobleaching as an input parameter

NASA Astrophysics Data System (ADS)

Kim, Michele M.; Finlay, Jarod C.; Zhu, Timothy C.

2015-03-01

A macroscopic singlet oxygen model for photodynamic therapy (PDT) has been used extensively to calculate the reacted singlet oxygen concentration for various photosensitizers. The four photophysical parameters (ξ, σ, β, δ) and threshold singlet oxygen dose ([1O2]r,sh) can be found for various drugs and drug-light intervals using a fitting algorithm. The input parameters for this model include the fluence, photosensitizer concentration, optical properties, and necrosis radius. An additional input variable of photobleaching was implemented in this study to optimize the results. Photobleaching was measured by using the pre-PDT and post-PDT sensitizer concentrations. Using the RIF model of murine fibrosarcoma, mice were treated with a linear source with fluence rates from 12 - 150 mW/cm and total fluences from 24 - 135 J/cm. The two main drugs investigated were benzoporphyrin derivative monoacid ring A (BPD) and 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH). Previously published photophysical parameters were fine-tuned and verified using photobleaching as the additional fitting parameter. Furthermore, photobleaching can be used as an indicator of the robustness of the model for the particular mouse experiment by comparing the experimental and model-calculated photobleaching ratio.

Dynamical properties of a minimally parameterized mathematical model for metronomic chemotherapy.

PubMed

Schättler, Heinz; Ledzewicz, Urszula; Amini, Behrooz

2016-04-01

A minimally parameterized mathematical model for low-dose metronomic chemotherapy is formulated that takes into account angiogenic signaling between the tumor and its vasculature and tumor inhibiting effects of tumor-immune system interactions. The dynamical equations combine a model for tumor development under angiogenic signaling formulated by Hahnfeldt et al. with a model for tumor-immune system interactions by Stepanova. The dynamical properties of the model are analyzed. Depending on the parameter values, the system encompasses a variety of medically realistic scenarios that range from cases when (i) low-dose metronomic chemotherapy is able to eradicate the tumor (all trajectories converge to a tumor-free equilibrium point) to situations when (ii) tumor dormancy is induced (a unique, globally asymptotically stable benign equilibrium point exists) to (iii) multi-stable situations that have both persistent benign and malignant behaviors separated by the stable manifold of an unstable equilibrium point and finally to (iv) situations when tumor growth cannot be overcome by low-dose metronomic chemotherapy. The model forms a basis for a more general study of chemotherapy when the main components of a tumor's microenvironment are taken into account.

Comparison between beta radiation dose distribution due to LDR and HDR ocular brachytherapy applicators using GATE Monte Carlo platform.

PubMed

Mostafa, Laoues; Rachid, Khelifi; Ahmed, Sidi Moussa

2016-08-01

Eye applicators with 90Sr/90Y and 106Ru/106Rh beta-ray sources are generally used in brachytherapy for the treatment of eye diseases as uveal melanoma. Whenever, radiation is used in treatment, dosimetry is essential. However, knowledge of the exact dose distribution is a critical decision-making to the outcome of the treatment. The Monte Carlo technique provides a powerful tool for calculation of the dose and dose distributions which helps to predict and determine the doses from different shapes of various types of eye applicators more accurately. The aim of this work consisted in using the Monte Carlo GATE platform to calculate the 3D dose distribution on a mathematical model of the human eye according to international recommendations. Mathematical models were developed for four ophthalmic applicators, two HDR 90Sr applicators SIA.20 and SIA.6, and two LDR 106Ru applicators, a concave CCB model and a flat CCB model. In present work, considering a heterogeneous eye phantom and the chosen tumor, obtained results with the use of GATE for mean doses distributions in a phantom and according to international recommendations show a discrepancy with respect to those specified by the manufacturers. The QC of dosimetric parameters shows that contrarily to the other applicators, the SIA.20 applicator is consistent with recommendations. The GATE platform show that the SIA.20 applicator present better results, namely the dose delivered to critical structures were lower compared to those obtained for the other applicators, and the SIA.6 applicator, simulated with MCNPX generates higher lens doses than those generated by GATE. Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Characterization of Neutropenia in Advanced Cancer Patients Following Palbociclib Treatment Using a Population Pharmacokinetic-Pharmacodynamic Modeling and Simulation Approach.

PubMed

Sun, Wan; O'Dwyer, Peter J; Finn, Richard S; Ruiz-Garcia, Ana; Shapiro, Geoffrey I; Schwartz, Gary K; DeMichele, Angela; Wang, Diane

2017-09-01

Neutropenia is the most commonly reported hematologic toxicity following treatment with palbociclib, a cyclin-dependent kinase 4/6 inhibitor approved for metastatic breast cancer. Using data from 185 advanced cancer patients receiving palbociclib in 3 clinical trials, a pharmacokinetic-pharmacodynamic model was developed to describe the time course of absolute neutrophil count (ANC) and quantify the exposure-response relationship for neutropenia. These analyses help in understanding neutropenia associated with palbociclib and its comparison with chemotherapy-induced neutropenia. In the model, palbociclib plasma concentration was related to its antiproliferative effect on precursor cells through drug-related parameters (ie, maximum estimated drug effect and concentration corresponding to 50% of the maximum effect), and neutrophil physiology was mimicked through system-related parameters (ie, mean transit time, baseline ANC, and feedback parameter). Sex and baseline albumin level were significant covariates for baseline ANC. It was demonstrated by different model evaluation approaches (eg, prediction-corrected visual predictive check and standardized visual predictive check) that the final model adequately described longitudinal ANC with good predictive capability. The established model suggested that higher palbociclib exposure was associated with lower longitudinal neutrophil counts. The ANC nadir was reached approximately 21 days after palbociclib treatment initiation. Consistent with their mechanisms of action, neutropenia associated with palbociclib (cytostatic) was rapidly reversible and noncumulative, with a notably weaker antiproliferative effect on precursor cells relative to chemotherapies (cytotoxic). This pharmacokinetic-pharmacodynamic model aids in predicting neutropenia and optimizing dosing for future palbociclib trials with different dosing regimen combinations. © 2017, The American College of Clinical Pharmacology.

Effect of Low-Dose MDCT and Iterative Reconstruction on Trabecular Bone Microstructure Assessment.

PubMed

Kopp, Felix K; Holzapfel, Konstantin; Baum, Thomas; Nasirudin, Radin A; Mei, Kai; Garcia, Eduardo G; Burgkart, Rainer; Rummeny, Ernst J; Kirschke, Jan S; Noël, Peter B

2016-01-01

We investigated the effects of low-dose multi detector computed tomography (MDCT) in combination with statistical iterative reconstruction algorithms on trabecular bone microstructure parameters. Twelve donated vertebrae were scanned with the routine radiation exposure used in our department (standard-dose) and a low-dose protocol. Reconstructions were performed with filtered backprojection (FBP) and maximum-likelihood based statistical iterative reconstruction (SIR). Trabecular bone microstructure parameters were assessed and statistically compared for each reconstruction. Moreover, fracture loads of the vertebrae were biomechanically determined and correlated to the assessed microstructure parameters. Trabecular bone microstructure parameters based on low-dose MDCT and SIR significantly correlated with vertebral bone strength. There was no significant difference between microstructure parameters calculated on low-dose SIR and standard-dose FBP images. However, the results revealed a strong dependency on the regularization strength applied during SIR. It was observed that stronger regularization might corrupt the microstructure analysis, because the trabecular structure is a very small detail that might get lost during the regularization process. As a consequence, the introduction of SIR for trabecular bone microstructure analysis requires a specific optimization of the regularization parameters. Moreover, in comparison to other approaches, superior noise-resolution trade-offs can be found with the proposed methods.

SU-F-T-194: Analyzing the Effect of Range Shifter Air Gap On TPS Dose Modeling Accuracy in Superficial PBS Proton Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shirey, R; Wu, H

2016-06-15

Purpose: Treatment planning systems (TPS) may not accurately model superficial dose distributions of range shifted proton pencil beam scanning (PBS) treatments. Numerous patient-specific QA tests performed on superficially treated PBS plans have shown a consistent overestimate of dose by the TPS. This study quantifies variations between TPS planned dose and measured dose as a function of range shifter air gap and treatment depths up to 5 cm. Methods: PBS treatment plans were created in the TPS to uniformly irradiate a volume of solid water. One plan was created for each range shifter position analyzed, and all plans utilized identical dosemore » optimization parameters. Each optimized plan was analyzed in the TPS to determine the planned dose at varying depths. A PBS proton therapy system with a 3.5 cm lucite range shifter delivered the treatment plans, and a parallel plate chamber embedded in RW3 solid water measured dose at shallow depths for each air gap. Differences between measured and planned doses were plotted and analyzed. Results: The data show that the TPS more accurately models superficial dose as the air gap between the range shifter and patient surface decreases. Air gaps less than 10 cm have an average dose difference of only 1.6%, whereas air gaps between 10 and 20 cm differ by 3.0% and gaps greater than 20 cm differ by 4.4%. Conclusion: This study has shown that the TPS is unable to accurately model superficial dose with a large range shifter air gap. Dose differences greater than 3% will likely cause QA failure, as many institutions analyze patient QA with a 3%/3mm gamma analysis. For superficial PBS therapy, range shifter positions should be chosen to keep the air gap less then 10 cm when patient setup and gantry geometry allow.« less

Using Generalized Equivalent Uniform Dose Atlases to Combine and Analyze Prospective Dosimetric and Radiation Pneumonitis Data From 2 Non-Small Cell Lung Cancer Dose Escalation Protocols

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu Fan; Yorke, Ellen D.; Belderbos, Jose S.A.

2013-01-01

Purpose: To demonstrate the use of generalized equivalent uniform dose (gEUD) atlas for data pooling in radiation pneumonitis (RP) modeling, to determine the dependence of RP on gEUD, to study the consistency between data sets, and to verify the increased statistical power of the combination. Methods and Materials: Patients enrolled in prospective phase I/II dose escalation studies of radiation therapy of non-small cell lung cancer at Memorial Sloan-Kettering Cancer Center (MSKCC) (78 pts) and the Netherlands Cancer Institute (NKI) (86 pts) were included; 10 (13%) and 14 (17%) experienced RP requiring steroids (RPS) within 6 months after treatment. gEUD wasmore » calculated from dose-volume histograms. Atlases for each data set were created using 1-Gy steps from exact gEUDs and RPS data. The Lyman-Kutcher-Burman model was fit to the atlas and exact gEUD data. Heterogeneity and inconsistency statistics for the fitted parameters were computed. gEUD maps of the probability of RPS rate {>=}20% were plotted. Results: The 2 data sets were homogeneous and consistent. The best fit values of the volume effect parameter a were small, with upper 95% confidence limit around 1.0 in the joint data. The likelihood profiles around the best fit a values were flat in all cases, making determination of the best fit a weak. All confidence intervals (CIs) were narrower in the joint than in the individual data sets. The minimum P value for correlations of gEUD with RPS in the joint data was .002, compared with P=.01 and .05 for MSKCC and NKI data sets, respectively. gEUD maps showed that at small a, RPS risk increases with gEUD. Conclusions: The atlas can be used to combine gEUD and RPS information from different institutions and model gEUD dependence of RPS. RPS has a large volume effect with the mean dose model barely included in the 95% CI. Data pooling increased statistical power.« less

Population pharmacokinetic/pharmacodynamic analysis of the bactericidal activities of sutezolid (PNU-100480) and its major metabolite against intracellular Mycobacterium tuberculosis in ex vivo whole-blood cultures of patients with pulmonary tuberculosis.

PubMed

Zhu, Tong; Friedrich, Sven O; Diacon, Andreas; Wallis, Robert S

2014-06-01

Sutezolid (PNU-100480 [U-480]) is an oxazolidinone antimicrobial being developed for the treatment of tuberculosis. An active sulfoxide metabolite (PNU-101603 [U-603]), which reaches concentrations in plasma several times those of the parent, has been reported to drive the killing of extracellular Mycobacterium tuberculosis by sutezolid in hollow-fiber culture. However, the relative contributions of the parent and metabolite against intracellular M. tuberculosis in vivo are not fully understood. The relationships between the plasma concentrations of U-480 and U-603 and intracellular whole-blood bactericidal activity (WBA) in ex vivo cultures were examined using a direct competitive population pharmacokinetic (PK)/pharmacodynamic 4-parameter sigmoid model. The data set included 690 PK determinations and 345 WBA determinations from 50 tuberculosis patients enrolled in a phase 2a sutezolid trial. The model parameters were solved iteratively. The median U-603/U-480 concentration ratio was 7.1 (range, 1 to 28). The apparent 50% inhibitory concentration of U-603 for intracellular M. tuberculosis was 17-fold greater than that of U-480 (90% confidence interval [CI], 9.9- to 53-fold). Model parameters were used to simulate in vivo activity after oral dosing with sutezolid at 600 mg twice a day (BID) and 1,200 mg once a day (QD). Divided dosing resulted in greater cumulative activity (-0.269 log10 per day; 90% CI, -0.237 to -0.293 log10 per day) than single daily dosing (-0.186 log10 per day; 90% CI, -0.160 to -0.208 log10 per day). U-480 accounted for 84% and 78% of the activity for BID and QD dosing, respectively, despite the higher concentrations of U-603. Killing of intracellular M. tuberculosis by orally administered sutezolid is mainly due to the activity of the parent compound. Taken together with the findings of other studies in the hollow-fiber model, these findings suggest that sutezolid and its metabolite act on different mycobacterial subpopulations. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Influence of exposure and geometric parameters on absorbed doses associated with common neuro-interventional procedures.

PubMed

Safari, Mohammad Javad; Wong, Jeannie Hsiu Ding; Jong, Wei Loong; Thorpe, Nathan; Cutajar, Dean; Rosenfeld, Anatoly; Ng, Kwan Hoong

2017-03-01

The purpose of this study was to investigate the effects of routine exposure parameters on patient's dose during neuro-interventional radiology procedures. We scrutinized the routine radiological exposure parameters during 58 clinical neuro-interventional procedures such as, exposure direction, magnification, frame rate, and distance between image receptor to patient's body and evaluate their effects on patient's dose using an anthropomorphic phantom. Radiation dose received by the occipital region, ears and eyes of the phantom were measured using MOSkin detectors. DSA imaging technique is a major contributor to patient's dose (80.9%) even though they are used sparingly (5.3% of total frame number). The occipital region of the brain received high dose largely from the frontal tube constantly placed under couch (73.7% of the total KAP). When rotating the frontal tube away from under the couch, the radiation dose to the occipital reduced by 40%. The use of magnification modes could increase radiation dose by 94%. Changing the image receptor to the phantom surface distance from 10 to 40cm doubled the radiation dose received by the patient's skin at the occipital region. Our findings provided important insights into the contribution of selected fluoroscopic exposure parameters and their impact on patient's dose during neuro-interventional radiology procedures. This study showed that the DSA imaging technique contributed to the highest patient's dose and judicial use of exposure parameters might assist interventional radiologists in effective skin and eye lens dose reduction for patients undergoing neuro-interventional procedures. Copyright © 2017 Associazione Italiana di Fisica Medica. All rights reserved.

Exposure of luminous marine bacteria to low-dose gamma-radiation.

PubMed

Kudryasheva, N S; Petrova, A S; Dementyev, D V; Bondar, A A

2017-04-01

The study addresses biological effects of low-dose gamma-radiation. Radioactive 137 Cs-containing particles were used as model sources of gamma-radiation. Luminous marine bacterium Photobacterium phosphoreum was used as a bioassay with the bioluminescent intensity as the physiological parameter tested. To investigate the sensitivity of the bacteria to the low-dose gamma-radiation exposure (≤250 mGy), the irradiation conditions were varied as follows: bioluminescence intensity was measured at 5, 10, and 20°С for 175, 100, and 47 h, respectively, at different dose rates (up to 4100 μGy/h). There was no noticeable effect of gamma-radiation at 5 and 10°С, while the 20°С exposure revealed authentic bioluminescence inhibition. The 20°С results of gamma-radiation exposure were compared to those for low-dose alpha- and beta-radiation exposures studied previously under comparable experimental conditions. In contrast to ionizing radiation of alpha and beta types, gamma-emission did not initiate bacterial bioluminescence activation (adaptive response). As with alpha- and beta-radiation, gamma-emission did not demonstrate monotonic dose-effect dependencies; the bioluminescence inhibition efficiency was found to be related to the exposure time, while no dose rate dependence was found. The sequence analysis of 16S ribosomal RNA gene did not reveal a mutagenic effect of low-dose gamma radiation. The exposure time that caused 50% bioluminescence inhibition was suggested as a test parameter for radiotoxicity evaluation under conditions of chronic low-dose gamma irradiation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Correlates of individual differences in compensatory nicotine self-administration in rats following a decrease in nicotine unit dose

PubMed Central

Harris, Andrew C.; Pentel, Paul R.; LeSage, Mark G.

2013-01-01

Rationale The ability of tobacco harm reduction strategies to produce significant reductions in toxin exposure is limited by compensatory increases in smoking behavior. Characterizing factors contributing to the marked individual variability in compensation may be useful for understanding this phenomenon and assessing the feasibility of harm reduction interventions. Objective To use an animal model of human compensatory smoking that involves a decrease in unit dose supporting nicotine self-administration (NSA) to examine potential contributors to individual differences in compensation. Methods Rats were trained for NSA during daily 23 hr sessions at a unit dose of 0.06 mg/kg/inf until responding was stable. The unit dose was then reduced to 0.03 mg/kg/inf for at least 10 sessions. Following reacquisition of NSA at the training dose and extinction, single-dose nicotine pharmacokinetic parameters were determined. Results Decreases in nicotine intake following dose reduction were proportionally less than the decrease in unit dose, indicating partial compensation. Compensatory increases in infusion rates were observed across the course of the 23 hr sessions. The magnitude of compensation differed considerably between rats. Rats exhibiting the highest baseline infusion rates exhibited the lowest levels of compensation. Nicotine pharmacokinetic parameters were not significantly correlated with compensation. Infusion rates immediately returned to pre-reduction levels when baseline conditions were restored. Conclusions These findings provide initial insights into correlates of individual differences in compensation following a reduction in nicotine unit dose. The present assay may be useful for characterizing mechanisms and potential consequences of the marked individual differences in compensatory smoking observed in humans. PMID:19475400

TH-CD-BRA-07: MRI-Linac Dosimetry: Parameters That Change in a Magnetic Field

DOE Office of Scientific and Technical Information (OSTI.GOV)

O’Brien, D. J.; Sawakuchi, G. O.

Purpose: In MRI-linac integrated systems, the presence of the magnetic (B-)field has a large impact of the dose-distribution and the dose-responses of detectors; yet established protocols and previous experience may lead to assumptions about the commissioning process that are no longer valid. This study quantifies parameters that change when performing dosimetry with an MRI-linac including beam quality specifiers and the effective-point-of-measurement (EPOM) of ionization chambers. Methods: We used the Geant4 Monte Carlo code for this work with physics parameters that pass the Fano cavity test to within 0.1% for the simulated conditions with and without a 1.5 T B-field. Amore » point source model with the energy distribution of an MRI-linac beam was used with and without the B-field to calculate the beam quality specifiers %dd(10)× and TPR{sup 20}{sub 10}, the variation of chamber response with orientation and the how the B-field affects the EPOM of ionization chambers by comparing depth-dose curves calculated in water to those generated by a model PTW30013 Farmer chamber. Results: The %dd(10)× changes by over 2% in the presence of the B-field while the TPR{sup 20}{sub 10} is unaffected. Ionization chamber dose-response is known to depend on the orientation w.r.t. the B-field, but two alternative perpendicular orientations (anti-parallel to each other) also differ in dose-response by over 1%. The B-field shifts the EPOM downstream (closer to the chamber center) but it is also shifted laterally by 0.27 times the chamber’s cavity radius. Conclusion: The EPOM is affected by the B-field and it even shifts laterally. The relationship between %dd(10)× and the Spencer-Attix stopping powers is also changed. Care must be taken when using chambers perpendicular to the field as the dose-response changes depending on which perpendicular orientation is used. All of these effects must be considered when performing dosimetry in B-fields and should be accounted for in future dosimetry protocols. This project was partially funded by Elekta Ltd.« less

Acute Normal Tissue Reactions in Head-and-Neck Cancer Patients Treated With IMRT: Influence of Dose and Association With Genetic Polymorphisms in DNA DSB Repair Genes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Werbrouck, Joke; Ruyck, Kim de; Duprez, Frederic

2009-03-15

Purpose: To investigate the association between dose-related parameters and polymorphisms in DNA DSB repair genes XRCC3 (c.-1843A>G, c.562-14A>G, c.722C>T), Rad51 (c.-3429G>C, c.-3392G>T), Lig4 (c.26C>T, c.1704T>C), Ku70 (c.-1310C>G), and Ku80 (c.2110-2408G>A) and the occurrence of acute reactions after radiotherapy. Materials and Methods: The study population consisted of 88 intensity-modulated radiation therapy (IMRT)-treated head-and-neck cancer patients. Mucositis, dermatitis, and dysphagia were scored using the Common Terminology Criteria (CTC) for Adverse Events v.3.0 scale. The population was divided into a CTC0-2 and CTC3+ group for the analysis of each acute effect. The influence of the dose on critical structures was analyzed using dose-volumemore » histograms. Genotypes were determined by polymerase chain reaction (PCR) combined with restriction fragment length polymorphism or PCR-single base extension assays. Results: The mean dose (D{sub mean}) to the oral cavity and constrictor pharyngeus (PC) muscles was significantly associated with the development of mucositis and dysphagia, respectively. These parameters were considered confounding factors in the radiogenomics analyses. The XRCC3c.722CT/TT and Ku70c.-1310CG/GG genotypes were significantly associated with the development of severe dysphagia (CTC3+). No association was found between the investigated polymorphisms and the development of mucositis or dermatitis. A risk analysis model for severe dysphagia, which was developed based on the XRCC3c.722CT/TT and Ku70c.-1310CG/GG genotypes and the PC dose, showed a sensitivity of 78.6% and a specificity of 77.6%. Conclusions: The XRCC3c.722C>T and Ku70c.-1310C>G polymorphisms as well as the D{sub mean} to the PC muscles were highly associated with the development of severe dysphagia after IMRT. The prediction model developed using these parameters showed a high sensitivity and specificity.« less

Skin dose mapping for fluoroscopically guided interventions.

PubMed

Johnson, Perry B; Borrego, David; Balter, Stephen; Johnson, Kevin; Siragusa, Daniel; Bolch, Wesley E

2011-10-01

To introduce a new skin dose mapping software system for interventional fluoroscopy dose assessment and to analyze the benefits and limitations of patient-phantom matching. In this study, a new software system was developed for visualizing patient skin dose during interventional fluoroscopy procedures. The system works by translating the reference point air kerma to the location of the patient's skin, which is represented by a computational model. In order to orient the model with the x-ray source, geometric parameters found within the radiation dose structured report (RDSR) are used along with a limited number of in-clinic measurements. The output of the system is a visual indication of skin dose mapped onto an anthropomorphic model at a resolution of 5 mm. In order to determine if patient-dependent and patient-sculpted models increase accuracy, peak skin dose was calculated for each of 26 patient-specific models and compared with doses calculated using an elliptical stylized model, a reference hybrid model, a matched patient-dependent model and one patient-sculpted model. Results were analyzed in terms of a percent difference using the doses calculated using the patient-specific model as the true standard. Anthropometric matching, including the use of both patient-dependent and patient-sculpted phantoms, was shown most beneficial for left lateral and anterior-posterior projections. In these cases, the percent difference using a reference model was between 8 and 20%, using a patient-dependent model between 7 and 15%, and using a patient-sculpted model between 3 and 7%. Under the table tube configurations produced errors less than 5% in most situations due to the flattening affects of the table and pad, and the fact that table height is the main determination of source-to-skin distance for these configurations. In addition to these results, several skin dose maps were produced and a prototype display system was placed on the in-clinic monitor of an interventional fluoroscopy system. The skin dose mapping program developed in this work represents a new tool that, as the RDSR becomes available through automated export or real-time streaming, can provide the interventional physician information needed to modify behavior when clinically appropriate. The program is nonproprietary and transferable, and also functions independent to the software systems already installed on the control room workstation. The next step will be clinical implementation where the workflow will be optimized along with further analysis of real-time capabilities.

Azithromycin to prevent bronchopulmonary dysplasia in ureaplasma-infected preterm infants: pharmacokinetics, safety, microbial response, and clinical outcomes with a 20-milligram-per-kilogram single intravenous dose.

PubMed

Viscardi, Rose M; Othman, Ahmed A; Hassan, Hazem E; Eddington, Natalie D; Abebe, Elias; Terrin, Michael L; Kaufman, David A; Waites, Ken B

2013-05-01

Ureaplasma respiratory tract colonization is associated with bronchopulmonary dysplasia (BPD) in preterm infants. Previously, we demonstrated that a single intravenous (i.v.) dose of azithromycin (10 mg/kg of body weight) is safe but inadequate to eradicate Ureaplasma spp. in preterm infants. We performed a nonrandomized, single-arm open-label study of the pharmacokinetics (PK) and safety of intravenous 20-mg/kg single-dose azithromycin in 13 mechanically ventilated neonates with a gestational age between 24 weeks 0 days and 28 weeks 6 days. Pharmacokinetic data from 25 neonates (12 dosed with 10 mg/kg i.v. and 13 dosed with 20 mg/kg i.v.) were analyzed using a population modeling approach. Using a two-compartment model with allometric scaling of parameters on body weight (WT), the population PK parameter estimates were as follows: clearance, 0.21 liter/h × WT(kg)(0.75) [WT(kg)(0.75) indicates that clearance was allometrically scaled on body weight (in kilograms) with a fixed exponent of 0.75]; intercompartmental clearance, 2.1 liters/h × WT(kg)(0.75); central volume of distribution (V), 1.97 liters × WT (kg); and peripheral V, 17.9 liters × WT (kg). There was no evidence of departure from dose proportionality in azithromycin exposure over the tested dose range. The calculated area under the concentration-time curve over 24 h in the steady state divided by the MIC90 (AUC24/MIC90) for the single dose of azithromycin (20 mg/kg) was 7.5 h. Simulations suggest that 20 mg/kg for 3 days will maintain azithromycin concentrations of >MIC50 of 1 μg/ml for this group of Ureaplasma isolates for ≥ 96 h after the first dose. Azithromycin was well tolerated with no drug-related adverse events. One of seven (14%) Ureaplasma-positive subjects and three of six (50%) Ureaplasma-negative subjects developed physiologic BPD. Ureaplasma was eradicated in all treated Ureaplasma-positive subjects. Simulations suggest that a multiple-dose regimen may be efficacious for microbial clearance, but the effect on BPD remains to be determined.

Azithromycin To Prevent Bronchopulmonary Dysplasia in Ureaplasma-Infected Preterm Infants: Pharmacokinetics, Safety, Microbial Response, and Clinical Outcomes with a 20-Milligram-per-Kilogram Single Intravenous Dose

PubMed Central

Othman, Ahmed A.; Hassan, Hazem E.; Eddington, Natalie D.; Abebe, Elias; Terrin, Michael L.; Kaufman, David A.; Waites, Ken B.

2013-01-01

Ureaplasma respiratory tract colonization is associated with bronchopulmonary dysplasia (BPD) in preterm infants. Previously, we demonstrated that a single intravenous (i.v.) dose of azithromycin (10 mg/kg of body weight) is safe but inadequate to eradicate Ureaplasma spp. in preterm infants. We performed a nonrandomized, single-arm open-label study of the pharmacokinetics (PK) and safety of intravenous 20-mg/kg single-dose azithromycin in 13 mechanically ventilated neonates with a gestational age between 24 weeks 0 days and 28 weeks 6 days. Pharmacokinetic data from 25 neonates (12 dosed with 10 mg/kg i.v. and 13 dosed with 20 mg/kg i.v.) were analyzed using a population modeling approach. Using a two-compartment model with allometric scaling of parameters on body weight (WT), the population PK parameter estimates were as follows: clearance, 0.21 liter/h × WT(kg)0.75 [WT(kg)0.75 indicates that clearance was allometrically scaled on body weight (in kilograms) with a fixed exponent of 0.75]; intercompartmental clearance, 2.1 liters/h × WT(kg)0.75; central volume of distribution (V), 1.97 liters × WT (kg); and peripheral V, 17.9 liters × WT (kg). There was no evidence of departure from dose proportionality in azithromycin exposure over the tested dose range. The calculated area under the concentration-time curve over 24 h in the steady state divided by the MIC90 (AUC24/MIC90) for the single dose of azithromycin (20 mg/kg) was 7.5 h. Simulations suggest that 20 mg/kg for 3 days will maintain azithromycin concentrations of >MIC50 of 1 μg/ml for this group of Ureaplasma isolates for ≥96 h after the first dose. Azithromycin was well tolerated with no drug-related adverse events. One of seven (14%) Ureaplasma-positive subjects and three of six (50%) Ureaplasma-negative subjects developed physiologic BPD. Ureaplasma was eradicated in all treated Ureaplasma-positive subjects. Simulations suggest that a multiple-dose regimen may be efficacious for microbial clearance, but the effect on BPD remains to be determined. PMID:23439637

Development and application of a set of mesh-based and age-dependent Chinese family phantoms for radiation protection dosimetry: Preliminary Data for external photon beams

NASA Astrophysics Data System (ADS)

Pi, Yifei; Zhang, Lian; Huo, Wanli; Feng, Mang; Chen, Zhi; Xu, X. George

2017-09-01

A group of mesh-based and age-dependent family phantoms for Chinese populations were developed in this study. We implemented a method for deforming original RPI-AM and RPI-AF models into phantoms of different ages: 5, 10 ,15 and adult. More than 120 organs for each model were processed to match with the values of the Chinese reference parameters within 0.5%. All of these phantoms were then converted to voxel format for Monte Carlo simulations. Dose coefficients for adult models were counted to compare with those of RPI-AM and RPI-AF. The results show that there are significant differences between absorbed doses of RPI phantoms and these of our adult phantoms at low energies. Comparisons for the dose coefficients among different ages and genders were also made. it was found that teenagers receive more radiation doses than adults under the same irradiation condition. This set of phantoms can be utilized to estimate dosimetry for Chinese population for radiation protection, medical imaging, and radiotherapy.

Effect of photon energy spectrum on dosimetric parameters of brachytherapy sources.

PubMed

Ghorbani, Mahdi; Mehrpouyan, Mohammad; Davenport, David; Ahmadi Moghaddas, Toktam

2016-06-01

The aim of this study is to quantify the influence of the photon energy spectrum of brachytherapy sources on task group No. 43 (TG-43) dosimetric parameters. Different photon spectra are used for a specific radionuclide in Monte Carlo simulations of brachytherapy sources. MCNPX code was used to simulate 125I, 103Pd, 169Yb, and 192Ir brachytherapy sources. Air kerma strength per activity, dose rate constant, radial dose function, and two dimensional (2D) anisotropy functions were calculated and isodose curves were plotted for three different photon energy spectra. The references for photon energy spectra were: published papers, Lawrence Berkeley National Laboratory (LBNL), and National Nuclear Data Center (NNDC). The data calculated by these photon energy spectra were compared. Dose rate constant values showed a maximum difference of 24.07% for 103Pd source with different photon energy spectra. Radial dose function values based on different spectra were relatively the same. 2D anisotropy function values showed minor differences in most of distances and angles. There was not any detectable difference between the isodose contours. Dosimetric parameters obtained with different photon spectra were relatively the same, however it is suggested that more accurate and updated photon energy spectra be used in Monte Carlo simulations. This would allow for calculation of reliable dosimetric data for source modeling and calculation in brachytherapy treatment planning systems.

Effect of photon energy spectrum on dosimetric parameters of brachytherapy sources

PubMed Central

Ghorbani, Mahdi; Davenport, David

2016-01-01

Abstract Aim The aim of this study is to quantify the influence of the photon energy spectrum of brachytherapy sources on task group No. 43 (TG-43) dosimetric parameters. Background Different photon spectra are used for a specific radionuclide in Monte Carlo simulations of brachytherapy sources. Materials and methods MCNPX code was used to simulate 125I, 103Pd, 169Yb, and 192Ir brachytherapy sources. Air kerma strength per activity, dose rate constant, radial dose function, and two dimensional (2D) anisotropy functions were calculated and isodose curves were plotted for three different photon energy spectra. The references for photon energy spectra were: published papers, Lawrence Berkeley National Laboratory (LBNL), and National Nuclear Data Center (NNDC). The data calculated by these photon energy spectra were compared. Results Dose rate constant values showed a maximum difference of 24.07% for 103Pd source with different photon energy spectra. Radial dose function values based on different spectra were relatively the same. 2D anisotropy function values showed minor differences in most of distances and angles. There was not any detectable difference between the isodose contours. Conclusions Dosimetric parameters obtained with different photon spectra were relatively the same, however it is suggested that more accurate and updated photon energy spectra be used in Monte Carlo simulations. This would allow for calculation of reliable dosimetric data for source modeling and calculation in brachytherapy treatment planning systems. PMID:27247558

Dose Titration Algorithm Tuning (DTAT) should supersede ‘the’ Maximum Tolerated Dose (MTD) in oncology dose-finding trials

PubMed Central

Norris, David C.

2017-01-01

Background. Absent adaptive, individualized dose-finding in early-phase oncology trials, subsequent ‘confirmatory’ Phase III trials risk suboptimal dosing, with resulting loss of statistical power and reduced probability of technical success for the investigational therapy. While progress has been made toward explicitly adaptive dose-finding and quantitative modeling of dose-response relationships, most such work continues to be organized around a concept of ‘the’ maximum tolerated dose (MTD). The purpose of this paper is to demonstrate concretely how the aim of early-phase trials might be conceived, not as ‘dose-finding’, but as dose titration algorithm (DTA)-finding. Methods. A Phase I dosing study is simulated, for a notional cytotoxic chemotherapy drug, with neutropenia constituting the critical dose-limiting toxicity. The drug’s population pharmacokinetics and myelosuppression dynamics are simulated using published parameter estimates for docetaxel. The amenability of this model to linearization is explored empirically. The properties of a simple DTA targeting neutrophil nadir of 500 cells/mm 3 using a Newton-Raphson heuristic are explored through simulation in 25 simulated study subjects. Results. Individual-level myelosuppression dynamics in the simulation model approximately linearize under simple transformations of neutrophil concentration and drug dose. The simulated dose titration exhibits largely satisfactory convergence, with great variance in individualized optimal dosing. Some titration courses exhibit overshooting. Conclusions. The large inter-individual variability in simulated optimal dosing underscores the need to replace ‘the’ MTD with an individualized concept of MTD i . To illustrate this principle, the simplest possible DTA capable of realizing such a concept is demonstrated. Qualitative phenomena observed in this demonstration support discussion of the notion of tuning such algorithms. Although here illustrated specifically in relation to cytotoxic chemotherapy, the DTAT principle appears similarly applicable to Phase I studies of cancer immunotherapy and molecularly targeted agents. PMID:28663782

Poster - 47: A parametrized prediction model of rectal toxicity in focal SBRT of low risk prostate cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stevens, Todd; Bauman, Glenn

There has been a recent trend towards watchful waiting in place of intervention for early stage prostate cancer (CaP). However, this approach can allow for disease progression, and subsequent whole-gland therapies such as prostatectomy and whole gland irradiation can result in functional deficits or rectal toxicities or both. A controversial alternative approach for this patient cohort is the use of focal therapy, where the treatment is focussed on an identified dominant index lesion (DIL). This work aims to investigate the treatment parameters for focal SBRT of the prostate under which clinically acceptable rectal NTCP levels can be achieved. For eachmore » of 25 low risk CaP patients, a hypothetical 2 cc DIL was modeled in the right-posterior quadrant of the prostate, and was used to build a PTV as the target for SBRT simulation. An SBRT prescriptions of 41 Gy and 37 Gy in 5 fractions were chosen, corresponding to the boost levels used in previous CaP dose escalation studies. DVH data were exported and used to calculate rectal NTCP values based on the Lyman-Kutcher-Burman (LKB) model using the QUANTEC reccommended model parameters. Rectal NTCP dependence on DIL-to-rectum separation, dose level, and DIL volume were investigated. The final goal of this ongoing work is to create a map of the maximum allowable prescription dose for a given patient geometry that achieves a clinically acceptable rectal NTCP level.« less

Acute radiation risk models

NASA Astrophysics Data System (ADS)

Smirnova, Olga

Biologically motivated mathematical models, which describe the dynamics of the major hematopoietic lineages (the thrombocytopoietic, lymphocytopoietic, granulocytopoietic, and erythropoietic systems) in acutely/chronically irradiated humans are developed. These models are implemented as systems of nonlinear differential equations, which variables and constant parameters have clear biological meaning. It is shown that the developed models are capable of reproducing clinical data on the dynamics of these systems in humans exposed to acute radiation in the result of incidents and accidents, as well as in humans exposed to low-level chronic radiation. Moreover, the averaged value of the "lethal" dose rates of chronic irradiation evaluated within models of these four major hematopoietic lineages coincides with the real minimal dose rate of lethal chronic irradiation. The demonstrated ability of the models of the human thrombocytopoietic, lymphocytopoietic, granulocytopoietic, and erythropoietic systems to predict the dynamical response of these systems to acute/chronic irradiation in wide ranges of doses and dose rates implies that these mathematical models form an universal tool for the investigation and prediction of the dynamics of the major human hematopoietic lineages for a vast pattern of irradiation scenarios. In particular, these models could be applied for the radiation risk assessment for health of astronauts exposed to space radiation during long-term space missions, such as voyages to Mars or Lunar colonies, as well as for health of people exposed to acute/chronic irradiation due to environmental radiological events.

Isothermal crystallization of gamma irradiated LDPE in the presence of oxygen

NASA Astrophysics Data System (ADS)

Lanfranconi, M. R.; Alvarez, V. A.; Perez, C. J.

2015-06-01

This work is focused on the study of the effect of oxygen on the isothermal crystallization process of gamma irradiated low density polyethylene (LDPE). The induction time increased with the dose indicating a retarding effect. On other hand, at the same dose, this parameter decreased with the augment in the oxygen content. The classical Avrami equation was used to analyze the crystallization kinetic of these materials. n values suggested that both, the dose and the oxygen content, did not affect the mechanism of crystals growth. An Arrhenius type equation was used for the rate constant (k). Used models correctly reproduced the experimental data. TTT diagrams of studied materials were constructed and also reflected the effects of the doses and the oxygen content.

Pharmacokinetic and Pharmacodynamic Modeling of Anidulafungin (LY303366): Reappraisal of Its Efficacy in Neutropenic Animal Models of Opportunistic Mycoses Using Optimal Plasma Sampling

PubMed Central

Groll, Andreas H.; Mickiene, Diana; Petraitiene, Ruta; Petraitis, Vidmantas; Lyman, Caron A.; Bacher, John S.; Piscitelli, Stephen C.; Walsh, Thomas J.

2001-01-01

The compartmental pharmacokinetics of anidulafungin (VER-002; formerly LY303366) in plasma were characterized with normal rabbits, and the relationships between drug concentrations and antifungal efficacy were assessed in clinically applicable infection models in persistently neutropenic animals. At intravenous dosages ranging from 0.1 to 20 mg/kg of body weight, anidulafungin demonstrated linear plasma pharmacokinetics that fitted best to a three-compartment open pharmacokinetic model. Following administration over 7 days, the mean (± standard error of the mean) peak plasma concentration (Cmax) increased from 0.46 ± 0.02 μg/ml at 0.1 mg/kg to 63.02 ± 2.93 μg/ml at 20 mg/kg, and the mean area under the concentration-time curve from 0 h to infinity (AUC0–∞) rose from 0.71 ± 0.04 to 208.80 ± 24.21 μg · h/ml. The mean apparent volume of distribution at steady state (Vss) ranged from 0.953 ± 0.05 to 1.636 ± 0.22 liter/kg (nonsignificant [NS]), and clearance ranged from 0.107 ± 0.01 to 0.149 ± 0.00 liter/kg/h (NS). Except for a significant prolongation of the terminal half-life and a trend toward an increased Vss at the higher end of the dosage range after multiple doses, no significant differences in pharmacokinetic parameters were noted in comparison to single-dose administration. Concentrations in tissue at trough after multiple dosing (0.1 to 10 mg/kg/day) were highest in lung and liver (0.85 ± 0.16 to 32.64 ± 2.03 and 0.32 ± 0.05 to 43.76 ± 1.62 μg/g, respectively), followed by spleen and kidney (0.24 ± 0.65 to 21.74 ± 1.86 and <0.20 to 16.92 ± 0.56, respectively). Measurable concentrations in brain tissue were found at dosages of ≥0.5 mg/kg (0.24 ± 0.02 to 3.90 ± 0.25). Implementation of optimal plasma sampling in persistently neutropenic rabbit infection models of disseminated candidiasis and pulmonary aspergillosis based on the Bayesian approach and model parameters from normal animals as priors revealed a significantly slower clearance (P < 0.05 for all dosage groups) with a trend toward higher AUC0–24 values, higher plasma concentrations at the end of the dosing interval, and a smaller volume of distribution (P < 0.05 to 0.193 for the various comparisons among dosage groups). Pharmacodynamic modeling using the residual fungal tissue burden in the main target sites as the primary endpoint and Cmax, AUC0–24, time during the dosing interval of 24 h with plasma drug concentration equaling or exceeding the MIC or the minimum fungicidal concentration for the isolate, and tissue concentrations as pharmacodynamic parameters showed predictable pharmacokinetic-pharmacodynamic relationships in experimental disseminated candidiasis that fitted well with an inhibitory sigmoid maximum effect pharmacodynamic model (r2, 0.492 to 0.819). However, no concentration-effect relationships were observed in experimental pulmonary aspergillosis using the residual fungal burden in lung tissue and survival as parameters of antifungal efficacy. Implementation of optimal plasma sampling in discriminative animal models of invasive fungal infections and pharmacodynamic modeling is a novel approach that holds promise of improving and accelerating our understanding of the action of antifungal compounds in vivo. PMID:11557479

Bayesian population analysis of a washin-washout physiologically based pharmacokinetic model for acetone

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moerk, Anna-Karin, E-mail: anna-karin.mork@ki.s; Jonsson, Fredrik; Pharsight, a Certara company, St. Louis, MO

2009-11-01

The aim of this study was to derive improved estimates of population variability and uncertainty of physiologically based pharmacokinetic (PBPK) model parameters, especially of those related to the washin-washout behavior of polar volatile substances. This was done by optimizing a previously published washin-washout PBPK model for acetone in a Bayesian framework using Markov chain Monte Carlo simulation. The sensitivity of the model parameters was investigated by creating four different prior sets, where the uncertainty surrounding the population variability of the physiological model parameters was given values corresponding to coefficients of variation of 1%, 25%, 50%, and 100%, respectively. The PBPKmore » model was calibrated to toxicokinetic data from 2 previous studies where 18 volunteers were exposed to 250-550 ppm of acetone at various levels of workload. The updated PBPK model provided a good description of the concentrations in arterial, venous, and exhaled air. The precision of most of the model parameter estimates was improved. New information was particularly gained on the population distribution of the parameters governing the washin-washout effect. The results presented herein provide a good starting point to estimate the target dose of acetone in the working and general populations for risk assessment purposes.« less

Sensitivity of disease parameters to flexible budesonide/formoterol treatment in an allergic rat model.

PubMed

Brange, Charlotte; Smailagic, Amir; Jansson, Anne-Helene; Middleton, Brian; Miller-Larsson, Anna; Taylor, John D; Silberstein, David S; Lal, Harbans

2009-02-01

Clinical studies show that flexible dosing (maintenance and symptom-driven dose adjustments) of budesonide and formoterol (BUD/FORM) improves control of asthma exacerbations as compared to fixed maintenance dosing protocols (maintenance therapy) even when the latter utilize higher BUD/FORM doses. This suggests that dose-response relationships for certain pathobiologic mechanisms in asthma shift over time. Here, we have conducted animal studies to address this issue. (1) To test in an animal asthma-like model whether it is possible to achieve the same or greater pharmacological control over bronchoconstriction and airway/lung inflammation, and with less total drug used, by flexible BUD/FORM dosing (upward adjustment of doses) in association with allergen challenges. (2) To determine whether the benefit requires adjustment of both drug components. Rats sensitized on days 0 and 7 were challenged intratracheally with ovalbumin on days 14 and 21. On days 13-21, rats were treated intratracheally with fixed maintenance or flexible BUD/FORM combinations. On day 22, rats were challenged with methacholine and lungs were harvested for analysis. A flexible BUD/FORM dosing regimen (using 3.3 times less total drug than the fixed maintenance high dose regimen), delivered the same or greater reductions of excised lung gas volume (a measure of gas trapped in lung by bronchoconstriction) and lung weight (a measure of inflammatory oedema). When either BUD or FORM alone was increased on days of challenge, the benefit of the flexible dose upward adjustment was lost. Flexible dosing of the BUD/FORM combination improves the pharmacological inhibition of allergen-induced bronchoconstriction and an inflammatory oedema in an allergic asthma-like rat model.

The use of new GAFCHROMIC EBT film for 125I seed dosimetry in Solid Water phantom.

PubMed

Chiu-Tsao, Sou-Tung; Medich, David; Munro, John

2008-08-01

Radiochromic film dosimetry has been extensively used for intravascular brachytherapy applications for near field within 1 cm from the sources. With the recent introduction of new model of radiochromic films, GAFCHROMIC EBT, with higher sensitivity than earlier models, it is promising to extend the distances out to 5 cm for low dose rate (LDR) source dosimetry. In this study, the use of new model GAFCHROMIC EBT film for 125I seed dosimetry in Solid Water was evaluated for radial distances from 0.06 cm out to 5 cm. A multiple film technique was employed for four 125I seeds (Implant Sciences model 3500) with NIST traceable air kerma strengths. Each experimental film was positioned in contact with a 125I seed in a Solid Water phantom. The products of the air kerma strength and exposure time ranged from 8 to 3158 U-h, with the initial air kerma strength of 6 U in a series of 25 experiments. A set of 25 calibration films each was sequentially exposed to one 125I seed at about 0.58 cm distance for doses from 0.1 to 33 Gy. A CCD camera based microdensitometer, with interchangeable green (520 nm) and red (665 nm) light boxes, was used to scan all the films with 0.2 mm pixel resolution. The dose to each 125I calibration film center was calculated using the air kerma strength of the seed (incorporating decay), exposure time, distance from seed center to film center, and TG43U1S1 recommended dosimetric parameters. Based on the established calibration curve, dose conversion from net optical density was achieved for each light source. The dose rate constant was determined as 0.991 cGy U(-1)h(-1) (+/-6.9%) and 1.014 cGy U(-1)h(-1) (+/-6.8%) from films scanned using green and red light sources, respectively. The difference between these two values was within the uncertainty of the measurement. Radial dose function and 2D anisotropy function were also determined. The results obtained using the two light sources corroborated each other. We found good agreement with the TG43U1S1 recommended values of radial dose function and 2D anisotropy function, to within the uncertainty of the measurement. We also verified the dosimetric parameters in the near field calculated by Rivard using Monte Carlo method. The radial dose function values in Solid Water were lower than those in water recommended by TG43U1S1, by about 2%, 3%, 7%, and 14% at 2, 3, 4, and 5 cm, respectively, partially due to the difference in the phantom material composition. Radiochromic film dosimetry using GAFCHROMIC EBT model is feasible in determining 2D dose distributions around low dose rate 125I seed. It is a viable alternative to TLD dosimetry for 125I seed dose characterization.

Impact of dose size in single fraction spatially fractionated (grid) radiotherapy for melanoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Hualin, E-mail: hualin.zhang@northwestern.edu, E-mail: hualinzhang@yahoo.com; Zhong, Hualiang; Barth, Rolf F.

2014-02-15

Purpose: To evaluate the impact of dose size in single fraction, spatially fractionated (grid) radiotherapy for selectively killing infiltrated melanoma cancer cells of different tumor sizes, using different radiobiological models. Methods: A Monte Carlo technique was employed to calculate the 3D dose distribution of a commercially available megavoltage grid collimator in a 6 MV beam. The linear-quadratic (LQ) and modified linear quadratic (MLQ) models were used separately to evaluate the therapeutic outcome of a series of single fraction regimens that employed grid therapy to treat both acute and late responding melanomas of varying sizes. The dose prescription point was atmore » the center of the tumor volume. Dose sizes ranging from 1 to 30 Gy at 100% dose line were modeled. Tumors were either touching the skin surface or having their centers at a depth of 3 cm. The equivalent uniform dose (EUD) to the melanoma cells and the therapeutic ratio (TR) were defined by comparing grid therapy with the traditional open debulking field. The clinical outcomes from recent reports were used to verify the authors’ model. Results: Dose profiles at different depths and 3D dose distributions in a series of 3D melanomas treated with grid therapy were obtained. The EUDs and TRs for all sizes of 3D tumors involved at different doses were derived through the LQ and MLQ models, and a practical equation was derived. The EUD was only one fifth of the prescribed dose. The TR was dependent on the prescribed dose and on the LQ parameters of both the interspersed cancer and normal tissue cells. The results from the LQ model were consistent with those of the MLQ model. At 20 Gy, the EUD and TR by the LQ model were 2.8% higher and 1% lower than by the MLQ, while at 10 Gy, the EUD and TR as defined by the LQ model were only 1.4% higher and 0.8% lower, respectively. The dose volume histograms of grid therapy for a 10 cm tumor showed different dosimetric characteristics from those of conventional radiotherapy. A significant portion of the tumor volume received a very large dose in grid therapy, which ensures significant tumor cell killing in these regions. Conversely, some areas received a relatively small dose, thereby sparing interspersed normal cells and increasing radiation tolerance. The radiobiology modeling results indicated that grid therapy could be useful for treating acutely responding melanomas infiltrating radiosensitive normal tissues. The theoretical model predictions were supported by the clinical outcomes. Conclusions: Grid therapy functions by selectively killing infiltrating tumor cells and concomitantly sparing interspersed normal cells. The TR depends on the radiosensitivity of the cell population, dose, tumor size, and location. Because the volumes of very high dose regions are small, the LQ model can be used safely to predict the clinical outcomes of grid therapy. When treating melanomas with a dose of 15 Gy or higher, single fraction grid therapy is clearly advantageous for sparing interspersed normal cells. The existence of a threshold fraction dose, which was found in the authors’ theoretical simulations, was confirmed by clinical observations.« less

A computational psychiatry approach identifies how alpha-2A noradrenergic agonist Guanfacine affects feature-based reinforcement learning in the macaque

PubMed Central

Hassani, S. A.; Oemisch, M.; Balcarras, M.; Westendorff, S.; Ardid, S.; van der Meer, M. A.; Tiesinga, P.; Womelsdorf, T.

2017-01-01

Noradrenaline is believed to support cognitive flexibility through the alpha 2A noradrenergic receptor (a2A-NAR) acting in prefrontal cortex. Enhanced flexibility has been inferred from improved working memory with the a2A-NA agonist Guanfacine. But it has been unclear whether Guanfacine improves specific attention and learning mechanisms beyond working memory, and whether the drug effects can be formalized computationally to allow single subject predictions. We tested and confirmed these suggestions in a case study with a healthy nonhuman primate performing a feature-based reversal learning task evaluating performance using Bayesian and Reinforcement learning models. In an initial dose-testing phase we found a Guanfacine dose that increased performance accuracy, decreased distractibility and improved learning. In a second experimental phase using only that dose we examined the faster feature-based reversal learning with Guanfacine with single-subject computational modeling. Parameter estimation suggested that improved learning is not accounted for by varying a single reinforcement learning mechanism, but by changing the set of parameter values to higher learning rates and stronger suppression of non-chosen over chosen feature information. These findings provide an important starting point for developing nonhuman primate models to discern the synaptic mechanisms of attention and learning functions within the context of a computational neuropsychiatry framework. PMID:28091572

SU-E-T-541: Measurement of CT Density Model Variations and the Impact On the Accuracy of Monte Carlo (MC) Dose Calculation in Stereotactic Body Radiation Therapy for Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xiang, H; Li, B; Behrman, R

2015-06-15

Purpose: To measure the CT density model variations between different CT scanners used for treatment planning and impact on the accuracy of MC dose calculation in lung SBRT. Methods: A Gammex electron density phantom (RMI 465) was scanned on two 64-slice CT scanners (GE LightSpeed VCT64) and a 16-slice CT (Philips Brilliance Big Bore CT). All three scanners had been used to acquire CT for CyberKnife lung SBRT treatment planning. To minimize the influences of beam hardening and scatter for improving reproducibility, three scans were acquired with the phantom rotated 120° between scans. The mean CT HU of each densitymore » insert, averaged over the three scans, was used to build the CT density models. For 14 patient plans, repeat MC dose calculations were performed by using the scanner-specific CT density models and compared to a baseline CT density model in the base plans. All dose re-calculations were done using the same plan beam configurations and MUs. Comparisons of dosimetric parameters included PTV volume covered by prescription dose, mean PTV dose, V5 and V20 for lungs, and the maximum dose to the closest critical organ. Results: Up to 50.7 HU variations in CT density models were observed over the baseline CT density model. For 14 patient plans examined, maximum differences in MC dose re-calculations were less than 2% in 71.4% of the cases, less than 5% in 85.7% of the cases, and 5–10% for 14.3% of the cases. As all the base plans well exceeded the clinical objectives of target coverage and OAR sparing, none of the observed differences led to clinically significant concerns. Conclusion: Marked variations of CT density models were observed for three different CT scanners. Though the differences can cause up to 5–10% differences in MC dose calculations, it was found that they caused no clinically significant concerns.« less

Is multidetector CT-based bone mineral density and quantitative bone microstructure assessment at the spine still feasible using ultra-low tube current and sparse sampling?

PubMed

Mei, Kai; Kopp, Felix K; Bippus, Rolf; Köhler, Thomas; Schwaiger, Benedikt J; Gersing, Alexandra S; Fehringer, Andreas; Sauter, Andreas; Münzel, Daniela; Pfeiffer, Franz; Rummeny, Ernst J; Kirschke, Jan S; Noël, Peter B; Baum, Thomas

2017-12-01

Osteoporosis diagnosis using multidetector CT (MDCT) is limited to relatively high radiation exposure. We investigated the effect of simulated ultra-low-dose protocols on in-vivo bone mineral density (BMD) and quantitative trabecular bone assessment. Institutional review board approval was obtained. Twelve subjects with osteoporotic vertebral fractures and 12 age- and gender-matched controls undergoing routine thoracic and abdominal MDCT were included (average effective dose: 10 mSv). Ultra-low radiation examinations were achieved by simulating lower tube currents and sparse samplings at 50%, 25% and 10% of the original dose. BMD and trabecular bone parameters were extracted in T10-L5. Except for BMD measurements in sparse sampling data, absolute values of all parameters derived from ultra-low-dose data were significantly different from those derived from original dose images (p<0.05). BMD, apparent bone fraction and trabecular thickness were still consistently lower in subjects with than in those without fractures (p<0.05). In ultra-low-dose scans, BMD and microstructure parameters were able to differentiate subjects with and without vertebral fractures, suggesting osteoporosis diagnosis is feasible. However, absolute values differed from original values. BMD from sparse sampling appeared to be more robust. This dose-dependency of parameters should be considered for future clinical use. • BMD and quantitative bone parameters are assessable in ultra-low-dose in vivo MDCT scans. • Bone mineral density does not change significantly when sparse sampling is applied. • Quantitative trabecular bone microstructure measurements are sensitive to dose reduction. • Osteoporosis subjects could be differentiated even at 10% of original dose. • Radiation exposure should be considered when comparing quantitative bone parameters.

Normal tissue complication probability model parameter estimation for xerostomia in head and neck cancer patients based on scintigraphy and quality of life assessments.

PubMed

Lee, Tsair-Fwu; Chao, Pei-Ju; Wang, Hung-Yu; Hsu, Hsuan-Chih; Chang, PaoShu; Chen, Wen-Cheng

2012-12-04

With advances in modern radiotherapy (RT), many patients with head and neck (HN) cancer can be effectively cured. However, xerostomia is a common complication in patients after RT for HN cancer. The purpose of this study was to use the Lyman-Kutcher-Burman (LKB) model to derive parameters for the normal tissue complication probability (NTCP) for xerostomia based on scintigraphy assessments and quality of life (QoL) questionnaires. We performed validation tests of the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) guidelines against prospectively collected QoL and salivary scintigraphic data. Thirty-one patients with HN cancer were enrolled. Salivary excretion factors (SEFs) measured by scintigraphy and QoL data from self-reported questionnaires were used for NTCP modeling to describe the incidence of grade 3+ xerostomia. The NTCP parameters estimated from the QoL and SEF datasets were compared. Model performance was assessed using Pearson's chi-squared test, Nagelkerke's R2, the area under the receiver operating characteristic curve, and the Hosmer-Lemeshow test. The negative predictive value (NPV) was checked for the rate of correctly predicting the lack of incidence. Pearson's chi-squared test was used to test the goodness of fit and association. Using the LKB NTCP model and assuming n=1, the dose for uniform irradiation of the whole or partial volume of the parotid gland that results in 50% probability of a complication (TD50) and the slope of the dose-response curve (m) were determined from the QoL and SEF datasets, respectively. The NTCP-fitted parameters for local disease were TD50=43.6 Gy and m=0.18 with the SEF data, and TD50=44.1 Gy and m=0.11 with the QoL data. The rate of grade 3+ xerostomia for treatment plans meeting the QUANTEC guidelines was specifically predicted, with a NPV of 100%, using either the QoL or SEF dataset. Our study shows the agreement between the NTCP parameter modeling based on SEF and QoL data, which gave a NPV of 100% with each dataset, and the QUANTEC guidelines, thus validating the cut-off values of 20 and 25 Gy. Based on these results, we believe that the QUANTEC 25/20-Gy spared-gland mean-dose guidelines are clinically useful for avoiding xerostomia in the HN cohort.

TH-E-BRF-06: Kinetic Modeling of Tumor Response to Fractionated Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhong, H; Gordon, J; Chetty, I

2014-06-15

Purpose: Accurate calibration of radiobiological parameters is crucial to predicting radiation treatment response. Modeling differences may have a significant impact on calibrated parameters. In this study, we have integrated two existing models with kinetic differential equations to formulate a new tumor regression model for calibrating radiobiological parameters for individual patients. Methods: A system of differential equations that characterizes the birth-and-death process of tumor cells in radiation treatment was analytically solved. The solution of this system was used to construct an iterative model (Z-model). The model consists of three parameters: tumor doubling time Td, half-life of dying cells Tr and cellmore » survival fraction SFD under dose D. The Jacobian determinant of this model was proposed as a constraint to optimize the three parameters for six head and neck cancer patients. The derived parameters were compared with those generated from the two existing models, Chvetsov model (C-model) and Lim model (L-model). The C-model and L-model were optimized with the parameter Td fixed. Results: With the Jacobian-constrained Z-model, the mean of the optimized cell survival fractions is 0.43±0.08, and the half-life of dying cells averaged over the six patients is 17.5±3.2 days. The parameters Tr and SFD optimized with the Z-model differ by 1.2% and 20.3% from those optimized with the Td-fixed C-model, and by 32.1% and 112.3% from those optimized with the Td-fixed L-model, respectively. Conclusion: The Z-model was analytically constructed from the cellpopulation differential equations to describe changes in the number of different tumor cells during the course of fractionated radiation treatment. The Jacobian constraints were proposed to optimize the three radiobiological parameters. The developed modeling and optimization methods may help develop high-quality treatment regimens for individual patients.« less

Critical Review of Selected Components of RIPD (Radiation-Induced Performance Decrement)

DTIC Science & Technology

2012-12-01

e in UG dis n Table 3. of the NAS of the NAS tive toxin A stem. This al vomiting leared at a ra ted by the e s for B and β rate const s of...protracted and fractionated doses. From data for acute doses ( King 1988), severity curves were constructed for the ferret. Model parameters were fit to...cytokine concentrations and bacterial infection,” Radiat. Res, 173(3):319– 332. King G.L., 1988. “Characterization of radiation-induced emesis in

A reaction limited in vivo dissolution model for the study of drug absorption: Towards a new paradigm for the biopharmaceutic classification of drugs.

PubMed

Macheras, Panos; Iliadis, Athanassios; Melagraki, Georgia

2018-05-30

The aim of this work is to develop a gastrointestinal (GI) drug absorption model based on a reaction limited model of dissolution and consider its impact on the biopharmaceutic classification of drugs. Estimates for the fraction of dose absorbed as a function of dose, solubility, reaction/dissolution rate constant and the stoichiometry of drug-GI fluids reaction/dissolution were derived by numerical solution of the model equations. The undissolved drug dose and the reaction/dissolution rate constant drive the dissolution rate and determine the extent of absorption when high-constant drug permeability throughout the gastrointestinal tract is assumed. Dose is an important element of drug-GI fluids reaction/dissolution while solubility exclusively acts as an upper limit for drug concentrations in the lumen. The 3D plots of fraction of dose absorbed as a function of dose and reaction/dissolution rate constant for highly soluble and low soluble drugs for different "stoichiometries" (0.7, 1.0, 2.0) of the drug-reaction/dissolution with the GI fluids revealed that high extent of absorption was found assuming high drug- reaction/dissolution rate constant and high drug solubility. The model equations were used to simulate in vivo supersaturation and precipitation phenomena. The model developed provides the theoretical basis for the interpretation of the extent of drug's absorption on the basis of the parameters associated with the drug-GI fluids reaction/dissolution. A new paradigm emerges for the biopharmaceutic classification of drugs, namely, a model independent biopharmaceutic classification scheme of four drug categories based on either the fulfillment or not of the current dissolution criteria and the high or low % drug metabolism. Copyright © 2018. Published by Elsevier B.V.

A method for modeling laterally asymmetric proton beamlets resulting from collimation

PubMed Central

Gelover, Edgar; Wang, Dongxu; Hill, Patrick M.; Flynn, Ryan T.; Gao, Mingcheng; Laub, Steve; Pankuch, Mark; Hyer, Daniel E.

2015-01-01

Purpose: To introduce a method to model the 3D dose distribution of laterally asymmetric proton beamlets resulting from collimation. The model enables rapid beamlet calculation for spot scanning (SS) delivery using a novel penumbra-reducing dynamic collimation system (DCS) with two pairs of trimmers oriented perpendicular to each other. Methods: Trimmed beamlet dose distributions in water were simulated with MCNPX and the collimating effects noted in the simulations were validated by experimental measurement. The simulated beamlets were modeled analytically using integral depth dose curves along with an asymmetric Gaussian function to represent fluence in the beam’s eye view (BEV). The BEV parameters consisted of Gaussian standard deviations (sigmas) along each primary axis (σx1,σx2,σy1,σy2) together with the spatial location of the maximum dose (μx,μy). Percent depth dose variation with trimmer position was accounted for with a depth-dependent correction function. Beamlet growth with depth was accounted for by combining the in-air divergence with Hong’s fit of the Highland approximation along each axis in the BEV. Results: The beamlet model showed excellent agreement with the Monte Carlo simulation data used as a benchmark. The overall passing rate for a 3D gamma test with 3%/3 mm passing criteria was 96.1% between the analytical model and Monte Carlo data in an example treatment plan. Conclusions: The analytical model is capable of accurately representing individual asymmetric beamlets resulting from use of the DCS. This method enables integration of the DCS into a treatment planning system to perform dose computation in patient datasets. The method could be generalized for use with any SS collimation system in which blades, leaves, or trimmers are used to laterally sharpen beamlets. PMID:25735287

Feasibility of a low-dose orbital CT protocol with a knowledge-based iterative model reconstruction algorithm for evaluating Graves' orbitopathy.

PubMed

Lee, Ho-Joon; Kim, Jinna; Kim, Ki Wook; Lee, Seung-Koo; Yoon, Jin Sook

2018-06-23

To evaluate the clinical feasibility of low-dose orbital CT with a knowledge-based iterative model reconstruction (IMR) algorithm for evaluating Graves' orbitopathy. Low-dose orbital CT was performed with a CTDI vol of 4.4 mGy. In 12 patients for whom prior or subsequent non-low-dose orbital CT data obtained within 12 months were available, background noise, SNR, and CNR were compared for images generated using filtered back projection (FBP), hybrid iterative reconstruction (iDose 4 ), and IMR and non-low-dose CT images. Comparison of clinically relevant measurements for Graves' orbitopathy, such as rectus muscle thickness and retrobulbar fat area, was performed in a subset of 6 patients who underwent CT for causes other than Graves' orbitopathy, by using the Wilcoxon signed-rank test. The lens dose estimated from skin dosimetry on a phantom was 4.13 mGy, which was on average 59.34% lower than that of the non-low-dose protocols. Image quality in terms of background noise, SNR, and CNR was the best for IMR, followed by non-low-dose CT, iDose 4 , and FBP, in descending order. A comparison of clinically relevant measurements revealed no significant difference in the retrobulbar fat area and the inferior and medial rectus muscle thicknesses between the low-dose and non-low-dose CT images. Low-dose CT with IMR may be performed without significantly affecting the measurement of prognostic parameters for Graves' orbitopathy while lowering the lens dose and image noise. Copyright © 2018 Elsevier Inc. All rights reserved.

Evaluation of an artificial intelligence guided inverse planning system: clinical case study.

PubMed

Yan, Hui; Yin, Fang-Fang; Willett, Christopher

2007-04-01

An artificial intelligence (AI) guided method for parameter adjustment of inverse planning was implemented on a commercial inverse treatment planning system. For evaluation purpose, four typical clinical cases were tested and the results from both plans achieved by automated and manual methods were compared. The procedure of parameter adjustment mainly consists of three major loops. Each loop is in charge of modifying parameters of one category, which is carried out by a specially customized fuzzy inference system. A physician prescribed multiple constraints for a selected volume were adopted to account for the tradeoff between prescription dose to the PTV and dose-volume constraints for critical organs. The searching process for an optimal parameter combination began with the first constraint, and proceeds to the next until a plan with acceptable dose was achieved. The initial setup of the plan parameters was the same for each case and was adjusted independently by both manual and automated methods. After the parameters of one category were updated, the intensity maps of all fields were re-optimized and the plan dose was subsequently re-calculated. When final plan arrived, the dose statistics were calculated from both plans and compared. For planned target volume (PTV), the dose for 95% volume is up to 10% higher in plans using the automated method than those using the manual method. For critical organs, an average decrease of the plan dose was achieved. However, the automated method cannot improve the plan dose for some critical organs due to limitations of the inference rules currently employed. For normal tissue, there was no significant difference between plan doses achieved by either automated or manual method. With the application of AI-guided method, the basic parameter adjustment task can be accomplished automatically and a comparable plan dose was achieved in comparison with that achieved by the manual method. Future improvements to incorporate case-specific inference rules are essential to fully automate the inverse planning process.

Radiation-Induced Leukemia at Doses Relevant to Radiation Therapy: Modeling Mechanisms and Estimating Risks

NASA Technical Reports Server (NTRS)

Shuryak, Igor; Sachs, Rainer K.; Hlatky, Lynn; Mark P. Little; Hahnfeldt, Philip; Brenner, David J.

2006-01-01

Because many cancer patients are diagnosed earlier and live longer than in the past, second cancers induced by radiation therapy have become a clinically significant issue. An earlier biologically based model that was designed to estimate risks of high-dose radiation induced solid cancers included initiation of stem cells to a premalignant state, inactivation of stem cells at high radiation doses, and proliferation of stem cells during cellular repopulation after inactivation. This earlier model predicted the risks of solid tumors induced by radiation therapy but overestimated the corresponding leukemia risks. Methods: To extend the model to radiation-induced leukemias, we analyzed in addition to cellular initiation, inactivation, and proliferation a repopulation mechanism specific to the hematopoietic system: long-range migration through the blood stream of hematopoietic stem cells (HSCs) from distant locations. Parameters for the model were derived from HSC biologic data in the literature and from leukemia risks among atomic bomb survivors v^ ho were subjected to much lower radiation doses. Results: Proliferating HSCs that migrate from sites distant from the high-dose region include few preleukemic HSCs, thus decreasing the high-dose leukemia risk. The extended model for leukemia provides risk estimates that are consistent with epidemiologic data for leukemia risk associated with radiation therapy over a wide dose range. For example, when applied to an earlier case-control study of 110000 women undergoing radiotherapy for uterine cancer, the model predicted an excess relative risk (ERR) of 1.9 for leukemia among women who received a large inhomogeneous fractionated external beam dose to the bone marrow (mean = 14.9 Gy), consistent with the measured ERR (2.0, 95% confidence interval [CI] = 0.2 to 6.4; from 3.6 cases expected and 11 cases observed). As a corresponding example for brachytherapy, the predicted ERR of 0.80 among women who received an inhomogeneous low-dose-rate dose to the bone marrow (mean = 2.5 Gy) was consistent with the measured ERR (0.62, 95% Cl =-0.2 to 1.9). Conclusions: An extended, biologically based model for leukemia that includes HSC initiation, inactivation, proliferation, and, uniquely for leukemia, long-range HSC migration predicts, %Kith reasonable accuracy, risks for radiationinduced leukemia associated with exposure to therapeutic doses of radiation.

An RBF-PSO based approach for modeling prostate cancer

NASA Astrophysics Data System (ADS)

Perracchione, Emma; Stura, Ilaria

2016-06-01

Prostate cancer is one of the most common cancers in men; it grows slowly and it could be diagnosed in an early stage by dosing the Prostate Specific Antigen (PSA). However, a relapse after the primary therapy could arise in 25 - 30% of cases and different growth characteristics of the new tumor are observed. In order to get a better understanding of the phenomenon, a two parameters growth model is considered. To estimate the parameters values identifying the disease risk level a novel approach, based on combining Particle Swarm Optimization (PSO) with meshfree interpolation methods, is proposed.

SU-E-I-15: Comparison of Radiation Dose for Radiography and EOS in Adolescent Scoliosis Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schueler, B; Walz-Flannigan, A

Purpose: To estimate patient radiation dose for whole spine imaging using EOS, a new biplanar slot-scanning radiographic system and compare with standard scoliosis radiography. Methods: The EOS imaging system (EOS Imaging, Paris, France) consists of two orthogonal x-ray fan beams which simultaneously acquire frontal and lateral projection images of a standing patient. The patient entrance skin air kerma was measured for each projection image using manufacturer-recommended exposure parameters for spine imaging. Organ and effective doses were estimated using a commercially-available Monte Carlo simulation program (PCXMC, STUK, Radiation and Nuclear Safety Authority, Helsinki, Finland) for a 15 year old mathematical phantommore » model. These results were compared to organ and effective dose estimated for scoliosis radiography using computed radiography (CR) with standard exposure parameters obtained from a survey of pediatric radiographic projections. Results: The entrance skin air kerma for EOS was found to be 0.18 mGy and 0.33 mGy for posterior-anterior (PA) and lateral projections, respectively. This compares to 0.76 mGy and 1.4 mGy for CR, PA and lateral projections. Effective dose for EOS (PA and lateral projections combined) is 0.19 mSv compared to 0.51 mSv for CR. Conclusion: The EOS slot-scanning radiographic system allows for reduced patient radiation dose in scoliosis patients as compared to standard CR radiography.« less

A COMPARATIVE INVESTIGATION OF THE INFLUENCE OF DERMAL APPENDAGES (HAIR FOLLICLES) ON THE PERCUTANEOUS ABSORPTION OF ORGANOPHOSPHORUS (OP) INSECTICIDES USING QSAR AND PBPK/PD MODELS FOR HUMAN RISK ASSESSMENT

EPA Science Inventory

The successful use of the Exposure Related Dose Estimating Model (ERDEM) for assessment of dermal exposure of humans to OP pesticides requires the input of representative and comparable input parameters. In the specific case of dermal exposure, regional anatomical variation in...

Evaluation of the Emergency Response Dose Assessment System(ERDAS)

NASA Technical Reports Server (NTRS)

Evans, Randolph J.; Lambert, Winifred C.; Manobianco, John T.; Taylor, Gregory E.; Wheeler, Mark M.; Yersavich, Ann M.

1996-01-01

The emergency response dose assessment system (ERDAS) is a protype software and hardware system configured to produce routine mesoscale meteorological forecasts and enhanced dispersion estimates on an operational basis for the Kennedy Space Center (KSC)/Cape Canaveral Air Station (CCAS) region. ERDAS provides emergency response guidance to operations at KSC/CCAS in the case of an accidental hazardous material release or an aborted vehicle launch. This report describes the evaluation of ERDAS including: evaluation of sea breeze predictions, comparison of launch plume location and concentration predictions, case study of a toxic release, evaluation of model sensitivity to varying input parameters, evaluation of the user interface, assessment of ERDA's operational capabilities, and a comparison of ERDAS models to the ocean breeze dry gultch diffusion model.

[Application of State Space model in the evaluation of the prevention and control for mumps].

PubMed

Luo, C; Li, R Z; Xu, Q Q; Xiong, P; Liu, Y X; Xue, F Z; Xu, Q; Li, X J

2017-09-10

Objective: To analyze the epidemiological characteristics of mumps in 2012 and 2014, and to explore the preventive effect of the second dose of mumps-containing vaccine (MuCV) in mumps in Shandong province. Methods: On the basis of certain model assumptions, a Space State model was formulated. Iterated Filter was applied to the epidemic model to estimate the parameters. Results: The basic reproduction number ( R (0)) for children in schools was 4.49 (95 %CI : 4.30-4.67) and 2.50 (95 %CI : 2.38-2.61) respectively for the year of 2012 and 2014. Conclusions: Space State model seems suitable for mumps prevalence description. The policy of 2-dose MuCV can effectively reduce the number of total patients. Children in schools are the key to reduce the mumps.

Use of DandD for dose assessment under NRC`s radiological criteria for license termination rule

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gallegos, D.P.; Brown, T.J.; Davis, P.A.

The Decontamination and Decommissioning (DandD) software package has been developed by Sandia National Laboratories for the Nuclear Regulatory Commission (NRC) specifically for the purpose of providing a user-friendly analytical tool to address the dose criteria contained in NRC`s Radiological Criteria for License Termination rule (10 CFR Part 20 Subpart E; NRC, 1997). Specifically, DandD embodies the NRC`s screening methodology to allow licensees to convert residual radioactivity contamination levels at their site to annual dose, in a manner consistent with both 10 CFR Part 20 and the corresponding implementation guidance developed by NRC. The screening methodology employs reasonably conservative scenarios, fatemore » and transport models, and default parameter values that have been developed to allow the NRC to quantitatively estimate the risk of releasing a site given only information about the level of contamination. Therefore, a licensee has the option of specifying only the level of contamination and running the code with the default parameter values, or in the case where site specific information is available to alter the appropriate parameter values and then calculate dose. DandD can evaluate dose for fur different scenarios: residential, building occupancy, building renovation, or drinking water. The screening methodology and DandD are part of a larger decision framework that allows and encourages licensees to optimize decisions on choice of alternative actions at their site, including collection of additional data and information. This decision framework is integrated into and documented in NRC`s technical guidance for decommissioning.« less

An oracle: antituberculosis pharmacokinetics-pharmacodynamics, clinical correlation, and clinical trial simulations to predict the future.

PubMed

Pasipanodya, Jotam; Gumbo, Tawanda

2011-01-01

Antimicrobial pharmacokinetic-pharmacodynamic (PK/PD) science and clinical trial simulations have not been adequately applied to the design of doses and dose schedules of antituberculosis regimens because many researchers are skeptical about their clinical applicability. We compared findings of preclinical PK/PD studies of current first-line antituberculosis drugs to findings from several clinical publications that included microbiologic outcome and pharmacokinetic data or had a dose-scheduling design. Without exception, the antimicrobial PK/PD parameters linked to optimal effect were similar in preclinical models and in tuberculosis patients. Thus, exposure-effect relationships derived in the preclinical models can be used in the design of optimal antituberculosis doses, by incorporating population pharmacokinetics of the drugs and MIC distributions in Monte Carlo simulations. When this has been performed, doses and dose schedules of rifampin, isoniazid, pyrazinamide, and moxifloxacin with the potential to shorten antituberculosis therapy have been identified. In addition, different susceptibility breakpoints than those in current use have been identified. These steps outline a more rational approach than that of current methods for designing regimens and predicting outcome so that both new and older antituberculosis agents can shorten therapy duration.

WE-H-BRA-01: BEST IN PHYSICS (THERAPY): Nano-Dosimetric Kinetic Model for Variable Relative Biological Effectiveness of Proton and Ion Beams

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abolfath, R; Bronk, L; Titt, U.

2016-06-15

Purpose: Recent clonogenic cell survival and γH2AX studies suggest proton relative biological effectiveness (RBE) may be a non-linear function of linear energy transfer (LET) in the distal edge of the Bragg peak and beyond. We sought to develop a multiscale model to account for non-linear response phenomena to aid in the optimization of intensity-modulated proton therapy. Methods: The model is based on first-principle simulations of proton track structures, including secondary ions, and an analytical derivation of the dependence on particle LET of the linear-quadratic (LQ) model parameters α and β. The derived formulas are an extension of the microdosimetric kineticmore » (MK) model that captures dissipative track structures and non-Poissonian distribution of DNA damage at the distal edge of the Bragg peak and beyond. Monte Carlo simulations were performed to confirm the non-linear dose-response characteristics arising from the non-Poisson distribution of initial DNA damage. Results: In contrast to low LET segments of the proton depth dose, from the beam entrance to the Bragg peak, strong deviations from non-dissipative track structures and Poisson distribution in the ionization events in the Bragg peak distal edge govern the non-linear cell response and result in the transformation α=(1+c-1 L) α-x+2(c-0 L+c-2 L^2 )(1+c-1 L) β-x and β=(1+c-1 L)^2 β-x. Here L is the charged particle LET, and c-0,c-1, and c-2 are functions of microscopic parameters and can be served as fitting parameters to the cell-survival data. In the low LET limit c-1, and c-2 are negligible hence the linear model proposed and used by Wilkins-Oelfke for the proton treatment planning system can be retrieved. The present model fits well the recent clonogenic survival data measured recently in our group in MDACC. Conclusion: The present hybrid method provides higher accuracy in calculating the RBE-weighted dose in the target and normal tissues.« less

In-vivo singlet oxygen threshold doses for PDT

PubMed Central

Zhu, Timothy C.; Kim, Michele M.; Liang, Xing; Finlay, Jarod C.; Busch, Theresa M.

2015-01-01

Objective Dosimetry of singlet oxygen (1O2) is of particular interest because it is the major cytotoxic agent causing biological effects for type-II photosensitizers during photodynamic therapy (PDT). An in-vivo model to determine the singlet oxygen threshold dose, [1O2]rx,sh, for PDT was developed. Material and methods An in-vivo radiation-induced fibrosarcoma (RIF) tumor mouse model was used to correlate the radius of necrosis to the calculation based on explicit PDT dosimetry of light fluence distribution, tissue optical properties, and photosensitizer concentrations. Inputs to the model include five photosensitizer-specific photochemical parameters along with [1O2]rx,sh. Photosensitizer-specific model parameters were determined for benzoporphyrin derivative monoacid ring A (BPD) and compared with two other type-II photosensitizers, Photofrin® and m-tetrahydroxyphenylchlorin (mTHPC) from the literature. Results The mean values (standard deviation) of the in-vivo [1O2]rx,sh are approximately 0.56 (0.26) and 0.72 (0.21) mM (or 3.6×107 and 4.6×107 singlet oxygen per cell to reduce the cell survival to 1/e) for Photofrin® and BPD, respectively, assuming that the fraction of generated singlet oxygen that interacts with the cell is 1. While the values for the photochemical parameters (ξ, σ, g, β) used for BPD were preliminary and may need further refinement, there is reasonable confidence for the values of the singlet oxygen threshold doses. Discussion In comparison, the [1O2]rx,sh value derived from in-vivo mouse study was reported to be 0.4 mM for mTHPC-PDT. However, the singlet oxygen required per cell is reported to be 9×108 per cell per 1/e fractional kill in an in-vitro mTHPC-PDT study on a rat prostate cancer cell line (MLL cells) and is reported to be 7.9 mM for a multicell in-vitro EMT6/Ro spheroid model for mTHPC-PDT. A theoretical analysis is provided to relate the number of in-vitro singlet oxygen required per cell to reach cell killing of 1/e to in-vivo singlet oxygen threshold dose (in mM). The sensitivity of threshold singlet oxygen dose for our experiment is examined. The possible influence of vascular vs. apoptotic cell killing mechanisms on the singlet oxygen threshold dose is discussed by comparing [1O2]rx,sh for BPD with 3 hr and 15 min drug-light-intervals, with the later being known to have a dominantly vascular effect. Conclusions The experimental results of threshold singlet oxygen concentration in an in-vivo RIF tumor model for Photofrin®, BPD, and mTHPC are about 20 times smaller than those observed in vitro. These results are consistent with knowledge that factors other than singlet oxygen-mediated tumor cell killing can contribute to PDT damage in-vivo. PMID:25927018

In-vivo singlet oxygen threshold doses for PDT.

PubMed

Zhu, Timothy C; Kim, Michele M; Liang, Xing; Finlay, Jarod C; Busch, Theresa M

2015-02-01

Dosimetry of singlet oxygen ( 1 O 2 ) is of particular interest because it is the major cytotoxic agent causing biological effects for type-II photosensitizers during photodynamic therapy (PDT). An in-vivo model to determine the singlet oxygen threshold dose, [ 1 O 2 ] rx,sh , for PDT was developed. An in-vivo radiation-induced fibrosarcoma (RIF) tumor mouse model was used to correlate the radius of necrosis to the calculation based on explicit PDT dosimetry of light fluence distribution, tissue optical properties, and photosensitizer concentrations. Inputs to the model include five photosensitizer-specific photochemical parameters along with [ 1 O 2 ] rx,sh . Photosensitizer-specific model parameters were determined for benzoporphyrin derivative monoacid ring A (BPD) and compared with two other type-II photosensitizers, Photofrin ® and m-tetrahydroxyphenylchlorin (mTHPC) from the literature. The mean values (standard deviation) of the in-vivo [ 1 O 2 ] rx,sh are approximately 0.56 (0.26) and 0.72 (0.21) mM (or 3.6×10 7 and 4.6×10 7 singlet oxygen per cell to reduce the cell survival to 1/e) for Photofrin ® and BPD, respectively, assuming that the fraction of generated singlet oxygen that interacts with the cell is 1. While the values for the photochemical parameters (ξ, σ, g , β) used for BPD were preliminary and may need further refinement, there is reasonable confidence for the values of the singlet oxygen threshold doses. In comparison, the [ 1 O 2 ] rx,sh value derived from in-vivo mouse study was reported to be 0.4 mM for mTHPC-PDT. However, the singlet oxygen required per cell is reported to be 9×10 8 per cell per 1/ e fractional kill in an in-vitro mTHPC-PDT study on a rat prostate cancer cell line (MLL cells) and is reported to be 7.9 mM for a multicell in-vitro EMT6/Ro spheroid model for mTHPC-PDT. A theoretical analysis is provided to relate the number of in-vitro singlet oxygen required per cell to reach cell killing of 1/ e to in-vivo singlet oxygen threshold dose (in mM). The sensitivity of threshold singlet oxygen dose for our experiment is examined. The possible influence of vascular vs. apoptotic cell killing mechanisms on the singlet oxygen threshold dose is discussed by comparing [ 1 O 2 ] rx,sh for BPD with 3 hr and 15 min drug-light-intervals, with the later being known to have a dominantly vascular effect. The experimental results of threshold singlet oxygen concentration in an in-vivo RIF tumor model for Photofrin ® , BPD, and mTHPC are about 20 times smaller than those observed in vitro . These results are consistent with knowledge that factors other than singlet oxygen-mediated tumor cell killing can contribute to PDT damage in-vivo .

Characterization of the ultrasonic attenuation coefficient and its frequency dependence in a polymer gel dosimeter.

PubMed

Crescenti, Remo A; Bamber, Jeffrey C; Partridge, Mike; Bush, Nigel L; Webb, Steve

2007-11-21

Research on polymer-gel dosimetry has been driven by the need for three-dimensional dosimetry, and because alternative dosimeters are unsatisfactory or too slow for that task. Magnetic resonance tomography is currently the most well-developed technique for determining radiation-induced changes in polymer structure, but quick low-cost alternatives remain of significant interest. In previous work, ultrasound attenuation and speed of sound were found to change as a function of absorbed radiation dose in polymer-gel dosimeters, although the investigations were restricted to one ultrasound frequency. Here, the ultrasound attenuation coefficient mu in one polymer gel (MAGIC) was investigated as a function of radiation dose D and as a function of ultrasonic frequency f in a frequency range relevant for imaging dose distributions. The nonlinearity of the frequency dependence was characterized, fitting a power-law model mu = af(b); the fitting parameters were examined for potential use as additional dose readout parameters. In the observed relationship between the attenuation coefficient and dose, the slopes in a quasi-linear dose range from 0 to 30 Gy were found to vary with the gel batch but lie between 0.0222 and 0.0348 dB cm(-1) Gy(-1) at 2.3 MHz, between 0.0447 and 0.0608 dB cm(-1) Gy(-1) at 4.1 MHz and between 0.0663 and 0.0880 dB cm(-1) Gy(-1) at 6.0 MHz. The mean standard deviation of the slope for all samples and frequencies was 15.8%. The slope was greater at higher frequencies, but so were the intra-batch fluctuations and intra-sample standard deviations. Further investigations are required to overcome the observed variability, which was largely associated with the sample preparation technique, before it can be determined whether any frequency is superior to others in terms of accuracy and precision in dose determination. Nevertheless, lower frequencies will allow measurements through larger samples. The fit parameter a of the frequency dependence, describing the attenuation coefficient at 1 MHz, was found to be dose dependent, which is consistent with our expectations, as polymerization is known to be associated with increased absorption of ultrasound. No significant dose dependence was found for the fit parameter b, which describes the nonlinearity with frequency. This is consistent with the increased absorption being due to the introduction of new relaxation processes with characteristic frequencies similar to those of existing processes. The data presented here will help with optimizing the design of future 3D dose-imaging systems using ultrasound methods.

Dosimetry in nuclear medicine therapy: radiobiology application and results.

PubMed

Strigari, L; Benassi, M; Chiesa, C; Cremonesi, M; Bodei, L; D'Andrea, M

2011-04-01

The linear quadratic model (LQM) has largely been used to assess the radiobiological damage to tissue by external beam fractionated radiotherapy and more recently has been extended to encompass a general continuous time varying dose rate protocol such as targeted radionuclide therapy (TRT). In this review, we provide the basic aspects of radiobiology, from a theoretical point of view, starting from the "four Rs" of radiobiology and introducing the biologically effective doses, which may be used to quantify the impact of a treatment on both tumors and normal tissues. We also present the main parameters required in the LQM, and illustrate the main models of tumor control probability and normal tissue complication probability and summarize the main dose-effect responses, reported in literature, which demonstrate the tentative link between targeted radiotherapy doses and those used in conventional radiotherapy. A better understanding of the radiobiology and mechanisms of action of TRT could contribute to describe the clinical data and guide the development of future compounds and the designing of prospective clinical trials.

Artificial neural network based gynaecological image-guided adaptive brachytherapy treatment planning correction of intra-fractional organs at risk dose variation

PubMed Central

Jaberi, Ramin; Aghamiri, Mahmoud Reza; Kirisits, Christian; Ghaderi, Reza

2017-01-01

Purpose Intra-fractional organs at risk (OARs) deformations can lead to dose variation during image-guided adaptive brachytherapy (IGABT). The aim of this study was to modify the final accepted brachytherapy treatment plan to dosimetrically compensate for these intra-fractional organs-applicators position variations and, at the same time, fulfilling the dosimetric criteria. Material and methods Thirty patients with locally advanced cervical cancer, after external beam radiotherapy (EBRT) of 45-50 Gy over five to six weeks with concomitant weekly chemotherapy, and qualified for intracavitary high-dose-rate (HDR) brachytherapy with tandem-ovoid applicators were selected for this study. Second computed tomography scan was done for each patient after finishing brachytherapy treatment with applicators in situ. Artificial neural networks (ANNs) based models were used to predict intra-fractional OARs dose-volume histogram parameters variations and propose a new final plan. Results A model was developed to estimate the intra-fractional organs dose variations during gynaecological intracavitary brachytherapy. Also, ANNs were used to modify the final brachytherapy treatment plan to compensate dosimetrically for changes in ‘organs-applicators’, while maintaining target dose at the original level. Conclusions There are semi-automatic and fast responding models that can be used in the routine clinical workflow to reduce individually IGABT uncertainties. These models can be more validated by more patients’ plans to be able to serve as a clinical tool. PMID:29441094

Historical Doses from Tritiated Water and Tritiated Hydrogen Gas Released to the Atmosphere from Lawrence Livermore National Laboratory (LLNL). Part 5. Accidental Releases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peterson, S

2007-08-15

Over the course of fifty-three years, LLNL had six acute releases of tritiated hydrogen gas (HT) and one acute release of tritiated water vapor (HTO) that were too large relative to the annual releases to be included as part of the annual releases from normal operations detailed in Parts 3 and 4 of the Tritium Dose Reconstruction (TDR). Sandia National Laboratories/California (SNL/CA) had one such release of HT and one of HTO. Doses to the maximally exposed individual (MEI) for these accidents have been modeled using an equation derived from the time-dependent tritium model, UFOTRI, and parameter values based onmore » expert judgment. All of these acute releases are described in this report. Doses that could not have been exceeded from the large HT releases of 1965 and 1970 were calculated to be 43 {micro}Sv (4.3 mrem) and 120 {micro}Sv (12 mrem) to an adult, respectively. Two published sets of dose predictions for the accidental HT release in 1970 are compared with the dose predictions of this TDR. The highest predicted dose was for an acute release of HTO in 1954. For this release, the dose that could not have been exceeded was estimated to have been 2 mSv (200 mrem), although, because of the high uncertainty about the predictions, the likely dose may have been as low as 360 {micro}Sv (36 mrem) or less. The estimated maximum exposures from the accidental releases were such that no adverse health effects would be expected. Appendix A lists all accidents and large routine puff releases that have occurred at LLNL and SNL/CA between 1953 and 2005. Appendix B describes the processes unique to tritium that must be modeled after an acute release, some of the time-dependent tritium models being used today, and the results of tests of these models.« less

Meth math: modeling temperature responses to methamphetamine.

PubMed

Molkov, Yaroslav I; Zaretskaia, Maria V; Zaretsky, Dmitry V

2014-04-15

Methamphetamine (Meth) can evoke extreme hyperthermia, which correlates with neurotoxicity and death in laboratory animals and humans. The objective of this study was to uncover the mechanisms of a complex dose dependence of temperature responses to Meth by mathematical modeling of the neuronal circuitry. On the basis of previous studies, we composed an artificial neural network with the core comprising three sequentially connected nodes: excitatory, medullary, and sympathetic preganglionic neuronal (SPN). Meth directly stimulated the excitatory node, an inhibitory drive targeted the medullary node, and, in high doses, an additional excitatory drive affected the SPN node. All model parameters (weights of connections, sensitivities, and time constants) were subject to fitting experimental time series of temperature responses to 1, 3, 5, and 10 mg/kg Meth. Modeling suggested that the temperature response to the lowest dose of Meth, which caused an immediate and short hyperthermia, involves neuronal excitation at a supramedullary level. The delay in response after the intermediate doses of Meth is a result of neuronal inhibition at the medullary level. Finally, the rapid and robust increase in body temperature induced by the highest dose of Meth involves activation of high-dose excitatory drive. The impairment in the inhibitory mechanism can provoke a life-threatening temperature rise and makes it a plausible cause of fatal hyperthermia in Meth users. We expect that studying putative neuronal sites of Meth action and the neuromediators involved in a detailed model of this system may lead to more effective strategies for prevention and treatment of hyperthermia induced by amphetamine-like stimulants.

Meth math: modeling temperature responses to methamphetamine

PubMed Central

Molkov, Yaroslav I.; Zaretskaia, Maria V.

2014-01-01

Methamphetamine (Meth) can evoke extreme hyperthermia, which correlates with neurotoxicity and death in laboratory animals and humans. The objective of this study was to uncover the mechanisms of a complex dose dependence of temperature responses to Meth by mathematical modeling of the neuronal circuitry. On the basis of previous studies, we composed an artificial neural network with the core comprising three sequentially connected nodes: excitatory, medullary, and sympathetic preganglionic neuronal (SPN). Meth directly stimulated the excitatory node, an inhibitory drive targeted the medullary node, and, in high doses, an additional excitatory drive affected the SPN node. All model parameters (weights of connections, sensitivities, and time constants) were subject to fitting experimental time series of temperature responses to 1, 3, 5, and 10 mg/kg Meth. Modeling suggested that the temperature response to the lowest dose of Meth, which caused an immediate and short hyperthermia, involves neuronal excitation at a supramedullary level. The delay in response after the intermediate doses of Meth is a result of neuronal inhibition at the medullary level. Finally, the rapid and robust increase in body temperature induced by the highest dose of Meth involves activation of high-dose excitatory drive. The impairment in the inhibitory mechanism can provoke a life-threatening temperature rise and makes it a plausible cause of fatal hyperthermia in Meth users. We expect that studying putative neuronal sites of Meth action and the neuromediators involved in a detailed model of this system may lead to more effective strategies for prevention and treatment of hyperthermia induced by amphetamine-like stimulants. PMID:24500434

Biophysical model for assessment of risk of acute exposures in combination with low level chronic irradiation

NASA Astrophysics Data System (ADS)

Smirnova, O. A.

A biophysical model is developed which describes the mortality dynamics in mammalian populations unexposed and exposed to radiation The model relates statistical biometric functions mortality rate life span probability density and life span probability with statistical characteristics and dynamics of a critical body system in individuals composing the population The model describing the dynamics of thrombocytopoiesis in nonirradiated and irradiated mammals is also developed this hematopoietic line being considered as the critical body system under exposures in question The mortality model constructed in the framework of the proposed approach was identified to reproduce the irradiation effects on populations of mice The most parameters of the thrombocytopoiesis model were determined from the data available in the literature on hematology and radiobiology the rest parameters were evaluated by fitting some experimental data on the dynamics of this system in acutely irradiated mice The successful verification of the thrombocytopoiesis model was fulfilled by the quantitative juxtaposition of the modeling predictions and experimental data on the dynamics of this system in mice exposed to either acute or chronic irradiation at wide ranges of doses and dose rates It is important that only experimental data on the mortality rate in nonirradiated population and the relevant statistical characteristics of the thrombocytopoiesis system in mice which are also available in the literature on radiobiology are needed for the final identification of

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ma, R; Zhu, X; Li, S

Purpose: High Dose Rate (HDR) brachytherapy forward planning is principally an iterative process; hence, plan quality is affected by planners’ experiences and limited planning time. Thus, this may lead to sporadic errors and inconsistencies in planning. A statistical tool based on previous approved clinical treatment plans would help to maintain the consistency of planning quality and improve the efficiency of second checking. Methods: An independent dose calculation tool was developed from commercial software. Thirty-three previously approved cervical HDR plans with the same prescription dose (550cGy), applicator type, and treatment protocol were examined, and ICRU defined reference point doses (bladder, vaginalmore » mucosa, rectum, and points A/B) along with dwell times were collected. Dose calculation tool then calculated appropriate range with a 95% confidence interval for each parameter obtained, which would be used as the benchmark for evaluation of those parameters in future HDR treatment plans. Model quality was verified using five randomly selected approved plans from the same dataset. Results: Dose variations appears to be larger at the reference point of bladder and mucosa as compared with rectum. Most reference point doses from verification plans fell between the predicted range, except the doses of two points of rectum and two points of reference position A (owing to rectal anatomical variations & clinical adjustment in prescription points, respectively). Similar results were obtained for tandem and ring dwell times despite relatively larger uncertainties. Conclusion: This statistical tool provides an insight into clinically acceptable range of cervical HDR plans, which could be useful in plan checking and identifying potential planning errors, thus improving the consistency of plan quality.« less

Assessment of normal tissue complications following prostate cancer irradiation: Comparison of radiation treatment modalities using NTCP models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takam, Rungdham; Bezak, Eva; Yeoh, Eric E.

2010-09-15

Purpose: Normal tissue complication probability (NTCP) of the rectum, bladder, urethra, and femoral heads following several techniques for radiation treatment of prostate cancer were evaluated applying the relative seriality and Lyman models. Methods: Model parameters from literature were used in this evaluation. The treatment techniques included external (standard fractionated, hypofractionated, and dose-escalated) three-dimensional conformal radiotherapy (3D-CRT), low-dose-rate (LDR) brachytherapy (I-125 seeds), and high-dose-rate (HDR) brachytherapy (Ir-192 source). Dose-volume histograms (DVHs) of the rectum, bladder, and urethra retrieved from corresponding treatment planning systems were converted to biological effective dose-based and equivalent dose-based DVHs, respectively, in order to account for differences inmore » radiation treatment modality and fractionation schedule. Results: Results indicated that with hypofractionated 3D-CRT (20 fractions of 2.75 Gy/fraction delivered five times/week to total dose of 55 Gy), NTCP of the rectum, bladder, and urethra were less than those for standard fractionated 3D-CRT using a four-field technique (32 fractions of 2 Gy/fraction delivered five times/week to total dose of 64 Gy) and dose-escalated 3D-CRT. Rectal and bladder NTCPs (5.2% and 6.6%, respectively) following the dose-escalated four-field 3D-CRT (2 Gy/fraction to total dose of 74 Gy) were the highest among analyzed treatment techniques. The average NTCP for the rectum and urethra were 0.6% and 24.7% for LDR-BT and 0.5% and 11.2% for HDR-BT. Conclusions: Although brachytherapy techniques resulted in delivering larger equivalent doses to normal tissues, the corresponding NTCPs were lower than those of external beam techniques other than the urethra because of much smaller volumes irradiated to higher doses. Among analyzed normal tissues, the femoral heads were found to have the lowest probability of complications as most of their volume was irradiated to lower equivalent doses compared to other tissues.« less

NTCP Modeling of Subacute/Late Laryngeal Edema Scored by Fiberoptic Examination

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rancati, Tiziana; Fiorino, Claudio, E-mail: fiorino.claudio@hsr.i; Sanguineti, Giuseppe

2009-11-01

Purpose: Finding best-fit parameters of normal tissue complication probability (NTCP) models for laryngeal edema after radiotherapy for head and neck cancer. Methods and Materials: Forty-eight patients were considered for this study who met the following criteria: (1) grossly uninvolved larynx, (2) no prior major surgery except for neck dissection and tonsillectomy, (3) at least one fiberoptic examination of the larynx within 2 years from radiotherapy, (4) minimum follow-up of 15 months. Larynx dose-volume histograms (DVHs) were corrected into a linear quadratic equivalent one at 2 Gy/fr with alpha/beta = 3 Gy. Subacute/late edema was prospectively scored at each follow-up examinationmore » according to the Radiation Therapy Oncology Group scale. G2-G3 edema within 15 months from RT was considered as our endpoint. Two NTCP models were considered: (1) the Lyman model with DVH reduced to the equivalent uniform dose (EUD; LEUD) and (2) the Logit model with DVH reduced to the EUD (LOGEUD). The parameters for the models were fit to patient data using a maximum likelihood analysis. Results: All patients had a minimum of 15 months follow-up (only 8/48 received concurrent chemotherapy): 25/48 (52.1%) experienced G2-G3 edema. Both NTCP models fit well the clinical data: with LOGEUD the relationship between EUD and NTCP can be described with TD50 = 46.7 +- 2.1 Gy, n = 1.41 +- 0.8 and a steepness parameter k = 7.2 +- 2.5 Gy. Best fit parameters for LEUD are n = 1.17 +- 0.6, m = 0.23 +- 0.07 and TD50 = 47.3 +- 2.1 Gy. Conclusions: A clear volume effect was found for edema, consistent with a parallel architecture of the larynx for this endpoint. On the basis of our findings, an EUD <30-35 Gy should drastically reduce the risk of G2-G3 edema.« less

Needle migration and dosimetric impact in high-dose-rate brachytherapy for prostate cancer evaluated by repeated MRI.

PubMed

Buus, Simon; Lizondo, Maria; Hokland, Steffen; Rylander, Susanne; Pedersen, Erik M; Tanderup, Kari; Bentzen, Lise

To quantify needle migration and dosimetric impact in high-dose-rate brachytherapy for prostate cancer and propose a threshold for needle migration. Twenty-four high-risk prostate cancer patients treated with an HDR boost of 2 × 8.5 Gy were included. Patients received an MRI for planning (MRI1), before (MRI2), and after treatment (MRI3). Time from needle insertion to MRI3 was ∼3 hours. Needle migration was evaluated from coregistered images: MRI1-MRI2 and MRI1-MRI3. Dose volume histogram parameters from the treatment plan based on MRI1 were related to parameters based on needle positions in MRI2 or MRI3. Regression was used to model the average needle migration per implant and change in D90 clinical target volume, CTV prostate+3mm . The model fit was used for estimating the dosimetric impact in equivalent dose in 2 Gy fractions for dose levels of 6, 8.5, 10, 15, and 19 Gy. Needle migration was on average 2.2 ± 1.8 mm SD from MRI1-MRI2 and 5.0 ± 3.0 mm SD from MRI1-MRI3. D90 CTV prostate+3mm was robust toward average needle migration ≤3 mm, whereas for migration >3 mm D90 decreased by 4.5% per mm. A 3 mm of needle migration resulted in a decrease of 0.9, 1.7, 2.3, 4.8, and 7.6 equivalent dose in 2 Gy fractions for dose levels of 6, 8.5, 10, 15, and 19 Gy, respectively. Substantial needle migration in high-dose-rate brachytherapy occurs frequently in 1-3 hours following needle insertion. A 3-mm threshold of needle migration is proposed, but 2 mm may be considered for dose levels ≥15 Gy. Copyright © 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Šefl, Martin, E-mail: martin.sefl@gmail.com; Kyriakou, Ioanna; Emfietzoglou, Dimitris, E-mail: demfietz@cc.uoi.gr

Purpose: To study theoretically the impact on cell survival of the radionuclide uptake rate inside tumor cells for a single administration of a radiopharmaceutical. Methods: The instantaneous-uptake model of O’Donoghue [“The impact of tumor cell proliferation in radioimmunotherapy,” Cancer 73, 974–980 (1994)] for a proliferating cell population irradiated by an exponentially decreasing dose-rate is here extended to allow for the monoexponential uptake of the radiopharmaceutical by the targeted cells. The time derivative of the survival curve is studied in detail deducing an expression for the minimum of the surviving fraction and the biologically effective dose (BED). Results: Surviving fractions aremore » calculated over a parameter range that is clinically relevant and broad enough to establish general trends. Specifically, results are presented for the therapy radionuclides Y-90, I-131, and P-32, assuming uptake half-times 1–24 h, extrapolated initial dose-rates 0.5–1 Gy h{sup −1}, and a biological clearance half-life of seven days. Representative radiobiological parameters for radiosensitive and rapidly proliferating tumor cells are used, with cell doubling time equal to 2 days and α-coefficient equal to 0.3 and 0.5 Gy{sup −1}. It is shown that neglecting the uptake phase of the radiopharmaceutical (i.e., assuming instantaneous-uptake) results in a sizeable over-estimation of cell-kill (i.e., under-estimation of cell survival) even for uptake half-times of only a few hours. The differences between the exponential-uptake model and the instantaneous-uptake model become larger for high peak dose-rates, slow uptakes, and (slightly) for long-lived radionuclides. Moreover, the sensitivity of the survival curve on the uptake model was found to be higher for the tumor cells with the larger α-coefficient. Conclusions: The exponential-uptake rate of the radiopharmaceutical inside targeted cells appears to have a considerable effect on the survival of a proliferating cell population and might need to be considered in radiobiological models of tumor cell-kill in radionuclide therapy.« less

Bladder accumulated dose in image-guided high-dose-rate brachytherapy for locally advanced cervical cancer and its relation to urinary toxicity

NASA Astrophysics Data System (ADS)

Zakariaee, Roja; Hamarneh, Ghassan; Brown, Colin J.; Gaudet, Marc; Aquino-Parsons, Christina; Spadinger, Ingrid

2016-12-01

The purpose of this study was to estimate locally accumulated dose to the bladder in multi-fraction high-dose-date (HDR) image-guided intracavitary brachytherapy (IG-ICBT) for cervical cancer, and study the locally-accumulated dose parameters as predictors of late urinary toxicity. A retrospective study of 60 cervical cancer patients who received five HDR IG-ICBT sessions was performed. The bladder outer and inner surfaces were segmented for all sessions and a bladder-wall contour point-set was created in MATLAB. The bladder-wall point-sets for each patient were registered using a deformable point-set registration toolbox called coherent point drift (CPD), and the fraction doses were accumulated. Various dosimetric and volumetric parameters were calculated using the registered doses, including r{{\\text{D}}n \\text{c{{\\text{m}}\\text{3}}}} (minimum dose to the most exposed n-cm3 volume of bladder wall), r V n Gy (wall volume receiving at least m Gy), and r\\text{EQD}{{2}n \\text{c{{\\text{m}}\\text{3}}}} (minimum equivalent biologically weighted dose to the most exposed n-cm3 of bladder wall), where n  =  1/2/5/10 and m  =  3/5/10. Minimum dose to contiguous 1 and 2 cm3 hot-spot volumes was also calculated. The unregistered dose volume histogram (DVH)-summed equivalent of r{{\\text{D}}n \\text{c{{\\text{m}}3}}} and r\\text{EQD}{{2}n \\text{c{{\\text{m}}3}}} parameters (i.e. s{{\\text{D}}n \\text{c{{\\text{m}}\\text{3}}}} and s\\text{EQD}{{2}n \\text{c{{\\text{m}}3}}} ) were determined for comparison. Late urinary toxicity was assessed using the LENT-SOMA scale, with toxicity Grade 0-1 categorized as Controls and Grade 2-4 as Cases. A two-sample t-test was used to identify the differences between the means of Control and Case groups for all parameters. A binomial logistic regression was also performed between the registered dose parameters and toxicity grouping. Seventeen patients were in the Case and 43 patients in the Control group. Contiguous values were on average 16 and 18% smaller than parameters for 1 and 2 cm3 volumes, respectively. Contiguous values were on average 26 and 27% smaller than parameters. The only statistically significant finding for Case versus Control based on both methods of analysis was observed for r V3 Gy (p  =  0.01). DVH-summed parameters based on unregistered structure volumes overestimated the bladder dose in our patients, particularly when contiguous high dose volumes were considered. The bladder-wall volume receiving at least 3 Gy of accumulated dose may be a parameter of interest in further investigations of Grade 2+  urinary toxicity.

Does High-Dose Antimicrobial Chemotherapy Prevent the Evolution of Resistance?

PubMed Central

Day, Troy; Read, Andrew F.

2016-01-01

High-dose chemotherapy has long been advocated as a means of controlling drug resistance in infectious diseases but recent empirical studies have begun to challenge this view. We develop a very general framework for modeling and understanding resistance emergence based on principles from evolutionary biology. We use this framework to show how high-dose chemotherapy engenders opposing evolutionary processes involving the mutational input of resistant strains and their release from ecological competition. Whether such therapy provides the best approach for controlling resistance therefore depends on the relative strengths of these processes. These opposing processes typically lead to a unimodal relationship between drug pressure and resistance emergence. As a result, the optimal drug dose lies at either end of the therapeutic window of clinically acceptable concentrations. We illustrate our findings with a simple model that shows how a seemingly minor change in parameter values can alter the outcome from one where high-dose chemotherapy is optimal to one where using the smallest clinically effective dose is best. A review of the available empirical evidence provides broad support for these general conclusions. Our analysis opens up treatment options not currently considered as resistance management strategies, and it also simplifies the experiments required to determine the drug doses which best retard resistance emergence in patients. PMID:26820986

Does High-Dose Antimicrobial Chemotherapy Prevent the Evolution of Resistance?

PubMed

Day, Troy; Read, Andrew F

2016-01-01

High-dose chemotherapy has long been advocated as a means of controlling drug resistance in infectious diseases but recent empirical studies have begun to challenge this view. We develop a very general framework for modeling and understanding resistance emergence based on principles from evolutionary biology. We use this framework to show how high-dose chemotherapy engenders opposing evolutionary processes involving the mutational input of resistant strains and their release from ecological competition. Whether such therapy provides the best approach for controlling resistance therefore depends on the relative strengths of these processes. These opposing processes typically lead to a unimodal relationship between drug pressure and resistance emergence. As a result, the optimal drug dose lies at either end of the therapeutic window of clinically acceptable concentrations. We illustrate our findings with a simple model that shows how a seemingly minor change in parameter values can alter the outcome from one where high-dose chemotherapy is optimal to one where using the smallest clinically effective dose is best. A review of the available empirical evidence provides broad support for these general conclusions. Our analysis opens up treatment options not currently considered as resistance management strategies, and it also simplifies the experiments required to determine the drug doses which best retard resistance emergence in patients.

An analytic linear accelerator source model for GPU-based Monte Carlo dose calculations.

PubMed

Tian, Zhen; Li, Yongbao; Folkerts, Michael; Shi, Feng; Jiang, Steve B; Jia, Xun

2015-10-21

Recently, there has been a lot of research interest in developing fast Monte Carlo (MC) dose calculation methods on graphics processing unit (GPU) platforms. A good linear accelerator (linac) source model is critical for both accuracy and efficiency considerations. In principle, an analytical source model should be more preferred for GPU-based MC dose engines than a phase-space file-based model, in that data loading and CPU-GPU data transfer can be avoided. In this paper, we presented an analytical field-independent source model specifically developed for GPU-based MC dose calculations, associated with a GPU-friendly sampling scheme. A key concept called phase-space-ring (PSR) was proposed. Each PSR contained a group of particles that were of the same type, close in energy and reside in a narrow ring on the phase-space plane located just above the upper jaws. The model parameterized the probability densities of particle location, direction and energy for each primary photon PSR, scattered photon PSR and electron PSR. Models of one 2D Gaussian distribution or multiple Gaussian components were employed to represent the particle direction distributions of these PSRs. A method was developed to analyze a reference phase-space file and derive corresponding model parameters. To efficiently use our model in MC dose calculations on GPU, we proposed a GPU-friendly sampling strategy, which ensured that the particles sampled and transported simultaneously are of the same type and close in energy to alleviate GPU thread divergences. To test the accuracy of our model, dose distributions of a set of open fields in a water phantom were calculated using our source model and compared to those calculated using the reference phase-space files. For the high dose gradient regions, the average distance-to-agreement (DTA) was within 1 mm and the maximum DTA within 2 mm. For relatively low dose gradient regions, the root-mean-square (RMS) dose difference was within 1.1% and the maximum dose difference within 1.7%. The maximum relative difference of output factors was within 0.5%. Over 98.5% passing rate was achieved in 3D gamma-index tests with 2%/2 mm criteria in both an IMRT prostate patient case and a head-and-neck case. These results demonstrated the efficacy of our model in terms of accurately representing a reference phase-space file. We have also tested the efficiency gain of our source model over our previously developed phase-space-let file source model. The overall efficiency of dose calculation was found to be improved by ~1.3-2.2 times in water and patient cases using our analytical model.

Prophylactic ranitidine treatment in critically ill children--a population pharmacokinetic study.

PubMed

Hawwa, Ahmed F; Westwood, Paul M; Collier, Paul S; Millership, Jeffrey S; Yakkundi, Shirish; Thurley, Gillian; Shields, Mike D; Nunn, Anthony J; Halliday, Henry L; McElnay, James C

2013-05-01

To characterize the population pharmacokinetics of ranitidine in critically ill children and to determine the influence of various clinical and demographic factors on its disposition. Data were collected prospectively from 78 paediatric patients (n = 248 plasma samples) who received oral or intravenous ranitidine for prophylaxis against stress ulcers, gastrointestinal bleeding or the treatment of gastro-oesophageal reflux. Plasma samples were analysed using high-performance liquid chromatography, and the data were subjected to population pharmacokinetic analysis using nonlinear mixed-effects modelling. A one-compartment model best described the plasma concentration profile, with an exponential structure for interindividual errors and a proportional structure for intra-individual error. After backward stepwise elimination, the final model showed a significant decrease in objective function value (-12.618; P < 0.001) compared with the weight-corrected base model. Final parameter estimates for the population were 32.1 l h(-1) for total clearance and 285 l for volume of distribution, both allometrically modelled for a 70 kg adult. Final estimates for absorption rate constant and bioavailability were 1.31 h(-1) and 27.5%, respectively. No significant relationship was found between age and weight-corrected ranitidine pharmacokinetic parameters in the final model, with the covariate for cardiac failure or surgery being shown to reduce clearance significantly by a factor of 0.46. Currently, ranitidine dose recommendations are based on children's weights. However, our findings suggest that a dosing scheme that takes into consideration both weight and cardiac failure/surgery would be more appropriate in order to avoid administration of higher or more frequent doses than necessary. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Dosimetric characterizations of GZP6 60Co high dose rate brachytherapy sources: application of superimposition method

PubMed Central

Bahreyni Toossi, Mohammad Taghi; Ghorbani, Mahdi; Mowlavi, Ali Asghar; Meigooni, Ali Soleimani

2012-01-01

Background Dosimetric characteristics of a high dose rate (HDR) GZP6 Co-60 brachytherapy source have been evaluated following American Association of Physicists in MedicineTask Group 43U1 (AAPM TG-43U1) recommendations for their clinical applications. Materials and methods MCNP-4C and MCNPX Monte Carlo codes were utilized to calculate dose rate constant, two dimensional (2D) dose distribution, radial dose function and 2D anisotropy function of the source. These parameters of this source are compared with the available data for Ralstron 60Co and microSelectron192Ir sources. Besides, a superimposition method was developed to extend the obtained results for the GZP6 source No. 3 to other GZP6 sources. Results The simulated value for dose rate constant for GZP6 source was 1.104±0.03 cGyh-1U-1. The graphical and tabulated radial dose function and 2D anisotropy function of this source are presented here. The results of these investigations show that the dosimetric parameters of GZP6 source are comparable to those for the Ralstron source. While dose rate constant for the two 60Co sources are similar to that for the microSelectron192Ir source, there are differences between radial dose function and anisotropy functions. Radial dose function of the 192Ir source is less steep than both 60Co source models. In addition, the 60Co sources are showing more isotropic dose distribution than the 192Ir source. Conclusions The superimposition method is applicable to produce dose distributions for other source arrangements from the dose distribution of a single source. The calculated dosimetric quantities of this new source can be introduced as input data to the GZP6 treatment planning system (TPS) and to validate the performance of the TPS. PMID:23077455

Inverse determination of the penalty parameter in penalized weighted least-squares algorithm for noise reduction of low-dose CBCT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Jing; Guan, Huaiqun; Solberg, Timothy

2011-07-15

Purpose: A statistical projection restoration algorithm based on the penalized weighted least-squares (PWLS) criterion can substantially improve the image quality of low-dose CBCT images. The performance of PWLS is largely dependent on the choice of the penalty parameter. Previously, the penalty parameter was chosen empirically by trial and error. In this work, the authors developed an inverse technique to calculate the penalty parameter in PWLS for noise suppression of low-dose CBCT in image guided radiotherapy (IGRT). Methods: In IGRT, a daily CBCT is acquired for the same patient during a treatment course. In this work, the authors acquired the CBCTmore » with a high-mAs protocol for the first session and then a lower mAs protocol for the subsequent sessions. The high-mAs projections served as the goal (ideal) toward, which the low-mAs projections were to be smoothed by minimizing the PWLS objective function. The penalty parameter was determined through an inverse calculation of the derivative of the objective function incorporating both the high and low-mAs projections. Then the parameter obtained can be used for PWLS to smooth the noise in low-dose projections. CBCT projections for a CatPhan 600 and an anthropomorphic head phantom, as well as for a brain patient, were used to evaluate the performance of the proposed technique. Results: The penalty parameter in PWLS was obtained for each CBCT projection using the proposed strategy. The noise in the low-dose CBCT images reconstructed from the smoothed projections was greatly suppressed. Image quality in PWLS-processed low-dose CBCT was comparable to its corresponding high-dose CBCT. Conclusions: A technique was proposed to estimate the penalty parameter for PWLS algorithm. It provides an objective and efficient way to obtain the penalty parameter for image restoration algorithms that require predefined smoothing parameters.« less

A broad scope knowledge based model for optimization of VMAT in esophageal cancer: validation and assessment of plan quality among different treatment centers.

PubMed

Fogliata, Antonella; Nicolini, Giorgia; Clivio, Alessandro; Vanetti, Eugenio; Laksar, Sarbani; Tozzi, Angelo; Scorsetti, Marta; Cozzi, Luca

2015-10-31

To evaluate the performance of a broad scope model-based optimisation process for volumetric modulated arc therapy applied to esophageal cancer. A set of 70 previously treated patients in two different institutions, were selected to train a model for the prediction of dose-volume constraints. The model was built with a broad-scope purpose, aiming to be effective for different dose prescriptions and tumour localisations. It was validated on three groups of patients from the same institution and from another clinic not providing patients for the training phase. Comparison of the automated plans was done against reference cases given by the clinically accepted plans. Quantitative improvements (statistically significant for the majority of the analysed dose-volume parameters) were observed between the benchmark and the test plans. Of 624 dose-volume objectives assessed for plan evaluation, in 21 cases (3.3 %) the reference plans failed to respect the constraints while the model-based plans succeeded. Only in 3 cases (<0.5 %) the reference plans passed the criteria while the model-based failed. In 5.3 % of the cases both groups of plans failed and in the remaining cases both passed the tests. Plans were optimised using a broad scope knowledge-based model to determine the dose-volume constraints. The results showed dosimetric improvements when compared to the benchmark data. Particularly the plans optimised for patients from the third centre, not participating to the training, resulted in superior quality. The data suggests that the new engine is reliable and could encourage its application to clinical practice.

Agreement Between Institutional Measurements and Treatment Planning System Calculations for Basic Dosimetric Parameters as Measured by the Imaging and Radiation Oncology Core-Houston

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kerns, James R.; Followill, David S.; Imaging and Radiation Oncology Core-Houston, The University of Texas Health Science Center-Houston, Houston, Texas

Purpose: To compare radiation machine measurement data collected by the Imaging and Radiation Oncology Core at Houston (IROC-H) with institutional treatment planning system (TPS) values, to identify parameters with large differences in agreement; the findings will help institutions focus their efforts to improve the accuracy of their TPS models. Methods and Materials: Between 2000 and 2014, IROC-H visited more than 250 institutions and conducted independent measurements of machine dosimetric data points, including percentage depth dose, output factors, off-axis factors, multileaf collimator small fields, and wedge data. We compared these data with the institutional TPS values for the same points bymore » energy, class, and parameter to identify differences and similarities using criteria involving both the medians and standard deviations for Varian linear accelerators. Distributions of differences between machine measurements and institutional TPS values were generated for basic dosimetric parameters. Results: On average, intensity modulated radiation therapy–style and stereotactic body radiation therapy–style output factors and upper physical wedge output factors were the most problematic. Percentage depth dose, jaw output factors, and enhanced dynamic wedge output factors agreed best between the IROC-H measurements and the TPS values. Although small differences were shown between 2 common TPS systems, neither was superior to the other. Parameter agreement was constant over time from 2000 to 2014. Conclusions: Differences in basic dosimetric parameters between machine measurements and TPS values vary widely depending on the parameter, although agreement does not seem to vary by TPS and has not changed over time. Intensity modulated radiation therapy–style output factors, stereotactic body radiation therapy–style output factors, and upper physical wedge output factors had the largest disagreement and should be carefully modeled to ensure accuracy.« less

Uncertainties in Assesment of the Vaginal Dose for Intracavitary Brachytherapy of Cervical Cancer using a Tandem-ring Applicator

DOE Office of Scientific and Technical Information (OSTI.GOV)

Berger, Daniel; Dimopoulos, Johannes; Georg, Petra

2007-04-01

Purpose: The vagina has not been widely recognized as organ at risk in brachytherapy for cervical cancer. No widely accepted dose parameters are available. This study analyzes the uncertainties in dose reporting for the vaginal wall using tandem-ring applicators. Methods and Materials: Organ wall contours were delineated on axial magnetic resonance (MR) slices to perform dose-volume histogram (DVH) analysis. Different DVH parameters were used in a feasibility study based on 40 magnetic resonance imaging (MRI)-based treatment plans of different cervical cancer patients. Dose to the most irradiated, 0.1 cm{sup 3}, 1 cm{sup 3}, 2 cm{sup 3}, and at defined pointsmore » on the ring surface and at 5-mm tissue depth were reported. Treatment-planning systems allow different methods of dose point definition. Film dosimetry was used to verify the maximum dose at the surface of the ring applicator in an experimental setup. Results: Dose reporting for the vagina is extremely sensitive to geometrical uncertainties with variations of 25% for 1 mm shifts. Accurate delineation of the vaginal wall is limited by the finite pixel size of MRI and available treatment-planning systems. No significant correlation was found between dose-point and dose-volume parameters. The DVH parameters were often related to noncontiguous volumes and were not able to detect very different situations of spatial dose distributions inside the vaginal wall. Deviations between measured and calculated doses were up to 21%. Conclusions: Reporting either point dose values or DVH parameters for the vaginal wall is based on high inaccuracies because of contouring and geometric positioning. Therefore, the use of prospective dose constraints for individual treatment plans is not to be recommended at present. However, for large patient groups treated within one protocol correlation with vaginal morbidity can be evaluated.« less

Terbinafine in combination with other antifungal agents for treatment of resistant or refractory mycoses: investigating optimal dosing regimens using a physiologically based pharmacokinetic model.

PubMed

Dolton, Michael J; Perera, Vidya; Pont, Lisa G; McLachlan, Andrew J

2014-01-01

Terbinafine is increasingly used in combination with other antifungal agents to treat resistant or refractory mycoses due to synergistic in vitro antifungal activity; high doses are commonly used, but limited data are available on systemic exposure, and no assessment of pharmacodynamic target attainment has been made. Using a physiologically based pharmacokinetic (PBPK) model for terbinafine, this study aimed to predict total and unbound terbinafine concentrations in plasma with a range of high-dose regimens and also calculate predicted pharmacodynamic parameters for terbinafine. Predicted terbinafine concentrations accumulated significantly during the first 28 days of treatment; the area under the concentration-time curve (AUC)/MIC ratios and AUC for the free, unbound fraction (fAUC)/MIC ratios increased by 54 to 62% on day 7 of treatment and by 80 to 92% on day 28 compared to day 1, depending on the dose regimen. Of the high-dose regimens investigated, 500 mg of terbinafine taken every 12 h provided the highest systemic exposure; on day 7 of treatment, the predicted AUC, maximum concentration (Cmax), and minimum concentration (Cmin) were approximately 4-fold, 1.9-fold, and 4.4-fold higher than with a standard-dose regimen of 250 mg once daily. Close agreement was seen between the concentrations predicted by the PBPK model and the observed concentrations, indicating good predictive performance. This study provides the first report of predicted terbinafine exposure in plasma with a range of high-dose regimens.

Tumor Control Probability Modeling for Stereotactic Body Radiation Therapy of Early-Stage Lung Cancer Using Multiple Bio-physical Models

PubMed Central

Liu, Feng; Tai, An; Lee, Percy; Biswas, Tithi; Ding, George X.; El Naqa, Isaam; Grimm, Jimm; Jackson, Andrew; Kong, Feng-Ming (Spring); LaCouture, Tamara; Loo, Billy; Miften, Moyed; Solberg, Timothy; Li, X Allen

2017-01-01

Purpose To analyze pooled clinical data using different radiobiological models and to understand the relationship between biologically effective dose (BED) and tumor control probability (TCP) for stereotactic body radiotherapy (SBRT) of early-stage non-small cell lung cancer (NSCLC). Method and Materials The clinical data of 1-, 2-, 3-, and 5-year actuarial or Kaplan-Meier TCP from 46 selected studies were collected for SBRT of NSCLC in the literature. The TCP data were separated for Stage T1 and T2 tumors if possible, otherwise collected for combined stages. BED was calculated at isocenters using six radiobiological models. For each model, the independent model parameters were determined from a fit to the TCP data using the least chi-square (χ2) method with either one set of parameters regardless of tumor stages or two sets for T1 and T2 tumors separately. Results The fits to the clinic data yield consistent results of large α/β ratios of about 20 Gy for all models investigated. The regrowth model that accounts for the tumor repopulation and heterogeneity leads to a better fit to the data, compared to other 5 models where the fits were indistinguishable between the models. The models based on the fitting parameters predict that the T2 tumors require about additional 1 Gy physical dose at isocenters per fraction (≤5 fractions) to achieve the optimal TCP when compared to the T1 tumors. Conclusion This systematic analysis of a large set of published clinical data using different radiobiological models shows that local TCP for SBRT of early-stage NSCLC has strong dependence on BED with large α/β ratios of about 20 Gy. The six models predict that a BED (calculated with α/β of 20) of 90 Gy is sufficient to achieve TCP ≥ 95%. Among the models considered, the regrowth model leads to a better fit to the clinical data. PMID:27871671

Joint Feedback Analysis Modeling of Nonesterified Fatty Acids in Obese Zucker Rats and Normal Sprague–Dawley Rats after Different Routes of Administration of Nicotinic Acid

PubMed Central

Tapani, Sofia; Almquist, Joachim; Leander, Jacob; Ahlström, Christine; Peletier, Lambertus A; Jirstrand, Mats; Gabrielsson, Johan

2014-01-01

Data were pooled from several studies on nicotinic acid (NiAc) intervention of fatty acid turnover in normal Sprague–Dawley and obese Zucker rats in order to perform a joint PKPD of data from more than 100 normal Sprague–Dawley and obese Zucker rats, exposed to several administration routes and rates. To describe the difference in pharmacodynamic parameters between obese and normal rats, we modified a previously published nonlinear mixed effects model describing tolerance and oscillatory rebound effects of NiAc on nonesterified fatty acids plasma concentrations. An important conclusion is that planning of experiments and dose scheduling cannot rely on pilot studies on normal animals alone. The obese rats have a less-pronounced concentration–response relationship and need higher doses to exhibit desired response. The relative level of fatty acid rebound after cessation of NiAc administration was also quantified in the two rat populations. Building joint normal-disease models with scaling parameter(s) to characterize the “degree of disease” can be a useful tool when designing informative experiments on diseased animals, particularly in the preclinical screen. Data were analyzed using nonlinear mixed effects modeling, for the optimization, we used an improved method for calculating the gradient than the usually adopted finite difference approximation. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2571–2584, 2014 PMID:24986056

Pharmacokinetic-Pharmacodynamic Model To Evaluate Intramuscular Tetracycline Treatment Protocols To Prevent Antimicrobial Resistance in Pigs

PubMed Central

Ahmad, Amais; Græsbøll, Kaare; Christiansen, Lasse Engbo; Toft, Nils; Matthews, Louise

2014-01-01

High instances of antimicrobial resistance are linked to both routine and excessive antimicrobial use, but excessive or inappropriate use represents an unnecessary risk. The competitive growth advantages of resistant bacteria may be amplified by the strain dynamics; in particular, the extent to which resistant strains outcompete susceptible strains under antimicrobial pressure may depend not only on the antimicrobial treatment strategies but also on the epidemiological parameters, such as the composition of the bacterial strains in a pig. This study evaluated how variation in the dosing protocol for intramuscular administration of tetracycline and the composition of bacterial strains in a pig affect the level of resistance in the intestine of a pig. Predictions were generated by a mathematical model of competitive growth of Escherichia coli strains in pigs under specified plasma concentration profiles of tetracycline. All dosing regimens result in a clear growth advantage for resistant strains. Short treatment duration was found to be preferable, since it allowed less time for resistant strains to outcompete the susceptible ones. Dosing frequency appeared to be ineffective at reducing the resistance levels. The number of competing strains had no apparent effect on the resistance level during treatment, but possession of fewer strains reduced the time to reach equilibrium after the end of treatment. To sum up, epidemiological parameters may have more profound influence on growth dynamics than dosing regimens and should be considered when designing improved treatment protocols. PMID:25547361

Effect of HMME-PDT with different parameters in rabbit ear model: a possible way for hypertrophic scarring

NASA Astrophysics Data System (ADS)

Cai, Hong; Gu, Ying; Zeng, Jing; Li, Shao-ran; Sun, Qiang; Wang, Ying; Shi, Dong-wen; Zhang, Lu-yong

2007-11-01

Background and Objective: Hypertrophic scar is a pathological scar that grows aberrantly by excessive deposition of collagens in the dermis. It is known that photodynamic therapy (PDT) contributes to a variety of diseases, however, the use of inhibiting scar formation has not been fully explored. The purpose of this study is to investigate the effect of HMME-PDT (Photodynamic therapy induced by Hematoporphyrin Monomethyl Ether) with different parameters on hypertrophic scar in rabbit ear. Materials and Methods: After the placement of 7-mm diameter dermal wounds on each ear, the acute model of dermal hypertrophic scar in the New Zealand white rabbits was established. Scar wounds were randomly separated into 2 groups: the experimental group received HMME-PDT with different parameters, and the control group received no special treatment. Specimens were harvested from scar wounds on postoperative day 28. Scar and hypertrophic index (HI) were observed by haematoxylin-eosin staining. Results: Compared with the control group, scar formation was inhibited by HMME-PDT in the experimental group with parameters as follows: photosensitizer dose 10mg/kg, power density 20mw/cm2, fluence 5J/cm2, meanwhile, HI was decreased significantly. Conclusion: HMME-PDT may play a role in inhibiting hypertrophic scarring in rabbit ear. The biological effect is determined by the dose of photosensitizer, interval between the injection of photosensitizer and irradiation, power density and energy fluence.

Insights into the mechanism of X-ray-induced disulfide-bond cleavage in lysozyme crystals based on EPR, optical absorption and X-ray diffraction studies

PubMed Central

Sutton, Kristin A.; Black, Paul J.; Mercer, Kermit R.; Garman, Elspeth F.; Owen, Robin L.; Snell, Edward H.; Bernhard, William A.

2013-01-01

Electron paramagnetic resonance (EPR) and online UV–visible absorption microspectrophotometry with X-ray crystallography have been used in a complementary manner to follow X-ray-induced disulfide-bond cleavage. Online UV–visible spectroscopy showed that upon X-irradiation, disulfide radicalization appeared to saturate at an absorbed dose of approximately 0.5–0.8 MGy, in contrast to the saturating dose of ∼0.2 MGy observed using EPR at much lower dose rates. The observations suggest that a multi-track model involving product formation owing to the interaction of two separate tracks is a valid model for radiation damage in protein crystals. The saturation levels are remarkably consistent given the widely different experimental parameters and the range of total absorbed doses studied. The results indicate that even at the lowest doses used for structural investigations disulfide bonds are already radicalized. Multi-track considerations offer the first step in a comprehensive model of radiation damage that could potentially lead to a combined computational and experimental approach to identifying when damage is likely to be present, to quantitate it and to provide the ability to recover the native unperturbed structure. PMID:24311579

A novel approach for estimating ingested dose associated with paracetamol overdose

PubMed Central

Zurlinden, Todd J.; Heard, Kennon

2015-01-01

Aim In cases of paracetamol (acetaminophen, APAP) overdose, an accurate estimate of tissue‐specific paracetamol pharmacokinetics (PK) and ingested dose can offer health care providers important information for the individualized treatment and follow‐up of affected patients. Here a novel methodology is presented to make such estimates using a standard serum paracetamol measurement and a computational framework. Methods The core component of the computational framework was a physiologically‐based pharmacokinetic (PBPK) model developed and evaluated using an extensive set of human PK data. Bayesian inference was used for parameter and dose estimation, allowing the incorporation of inter‐study variability, and facilitating the calculation of uncertainty in model outputs. Results Simulations of paracetamol time course concentrations in the blood were in close agreement with experimental data under a wide range of dosing conditions. Also, predictions of administered dose showed good agreement with a large collection of clinical and emergency setting PK data over a broad dose range. In addition to dose estimation, the platform was applied for the determination of optimal blood sampling times for dose reconstruction and quantitation of the potential role of paracetamol conjugate measurement on dose estimation. Conclusions Current therapies for paracetamol overdose rely on a generic methodology involving the use of a clinical nomogram. By using the computational framework developed in this study, serum sample data, and the individual patient's anthropometric and physiological information, personalized serum and liver pharmacokinetic profiles and dose estimate could be generated to help inform an individualized overdose treatment and follow‐up plan. PMID:26441245

A novel approach for estimating ingested dose associated with paracetamol overdose.

PubMed

Zurlinden, Todd J; Heard, Kennon; Reisfeld, Brad

2016-04-01

In cases of paracetamol (acetaminophen, APAP) overdose, an accurate estimate of tissue-specific paracetamol pharmacokinetics (PK) and ingested dose can offer health care providers important information for the individualized treatment and follow-up of affected patients. Here a novel methodology is presented to make such estimates using a standard serum paracetamol measurement and a computational framework. The core component of the computational framework was a physiologically-based pharmacokinetic (PBPK) model developed and evaluated using an extensive set of human PK data. Bayesian inference was used for parameter and dose estimation, allowing the incorporation of inter-study variability, and facilitating the calculation of uncertainty in model outputs. Simulations of paracetamol time course concentrations in the blood were in close agreement with experimental data under a wide range of dosing conditions. Also, predictions of administered dose showed good agreement with a large collection of clinical and emergency setting PK data over a broad dose range. In addition to dose estimation, the platform was applied for the determination of optimal blood sampling times for dose reconstruction and quantitation of the potential role of paracetamol conjugate measurement on dose estimation. Current therapies for paracetamol overdose rely on a generic methodology involving the use of a clinical nomogram. By using the computational framework developed in this study, serum sample data, and the individual patient's anthropometric and physiological information, personalized serum and liver pharmacokinetic profiles and dose estimate could be generated to help inform an individualized overdose treatment and follow-up plan. © 2015 The British Pharmacological Society.

Using Chemical Structure Information to Predict In Vitro Pharmacokinetic Parameters (SOT)

EPA Science Inventory

Toxicokinetic data are key for relating exposure and internal dose when building in vitro-based risk assessment models. However, conducting in vivo toxicokinetic studies has time and cost limitations, and in vitro toxicokinetic data is available only for a limited set of chemical...

CT dose reduction in children.

PubMed

Vock, Peter

2005-11-01

World wide, the number of CT studies in children and the radiation exposure by CT increases. The same energy dose has a greater biological impact in children than in adults, and scan parameters have to be adapted to the smaller diameter of the juvenile body. Based on seven rules, a practical approach to paediatric CT is shown: Justification and patient preparation are important steps before scanning, and they differ from the preparation of adult patients. The subsequent choice of scan parameters aims at obtaining the minimal signal-to-noise ratio and volume coverage needed in a specific medical situation; exposure can be divided in two aspects: the CT dose index determining energy deposition per rotation and the dose-length product (DLP) determining the volume dose. DLP closely parallels the effective dose, the best parameter of the biological impact. Modern scanners offer dose modulation to locally minimise exposure while maintaining image quality. Beyond the selection of the physical parameters, the dose can be kept low by scanning the minimal length of the body and by avoiding any non-qualified repeated scanning of parts of the body. Following these rules, paediatric CT examinations of good quality can be obtained at a reasonable cost of radiation exposure.

Efficacy of multiple exposure with low level He-Ne laser dose on acute wound healing: a pre-clinical study

NASA Astrophysics Data System (ADS)

Prabhu, Vijendra; Rao, Bola Sadashiva S.; Mahato, Krishna Kishore

2014-02-01

Investigations on the use of Low Level Laser Therapy (LLLT) for wound healing especially with the red laser light have demonstrated its pro-healing potential on a variety of pre-clinical and surgical wounds. However, until now, in LLLT the effect of multiple exposure of low dose laser irradiation on acute wound healing on well-designed pre-clinical model is not much explored. The present study aimed to investigate the effect of multiple exposure of low dose Helium Neon laser on healing progression of full thickness excision wounds in Swiss albino mice. Further, the efficacy of the multiple exposure of low dose laser irradiation was compared with the single exposure of optimum dose. Full thickness excision wounds (circular) of 15 mm diameter were created, and subsequently illuminated with the multiple exposures (1, 2, 3, 4 and 5 exposure/ week until healing) of He-Ne (632.8 nm, 4.02 mWcm-2) laser at 0.5 Jcm-2 along with single exposure of optimum laser dose (2 J/cm-2) and un-illuminated controls. Classical biophysical parameters such as contraction kinetics, area under the curve and the mean healing time were documented as the assessment parameters to examine the efficacy of multiple exposures with low level laser dose. Experimental findings substantiated that either single or multiple exposures of 0.5 J/cm2 failed to produce any detectable alterations on wound contraction, area under the curve and mean healing time compared to single exposure of optimum dose (2 Jcm-2) and un-illuminated controls. Single exposure of optimum, laser dose was found to be ideal for acute wound healing.

CIRMIS Data system. Volume 2. Program listings

DOE Office of Scientific and Technical Information (OSTI.GOV)

Friedrichs, D.R.

1980-01-01

The Assessment of Effectiveness of Geologic Isolation Systems (AEGIS) Program is developing and applying the methodology for assessing the far-field, long-term post-closure safety of deep geologic nuclear waste repositories. AEGIS is being performed by Pacific Northwest Laboratory (PNL) under contract with the Office of Nuclear Waste Isolation (OWNI) for the Department of Energy (DOE). One task within AEGIS is the development of methodology for analysis of the consequences (water pathway) from loss of repository containment as defined by various release scenarios. Analysis of the long-term, far-field consequences of release scenarios requires the application of numerical codes which simulate the hydrologicmore » systems, model the transport of released radionuclides through the hydrologic systems, model the transport of released radionuclides through the hydrologic systems to the biosphere, and, where applicable, assess the radiological dose to humans. The various input parameters required in the analysis are compiled in data systems. The data are organized and prepared by various input subroutines for utilization by the hydraulic and transport codes. The hydrologic models simulate the groundwater flow systems and provide water flow directions, rates, and velocities as inputs to the transport models. Outputs from the transport models are basically graphs of radionuclide concentration in the groundwater plotted against time. After dilution in the receiving surface-water body (e.g., lake, river, bay), these data are the input source terms for the dose models, if dose assessments are required.The dose models calculate radiation dose to individuals and populations. CIRMIS (Comprehensive Information Retrieval and Model Input Sequence) Data System is a storage and retrieval system for model input and output data, including graphical interpretation and display. This is the second of four volumes of the description of the CIRMIS Data System.« less

WE-D-BRE-07: Variance-Based Sensitivity Analysis to Quantify the Impact of Biological Uncertainties in Particle Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kamp, F.; Brueningk, S.C.; Wilkens, J.J.

Purpose: In particle therapy, treatment planning and evaluation are frequently based on biological models to estimate the relative biological effectiveness (RBE) or the equivalent dose in 2 Gy fractions (EQD2). In the context of the linear-quadratic model, these quantities depend on biological parameters (α, β) for ions as well as for the reference radiation and on the dose per fraction. The needed biological parameters as well as their dependency on ion species and ion energy typically are subject to large (relative) uncertainties of up to 20–40% or even more. Therefore it is necessary to estimate the resulting uncertainties in e.g.more » RBE or EQD2 caused by the uncertainties of the relevant input parameters. Methods: We use a variance-based sensitivity analysis (SA) approach, in which uncertainties in input parameters are modeled by random number distributions. The evaluated function is executed 10{sup 4} to 10{sup 6} times, each run with a different set of input parameters, randomly varied according to their assigned distribution. The sensitivity S is a variance-based ranking (from S = 0, no impact, to S = 1, only influential part) of the impact of input uncertainties. The SA approach is implemented for carbon ion treatment plans on 3D patient data, providing information about variations (and their origin) in RBE and EQD2. Results: The quantification enables 3D sensitivity maps, showing dependencies of RBE and EQD2 on different input uncertainties. The high number of runs allows displaying the interplay between different input uncertainties. The SA identifies input parameter combinations which result in extreme deviations of the result and the input parameter for which an uncertainty reduction is the most rewarding. Conclusion: The presented variance-based SA provides advantageous properties in terms of visualization and quantification of (biological) uncertainties and their impact. The method is very flexible, model independent, and enables a broad assessment of uncertainties. Supported by DFG grant WI 3745/1-1 and DFG cluster of excellence: Munich-Centre for Advanced Photonics.« less

Statistical optimization and artificial neural network modeling for acridine orange dye degradation using in-situ synthesized polymer capped ZnO nanoparticles.

PubMed

Dhiman, Nitesh; Markandeya; Singh, Amrita; Verma, Neeraj K; Ajaria, Nidhi; Patnaik, Satyakam

2017-05-01

ZnO NPs were synthesized by a prudent green chemistry approach in presence of polyacrylamide grafted guar gum polymer (pAAm-g-GG) to ensure uniform morphology, and functionality and appraised for their ability to degrade photocatalytically Acridine Orange (AO) dye. These ZnO@pAAm-g-GG NPs were thoroughly characterized by various spectroscopic, XRD and electron microscopic techniques. The relative quantity of ZnO NPs in polymeric matrix has been estimated by spectro-analytical procedure; AAS and TGA analysis. The impact of process parameters viz. NP's dose, contact time and AO dye concentration on percentage photocatalytic degradation of AO dyes were evaluated using multivariate optimizing tools, Response Surface Methodology (RSM) involving Box-Behnken Design (BBD) and Artificial Neural Network (ANN). Congruity of the BBD statistical model was implied by R 2 value 0.9786 and F-value 35.48. At RSM predicted optimal condition viz. ZnO@pAAm-g-GG NP's dose of 0.2g/L, contact time of 210min and AO dye concentration 10mg/L, a maximum of 98% dye degradation was obtained. ANOVA indicated appropriateness of the model for dye degradation owing to "Prob.>F" less than 0.05 for variable parameters. We further, employed three layers feed forward ANN model for validating the BBD process parameters and suitability of our chosen model. The evaluation of Levenberg-Marquardt algorithm (ANN1) and Gradient Descent with adaptive learning rate (ANN2) model employed to scrutinize the best method and found experimental values of AO dye degradation were in close to those with predicated value of ANN 2 modeling with minimum error. Copyright © 2017 Elsevier Inc. All rights reserved.

A combined accelerator mass spectrometry-positron emission tomography human microdose study with 14C- and 11C-labelled verapamil

PubMed Central

Wagner, Claudia C; Simpson, Marie; Zeitlinger, Markus; Bauer, Martin; Karch, Rudolf; Abrahim, Aiman; Feurstein, Thomas; Schütz, Matthias; Kletter, Kurt; Müller, Markus; Lappin, Graham; Langer, Oliver

2013-01-01

Background and Objective In microdose studies, the pharmacokinetic (PK) profile of a drug in blood after administration of a dose up to 100 μg is measured with sensitive analytical techniques, such as accelerator mass spectrometry (AMS). As most drugs exert their effect in tissue rather than blood, methodology is needed for extending PK analysis to different tissue compartments. In the present study, we combined, for the first time, AMS analysis with positron emission tomography (PET) in order to determine the PK profile of the model drug verapamil in plasma and brain of humans. In order to assess PK dose-linearity of verapamil, data were acquired and compared after administration of an intravenous (iv) microdose and an iv microdose dosed concomitantly with an oral therapeutic dose. Methods Six healthy male volunteers received an iv microdose (0.05 mg) (period 1) and an iv microdose dosed concomitantly with an oral therapeutic dose (80 mg) of verapamil (period 2) in a randomized, cross-over, two-period study design. The iv dose was a mixture of (R/S)-[14C]verapamil and (R)-[11C]verapamil and the oral dose was unlabelled racemic verapamil. Brain distribution of radioactivity was measured with PET whereas plasma PK of (R)- and (S)-verapamil was determined with AMS. PET data were analyzed by kinetic modeling to estimate the rate constants for transfer of radioactivity across the blood-brain barrier. Results Most PK parameters of (R)- and (S)-verapamil as well as parameters describing exchange of radioactivity between plasma and brain (K1=0.030±0.003 and 0.031±0.005 mL·mL−1·min−1 and k2=0.099±0.006 and 0.095±0.008 min−1 for period 1 and 2, respectively) were not statistically different between the two periods although there was a trend for non-linear kinetics for the (R)-enantiomer. On the other hand, all PK parameters (except for t1/2) differed significantly between the (R)- and (S)-enantiomers for both periods. Cmax, AUC(0-24) and AUC(0-inf) were higher and CL, V and VSS were lower for the (R)- than for the (S)-enantiomer. Conclusion Combining AMS and PET microdosing allows long term PK data along with information on drug tissue distribution to be acquired in the same subjects thus making it a promising approach to maximize data output from a single clinical study. PMID:21142292

Comparison of Acuros (AXB) and Anisotropic Analytical Algorithm (AAA) for dose calculation in treatment of oesophageal cancer: effects on modelling tumour control probability.

PubMed

Padmanaban, Sriram; Warren, Samantha; Walsh, Anthony; Partridge, Mike; Hawkins, Maria A

2014-12-23

To investigate systematic changes in dose arising when treatment plans optimised using the Anisotropic Analytical Algorithm (AAA) are recalculated using Acuros XB (AXB) in patients treated with definitive chemoradiotherapy (dCRT) for locally advanced oesophageal cancers. We have compared treatment plans created using AAA with those recalculated using AXB. Although the Anisotropic Analytical Algorithm (AAA) is currently more widely used in clinical routine, Acuros XB (AXB) has been shown to more accurately calculate the dose distribution, particularly in heterogeneous regions. Studies to predict clinical outcome should be based on modelling the dose delivered to the patient as accurately as possible. CT datasets from ten patients were selected for this retrospective study. VMAT (Volumetric modulated arc therapy) plans with 2 arcs, collimator rotation ± 5-10° and dose prescription 50 Gy / 25 fractions were created using Varian Eclipse (v10.0). The initial dose calculation was performed with AAA, and AXB plans were created by re-calculating the dose distribution using the same number of monitor units (MU) and multileaf collimator (MLC) files as the original plan. The difference in calculated dose to organs at risk (OAR) was compared using dose-volume histogram (DVH) statistics and p values were calculated using the Wilcoxon signed rank test. The potential clinical effect of dosimetric differences in the gross tumour volume (GTV) was evaluated using three different TCP models from the literature. PTV Median dose was apparently 0.9 Gy lower (range: 0.5 Gy - 1.3 Gy; p < 0.05) for VMAT AAA plans re-calculated with AXB and GTV mean dose was reduced by on average 1.0 Gy (0.3 Gy -1.5 Gy; p < 0.05). An apparent difference in TCP of between 1.2% and 3.1% was found depending on the choice of TCP model. OAR mean dose was lower in the AXB recalculated plan than the AAA plan (on average, dose reduction: lung 1.7%, heart 2.4%). Similar trends were seen for CRT plans. Differences in dose distribution are observed with VMAT and CRT plans recalculated with AXB particularly within soft tissue at the tumour/lung interface, where AXB has been shown to more accurately represent the true dose distribution. AAA apparently overestimates dose, particularly the PTV median dose and GTV mean dose, which could result in a difference in TCP model parameters that reaches clinical significance.

SU-F-19A-05: Experimental and Monte Carlo Characterization of the 1 Cm CivaString 103Pd Brachytherapy Source

DOE Office of Scientific and Technical Information (OSTI.GOV)

Reed, J; Micka, J; Culberson, W

Purpose: To determine the in-air azimuthal anisotropy and in-water dose distribution for the 1 cm length of the CivaString {sup 103}Pd brachytherapy source through measurements and Monte Carlo (MC) simulations. American Association of Physicists in Medicine Task Group No. 43 (TG-43) dosimetry parameters were also determined for this source. Methods: The in-air azimuthal anisotropy of the source was measured with a NaI scintillation detector and simulated with the MCNP5 radiation transport code. Measured and simulated results were normalized to their respective mean values and compared. The TG-43 dose-rate constant, line-source radial dose function, and 2D anisotropy function for this sourcemore » were determined from LiF:Mg,Ti thermoluminescent dosimeter (TLD) measurements and MC simulations. The impact of {sup 103}Pd well-loading variability on the in-water dose distribution was investigated using MC simulations by comparing the dose distribution for a source model with four wells of equal strength to that for a source model with strengths increased by 1% for two of the four wells. Results: NaI scintillation detector measurements and MC simulations of the in-air azimuthal anisotropy showed that ≥95% of the normalized data were within 1.2% of the mean value. TLD measurements and MC simulations of the TG-43 dose-rate constant, line-source radial dose function, and 2D anisotropy function agreed to within the experimental TLD uncertainties (k=2). MC simulations showed that a 1% variability in {sup 103}Pd well-loading resulted in changes of <0.1%, <0.1%, and <0.3% in the TG-43 dose-rate constant, radial dose distribution, and polar dose distribution, respectively. Conclusion: The CivaString source has a high degree of azimuthal symmetry as indicated by the NaI scintillation detector measurements and MC simulations of the in-air azimuthal anisotropy. TG-43 dosimetry parameters for this source were determined from TLD measurements and MC simulations. {sup 103}Pd well-loading variability results in minimal variations in the in-water dose distribution according to MC simulations. This work was partially supported by CivaTech Oncology, Inc. through an educational grant for Joshua Reed, John Micka, Wesley Culberson, and Larry DeWerd and through research support for Mark Rivard.« less

Comparison of dosimetric and radiobiological parameters on plans for prostate stereotactic body radiotherapy using an endorectal balloon for different dose-calculation algorithms and delivery-beam modes

NASA Astrophysics Data System (ADS)

Kang, Sang-Won; Suh, Tae-Suk; Chung, Jin-Beom; Eom, Keun-Yong; Song, Changhoon; Kim, In-Ah; Kim, Jae-Sung; Lee, Jeong-Woo; Cho, Woong

2017-02-01

The purpose of this study was to evaluate the impact of dosimetric and radiobiological parameters on treatment plans by using different dose-calculation algorithms and delivery-beam modes for prostate stereotactic body radiation therapy using an endorectal balloon. For 20 patients with prostate cancer, stereotactic body radiation therapy (SBRT) plans were generated by using a 10-MV photon beam with flattening filter (FF) and flattening-filter-free (FFF) modes. The total treatment dose prescribed was 42.7 Gy in 7 fractions to cover at least 95% of the planning target volume (PTV) with 95% of the prescribed dose. The dose computation was initially performed using an anisotropic analytical algorithm (AAA) in the Eclipse treatment planning system (Varian Medical Systems, Palo Alto, CA) and was then re-calculated using Acuros XB (AXB V. 11.0.34) with the same monitor units and multileaf collimator files. The dosimetric and the radiobiological parameters for the PTV and organs at risk (OARs) were analyzed from the dose-volume histogram. An obvious difference in dosimetric parameters between the AAA and the AXB plans was observed in the PTV and rectum. Doses to the PTV, excluding the maximum dose, were always higher in the AAA plans than in the AXB plans. However, doses to the other OARs were similar in both algorithm plans. In addition, no difference was observed in the dosimetric parameters for different delivery-beam modes when using the same algorithm to generate plans. As a result of the dosimetric parameters, the radiobiological parameters for the two algorithm plans presented an apparent difference in the PTV and the rectum. The average tumor control probability of the AAA plans was higher than that of the AXB plans. The average normal tissue complication probability (NTCP) to rectum was lower in the AXB plans than in the AAA plans. The AAA and the AXB plans yielded very similar NTCPs for the other OARs. In plans using the same algorithms, the NTCPs for delivery-beam modes showed no differences. This study demonstrated that the dosimetric and the radiobiological parameters for the PTV and the rectum affected the dose-calculation algorithms for prostate SBRT using an endorectal balloon. However, the dosimetric and the radiobiological parameters in the AAA and the AXB plans for other OARs were similar. Furthermore, difference between the dosimetric and the radiobiological parameters for different delivery-beam modes were not found when the same algorithm was used to generate the treatment plan.

SU-C-BRC-04: Efficient Dose Calculation Algorithm for FFF IMRT with a Simplified Bivariate Gaussian Source Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, F; Park, J; Barraclough, B

2016-06-15

Purpose: To develop an efficient and accurate independent dose calculation algorithm with a simplified analytical source model for the quality assurance and safe delivery of Flattening Filter Free (FFF)-IMRT on an Elekta Versa HD. Methods: The source model consisted of a point source and a 2D bivariate Gaussian source, respectively modeling the primary photons and the combined effect of head scatter, monitor chamber backscatter and collimator exchange effect. The in-air fluence was firstly calculated by back-projecting the edges of beam defining devices onto the source plane and integrating the visible source distribution. The effect of the rounded MLC leaf end,more » tongue-and-groove and interleaf transmission was taken into account in the back-projection. The in-air fluence was then modified with a fourth degree polynomial modeling the cone-shaped dose distribution of FFF beams. Planar dose distribution was obtained by convolving the in-air fluence with a dose deposition kernel (DDK) consisting of the sum of three 2D Gaussian functions. The parameters of the source model and the DDK were commissioned using measured in-air output factors (Sc) and cross beam profiles, respectively. A novel method was used to eliminate the volume averaging effect of ion chambers in determining the DDK. Planar dose distributions of five head-and-neck FFF-IMRT plans were calculated and compared against measurements performed with a 2D diode array (MapCHECK™) to validate the accuracy of the algorithm. Results: The proposed source model predicted Sc for both 6MV and 10MV with an accuracy better than 0.1%. With a stringent gamma criterion (2%/2mm/local difference), the passing rate of the FFF-IMRT dose calculation was 97.2±2.6%. Conclusion: The removal of the flattening filter represents a simplification of the head structure which allows the use of a simpler source model for very accurate dose calculation. The proposed algorithm offers an effective way to ensure the safe delivery of FFF-IMRT.« less

TH-AB-201-10: Portal Dosimetry with Elekta IViewDose:Performance of the Simplified Commissioning Approach Versus Full Commissioning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kydonieos, M; Folgueras, A; Florescu, L

2016-06-15

Purpose: Elekta recently developed a solution for in-vivo EPID dosimetry (iViewDose, Elekta AB, Stockholm, Sweden) in conjunction with the Netherlands Cancer Institute (NKI). This uses a simplified commissioning approach via Template Commissioning Models (TCMs), consisting of a subset of linac-independent pre-defined parameters. This work compares the performance of iViewDose using a TCM commissioning approach with that corresponding to full commissioning. Additionally, the dose reconstruction based on the simplified commissioning approach is validated via independent dose measurements. Methods: Measurements were performed at the NKI on a VersaHD™ (Elekta AB, Stockholm, Sweden). Treatment plans were generated with Pinnacle 9.8 (Philips Medical Systems,more » Eindhoven, The Netherlands). A farmer chamber dose measurement and two EPID images were used to create a linac-specific commissioning model based on a TCM. A complete set of commissioning measurements was collected and a full commissioning model was created.The performance of iViewDose based on the two commissioning approaches was compared via a series of set-to-work tests in a slab phantom. In these tests, iViewDose reconstructs and compares EPID to TPS dose for square fields, IMRT and VMAT plans via global gamma analysis and isocentre dose difference. A clinical VMAT plan was delivered to a homogeneous Octavius 4D phantom (PTW, Freiburg, Germany). Dose was measured with the Octavius 1500 array and VeriSoft software was used for 3D dose reconstruction. EPID images were acquired. TCM-based iViewDose and 3D Octavius dose distributions were compared against the TPS. Results: For both the TCM-based and the full commissioning approaches, the pass rate, mean γ and dose difference were >97%, <0.5 and <2.5%, respectively. Equivalent gamma analysis results were obtained for iViewDose (TCM approach) and Octavius for a VMAT plan. Conclusion: iViewDose produces similar results with the simplified and full commissioning approaches. Good agreement is obtained between iViewDose (simplified approach) and the independent measurement tool. This research is funded by Elekta Limited.« less

Cost-effectiveness of hepatitis A vaccination in Indonesia.

PubMed

Suwantika, Auliya A; Beutels, Philippe; Postma, Maarten J

2014-01-01

This study aims to assess the cost-effectiveness of hepatitis A immunization in Indonesia, including an explicit comparison between one-dose and two-dose vaccines. An age-structured cohort model based on a decision tree was developed for the 2012 Indonesia birth cohort. Using the model, we made a comparison on the use of two-dose and one-dose vaccines. The model involved a 70-year time horizon with 1-month cycles for children less than 2 years old and annually thereafter. Monte Carlo simulations were used to examine the economic acceptability and affordability of the hepatitis A vaccination. Vaccination would save US$ 3,795,148 and US$ 2,892,920 from the societal perspective, for the two-dose and one-dose vaccine schedules, respectively, in the context of hepatitis A treatment. It also would save 8917 and 6614 discounted quality-adjusted-life-years (QALYs), respectively. With the vaccine price of US$ 3.21 per dose, the implementation of single dose vaccine would yield an incremental cost-effectiveness ratio (ICER) of US$ 4933 per QALY gained versus no vaccination, whereas the two-dose versus one-dose schedule would cost US$ 14 568 per QALY gained. Considering the 2012 gross-domestic-product (GDP) per capita in Indonesia of US$ 3557, the results indicate that hepatitis A vaccination would be a cost-effective intervention, both for the two-dose and one-dose vaccine schedules in isolation, but two-dose vaccination would no longer be cost-effective if one-dose vaccination is a feasible option. Vaccination would be 100% affordable at budgets of US$ 71,408 000 and US$ 37,690,000 for the implementation of the two-dose and one-dose vaccine schedules, respectively. The implementation of hepatitis A vaccination in Indonesia would be a cost-effective health intervention under the market vaccine price. Given the budget limitations, the use of a one-dose-vaccine schedule would be more realistic to be applied than a two-dose schedule. The vaccine price, mortality rate and discount rate were the most influential parameters impacting the ICERs.

Cost-effectiveness of hepatitis A vaccination in Indonesia

PubMed Central

Suwantika, Auliya A; Beutels, Philippe; Postma, Maarten J

2014-01-01

Objective This study aims to assess the cost-effectiveness of hepatitis A immunization in Indonesia, including an explicit comparison between one-dose and two-dose vaccines. Methods An age-structured cohort model based on a decision tree was developed for the 2012 Indonesia birth cohort. Using the model, we made a comparison on the use of two-dose and one-dose vaccines. The model involved a 70-year time horizon with 1-month cycles for children less than 2 years old and annually thereafter. Monte Carlo simulations were used to examine the economic acceptability and affordability of the hepatitis A vaccination. Results Vaccination would save US$ 3 795 148 and US$ 2 892 920 from the societal perspective, for the two-dose and one-dose vaccine schedules, respectively, in the context of hepatitis A treatment. It also would save 8917 and 6614 discounted quality-adjusted-life-years (QALYs), respectively. With the vaccine price of US$ 3.21 per dose, the implementation of single dose vaccine would yield an incremental cost-effectiveness ratio (ICER) of US$ 4933 per QALY gained versus no vaccination, whereas the two-dose versus one-dose schedule would cost US$ 14 568 per QALY gained. Considering the 2012 gross-domestic-product (GDP) per capita in Indonesia of US$ 3557, the results indicate that hepatitis A vaccination would be a cost-effective intervention, both for the two-dose and one-dose vaccine schedules in isolation, but two-dose vaccination would no longer be cost-effective if one-dose vaccination is a feasible option. Vaccination would be 100% affordable at budgets of US$ 71 408 000 and US$ 37 690 000 for the implementation of the two-dose and one-dose vaccine schedules, respectively. Conclusions The implementation of hepatitis A vaccination in Indonesia would be a cost-effective health intervention under the market vaccine price. Given the budget limitations, the use of a one-dose-vaccine schedule would be more realistic to be applied than a two-dose schedule. The vaccine price, mortality rate and discount rate were the most influential parameters impacting the ICERs. PMID:25424941

A study of dose-proportionality in the pharmacokinetics of the oral direct renin inhibitor aliskiren in healthy subjects.

PubMed

Limoges, D; Dieterich, H A; Yeh, C-M; Vaidyanathan, S; Howard, D; Dole, W P

2008-05-01

To evaluate the dose-proportionality of the pharmacokinetics of aliskiren, the first in a new class of orally active direct renin inhibitors approved for the treatment of hypertension. This was an open-label, single-center, single-dose, randomized, 4-period crossover study. Following a 21-day screening period, 32 healthy male or female subjects (ages 18 - 45 years) were randomized to 1 of 4 aliskiren dosing sequence groups (8 subjects per group): 75, 150, 300 and 600 mg. Blood samples were obtained for determination of plasma aliskiren concentrations (HPLC/MS/MS) for 96 h post dose. Log-transformed pharmacokinetic parameters AUC and C(max) were analyzed to determine dose-proportionality using the power model, parameter = A*(Dose)(beta), where A = intercept and beta = dose-proportionality coefficient. The predefined dose-proportionality criteria over the dose range 75 â 600 mg were 90% confidence intervals (CI) for beta contained within the range 0.89 - 1.11. AUC and Cmax values increased with increasing doses of aliskiren. Both AUC and C(max) were associated with high variability (coefficient of variation 55 - 64% for AUC and 59 - 117% for C(max)). The estimated proportionality coefficients (beta) for AUC(0-infiniti), AUC(0-t) and C(max) were 1.18 (90% CI 1.10, 1.25), 1.29 (90% CI 1.22, 1.36) and 1.42 (90% CI 1.31, 1.52), respectively. Dose-proportionality was, therefore, not demonstrated across the entire 8-fold dose range. For the clinical dose range of 150 â 300 mg, increases of 2.3- and 2.6-fold were observed for AUC and C(max), respectively. All doses of aliskiren were well tolerated. Exposure to aliskiren was greater than proportional over the dose range of 75 - 600 mg. Over the therapeutic dose range of 150 â 300 mg approved for the treatment of hypertension, AUC and Cmax increased by 2.3- and 2.6-fold, respectively. The pharmacokinetics of aliskiren show relatively high intersubject variability.

SU-E-T-295: Simultaneous Beam Sampling and Aperture Shape Optimization for Station Parameter Optimized Radiation Therapy (SPORT)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zarepisheh, M; Li, R; Xing, L

Purpose: Station Parameter Optimized Radiation Therapy (SPORT) was recently proposed to fully utilize the technical capability of emerging digital LINACs, in which the station parameters of a delivery system, (such as aperture shape and weight, couch position/angle, gantry/collimator angle) are optimized altogether. SPORT promises to deliver unprecedented radiation dose distributions efficiently, yet there does not exist any optimization algorithm to implement it. The purpose of this work is to propose an optimization algorithm to simultaneously optimize the beam sampling and aperture shapes. Methods: We build a mathematical model whose variables are beam angles (including non-coplanar and/or even nonisocentric beams) andmore » aperture shapes. To solve the resulting large scale optimization problem, we devise an exact, convergent and fast optimization algorithm by integrating three advanced optimization techniques named column generation, gradient method, and pattern search. Column generation is used to find a good set of aperture shapes as an initial solution by adding apertures sequentially. Then we apply the gradient method to iteratively improve the current solution by reshaping the aperture shapes and updating the beam angles toward the gradient. Algorithm continues by pattern search method to explore the part of the search space that cannot be reached by the gradient method. Results: The proposed technique is applied to a series of patient cases and significantly improves the plan quality. In a head-and-neck case, for example, the left parotid gland mean-dose, brainstem max-dose, spinal cord max-dose, and mandible mean-dose are reduced by 10%, 7%, 24% and 12% respectively, compared to the conventional VMAT plan while maintaining the same PTV coverage. Conclusion: Combined use of column generation, gradient search and pattern search algorithms provide an effective way to optimize simultaneously the large collection of station parameters and significantly improves quality of resultant treatment plans as compared with conventional VMAT or IMRT treatments.« less

Dose–Volume Relationships Associated With Temporal Lobe Radiation Necrosis After Skull Base Proton Beam Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

McDonald, Mark W., E-mail: markmcdonaldmd@gmail.com; Indiana University Health Proton Therapy Center, Bloomington, Indiana; Linton, Okechukwu R.

Purpose: We evaluated patient and treatment parameters correlated with development of temporal lobe radiation necrosis. Methods and Materials: This was a retrospective analysis of a cohort of 66 patients treated for skull base chordoma, chondrosarcoma, adenoid cystic carcinoma, or sinonasal malignancies between 2005 and 2012, who had at least 6 months of clinical and radiographic follow-up. The median radiation dose was 75.6 Gy (relative biological effectiveness [RBE]). Analyzed factors included gender, age, hypertension, diabetes, smoking status, use of chemotherapy, and the absolute dose:volume data for both the right and left temporal lobes, considered separately. A generalized estimating equation (GEE) regression analysis evaluatedmore » potential predictors of radiation necrosis, and the median effective concentration (EC50) model estimated dose–volume parameters associated with radiation necrosis. Results: Median follow-up time was 31 months (range 6-96 months) and was 34 months in patients who were alive. The Kaplan-Meier estimate of overall survival at 3 years was 84.9%. The 3-year estimate of any grade temporal lobe radiation necrosis was 12.4%, and for grade 2 or higher radiation necrosis was 5.7%. On multivariate GEE, only dose–volume relationships were associated with the risk of radiation necrosis. In the EC50 model, all dose levels from 10 to 70 Gy (RBE) were highly correlated with radiation necrosis, with a 15% 3-year risk of any-grade temporal lobe radiation necrosis when the absolute volume of a temporal lobe receiving 60 Gy (RBE) (aV60) exceeded 5.5 cm{sup 3}, or aV70 > 1.7 cm{sup 3}. Conclusions: Dose–volume parameters are highly correlated with the risk of developing temporal lobe radiation necrosis. In this study the risk of radiation necrosis increased sharply when the temporal lobe aV60 exceeded 5.5 cm{sup 3} or aV70 > 1.7 cm{sup 3}. Treatment planning goals should include constraints on the volume of temporal lobes receiving higher dose. The EC50 model provides suggested dose–volume temporal lobe constraints for conventionally fractionated high-dose skull base radiation therapy.« less

Integrated pharmacokinetics/pharmacodynamics parameters-based dosing guidelines of enrofloxacin in grass carp Ctenopharyngodon idella to minimize selection of drug resistance.

PubMed

Xu, Lijuan; Wang, Hao; Yang, Xianle; Lu, Liqun

2013-06-25

Antibiotic resistance has become a serious global problem and is steadily increasing worldwide in almost every bacterial species treated with antibiotics. In aquaculture, the therapeutic options for the treatment of A. hydrophila infection were only limited to several antibiotics, which contributed for the fast-speed emergence of drug tolerance. Accordingly, the aim of this study was to establish a medication regimen to prevent drug resistant bacteria. To determine a rational therapeutic guideline, integrated pharmacodynamics and pharmacokinetics parameters were based to predict dose and dosage interval of enrofloxacin in grass carp Ctenopharyngodon idella infected by a field-isolated A. hydrophila strain. The pathogenic A. hydrophila strain (AH10) in grass carp was identified and found to be sensitive to enrofloxacin. The mutant selection window (MSW) of enrofloxacin on isolate AH10 was determined to be 0.5-3 μg/mL based on the mutant prevention concentration (MPC) and minimum inhibitory concentration (MIC) value. By using high-performance liquid chromatography (HPLC) system, the Pharmacokinetic (PK) parameters of enrofloxacin and its metabolite ciprofloxacin in grass carp were monitored after a single oral gavage of 10, 20, 30 μg enrofloxacin per g body weight. Dosing of 30 μg/g resulted in serum maximum concentration (Cmax) of 7.151 μg/mL, and concentration in serum was above MPC till 24 h post the single dose. Once-daily dosing of 30 μg/g was determined to be the rational choice for controlling AH10 infection and preventing mutant selection in grass carp. Data of mean residue time (MRT) and body clearance (CLz) indicated that both enrofloxacin and its metabolite ciprofloxacin present similar eliminating rate and pattern in serum, muscle and liver. A withdraw time of more than 32 d was suggested based on the drug eliminating rate and pharmacokinetic model described by a polyexponential equation. Based on integrated PK/PD parameters (AUC/MIC, Cmax/MIC, and T>MPC), the results of this study established a principle, for the first time, on drawing accurate dosing guideline for pharmacotherapy against A. hydrophila strain (AH10) for prevention of drug-resistant mutants. Our approach in combining PK data with PD parameters (including MPC and MSW) was the new effort in aquaculture to face the challenge of drug resistance by drawing a specific dosage guideline of antibiotics.

SU-E-J-274: Responses of Medulloblastoma Cells to Radiation Dosimetric Parameters in Intensity-Modulated Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, J; Molecular Imaging Program at Stanford, Stanford, CA; Bio-X Program, Stanford, CA

2015-06-15

Purpose: To evaluate radiation responses of the medulloblastoma cell line Daoy in intensity-modulated radiation therapy (IMRT), quantitative variations to variable radiation dosimetic parameters were tracked by bioluminescent images (BLIs). Methods: The luciferase and green fluorescent protein positive Daoy cells were cultured on dishes. The medulloblastoma cells irradiated to different dose rate, interval of fractionated doses, field margin and misalignment, and dose uniformity in IMRT were monitored using bioluminescent images. The cultured cells were placed into a dedicated acrylic phantom to deliver intensity-modulated fluences and calculate accurate predicted dose distribution. The radiation with dose rate from 0.5 Gy/min to 15 Gy/minmore » was irradiated by adjusting monitor unit per minute and source-to-surface distances. The intervals of fractionated dose delivery were changed considering the repair time of double strand breaks (DSB) revealed by straining of gamma-H2AX.The effect of non-uniform doses on the cells were visualized by registering dose distributions and BLIs. The viability according to dosimetric parameters was correlated with bioluminescent intensities for cross-check of radiation responses. Results: The DSB and cell responses due to the first fractionated dose delivery significantly affected final tumor control rather than other parameters. The missing tumor volumes due to the smaller field margin than the tumor periphery or field misalignment caused relapse of cell responses on BLIs. The dose rate and gradient had effect on initial responses but could not bring out the distinguishable killing effect on cancer cells. Conclusion: Visualized and quantified bioluminescent images were useful to correlate the dose distributions with spatial radiation effects on cells. This would derive the effective combination of dose delivery parameters and fractionation. Radiation responses in particular IMRT configuration could be reflected to image based-dose re-optimization.« less

Proton irradiation studies on Al and Al5083 alloy

NASA Astrophysics Data System (ADS)

Bhattacharyya, P.; Gayathri, N.; Bhattacharya, M.; Gupta, A. Dutta; Sarkar, Apu; Dhar, S.; Mitra, M. K.; Mukherjee, P.

2017-10-01

The change in the microstructural parameters and microhardness values in 6.5 MeV proton irradiated pure Al and Al5083 alloy samples have been evaluated using different model based techniques of X-ray diffraction Line Profile Analysis (XRD) and microindendation techniques. The detailed line profile analysis of the XRD data showed that the domain size increases and saturates with irradiation dose both in the case of Al and Al5083 alloy. The corresponding microstrain values did not show any change with irradiation dose in the case of the pure Al but showed an increase at higher irradiation doses in the case of Al5083 alloy. The microindendation results showed that unirradiated Al5083 alloy has higher hardness value compared to that of unirradiated pure Al. The hardness increased marginally with irradiation dose in the case of Al5083, whereas for pure Al, there was no significant change with dose.

Methods for CT automatic exposure control protocol translation between scanner platforms.

PubMed

McKenney, Sarah E; Seibert, J Anthony; Lamba, Ramit; Boone, John M

2014-03-01

An imaging facility with a diverse fleet of CT scanners faces considerable challenges when propagating CT protocols with consistent image quality and patient dose across scanner makes and models. Although some protocol parameters can comfortably remain constant among scanners (eg, tube voltage, gantry rotation time), the automatic exposure control (AEC) parameter, which selects the overall mA level during tube current modulation, is difficult to match among scanners, especially from different CT manufacturers. Objective methods for converting tube current modulation protocols among CT scanners were developed. Three CT scanners were investigated, a GE LightSpeed 16 scanner, a GE VCT scanner, and a Siemens Definition AS+ scanner. Translation of the AEC parameters such as noise index and quality reference mAs across CT scanners was specifically investigated. A variable-diameter poly(methyl methacrylate) phantom was imaged on the 3 scanners using a range of AEC parameters for each scanner. The phantom consisted of 5 cylindrical sections with diameters of 13, 16, 20, 25, and 32 cm. The protocol translation scheme was based on matching either the volumetric CT dose index or image noise (in Hounsfield units) between two different CT scanners. A series of analytic fit functions, corresponding to different patient sizes (phantom diameters), were developed from the measured CT data. These functions relate the AEC metric of the reference scanner, the GE LightSpeed 16 in this case, to the AEC metric of a secondary scanner. When translating protocols between different models of CT scanners (from the GE LightSpeed 16 reference scanner to the GE VCT system), the translation functions were linear. However, a power-law function was necessary to convert the AEC functions of the GE LightSpeed 16 reference scanner to the Siemens Definition AS+ secondary scanner, because of differences in the AEC functionality designed by these two companies. Protocol translation on the basis of quantitative metrics (volumetric CT dose index or measured image noise) is feasible. Protocol translation has a dependency on patient size, especially between the GE and Siemens systems. Translation schemes that preserve dose levels may not produce identical image quality. Copyright © 2014 American College of Radiology. Published by Elsevier Inc. All rights reserved.

Pharmacokinetics of oral hydrocortisone - Results and implications from a randomized controlled trial.

PubMed

Werumeus Buning, Jorien; Touw, Daan J; Brummelman, Pauline; Dullaart, Robin P F; van den Berg, Gerrit; van der Klauw, Melanie M; Kamp, Jasper; Wolffenbuttel, Bruce H R; van Beek, André P

2017-06-01

This study aimed at comparing pharmacokinetics of two different doses of hydrocortisone (HC) in patients with secondary adrenal insufficiency (SAI). Forty-six patients with SAI participated in this randomized double-blind crossover study. Patients received two different doses of HC (0.2-0.3mg HC/kg body weight/day and 0.4-0.6mg HC/kg body weight/day). One- and two-compartment population models for plasma free cortisol, plasma total cortisol and salivary cortisol were parameterized. The individual pharmacokinetic parameters clearance (CL), volume of distribution (V d ), elimination half-life (t 1/2 ), maximum concentration (C max ), and area under the curve (AUC) were calculated. The one-compartment models gave a better description of the data compared to the two-compartment models. Weight-adjusted dosing reduced variability in cortisol exposure with comparable AUCs between weight groups. However, there was large inter-individual variation in CL and V d of plasma free cortisol, plasma total cortisol and salivary cortisol. As a consequence, AUC 24h varied more than 10 fold. Cortisol exposure was increased with the higher dose, but this was dose proportional only for free cortisol concentrations and not for total cortisol. Cortisol concentrations after a doubling of the dose were only dose proportional for free cortisol. HC pharmacokinetics can differ up to 10-fold inter-individually and individual adjustment of treatment doses may be necessary. Doubling of the HC dose in fast metabolizers (patients that showed relative low AUC and thus high clearance compared to other patients), does not result in significantly enhanced exposure during large parts of the day and these patients may need other management strategies. Copyright © 2017 Elsevier Inc. All rights reserved.

Evaluating analytical ionization quenching correction models for 3D liquid organic scintillator detector

NASA Astrophysics Data System (ADS)

Alsanea, F.; Beddar, S.

2017-05-01

Proton therapy offers dosimetric advantage over conventional photon therapy due to the finite range of the proton beam, which improves dose conformity. However, one of the main challenges of proton beam therapy is verification of the complex treatment plans delivered to a patient. Thus, 3D measurements are needed to verify the complex dose distribution. A 3D organic scintillator detector is capable of such measurements. However, organic scintillators exhibit a non-linear relation to the ionization density called ionization quenching. The ionization quenching phenomenon in organic scintillators must be accounted for to obtain accurate dose measurements. We investigated the energy deposition by secondary electrons (EDSE) model to explain ionization quenching in 3D liquid organic scintillator when exposed to proton beams. The EDSE model was applied to volumetric scintillation measurement of proton pencil beam with energies of 85.6, 100.9, 144.9 and 161.9 MeV. The quenching parameter in EDSE model ρq was determined by plotting the total light output vs the initial energy of the ion. The results were compared to the Birks semi-empirical formula of scintillation light emission.

Improved prediction of tacrolimus concentrations early after kidney transplantation using theory-based pharmacokinetic modelling.

PubMed

Størset, Elisabet; Holford, Nick; Hennig, Stefanie; Bergmann, Troels K; Bergan, Stein; Bremer, Sara; Åsberg, Anders; Midtvedt, Karsten; Staatz, Christine E

2014-09-01

The aim was to develop a theory-based population pharmacokinetic model of tacrolimus in adult kidney transplant recipients and to externally evaluate this model and two previous empirical models. Data were obtained from 242 patients with 3100 tacrolimus whole blood concentrations. External evaluation was performed by examining model predictive performance using Bayesian forecasting. Pharmacokinetic disposition parameters were estimated based on tacrolimus plasma concentrations, predicted from whole blood concentrations, haematocrit and literature values for tacrolimus binding to red blood cells. Disposition parameters were allometrically scaled to fat free mass. Tacrolimus whole blood clearance/bioavailability standardized to haematocrit of 45% and fat free mass of 60 kg was estimated to be 16.1 l h−1 [95% CI 12.6, 18.0 l h−1]. Tacrolimus clearance was 30% higher (95% CI 13, 46%) and bioavailability 18% lower (95% CI 2, 29%) in CYP3A5 expressers compared with non-expressers. An Emax model described decreasing tacrolimus bioavailability with increasing prednisolone dose. The theory-based model was superior to the empirical models during external evaluation displaying a median prediction error of −1.2% (95% CI −3.0, 0.1%). Based on simulation, Bayesian forecasting led to 65% (95% CI 62, 68%) of patients achieving a tacrolimus average steady-state concentration within a suggested acceptable range. A theory-based population pharmacokinetic model was superior to two empirical models for prediction of tacrolimus concentrations and seemed suitable for Bayesian prediction of tacrolimus doses early after kidney transplantation.

Population Pharmacokinetics of Intravenous Methotrexate in Patients with Hematological Malignancies: Utilization of Routine Clinical Monitoring Parameters.

PubMed

Nader, Ahmed; Zahran, Noran; Alshammaa, Aya; Altaweel, Heba; Kassem, Nancy; Wilby, Kyle John

2017-04-01

Clinical response to methotrexate in cancer is variable and depends on several factors including serum drug exposure. This study aimed to develop a population pharmacokinetic model describing methotrexate disposition in cancer patients using retrospective chart review data available from routine clinical practice. A retrospective review of medical records was conducted for cancer patients in Qatar. Relevant data (methotrexate dosing/concentrations from multiple occasions, patient history, and laboratory values) were extracted and analyzed using NONMEM VII ® . A population pharmacokinetic model was developed and used to estimate inter-individual and inter-occasion variability terms on methotrexate pharmacokinetic parameters, as well as patient factors affecting methotrexate pharmacokinetics. Methotrexate disposition was described by a two-compartment model with clearance (CL) of 15.7 L/h and central volume of distribution (V c ) of 79.2 L. Patient weight and hematocrit levels were significant covariates on methotrexate V c and CL, respectively. Methotrexate CL changed by 50 % with changes in hematocrit levels from 23 to 50 %. Inter-occasion variability in methotrexate CL was estimated for patients administered the drug on multiple occasions (48 and 31 % for 2nd and 3rd visits, respectively). Therapeutic drug monitoring data collected during routine clinical practice can provide a useful tool for understanding factors affecting methotrexate pharmacokinetics. Patient weight and hematocrit levels may play a clinically important role in determining methotrexate serum exposure and dosing requirements. Future prospective studies are needed to validate results of the developed model and evaluate its usefulness to predict methotrexate exposure and optimize dosing regimens.

Assessment of effectiveness of geologic isolation systems. CIRMIS data system. Volume 4. Driller's logs, stratigraphic cross section and utility routines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Friedrichs, D.R.

1980-01-01

The Assessment of Effectiveness of Geologic Isolation Systems (AEGIS) Program is developing and applying the methodology for assessing the far-field, long-term post-closure safety of deep geologic nuclear waste repositories. AEGIS is being performed by Pacific Northwest Laboratory (PNL) under contract with the Office of Nuclear Waste Isolation (ONWI) for the Department of Energy (DOE). One task within AEGIS is the development of methodology for analysis of the consequences (water pathway) from loss of repository containment as defined by various release scenarios. Analysis of the long-term, far-field consequences of release scenarios requires the application of numerical codes which simulate the hydrologicmore » systems, model the transport of released radionuclides through the hydrologic systems to the biosphere, and, where applicable, assess the radiological dose to humans. The various input parameters required in the analysis are compiled in data systems. The data are organized and prepared by various input subroutines for use by the hydrologic and transport codes. The hydrologic models simulate the groundwater flow systems and provide water flow directions, rates, and velocities as inputs to the transport models. Outputs from the transport models are basically graphs of radionuclide concentration in the groundwater plotted against time. After dilution in the receiving surface-water body (e.g., lake, river, bay), these data are the input source terms for the dose models, if dose assessments are required. The dose models calculate radiation dose to individuals and populations. CIRMIS (Comprehensive Information Retrieval and Model Input Sequence) Data System is a storage and retrieval system for model input and output data, including graphical interpretation and display. This is the fourth of four volumes of the description of the CIRMIS Data System.« less

PWR Facility Dose Modeling Using MCNP5 and the CADIS/ADVANTG Variance-Reduction Methodology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Blakeman, Edward D; Peplow, Douglas E.; Wagner, John C

2007-09-01

The feasibility of modeling a pressurized-water-reactor (PWR) facility and calculating dose rates at all locations within the containment and adjoining structures using MCNP5 with mesh tallies is presented. Calculations of dose rates resulting from neutron and photon sources from the reactor (operating and shut down for various periods) and the spent fuel pool, as well as for the photon source from the primary coolant loop, were all of interest. Identification of the PWR facility, development of the MCNP-based model and automation of the run process, calculation of the various sources, and development of methods for visually examining mesh tally filesmore » and extracting dose rates were all a significant part of the project. Advanced variance reduction, which was required because of the size of the model and the large amount of shielding, was performed via the CADIS/ADVANTG approach. This methodology uses an automatically generated three-dimensional discrete ordinates model to calculate adjoint fluxes from which MCNP weight windows and source bias parameters are generated. Investigative calculations were performed using a simple block model and a simplified full-scale model of the PWR containment, in which the adjoint source was placed in various regions. In general, it was shown that placement of the adjoint source on the periphery of the model provided adequate results for regions reasonably close to the source (e.g., within the containment structure for the reactor source). A modification to the CADIS/ADVANTG methodology was also studied in which a global adjoint source is weighted by the reciprocal of the dose response calculated by an earlier forward discrete ordinates calculation. This method showed improved results over those using the standard CADIS/ADVANTG approach, and its further investigation is recommended for future efforts.« less

Improved dose-volume histogram estimates for radiopharmaceutical therapy by optimizing quantitative SPECT reconstruction parameters

NASA Astrophysics Data System (ADS)

Cheng, Lishui; Hobbs, Robert F.; Segars, Paul W.; Sgouros, George; Frey, Eric C.

2013-06-01

In radiopharmaceutical therapy, an understanding of the dose distribution in normal and target tissues is important for optimizing treatment. Three-dimensional (3D) dosimetry takes into account patient anatomy and the nonuniform uptake of radiopharmaceuticals in tissues. Dose-volume histograms (DVHs) provide a useful summary representation of the 3D dose distribution and have been widely used for external beam treatment planning. Reliable 3D dosimetry requires an accurate 3D radioactivity distribution as the input. However, activity distribution estimates from SPECT are corrupted by noise and partial volume effects (PVEs). In this work, we systematically investigated OS-EM based quantitative SPECT (QSPECT) image reconstruction in terms of its effect on DVHs estimates. A modified 3D NURBS-based Cardiac-Torso (NCAT) phantom that incorporated a non-uniform kidney model and clinically realistic organ activities and biokinetics was used. Projections were generated using a Monte Carlo (MC) simulation; noise effects were studied using 50 noise realizations with clinical count levels. Activity images were reconstructed using QSPECT with compensation for attenuation, scatter and collimator-detector response (CDR). Dose rate distributions were estimated by convolution of the activity image with a voxel S kernel. Cumulative DVHs were calculated from the phantom and QSPECT images and compared both qualitatively and quantitatively. We found that noise, PVEs, and ringing artifacts due to CDR compensation all degraded histogram estimates. Low-pass filtering and early termination of the iterative process were needed to reduce the effects of noise and ringing artifacts on DVHs, but resulted in increased degradations due to PVEs. Large objects with few features, such as the liver, had more accurate histogram estimates and required fewer iterations and more smoothing for optimal results. Smaller objects with fine details, such as the kidneys, required more iterations and less smoothing at early time points post-radiopharmaceutical administration but more smoothing and fewer iterations at later time points when the total organ activity was lower. The results of this study demonstrate the importance of using optimal reconstruction and regularization parameters. Optimal results were obtained with different parameters at each time point, but using a single set of parameters for all time points produced near-optimal dose-volume histograms.

DOSE-DEPENDENCY OF 2-ACETYLAMINOFLUORENE BINDING TO LIVER DNA AND HEMOGLOBIN IN MICE AND RATS

EPA Science Inventory

The carcinogenic activity of 2-acetylaminofluorene (2-AAF) in mice and rats has been accurately described so that it is a suitable archetypical chemical for investigations of parameters of cross-species variation. The results of the study supported a pharmacokinetic model that re...

a Biokinetic Model for CESIUM-137 in the Fetus

NASA Astrophysics Data System (ADS)

Jones, Karen Lynn

1995-01-01

Previously, there was no method to determine the dose to the embryo, fetus, fetal organs or placenta from radionuclides within the embryo, fetus, or placenta. In the past, the dose to the fetus was assumed to be equivalent to the dose to the uterus. Watson estimated specific absorbed fractions from various maternal organs to the uterine contents which included the fetus, placenta, and amniotic fluid and Sikov estimated the absorbed dose to the embryo/fetus after assuming 1 uCi of radioactivity was made available to the maternal blood.^{1,2} However, this method did not allow for the calculation of a dose to individual fetal organs or the placenta. The radiation dose to the embryo or fetus from Cs-137 in the fetus and placenta due to a chronic ingestion by the mother was determined. The fraction of Cs-137 in the maternal plasma crossing the placenta to the fetal plasma was estimated. The absorbed dose from Cs-137 in each modelled fetal organ was estimated. Since there has been more research regarding potassium in the human body, and particularly in the pregnant woman, a biokinetic model for potassium was developed first and used as a basis and confirmation of the cesium model. Available pertinent information in physiology, embryology, biokinetics, and radiation dosimetry was utilized. Due to the rapid growth of the fetus and placenta, the pregnancy was divided into four gestational periods. The numerous physiological changes that occurred during pregnancy were considered and an appropriate biokinetic model was developed for each of the gestational periods. The amount of cesium in the placenta, embryo, and fetus was estimated for each period. The dose to the fetus from cesium deposited in the embryo or fetus and in the placenta was determined for each period using Medical Internal Radiation Dosimetry (MIRD) methodology. An uncertainty analysis was also performed to account for the variability of the parameters in the biokinetic model based on the experimental data. The uncertainty in the dose estimate was calculated by propagation of errors after determining the uncertainty in the fetal and placenta mass estimates and the effective half-life.

Soiling of window glass of building façades: a new Dose-Response Function based on the mass of deposited particles

NASA Astrophysics Data System (ADS)

Ionescu, Anda; Lefèvre, Roger

2017-04-01

Materials used in building façades are subject to different types of weathering, an important one being soiling. The material studied here is the silica-soda-lime glass, used for windows and contemporaneous façades. Glass weathering in a polluted environment, sheltered from rain, is dominated by soiling. This phenomenon can be expressed either by an optical parameter, the haze, or by the mass of Deposited and Neoformed Particles by unit of glass surface (DNPs). By contrast to the haze, which is an optical parameter requiring an expensive technology (spectrophotometry), measuring DNPs is much simpler: the glass sample is weighed before and after exposure and the result, divided by the sample surface. After the development of a previous Dose-Response Function (DRF) expressing soiling evolution through haze, this study focuses on the development of a new DRF for soiling expressed in terms of DNPs mass, sheltered from rain. The development of this DRF follows a statistical approach. The general form proposed for the DRF is: DNPs=A(dose1, dose2, …., dosen).g(t) where g(t) represents the temporal trend obtained from standardized data. Data standardization has been employed in order to obtain a general trend independent of the environmental characteristics of the monitoring site. According to previous studies and physical considerations, the analytical form of the temporal trend g(t) was expressed by a function admitting an horizontal asymptote: the saturation level of soling. Ten monitoring campaigns (performed at different European sites) were used; the longest one runs up to 2102 days and the shortest ones, up to 365 days, with 14 to 5 records, respectively. Two different models were fitted by a non-linear regression: the Hill's model and a decreasing exponential model. Both models performed well (R2 ranging from 0.73 to 0.76) and they were further tested in order to get the final form of the DRF. The amplitude function A was considered as a linear combination of the different doses. A multiple linear regression was then applied to doses multiplied by the temporal trend function g permitting to obtain the regression coefficients of the amplitude function A. Another database was used, containing the monitoring values for SO2, NO2 and PM10 concentrations, as well as temperature and relative humidity, monitored at 19 European sites. The correlation between pollution concentrations was taken into account and led to a selection of pollutants in order to avoid numerical instability in the regression procedure. The meteorological parameters didn't have a statistical impact, so they were not considered as doses. A DRF for DNPs could be established using SO2 and PM10 concentrations and the Hill model for the g(t) trend with a determination coefficient of 0.7. This DRF was then used to plot the annual DNPs evolution from 1500 to 2100 in Paris and compared to the same curve expressed in terms of Haze for the same period. The obtained evolution is comparable and reveals an important peak corresponding to the industrial period.

Dosimetry for 131Cs and 125I seeds in solid water phantom using radiochromic EBT film.

PubMed

Chiu-Tsao, Sou-Tung; Napoli, John J; Davis, Stephen D; Hanley, Joseph; Rivard, Mark J

2014-09-01

To measure the 2D dose distributions with submillimeter resolution for (131)Cs (model CS-1 Rev2) and (125)I (model 6711) seeds in a Solid Water phantom using radiochromic EBT film for radial distances from 0.06cm to 5cm. To determine the TG-43 dosimetry parameters in water by applying Solid Water to liquid water correction factors generated from Monte Carlo simulations. Each film piece was positioned horizontally above and in close contact with a (131)Cs or (125)I seed oriented horizontally in a machined groove at the center of a Solid Water phantom, one film at a time. A total of 74 and 50 films were exposed to the (131)Cs and (125)I seeds, respectively. Different film sizes were utilized to gather data in different distance ranges. The exposure time varied according to the seed air-kerma strength and film size in order to deliver doses in the range covered by the film calibration curve. Small films were exposed for shorter times to assess the near field, while larger films were exposed for longer times in order to assess the far field. For calibration, films were exposed to either 40kV (M40) or 50kV (M50) x-rays in air at 100.0cm SSD with doses ranging from 0.2Gy to 40Gy. All experimental, calibration and background films were scanned at a 0.02cmpixel resolution using a CCD camera-based microdensitometer with a green light source. Data acquisition and scanner uniformity correction were achieved with Microd3 software. Data analysis was performed using ImageJ, FV, IDL and Excel software packages. 2D dose distributions were based on the calibration curve established for 50kV x-rays. The Solid Water to liquid water medium correction was calculated using the MCNP5 Monte Carlo code. Subsequently, the TG-43 dosimetry parameters in liquid water medium were determined. Values for the dose-rate constants using EBT film were 1.069±0.036 and 0.923±0.031cGyU(-1)h(-1) for (131)Cs and (125)I seed, respectively. The corresponding values determined using the Monte Carlo method were 1.053±0.014 and 0.924±0.016cGyU(-1)h(-1) for (131)Cs and (125)I seed, respectively. The radial dose functions obtained with EBT film measurements and Monte Carlo simulations were plotted for radial distances up to 5cm, and agreed within the uncertainty of the two methods. The 2D anisotropy functions obtained with both methods also agreed within their uncertainties. EBT film dosimetry in a Solid Water phantom is a viable method for measuring (131)Cs (model CS-1 Rev2) and (125)I (model 6711) brachytherapy seed dose distributions with submillimeter resolution. With the Solid Water to liquid water correction factors generated from Monte Carlo simulations, the measured TG-43 dosimetry parameters in liquid water for these two seed models were found to be in good agreement with those in the literature. Copyright © 2014 Elsevier Ltd. All rights reserved.

Calcium kinetics with microgram stable isotope doses and saliva sampling

NASA Technical Reports Server (NTRS)

Smith, S. M.; Wastney, M. E.; Nyquist, L. E.; Shih, C. Y.; Wiesmann, H.; Nillen, J. L.; Lane, H. W.

1996-01-01

Studies of calcium kinetics require administration of tracer doses of calcium and subsequent repeated sampling of biological fluids. This study was designed to develop techniques that would allow estimation of calcium kinetics by using small (micrograms) doses of isotopes instead of the more common large (mg) doses to minimize tracer perturbation of the system and reduce cost, and to explore the use of saliva sampling as an alternative to blood sampling. Subjects received an oral dose (133 micrograms) of 43Ca and an i.v. dose (7.7 micrograms) of 46Ca. Isotopic enrichment in blood, urine, saliva and feces was well above thermal ionization mass spectrometry measurement precision up to 170 h after dosing. Fractional calcium absorptions determined from isotopic ratios in blood, urine and saliva were similar. Compartmental modeling revealed that kinetic parameters determined from serum or saliva data were similar, decreasing the necessity for blood samples. It is concluded from these results that calcium kinetics can be assessed with micrograms doses of stable isotopes, thereby reducing tracer costs and with saliva samples, thereby reducing the amount of blood needed.

Quantifying Unnecessary Normal Tissue Complication Risks due to Suboptimal Planning: A Secondary Study of RTOG 0126.

PubMed

Moore, Kevin L; Schmidt, Rachel; Moiseenko, Vitali; Olsen, Lindsey A; Tan, Jun; Xiao, Ying; Galvin, James; Pugh, Stephanie; Seider, Michael J; Dicker, Adam P; Bosch, Walter; Michalski, Jeff; Mutic, Sasa

2015-06-01

The purpose of this study was to quantify the frequency and clinical severity of quality deficiencies in intensity modulated radiation therapy (IMRT) planning in the Radiation Therapy Oncology Group 0126 protocol. A total of 219 IMRT patients from the high-dose arm (79.2 Gy) of RTOG 0126 were analyzed. To quantify plan quality, we used established knowledge-based methods for patient-specific dose-volume histogram (DVH) prediction of organs at risk and a Lyman-Kutcher-Burman (LKB) model for grade ≥2 rectal complications to convert DVHs into normal tissue complication probabilities (NTCPs). The LKB model was validated by fitting dose-response parameters relative to observed toxicities. The 90th percentile (22 of 219) of plans with the lowest excess risk (difference between clinical and model-predicted NTCP) were used to create a model for the presumed best practices in the protocol (pDVH0126,top10%). Applying the resultant model to the entire sample enabled comparisons between DVHs that patients could have received to DVHs they actually received. Excess risk quantified the clinical impact of suboptimal planning. Accuracy of pDVH predictions was validated by replanning 30 of 219 patients (13.7%), including equal numbers of presumed "high-quality," "low-quality," and randomly sampled plans. NTCP-predicted toxicities were compared to adverse events on protocol. Existing models showed that bladder-sparing variations were less prevalent than rectum quality variations and that increased rectal sparing was not correlated with target metrics (dose received by 98% and 2% of the PTV, respectively). Observed toxicities were consistent with current LKB parameters. Converting DVH and pDVH0126,top10% to rectal NTCPs, we observed 94 of 219 patients (42.9%) with ≥5% excess risk, 20 of 219 patients (9.1%) with ≥10% excess risk, and 2 of 219 patients (0.9%) with ≥15% excess risk. Replanning demonstrated the predicted NTCP reductions while maintaining the volume of the PTV receiving prescription dose. An equivalent sample of high-quality plans showed fewer toxicities than low-quality plans, 6 of 73 versus 10 of 73 respectively, although these differences were not significant (P=.21) due to insufficient statistical power in this retrospective study. Plan quality deficiencies in RTOG 0126 exposed patients to substantial excess risk for rectal complications. Copyright © 2015 Elsevier Inc. All rights reserved.

Detection of erythropoietin misuse by the Athlete Biological Passport combined with reticulocyte percentage.

PubMed

Bejder, Jacob; Aachmann-Andersen, Niels Jacob; Bonne, Thomas Christian; Olsen, Niels Vidiendal; Nordsborg, Nikolai Baastrup

2016-10-01

The sensitivity of the adaptive model of the Athlete Biological Passport (ABP) and reticulocyte percentage (ret%) in detection of recombinant human erythropoietin (rHuEPO) misuse was evaluated using both a long-term normal dose and a brief high dose treatment regime. Sixteen subjects received either 65 IU rHuEPO × kg -1 every second day for two weeks (normal-dose), 390 IU rHuEPO × kg -1 on three consecutive days (high-dose), or frequent placebo treatment for 13 days in a randomized, placebo-controlled, double-blind crossover design. Blood variables were measured 4, 11, and 25 days following treatment initiation. The ABP based on haemoglobin concentration ([Hb]) and OFF-hr score ([Hb] - 60 × √ret%) yielded atypical profiles following both normal-dose and high-dose treatment (0 %, 31 %, 13 % vs. 21 %, 33 %, 20 % at days 4, 11, and 25 after normal and high dose, respectively). Including ret% as a stand-alone marker for atypical blood profiles increased (P < 0.05) the sensitivity of the adaptive model at day 11 to 63 % and 67 % for normal-dose and high-dose rHuEPO administration, respectively. In conclusion, ~30 % of subjects injecting a normal-dose rHuEPO for two weeks or a high-dose rHuEPO for three days will present an atypical ABP profile. Including ret% as a stand-alone parameter improves the sensitivity two-fold. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Acute Toxicity Study of Zerumbone-Loaded Nanostructured Lipid Carrier on BALB/c Mice Model

PubMed Central

Rahman, Heshu Sulaiman; Rasedee, Abdullah; Othman, Hemn Hassan; Chartrand, Max Stanley; Namvar, Farideh; Abdul Samad, Nozlena; Andas, Reena Joys; Ng, Kuan Beng; How, Chee Wun

2014-01-01

Zerumbone- (ZER-) loaded nanostructure lipid carrier (NLC) (ZER-NLC) prepared for its antileukemia effect in vitro was evaluated for its toxicological effects by observing changes in the liver, kidney, spleen, lung, heart, and brain tissues, serum biochemical parameters, total haemogram, and bone marrow stem cells. The acute toxicity study for ZER-NLC was conducted by orally treating BALB/c mice with a single dose with either water, olive oil, ZER, NLC, or ZER-NLC for 14 days. The animals were observed for clinical and behavioral abnormalities, toxicological symptoms, feed consumption, and gross appearance. The liver, kidney, heart, lung, spleen, and brain tissues were assessed histologically. Total haemogram was counted by hemocytometry and microhematocrit reader. Bone marrow examination in terms of cellular morphology was done by Wright staining with bone marrow smear. Furthermore, serum biochemical parameters were determined spectrophotometrically. Grossly all treated mice, their investigated tissues, serum biochemical parameters, total haemogram, and bone marrow were normal. At oral doses of 100 and 200 mg/kg ZER-NLC there was no sign of toxicity or mortality in BALB/c mice. This study suggests that the 50% lethal dose (LD50) of ZER-NLC is higher than 200 mg/kg, thus, safe by oral administration. PMID:25276798

Acute toxicity study of zerumbone-loaded nanostructured lipid carrier on BALB/c mice model.

PubMed

Rahman, Heshu Sulaiman; Rasedee, Abdullah; Othman, Hemn Hassan; Chartrand, Max Stanley; Namvar, Farideh; Yeap, Swee Keong; Abdul Samad, Nozlena; Andas, Reena Joys; Muhammad Nadzri, Nabilah; Anasamy, Theebaa; Ng, Kuan Beng; How, Chee Wun

2014-01-01

Zerumbone- (ZER-) loaded nanostructure lipid carrier (NLC) (ZER-NLC) prepared for its antileukemia effect in vitro was evaluated for its toxicological effects by observing changes in the liver, kidney, spleen, lung, heart, and brain tissues, serum biochemical parameters, total haemogram, and bone marrow stem cells. The acute toxicity study for ZER-NLC was conducted by orally treating BALB/c mice with a single dose with either water, olive oil, ZER, NLC, or ZER-NLC for 14 days. The animals were observed for clinical and behavioral abnormalities, toxicological symptoms, feed consumption, and gross appearance. The liver, kidney, heart, lung, spleen, and brain tissues were assessed histologically. Total haemogram was counted by hemocytometry and microhematocrit reader. Bone marrow examination in terms of cellular morphology was done by Wright staining with bone marrow smear. Furthermore, serum biochemical parameters were determined spectrophotometrically. Grossly all treated mice, their investigated tissues, serum biochemical parameters, total haemogram, and bone marrow were normal. At oral doses of 100 and 200 mg/kg ZER-NLC there was no sign of toxicity or mortality in BALB/c mice. This study suggests that the 50% lethal dose (LD50) of ZER-NLC is higher than 200 mg/kg, thus, safe by oral administration.

A Web-Based System for Bayesian Benchmark Dose Estimation.

PubMed

Shao, Kan; Shapiro, Andrew J

2018-01-11

Benchmark dose (BMD) modeling is an important step in human health risk assessment and is used as the default approach to identify the point of departure for risk assessment. A probabilistic framework for dose-response assessment has been proposed and advocated by various institutions and organizations; therefore, a reliable tool is needed to provide distributional estimates for BMD and other important quantities in dose-response assessment. We developed an online system for Bayesian BMD (BBMD) estimation and compared results from this software with U.S. Environmental Protection Agency's (EPA's) Benchmark Dose Software (BMDS). The system is built on a Bayesian framework featuring the application of Markov chain Monte Carlo (MCMC) sampling for model parameter estimation and BMD calculation, which makes the BBMD system fundamentally different from the currently prevailing BMD software packages. In addition to estimating the traditional BMDs for dichotomous and continuous data, the developed system is also capable of computing model-averaged BMD estimates. A total of 518 dichotomous and 108 continuous data sets extracted from the U.S. EPA's Integrated Risk Information System (IRIS) database (and similar databases) were used as testing data to compare the estimates from the BBMD and BMDS programs. The results suggest that the BBMD system may outperform the BMDS program in a number of aspects, including fewer failed BMD and BMDL calculations and estimates. The BBMD system is a useful alternative tool for estimating BMD with additional functionalities for BMD analysis based on most recent research. Most importantly, the BBMD has the potential to incorporate prior information to make dose-response modeling more reliable and can provide distributional estimates for important quantities in dose-response assessment, which greatly facilitates the current trend for probabilistic risk assessment. https://doi.org/10.1289/EHP1289.

Pharmacokinetics, microbial response, and pulmonary outcomes of multidose intravenous azithromycin in preterm infants at risk for Ureaplasma respiratory colonization.

PubMed

Merchan, L Marcela; Hassan, Hazem E; Terrin, Michael L; Waites, Ken B; Kaufman, David A; Ambalavanan, Namasivayam; Donohue, Pamela; Dulkerian, Susan J; Schelonka, Robert; Magder, Laurence S; Shukla, Sagar; Eddington, Natalie D; Viscardi, Rose M

2015-01-01

The study objectives were to refine the population pharmacokinetics (PK) model, determine microbial clearance, and assess short-term pulmonary outcomes of multiple-dose azithromycin treatment in preterm infants at risk for Ureaplasma respiratory colonization. Fifteen subjects (7 of whom were Ureaplasma positive) received intravenous azithromycin at 20 mg/kg of body weight every 24 h for 3 doses. Azithromycin concentrations were determined in plasma samples obtained up to 168 h post-first dose by using a validated liquid chromatography-tandem mass spectrometry method. Respiratory samples were obtained predose and at three time points post-last dose for Ureaplasma culture, PCR, antibiotic susceptibility testing, and cytokine concentration determinations. Pharmacokinetic data from these 15 subjects as well as 25 additional subjects (who received either a single 10-mg/kg dose [n = 12] or a single 20-mg/kg dose [n = 13]) were analyzed by using a nonlinear mixed-effect population modeling (NONMEM) approach. Pulmonary outcomes were assessed at 36 weeks post-menstrual age and 6 months adjusted age. A 2-compartment model with all PK parameters allometrically scaled on body weight best described the azithromycin pharmacokinetics in preterm neonates. The population pharmacokinetics parameter estimates for clearance, central volume of distribution, intercompartmental clearance, and peripheral volume of distribution were 0.15 liters/h · kg(0.75), 1.88 liters · kg, 1.79 liters/h · kg(0.75), and 13 liters · kg, respectively. The estimated area under the concentration-time curve over 24 h (AUC24)/MIC90 value was ∼ 4 h. All posttreatment cultures were negative, and there were no drug-related adverse events. One Ureaplasma-positive infant died at 4 months of age, but no survivors were hospitalized for respiratory etiologies during the first 6 months (adjusted age). Thus, a 3-day course of 20 mg/kg/day intravenous azithromycin shows preliminary efficacy in eradicating Ureaplasma spp. from the preterm respiratory tract. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

SU-F-BRD-08: A Novel Technique to Derive a Clinically-Acceptable Beam Model for Proton Pencil-Beam Scanning in a Commercial Treatment Planning System

DOE Office of Scientific and Technical Information (OSTI.GOV)

Scholey, J. E.; Lin, L.; Ainsley, C. G.

2015-06-15

Purpose: To evaluate the accuracy and limitations of a commercially-available treatment planning system’s (TPS’s) dose calculation algorithm for proton pencil-beam scanning (PBS) and present a novel technique to efficiently derive a clinically-acceptable beam model. Methods: In-air fluence profiles of PBS spots were modeled in the TPS alternately as single-(SG) and double-Gaussian (DG) functions, based on fits to commissioning data. Uniform-fluence, single-energy-layer square fields of various sizes and energies were calculated with both beam models and delivered to water. Dose was measured at several depths. Motivated by observed discrepancies in measured-versus-calculated dose comparisons, a third model was constructed based on double-Gaussianmore » parameters contrived through a novel technique developed to minimize these differences (DGC). Eleven cuboid-dose-distribution-shaped fields with varying range/modulation and field size were subsequently generated in the TPS, using each of the three beam models described, and delivered to water. Dose was measured at the middle of each spread-out Bragg peak. Results: For energies <160 MeV, the DG model fit square-field measurements to <2% at all depths, while the SG model could disagree by >6%. For energies >160 MeV, both SG and DG models fit square-field measurements to <1% at <4 cm depth, but could exceed 6% deeper. By comparison, disagreement with the DGC model was always <3%. For the cuboid plans, calculation-versus-measured percent dose differences exceeded 7% for the SG model, being larger for smaller fields. The DG model showed <3% disagreement for all field sizes in shorter-range beams, although >5% differences for smaller fields persisted in longer-range beams. In contrast, the DGC model predicted measurements to <2% for all beams. Conclusion: Neither the TPS’s SG nor DG models, employed as intended, are ideally suited for routine clinical use. However, via a novel technique to be presented, its DG model can be tuned judiciously to yield acceptable results.« less

Pharmacokinetic analysis of flomoxef in children undergoing cardiopulmonary bypass and modified ultrafiltration.

PubMed

Masuda, Zenichi; Kurosaki, Yuji; Ishino, Kozo; Yamauchi, Keita; Sano, Shunji

2008-04-01

Cardiopulmonary bypass (CPB) induces changes in the pharmacokinetics of drugs. The purpose of this study was to model the pharmacokinetics of flomoxef, a cephalosporin antibiotic, in pediatric cardiac surgery. Each patient received a flomoxef dose of 30 mg/kg as a bolus after the induction of anesthesia and an additional dose (1 g for a child weighing < 10 kg, 2 g for > or = 10 kg) was injected into the CPB prime. Modified ultrafiltration (MUF) was routinely performed. Blood samples, urine, and ultrafiltrate were collected. In seven patients (group I), serum flomoxef concentration-time courses were analyzed by a modified two-compartment model. Utilizing the estimated parameters, serum concentrations were simulated in another eight patients (group II). The initiation of CPB resulted in an abrupt increase in serum flomoxef concentrations in group I; however, concentrations declined biexponentially. The amount of excreted flomoxef in the urine and by MUF was 47% +/- 8% of the total administered dose. In group II, an excellent fit was found between the values calculated by the program and the observed serum concentrations expressed; most of the performance errors were <1.0. There was no difference in any kinetic parameter between group I and groups I + II (n = 15). The pharmacokinetics of flomoxef in children undergoing CPB and MUF were well fitted to a modified two-compartment model. Using the kinetic data from this study, the individualization of dosage regimens for prophylactic use of flomoxef might be possible.

A new model for volume recombination in plane-parallel chambers in pulsed fields of high dose-per-pulse

NASA Astrophysics Data System (ADS)

Gotz, M.; Karsch, L.; Pawelke, J.

2017-11-01

In order to describe the volume recombination in a pulsed radiation field of high dose-per-pulse this study presents a numerical solution of a 1D transport model of the liberated charges in a plane-parallel ionization chamber. In addition, measurements were performed on an Advanced Markus ionization chamber in a pulsed electron beam to obtain suitable data to test the calculation. The experiment used radiation pulses of 4 μs duration and variable dose-per-pulse values up to about 1 Gy, as well as pulses of variable duration up to 308 μs at constant dose-per-pulse values between 85 mGy and 400 mGy. Those experimental data were compared to the developed numerical model and existing descriptions of volume recombination. At low collection voltages the observed dose-per-pulse dependence of volume recombination can be approximated by the existing theory using effective parameters. However, at high collection voltages large discrepancies are observed. The developed numerical model shows much better agreement with the observations and is able to replicate the observed behavior over the entire range of dose-per-pulse values and collection voltages. Using the developed numerical model, the differences between observation and existing theory are shown to be the result of a large fraction of the charge being collected as free electrons and the resultant distortion of the electric field inside the chamber. Furthermore, the numerical solution is able to calculate recombination losses for arbitrary pulse durations in good agreement with the experimental data, an aspect not covered by current theory. Overall, the presented numerical solution of the charge transport model should provide a more flexible tool to describe volume recombination for high dose-per-pulse values as well as for arbitrary pulse durations and repetition rates.