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.

Clinical response and symptomatic remission in short- and long-term trials of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder.

PubMed

Mattingly, Greg W; Weisler, Richard H; Young, Joel; Adeyi, Ben; Dirks, Bryan; Babcock, Thomas; Lasser, Robert; Scheckner, Brian; Goodman, David W

2013-01-29

Despite the overall high degree of response to pharmacotherapy, consensus is lacking on how to judge clinical response or define optimal treatment/remission when treating adults with attention-deficit/hyperactivity disorder (ADHD). This study examined clinical response and symptomatic remission in analyses of 2 studies of lisdexamfetamine dimesylate (LDX) in adults with ADHD. In a 4-week, double-blind, forced-dose trial, adults with ADHD were randomized to LDX 30, 50, and 70 mg/day (mg/d) or placebo. In a second, open-label, follow-up trial, adults entering from the 4-week study were titrated to an "optimal" LDX dose (30 mg/d [n=44], 50 mg/d [n=112], and 70 mg/d [n=171]) over 4 weeks, and maintained for 11 additional months. The ADHD Rating Scale IV (ADHD-RS-IV) with adult prompts and the Clinical Global Impressions-Improvement (CGI-I) scale assessed efficacy. Clinical response was defined, post hoc, as ≥30% reduction from baseline in ADHD-RS-IV and CGI-I rating of 1 or 2; symptomatic remission was defined as ADHD-RS-IV total score ≤18. Log rank analysis examined overall significance among the treatment groups in time to response or remission. Four hundred and fourteen participants in the 4-week study and 345 in the open-label, extension study were included in the efficacy populations. All LDX groups improved by ADHD-RS-IV and CGI-I scores in both studies. In the 4-week study (n=414), 69.3% responded and 45.5% achieved remission with LDX (all doses); 37.1% responded and 16.1% achieved remission with placebo; time (95% CI) to median clinical response (all LDX doses) was 15.0 (15.0, 17.0) days and to remission was 31.0 (28.0, 37.0) days (P<.0001 overall). In the open-label study, with LDX (all doses), 313 (95.7%) and 278 (85.0%) of 327 participants with evaluable maintenance-phase data met criteria for response and remission, respectively. Of participants who completed dose optimization, 75.2% remained responders and 65.7% remained in remission in the 12-month study. Overall, 285 (82.6%) and 227 (65.8%) of 345 participants were responders and remitters, respectively, at their final visits. In the long-term study, with open-label, dose-optimized LDX treatment, most adults with ADHD achieved clinical response and/or symptomatic remission; almost two-thirds maintained symptomatic remission over the remaining 11 months. Clinical Trial Numbers: NCT00334880 and NCT01070394CLINICAL TRIAL REGISTRY: clinicaltrials.gov.

Seeking Beta: Experimental Considerations and Theoretical Implications Regarding the Detection of Curvature in Dose-Response Relationships for Chromosome Aberrations.

PubMed

Shuryak, Igor; Loucas, Bradford D; Cornforth, Michael N

2017-01-01

The concept of curvature in dose-response relationships figures prominently in radiation biology, encompassing a wide range of interests including radiation protection, radiotherapy and fundamental models of radiation action. In this context, the ability to detect even small amounts of curvature becomes important. Standard (ST) statistical approaches used for this purpose typically involve least-squares regression, followed by a test on sums of squares. Because we have found that these methods are not particularly robust, we investigated an alternative information theoretic (IT) approach, which involves Poisson regression followed by information-theoretic model selection. Our first objective was to compare the performances of the ST and IT methods by using them to analyze mFISH data on gamma-ray-induced simple interchanges in human lymphocytes, and on Monte Carlo simulated data. Real and simulated data sets that contained small-to-moderate curvature were deliberately selected for this exercise. The IT method tended to detect curvature with higher confidence than the ST method. The finding of curvature in the dose response for true simple interchanges is discussed in the context of fundamental models of radiation action. Our second objective was to optimize the design of experiments aimed specifically at detecting curvature. We used Monte Carlo simulation to investigate the following parameters. Constrained by available resources (i.e., the total number of cells to be scored) these include: the optimal number of dose points to use; the best way to apportion the total number of cells among these dose points; and the spacing of dose intervals. Counterintuitively, our simulation results suggest that 4-5 radiation doses were typically optimal, whereas adding more dose points may actually prove detrimental. Superior results were also obtained by implementing unequal dose spacing and unequal distributions in the number of cells scored at each dose.

Dose requirements of alfentanil to eliminate autonomic responses during rapid-sequence induction with thiopental 4 mg/kg and rocuronium 0.6 mg/kg.

PubMed

Abou-Arab, Mohammad H; Rostrup, Morten; Heier, Tom

2016-12-01

Opioids are integral part of anesthesia induction, but information on optimal dosing is limited. We aimed to determine doses of alfentanil needed to eliminate increases in 5 autonomic response variables (plasma concentrations of epinephrine, norepinephrine and vasopressin, arterial blood pressure [ABP], and heart rate) during rapid-sequence induction of anesthesia with thiopental 4 mg/kg and rocuronium 0.6 mg/kg. Prospective, randomized, observer-blinded, interventional clinical study. Large academic institution. Eighty-four healthy patients, aged 18 to 55 years, received 1 of 7 assessor-blinded doses of alfentanil (0, 10, 20, 30, 40, 50, and 60 μg/kg) together with thiopental 4 mg/kg and rocuronium 0.6 mg/kg, administered in rapid succession (15 seconds). Laryngoscopy was initiated 40 seconds after rocuronium, and tracheal intubation was concluded within 15 seconds thereafter. An indwelling radial artery catheter was used for hemodynamic monitoring and blood sampling. Relationships between alfentanil dose and response variables were tested with linear regression, and the influence of covariates (sex, body weight, and age) was determined. Alfentanil dose needed to prevent increases in ABP >10% above baseline with 95% probability was estimated with logistic regression. Significant relationships were determined between alfentanil dose and response variables. Clinically interesting influence of covariates was not found. Alfentanil 55 μg/kg was needed to prevent increases in ABP postintubation >10% above baseline with 95% probability. One individual needed a bolus of vasopressor postintubation. Optimal control of autonomic responses during rapid-sequence induction was achieved with clinically relevant doses of alfentanil in healthy patients anesthetized with thiopental 4 mg/kg and rocuronium 0.6 mg/kg. Copyright © 2016 Elsevier Inc. All rights reserved.

Optimal allocation of the limited oral cholera vaccine supply between endemic and epidemic settings.

PubMed

Moore, Sean M; Lessler, Justin

2015-10-06

The World Health Organization (WHO) recently established a global stockpile of oral cholera vaccine (OCV) to be preferentially used in epidemic response (reactive campaigns) with any vaccine remaining after 1 year allocated to endemic settings. Hence, the number of cholera cases or deaths prevented in an endemic setting represents the minimum utility of these doses, and the optimal risk-averse response to any reactive vaccination request (i.e. the minimax strategy) is one that allocates the remaining doses between the requested epidemic response and endemic use in order to ensure that at least this minimum utility is achieved. Using mathematical models, we find that the best minimax strategy is to allocate the majority of doses to reactive campaigns, unless the request came late in the targeted epidemic. As vaccine supplies dwindle, the case for reactive use of the remaining doses grows stronger. Our analysis provides a lower bound for the amount of OCV to keep in reserve when responding to any request. These results provide a strategic context for the fulfilment of requests to the stockpile, and define allocation strategies that minimize the number of OCV doses that are allocated to suboptimal situations. © 2015 The Authors.

TU-D-201-07: Severity Indication in High Dose Rate Brachytherapy Emergency Response Procedure

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

Li, K; Rustad, F

Purpose: Understanding the corresponding dose to different staff during the High Dose Rate (HDR) Brachytherapy emergency response procedure could help to develop a strategy in efficiency and effective action. In this study, the variation and risk analysis methodology was developed to simulation the HDR emergency response procedure based on severity indicator. Methods: A GammaMedplus iX HDR unit from Varian Medical System was used for this simulation. The emergency response procedure was decomposed based on risk management methods. Severity indexes were used to identify the impact of a risk occurrence on the step including dose to patient and dose to operationmore » staff by varying the time, HDR source activity, distance from the source to patient and staff and the actions. These actions in 7 steps were to press the interrupt button, press emergency shutoff switch, press emergency button on the afterloader keypad, turn emergency hand-crank, remove applicator from the patient, disconnect transfer tube and move afterloader from the patient, and execute emergency surgical recovery. Results: Given the accumulated time in second at the assumed 7 steps were 15, 5, 30, 15, 180, 120, 1800, and the dose rate of HDR source is 10 Ci, the accumulated dose in cGy to patient at 1cm distance were 188, 250, 625, 813, 3063, 4563 and 27063, and the accumulated exposure in rem to operator at outside the vault, 1m and 10cm distance were 0.0, 0.0, 0.1, 0.1, 22.6, 37.6 and 262.6. The variation was determined by the operators in action at different time and distance from the HDR source. Conclusion: The time and dose were estimated for a HDR unit emergency response procedure. It provided information in making optimal decision during the emergency procedure. Further investigation would be to optimize and standardize the responses for other emergency procedure by time-spatial-dose severity function.« less

Optimization of composite coagulant made from polyferric chloride and tapioca starch in landfill leachate treatment

NASA Astrophysics Data System (ADS)

Shaylinda, M. Z. N.; Hamidi, A. A.; Mohd, N. A.; Ariffin, A.; Irvan, D.; Hazreek, Z. A. M.; Nizam, Z. M.

2018-04-01

In this research, the performance of polyferric chloride and tapioca flour as composite coagulants for partially stabilized leachate was investigated. Response surface methodology (RSM) was used to optimize the coagulation and flocculation process of partially stabilized leachate. Central composite design a standard design tool in RSM was applied to evaluate the interactions and effects of dose and pH. Dose 0.2 g/L Fe and pH 4.71 were the optimum value suggested by RSM. Experimental test based on the optimum condition, resulted in 95.9%, 94.6% and 50.4% of SS, color and COD removals, respectively. The percentage difference recorded between experimental and model responses was <5%. Therefore, it can be concluded that RSM was an appropriate optimization tool for coagulation and flocculation process.

An optimized computational method for determining the beta dose distribution using a multiple-element thermoluminescent dosimeter system.

PubMed

Shen, L; Levine, S H; Catchen, G L

1987-07-01

This paper describes an optimization method for determining the beta dose distribution in tissue, and it describes the associated testing and verification. The method uses electron transport theory and optimization techniques to analyze the responses of a three-element thermoluminescent dosimeter (TLD) system. Specifically, the method determines the effective beta energy distribution incident on the dosimeter system, and thus the system performs as a beta spectrometer. Electron transport theory provides the mathematical model for performing the optimization calculation. In this calculation, parameters are determined that produce calculated doses for each of the chip/absorber components in the three-element TLD system. The resulting optimized parameters describe an effective incident beta distribution. This method can be used to determine the beta dose specifically at 7 mg X cm-2 or at any depth of interest. The doses at 7 mg X cm-2 in tissue determined by this method are compared to those experimentally determined using an extrapolation chamber. For a great variety of pure beta sources having different incident beta energy distributions, good agreement is found. The results are also compared to those produced by a commonly used empirical algorithm. Although the optimization method produces somewhat better results, the advantage of the optimization method is that its performance is not sensitive to the specific method of calibration.

TU-AB-303-01: A Feasibility Study for Dynamic Adaptive Therapy of Non-Small Cell Lung Cancer

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

Kim, M; Phillips, M

2015-06-15

Purpose: To compare plans for NSCLC optimized using Dynamic Adaptive Therapy (DAT) with conventional IMRT optimization. DAT adapts plans based on changes in the target volume by using dynamic programing techniques to consider expected changes into the optimization process. Information gathered during treatment, e.g. from CBCT, is incorporated into the optimization. Methods and materials: DAT is formulated using stochastic control formalism, which minimizes the total expected number of tumor cells at the end of a treatment course subject to uncertainty inherent in the tumor response and organs-at-risk (OAR) dose constraints. This formulation allows for non-stationary dose distribution as well asmore » non-stationary fractional dose as needed to achieve a series of optimal plans that are conformal to tumor over time. Sixteen phantom cases with various sizes and locations of tumors, and OAR geometries were generated. Each case was planned with DAT and conventional IMRT (60Gy/30fx). Tumor volume change over time was obtained by using, daily MVCT-based, two-level cell population model. Monte Carlo simulations have been performed for each treatment course to account for uncertainty in tumor response. Same OAR dose constraints were applied for both methods. The frequency of plan modification was varied to 1, 2, 5 (weekly), and 29 (daily). The final average tumor dose and OAR doses have been compared to quantify the potential benefit of DAT. Results: The average tumor max, min, mean, and D95 resulted from DAT were 124.0–125.2%, 102.1–114.7%, 113.7–123.4%, and 102.0–115.9% (range dependent on the frequency of plan modification) of those from conventional IMRT. Cord max, esophagus max, lung mean, heart mean, and unspecified tissue D05 resulted from AT were 84–102.4%, 99.8–106.9%, 66.9–85.6%, 58.2–78.8%, and 85.2–94.0% of those from conventional IMRT. Conclusions: Significant tumor dose increase and OAR dose reduction, especially with parallel OAR with mean or dose-volume constraints, can be achieved using DAT.« 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.

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.

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose.

PubMed

Lever, Melissa; Lim, Hong-Sheng; Kruger, Philipp; Nguyen, John; Trendel, Nicola; Abu-Shah, Enas; Maini, Philip Kumar; van der Merwe, Philip Anton; Dushek, Omer

2016-10-25

T cells must respond differently to antigens of varying affinity presented at different doses. Previous attempts to map peptide MHC (pMHC) affinity onto T-cell responses have produced inconsistent patterns of responses, preventing formulations of canonical models of T-cell signaling. Here, a systematic analysis of T-cell responses to 1 million-fold variations in both pMHC affinity and dose produced bell-shaped dose-response curves and different optimal pMHC affinities at different pMHC doses. Using sequential model rejection/identification algorithms, we identified a unique, minimal model of cellular signaling incorporating kinetic proofreading with limited signaling coupled to an incoherent feed-forward loop (KPL-IFF) that reproduces these observations. We show that the KPL-IFF model correctly predicts the T-cell response to antigen copresentation. Our work offers a general approach for studying cellular signaling that does not require full details of biochemical pathways.

Multiparameter optimization of mammography: an update

NASA Astrophysics Data System (ADS)

Jafroudi, Hamid; Muntz, E. P.; Jennings, Robert J.

1994-05-01

Previously in this forum we have reported the application of multiparameter optimization techniques to the design of a minimum dose mammography system. The approach used a reference system to define the physical imaging performance required and the dose to which the dose for the optimized system should be compared. During the course of implementing the resulting design in hardware suitable for laboratory testing, the state of the art in mammographic imaging changed, so that the original reference system, which did not have a grid, was no longer appropriate. A reference system with a grid was selected in response to this change, and at the same time the optimization procedure was modified, to make it more general and to facilitate study of the optimized design under a variety of conditions. We report the changes in the procedure, and the results obtained using the revised procedure and the up- to-date reference system. Our results, which are supported by laboratory measurements, indicate that the optimized design can image small objects as well as the reference system using only about 30% of the dose required by the reference system. Hardware meeting the specification produced by the optimization procedure and suitable for clinical use is currently under evaluation in the Diagnostic Radiology Department at the Clinical Center, NH.

A randomized, double-blind, dose-finding Phase II study to evaluate immunogenicity and safety of the third generation smallpox vaccine candidate IMVAMUNE®

PubMed Central

von Krempelhuber, Alfred; Vollmar, Jens; Pokorny, Rolf; Rapp, Petra; Wulff, Niels; Petzold, Barbara; Handley, Amanda; Mateo, Lyn; Siersbol, Henriette; Kollaritsch, Herwig; Chaplin, Paul

2009-01-01

IMVAMUNE® is a Modified Vaccinia Ankara-based virus that is being developed as a safer 3rd generation smallpox vaccine. In order to determine the optimal dose for further development, a double-blind, randomized Phase II trial was performed testing three different doses of IMVAMUNE® in 164 healthy volunteers. All three IMVAMUNE® doses displayed a favourable safety profile, with local reactions as the most frequent observation. The 1×108 TCID50 IMVAMUNE® dose induced a total antibody response in 94% of the subjects following the first vaccination and the highest peak seroconversion rates by ELISA (100%) and PRNT (71%). This IMVAMUNE® dose was considered to be optimal for the further clinical development of this highly attenuated poxvirus as a safer smallpox vaccine. PMID:19944151

Immune suppression with supraoptimal doses of antigen in contact sensitivity. I. Demonstration of suppressor cells and their sensitivity to cyclophosphamide.

PubMed

Sy, M S; Miller, S D; Claman, H N

1977-07-01

Immunologic suppression was induced in a mouse model of contact sensitization to DNFB by using supraoptimal doses of antigen. In these studies, in vivo measurement of ear swelling as an indication of immunologic responsiveness correlated well with measurement of in vitro antigen-induced cell proliferation. This unresponsiveness was specific, since supraoptimal doses of DNFB did not interfere with the development of contact sensitivity to another contactant, oxazolone. The decrease in responsiveness is a form of active suppression, as lymphoid cells from supraoptimally sensitized donors transferred suppression to normal recipients. Furthermore, pretreatment with cyclophosphamide (Cy) reversed the suppression seen in supraoptimally sensitized animals but had no effect on the optimal sensitization regimen. These results indicate that supraoptimal doses of contactants can activate suppressor cells and that precursors of these cells are sensitive to Cy. Such suppressors regenerate within 7 to 14 days after Cy treatment. The ability of Cy pretreatment to affect supraoptimal sensitization without affecting optimal sensitization confirms other reports indicating that the observed results of Cy treatment depend critically upon the dose of antigen used.

Quantitative structure - mesothelioma Potency Model Optimization for Complex Mixtures of Elongated Particles in Rat Pleura

EPA Science Inventory

Cancer potencies of mineral and synthetic elongated particle (EP) mixtures, including fibers from asbestos, are influenced by changes in fiber dose composition, bioavailability and biodurability in combination with relevant cytotoxic dose-response relationships. A unique and com...

The frequency of U-shaped dose responses in the toxicological literature.

PubMed

Calabrese, E J; Baldwin, L A

2001-08-01

Hormesis has been defined as a dose-response relationship in which there is a stimulatory response at low doses, but an inhibitory response at high doses, resulting in a U- or inverted U-shaped dose response. To assess the proportion of studies satisfying criteria for evidence of hormesis, a database was created from published toxicological literature using rigorous a priori entry and evaluative criteria. One percent (195 out of 20,285) of the published articles contained 668 dose-response relationships that met the entry criteria. Subsequent application of evaluative criteria revealed that 245 (37% of 668) dose-response relationships from 86 articles (0.4% of 20,285) satisfied requirements for evidence of hormesis. Quantitative evaluation of false-positive and false-negative responses indicated that the data were not very susceptible to such influences. A complementary analysis of all dose responses assessed by hypothesis testing or distributional analyses, where the units of comparison were treatment doses below the NOAEL, revealed that of 1089 doses below the NOAEL, 213 (19.5%) satisfied statistical significance or distributional data evaluative criteria for hormesis, 869 (80%) did not differ from the control, and 7 (0.6%) displayed evidence of false-positive values. The 32.5-fold (19.5% vs 0.6%) greater occurrence of hormetic responses than a response of similar magnitude in the opposite (negative) direction strongly supports the nonrandom nature of hormetic responses. This study, which provides the first documentation of a data-derived frequency of hormetic responses in the toxicologically oriented literature, indicates that when the study design satisfies a priori criteria (i.e., a well-defined NOAEL, > or = 2 doses below the NOAEL, and the end point measured has the capacity to display either stimulatory or inhibitory responses), hormesis is frequently encountered and is broadly represented according to agent, model, and end point. These findings have broad-based implications for study design, risk assessment methods, and the establishment of optimal drug doses and suggest important evolutionarily adaptive strategies for dose-response relationships.

Quantitative structure - mesothelioma potency model optimization for complex mixtures of elongated particles in rat pleura: A retrospective study

EPA Science Inventory

Cancer potencies of mineral and synthetic elongated particle (EP) mixtures, including asbestos fibers, are influenced by changes in fiber dose composition, bioavailability, and biodurability in combination with relevant cytotoxic dose-response relationships. A unique and compreh...

The dose-response of salvage radiotherapy following radical prostatectomy: A systematic review and meta-analysis.

PubMed

King, Christopher R

2016-11-01

To date neither the optimal radiotherapy dose nor the existence of a dose-response has been established for salvage RT (SRT). A systematic review from 1996 to 2015 and meta-analysis was performed to identify the pathologic, clinical and treatment factors associated with relapse-free survival (RFS) after SRT (uniformly defined as a PSA>0.2ng/mL or rising above post-SRT nadir). A sigmoidal dose-response curve was objectively fitted and a non-parametric statistical test used to determine significance. 71 studies (10,034 patients) satisfied the meta-analysis criteria. SRT dose (p=0.0001), PSA prior to SRT (p=0.0009), ECE+ (p=0.039) and SV+ (p=0.046) had significant associations with RFS. Statistical analyses confirmed the independence of SRT dose-response. Omission of series with ADT did not alter results. Dose-response is well fit by a sigmoidal curve (p=0.0001) with a TCD 50 of 65.8Gy, with a dose of 70Gy achieving 58.4% RFS vs. 38.5% for 60Gy. A 2.0% [95% CI 1.1-3.2] improvement in RFS is achieved for each Gy. The SRT dose-response remarkably parallels that for definitive RT of localized disease. This study provides level 2a evidence for dose-escalated SRT>70Gy. The presence of an SRT dose-response for microscopic disease supports the hypothesis that prostate cancer is inherently radio-resistant. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A swinging seesaw as a novel model mechanism for time-dependent hormesis under dose-dependent stimulatory and inhibitory effects: A case study on the toxicity of antibacterial chemicals to Aliivibrio fischeri.

PubMed

Sun, Haoyu; Calabrese, Edward J; Zheng, Min; Wang, Dali; Pan, Yongzheng; Lin, Zhifen; Liu, Ying

2018-08-01

Hormesis occurs frequently in broadly ranging biological areas (e.g. plant biology, microbiology, biogerontology), toxicology, pharmacology and medicine. While numerous mechanisms (e.g. receptor and pathway mediated pathway responses) account for stimulatory and inhibitory features of hormetic dose responses, the vast majority emphasizes the inclusion of many doses but only one timepoint or use of a single optimized dose that is assessed over a broad range of timepoints. In this paper, a toxicity study was designed using a large number of properly spaced doses with responses determined over a large number of timepoints, which could help us reveal the underlying mechanism of hormesis. We present the results of a dose-time-response study on hormesis using five antibacterial chemicals on the bioluminescence of Aliivibrio fischeri, measuring expression of protein mRNA based on quorum sensing, simulating bioluminescent reaction and analyzing toxic actions of test chemicals. The findings show dose-time-dependent responses conforming to the hormetic dose-response model, while revealing unique response dynamics between agent induced stimulatory and inhibitory effects within bacterial growth phase dynamics. These dynamic dose-time features reveal a type of biological seesaw model that integrates stimulatory and inhibitory responses within unique growth phase, dose and time features, which has faultlessly explained the time-dependent hormetic phenomenon induced by five antibacterial chemicals (characterized by low-dose stimulation and high-dose inhibition). This study offers advances in understanding cellular dynamics, the biological integration of diverse and opposing responses and their role in evolutionary adaptive strategies to chemicals, which can provide new insight into the mechanistic investigation of hormesis. Copyright © 2018 Elsevier Ltd. All rights reserved.

OPTIMIZING THE PRECISION OF TOXICITY THRESHOLD ESTIMATION USING A TWO-STAGE EXPERIMENTAL DESIGN

EPA Science Inventory

An important consideration for risk assessment is the existence of a threshold, i.e., the highest toxicant dose where the response is not distinguishable from background. We have developed methodology for finding an experimental design that optimizes the precision of threshold mo...

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

PubMed Central

Lever, Melissa; Lim, Hong-Sheng; Kruger, Philipp; Nguyen, John; Trendel, Nicola; Abu-Shah, Enas; Maini, Philip Kumar; van der Merwe, Philip Anton

2016-01-01

T cells must respond differently to antigens of varying affinity presented at different doses. Previous attempts to map peptide MHC (pMHC) affinity onto T-cell responses have produced inconsistent patterns of responses, preventing formulations of canonical models of T-cell signaling. Here, a systematic analysis of T-cell responses to 1 million-fold variations in both pMHC affinity and dose produced bell-shaped dose–response curves and different optimal pMHC affinities at different pMHC doses. Using sequential model rejection/identification algorithms, we identified a unique, minimal model of cellular signaling incorporating kinetic proofreading with limited signaling coupled to an incoherent feed-forward loop (KPL-IFF) that reproduces these observations. We show that the KPL-IFF model correctly predicts the T-cell response to antigen copresentation. Our work offers a general approach for studying cellular signaling that does not require full details of biochemical pathways. PMID:27702900

Clinical response and symptomatic remission in short- and long-term trials of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder

PubMed Central

2013-01-01

Background Despite the overall high degree of response to pharmacotherapy, consensus is lacking on how to judge clinical response or define optimal treatment/remission when treating adults with attention-deficit/hyperactivity disorder (ADHD). This study examined clinical response and symptomatic remission in analyses of 2 studies of lisdexamfetamine dimesylate (LDX) in adults with ADHD. Methods In a 4-week, double-blind, forced-dose trial, adults with ADHD were randomized to LDX 30, 50, and 70 mg/day (mg/d) or placebo. In a second, open-label, follow-up trial, adults entering from the 4-week study were titrated to an “optimal” LDX dose (30 mg/d [n=44], 50 mg/d [n=112], and 70 mg/d [n=171]) over 4 weeks, and maintained for 11 additional months. The ADHD Rating Scale IV (ADHD-RS-IV) with adult prompts and the Clinical Global Impressions-Improvement (CGI-I) scale assessed efficacy. Clinical response was defined, post hoc, as ≥30% reduction from baseline in ADHD-RS-IV and CGI-I rating of 1 or 2; symptomatic remission was defined as ADHD-RS-IV total score ≤18. Log rank analysis examined overall significance among the treatment groups in time to response or remission. Results Four hundred and fourteen participants in the 4-week study and 345 in the open-label, extension study were included in the efficacy populations. All LDX groups improved by ADHD-RS-IV and CGI-I scores in both studies. In the 4-week study (n=414), 69.3% responded and 45.5% achieved remission with LDX (all doses); 37.1% responded and 16.1% achieved remission with placebo; time (95% CI) to median clinical response (all LDX doses) was 15.0 (15.0, 17.0) days and to remission was 31.0 (28.0, 37.0) days (P<.0001 overall). In the open-label study, with LDX (all doses), 313 (95.7%) and 278 (85.0%) of 327 participants with evaluable maintenance-phase data met criteria for response and remission, respectively. Of participants who completed dose optimization, 75.2% remained responders and 65.7% remained in remission in the 12-month study. Overall, 285 (82.6%) and 227 (65.8%) of 345 participants were responders and remitters, respectively, at their final visits. Conclusion In the long-term study, with open-label, dose-optimized LDX treatment, most adults with ADHD achieved clinical response and/or symptomatic remission; almost two-thirds maintained symptomatic remission over the remaining 11 months. Trial registration Clinical Trial Numbers: NCT00334880 and NCT01070394 Clinical Trial Registry: clinicaltrials.gov URLs http://www.clinicaltrials.gov/show/NCT00334880 http://www.clinicaltrials.gov/ct2/show/NCT01070394?term=NCT01070394&rank=1 PMID:23356790

Clinical application of a nomogram based on age, serum FSH and AMH to select the FSH starting dose in IVF/ICSI cycles: a retrospective two-centres study.

PubMed

Papaleo, Enrico; Zaffagnini, Stefano; Munaretto, Maria; Vanni, Valeria Stella; Rebonato, Giorgia; Grisendi, Valentina; Di Paola, Rossana; La Marca, Antonio

2016-12-01

To externally validate a nomogram based on ovarian reserve markers as a tool to optimize the FSH starting dose in IVF/ICSI cycles. A two-centres retrospective study including 398 infertile women undergoing their first IVF/ICSI cycle (June 2013-June 2014). IVF data were retrieved from two independent IVF centres in Italy (San Raffaele Hospital, Centre 1; Verona Hospital, Centre 2). A central lab for the routine measurement of AMH and FSH was used for both centres. All women were treated based on physical and hormonal characteristics according to locally adopted protocols. The nomogram was then retrospectively applied to the patients comparing the calculated starting dose to the one actually given. In Centre 1, 64/131 women (48.8%) had an ovarian response below the target. While 45 of these patients were treated with a maximal FSH starting dose (≥225 IU), n=19/131 (14.5%) were treated with a submaximal dose. The vast majority of them (n=17/19) would have received a higher FSH starting dose by using the nomogram. Seventeen patients (n=17/131) had hyper response and about half of them would have been treated with a reduced FSH starting dose according to the nomogram. In Centre 2, 142/267 patients (53.2%) had an ovarian response below the target. While 136 of these were treated with a maximal FSH starting dose (≥225 IU), n=6/267 were treated with a submaximal dose. The majority of them (n=5/6) would have received a higher FSH starting dose. Thirty-two (n=32/267) patients had hyper response and more than half of them would have been treated with a reduced FSH dose. In both Centres, applying the nomogram would have resulted in more appropriate FSH starting doses compared to the the ones actually given based on clinicians choices. The use of an objective algorithm based on patient's age, serum FSH and AMH levels may thus be an effective advice on the selection of the tailored FSH starting dose. Hence, the use of this easily available nomogram could increase the proportion of patients achieving the optimal ovarian response. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Development, Optimization, and Validation of a Microplate Bioassay for Relative Potency Determination of Linezolid Using a Design Space Concept, and its Measurement Uncertainty.

PubMed

Saviano, Alessandro Morais; Francisco, Fabiane Lacerda; Ostronoff, Celina Silva; Lourenço, Felipe Rebello

2015-01-01

The aim of this study was to develop, optimize, and validate a microplate bioassay for relative potency determination of linezolid in pharmaceutical samples using quality-by-design and design space approaches. In addition, a procedure is described for estimating relative potency uncertainty based on microbiological response variability. The influence of culture media composition was studied using a factorial design and a central composite design was adopted to study the influence of inoculum proportion and triphenyltetrazolium chloride in microbial growth. The microplate bioassay was optimized regarding the responses of low, medium, and high doses of linezolid, negative and positive controls, and the slope, intercept, and correlation coefficient of dose-response curves. According to optimization results, design space ranges were established using: (a) low (1.0 μg/mL), medium (2.0 μg/mL), and high (4.0 μg/mL) doses of pharmaceutical samples and linezolid chemical reference substance; (b) Staphylococcus aureus ATCC 653 in an inoculum proportion of 10%; (c) antibiotic No. 3 culture medium pH 7.0±0.1; (d) 6 h incubation at 37.0±0.1ºC; and (e) addition of 50 μL of 0.5% (w/v) triphenyltetrazolium chloride solution. The microplate bioassay was linear (r2=0.992), specific, precise (repeatability RSD=2.3% and intermediate precision RSD=4.3%), accurate (mean recovery=101.4%), and robust. The overall measurement uncertainty was reasonable considering the increased variability inherent in microbiological response. Final uncertainty was comparable with those obtained with other microbiological assays, as well as chemical methods.

Factors associated with the immune response to hepatitis A vaccination in HIV-infected patients in the era of highly active antiretroviral therapy.

PubMed

Mena, Guillermo; García-Basteiro, Alberto L; Llupià, Anna; Díez, Consolación; Costa, Josep; Gatell, Josep-María; García, Felipe; Bayas, José-María

2013-08-12

HIV seropositivity is considered a risk factor for complications in hepatitis A virus (HAV) infection. HAV vaccination schedules are widely implemented in HIV-infected patients, but the immune response remains impaired. We analysed the response to vaccination (antiHAV titres ≥20IU/l) in 282 HIV-infected patients included in a standard (1440 Elisa Units (EU) at 0, 6 months) or rapidly accelerated schedule (720 EU at 0, 7, 21 days and 6 months) between 1997 and 2009. Factors associated with the response to vaccination were analysed using logistic regression. The overall response rate was 73.4%. Male sex (OR: 0.16, 95% CI 0.05-0.51) and hepatitis C virus co-infection (OR: 0.30, 95% CI 0.14-0.74) were associated with a lower probability of response. Protective antibody response was associated with a higher CD4/CD8 ratio (OR: 3.69, 95% CI 1.3-10.5) and having received two doses of standard schedule (compared with patients receiving only one dose of the same schedule) (OR: 2.51, 95% CI 1.22-5.15). Three doses of the rapidly accelerated schedule were not more effective than a single dose of 1440 EU (OR: 1.32, 95% CI 0.48-3.63). The low responses observed in patients receiving a single dose suggest the need to emphasize adhesion to vaccination protocols to avoid failure. The CD4/CD8 ratio may be considered as an immune status marker which could help to better choose the moment of vaccination. Our findings underscore the importance of identifying strategies that optimize the timing and effectiveness of hepatitis A vaccination in HIV-infected patients and of the need for further studies on individual factors such as sex and hepatitis C co-infection that may affect the response to vaccination. Likewise, the sub-optimal effectiveness of three doses of 720 EU in the rapidly accelerated schedule, if confirmed in future studies, might lead to a revision of the current schedule recommended for HIV-infected travellers. Copyright © 2013 Elsevier Ltd. All rights reserved.

Bayesian Dose-Response Modeling in Sparse Data

NASA Astrophysics Data System (ADS)

Kim, Steven B.

This book discusses Bayesian dose-response modeling in small samples applied to two different settings. The first setting is early phase clinical trials, and the second setting is toxicology studies in cancer risk assessment. In early phase clinical trials, experimental units are humans who are actual patients. Prior to a clinical trial, opinions from multiple subject area experts are generally more informative than the opinion of a single expert, but we may face a dilemma when they have disagreeing prior opinions. In this regard, we consider compromising the disagreement and compare two different approaches for making a decision. In addition to combining multiple opinions, we also address balancing two levels of ethics in early phase clinical trials. The first level is individual-level ethics which reflects the perspective of trial participants. The second level is population-level ethics which reflects the perspective of future patients. We extensively compare two existing statistical methods which focus on each perspective and propose a new method which balances the two conflicting perspectives. In toxicology studies, experimental units are living animals. Here we focus on a potential non-monotonic dose-response relationship which is known as hormesis. Briefly, hormesis is a phenomenon which can be characterized by a beneficial effect at low doses and a harmful effect at high doses. In cancer risk assessments, the estimation of a parameter, which is known as a benchmark dose, can be highly sensitive to a class of assumptions, monotonicity or hormesis. In this regard, we propose a robust approach which considers both monotonicity and hormesis as a possibility. In addition, We discuss statistical hypothesis testing for hormesis and consider various experimental designs for detecting hormesis based on Bayesian decision theory. Past experiments have not been optimally designed for testing for hormesis, and some Bayesian optimal designs may not be optimal under a wrong parametric assumption. In this regard, we consider a robust experimental design which does not require any parametric assumption.

Using machine learning to model dose-response relationships.

PubMed

Linden, Ariel; Yarnold, Paul R; Nallamothu, Brahmajee K

2016-12-01

Establishing the relationship between various doses of an exposure and a response variable is integral to many studies in health care. Linear parametric models, widely used for estimating dose-response relationships, have several limitations. This paper employs the optimal discriminant analysis (ODA) machine-learning algorithm to determine the degree to which exposure dose can be distinguished based on the distribution of the response variable. By framing the dose-response relationship as a classification problem, machine learning can provide the same functionality as conventional models, but can additionally make individual-level predictions, which may be helpful in practical applications like establishing responsiveness to prescribed drug regimens. Using data from a study measuring the responses of blood flow in the forearm to the intra-arterial administration of isoproterenol (separately for 9 black and 13 white men, and pooled), we compare the results estimated from a generalized estimating equations (GEE) model with those estimated using ODA. Generalized estimating equations and ODA both identified many statistically significant dose-response relationships, separately by race and for pooled data. Post hoc comparisons between doses indicated ODA (based on exact P values) was consistently more conservative than GEE (based on estimated P values). Compared with ODA, GEE produced twice as many instances of paradoxical confounding (findings from analysis of pooled data that are inconsistent with findings from analyses stratified by race). Given its unique advantages and greater analytic flexibility, maximum-accuracy machine-learning methods like ODA should be considered as the primary analytic approach in dose-response applications. © 2016 John Wiley & Sons, Ltd.

Nanodosimetry-Based Plan Optimization for Particle Therapy

PubMed Central

Schulte, Reinhard W.

2015-01-01

Treatment planning for particle therapy is currently an active field of research due uncertainty in how to modify physical dose in order to create a uniform biological dose response in the target. A novel treatment plan optimization strategy based on measurable nanodosimetric quantities rather than biophysical models is proposed in this work. Simplified proton and carbon treatment plans were simulated in a water phantom to investigate the optimization feasibility. Track structures of the mixed radiation field produced at different depths in the target volume were simulated with Geant4-DNA and nanodosimetric descriptors were calculated. The fluences of the treatment field pencil beams were optimized in order to create a mixed field with equal nanodosimetric descriptors at each of the multiple positions in spread-out particle Bragg peaks. For both proton and carbon ion plans, a uniform spatial distribution of nanodosimetric descriptors could be obtained by optimizing opposing-field but not single-field plans. The results obtained indicate that uniform nanodosimetrically weighted plans, which may also be radiobiologically uniform, can be obtained with this approach. Future investigations need to demonstrate that this approach is also feasible for more complicated beam arrangements and that it leads to biologically uniform response in tumor cells and tissues. PMID:26167202

Low dose intranasal oxytocin delivered with Breath Powered device dampens amygdala response to emotional stimuli: A peripheral effect-controlled within-subjects randomized dose-response fMRI trial.

PubMed

Quintana, Daniel S; Westlye, Lars T; Alnæs, Dag; Rustan, Øyvind G; Kaufmann, Tobias; Smerud, Knut T; Mahmoud, Ramy A; Djupesland, Per G; Andreassen, Ole A

2016-07-01

It is unclear if and how exogenous oxytocin (OT) reaches the brain to improve social behavior and cognition and what is the optimal dose for OT response. To better understand the delivery routes of intranasal OT administration to the brain and the dose-response, we compared amygdala response to facial stimuli by means of functional magnetic resonance imaging (fMRI) in four treatment conditions, including two different doses of intranasal OT using a novel Breath Powered device, intravenous (IV) OT, which provided similar concentrations of blood plasma OT, and placebo. We adopted a randomized, double-blind, double-dummy, crossover design, with 16 healthy male adults administering a single-dose of these four treatments. We observed a treatment effect on right amygdala activation during the processing of angry and happy face stimuli, with pairwise comparisons revealing reduced activation after the 8IU low dose intranasal treatment compared to placebo. These data suggest the dampening of amygdala activity in response to emotional stimuli occurs via direct intranasal delivery pathways rather than across the blood-brain barrier via systemically circulating OT. This trial is registered at the U.S. National Institutes of Health clinical trial registry (www.clinicaltrials.gov; NCT01983514) and as EudraCT no. 2013-001608-12. Copyright © 2016 Elsevier Ltd. All rights reserved.

Proof of concept and dose estimation with binary responses under model uncertainty.

PubMed

Klingenberg, B

2009-01-30

This article suggests a unified framework for testing Proof of Concept (PoC) and estimating a target dose for the benefit of a more comprehensive, robust and powerful analysis in phase II or similar clinical trials. From a pre-specified set of candidate models, we choose the ones that best describe the observed dose-response. To decide which models, if any, significantly pick up a dose effect, we construct the permutation distribution of the minimum P-value over the candidate set. This allows us to find critical values and multiplicity adjusted P-values that control the familywise error rate of declaring any spurious effect in the candidate set as significant. Model averaging is then used to estimate a target dose. Popular single or multiple contrast tests for PoC, such as the Cochran-Armitage, Dunnett or Williams tests, are only optimal for specific dose-response shapes and do not provide target dose estimates with confidence limits. A thorough evaluation and comparison of our approach to these tests reveal that its power is as good or better in detecting a dose-response under various shapes with many more additional benefits: It incorporates model uncertainty in PoC decisions and target dose estimation, yields confidence intervals for target dose estimates and extends to more complicated data structures. We illustrate our method with the analysis of a Phase II clinical trial. Copyright (c) 2008 John Wiley & Sons, Ltd.

Antibody Secreting Cell Responses following Vaccination with Bivalent Oral Cholera Vaccine among Haitian Adults.

PubMed

Matias, Wilfredo R; Falkard, Brie; Charles, Richelle C; Mayo-Smith, Leslie M; Teng, Jessica E; Xu, Peng; Kováč, Pavol; Ryan, Edward T; Qadri, Firdausi; Franke, Molly F; Ivers, Louise C; Harris, Jason B

2016-06-01

The bivalent whole-cell (BivWC) oral cholera vaccine (Shanchol) is effective in preventing cholera. However, evaluations of immune responses following vaccination with BivWC have been limited. To determine whether BivWC induces significant mucosal immune responses, we measured V. cholerae O1 antigen-specific antibody secreting cell (ASC) responses following vaccination. We enrolled 24 Haitian adults in this study, and administered doses of oral BivWC vaccine 14 days apart (day 0 and day 14). We drew blood at baseline, and 7 days following each vaccine dose (day 7 and 21). Peripheral blood mononuclear cells (PBMCs) were isolated, and ASCs were enumerated using an ELISPOT assay. Significant increases in Ogawa (6.9 cells per million PBMCs) and Inaba (9.5 cells per million PBMCs) OSP-specific IgA ASCs were detected 7 days following the first dose (P < 0.001), but not the second dose. The magnitude of V. cholerae-specific ASC responses did not appear to be associated with recent exposure to cholera. ASC responses measured against the whole lipolysaccharide (LPS) antigen and the OSP moiety of LPS were equivalent, suggesting that all or nearly all of the LPS response targets the OSP moiety. Immunization with the BivWC oral cholera vaccine induced ASC responses among a cohort of healthy adults in Haiti after a single dose. The second dose of vaccine resulted in minimal ASC responses over baseline, suggesting that the current dosing schedule may not be optimal for boosting mucosal immune responses to V. cholerae antigens for adults in a cholera-endemic area.

Dashboard systems: Pharmacokinetic/pharmacodynamic mediated dose optimization for monoclonal antibodies.

PubMed

Mould, Diane R; Dubinsky, Marla C

2015-03-01

Many marketed drugs exhibit high variability in exposure and response. While these drugs are efficacious in their approved indications, finding appropriate dose regimens for individual patients is not straightforward. Similar dose adjustment problems are also seen with drugs that have a complex relationship between exposure and response and/or a narrow therapeutic window. This is particularly true for monoclonal antibodies, where prolonged dosing at a sub-therapeutic dose can also elicit anti-drug antibodies which will further compromise safety and efficacy. Thus, finding appropriate doses quickly would represent a substantial improvement in healthcare. Dashboard systems, which are decision-support tools, offer an improved, convenient means of tailoring treatment for individual patients. This article reviews the clinical need for this approach, particularly with monoclonal antibodies, the design, development, and testing of such systems, and the likely benefits of dashboard systems in clinical practice. We focus on infliximab for reference. © 2015, The American College of Clinical Pharmacology.

Use of borated polyethylene to improve low energy response of a prompt gamma based neutron dosimeter

NASA Astrophysics Data System (ADS)

Priyada, P.; Ashwini, U.; Sarkar, P. K.

2016-05-01

The feasibility of using a combined sample of borated polyethylene and normal polyethylene to estimate neutron ambient dose equivalent from measured prompt gamma emissions is investigated theoretically to demonstrate improvements in low energy neutron dose response compared to only polyethylene. Monte Carlo simulations have been carried out using the FLUKA code to calculate the response of boron, hydrogen and carbon prompt gamma emissions to mono energetic neutrons. The weighted least square method is employed to arrive at the best linear combination of these responses that approximates the ICRP fluence to dose conversion coefficients well in the energy range of 10-8 MeV to 14 MeV. The configuration of the combined system is optimized through FLUKA simulations. The proposed method is validated theoretically with five different workplace neutron spectra with satisfactory outcome.

Impact of adherence on the outcome of antiviral therapy for chronic hepatitis C.

PubMed

Mulhall, Brian P; Younossi, Zobair

2005-01-01

Nearly 4 million people in the United States have evidence of hepatitis C infection (HCV), representing a significant cause of cirrhosis and liver cancer as well a major burden to our healthcare systems and society. Antiviral therapy can successfully eradicate HCV over the long term, potentially reducing the risk of progression and improving patients' quality of life. The currently preferred HCV treatment is a combination of pegylated interferon alfa and ribavirin, which can achieve an overall sustained viral eradication rate of 55%. The duration of this treatment is typically determined by HCV genotype and the patient's early virologic response to the antiviral regimen. Evidence has accumulated over the past few years to indicate that close adherence to the optimal antiviral regimen can enhance sustained virologic response. But optimal treatment outcomes require diligence and careful management of side effects related to combination therapy. Although reducing the dose of pegylated interferon alfa, ribavirin, or both can effectively treat side effects, suboptimal doses of this regimen, especially ribavirin, may negatively affect virologic response. An alternative strategy is to use growth factors to treat cytopenias. This strategy can obviate dose reductions while potentially improving patients' quality of life. Patient support seems especially important early after the initiation of antiviral therapy. Encouraging study findings involving the growth factors, epoetin alfa and darbepoetin alfa, suggest improved anemia and quality of life while maintaining the optimal ribavirin dose. Future work should be aimed at providing stronger evidence for the use of these "supportive products" during anti-HCV therapy. As we strive to develop better treatment options for our HCV patients, the importance of adhering to the treatment regimen continues to play a central role. Effective side effect management is crucial for the success of this treatment because adherence is negatively affected by side effects related to the antiviral regimen. By identifying and addressing the important side effects of combination therapy for HCV, adherence to treatment can be improved and optimal outcomes can be achieved.

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

Jeong, J; Deasy, J O

Purpose: Concurrent chemo-radiation therapy (CCRT) has become a more common cancer treatment option with a better tumor control rate for several tumor sites, including head and neck and lung cancer. In this work, possible optimal chemotherapy schedules were investigated by implementing chemotherapy cell-kill into a tumor response model of RT. Methods: The chemotherapy effect has been added into a published model (Jeong et al., PMB (2013) 58:4897), in which the tumor response to RT can be simulated with the effects of hypoxia and proliferation. Based on the two-compartment pharmacokinetic model, the temporal concentration of chemotherapy agent was estimated. Log cell-killmore » was assumed and the cell-kill constant was estimated from the observed increase in local control due to concurrent chemotherapy. For a simplified two cycle CCRT regime, several different starting times and intervals were simulated with conventional RT regime (2Gy/fx, 5fx/wk). The effectiveness of CCRT was evaluated in terms of reduction in radiation dose required for 50% of control to find the optimal chemotherapy schedule. Results: Assuming the typical slope of dose response curve (γ50=2), the observed 10% increase in local control rate was evaluated to be equivalent to an extra RT dose of about 4 Gy, from which the cell-kill rate of chemotherapy was derived to be about 0.35. Best response was obtained when chemotherapy was started at about 3 weeks after RT began. As the interval between two cycles decreases, the efficacy of chemotherapy increases with broader range of optimal starting times. Conclusion: The effect of chemotherapy has been implemented into the resource-conservation tumor response model to investigate CCRT. The results suggest that the concurrent chemotherapy might be more effective when delayed for about 3 weeks, due to lower tumor burden and a larger fraction of proliferating cells after reoxygenation.« less

Prediction of an Optimal Dose of Aripiprazole in the Treatment of Schizophrenia From Plasma Concentrations of Aripiprazole Plus Its Active Metabolite Dehydroaripiprazole at Week 1.

PubMed

Nagai, Goyo; Mihara, Kazuo; Nakamura, Akifumi; Nemoto, Kenji; Kagawa, Shoko; Suzuki, Takeshi; Kondo, Tsuyoshi

2017-02-01

It has been suggested that a plasma trough concentration of aripiprazole plus its active metabolite, dehydroaripiprazole of 225 ng/mL is a threshold for a good therapeutic response in the treatment of acutely exacerbated patients with schizophrenia. The present study investigated whether or not an optimal dose of aripiprazole could be predicted from these concentrations at week 1. The subjects were 26 inpatients with schizophrenia, who received aripiprazole once a day for 3 weeks. The daily doses were 12 mg for the first week and 24 mg for the next 2 weeks. No other drugs except biperiden and flunitrazepam were coadministered. Blood samples were taken at weeks 1 and 3 after the treatment. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass-spectrometric detection. There was a significant linear relationship between the plasma concentrations of aripiprazole plus dehydroaripiprazole at weeks 1 (x) and 3 (y) (P < 0.001). Regression equation was y = 2.580x + 34.86 (R = 0.698). Based on the equation, a nomogram to estimate an optimal dose of aripiprazole could be constructed. The present study suggests that an optimal dose of aripiprazole for the treatment of patients with schizophrenia can be predicted from the plasma concentrations of the sum of the 2 compounds at week 1.

Optimized Dose Distribution of Gammamed Plus Vaginal Cylinders

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

Supe, Sanjay S.; Bijina, T.K.; Varatharaj, C.

2009-04-01

Endometrial carcinoma is the most common malignancy arising in the female genital tract. Intracavitary vaginal cuff irradiation may be given alone or with external beam irradiation in patients determined to be at risk for locoregional recurrence. Vaginal cylinders are often used to deliver a brachytherapy dose to the vaginal apex and upper vagina or the entire vaginal surface in the management of postoperative endometrial cancer or cervical cancer. The dose distributions of HDR vaginal cylinders must be evaluated carefully, so that clinical experiences with LDR techniques can be used in guiding optimal use of HDR techniques. The aim of thismore » study was to optimize dose distribution for Gammamed plus vaginal cylinders. Placement of dose optimization points was evaluated for its effect on optimized dose distributions. Two different dose optimization point models were used in this study, namely non-apex (dose optimization points only on periphery of cylinder) and apex (dose optimization points on periphery and along the curvature including the apex points). Thirteen dwell positions were used for the HDR dosimetry to obtain a 6-cm active length. Thus 13 optimization points were available at the periphery of the cylinder. The coordinates of the points along the curvature depended on the cylinder diameters and were chosen for each cylinder so that four points were distributed evenly in the curvature portion of the cylinder. Diameter of vaginal cylinders varied from 2.0 to 4.0 cm. Iterative optimization routine was utilized for all optimizations. The effects of various optimization routines (iterative, geometric, equal times) was studied for the 3.0-cm diameter vaginal cylinder. The effect of source travel step size on the optimized dose distributions for vaginal cylinders was also evaluated. All optimizations in this study were carried for dose of 6 Gy at dose optimization points. For both non-apex and apex models of vaginal cylinders, doses for apex point and three dome points were higher for the apex model compared with the non-apex model. Mean doses to the optimization points for both the cylinder models and all the cylinder diameters were 6 Gy, matching with the prescription dose of 6 Gy. Iterative optimization routine resulted in the highest dose to apex point and dome points. The mean dose for optimization point was 6.01 Gy for iterative optimization and was much higher than 5.74 Gy for geometric and equal times routines. Step size of 1 cm gave the highest dose to the apex point. This step size was superior in terms of mean dose to optimization points. Selection of dose optimization points for the derivation of optimized dose distributions for vaginal cylinders affects the dose distributions.« less

Photothermal monitoring of interaction of carcinoma cells with cytostatic drugs in vitro

NASA Astrophysics Data System (ADS)

Lapotko, Dmitri; Hanna, Ehab; Cannon, Martin

2003-06-01

Background/problem. Monitoring of tumor response to cancer chemotherapy and dose optimization for specific patients are the key factors for successful application of anti-tumor drugs. Using patient's tumor cells for preliminary in vitro drug screening may allow optimal selection of drug type and dose. Method. Single cell state was studied with photothermal microscope. Carcinoma cells were irradiated at 427 nm with 8 ns laser pulse with energy 30 - 40 μJ. Cell photothermal (PT) response amplitude and shape from each cell were analyzed and amount of cells that produced specific PT response was used as PT parameter. Parallel experiment included cell viability control. Results were obtained for two cytotoxic chemotherapy agents -- Platinol-aq and Adrucil. Incubation of cell suspensions for 90 min at 20 and 37°C caused changes in cell PT parameters. Reaction of carcinoma cells to the drug was very similar to reaction of hepatocytes to respiratory chain inhibition and reaction of RBC to osmotic pressure decrease. PT effect was found to be dose-dependent. PT method allows detecting drug-induced changes before cell death or morphological changes and therefore can be fast and sensitive modality for control of chemotherapy.

Optimal Clinical Doses of Faropenem, Linezolid, and Moxifloxacin in Children With Disseminated Tuberculosis: Goldilocks

PubMed Central

Srivastava, Shashikant; Deshpande, Devyani; Pasipanodya, Jotam; Nuermberger, Eric; Swaminathan, Soumya; Gumbo, Tawanda

2016-01-01

Background. When treated with the same antibiotic dose, children achieve different 0- to 24-hour area under the concentration-time curves (AUC0–24) because of maturation and between-child physiological variability on drug clearance. Children are also infected by Mycobacterium tuberculosis isolates with different antibiotic minimum inhibitory concentrations (MICs). Thus, each child will achieve different AUC0–24/MIC ratios when treated with the same dose. Methods. We used 10 000-subject Monte Carlo experiments to identify the oral doses of linezolid, moxifloxacin, and faropenem that would achieve optimal target exposures associated with optimal efficacy in children with disseminated tuberculosis. The linezolid and moxifloxacin exposure targets were AUC0–24/MIC ratios of 62 and 122, and a faropenem percentage of time above MIC >60%, in combination therapy. A linezolid AUC0–24 of 93.4 mg × hour/L was target for toxicity. Population pharmacokinetic parameters of each drug and between-child variability, as well as MIC distribution, were used, and the cumulative fraction of response (CFR) was calculated. We also considered drug penetration indices into meninges, bone, and peritoneum. Results. The linezolid dose of 15 mg/kg in full-term neonates and infants aged up to 3 months and 10 mg/kg in toddlers, administered once daily, achieved CFR ≥ 90%, with <10% achieving linezolid AUC0–24 associated with toxicity. The moxifloxacin dose of 25 mg/kg/day achieved a CFR > 90% in infants, but the optimal dose was 20 mg/kg/day in older children. The faropenem medoxomil optimal dosage was 30 mg/kg 3–4 times daily. Conclusions. The regimen and doses of linezolid, moxifloxacin, and faropenem identified are proposed to be adequate for all disseminated tuberculosis syndromes, whether drug-resistant or -susceptible. PMID:27742641

Defining the Optimal Selenium Dose for Prostate Cancer Risk Reduction: Insights from the U-Shaped Relationship Between Selenium Status, DNA Damage, and Apoptosis

USDA-ARS?s Scientific Manuscript database

Our work in dogs has revealed a U-shaped dose response between selenium status and prostatic DNA damage that remarkably parallels the relationship between dietary selenium and prostate cancer risk in men, suggesting that more selenium is not necessarily better. Herein, we extend this canine work to ...

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

Dose-finding study of carbamylated monomeric allergoid tablets in grass-allergic rhinoconjunctivitis patients.

PubMed

Mösges, Ralph; Rohdenburg, Christina; Eichel, Andrea; Zadoyan, Gregor; Kasche, Elena-Manja; Shah-Hosseini, Kija; Lehmacher, Walter; Schmalz, Petra; Compalati, Enrico

2017-11-01

To determine the optimal effective and safe dose of sublingual immunotherapy tablets containing carbamylated monomeric allergoids in patients with grass pollen-induced allergic rhinoconjunctivitis. In this prospective, randomized, double-blind, active-controlled, multicenter, Phase II study, four different daily doses were applied preseasonally for 12 weeks. Of 158 randomized adults, 155 subjects (safety population) received 300 units of allergy (UA)/day (n = 36), 600 UA/day (n = 43), 1000 UA/day (n = 39), or 2000 UA/day (n = 37). After treatment, 54.3, 47.6, 59.0 and 51.4% of patients, respectively, ceased to react to the highest allergen concentration in a conjunctival provocation test. Furthermore, the response threshold improved in 70.4, 62.9, 76.7 and 66.7% of patients, respectively. No serious adverse events occurred. This study found 1000 UA/day to be the optimal effective and safe dose.

Optimizing Chemotherapy Dose and Schedule by Norton-Simon Mathematical Modeling

PubMed Central

Traina, Tiffany A.; Dugan, Ute; Higgins, Brian; Kolinsky, Kenneth; Theodoulou, Maria; Hudis, Clifford A.; Norton, Larry

2011-01-01

Background To hasten and improve anticancer drug development, we created a novel approach to generating and analyzing preclinical dose-scheduling data so as to optimize benefit-to-toxicity ratios. Methods We applied mathematical methods based upon Norton-Simon growth kinetic modeling to tumor-volume data from breast cancer xenografts treated with capecitabine (Xeloda®, Roche) at the conventional schedule of 14 days of treatment followed by a 7-day rest (14 - 7). Results The model predicted that 7 days of treatment followed by a 7-day rest (7 - 7) would be superior. Subsequent preclinical studies demonstrated that this biweekly capecitabine schedule allowed for safe delivery of higher daily doses, improved tumor response, and prolonged animal survival. Conclusions We demonstrated that the application of Norton-Simon modeling to the design and analysis of preclinical data predicts an improved capecitabine dosing schedule in xenograft models. This method warrants further investigation and application in clinical drug development. PMID:20519801

Optimizing global liver function in radiation therapy treatment planning

NASA Astrophysics Data System (ADS)

Wu, Victor W.; Epelman, Marina A.; Wang, Hesheng; Romeijn, H. Edwin; Feng, Mary; Cao, Yue; Ten Haken, Randall K.; Matuszak, Martha M.

2016-09-01

Liver stereotactic body radiation therapy (SBRT) patients differ in both pre-treatment liver function (e.g. due to degree of cirrhosis and/or prior treatment) and radiosensitivity, leading to high variability in potential liver toxicity with similar doses. This work investigates three treatment planning optimization models that minimize risk of toxicity: two consider both voxel-based pre-treatment liver function and local-function-based radiosensitivity with dose; one considers only dose. Each model optimizes different objective functions (varying in complexity of capturing the influence of dose on liver function) subject to the same dose constraints and are tested on 2D synthesized and 3D clinical cases. The normal-liver-based objective functions are the linearized equivalent uniform dose (\\ell \\text{EUD} ) (conventional ‘\\ell \\text{EUD} model’), the so-called perfusion-weighted \\ell \\text{EUD} (\\text{fEUD} ) (proposed ‘fEUD model’), and post-treatment global liver function (GLF) (proposed ‘GLF model’), predicted by a new liver-perfusion-based dose-response model. The resulting \\ell \\text{EUD} , fEUD, and GLF plans delivering the same target \\ell \\text{EUD} are compared with respect to their post-treatment function and various dose-based metrics. Voxel-based portal venous liver perfusion, used as a measure of local function, is computed using DCE-MRI. In cases used in our experiments, the GLF plan preserves up to 4.6 % ≤ft(7.5 % \\right) more liver function than the fEUD (\\ell \\text{EUD} ) plan does in 2D cases, and up to 4.5 % ≤ft(5.6 % \\right) in 3D cases. The GLF and fEUD plans worsen in \\ell \\text{EUD} of functional liver on average by 1.0 Gy and 0.5 Gy in 2D and 3D cases, respectively. Liver perfusion information can be used during treatment planning to minimize the risk of toxicity by improving expected GLF; the degree of benefit varies with perfusion pattern. Although fEUD model optimization is computationally inexpensive and often achieves better GLF than \\ell \\text{EUD} model optimization does, the GLF model directly optimizes a more clinically relevant metric and can further improve fEUD plan quality.

Optimization of photocatalytic degradation of methyl blue using silver ion doped titanium dioxide by combination of experimental design and response surface approach.

PubMed

Sahoo, C; Gupta, A K

2012-05-15

Photocatalytic degradation of methyl blue (MYB) was studied using Ag(+) doped TiO(2) under UV irradiation in a batch reactor. Catalytic dose, initial concentration of dye and pH of the reaction mixture were found to influence the degradation process most. The degradation was found to be effective in the range catalytic dose (0.5-1.5g/L), initial dye concentration (25-100ppm) and pH of reaction mixture (5-9). Using the three factors three levels Box-Behnken design of experiment technique 15 sets of experiments were designed considering the effective ranges of the influential parameters. The results of the experiments were fitted to two quadratic polynomial models developed using response surface methodology (RSM), representing functional relationship between the decolorization and mineralization of MYB and the experimental parameters. Design Expert software version 8.0.6.1 was used to optimize the effects of the experimental parameters on the responses. The optimum values of the parameters were dose of Ag(+) doped TiO(2) 0.99g/L, initial concentration of MYB 57.68ppm and pH of reaction mixture 7.76. Under the optimal condition the predicted decolorization and mineralization rate of MYB were 95.97% and 80.33%, respectively. Regression analysis with R(2) values >0.99 showed goodness of fit of the experimental results with predicted values. Copyright © 2012 Elsevier B.V. All rights reserved.

Immuno-oncology Clinical Trial Design: Limitations, Challenges, and Opportunities

PubMed Central

Baik, Christina S.; Rubin, Eric H.; Forde, Patrick M.; Mehnert, Janice M.; Collyar, Deborah; Butler, Marcus O.; Dixon, Erica L.; Chow, Laura Q.M.

2017-01-01

Recent advances in immuno-oncology and regulatory approvals have been rapid and paradigm shifting in many difficult-to-treat malignancies. Despite immune checkpoint inhibitor therapy becoming the standard of care across multiple tumor types, there are many unanswered questions that need to be addressed before this therapeutic modality can be fully harnessed. Areas of limitations include treatment of patients not sufficiently represented in clinical trials, uncertainty of the optimal treatment dosing and duration, and lack of understanding regarding long-term immune related toxicities and atypical tumor responses. Patients such as those with autoimmune disease, chronic viral infections, limited performance status, and brain metastases were often excluded from initial trials due to concerns of safety. However, limited data suggest that some of these patients can benefit from therapy with manageable toxicities; thus, future studies should incorporate these patients to clearly define safety and efficacy. There are still controversies regarding the optimal dosing strategy that can vary from weight-based to flat dosing, with undefined treatment duration. Further elucidation of the optimal dosing approach and evaluation of predictive biomarkers should be incorporated in the design of future trials. Finally, there are long-term immune-mediated toxicities, atypical tumor responses such as pseudoprogression and endpoints unique to immuno-oncology that are not adequately captured by traditional trial designs; thus, novel study designs are needed. In this article, we discuss in detail the above challenges and propose needed areas of research for exploration and incorporation in the next generation of immuno-oncology clinical trials. PMID:28864727

A randomized controlled trial investigating the use of a predictive nomogram for the selection of the FSH starting dose in IVF/ICSI cycles.

PubMed

Allegra, Adolfo; Marino, Angelo; Volpes, Aldo; Coffaro, Francesco; Scaglione, Piero; Gullo, Salvatore; La Marca, Antonio

2017-04-01

The number of oocytes retrieved is a relevant intermediate outcome in women undergoing IVF/intracytoplasmic sperm injection (ICSI). This trial compared the efficiency of the selection of the FSH starting dose according to a nomogram based on multiple biomarkers (age, day 3 FSH, anti-Müllerian hormone) versus an age-based strategy. The primary outcome measure was the proportion of women with an optimal number of retrieved oocytes defined as 8-14. At their first IVF/ICSI cycle, 191 patients underwent a long gonadotrophin-releasing hormone agonist protocol and were randomized to receive a starting dose of recombinant (human) FSH, based on their age (150 IU if ≤35 years, 225 IU if >35 years) or based on the nomogram. Optimal response was observed in 58/92 patients (63%) in the nomogram group and in 42/99 (42%) in the control group (+21%, 95% CI = 0.07 to 0.35, P = 0.0037). No significant differences were found in the clinical pregnancy rate or the number of embryos cryopreserved per patient. The study showed that the FSH starting dose selected according to ovarian reserve is associated with an increase in the proportion of patients with an optimal response: large trials are recommended to investigate any possible effect on the live-birth rate. Copyright © 2017 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Estimating adolescent sleep need using dose-response modeling.

PubMed

Short, Michelle A; Weber, Nathan; Reynolds, Chelsea; Coussens, Scott; Carskadon, Mary A

2018-04-01

This study will (1) estimate the nightly sleep need of human adolescents, (2) determine the time course and severity of sleep-related deficits when sleep is reduced below this optimal quantity, and (3) determine whether sleep restriction perturbs the circadian system as well as the sleep homeostat. Thirty-four adolescents aged 15 to 17 years spent 10 days and nine nights in the sleep laboratory. Between two baseline nights and two recovery nights with 10 hours' time in bed (TIB) per night, participants experienced either severe sleep restriction (5-hour TIB), moderate sleep restriction (7.5-hour TIB), or no sleep restriction (10-hour TIB) for five nights. A 10-minute psychomotor vigilance task (PVT; lapse = response after 500 ms) and the Karolinska Sleepiness Scale were administered every 3 hours during wake. Salivary dim-light melatonin onset was calculated at baseline and after four nights of each sleep dose to estimate circadian phase. Dose-dependent deficits to sleep duration, circadian phase timing, lapses of attention, and subjective sleepiness occurred. Less TIB resulted in less sleep, more lapses of attention, greater subjective sleepiness, and larger circadian phase delays. Sleep need estimated from 10-hour TIB sleep opportunities was approximately 9 hours, while modeling PVT lapse data suggested that 9.35 hours of sleep is needed to maintain optimal sustained attention performance. Sleep restriction perturbs homeostatic and circadian systems, leading to dose-dependent deficits to sustained attention and sleepiness. Adolescents require more sleep for optimal functioning than typically obtained.

Functional heartburn: the stimulus, the pain, and the brain

PubMed Central

Fass, R; Tougas, G

2002-01-01

Functional heartburn is a common disorder and appears to be composed of several distinct subgroups. Identifying the different subgroups based on clinical history only is not achievable at present. The mechanisms responsible for pain, clinical characteristics, and the optimal therapeutic approach remain poorly understood. Response to potent antireflux treatment is relatively limited. Current and future treatment strategies for functional heartburn patients who have failed standard dose proton pump inhibitors (PPIs) include increased PPI dose in some, as well as addition of pain modulators in others. PMID:12427796

Optimization of radiation treatment of ginger ( Zingiber officinale) rhizomes using response surface methodology

NASA Astrophysics Data System (ADS)

Nketsia-Tabiri, Josephine

1998-06-01

The effects of pre-irradiation storage time (7-21 days), radiation dose (0-75 Gy) and post-irradiation storage time (2-20 weeks) on sprouting, wrinkling and weight loss of ginger was investigated using a central composite rotatable design. Predictive models developed for all three responses were highly significant. Weight loss and wrinkling decreased as pre-irradiation storage time increased. Dose and post-irradiation storage time had significant interactive effects on weight loss and sprouting. Processing conditions for achieving minimal sprouting resulted in maximum weight loss and wrinkling.

Estimation of the optimal dosing regimen of escitalopram in dogs: A dose occupancy study with [11C]DASB

PubMed Central

Polis, Ingeborgh; Dockx, Robrecht; Vlerick, Lise; Dobbeleir, Andre; Goethals, Ingeborg; Saunders, Jimmy; Sadones, Nele; Baeken, Chris; De Vos, Filip; Peremans, Kathelijne

2017-01-01

Although the favourable characteristics of escitalopram as being the most selective serotonin reuptake inhibitor and having an increased therapeutic efficacy via binding on an additional allosteric binding site of the serotonin transporter, its dosing regimen has not yet been optimized for its use in dogs. This study aimed to estimate the optimal dosing frequency and the required dose for achieving 80% occupancy of the serotonin transporters in the basal ganglia. The dosing frequency was investigated by determining the elimination half-life after a four day oral pre-treatment period with 0.83 mg/kg escitalopram (3 administrations/day) and a subsequent i.v. injection 0.83 mg/kg. Blood samples were taken up to 12 hours after i.v. injection and the concentration of escitalopram in plasma was analysed via LC-MSMS. The dose-occupancy relationship was then determined by performing two PET scans in five adult beagles: a baseline PET scan and a second scan after steady state conditions were achieved following oral treatment with a specific dose of escitalopram ranging from 0.5 to 2.5 mg/kg/day. As the elimination half-life was determined to be 6.7 hours a dosing frequency of three administrations a day was proposed for the second part of the study. Further it was opted for a treatment period of four days, which well exceeded the minimum period to achieve steady state conditions. The optimal dosing regimen to achieve 80% occupancy in the basal ganglia and elicit a therapeutic effect, was calculated to be 1.85 mg/kg/day, divided over three administrations. Under several circumstances, such as insufficient response to other SSRIs, concurrent drug intake or in research studies focused on SERT, the use of escitalopram can be preferred over the use of the already for veterinary use registered fluoxetine, however, in case of long-term treatment with escitalopram, regularly cardiac screening is recommended. PMID:28644875

Estimation of the optimal dosing regimen of escitalopram in dogs: A dose occupancy study with [11C]DASB.

PubMed

Taylor, Olivia; Van Laeken, Nick; Polis, Ingeborgh; Dockx, Robrecht; Vlerick, Lise; Dobbeleir, Andre; Goethals, Ingeborg; Saunders, Jimmy; Sadones, Nele; Baeken, Chris; De Vos, Filip; Peremans, Kathelijne

2017-01-01

Although the favourable characteristics of escitalopram as being the most selective serotonin reuptake inhibitor and having an increased therapeutic efficacy via binding on an additional allosteric binding site of the serotonin transporter, its dosing regimen has not yet been optimized for its use in dogs. This study aimed to estimate the optimal dosing frequency and the required dose for achieving 80% occupancy of the serotonin transporters in the basal ganglia. The dosing frequency was investigated by determining the elimination half-life after a four day oral pre-treatment period with 0.83 mg/kg escitalopram (3 administrations/day) and a subsequent i.v. injection 0.83 mg/kg. Blood samples were taken up to 12 hours after i.v. injection and the concentration of escitalopram in plasma was analysed via LC-MSMS. The dose-occupancy relationship was then determined by performing two PET scans in five adult beagles: a baseline PET scan and a second scan after steady state conditions were achieved following oral treatment with a specific dose of escitalopram ranging from 0.5 to 2.5 mg/kg/day. As the elimination half-life was determined to be 6.7 hours a dosing frequency of three administrations a day was proposed for the second part of the study. Further it was opted for a treatment period of four days, which well exceeded the minimum period to achieve steady state conditions. The optimal dosing regimen to achieve 80% occupancy in the basal ganglia and elicit a therapeutic effect, was calculated to be 1.85 mg/kg/day, divided over three administrations. Under several circumstances, such as insufficient response to other SSRIs, concurrent drug intake or in research studies focused on SERT, the use of escitalopram can be preferred over the use of the already for veterinary use registered fluoxetine, however, in case of long-term treatment with escitalopram, regularly cardiac screening is recommended.

Modeling adverse event counts in phase I clinical trials of a cytotoxic agent.

PubMed

Muenz, Daniel G; Braun, Thomas M; Taylor, Jeremy Mg

2018-05-01

Background/Aims The goal of phase I clinical trials for cytotoxic agents is to find the maximum dose with an acceptable risk of severe toxicity. The most common designs for these dose-finding trials use a binary outcome indicating whether a patient had a dose-limiting toxicity. However, a patient may experience multiple toxicities, with each toxicity assigned an ordinal severity score. The binary response is then obtained by dichotomizing a patient's richer set of data. We contribute to the growing literature on new models to exploit this richer toxicity data, with the goal of improving the efficiency in estimating the maximum tolerated dose. Methods We develop three new, related models that make use of the total number of dose-limiting and low-level toxicities a patient experiences. We use these models to estimate the probability of having at least one dose-limiting toxicity as a function of dose. In a simulation study, we evaluate how often our models select the true maximum tolerated dose, and we compare our models with the continual reassessment method, which uses binary data. Results Across a variety of simulation settings, we find that our models compare well against the continual reassessment method in terms of selecting the true optimal dose. In particular, one of our models which uses dose-limiting and low-level toxicity counts beats or ties the other models, including the continual reassessment method, in all scenarios except the one in which the true optimal dose is the highest dose available. We also find that our models, when not selecting the true optimal dose, tend to err by picking lower, safer doses, while the continual reassessment method errs more toward toxic doses. Conclusion Using dose-limiting and low-level toxicity counts, which are easily obtained from data already routinely collected, is a promising way to improve the efficiency in finding the true maximum tolerated dose in phase I trials.

SU-F-J-133: Adaptive Radiation Therapy with a Four-Dimensional Dose Calculation Algorithm That Optimizes Dose Distribution Considering Breathing Motion

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

Ali, I; Algan, O; Ahmad, S

Purpose: To model patient motion and produce four-dimensional (4D) optimized dose distributions that consider motion-artifacts in the dose calculation during the treatment planning process. Methods: An algorithm for dose calculation is developed where patient motion is considered in dose calculation at the stage of the treatment planning. First, optimal dose distributions are calculated for the stationary target volume where the dose distributions are optimized considering intensity-modulated radiation therapy (IMRT). Second, a convolution-kernel is produced from the best-fitting curve which matches the motion trajectory of the patient. Third, the motion kernel is deconvolved with the initial dose distribution optimized for themore » stationary target to produce a dose distribution that is optimized in four-dimensions. This algorithm is tested with measured doses using a mobile phantom that moves with controlled motion patterns. Results: A motion-optimized dose distribution is obtained from the initial dose distribution of the stationary target by deconvolution with the motion-kernel of the mobile target. This motion-optimized dose distribution is equivalent to that optimized for the stationary target using IMRT. The motion-optimized and measured dose distributions are tested with the gamma index with a passing rate of >95% considering 3% dose-difference and 3mm distance-to-agreement. If the dose delivery per beam takes place over several respiratory cycles, then the spread-out of the dose distributions is only dependent on the motion amplitude and not affected by motion frequency and phase. This algorithm is limited to motion amplitudes that are smaller than the length of the target along the direction of motion. Conclusion: An algorithm is developed to optimize dose in 4D. Besides IMRT that provides optimal dose coverage for a stationary target, it extends dose optimization to 4D considering target motion. This algorithm provides alternative to motion management techniques such as beam-gating or breath-holding and has potential applications in adaptive radiation therapy.« less

A 3D correction method for predicting the readings of a PinPoint chamber on the CyberKnife® M6™ machine

NASA Astrophysics Data System (ADS)

Zhang, Yongqian; Brandner, Edward; Ozhasoglu, Cihat; Lalonde, Ron; Heron, Dwight E.; Saiful Huq, M.

2018-02-01

The use of small fields in radiation therapy techniques has increased substantially in particular in stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT). However, as field size reduces further still, the response of the detector changes more rapidly with field size, and the effects of measurement uncertainties become increasingly significant due to the lack of lateral charged particle equilibrium, spectral changes as a function of field size, detector choice, and subsequent perturbations of the charged particle fluence. This work presents a novel 3D dose volume-to-point correction method to predict the readings of a 0.015 cc PinPoint chamber (PTW 31014) for both small static-fields and composite-field dosimetry formed by fixed cones on the CyberKnife® M6™ machine. A 3D correction matrix is introduced to link the 3D dose distribution to the response of the PinPoint chamber in water. The parameters of the correction matrix are determined by modeling its 3D dose response in circular fields created using the 12 fixed cones (5 mm-60 mm) on a CyberKnife® M6™ machine. A penalized least-square optimization problem is defined by fitting the calculated detector reading to the experimental measurement data to generate the optimal correction matrix; the simulated annealing algorithm is used to solve the inverse optimization problem. All the experimental measurements are acquired for every 2 mm chamber shift in the horizontal planes for each field size. The 3D dose distributions for the measurements are calculated using the Monte Carlo calculation with the MultiPlan® treatment planning system (Accuray Inc., Sunnyvale, CA, USA). The performance evaluation of the 3D conversion matrix is carried out by comparing the predictions of the output factors (OFs), off-axis ratios (OARs) and percentage depth dose (PDD) data to the experimental measurement data. The discrepancy of the measurement and the prediction data for composite fields is also performed for clinical SRS plans. The optimization algorithm used for generating the optimal correction factors is stable, and the resulting correction factors were smooth in the spatial domain. The measurement and prediction of OFs agree closely with percentage differences of less than 1.9% for all the 12 cones. The discrepancies between the prediction and the measurement PDD readings at 50 mm and 80 mm depth are 1.7% and 1.9%, respectively. The percentage differences of OARs between measurement and prediction data are less than 2% in the low dose gradient region, and 2%/1 mm discrepancies are observed within the high dose gradient regions. The differences between the measurement and prediction data for all the CyberKnife based SRS plans are less than 1%. These results demonstrate the existence and efficiency of the novel 3D correction method for small field dosimetry. The 3D correction matrix links the 3D dose distribution and the reading of the PinPoint chamber. The comparison between the predicted reading and the measurement data for static small fields (OFs, OARs and PDDs) yield discrepancies within 2% for low dose gradient regions and 2%/1 mm for high dose gradient regions; the discrepancies between the predicted and the measurement data are less than 1% for all the SRS plans. The 3D correction method provides an access to evaluate the clinical measurement data and can be applied to non-standard composite fields intensity modulated radiation therapy point dose verification.

A Dose-Response Study of Inactivated Low Pathogenic Avian Influenza H9N2 Virus in Specific-Pathogen-Free and Commercial Broiler Chickens.

PubMed

Kilany, Walid H; Ali, Ahmed; Bazid, Abdel-Hamid I; El-Deeb, Ayman H; El-Abideen, Mohamed A Zain; Sayed, Magdy El; El-Kady, Magdy F

2016-05-01

Since the first report of low pathogenic avian influenza (LPAI) H9N2 virus in Egypt in 2011, the Egyptian poultry industry has suffered from unexpected economic losses as a result of the wide spread of LPAI H9N2. Hence, inactivated H9N2 vaccines have been included in the vaccination programs of different poultry production sectors. The optimal antigen content of avian influenza virus vaccines is essential to reach protective antibody titers. In this study, the correlation between antigen content (based on hemagglutinating units [HAU]) and postvaccination (PV) antibody response of H9N2 inactivated vaccine was studied. Five different vaccine antigen loads (128, 200, 250, 300, and 350 HAU formulas/dose) were investigated in commercial broiler and specific-pathogen-free (SPF) chickens. Vaccine safety and PV antibody responses were monitored. At the fourth week PV only SPF vaccinated groups (128, 200, 250, and 300 HAU/dose) were challenged using LPAI H9N2 (A/Ck/EG/114940v/NLQP/11) virus with 10(6) EID50/bird. Oropharyngeal swabs were used to monitor virus shedding at 2, 4, 6, and 10 days postchallenge. Results showed that all vaccine formulations were well tolerated, and the highest antibody titers were observed in birds vaccinated with higher HAU. Vaccines containing 128 and 200 HAU/dose did not induce the required protective HI titers by 3 wk PV. Meanwhile, the challenge experiment in SPF chickens showed that 250 and 300 HAU vaccine doses were required to reduce the level and duration of virus shedding. Study results thus suggest that inactivated H9N2 vaccines containing at least 250 HAU/dose will induce the optimal protective titers and minimize virus shedding in SPF chickens.

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.

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

Therapeutic Drug Monitoring Guides the Management of Crohn's Patients with Secondary Loss of Response to Adalimumab.

PubMed

Restellini, Sophie; Chao, Che-Yung; Lakatos, Peter L; Aruljothy, Achuthan; Aziz, Haya; Kherad, Omar; Bitton, Alain; Wild, Gary; Afif, Waqqas; Bessissow, Talat

2018-04-13

Managing loss of response (LOR) in Crohn's disase (CD) patients remains challenging. Compelling evidence supports therapeutic drug monitoring (TDM) to guide management in patients on infliximab, but data for other biologics are less robust. We aimed to asses if empiric dose escalation led to improved clinical outcome in addition to TDM-guided optimization in CD patients with LOR to adalimumab (ADA). Retrospective chart review of patients followed between 2014 and 2016 at McGill IBD Center with index TDM for LOR to ADA was performed. Primary outcomes were composite remission at 3, 6, and 12 months in those with empiric adjustments versus TDM-guided optimization. There were 104 patients (54.8% men) who were included in the study. Of this group, 81 patients (77.9%) had serum level (SL) ≥5µg/ml at index TDM with a median value of 12µg/ml (IQR 6.1-16.5). There were 10 patients (9.6%) who had undetectable SL with high anti-ADA antibodies and 48 (46.2%) received empiric escalation. TDM led to change in treatment in 58 patients (55.8%). Among them, 28 (48.3%) had discontinued ADA, 12 (21.7%) had addition of immunomodulator or steroid, and 18 (31%) had ADA dose escalation. Empiric dose escalation before TDM-based optimization was not associated with improved outcomes at 3, 6, and 12 months, irrespective of SL levels. Clear SL cutoff associated with composite remission was not identified. Our data do not support empiric dose adjustment beyond that based on the result of the TDM in patients with LOR to ADA. TDM limits unnecessary dose escalation and provides appropriate treatment strategy without compromising clinical outcomes. 10.1093/ibd/izy044_video1izy044.video15768828880001.

Reducing radiation dose to the female breast during conventional and dedicated breast computed tomography

NASA Astrophysics Data System (ADS)

Rupcich, Franco John

The purpose of this study was to quantify the effectiveness of techniques intended to reduce dose to the breast during CT coronary angiography (CTCA) scans with respect to task-based image quality, and to evaluate the effectiveness of optimal energy weighting in improving contrast-to-noise ratio (CNR), and thus the potential for reducing breast dose, during energy-resolved dedicated breast CT. A database quantifying organ dose for several radiosensitive organs irradiated during CTCA, including the breast, was generated using Monte Carlo simulations. This database facilitates estimation of organ-specific dose deposited during CTCA protocols using arbitrary x-ray spectra or tube-current modulation schemes without the need to run Monte Carlo simulations. The database was used to estimate breast dose for simulated CT images acquired for a reference protocol and five protocols intended to reduce breast dose. For each protocol, the performance of two tasks (detection of signals with unknown locations) was compared over a range of breast dose levels using a task-based, signal-detectability metric: the estimator of the area under the exponential free-response relative operating characteristic curve, AFE. For large-diameter/medium-contrast signals, when maintaining equivalent AFE, the 80 kV partial, 80 kV, 120 kV partial, and 120 kV tube-current modulated protocols reduced breast dose by 85%, 81%, 18%, and 6%, respectively, while the shielded protocol increased breast dose by 68%. Results for the small-diameter/high-contrast signal followed similar trends, but with smaller magnitude of the percent changes in dose. The 80 kV protocols demonstrated the greatest reduction to breast dose, however, the subsequent increase in noise may be clinically unacceptable. Tube output for these protocols can be adjusted to achieve more desirable noise levels with lesser dose reduction. The improvement in CNR of optimally projection-based and image-based weighted images relative to photon-counting was investigated for six different energy bin combinations using a bench-top energy-resolving CT system with a cadmium zinc telluride (CZT) detector. The non-ideal spectral response reduced the CNR for the projection-based weighted images, while image-based weighting improved CNR for five out of the six investigated bin combinations, despite this non-ideal response, indicating potential for image-based weighting to reduce breast dose during dedicated breast CT.

Characterization of MOSFET detectors for in vivo dosimetry in interventional radiology and for dose reconstruction in case of overexposure.

PubMed

Bassinet, Céline; Huet, Christelle; Baumann, Marion; Etard, Cécile; Réhel, Jean-Luc; Boisserie, Gilbert; Debroas, Jacques; Aubert, Bernard; Clairand, Isabelle

2013-04-01

As MOSFET (Metal Oxide Semiconductor Field Effect Transistor) detectors allow dose measurements in real time, the interest in these dosimeters is growing. The aim of this study was to investigate the dosimetric properties of commercially available TN-502RD-H MOSFET silicon detectors (Best Medical Canada, Ottawa, Canada) in order to use them for in vivo dosimetry in interventional radiology and for dose reconstruction in case of overexposure. Reproducibility of the measurements, dose rate dependence, and dose response of the MOSFET detectors have been studied with a Co source. Influence of the dose rate, frequency, and pulse duration on MOSFET responses has also been studied in pulsed x-ray fields. Finally, in order to validate the integrated dose given by MOSFET detectors, MOSFETs and TLDs (LiF:Mg,Cu,P) were fixed on an Alderson-Rando phantom in the conditions of an interventional neuroradiology procedure, and their responses have been compared. The results of this study show the suitability of MOSFET detectors for in vivo dosimetry in interventional radiology and for dose reconstruction in case of accident, provided a well-corrected energy dependence, a pulse duration equal to or higher than 10 ms, and an optimized contact between the detector and the skin of the patient are achieved.

A forced titration study of the antioxidant and immunomodulatory effects of Ambrotose AO supplement

PubMed Central

2010-01-01

Background Oxidative stress plays a role in acute and chronic inflammatory disease and antioxidant supplementation has demonstrated beneficial effects in the treatment of these conditions. This study was designed to determine the optimal dose of an antioxidant supplement in healthy volunteers to inform a Phase 3 clinical trial. Methods The study was designed as a combined Phase 1 and 2 open label, forced titration dose response study in healthy volunteers (n = 21) to determine both acute safety and efficacy. Participants received a dietary supplement in a forced titration over five weeks commencing with a no treatment baseline through 1, 2, 4 and 8 capsules. The primary outcome measurement was ex vivo changes in serum oxygen radical absorbance capacity (ORAC). The secondary outcome measures were undertaken as an exploratory investigation of immune function. Results A significant increase in antioxidant activity (serum ORAC) was observed between baseline (no capsules) and the highest dose of 8 capsules per day (p = 0.040) representing a change of 36.6%. A quadratic function for dose levels was fitted in order to estimate a dose response curve for estimating the optimal dose. The quadratic component of the curve was significant (p = 0.047), with predicted serum ORAC scores increasing from the zero dose to a maximum at a predicted dose of 4.7 capsules per day and decreasing for higher doses. Among the secondary outcome measures, a significant dose effect was observed on phagocytosis of granulocytes, and a significant increase was also observed on Cox 2 expression. Conclusion This study suggests that Ambrotose AO® capsules appear to be safe and most effective at a dosage of 4 capsules/day. It is important that this study is not over interpreted; it aimed to find an optimal dose to assess the dietary supplement using a more rigorous clinical trial design. The study achieved this aim and demonstrated that the dietary supplement has the potential to increase antioxidant activity. The most significant limitation of this study was that it was open label Phase 1/Phase 2 trial and is subject to potential bias that is reduced with the use of randomization and blinding. To confirm the benefits of this dietary supplement these effects now need to be demonstrated in a Phase 3 randomised controlled trial (RCT). Trial Registration Australian and New Zealand Clinical Trials Register: ACTRN12605000258651 PMID:20433711

Research in Prevention and Treatment of Noise-Induced Hearing Loss (NIHL)

DTIC Science & Technology

2016-06-01

The current study identified optimal protective D-methionine (D-met) dose and delayed time response from steady state and impulse noise -induced hearing loss (NIHL) in groups of Chinchillas laniger (n=10/group).

Reliability Methods for Shield Design Process

NASA Technical Reports Server (NTRS)

Tripathi, R. K.; Wilson, J. W.

2002-01-01

Providing protection against the hazards of space radiation is a major challenge to the exploration and development of space. The great cost of added radiation shielding is a potential limiting factor in deep space operations. In this enabling technology, we have developed methods for optimized shield design over multi-segmented missions involving multiple work and living areas in the transport and duty phase of space missions. The total shield mass over all pieces of equipment and habitats is optimized subject to career dose and dose rate constraints. An important component of this technology is the estimation of two most commonly identified uncertainties in radiation shield design, the shielding properties of materials used and the understanding of the biological response of the astronaut to the radiation leaking through the materials into the living space. The largest uncertainty, of course, is in the biological response to especially high charge and energy (HZE) ions of the galactic cosmic rays. These uncertainties are blended with the optimization design procedure to formulate reliability-based methods for shield design processes. The details of the methods will be discussed.

Application of response surface methodology (RSM) for the removal of methylene blue dye from water by nano zero-valent iron (NZVI).

PubMed

Khosravi, Morteza; Arabi, Simin

In this study, iron zero-valent nanoparticles were synthesized, characterized and studied for removal of methylene blue dye in water solution. The reactions were mathematically described as the function of parameters such as nano zero-valent iron (NZVI) dose, pH, contact time and initial dye concentration, and were modeled by the use of response surface methodology. These experiments were carried out as a central composite design consisting of 30 experiments determined by the 2(4) full factorial designs with eight axial points and six center points. The results revealed that the optimal conditions for dye removal were NZVI dose 0.1-0.9 g/L, pH 3-11, contact time 20-100 s, and initial dye concentration 10-50 mg/L, respectively. Under these optimal values of process parameters, the dye removal efficiency of 92.87% was observed, which very close to the experimental value (92.21%) in batch experiment. In the optimization, R(2) and R(2)adj correlation coefficients for the model were evaluated as 0.96 and 0.93, respectively.

Optimization of radiotherapy. Some notes on the principles and practice of optimization in cancer treatment and implications for clinical research.

PubMed

Andrews, J R

1981-01-01

Two methods dominate cancer treatment--one, the traditional best practice, individualized treatment method and two, the a priori determined decision method of the interinstitutional, cooperative, clinical trial. In the first, choices are infinite and can be made at the time of treatment; in the second, choices are finite and are made in advance of treatment on a random basis. Neither method systematically selects, identifies, or formalizes the optimum level of effect in the treatment chosen. Of the two, it can be argued that the first, other things being equal, is more likely to select the optimum treatment. The determination of level of effect for the optimization of cancer treatment requires the generation of dose-response relationships for both benefit and risk and the introduction of benefit and risk considerations and judgements. The clinical trial, as presently constituted, doses not yield this kind of information, it being, generally, of the binary yes or no, better or worse type. The best practice, individualized treatment method can yield, when adequately documented, both a range of dose-response relationships and a variety of benefit and risk considerations. The presentation will be limited to a consideration of a single modality of cancer treatment, radiation therapy, but an analogy with other modalities of cancer treatment will be inferred. Criteria for optimization will be developed and graphic means for its identification and formalization will be demonstrated with examples taken from the radiotherapy literature. The general problem of optimization theory and practice will be discussed; the necessity for its exploration in relation to the increasing complexity of cancer treatment will be developed; and recommendations for clinical research will be made including a proposal for the support of clinics as an alternative to the support of programs.

SPIRIT: A seamless phase I/II randomized design for immunotherapy trials.

PubMed

Guo, Beibei; Li, Daniel; Yuan, Ying

2018-06-07

Immunotherapy-treatments that enlist the immune system to battle tumors-has received widespread attention in cancer research. Due to its unique features and mechanisms for treating cancer, immunotherapy requires novel clinical trial designs. We propose a Bayesian seamless phase I/II randomized design for immunotherapy trials (SPIRIT) to find the optimal biological dose (OBD) defined in terms of the restricted mean survival time. We jointly model progression-free survival and the immune response. Progression-free survival is used as the primary endpoint to determine the OBD, and the immune response is used as an ancillary endpoint to quickly screen out futile doses. Toxicity is monitored throughout the trial. The design consists of two seamlessly connected stages. The first stage identifies a set of safe doses. The second stage adaptively randomizes patients to the safe doses identified and uses their progression-free survival and immune response to find the OBD. The simulation study shows that the SPIRIT has desirable operating characteristics and outperforms the conventional design. Copyright © 2018 John Wiley & Sons, Ltd.

Accurate EPR radiosensitivity calibration using small sample masses

NASA Astrophysics Data System (ADS)

Hayes, R. B.; Haskell, E. H.; Barrus, J. K.; Kenner, G. H.; Romanyukha, A. A.

2000-03-01

We demonstrate a procedure in retrospective EPR dosimetry which allows for virtually nondestructive sample evaluation in terms of sample irradiations. For this procedure to work, it is shown that corrections must be made for cavity response characteristics when using variable mass samples. Likewise, methods are employed to correct for empty tube signals, sample anisotropy and frequency drift while considering the effects of dose distribution optimization. A demonstration of the method's utility is given by comparing sample portions evaluated using both the described methodology and standard full sample additive dose techniques. The samples used in this study are tooth enamel from teeth removed during routine dental care. We show that by making all the recommended corrections, very small masses can be both accurately measured and correlated with measurements of other samples. Some issues relating to dose distribution optimization are also addressed.

Randomized, Multicenter Study of Gefitinib Dose-escalation in Advanced Non-small-cell Lung Cancer Patients Achieved Stable Disease after One-month Gefitinib Treatment

PubMed Central

Xue, Cong; Hong, Shaodong; Li, Ning; Feng, Weineng; Jia, Jun; Peng, Jiewen; Lin, Daren; Cao, Xiaolong; Wang, Siyang; Zhang, Weimin; Zhang, Hongyu; Dong, Wei; Zhang, Li

2015-01-01

There is no consensus on the optimal treatment for patients with advanced non-small-cell lung cancer (NSCLC) and stable disease (SD) after gefitinib therapy. This randomized, open-label, multicenter study aimed to explore whether dose-escalation of gefitinib would improve response and survival in NSCLC patients who achieved SD after one-month of standard gefitinib dosage. Between May 2009 and January 2012, 466 patients were enrolled and 100 eligible patients were randomized (1:1) to receive either a higher dose (500 mg/d; H group) or to continue standard dose (250 mg/d; S group) of gefitinib. Objective response rate (ORR) was similar between the two groups (12.5% vs 12.5%, p = 1.000). There were no significant differences regarding progression-free survival (PFS) and overall survival (OS) between both arms (H group vs S group: median PFS, 5.30 months vs 6.23 months, p = 0.167; median OS, 13.70 months vs 18.87 months, p = 0.156). Therefore, dose-escalation of gefitinib does not confer a response or survival advantage in patients who achieve SD with one month of standard-dose gefitinib treatment. PMID:26216071

Effects of luteinizing hormone-releasing hormone and arginine-vasotocin on the sperm-release response of Günther's Toadlet, Pseudophryne guentheri

PubMed Central

2010-01-01

Background Luteinizing hormone-releasing hormone (LHRH) is an exogenous hormone commonly used to induce spermiation in anuran amphibians. Over the past few decades, the LHRH dose administered to individuals and the frequency of injection has been highly variable. The sperm-release responses reported have been correspondingly diverse, highlighting a need to quantify dose-response relationships on a species-specific basis. This study on the Australian anuran Pseudophryne guentheri first evaluated the spermiation response of males administered one of five LHRHa doses, and second, determined whether AVT administered in combination with the optimal LHRHa dose improved sperm-release. Methods Male toadlets were administered a single dose of 0, 1, 2, 4 or 8 micrograms/g body weight of LHRHa. A 4 micrograms/g dose of AVT was administered alone or in combination with 2 micrograms/g LHRHa. Spermiation responses were evaluated at 3, 7 and 12 h post hormone administration (PA), and sperm number and viability were quantified using fluorescent microscopy. Results LHRHa administration was highly effective at inducing spermiation in P. guentheri, with 100% of hormone-treated males producing sperm during the experimental period. The number of sperm released in response to 2 micrograms/g LHRHa was greater than all other doses administered and sperm viability was highest in the 1 microgram/g treatment. The administration of AVT alone or in combination with LHRHa resulted in the release of significantly lower sperm numbers. Conclusion Overall, results from this study suggest that in P. guentheri, LHRHa is effective at inducing spermiation, but that AVT inhibits sperm-release. PMID:21059269

The dose response relation for rat spinal cord paralysis analyzed in terms of the effective size of the functional subunit

NASA Astrophysics Data System (ADS)

Adamus-Górka, Magdalena; Mavroidis, Panayiotis; Brahme, Anders; Lind, Bengt K.

2008-11-01

Radiobiological models for estimating normal tissue complication probability (NTCP) are increasingly used in order to quantify or optimize the clinical outcome of radiation therapy. A good NTCP model should fulfill at least the following two requirements: (a) it should predict the sigmoid shape of the corresponding dose-response curve and (b) it should accurately describe the probability of a specified response for arbitrary non-uniform dose delivery for a given endpoint as accurately as possible, i.e. predict the volume dependence. In recent studies of the volume effect of a rat spinal cord after irradiation with narrow and broad proton beams the authors claim that none of the existing NTCP models is able to describe their results. Published experimental data have been used here to try to quantify the change in the effective dose (D50) causing 50% response for different field sizes. The present study was initiated to describe the induction of white matter necrosis in a rat spinal cord after irradiation with narrow proton beams in terms of the mean dose to the effective volume of the functional subunit (FSU). The physically delivered dose distribution was convolved with a function describing the effective size or, more accurately, the sensitivity distribution of the FSU to obtain the effective mean dose deposited in it. This procedure allows the determination of the mean D50 value of the FSUs of a certain size which is of interest for example if the cell nucleus of the oligodendrocyte is the sensitive target. Using the least-squares method to compare the effective doses for different sizes of the functional subunits with the experimental data the best fit was obtained with a length of about 9 mm. For the non-uniform dose distributions an effective FSU length of 8 mm gave the optimal fit with the probit dose-response model. The method could also be used to interpret the so-called bath and shower experiments where the heterogeneous dose delivery was used in the convolution process. The assumption of an effective FSU size is consistent with most of the effects seen when different portions of the rat spinal cord are irradiated to different doses. The effective FSU length from these experiments is about 8.5 ± 0.5 mm. This length could be interpreted as an effective size of the functional subunits in a rat spinal cord, where multiple myelin sheaths are connected by a single oligodendrocyte and repair is limited by the range of oligodendrocyte progenitor cell diffusion. It was even possible to suggest a more likely than uniform effective FSU sensitivity distribution from the experimental data.

Experimental design and response surface modelling for optimization of vat dye from water by nano zero valent iron (NZVI).

PubMed

Arabi, Simin; Sohrabi, Mahmoud Reza

2013-01-01

In this study, NZVI particles was prepared and studied for the removal of vat green 1 dye from aqueous solution. A four-factor central composite design (CCD) combined with response surface modeling (RSM) to evaluate the combined effects of variables as well as optimization was employed for maximizing the dye removal by prepared NZVI based on 30 different experimental data obtained in a batch study. Four independent variables, viz. NZVI dose (0.1-0.9 g/L), pH (1.5-9.5), contact time (20-100 s), and initial dye concentration (10-50 mg/L) were transform to coded values and quadratic model was built to predict the responses. The significant of independent variables and their interactions were tested by the analysis of variance (ANOVA). Adequacy of the model was tested by the correlation between experimental and predicted values of the response and enumeration of prediction errors. The ANOVA results indicated that the proposed model can be used to navigate the design space. Optimization of the variables for maximum adsorption of dye by NZVI particles was performed using quadratic model. The predicted maximum adsorption efficiency (96.97%) under the optimum conditions of the process variables (NZVI dose 0.5 g/L, pH 4, contact time 60 s, and initial dye concentration 30 mg/L) was very close to the experimental value (96.16%) determined in batch experiment. In the optimization, R2 and R2adj correlation coefficients for the model were evaluated as 0.95 and 0.90, respectively.

Pharmacometric Approaches to Personalize Use of Primarily Renally Eliminated Antibiotics in Preterm and Term Neonates.

PubMed

Wilbaux, Mélanie; Fuchs, Aline; Samardzic, Janko; Rodieux, Frédérique; Csajka, Chantal; Allegaert, Karel; van den Anker, Johannes N; Pfister, Marc

2016-08-01

Sepsis remains a major cause of mortality and morbidity in neonates, and, as a consequence, antibiotics are the most frequently prescribed drugs in this vulnerable patient population. Growth and dynamic maturation processes during the first weeks of life result in large inter- and intrasubject variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics. In this review we (1) summarize the available population PK data and models for primarily renally eliminated antibiotics, (2) discuss quantitative approaches to account for effects of growth and maturation processes on drug exposure and response, (3) evaluate current dose recommendations, and (4) identify opportunities to further optimize and personalize dosing strategies of these antibiotics in preterm and term neonates. Although population PK models have been developed for several of these drugs, exposure-response relationships of primarily renally eliminated antibiotics in these fragile infants are not well understood, monitoring strategies remain inconsistent, and consensus on optimal, personalized dosing of these drugs in these patients is absent. Tailored PK/PD studies and models are useful to better understand relationships between drug exposures and microbiological or clinical outcomes. Pharmacometric modeling and simulation approaches facilitate quantitative evaluation and optimization of treatment strategies. National and international collaborations and platforms are essential to standardize and harmonize not only studies and models but also monitoring and dosing strategies. Simple bedside decision tools assist clinical pharmacologists and neonatologists in their efforts to fine-tune and personalize the use of primarily renally eliminated antibiotics in term and preterm neonates. © 2016, The American College of Clinical Pharmacology.

Randomised controlled trials define shape of dose-response for Pollinex Quattro Birch allergoid immunotherapy.

PubMed

Worm, Margitta; Higenbottam, Tim; Pfaar, Oliver; Mösges, Ralph; Aberer, Werner; Gunawardena, Kulasiri; Wessiepe, Dorothea; Lee, Denise; Kramer, Matthias F; Skinner, Murray; Lees, Bev; Zielen, Stefan

2018-05-19

The Birch Allergoid, Tyrosine Adsorbate, Monophosphoryl Lipid A (POLLINEX ® Quattro Plus 1.0 ml Birch 100%) is an effective, well-tolerated short course subcutaneous immunotherapy. We performed two phase II studies to determine its optimal cumulative dose. The studies were conducted in Germany, Austria and Poland (EudraCT numbers: 2012-004336-28 PQBirch203 and 2015-000984-15 PQBirch204) using a wide range of cumulative doses. In both studies, subjects were administered 6 therapy injections weekly outside the pollen season. Conjunctival Provocation Tests were performed at screening, baseline and 3-4 weeks after completing treatment, to quantify the reduction of Total Symptom Scores (as the primary endpoint) with each cumulative dose. Multiple Comparison Procedure and Modelling analysis was used to test for the dose-response, shape of the curve, and estimation of the median effective dose (ED 50 ), a measure of potency. Statistically significant dose-responses (p<0.01 & 0.001) were seen respectively. The highest cumulative dose in PQBirch204 (27300 standardised units [SU]) approached a plateau. Potency of the PQ Birch was demonstrated by an ED 50 2723 SU, just over half the current dose. Prevalence of treatment-emergent adverse events was similar for active doses, most being short-lived and mild. Compliance was over 85% in all groups. Increasing the cumulative dose of PQ Birch 5.5-fold from 5100 to 27300 SU achieved an absolute point difference from placebo of 1.91, a relative difference 32.3% and an increase of efficacy of 50%, without compromising safety. The cumulative dose-response was confirmed to be curvilinear in shape. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

HEXAMETHONIUM AND HYDRALAZINE HYDROCHLORIDE—For Treatment of Hypertension

PubMed Central

Stuppy, Laurence J.

1954-01-01

Twenty-one patients have been treated for hypertension with oral doses of hexamethonium salts, Apresoline® or combinations of both. Three of 18 patients had good or excellent response to hexamethonium alone. Five of 13 treated with hexamethonium salts plus Apresoline had good or excellent results, as did 8 of 14 treated with Apresoline alone. The addition of very small doses of hexamethonium chloride to optimal doses of Apresoline improved the effect of the Apresoline in three patients. Postural hypotension and constipation due to hexamethonium were the most serious undesirable effects. PMID:13126825

Progesterone in experimental permanent stroke: a dose-response and therapeutic time-window study

PubMed Central

Wali, Bushra; Ishrat, Tauheed; Won, Soonmi; Stein, Donald G.

2014-01-01

Currently, the only approved treatment for ischaemic stroke is tissue plasminogen activator, a clot-buster. This treatment can have dangerous consequences if not given within the first 4 h after stroke. Our group and others have shown progesterone to be beneficial in preclinical studies of stroke, but a progesterone dose-response and time-window study is lacking. We tested male Sprague-Dawley rats (12 months old) with permanent middle cerebral artery occlusion or sham operations on multiple measures of sensory, motor and cognitive performance. For the dose-response study, animals received intraperitoneal injections of progesterone (8, 16 or 32 mg/kg) at 1 h post-occlusion, and subcutaneous injections at 6 h and then once every 24 h for 7 days. For the time-window study, the optimal dose of progesterone was given starting at 3, 6 or 24 h post-stroke. Behavioural recovery was evaluated at repeated intervals. Rats were killed at 22 days post-stroke and brains extracted for evaluation of infarct volume. Both 8 and 16 mg/kg doses of progesterone produced attenuation of infarct volume compared with the placebo, and improved functional outcomes up to 3 weeks after stroke on locomotor activity, grip strength, sensory neglect, gait impairment, motor coordination and spatial navigation tests. In the time-window study, the progesterone group exhibited substantial neuroprotection as late as 6 h after stroke onset. Compared with placebo, progesterone showed a significant reduction in infarct size with 3- and 6-h delays. Moderate doses (8 and 16 mg/kg) of progesterone reduced infarct size and improved functional deficits in our clinically relevant model of stroke. The 8 mg/kg dose was optimal in improving motor, sensory and memory function, and this effect was observed over a large therapeutic time window. Progesterone shows promise as a potential therapeutic agent and should be examined for safety and efficacy in a clinical trial for ischaemic stroke. PMID:24374329

Low- and high-dose laser irradiation effects on cell migration and destruction

NASA Astrophysics Data System (ADS)

Layton, Elivia; Gallagher, Kyra A.; Zukerman, Sara; Stevens, Brianna; Zhou, Feifan; Liu, Hong; Chen, Wei R.

2018-02-01

Metastases are the cause of more than 90 percent of cancer-related deaths. Current treatment methods, including chemotherapy, radiation, and surgery, fail to target the metastases effectively. One potential treatment for metastatic cancer is laser immunotherapy (LIT). LIT combines the use of a photothermal laser with an immunoadjuvant, Glycated Chitosan (GC). GC combined with single-walled carbon nanotubes (SWNTs) has proven to be a viable alternative to traditional cancer treatment methods, when under irradiation of laser with appropriate wavelength. In this study, the effects of low dose and high dose laser irradiation on metastatic pancreatic cancer cell migration were observed. It was found that low dose irradiation increased the migration rate, but the high dose irradiation significantly decreased the migration rate of the cancer cells. When using LIT, the goal is to kill tumor cells and to prompt the correct immune response. If the tumor were irradiated with a low dose, it would promote metastasis. If the dose of irradiation were too high, it would destroy the entire tumor and the immune response would not recognize the tumor. Therefore, the laser dose plays an important role in LIT, particularly when using SWNT as light absorbing agent. Our results from this study will delineate the optimal laser irradiation dose for destroying tumor cells and at the same time preserve and release tumor antigens as a precursor of antitumor immune response.

Development of a pharmacokinetic-guided dose individualization strategy for hydroxyurea treatment in children with sickle cell anaemia.

PubMed

Dong, Min; McGann, Patrick T; Mizuno, Tomoyuki; Ware, Russell E; Vinks, Alexander A

2016-04-01

Hydroxyurea has emerged as the primary disease-modifying therapy for patients with sickle cell anaemia (SCA). The laboratory and clinical benefits of hydroxyurea are optimal at maximum tolerated dose (MTD), but the current empirical dose escalation process often takes up to 12 months. The purpose of this study was to develop a pharmacokinetic-guided dosing strategy to reduce the time required to reach hydroxyurea MTD in children with SCA. Pharmacokinetic (PK) data from the HUSTLE trial (NCT00305175) were used to develop a population PK model using non-linear mixed effects modelling (nonmem 7.2). A D-optimal sampling strategy was developed to estimate individual PK and hydroxyurea exposure (area under the concentration-time curve (AUC)). The initial AUC target was derived from HUSTLE clinical data and defined as the mean AUC at MTD. PK profiles were best described by a one compartment with Michaelis-Menten elimination and a transit absorption model. Body weight and cystatin C were identified as significant predictors of hydroxyurea clearance. The following clinically feasible sampling times are included in a new prospective protocol: pre-dose (baseline), 15-20 min, 50-60 min and 3 h after an initial 20 mg kg(-1) oral dose. The mean target AUC(0,∞) for initial dose titration was 115 mg l(-1)  h. We developed a PK model-based individualized dosing strategy for the prospective Therapeutic Response Evaluation and Adherence Trial (TREAT, ClinicalTrials.gov NCT02286154). This approach has the potential to optimize the dose titration of hydroxyurea therapy for children with SCA, such that the clinical benefits at MTD are achieved more quickly. © 2015 The British Pharmacological Society.

Development of a pharmacokinetic‐guided dose individualization strategy for hydroxyurea treatment in children with sickle cell anaemia

PubMed Central

Dong, Min; McGann, Patrick T.; Mizuno, Tomoyuki; Ware, Russell E.

2016-01-01

AIMS Hydroxyurea has emerged as the primary disease‐modifying therapy for patients with sickle cell anaemia (SCA). The laboratory and clinical benefits of hydroxyurea are optimal at maximum tolerated dose (MTD), but the current empirical dose escalation process often takes up to 12 months. The purpose of this study was to develop a pharmacokinetic‐guided dosing strategy to reduce the time required to reach hydroxyurea MTD in children with SCA. Methods Pharmacokinetic (PK) data from the HUSTLE trial (NCT00305175) were used to develop a population PK model using non‐linear mixed effects modelling (nonmem 7.2). A D‐optimal sampling strategy was developed to estimate individual PK and hydroxyurea exposure (area under the concentration–time curve (AUC)). The initial AUC target was derived from HUSTLE clinical data and defined as the mean AUC at MTD. Results PK profiles were best described by a one compartment with Michaelis–Menten elimination and a transit absorption model. Body weight and cystatin C were identified as significant predictors of hydroxyurea clearance. The following clinically feasible sampling times are included in a new prospective protocol: pre‐dose (baseline), 15–20 min, 50–60 min and 3 h after an initial 20 mg kg–1 oral dose. The mean target AUC(0,∞) for initial dose titration was 115 mg l–1 h. Conclusion We developed a PK model‐based individualized dosing strategy for the prospective Therapeutic Response Evaluation and Adherence Trial (TREAT, ClinicalTrials.gov NCT02286154). This approach has the potential to optimize the dose titration of hydroxyurea therapy for children with SCA, such that the clinical benefits at MTD are achieved more quickly. PMID:26615061

Biphasic Dose Response in Low Level Light Therapy – An Update

PubMed Central

Huang, Ying-Ying; Sharma, Sulbha K; Carroll, James; Hamblin, Michael R

2011-01-01

Low-level laser (light) therapy (LLLT) has been known since 1967 but still remains controversial due to incomplete understanding of the basic mechanisms and the selection of inappropriate dosimetric parameters that led to negative studies. The biphasic dose-response or Arndt-Schulz curve in LLLT has been shown both in vitro studies and in animal experiments. This review will provide an update to our previous (Huang et al. 2009) coverage of this topic. In vitro mediators of LLLT such as adenosine triphosphate (ATP) and mitochondrial membrane potential show biphasic patterns, while others such as mitochondrial reactive oxygen species show a triphasic dose-response with two distinct peaks. The Janus nature of reactive oxygen species (ROS) that may act as a beneficial signaling molecule at low concentrations and a harmful cytotoxic agent at high concentrations, may partly explain the observed responses in vivo. Transcranial LLLT for traumatic brain injury (TBI) in mice shows a distinct biphasic pattern with peaks in beneficial neurological effects observed when the number of treatments is varied, and when the energy density of an individual treatment is varied. Further understanding of the extent to which biphasic dose responses apply in LLLT will be necessary to optimize clinical treatments. PMID:22461763

Dose to mass for evaluation and optimization of lung cancer radiation therapy.

PubMed

Tyler Watkins, William; Moore, Joseph A; Hugo, Geoffrey D; Siebers, Jeffrey V

2017-11-01

To evaluate potential organ at risk dose-sparing by using dose-mass-histogram (DMH) objective functions compared with dose-volume-histogram (DVH) objective functions. Treatment plans were retrospectively optimized for 10 locally advanced non-small cell lung cancer patients based on DVH and DMH objectives. DMH-objectives were the same as DVH objectives, but with mass replacing volume. Plans were normalized to dose to 95% of the PTV volume (PTV-D95v) or mass (PTV-D95m). For a given optimized dose, DVH and DMH were intercompared to ascertain dose-to-volume vs. dose-to-mass differences. Additionally, the optimized doses were intercompared using DVH and DMH metrics to ascertain differences in optimized plans. Mean dose to volume, D v ‾, mean dose to mass, D M ‾, and fluence maps were intercompared. For a given dose distribution, DVH and DMH differ by >5% in heterogeneous structures. In homogeneous structures including heart and spinal cord, DVH and DMH are nearly equivalent. At fixed PTV-D95v, DMH-optimization did not significantly reduce dose to OARs but reduced PTV-D v ‾ by 0.20±0.2Gy (p=0.02) and PTV-D M ‾ by 0.23±0.3Gy (p=0.02). Plans normalized to PTV-D95m also result in minor PTV dose reductions and esophageal dose sparing (D v ‾ reduced 0.45±0.5Gy, p=0.02 and D M ‾ reduced 0.44±0.5Gy, p=0.02) compared to DVH-optimized plans. Optimized fluence map comparisons indicate that DMH optimization reduces dose in the periphery of lung PTVs. DVH- and DMH-dose indices differ by >5% in lung and lung target volumes for fixed dose distributions, but optimizing DMH did not reduce dose to OARs. The primary difference observed in DVH- and DMH-optimized plans were variations in fluence to the periphery of lung target PTVs, where low density lung surrounds tumor. Copyright © 2017 Elsevier B.V. All rights reserved.

The effect of statistical noise on IMRT plan quality and convergence for MC-based and MC-correction-based optimized treatment plans.

PubMed

Siebers, Jeffrey V

2008-04-04

Monte Carlo (MC) is rarely used for IMRT plan optimization outside of research centres due to the extensive computational resources or long computation times required to complete the process. Time can be reduced by degrading the statistical precision of the MC dose calculation used within the optimization loop. However, this eventually introduces optimization convergence errors (OCEs). This study determines the statistical noise levels tolerated during MC-IMRT optimization under the condition that the optimized plan has OCEs <100 cGy (1.5% of the prescription dose) for MC-optimized IMRT treatment plans.Seven-field prostate IMRT treatment plans for 10 prostate patients are used in this study. Pre-optimization is performed for deliverable beams with a pencil-beam (PB) dose algorithm. Further deliverable-based optimization proceeds using: (1) MC-based optimization, where dose is recomputed with MC after each intensity update or (2) a once-corrected (OC) MC-hybrid optimization, where a MC dose computation defines beam-by-beam dose correction matrices that are used during a PB-based optimization. Optimizations are performed with nominal per beam MC statistical precisions of 2, 5, 8, 10, 15, and 20%. Following optimizer convergence, beams are re-computed with MC using 2% per beam nominal statistical precision and the 2 PTV and 10 OAR dose indices used in the optimization objective function are tallied. For both the MC-optimization and OC-optimization methods, statistical equivalence tests found that OCEs are less than 1.5% of the prescription dose for plans optimized with nominal statistical uncertainties of up to 10% per beam. The achieved statistical uncertainty in the patient for the 10% per beam simulations from the combination of the 7 beams is ~3% with respect to maximum dose for voxels with D>0.5D(max). The MC dose computation time for the OC-optimization is only 6.2 minutes on a single 3 Ghz processor with results clinically equivalent to high precision MC computations.

Time and dose-response effects of honokiol on UVB-induced skin cancer development.

PubMed

Guillermo, Ruth F; Chilampalli, Chandeshwari; Zhang, Xiaoying; Zeman, David; Fahmy, Hesham; Dwivedi, Chandradhar

2012-06-01

Honokiol has shown chemopreventive effects in chemically-induced and UVB-induced skin cancer in mice. In this investigation, we assessed the time-effects of a topical low dose of honokiol (30 μg), and then the effects of different honokiol doses (30, 45, and 60 μg) on a UVB-induced skin cancer model to find an optimal dose and time for desirable chemopreventive effects. UVB radiation (30 mJ/cm(2), 5 days/week for 25 or 27 weeks) was used to induce skin carcinogenesis in SKH-1 mice. For the time-response experiment 30 μg honokiol in acetone was applied topically to the animals before the UVB exposure (30 min, 1 h, and 2 h) and after the UVB exposure (immediately, 30 min, and 1 h). Control groups were treated with acetone. For the dose-response study, animals were treated topically with acetone or honokiol (30, 45, and 60 μg) one hour before the UVB exposure. In the time-response experiment, honokiol inhibited skin tumor multiplicity by 49-58% while reducing tumor volumes by 70-89%. In the dose-response study, honokiol (30, 45, and 60 μg) significantly decreased skin tumor multiplicity by 36-78% in a dose-dependent manner, while tumor area was reduced by 76-94%. Honokiol (60 μg) significantly reduced tumor incidence by 40% as compared to control group. Honokiol applied in very low doses (30 μg) either before or after UVB radiation shows chemopreventive effects. Honokiol (30, 45, and 60 μg) prevents UVB-induced skin cancer in a dose-dependent manner. Honokiol can be an effective chemopreventive agent against skin cancer.

Optimization of Methylphenidate Extended-Release Chewable Tablet Dose in Children with ADHD: Open-Label Dose Optimization in a Laboratory Classroom Study.

PubMed

Wigal, Sharon B; Childress, Ann; Berry, Sally A; Belden, Heidi W; Chappell, Phillip; Wajsbrot, Dalia B; Nagraj, Praneeta; Abbas, Richat; Palumbo, Donna

2018-06-01

To examine methylphenidate extended-release chewable tablets (MPH ERCT) dose patterns, attention-deficit/hyperactivity disorder (ADHD) symptom scores, and safety during the 6-week, open-label (OL) dose-optimization period of a phase 3, laboratory classroom study. Boys and girls (6-12 years) diagnosed with ADHD were enrolled. MPH ERCT was initiated at 20 mg/day; participants were titrated in 10-20 mg/day increments weekly based on efficacy and tolerability (maximum dose, 60 mg/day). Dose-optimization period efficacy assessments included the ADHD Rating Scale (ADHD-RS-IV), analyzed by week in a post hoc analysis using a mixed-effects model for repeated measures with final optimized dose (20, 30/40, or 50/60 mg), visit, final optimized dose and visit interaction, and baseline score as terms. Adverse events (AEs) and concomitant medications were collected throughout the study. Mean MPH ERCT daily dose increased weekly from 29.4 mg/day after the first dose adjustment at week 1 (n = 90) to 42.8 mg/day after the final adjustment at week 5 (n = 86). Final optimized MPH ERCT dose ranged from 20 to 60 mg/day. Mean final optimized MPH ERCT dose ranged from 40.0 mg/day in 6-8 year-old participants to 44.8 mg/day for 11-12 year-old participants. There was a progressive decrease in mean (standard deviation) ADHD-RS-IV total score from 40.1 (8.72) at baseline to 12.4 (7.88) at OL week 5, with similar improvement patterns for hyperactivity/impulsivity and inattentiveness subscale scores. Participants optimized to MPH ERCT 50/60 mg/day had a significantly higher mean (standard error) ADHD-RS-IV score at baseline compared with participants optimized to MPH ERCT 20 mg/day (42.4 [1.34] vs. 35.1 [2.55]; p = 0.013). Treatment-emergent AEs were reported by 65/90 (72.2%) participants in the dose-optimization period. Dose-optimization period results describing relationships between change in ADHD symptom scores and final optimized MPH ERCT dose will be valuable for clinicians optimizing MPH ERCT dose.

Dose-mass inverse optimization for minimally moving thoracic lesions

NASA Astrophysics Data System (ADS)

Mihaylov, I. B.; Moros, E. G.

2015-05-01

In the past decade, several different radiotherapy treatment plan evaluation and optimization schemes have been proposed as viable approaches, aiming for dose escalation or an increase of healthy tissue sparing. In particular, it has been argued that dose-mass plan evaluation and treatment plan optimization might be viable alternatives to the standard of care, which is realized through dose-volume evaluation and optimization. The purpose of this investigation is to apply dose-mass optimization to a cohort of lung cancer patients and compare the achievable healthy tissue sparing to that one achievable through dose-volume optimization. Fourteen non-small cell lung cancer (NSCLC) patient plans were studied retrospectively. The range of tumor motion was less than 0.5 cm and motion management in the treatment planning process was not considered. For each case, dose-volume (DV)-based and dose-mass (DM)-based optimization was performed. Nine-field step-and-shoot IMRT was used, with all of the optimization parameters kept the same between DV and DM optimizations. Commonly used dosimetric indices (DIs) such as dose to 1% the spinal cord volume, dose to 50% of the esophageal volume, and doses to 20 and 30% of healthy lung volumes were used for cross-comparison. Similarly, mass-based indices (MIs), such as doses to 20 and 30% of healthy lung masses, 1% of spinal cord mass, and 33% of heart mass, were also tallied. Statistical equivalence tests were performed to quantify the findings for the entire patient cohort. Both DV and DM plans for each case were normalized such that 95% of the planning target volume received the prescribed dose. DM optimization resulted in more organs at risk (OAR) sparing than DV optimization. The average sparing of cord, heart, and esophagus was 23, 4, and 6%, respectively. For the majority of the DIs, DM optimization resulted in lower lung doses. On average, the doses to 20 and 30% of healthy lung were lower by approximately 3 and 4%, whereas lung volumes receiving 2000 and 3000 cGy were lower by 3 and 2%, respectively. The behavior of MIs was very similar. The statistical analyses of the results again indicated better healthy anatomical structure sparing with DM optimization. The presented findings indicate that dose-mass-based optimization results in statistically significant OAR sparing as compared to dose-volume-based optimization for NSCLC. However, the sparing is case-dependent and it is not observed for all tallied dosimetric endpoints.

The effect of glucose dose and fasting interval on cognitive function: a double-blind, placebo-controlled, six-way crossover study.

PubMed

Owen, Lauren; Scholey, Andrew B; Finnegan, Yvonne; Hu, Henglong; Sünram-Lea, Sandra I

2012-04-01

Previous research has identified a number of factors that appear to moderate the behavioural response to glucose administration. These include physiological state, dose, types of cognitive tasks used and level of cognitive demand. Another potential moderating factor is the length of the fasting interval prior to a glucose load. Therefore, we aimed to examine the effect of glucose dose and fasting interval on mood and cognitive function. The current study utilised a double-blind, placebo-controlled, balanced, six period crossover design to examine potential interactions between length of fasting interval (2 versus 12 hours) and optimal dose for cognition enhancement. Results demonstrated that the higher dose (60 g) increased working memory performance following an overnight fast, whereas the lower dose (25 g) enhanced working memory performance following a 2-h fast. The data suggest that optimal glucose dosage may differ under different conditions of depleted blood glucose resources. In addition, glucoregulation was observed to be a moderating factor. However, further research is needed to develop a model of the moderating and mediating factors under which glucose facilitation is best achieved.

Comparison of dose volume parameters evaluated using three forward planning – optimization techniques in cervical cancer brachytherapy involving two applicators

PubMed Central

Basu-Roy, Somapriya; Kar, Sanjay Kumar; Das, Sounik; Lahiri, Annesha

2017-01-01

Purpose This study is intended to compare dose-volume parameters evaluated using different forward planning- optimization techniques, involving two applicator systems in intracavitary brachytherapy for cervical cancer. It looks for the best applicator-optimization combination to fulfill recommended dose-volume objectives in different high-dose-rate (HDR) fractionation schedules. Material and methods We used tandem-ring and Fletcher-style tandem-ovoid applicator in same patients in two fractions of brachytherapy. Six plans were generated for each patient utilizing 3 forward optimization techniques for each applicator used: equal dwell weight/times (‘no optimization’), ‘manual dwell weight/times’, and ‘graphical’. Plans were normalized to left point A and dose of 8 Gy was prescribed. Dose volume and dose point parameters were compared. Results Without graphical optimization, maximum width and thickness of volume enclosed by 100% isodose line, dose to 90%, and 100% of clinical target volume (CTV); minimum, maximum, median, and average dose to both rectum and bladder are significantly higher with Fletcher applicator. Even if it is done, dose to both points B, minimum dose to CTV, and treatment time; dose to 2 cc (D2cc) rectum and rectal point etc.; D2cc, minimum, maximum, median, and average dose to sigmoid colon; D2cc of bladder remain significantly higher with this applicator. Dose to bladder point is similar (p > 0.05) between two applicators, after all optimization techniques. Conclusions Fletcher applicator generates higher dose to both CTV and organs at risk (2 cc volumes) after all optimization techniques. Dose restriction to rectum is possible using graphical optimization only during selected HDR fractionation schedules. Bladder always receives dose higher than recommended, and 2 cc sigmoid colon always gets permissible dose. Contrarily, graphical optimization with ring applicators fulfills all dose volume objectives in all HDR fractionations practiced. PMID:29204164

Application of PK/PD Modeling in Veterinary Field: Dose Optimization and Drug Resistance Prediction

PubMed Central

Ahmad, Ijaz; Huang, Lingli; Hao, Haihong; Sanders, Pascal; Yuan, Zonghui

2016-01-01

Among veterinary drugs, antibiotics are frequently used. The true mean of antibiotic treatment is to administer dose of drug that will have enough high possibility of attaining the preferred curative effect, with adequately low chance of concentration associated toxicity. Rising of antibacterial resistance and lack of novel antibiotic is a global crisis; therefore there is an urgent need to overcome this problem. Inappropriate antibiotic selection, group treatment, and suboptimal dosing are mostly responsible for the mentioned problem. One approach to minimizing the antibacterial resistance is to optimize the dosage regimen. PK/PD model is important realm to be used for that purpose from several years. PK/PD model describes the relationship between drug potency, microorganism exposed to drug, and the effect observed. Proper use of the most modern PK/PD modeling approaches in veterinary medicine can optimize the dosage for patient, which in turn reduce toxicity and reduce the emergence of resistance. The aim of this review is to look at the existing state and application of PK/PD in veterinary medicine based on in vitro, in vivo, healthy, and disease model. PMID:26989688

Maximizing Tumor Immunity With Fractionated Radiation

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

Schaue, Doerthe, E-mail: dschaue@mednet.ucla.edu; Ratikan, Josephine A.; Iwamoto, Keisuke S.

Purpose: Technologic advances have led to increased clinical use of higher-sized fractions of radiation dose and higher total doses. How these modify the pathways involved in tumor cell death, normal tissue response, and signaling to the immune system has been inadequately explored. Here we ask how radiation dose and fraction size affect antitumor immunity, the suppression thereof, and how this might relate to tumor control. Methods and Materials: Mice bearing B16-OVA murine melanoma were treated with up to 15 Gy radiation given in various-size fractions, and tumor growth followed. The tumor-specific immune response in the spleen was assessed by interferon-{gamma}more » enzyme-linked immunospot (ELISPOT) assay with ovalbumin (OVA) as the surrogate tumor antigen and the contribution of regulatory T cells (Tregs) determined by the proportion of CD4{sup +}CD25{sup hi}Foxp3{sup +} T cells. Results: After single doses, tumor control increased with the size of radiation dose, as did the number of tumor-reactive T cells. This was offset at the highest dose by an increase in Treg representation. Fractionated treatment with medium-size radiation doses of 7.5 Gy/fraction gave the best tumor control and tumor immunity while maintaining low Treg numbers. Conclusions: Radiation can be an immune adjuvant, but the response varies with the size of dose per fraction. The ultimate challenge is to optimally integrate cancer immunotherapy into radiation therapy.« less

Reduced tyrosine kinase inhibitor dose is predicted to be as effective as standard dose in chronic myeloid leukemia: A simulation study based on phase 3 trial data.

PubMed

Fassoni, Artur C; Baldow, Christoph; Roeder, Ingo; Glauche, Ingmar

2018-06-28

Continuing tyrosine kinase inhibitor mediated targeting of the BCR-ABL1 oncoprotein is the standard therapy for chronic myeloid leukemia and allows for a sustained disease control in the majority of patients. While therapy cessation for patients appeared as a safe option for about half of the optimally responding patients, a systematic assessment of long-term tyrosine kinase inhibitor dose de-escalation is missing. We use a mathematical model to analyze and consistently describe biphasic treatment responses from tyrosine kinase inhibitor treated patients from two independent clinical phase-3 trials. Scale estimates reveal that drug efficiency determines the initial response while the long-term behavior is limited by the rare activation of leukemic stem cells. We use this mathematical framework to investigate the influence of different dosing regimens on the treatment outcome. We provide strong evidence suggesting that tyrosine kinase inhibitor dose de-escalation (at least 50%) does not lead to a reduction of long-term treatment efficiency for most patients, which have already achieved sustained remission, and maintains the secondary decline of BCR-ABL1 levels. We demonstrate that continuous BCR-ABL1 monitoring provides patient-specific predictions of an optimal reduced dose not decreasing the anti-leukemic effect on residual leukemic stem cells. Our results are consistent with the interim results of the DESTINY trial and provide clinically testable predictions. Our results suggest that dose halving should be considered as a long-term treatment option for well-responding chronic myeloid leukemia patients under continuing maintenance therapy with tyrosine kinase inhibitors. We emphasize the clinical potential of this approach to reduce treatment-related side-effects and therapy costs. Copyright © 2018, Ferrata Storti Foundation.

A Prospective, Randomized, Open-Label, Blinded, Endpoint Study Exploring Platelet Response to Half-Dose Prasugrel and Ticagrelor in Patients with the Acute Coronary Syndrome: HOPE-TAILOR Study.

PubMed

Jin, Cai De; Kim, Moo Hyun; Bang, Junghee; Serebruany, Victor

The optimal dosing of novel oral P2Y12 receptor platelet inhibitors such as prasugrel or ticagrelor is unclear and especially challenging in East Asians. We hypothesize that half-dose prasugrel and ticagrelor may be sufficient for long-term maintenance management in Korean patients with the acute coronary syndrome (ACS) compared with conventional dosages. HOPE-TAILOR (Half Dose of Prasugrel and Ticagrelor in Platelet Response after Acute Coronary Syndromes) is a prospective, randomized, open-label, blinded, endpoint (PROBE) single-center, clinical trial. A total of 100 patients with ACS undergoing drug-eluting stent implantation will be randomly assigned to prasugrel, ticagrelor, or clopidogrel, and the patients in each treatment group will receive 1-month therapy with 100 mg q.d. aspirin plus prasugrel 10 mg q.d., ticagrelor 90 mg b.i.d., or clopidogrel 75 mg q.d., followed by half-dose prasugrel 5 mg q.d. or ticagrelor 45 mg b.i.d. for maintenance treatment but without clopidogrel dose reduction. The primary endpoint will be optimal platelet reactivity 3 months after coronary intervention, defined by VerifyNow Analyzer (PRU: 85-208) and vasodilator-stimulated phosphoprotein P2Y12 flow cytometry assay (platelet reactivity indices: 16-50%). Clinical outcomes will also be assessed, including major efficacy (composite of cardiac death, nonfatal myocardial infarction, repeat revascularization, or stroke) and safety (bleeding ≥2 according to the Bleeding Academic Research Consortium). HOPE-TAILOR is a prospective, randomized, open-label, blinded, endpoint study to explore the efficacy and safety of novel P2Y12 receptor inhibitors administered orally at half the dose in Korean patients with ACS. The results will be available late in 2017. © 2017 S. Karger AG, Basel.

Proceedings of the 2016 Clinical Nutrition Week Research Workshop-The Optimal Dose of Protein Provided to Critically Ill Patients.

PubMed

Heyland, Daren K; Rooyakers, Olav; Mourtzakis, Marina; Stapleton, Renee D

2017-02-01

Recent literature has created considerable confusion about the optimal amount of protein/amino acids that should be provided to the critically ill patient. In fact, the evidentiary basis that directly tries to answer this question is relatively small. As a clinical nutrition research community, there is an urgent need to develop the optimal methods to assess the impact of exogenous protein/amino acid administration in the intensive care unit setting. That assessment can be conducted at various levels: (1) impact on stress response pathways, (2) impact on muscle synthesis and protein balance, (3) impact on muscle mass and function, and (4) impact on the patient's recovery. The objective of this research workshop was to review current literature relating to protein/amino acid administration for the critically ill patient and clinical outcomes and to discuss the key measurement and methodological features of future studies that should be done to inform the optimal protein/amino acid dose provided to critically ill patients.

Design considerations and analysis planning of a phase 2a proof of concept study in rheumatoid arthritis in the presence of possible non-monotonicity.

PubMed

Liu, Feng; Walters, Stephen J; Julious, Steven A

2017-10-02

It is important to quantify the dose response for a drug in phase 2a clinical trials so the optimal doses can then be selected for subsequent late phase trials. In a phase 2a clinical trial of new lead drug being developed for the treatment of rheumatoid arthritis (RA), a U-shaped dose response curve was observed. In the light of this result further research was undertaken to design an efficient phase 2a proof of concept (PoC) trial for a follow-on compound using the lessons learnt from the lead compound. The planned analysis for the Phase 2a trial for GSK123456 was a Bayesian Emax model which assumes the dose-response relationship follows a monotonic sigmoid "S" shaped curve. This model was found to be suboptimal to model the U-shaped dose response observed in the data from this trial and alternatives approaches were needed to be considered for the next compound for which a Normal dynamic linear model (NDLM) is proposed. This paper compares the statistical properties of the Bayesian Emax model and NDLM model and both models are evaluated using simulation in the context of adaptive Phase 2a PoC design under a variety of assumed dose response curves: linear, Emax model, U-shaped model, and flat response. It is shown that the NDLM method is flexible and can handle a wide variety of dose-responses, including monotonic and non-monotonic relationships. In comparison to the NDLM model the Emax model excelled with higher probability of selecting ED90 and smaller average sample size, when the true dose response followed Emax like curve. In addition, the type I error, probability of incorrectly concluding a drug may work when it does not, is inflated with the Bayesian NDLM model in all scenarios which would represent a development risk to pharmaceutical company. The bias, which is the difference between the estimated effect from the Emax and NDLM models and the simulated value, is comparable if the true dose response follows a placebo like curve, an Emax like curve, or log linear shape curve under fixed dose allocation, no adaptive allocation, half adaptive and adaptive scenarios. The bias though is significantly increased for the Emax model if the true dose response follows a U-shaped curve. In most cases the Bayesian Emax model works effectively and efficiently, with low bias and good probability of success in case of monotonic dose response. However, if there is a belief that the dose response could be non-monotonic then the NDLM is the superior model to assess the dose response.

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.

Recommendations for optimizing methotrexate treatment for patients with rheumatoid arthritis

PubMed Central

Bello, Alfonso E; Perkins, Elizabeth L; Jay, Randy; Efthimiou, Petros

2017-01-01

Methotrexate (MTX) remains the cornerstone therapy for patients with rheumatoid arthritis (RA), with well-established safety and efficacy profiles and support in international guidelines. Clinical and radiologic results indicate benefits of MTX monotherapy and combination with other agents, yet patients may not receive optimal dosing, duration, or route of administration to maximize their response to this drug. This review highlights best practices for MTX use in RA patients. First, to improve the response to oral MTX, a high initial dose should be administered followed by rapid titration. Importantly, this approach does not appear to compromise safety or tolerability for patients. Treatment with oral MTX, with appropriate dose titration, then should be continued for at least 6 months (as long as the patient experiences some response to treatment within 3 months) to achieve an accurate assessment of treatment efficacy. If oral MTX treatment fails due to intolerability or inadequate response, the patient may be “rescued” by switching to subcutaneous delivery of MTX. Consideration should also be given to starting with subcutaneous MTX given its favorable bioavailability and pharmacodynamic profile over oral delivery. Either initiation of subcutaneous MTX therapy or switching from oral to subcutaneous administration improves persistence with treatment. Upon transition from oral to subcutaneous delivery, MTX dosage should be maintained, rather than increased, and titration should be performed as needed. Similarly, if another RA treatment is necessary to control the disease, the MTX dosage and route of administration should be maintained, with titration as needed. PMID:28435338

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.

Responses to simulated nitrogen deposition by the neotropical epiphytic orchid Laelia speciosa

PubMed Central

Díaz-Álvarez, Edison A.; Lindig-Cisneros, Roberto

2015-01-01

Potential ecophysiological responses to nitrogen deposition, which is considered to be one of the leading causes for global biodiversity loss, were studied for the endangered endemic Mexican epiphytic orchid, Laelia speciosa, via a shadehouse dose-response experiment (doses were 2.5, 5, 10, 20, 40, and 80 kg N ha−1 yr−1) in order to assess the potential risk facing this orchid given impending scenarios of nitrogen deposition. Lower doses of nitrogen of up to 20 kg N ha yr−1, the dose that led to optimal plant performance, acted as fertilizer. For instance, the production of leaves and pseudobulbs were respectively 35% and 36% greater for plants receiving 20 kg N ha yr−1 than under any other dose. Also, the chlorophyll content and quantum yield peaked at 0.66 ± 0.03 g m−2 and 0.85 ± 0.01, respectively, for plants growing under the optimum dose. In contrast, toxic effects were observed at the higher doses of 40 and 80 kg N ha yr−1. The δ13C for leaves averaged −14.7 ± 0.2‰ regardless of the nitrogen dose. In turn, δ15N decreased as the nitrogen dose increased from 0.9 ± 0.1‰ under 2.5 kg N ha−1yr−1 to −3.1 ± 0.2‰ under 80 kg N ha−1yr−1, indicating that orchids preferentially assimilate NH4+ rather than NO3− of the solution under higher doses of nitrogen. Laelia speciosa showed a clear response to inputs of nitrogen, thus, increasing rates of atmospheric nitrogen deposition can pose an important threat for this species. PMID:26131375

Update 2014: advances to optimize 6-mercaptopurine and azathioprine to reduce toxicity and improve efficacy in the management of IBD.

PubMed

Amin, Jaimin; Huang, Brian; Yoon, Jessica; Shih, David Q

2015-02-01

The thiopurine drugs, 6-mercaptopurine (6-MP) and azathioprine (AZA), remain as a mainstay therapy in inflammatory bowel disease (IBD). Differences in metabolism of these drugs lead to individual variation in thiopurine metabolite levels that can determine its therapeutic efficacy and development of adverse reactions. In this update, we will review thiopurine metabolic pathway along with the up-to-date approaches in administering thiopurine medications based on the current literature. A search of the PubMed database by 2 independent reviewers identifying 98 articles evaluating thiopurine metabolism and IBD management. Monitoring thiopurine metabolites can assist physicians in optimizing 6-MP and AZA therapy in treating patients with IBD. Of the dosing strategies reviewed, we found evidence for monitoring thiopurine metabolite level, use of allopurinol with thiopurine, use of mesalamine with thiopurine, combination therapy with thiopurine and anti-tumor necrosis factor agents, and split dosing of AZA or 6-MP to optimize thiopurine therapy and minimize adverse effects in IBD. Based on the currently available literature, various dosing strategies to improve therapeutic response and reduce adverse reactions can be considered, including use of allopurinol with thiopurine, use of mesalamine with thiopurine, combination therapy with thiopurine and anti-tumor necrosis factor agents, and split dosing of thiopurine.

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

Zhang, P; Kuo, L; Yorke, E

Purpose: To develop a biological modeling strategy which incorporates the response observed on the mid-treatment PET/CT into a dose escalation design for adaptive radiotherapy of non-small-cell lung cancer. Method: FDG-PET/CT was acquired midway through standard fractionated treatment and registered to pre-treatment planning PET/CT to evaluate radiation response of lung cancer. Each mid-treatment PET voxel was assigned the median SUV inside a concentric 1cm-diameter sphere to account for registration and imaging uncertainties. For each voxel, the planned radiation dose, pre- and mid-treatment SUVs were used to parameterize the linear-quadratic model, which was then utilized to predict the SUV distribution after themore » full prescribed dose. Voxels with predicted post-treatment SUV≥2 were identified as the resistant target (response arm). An adaptive simultaneous integrated boost was designed to escalate dose to the resistant target as high as possible, while keeping prescription dose to the original target and lung toxicity intact. In contrast, an adaptive target volume was delineated based only on the intensity of mid-treatment PET/CT (intensity arm), and a similar adaptive boost plan was optimized. The dose escalation capability of the two approaches was compared. Result: Images of three patients were used in this planning study. For one patient, SUV prediction indicated complete response and no necessary dose escalation. For the other two, resistant targets defined in the response arm were multifocal, and on average accounted for 25% of the pre-treatment target, compared to 67% in the intensity arm. The smaller response arm targets led to a 6Gy higher mean target dose in the adaptive escalation design. Conclusion: This pilot study suggests that adaptive dose escalation to a biologically resistant target predicted from a pre- and mid-treatment PET/CT may be more effective than escalation based on the mid-treatment PET/CT alone. More plans and ultimately clinical protocols are needed to validate this approach. MSKCC has a research agreement with Varian Medical System.« less

Translational PK/PD of Anti-Infective Therapeutics

PubMed Central

Rathi, Chetan; Lee, Richard E.; Meibohm, Bernd

2016-01-01

Translational PK/PD modeling has emerged as a critical technique for quantitative analysis of the relationship between dose, exposure and response of antibiotics. By combining model components for pharmacokinetics, bacterial growth kinetics and concentration-dependent drug effects, these models are able to quantitatively capture and simulate the complex interplay between antibiotic, bacterium and host organism. Fine-tuning of these basic model structures allows to further account for complicating factors such as resistance development, combination therapy, or host responses. With this tool set at hand, mechanism-based PK/PD modeling and simulation allows to develop optimal dosing regimens for novel and established antibiotics for maximum efficacy and minimal resistance development. PMID:27978987

Older patients with chronic myeloid leukemia (≥65 years) profit more from higher imatinib doses than younger patients: a subanalysis of the randomized CML-Study IV.

PubMed

Proetel, Ulrike; Pletsch, Nadine; Lauseker, Michael; Müller, Martin C; Hanfstein, Benjamin; Krause, Stefan W; Kalmanti, Lida; Schreiber, Annette; Heim, Dominik; Baerlocher, Gabriela M; Hofmann, Wolf-Karsten; Lange, Elisabeth; Einsele, Hermann; Wernli, Martin; Kremers, Stephan; Schlag, Rudolf; Müller, Lothar; Hänel, Mathias; Link, Hartmut; Hertenstein, Bernd; Pfirrman, Markus; Hochhaus, Andreas; Hasford, Joerg; Hehlmann, Rüdiger; Saußele, Susanne

2014-07-01

The impact of imatinib dose on response rates and survival in older patients with chronic myeloid leukemia in chronic phase has not been studied well. We analyzed data from the German CML-Study IV, a randomized five-arm treatment optimization study in newly diagnosed BCR-ABL-positive chronic myeloid leukemia in chronic phase. Patients randomized to imatinib 400 mg/day (IM400) or imatinib 800 mg/day (IM800) and stratified according to age (≥65 years vs. <65 years) were compared regarding dose, response, adverse events, rates of progression, and survival. The full 800 mg dose was given after a 6-week run-in period with imatinib 400 mg/day. The dose could then be reduced according to tolerability. A total of 828 patients were randomized to IM400 or IM800. Seven hundred eighty-four patients were evaluable (IM400, 382; IM800, 402). One hundred ten patients (29 %) on IM400 and 83 (21 %) on IM800 were ≥65 years. The median dose per day was lower for patients ≥65 years on IM800, with the highest median dose in the first year (466 mg/day for patients ≥65 years vs. 630 mg/day for patients <65 years). Older patients on IM800 achieved major molecular remission and deep molecular remission as fast as younger patients, in contrast to standard dose imatinib with which older patients achieved remissions much later than younger patients. Grades 3 and 4 adverse events were similar in both age groups. Five-year relative survival for older patients was comparable to that of younger patients. We suggest that the optimal dose for older patients is higher than 400 mg/day. ClinicalTrials.gov identifier: NCT00055874

A feasibility study of dynamic adaptive radiotherapy for nonsmall cell lung cancer

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

Kim, Minsun, E-mail: mk688@uw.edu; Phillips, Mark H.

2016-05-15

Purpose: The final state of the tumor at the end of a radiotherapy course is dependent on the doses given in each fraction during the treatment course. This study investigates the feasibility of using dynamic adaptive radiotherapy (DART) in treating lung cancers assuming CBCT is available to observe midtreatment tumor states. DART adapts treatment plans using a dynamic programming technique to consider the expected changes of the tumor in the optimization process. Methods: DART is constructed using a stochastic control formalism framework. It minimizes the total expected number of tumor cells at the end of a treatment course, which ismore » equivalent to maximizing tumor control probability, subject to the uncertainty inherent in the tumor response. This formulation allows for nonstationary dose distributions as well as nonstationary fractional doses as needed to achieve a series of optimal plans that are conformal to the tumor over time, i.e., spatiotemporally optimal plans. Sixteen phantom cases with various sizes and locations of tumors and organs-at-risk (OAR) were generated using in-house software. Each case was planned with DART and conventional IMRT prescribing 60 Gy in 30 fractions. The observations of the change in the tumor volume over a treatment course were simulated using a two-level cell population model. Monte Carlo simulations of the treatment course for each case were run to account for uncertainty in the tumor response. The same OAR dose constraints were applied for both methods. The frequency of replanning was varied between 1, 2, 5 (weekly), and 29 times (daily). The final average tumor dose and OAR doses have been compared to quantify the potential dosimetric benefits of DART. Results: The average tumor max, min, mean, and D95 doses using DART relative to these using conventional IMRT were 124.0%–125.2%, 102.1%–114.7%, 113.7%–123.4%, and 102.0%–115.9% (range dependent on the frequency of replanning). The average relative maximum doses for the cord and esophagus, mean doses for the heart and lungs, and D05 for the unspecified tissue resulting 84%–102.4%, 99.8%–106.9%, 66.9%–85.6%, 58.2%–78.8%, and 85.2%–94.0%, respectively. Conclusions: It is feasible to apply DART to the treatment of NSCLC using CBCT to observe the midtreatment tumor state. Potential increases in the tumor dose and reductions in the OAR dose, particularly for parallel OARs with mean or dose–volume constraints, could be achieved using DART compared to nonadaptive IMRT.« less

Decision Support Model to Optimize Site Characterization Activities Taken in Compliance with the Comprehensive Environmental Response Compensation and Liability Act

DTIC Science & Technology

1995-12-01

Contingency Plan ............................... 10 Table 2: Summary of Inhalation Emission Factors (K) for Equation ( 1 ...surveys for exposure factors commonly used in risk assessment (EPA, 1989a: 1 - 1 ). Exposure can take place via three possible routes, the inhalation ...Equation ( 1 ) calculates the dose for the inhalation route (USEPA, 1991 a:51-52; USEPA, 1989b:6-44). Dose - (C)(IRXETXEFXED) (K)(BWXAT) where C

Evaluating optimal therapy robustness by virtual expansion of a sample population, with a case study in cancer immunotherapy

PubMed Central

Barish, Syndi; Ochs, Michael F.; Sontag, Eduardo D.; Gevertz, Jana L.

2017-01-01

Cancer is a highly heterogeneous disease, exhibiting spatial and temporal variations that pose challenges for designing robust therapies. Here, we propose the VEPART (Virtual Expansion of Populations for Analyzing Robustness of Therapies) technique as a platform that integrates experimental data, mathematical modeling, and statistical analyses for identifying robust optimal treatment protocols. VEPART begins with time course experimental data for a sample population, and a mathematical model fit to aggregate data from that sample population. Using nonparametric statistics, the sample population is amplified and used to create a large number of virtual populations. At the final step of VEPART, robustness is assessed by identifying and analyzing the optimal therapy (perhaps restricted to a set of clinically realizable protocols) across each virtual population. As proof of concept, we have applied the VEPART method to study the robustness of treatment response in a mouse model of melanoma subject to treatment with immunostimulatory oncolytic viruses and dendritic cell vaccines. Our analysis (i) showed that every scheduling variant of the experimentally used treatment protocol is fragile (nonrobust) and (ii) discovered an alternative region of dosing space (lower oncolytic virus dose, higher dendritic cell dose) for which a robust optimal protocol exists. PMID:28716945

Feasibility of a semiconductor dosimeter to monitor skin dose in interventional radiology.

PubMed

Meyer, P; Regal, R; Jung, M; Siffert, P; Mertz, L; Constantinesco, A

2001-10-01

The design and preliminary test results of a semiconductor silicon dosimeter are presented in this article. Use of this dosimeter is foreseen for real-time skin dose control in interventional radiology. The strong energy dependence of this kind of radiation detector is well overcome by filtering the silicon diode. Here, the optimal filter features have been calculated by numerical Monte Carlo simulations. A prototype has been built and tested in a radiological facility. The first experimental results show a good match between the filtered semiconductor diode response and an ionization chamber response, within 2% fluctuation in a 2.2 to 4.1 mm Al half-value layer (HVL) energy range. Moreover, the semiconductor sensor response is linear from 0.02 Gy/min to at least 6.5 Gy/min, covering the whole dose rate range found in interventional radiology. The results show that a semiconductor dosimeter could be used to monitor skin dose during the majority of procedures using x-rays below 150 keV. The use of this device may assist in avoiding radiation-induced skin injuries and lower radiation levels during interventional procedures.

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.

Pharmacokinetic Dashboard-Recommended Dosing Is Different than Standard of Care Dosing in Infliximab-Treated Pediatric IBD Patients.

PubMed

Dubinsky, Marla C; Phan, Becky L; Singh, Namita; Rabizadeh, Shervin; Mould, Diane R

2017-01-01

Standard of care (SOC; combination of 5-10 mg/kg and an interval every 6-8 weeks) dosing of infliximab (IFX) is associated with significant loss of response. Dashboards using covariates that influence IFX pharmacokinetics (PK) may be a more precise way of optimizing anti-TNF dosing. We tested a prototype dashboard to compare forecasted dosing regimens with actual administered regimens and SOC. Fifty IBD patients completing IFX induction were monitored during maintenance (weeks 14-54). Clinical and laboratory data were collected at each infusion; serum was analyzed for IFX concentrations and anti-drug antibodies (ADA) at weeks 14 and 54 (Prometheus Labs, San Diego). Dosing was blinded to PK data. Dashboard-based assessments were conducted on de-identified clinical, laboratory, and PK data. Bayesian algorithms were used to forecast individualized troughs and determine optimal dosing to maintain target trough concentrations (3 μg/mL). Dashboard forecasted dosing post-week 14 was compared to actual administered dose and frequency and SOC. Using week 14 clinical data only, the dashboard recommended either a dose or an interval change (<0.5 mg/kg or <1 week difference) in 43/50 patients; only 44% recommended to have SOC dosing. When IFX14 concentration and ADA status were added to clinical data, dose and/or interval changes based on actual dosing were recommended in 48/50 (96%) patients; SOC dosing was recommended in only 11/50 (22%). Dashboard recommended SOC IFX dosing in a minority of patients. Dashboards will be an important tool to individualize IFX dosing to improve treatment durability.

A new Monte Carlo-based treatment plan optimization approach for intensity modulated radiation therapy.

PubMed

Li, Yongbao; Tian, Zhen; Shi, Feng; Song, Ting; Wu, Zhaoxia; Liu, Yaqiang; Jiang, Steve; Jia, Xun

2015-04-07

Intensity-modulated radiation treatment (IMRT) plan optimization needs beamlet dose distributions. Pencil-beam or superposition/convolution type algorithms are typically used because of their high computational speed. However, inaccurate beamlet dose distributions may mislead the optimization process and hinder the resulting plan quality. To solve this problem, the Monte Carlo (MC) simulation method has been used to compute all beamlet doses prior to the optimization step. The conventional approach samples the same number of particles from each beamlet. Yet this is not the optimal use of MC in this problem. In fact, there are beamlets that have very small intensities after solving the plan optimization problem. For those beamlets, it may be possible to use fewer particles in dose calculations to increase efficiency. Based on this idea, we have developed a new MC-based IMRT plan optimization framework that iteratively performs MC dose calculation and plan optimization. At each dose calculation step, the particle numbers for beamlets were adjusted based on the beamlet intensities obtained through solving the plan optimization problem in the last iteration step. We modified a GPU-based MC dose engine to allow simultaneous computations of a large number of beamlet doses. To test the accuracy of our modified dose engine, we compared the dose from a broad beam and the summed beamlet doses in this beam in an inhomogeneous phantom. Agreement within 1% for the maximum difference and 0.55% for the average difference was observed. We then validated the proposed MC-based optimization schemes in one lung IMRT case. It was found that the conventional scheme required 10(6) particles from each beamlet to achieve an optimization result that was 3% difference in fluence map and 1% difference in dose from the ground truth. In contrast, the proposed scheme achieved the same level of accuracy with on average 1.2 × 10(5) particles per beamlet. Correspondingly, the computation time including both MC dose calculations and plan optimizations was reduced by a factor of 4.4, from 494 to 113 s, using only one GPU card.

Choosing the optimal dose in sublingual immunotherapy: Rationale for the 300 index of reactivity dose.

PubMed

Demoly, Pascal; Passalacqua, Gianni; Calderon, Moises A; Yalaoui, Tarik

2015-01-01

Sublingual immunotherapy (SLIT) is an effective and well-tolerated method of treating allergic respiratory diseases associated with seasonal and perennial allergens. In contrast to the subcutaneous route, SLIT requires a much greater amount of antigen to achieve a clinical effect. Many studies have shown that SLIT involves a dose-response relationship, and therefore it is important to use a proven clinically effective dose from the onset of treatment, because low doses are ineffective and very high doses may increase the risk of side effects. A well-defined standardization of allergen content is also crucial to ensure consistent quality, potency and appropriate immunomodulatory action of the SLIT product. Several methods of measuring antigenicity are used by manufacturers of SLIT products, including the index of reactivity (IR), standardized quality tablet unit, and bioequivalent allergy unit. A large body of evidence has established the 300 IR dose of SLIT as offering optimal efficacy and tolerability for allergic rhinitis due to grass and birch pollen and HDM, and HDM-induced moderate, persistent allergic asthma. The 300 IR dose also offers consistency of dosing across a variety of different allergens, and is associated with higher rates of adherence and patient satisfaction. Studies in patients with grass pollen allergies showed that the 300 IR dose has a rapid onset of action, is effective in both adults and children in the short term and, when administered pre-coseasonally in the long term, and maintains the clinical benefit, even after cessation of treatment. In patients with HDM-associated AR and/or asthma, the 300 IR dose also demonstrated significant improvements in symptoms and quality of life, and significantly decreased use of symptomatic medication. The 300 IR dose is well tolerated, with adverse events generally being of mild or moderate severity, declining in frequency and severity over time and in the subsequent courses. We discuss herein the most important factors that affect the selection of the optimal dose of SLIT with natural allergens, and review the rationale and evidence supporting the use of the 300 IR dose.

SU-F-J-94: Development of a Plug-in Based Image Analysis Tool for Integration Into Treatment Planning

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

Owen, D; Anderson, C; Mayo, C

Purpose: To extend the functionality of a commercial treatment planning system (TPS) to support (i) direct use of quantitative image-based metrics within treatment plan optimization and (ii) evaluation of dose-functional volume relationships to assist in functional image adaptive radiotherapy. Methods: A script was written that interfaces with a commercial TPS via an Application Programming Interface (API). The script executes a program that performs dose-functional volume analyses. Written in C#, the script reads the dose grid and correlates it with image data on a voxel-by-voxel basis through API extensions that can access registration transforms. A user interface was designed through WinFormsmore » to input parameters and display results. To test the performance of this program, image- and dose-based metrics computed from perfusion SPECT images aligned to the treatment planning CT were generated, validated, and compared. Results: The integration of image analysis information was successfully implemented as a plug-in to a commercial TPS. Perfusion SPECT images were used to validate the calculation and display of image-based metrics as well as dose-intensity metrics and histograms for defined structures on the treatment planning CT. Various biological dose correction models, custom image-based metrics, dose-intensity computations, and dose-intensity histograms were applied to analyze the image-dose profile. Conclusion: It is possible to add image analysis features to commercial TPSs through custom scripting applications. A tool was developed to enable the evaluation of image-intensity-based metrics in the context of functional targeting and avoidance. In addition to providing dose-intensity metrics and histograms that can be easily extracted from a plan database and correlated with outcomes, the system can also be extended to a plug-in optimization system, which can directly use the computed metrics for optimization of post-treatment tumor or normal tissue response models. Supported by NIH - P01 - CA059827.« less

Implementation of a dose gradient method into optimization of dose distribution in prostate cancer 3D-CRT plans

PubMed Central

Giżyńska, Marta K.; Kukołowicz, Paweł F.; Kordowski, Paweł

2014-01-01

Aim The aim of this work is to present a method of beam weight and wedge angle optimization for patients with prostate cancer. Background 3D-CRT is usually realized with forward planning based on a trial and error method. Several authors have published a few methods of beam weight optimization applicable to the 3D-CRT. Still, none on these methods is in common use. Materials and methods Optimization is based on the assumption that the best plan is achieved if dose gradient at ICRU point is equal to zero. Our optimization algorithm requires beam quality index, depth of maximum dose, profiles of wedged fields and maximum dose to femoral heads. The method was tested for 10 patients with prostate cancer, treated with the 3-field technique. Optimized plans were compared with plans prepared by 12 experienced planners. Dose standard deviation in target volume, and minimum and maximum doses were analyzed. Results The quality of plans obtained with the proposed optimization algorithms was comparable to that prepared by experienced planners. Mean difference in target dose standard deviation was 0.1% in favor of the plans prepared by planners for optimization of beam weights and wedge angles. Introducing a correction factor for patient body outline for dose gradient at ICRU point improved dose distribution homogeneity. On average, a 0.1% lower standard deviation was achieved with the optimization algorithm. No significant difference in mean dose–volume histogram for the rectum was observed. Conclusions Optimization shortens very much time planning. The average planning time was 5 min and less than a minute for forward and computer optimization, respectively. PMID:25337411

Evaluation of hybrid inverse planning and optimization (HIPO) algorithm for optimization in real-time, high-dose-rate (HDR) brachytherapy for prostate.

PubMed

Pokharel, Shyam; Rana, Suresh; Blikenstaff, Joseph; Sadeghi, Amir; Prestidge, Bradley

2013-07-08

The purpose of this study is to investigate the effectiveness of the HIPO planning and optimization algorithm for real-time prostate HDR brachytherapy. This study consists of 20 patients who underwent ultrasound-based real-time HDR brachytherapy of the prostate using the treatment planning system called Oncentra Prostate (SWIFT version 3.0). The treatment plans for all patients were optimized using inverse dose-volume histogram-based optimization followed by graphical optimization (GRO) in real time. The GRO is manual manipulation of isodose lines slice by slice. The quality of the plan heavily depends on planner expertise and experience. The data for all patients were retrieved later, and treatment plans were created and optimized using HIPO algorithm with the same set of dose constraints, number of catheters, and set of contours as in the real-time optimization algorithm. The HIPO algorithm is a hybrid because it combines both stochastic and deterministic algorithms. The stochastic algorithm, called simulated annealing, searches the optimal catheter distributions for a given set of dose objectives. The deterministic algorithm, called dose-volume histogram-based optimization (DVHO), optimizes three-dimensional dose distribution quickly by moving straight downhill once it is in the advantageous region of the search space given by the stochastic algorithm. The PTV receiving 100% of the prescription dose (V100) was 97.56% and 95.38% with GRO and HIPO, respectively. The mean dose (D(mean)) and minimum dose to 10% volume (D10) for the urethra, rectum, and bladder were all statistically lower with HIPO compared to GRO using the student pair t-test at 5% significance level. HIPO can provide treatment plans with comparable target coverage to that of GRO with a reduction in dose to the critical structures.

Placebo-controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression.

PubMed

Loo, C K; Gálvez, V; O'Keefe, E; Mitchell, P B; Hadzi-Pavlovic, D; Leyden, J; Harper, S; Somogyi, A A; Lai, R; Weickert, C S; Glue, P

2016-07-01

This pilot study assessed the feasibility, efficacy and safety of an individual dose-titration approach, and of the intravenous (IV), intramuscular (IM) and subcutaneous (SC) routes for treating depression with ketamine. Fifteen treatment-refractory depressed participants received ketamine or midazolam (control treatment) in a multiple crossover, double-blind study. Ketamine was administered by IV (n = 4), IM (n = 5) or SC (n = 6) injection. Dose titration commenced at 0.1 mg/kg, increasing by 0.1 mg/kg up to 0.5 mg/kg, given in separate treatment sessions separated by ≥1 week, with one placebo control treatment randomly inserted. Mood, psychotomimetic and hemodynamic effects were assessed and plasma ketamine concentrations assayed. Twelve participants achieved response and remission criteria, achieved at doses as low as 0.1 mg/kg. All three routes of administration resulted in comparable antidepressant effects. Fewest adverse effects were noted with the SC route. Antidepressant response, adverse effects and ketamine concentrations were dose-related. Antidepressant response occurred at a range of doses and at <0.5 mg/kg. The dose-titration approach is a practical method for optimizing the efficacy - side-effects trade-off on an individual patient basis. This pilot study provides preliminary evidence for SC injection as a practical, feasible and efficacious treatment approach. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Drug Response and Resistance in Advanced NF1-Associated Cancers

DTIC Science & Technology

2013-04-01

administering high doses of cytarabine in combination with an anthracycline agent such as daunorubicin (51). These aggressive regimens induce remissions in...liposomal formulation that contains cytarabine and daunorubicin at an optimized ratio to enhance AML killing without added toxicity(52). CPX-351 in

Treatment of aplastic anaemia with lower-dose anti-thymocyte globulin produces similar response rates and survival as per standard dose anti-thymocyte globulin schedules.

PubMed

Scott, A; Morris, K; Butler, J; Mills, A K; Kennedy, G A

2016-10-01

Aplastic anaemia (AA) is a rare acquired bone marrow failure syndrome resulting from the immune-mediated destruction of haemopoietic stem cells. For adults in whom first-line haemopoietic progenitor cell transplantation is not feasible, combination anti-thymocyte globulin (ATGAM) plus cyclosporine A is standard therapy; however, there are minimal data available regarding the optimal ATGAM dosage in terms of efficacy and survival. Our institutions have historically used different dosing protocols of ATGAM in the treatment of AA. We aimed to review the outcome of AA patients treated with these protocols and compare them to the published literature. We conducted a retrospective study of 31 adults who received first-line ATGAM for AA and compared response rates and survival between cohorts who received standard (40 mg/kg/day D1-4) versus lower-dose (15 mg/kg/day D1-5) ATGAM schedules. There were similar rates of response (64 vs 71%, P = 1.0), relapse (33 vs 33%, P = 1.0), transformation (14 vs 24%, P = 0.66) or infection (43 vs 47%, P = 1.0), respectively, between standard and lower-dose cohorts. At a median follow up of 24 months, there was no statistical difference between standard and lower-dose cohorts in either event-free (42.2 vs 64.7%, P = 0.91) or overall survival (73.1 vs 88.2%, P = 0.75). Our experience suggests that lower-dose ATGAM at 15 mg/kg/day D1-5 as treatment of AA produces similar responses and outcomes as per standard-dose ATGAM schedules. Prospective trials comparing ATGAM dose schedules in AA are warranted. © 2016 Royal Australasian College of Physicians.

Topical ketoprofen nanogel: artificial neural network optimization, clustered bootstrap validation, and in vivo activity evaluation based on longitudinal dose response modeling.

PubMed

Elkomy, Mohammed H; Elmenshawe, Shahira F; Eid, Hussein M; Ali, Ahmed M A

2016-11-01

This work aimed at investigating the potential of solid lipid nanoparticles (SLN) as carriers for topical delivery of Ketoprofen (KP); evaluating a novel technique incorporating Artificial Neural Network (ANN) and clustered bootstrap for optimization of KP-loaded SLN (KP-SLN); and demonstrating a longitudinal dose response (LDR) modeling-based approach to compare the activity of topical non-steroidal anti-inflammatory drug formulations. KP-SLN was fabricated by a modified emulsion/solvent evaporation method. Box-Behnken design was implemented to study the influence of glycerylpalmitostearate-to-KP ratio, Tween 80, and lecithin concentrations on particle size, entrapment efficiency, and amount of drug permeated through rat skin in 24 hours. Following clustered bootstrap ANN optimization, the optimized KP-SLN was incorporated into an aqueous gel and evaluated for rheology, in vitro release, permeability, skin irritation and in vivo activity using carrageenan-induced rat paw edema model and LDR mathematical model to analyze the time course of anti-inflammatory effect at various application durations. Lipid-to-drug ratio of 7.85 [bootstrap 95%CI: 7.63-8.51], Tween 80 of 1.27% [bootstrap 95%CI: 0.601-2.40%], and Lecithin of 0.263% [bootstrap 95%CI: 0.263-0.328%] were predicted to produce optimal characteristics. Compared with profenid® gel, the optimized KP-SLN gel exhibited slower release, faster permeability, better texture properties, greater efficacy, and similar potency. SLNs are safe and effective permeation enhancers. ANN coupled with clustered bootstrap is a useful method for finding optimal solutions and estimating uncertainty associated with them. LDR models allow mechanistic understanding of comparative in vivo performances of different topical formulations, and help design efficient dermatological bioequivalence assessment methods.

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

Internal photon and electron dosimetry of the newborn patient—a hybrid computational phantom study

NASA Astrophysics Data System (ADS)

Wayson, Michael; Lee, Choonsik; Sgouros, George; Treves, S. Ted; Frey, Eric; Bolch, Wesley E.

2012-03-01

Estimates of radiation absorbed dose to organs of the nuclear medicine patient are a requirement for administered activity optimization and for stochastic risk assessment. Pediatric patients, and in particular the newborn child, represent that portion of the patient population where such optimization studies are most crucial owing to the enhanced tissue radiosensitivities and longer life expectancies of this patient subpopulation. In cases where whole-body CT imaging is not available, phantom-based calculations of radionuclide S values—absorbed dose to a target tissue per nuclear transformation in a source tissue—are required for dose and risk evaluation. In this study, a comprehensive model of electron and photon dosimetry of the reference newborn child is presented based on a high-resolution hybrid-voxel phantom from the University of Florida (UF) patient model series. Values of photon specific absorbed fraction (SAF) were assembled for both the reference male and female newborn using the radiation transport code MCNPX v2.6. Values of electron SAF were assembled in a unique and time-efficient manner whereby the collisional and radiative components of organ dose--for both self- and cross-dose terms—were computed separately. Dose to the newborn skeletal tissues were assessed via fluence-to-dose response functions reported for the first time in this study. Values of photon and electron SAFs were used to assemble a complete set of S values for some 16 radionuclides commonly associated with molecular imaging of the newborn. These values were then compared to those available in the OLINDA/EXM software. S value ratios for organ self-dose ranged from 0.46 to 1.42, while similar ratios for organ cross-dose varied from a low of 0.04 to a high of 3.49. These large discrepancies are due in large part to the simplistic organ modeling in the stylized newborn model used in the OLINDA/EXM software. A comprehensive model of internal dosimetry is presented in this study for the newborn nuclear medicine patient based upon the UF hybrid computational phantom. Photon dose response functions, photon and electron SAFs, and tables of radionuclide S values for the newborn child--both male and female--are given in a series of four electronic annexes available at stacks.iop.org/pmb/57/1433/mmedia. These values can be applied to optimization studies of image quality and stochastic risk for this most vulnerable class of pediatric patients.

Sustained response to standard dose osimertinib in a patient with plasma T790M-positive leptomeningeal metastases from primary lung adenocarcinoma.

PubMed

Chan, Oscar Siu-Hong; Leung, Warren Kam-Wing; Yeung, Rebecca Mei-Wan

2017-12-01

A 44-year-old male, never smoker, suffers from stage IV adenocarcinoma of the right lung with epidermal growth factor receptor (EGFR) exon-21 L858R point mutation on initial presentation. After 23 months of treatment with gefitinib, intercalated with multiple courses of radiotherapy, leptomeningeal metastases (LMs) developed. Acquired T790M mutation was confirmed by the droplet digital polymerase chain reaction plasma EGFR test. After switching to osimertinib at the standard dose, his neurocognitive function improved clinically, coupled with sustained radiological improvement. As this clinical entity is underrepresented in clinical trials, the practicability of plasma EGFR testing and the optimal dose-response relationship of osimertinib in T790M-positive lung cancer complicated with LM deserves further exploration. © 2017 John Wiley & Sons Australia, Ltd.

The role of thiopurine metabolites in inflammatory bowel disease and rheumatological disorders.

PubMed

Friedman, Antony B; Sparrow, Miles P; Gibson, Peter R

2014-02-01

Thiopurines have been a cornerstone of medical management of patients with inflammatory bowel disease(IBD) and many rheumatological disorders. The thiopurines are metabolized to their end products, 6-methymercaptopurine (6MMP) and the 6-thioguanine nucleotides (6TGN), with 6TGN being responsible for thiopurine efficacy by causing apoptosis and preventing activation and proliferation of T-lymphocytes. In IBD, conventional weight-based dosing with thiopurines leads to an inadequate response in many patients. Utilizing measurement of these metabolites and then employing dose optimization strategies has led to markedly improved outcomes in IBD. Switching between thiopurines as well as the addition of low-dose allopurinol can overcome adverse events and elevate 6TGN levels into the therapeutic window. There is a paucity of data on thiopurine metabolites in rheumatological diseases and further research is required.

The immunological response created by interstitial and non-invasive laser immunotherapy

NASA Astrophysics Data System (ADS)

Bahavar, Cody F.; Zhou, Feifan; Hasanjee, Aamr M.; West, Connor L.; Nordquist, Robert E.; Hode, Tomas; Liu, Hong; Chen, Wei R.

2015-03-01

Laser immunotherapy (LIT) is an innovative cancer modality that uses laser irradiation and immunological stimulation to treat late-stage, metastatic cancers. LIT can be performed through either interstitial or non-invasive laser irradiation. Although LIT is still in development, recent clinical trials have shown that it can be used to successfully treat patients with late-stage breast cancer and melanoma. The development of LIT has been focused on creating an optimal immune response created by irradiating the tumor. One important factor that could enhance the immune response is the duration of laser irradiation. Irradiating the tumor for a shorter or longer amount of time could weaken the immune response created by LIT. Another factor that could weaken this immune response is the proliferation of regulatory T cells (TRegs) in response to the laser irradiation. However, low dose cyclophosphamide (CY) can help suppress the proliferation of TRegs and help create a more optimal immune response. An additional factor that could weaken the effectiveness of LIT is the selectivity of the laser. If LIT is performed non-invasively, then deeply embedded tumors and highly pigmented skin could cause an uneven temperature distribution inside the tumor. To solve this problem, an immunologically modified carbon nanotube system was created by using an immunoadjuvant known as glycated chitosan (GC) as a surfactant for single-walled carbon nanotubes (SWNTs) to immunologically modify SWNTs. SWNT-GC retains the optical properties of SWNTs and the immunological functions of GC to help increase the selectivity of the laser and create a more optimal immune response. In this preliminary study, tumor-bearing rats were treated with LIT either interstitially by an 805-nm laser with GC and low-dose CY, or non-invasively by a 980-nm laser with SWNT-GC. The goal was to observe the effects of CY on the immune response induced by LIT and to also determine the effect of irradiation duration for interstitial and noninvasive LIT.

Directional interstitial brachytherapy from simulation to application

NASA Astrophysics Data System (ADS)

Lin, Liyong

Organs at risk (OAR) are sometimes adjacent to or embedded in or overlap with the clinical target volume (CTV) to be treated. The purpose of this PhD study is to develop directionally low energy gamma-emitting interstitial brachytherapy sources. These sources can be applied between OAR to selectively reduce hot spots in the OARs and normal tissues. The reduction of dose over undesired regions can expand patient eligibility or reduce toxicities for the treatment by conventional interstitial brachytherapy. This study covers the development of a directional source from design optimization to construction of the first prototype source. The Monte Carlo code MCNP was used to simulate the radiation transport for the designs of directional sources. We have made a special construction kit to assemble radioactive and gold-shield components precisely into D-shaped titanium containers of the first directional source. Directional sources have a similar dose distribution as conventional sources on the treated side but greatly reduced dose on the shielded side, with a sharp dose gradient between them. A three-dimensional dose deposition kernel for the 125I directional source has been calculated. Treatment plans can use both directional and conventional 125I sources at the same source strength for low-dose-rate (LDR) implants to optimize the dose distributions. For prostate tumors, directional 125I LDR brachytherapy can potentially reduce genitourinary and gastrointestinal toxicities and improve potency preservation for low risk patients. The combination of better dose distribution of directional implants and better therapeutic ratio between tumor response and late reactions enables a novel temporary LDR treatment, as opposed to permanent or high-dose-rate (HDR) brachytherapy for the intermediate risk T2b and high risk T2c tumors. Supplemental external-beam treatments can be shortened with a better brachytherapy boost for T3 tumors. In conclusion, we have successfully finished the design optimization and construction of the first prototype directional source. Potential clinical applications and potential benefits of directional sources have been shown for prostate and breast tumors.

Defining the optimal dose of rifapentine for pulmonary tuberculosis: Exposure–response relations from two phase II clinical trials

PubMed Central

Savic, RM; MacKenzie, WR; Engle, M; Whitworth, WC; Johnson, JL; Nsubuga, P; Nahid, P; Nguyen, NV; Peloquin, CA; Dooley, KE; Dorman, SE

2017-01-01

Rifapentine is a highly active antituberculosis antibiotic with treatment‐shortening potential; however, exposure–response relations and the dose needed for maximal bactericidal activity have not been established. We used pharmacokinetic/pharmacodynamic data from 657 adults with pulmonary tuberculosis participating in treatment trials to compare rifapentine (n = 405) with rifampin (n = 252) as part of intensive‐phase therapy. Population pharmacokinetic/pharmacodynamic analyses were performed with nonlinear mixed‐effects modeling. Time to stable culture conversion of sputum to negative was determined in cultures obtained over 4 months of therapy. Rifapentine exposures were lower in participants who were coinfected with human immunodeficiency virus, black, male, or fasting when taking drug. Rifapentine exposure, large lung cavity size, and geographic region were independently associated with time to culture conversion in liquid media. Maximal treatment efficacy is likely achieved with rifapentine at 1,200 mg daily. Patients with large lung cavities appear less responsive to treatment, even at high rifapentine doses. PMID:28124478

Linear energy transfer incorporated intensity modulated proton therapy optimization

NASA Astrophysics Data System (ADS)

Cao, Wenhua; Khabazian, Azin; Yepes, Pablo P.; Lim, Gino; Poenisch, Falk; Grosshans, David R.; Mohan, Radhe

2018-01-01

The purpose of this study was to investigate the feasibility of incorporating linear energy transfer (LET) into the optimization of intensity modulated proton therapy (IMPT) plans. Because increased LET correlates with increased biological effectiveness of protons, high LETs in target volumes and low LETs in critical structures and normal tissues are preferred in an IMPT plan. However, if not explicitly incorporated into the optimization criteria, different IMPT plans may yield similar physical dose distributions but greatly different LET, specifically dose-averaged LET, distributions. Conventionally, the IMPT optimization criteria (or cost function) only includes dose-based objectives in which the relative biological effectiveness (RBE) is assumed to have a constant value of 1.1. In this study, we added LET-based objectives for maximizing LET in target volumes and minimizing LET in critical structures and normal tissues. Due to the fractional programming nature of the resulting model, we used a variable reformulation approach so that the optimization process is computationally equivalent to conventional IMPT optimization. In this study, five brain tumor patients who had been treated with proton therapy at our institution were selected. Two plans were created for each patient based on the proposed LET-incorporated optimization (LETOpt) and the conventional dose-based optimization (DoseOpt). The optimized plans were compared in terms of both dose (assuming a constant RBE of 1.1 as adopted in clinical practice) and LET. Both optimization approaches were able to generate comparable dose distributions. The LET-incorporated optimization achieved not only pronounced reduction of LET values in critical organs, such as brainstem and optic chiasm, but also increased LET in target volumes, compared to the conventional dose-based optimization. However, on occasion, there was a need to tradeoff the acceptability of dose and LET distributions. Our conclusion is that the inclusion of LET-dependent criteria in the IMPT optimization could lead to similar dose distributions as the conventional optimization but superior LET distributions in target volumes and normal tissues. This may have substantial advantages in improving tumor control and reducing normal tissue toxicities.

Case Example of Dose Optimization Using Data From Bortezomib Dose-Finding Clinical Trials

PubMed Central

Backenroth, Daniel; Cheung, Ying Kuen Ken; Hershman, Dawn L.; Vulih, Diana; Anderson, Barry; Ivy, Percy; Minasian, Lori

2016-01-01

Purpose The current dose-finding methodology for estimating the maximum tolerated dose of investigational anticancer agents is based on the cytotoxic chemotherapy paradigm. Molecularly targeted agents (MTAs) have different toxicity profiles, which may lead to more long-lasting mild or moderate toxicities as well as to late-onset and cumulative toxicities. Several approved MTAs have been poorly tolerated during long-term administration, leading to postmarketing dose optimization studies to re-evaluate the optimal treatment dose. Using data from completed bortezomib dose-finding trials, we explore its toxicity profile, optimize its dose, and examine the appropriateness of current designs for identifying an optimal dose. Patients and Methods We classified the toxicities captured from 481 patients in 14 bortezomib dose-finding studies conducted through the National Cancer Institute Cancer Therapy Evaluation Program, computed the incidence of late-onset toxicities, and compared the incidence of dose-limiting toxicities (DLTs) among groups of patients receiving different doses of bortezomib. Results A total of 13,008 toxicities were captured: 46% of patients’ first DLTs and 88% of dose reductions or discontinuations of treatment because of toxicity were observed after the first cycle. Moreover, for the approved dose of 1.3 mg/m2, the estimated cumulative incidence of DLT was > 50%, and the estimated cumulative incidence of dose reduction or treatment discontinuation because of toxicity was nearly 40%. Conclusions When considering the entire course of treatment, the approved bortezomib dose exceeds the conventional ceiling DLT rate of 20% to 33%. Retrospective analysis of trial data provides an opportunity for dose optimization of MTAs. Future dose-finding studies of MTAs should take into account late-onset toxicities to ensure that a tolerable dose is identified for future efficacy and comparative trials. PMID:26926682

Case Example of Dose Optimization Using Data From Bortezomib Dose-Finding Clinical Trials.

PubMed

Lee, Shing M; Backenroth, Daniel; Cheung, Ying Kuen Ken; Hershman, Dawn L; Vulih, Diana; Anderson, Barry; Ivy, Percy; Minasian, Lori

2016-04-20

The current dose-finding methodology for estimating the maximum tolerated dose of investigational anticancer agents is based on the cytotoxic chemotherapy paradigm. Molecularly targeted agents (MTAs) have different toxicity profiles, which may lead to more long-lasting mild or moderate toxicities as well as to late-onset and cumulative toxicities. Several approved MTAs have been poorly tolerated during long-term administration, leading to postmarketing dose optimization studies to re-evaluate the optimal treatment dose. Using data from completed bortezomib dose-finding trials, we explore its toxicity profile, optimize its dose, and examine the appropriateness of current designs for identifying an optimal dose. We classified the toxicities captured from 481 patients in 14 bortezomib dose-finding studies conducted through the National Cancer Institute Cancer Therapy Evaluation Program, computed the incidence of late-onset toxicities, and compared the incidence of dose-limiting toxicities (DLTs) among groups of patients receiving different doses of bortezomib. A total of 13,008 toxicities were captured: 46% of patients' first DLTs and 88% of dose reductions or discontinuations of treatment because of toxicity were observed after the first cycle. Moreover, for the approved dose of 1.3 mg/m(2), the estimated cumulative incidence of DLT was > 50%, and the estimated cumulative incidence of dose reduction or treatment discontinuation because of toxicity was nearly 40%. When considering the entire course of treatment, the approved bortezomib dose exceeds the conventional ceiling DLT rate of 20% to 33%. Retrospective analysis of trial data provides an opportunity for dose optimization of MTAs. Future dose-finding studies of MTAs should take into account late-onset toxicities to ensure that a tolerable dose is identified for future efficacy and comparative trials. © 2016 by American Society of Clinical Oncology.

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

Swanson, K; Corwin, D; Rockne, R

Purpose: To demonstrate a method of generating patient-specific, biologically-guided radiation therapy (RT) plans and to quantify and predict response to RT in glioblastoma. We investigate the biological correlates and imaging physics driving T2-MRI based response to radiation therapy using an MRI simulator. Methods: We have integrated a patient-specific biomathematical model of glioblastoma proliferation, invasion and radiotherapy with a multiobjective evolutionary algorithm for intensity-modulated RT optimization to construct individualized, biologically-guided plans. Patient-individualized simulations of the standard-of-care and optimized plans are compared in terms of several biological metrics quantified on MRI. An extension of the PI model is used to investigate themore » role of angiogenesis and its correlates in glioma response to therapy with the Proliferation-Invasion-Hypoxia- Necrosis-Angiogenesis model (PIHNA). The PIHNA model is used with a brain tissue phantom to predict tumor-induced vasogenic edema, tumor and tissue density that is used in a multi-compartmental MRI signal equation for generation of simulated T2- weighted MRIs. Results: Applying a novel metric of treatment response (Days Gained) to the patient-individualized simulation results predicted that the optimized RT plans would have a significant impact on delaying tumor progression, with Days Gained increases from 21% to 105%. For the T2- MRI simulations, initial validation tests compared average simulated T2 values for white matter, tumor, and peripheral edema to values cited in the literature. Simulated results closely match the characteristic T2 value for each tissue. Conclusion: Patient-individualized simulations using the combination of a biomathematical model with an optimization algorithm for RT generated biologically-guided doses that decreased normal tissue dose and increased therapeutic ratio with the potential to improve survival outcomes for treatment of glioblastoma. Simulated T2-MRI is shown to be consistent with known physics of MRI and can be used to further investigate biological drivers of imaging-based response to RT.« less

Methylphenidate dose optimization for ADHD treatment: review of safety, efficacy, and clinical necessity

PubMed Central

Huss, Michael; Duhan, Praveen; Gandhi, Preetam; Chen, Chien-Wei; Spannhuth, Carsten; Kumar, Vinod

2017-01-01

Attention-deficit/hyperactivity disorder (ADHD) is a chronic psychiatric disorder characterized by hyperactivity and/or inattention and is often associated with a substantial impact on psychosocial functioning. Methylphenidate (MPH), a central nervous system stimulant, is commonly used for pharmacological treatment of adults and children with ADHD. Current practice guidelines recommend optimizing MPH dosage to individual patient needs; however, the clinical benefits of individual dose optimization compared with fixed-dose regimens remain unclear. Here we review the available literature on MPH dose optimization from clinical trials and real-world experience on ADHD management. In addition, we report safety and efficacy data from the largest MPH modified-release long-acting Phase III clinical trial conducted to examine benefits of dose optimization in adults with ADHD. Overall, MPH is an effective ADHD treatment with a good safety profile; data suggest that dose optimization may enhance the safety and efficacy of treatment. Further research is required to establish the extent to which short-term clinical benefits of MPH dose optimization translate into improved long-term outcomes for patients with ADHD. PMID:28740389

Methylphenidate dose optimization for ADHD treatment: review of safety, efficacy, and clinical necessity.

PubMed

Huss, Michael; Duhan, Praveen; Gandhi, Preetam; Chen, Chien-Wei; Spannhuth, Carsten; Kumar, Vinod

2017-01-01

Attention-deficit/hyperactivity disorder (ADHD) is a chronic psychiatric disorder characterized by hyperactivity and/or inattention and is often associated with a substantial impact on psychosocial functioning. Methylphenidate (MPH), a central nervous system stimulant, is commonly used for pharmacological treatment of adults and children with ADHD. Current practice guidelines recommend optimizing MPH dosage to individual patient needs; however, the clinical benefits of individual dose optimization compared with fixed-dose regimens remain unclear. Here we review the available literature on MPH dose optimization from clinical trials and real-world experience on ADHD management. In addition, we report safety and efficacy data from the largest MPH modified-release long-acting Phase III clinical trial conducted to examine benefits of dose optimization in adults with ADHD. Overall, MPH is an effective ADHD treatment with a good safety profile; data suggest that dose optimization may enhance the safety and efficacy of treatment. Further research is required to establish the extent to which short-term clinical benefits of MPH dose optimization translate into improved long-term outcomes for patients with ADHD.

Suboptimal Antituberculosis Drug Concentrations and Outcomes in Small and HIV-Coinfected Children in India: Recommendations for Dose Modifications.

PubMed

Guiastrennec, Benjamin; Ramachandran, Geetha; Karlsson, Mats O; Kumar, A K Hemanth; Bhavani, Perumal Kannabiran; Gangadevi, N Poorana; Swaminathan, Soumya; Gupta, Amita; Dooley, Kelly E; Savic, Radojka M

2017-12-16

This work aimed to evaluate the once-daily antituberculosis treatment as recommended by the new Indian pediatric guidelines. Isoniazid, rifampin, and pyrazinamide concentration-time profiles and treatment outcome were obtained from 161 Indian children with drug-sensitive tuberculosis undergoing thrice-weekly dosing as per previous Indian pediatric guidelines. The exposure-response relationships were established using a population pharmacokinetic-pharmacodynamic approach. Rifampin exposure was identified as the unique predictor of treatment outcome. Consequently, children with low body weight (4-7 kg) and/or HIV infection, who displayed the lowest rifampin exposure, were associated with the highest probability of unfavorable treatment (therapy failure, death) outcome (P unfavorable ). Model-based simulation of optimized (P unfavorable ≤ 5%) rifampin once-daily doses were suggested per treatment weight band and HIV coinfection status (33% and 190% dose increase, respectively, from the new Indian guidelines). The established dose-exposure-response relationship could be pivotal in the development of future pediatric tuberculosis treatment guidelines. © 2017, The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Spatial frequency performance limitations of radiation dose optimization and beam positioning

NASA Astrophysics Data System (ADS)

Stewart, James M. P.; Stapleton, Shawn; Chaudary, Naz; Lindsay, Patricia E.; Jaffray, David A.

2018-06-01

The flexibility and sophistication of modern radiotherapy treatment planning and delivery methods have advanced techniques to improve the therapeutic ratio. Contemporary dose optimization and calculation algorithms facilitate radiotherapy plans which closely conform the three-dimensional dose distribution to the target, with beam shaping devices and image guided field targeting ensuring the fidelity and accuracy of treatment delivery. Ultimately, dose distribution conformity is limited by the maximum deliverable dose gradient; shallow dose gradients challenge techniques to deliver a tumoricidal radiation dose while minimizing dose to surrounding tissue. In this work, this ‘dose delivery resolution’ observation is rigorously formalized for a general dose delivery model based on the superposition of dose kernel primitives. It is proven that the spatial resolution of a delivered dose is bounded by the spatial frequency content of the underlying dose kernel, which in turn defines a lower bound in the minimization of a dose optimization objective function. In addition, it is shown that this optimization is penalized by a dose deposition strategy which enforces a constant relative phase (or constant spacing) between individual radiation beams. These results are further refined to provide a direct, analytic method to estimate the dose distribution arising from the minimization of such an optimization function. The efficacy of the overall framework is demonstrated on an image guided small animal microirradiator for a set of two-dimensional hypoxia guided dose prescriptions.

Optimization strategies for radiation induced grafting of 4-vinylpyridine onto poly(ethylene-co-tetraflouroethene) film using Box-Behnken design

NASA Astrophysics Data System (ADS)

Mahmoud Nasef, Mohamed; Shamsaei, Ezzatollah; Ghassemi, Payman; Ahmed Aly, Amgad; Hamid Yahaya, Abdul

2012-04-01

The radiation induced grafting of 4-vinylpyridine (4-VP) onto poly(ethylene-co-tetrafluoroethene) (ETFE) was optimized using the Box-Behnken factorial design available in the response surface method (RSM). The optimized grafting parameters; absorbed dose, monomer concentration, grafting time and reaction temperature were varied in four levels to quantify their effect on the grafting yield (GY). The validity of the statistical model was supported by the small deviation between the predicted (GY=61%) and experimental (GY=57%) values. The optimum conditions for enhancing GY were determined at the following values: monomer concentration of 48 vol%, absorbed dose of 64 kGy, reaction time of 4 h and temperature of 68 °C. A comparison was made between the optimization model developed for the present grafting system and that for grafting of 1-vinylimidazole (1-VIm) onto ETFE to confirm the validly and reliability of the Box-Behnken for the optimization of various radiation induced grafting reactions. Fourier transform infrared (FTIR), thermogravimetric analysis (TGA) and X-ray diffraction (XRD) were used to investigate the properties of the obtained films and provide evidence for grafting.

Optimal methotrexate dose is associated with better clinical outcomes than non-optimal dose in daily practice: results from the ESPOIR early arthritis cohort.

PubMed

Gaujoux-Viala, Cécile; Rincheval, Nathalie; Dougados, Maxime; Combe, Bernard; Fautrel, Bruno

2017-12-01

Although methotrexate (MTX) is the consensual first-line disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis (RA), substantial heterogeneity remains with its prescription and dosage, which are often not optimal. To evaluate the symptomatic and structural impact of optimal MTX dose in patients with early RA in daily clinical practice over 2 years. Patients included in the early arthritis ESPOIR cohort who fulfilled the ACR-EULAR (American College of Rheumatology/European League against Rheumatism) criteria for RA and received MTX as a first DMARD were assessed. Optimal MTX dose was defined as ≥10 mg/week during the first 3 months, with escalation to ≥20 mg/week or 0.3 mg/kg/week at 6 months without Disease Activity Score in 28 joints remission. Symptomatic and structural efficacy with and without optimal MTX dose was assessed by generalised logistic regression with adjustment for appropriate variables. Within the first year of follow-up, 314 patients (53%) with RA received MTX as a first DMARD (mean dose 12.2±3.8 mg/week). Only 26.4% (n=76) had optimal MTX dose. After adjustment, optimal versus non-optimal MTX dose was more efficient in achieving ACR-EULAR remission at 1 year (OR 4.28 (95% CI 1.86 to 9.86)) and normal functioning (Health Assessment Questionnaire ≤0.5; OR at 1 year 4.36 (95% CI 2.03 to 9.39)), with no effect on radiological progression. Results were similar during the second year. Optimal MTX dose is more efficacious than non-optimal dose for remission and function in early arthritis in daily practice, with no impact on radiological progression over 2 years. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Dietary protein intake, energy deficit, and nitrogen balance in normal-weight adults: a randomized controlled

USDA-ARS?s Scientific Manuscript database

Consuming protein at levels higher than the recommended dietary allowance (RDA) may be metabolically advantageous for overweight and obese individuals attempting weight loss. However, the dose-response characteristics that define the optimal level of dietary protein necessary to sustain measures of...

SU-D-202-01: Functional Lung Avoidance and Response-Adaptive Escalation (FLARE) RT: Feasibility of a Precision Radiation Oncology Strategy

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

Bowen, S; Lee, E; Miyaoka, R

Purpose: NSCLC patient RT is planned without consideration of spatial heterogeneity in lung function or tumor response, which may have contributed to failed uniform dose escalation in a randomized trial. The feasibility of functional lung avoidance and response-adaptive escalation (FLARE) RT to reduce dose to [{sup 99m}Tc]MAA-SPECT/CT perfused lung while redistributing 74Gy within [{sup 18}F]FDG-PET/CT biological target volumes was assessed. Methods: Eight Stage IIB–IIIB NSCLC patients underwent FDG-PET/CT and MAA-SPECT/CT treatment planning scans. Perfused lung objectives were derived from scatter/collimator/attenuation-corrected MAA-SPECT uptake relative to ITV-subtracted lung to maintain <20Gy mean lung dose (MLD). Prescriptions included 60Gy to PTV and concomitantmore » boost of 74Gy mean to biological target volumes (BTV=GTV+PET margin) scaled to each BTV voxel by relative FDG-PET SUV. Dose-painting-by-numbers prescriptions were integrated into commercial TPS via previously reported ROI discretization. Dose constraints for lung, heart, cord, and esophagus were defined. FLARE RT plans were optimized with VMAT, proton pencil beam scanning (PBS) with 3%-3mm robust optimization, and combination PBS (avoidance) plus VMAT (escalation). Dosimetric differences were evaluated by Friedman non-parametric paired test with multiple sampling correction. Results: PTV and normal tissue objectives were not violated in 24 FLARE RT plans. Population median of mean BTV dose was 73.7Gy (68.5–75.5Gy), mean FDG-PET peak dose was 89.7Gy (73.5–103Gy), MLD was 12.3Gy (7.5–19.6Gy), and perfused MLD was 4.8Gy (0.9–12.1Gy). VMAT achieved higher dose to the FDG-PET peak subvolume (p=0.01), while PBS delivered lower dose to lung (p<0.001). Voxelwise linear correlation between BTV dose and FDG-PET uptake was higher for VMAT (R=0.93) and PBS+VMAT (R=0.94) compared to PBS alone (R=0.89). Conclusion: FLARE RT is feasible with VMAT and PBS. A combination of PBS for functional lung avoidance and VMAT for FDG-PET dose escalation balances target/normal tissue objective tradeoffs. These results support future testing of FLARE RT safety and efficacy within a precision radiation oncology trial. This work was supported by a Research Scholar grant from the Radiological Society of North American Research & Education Foundation.« less

SU-F-J-86: Method to Include Tissue Dose Response Effect in Deformable Image Registration

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

Zhu, J; Liang, J; Chen, S

Purpose: Organ changes shape and size during radiation treatment due to both mechanical stress and radiation dose response. However, the dose response induced deformation has not been considered in conventional deformable image registration (DIR). A novel DIR approach is proposed to include both tissue elasticity and radiation dose induced organ deformation. Methods: Assuming that organ sub-volume shrinkage was proportional to the radiation dose induced cell killing/absorption, the dose induced organ volume change was simulated applying virtual temperature on each sub-volume. Hence, both stress and heterogeneity temperature induced organ deformation. Thermal stress finite element method with organ surface boundary condition wasmore » used to solve deformation. Initial boundary correspondence on organ surface was created from conventional DIR. Boundary condition was updated by an iterative optimization scheme to minimize elastic deformation energy. The registration was validated on a numerical phantom. Treatment dose was constructed applying both the conventional DIR and the proposed method using daily CBCT image obtained from HN treatment. Results: Phantom study showed 2.7% maximal discrepancy with respect to the actual displacement. Compared with conventional DIR, subvolume displacement difference in a right parotid had the mean±SD (Min, Max) to be 1.1±0.9(−0.4∼4.8), −0.1±0.9(−2.9∼2.4) and −0.1±0.9(−3.4∼1.9)mm in RL/PA/SI directions respectively. Mean parotid dose and V30 constructed including the dose response induced shrinkage were 6.3% and 12.0% higher than those from the conventional DIR. Conclusion: Heterogeneous dose distribution in normal organ causes non-uniform sub-volume shrinkage. Sub-volume in high dose region has a larger shrinkage than the one in low dose region, therefore causing more sub-volumes to move into the high dose area during the treatment course. This leads to an unfavorable dose-volume relationship for the normal organ. Without including this effect in DIR, treatment dose in normal organ could be underestimated affecting treatment evaluation and planning modification. Acknowledgement: Partially Supported by Elekta Research Grant.« less

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.

Technical considerations for implementation of x-ray CT polymer gel dosimetry.

PubMed

Hilts, M; Jirasek, A; Duzenli, C

2005-04-21

Gel dosimetry is the most promising 3D dosimetry technique in current radiation therapy practice. X-ray CT has been shown to be a feasible method of reading out polymer gel dosimeters and, with the high accessibility of CT scanners to cancer hospitals, presents an exciting possibility for clinical implementation of gel dosimetry. In this study we report on technical considerations for implementation of x-ray CT polymer gel dosimetry. Specifically phantom design, CT imaging methods, imaging time requirements and gel dose response are investigated. Where possible, recommendations are made for optimizing parameters to enhance system performance. The dose resolution achievable with an optimized system is calculated given voxel size and imaging time constraints. Results are compared with MRI and optical CT polymer gel dosimetry results available in the literature.

Time-gated scintillator imaging for real-time optical surface dosimetry in total skin electron therapy.

PubMed

Bruza, Petr; Gollub, Sarah L; Andreozzi, Jacqueline M; Tendler, Irwin I; Williams, Benjamin B; Jarvis, Lesley A; Gladstone, David J; Pogue, Brian W

2018-05-02

The purpose of this study was to measure surface dose by remote time-gated imaging of plastic scintillators. A novel technique for time-gated, intensified camera imaging of scintillator emission was demonstrated, and key parameters influencing the signal were analyzed, including distance, angle and thickness. A set of scintillator samples was calibrated by using thermo-luminescence detector response as reference. Examples of use in total skin electron therapy are described. The data showed excellent room light rejection (signal-to-noise ratio of scintillation SNR  ≈  470), ideal scintillation dose response linearity, and 2% dose rate error. Individual sample scintillation response varied by 7% due to sample preparation. Inverse square distance dependence correction and lens throughput error (8% per meter) correction were needed. At scintillator-to-source angle and observation angle  <50°, the radiant energy fluence error was smaller than 1%. The achieved standard error of the scintillator cumulative dose measurement compared to the TLD dose was 5%. The results from this proof-of-concept study documented the first use of small scintillator targets for remote surface dosimetry in ambient room lighting. The measured dose accuracy renders our method to be comparable to thermo-luminescent detector dosimetry, with the ultimate realization of accuracy likely to be better than shown here. Once optimized, this approach to remote dosimetry may substantially reduce the time and effort required for surface dosimetry.

Time-gated scintillator imaging for real-time optical surface dosimetry in total skin electron therapy

NASA Astrophysics Data System (ADS)

Bruza, Petr; Gollub, Sarah L.; Andreozzi, Jacqueline M.; Tendler, Irwin I.; Williams, Benjamin B.; Jarvis, Lesley A.; Gladstone, David J.; Pogue, Brian W.

2018-05-01

The purpose of this study was to measure surface dose by remote time-gated imaging of plastic scintillators. A novel technique for time-gated, intensified camera imaging of scintillator emission was demonstrated, and key parameters influencing the signal were analyzed, including distance, angle and thickness. A set of scintillator samples was calibrated by using thermo-luminescence detector response as reference. Examples of use in total skin electron therapy are described. The data showed excellent room light rejection (signal-to-noise ratio of scintillation SNR  ≈  470), ideal scintillation dose response linearity, and 2% dose rate error. Individual sample scintillation response varied by 7% due to sample preparation. Inverse square distance dependence correction and lens throughput error (8% per meter) correction were needed. At scintillator-to-source angle and observation angle  <50°, the radiant energy fluence error was smaller than 1%. The achieved standard error of the scintillator cumulative dose measurement compared to the TLD dose was 5%. The results from this proof-of-concept study documented the first use of small scintillator targets for remote surface dosimetry in ambient room lighting. The measured dose accuracy renders our method to be comparable to thermo-luminescent detector dosimetry, with the ultimate realization of accuracy likely to be better than shown here. Once optimized, this approach to remote dosimetry may substantially reduce the time and effort required for surface dosimetry.

SU-E-T-280: Reconstructed Rectal Wall Dose Map-Based Verification of Rectal Dose Sparing Effect According to Rectum Definition Methods and Dose Perturbation by Air Cavity in Endo-Rectal Balloon

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

Park, J; Research Institute of Biomedical Engineering, The Catholic University of Korea, Seoul; Park, H

Purpose: Dosimetric effect and discrepancy according to the rectum definition methods and dose perturbation by air cavity in an endo-rectal balloon (ERB) were verified using rectal-wall (Rwall) dose maps considering systematic errors in dose optimization and calculation accuracy in intensity-modulated radiation treatment (IMRT) for prostate cancer patients. Methods: When the inflated ERB having average diameter of 4.5 cm and air volume of 100 cc is used for patient, Rwall doses were predicted by pencil-beam convolution (PBC), anisotropic analytic algorithm (AAA), and AcurosXB (AXB) with material assignment function. The errors of dose optimization and calculation by separating air cavity from themore » whole rectum (Rwhole) were verified with measured rectal doses. The Rwall doses affected by the dose perturbation of air cavity were evaluated using a featured rectal phantom allowing insert of rolled-up gafchromic films and glass rod detectors placed along the rectum perimeter. Inner and outer Rwall doses were verified with reconstructed predicted rectal wall dose maps. Dose errors and extent at dose levels were evaluated with estimated rectal toxicity. Results: While AXB showed insignificant difference of target dose coverage, Rwall doses underestimated by up to 20% in dose optimization for the Rwhole than Rwall at all dose range except for the maximum dose. As dose optimization for Rwall was applied, the Rwall doses presented dose error less than 3% between dose calculation algorithm except for overestimation of maximum rectal dose up to 5% in PBC. Dose optimization for Rwhole caused dose difference of Rwall especially at intermediate doses. Conclusion: Dose optimization for Rwall could be suggested for more accurate prediction of rectal wall dose prediction and dose perturbation effect by air cavity in IMRT for prostate cancer. This research was supported by the Leading Foreign Research Institute Recruitment Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (MSIP) (Grant No. 200900420)« less

Open-label dose optimization of methylphenidate modified release long acting (MPH-LA): a post hoc analysis of real-life titration from a 40-week randomized trial.

PubMed

Huss, Michael; Ginsberg, Ylva; Arngrim, Torben; Philipsen, Alexandra; Carter, Katherine; Chen, Chien-Wei; Gandhi, Preetam; Kumar, Vinod

2014-09-01

In the management of attention-deficit hyperactivity disorder (ADHD) in adults it is important to recognize that individual patients respond to a wide range of methylphenidate doses. Studies with methylphenidate modified release long acting (MPH-LA) in children have reported the need for treatment optimization for improved outcomes. We report the results from a post hoc analysis of a 5-week dose optimization phase from a large randomized, placebo-controlled, multicenter 40-week study (9-week double-blind dose confirmation phase, 5-week open-label dose optimization phase, and 26-week double-blind maintenance of effect phase). Patients entering the open-label dose optimization phase initiated treatment with MPH-LA 20 mg/day; up/down titrated to their optimal dose (at which there was balance between control of symptoms and side effects) of 40, 60, or 80 mg/day in increments of 20 mg/week by week 12 or 13. Safety was assessed by monitoring the adverse events (AEs) and serious AEs. Efficacy was assessed by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, Attention-Deficit Hyperactivity Disorder Rating Scale (DSM-IV ADHD RS) and Sheehan Disability Scale (SDS) total scores. At the end of the dose confirmation phase, similar numbers of patients were treated optimally with each of the 40, 60, and 80 mg/day doses (152, 177, and 160, respectively) for MPH-LA. Mean improvement from baseline in the dose confirmation phase in total scores of DSM-IV ADHD RS and SDS were 23.5 ± 9.90 and 9.7 ± 7.36, respectively. Dose optimization with MPH-LA (40, 60, or 80 mg/day) improved treatment outcomes and was well-tolerated in adult ADHD patients.

Isotonic Regression Based-Method in Quantitative High-Throughput Screenings for Genotoxicity

PubMed Central

Fujii, Yosuke; Narita, Takeo; Tice, Raymond Richard; Takeda, Shunich

2015-01-01

Quantitative high-throughput screenings (qHTSs) for genotoxicity are conducted as part of comprehensive toxicology screening projects. The most widely used method is to compare the dose-response data of a wild-type and DNA repair gene knockout mutants, using model-fitting to the Hill equation (HE). However, this method performs poorly when the observed viability does not fit the equation well, as frequently happens in qHTS. More capable methods must be developed for qHTS where large data variations are unavoidable. In this study, we applied an isotonic regression (IR) method and compared its performance with HE under multiple data conditions. When dose-response data were suitable to draw HE curves with upper and lower asymptotes and experimental random errors were small, HE was better than IR, but when random errors were big, there was no difference between HE and IR. However, when the drawn curves did not have two asymptotes, IR showed better performance (p < 0.05, exact paired Wilcoxon test) with higher specificity (65% in HE vs. 96% in IR). In summary, IR performed similarly to HE when dose-response data were optimal, whereas IR clearly performed better in suboptimal conditions. These findings indicate that IR would be useful in qHTS for comparing dose-response data. PMID:26673567

Diagnosis and management of primary central nervous system lymphoma.

PubMed

Han, Catherine H; Batchelor, Tracy T

2017-11-15

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal non-Hodgkin lymphoma (NHL) that is confined to the brain, eyes, spinal cord, or leptomeninges without systemic involvement. The overall prognosis, diagnosis, and management of PCNSL differ from those for other types of NHL. Prompt diagnosis and initiation of treatment are vital for improving clinical outcomes. PCNSL is responsive to radiation therapy; however, whole-brain radiotherapy (WBRT) inadequately controls the disease when it is used alone, and its delayed neurotoxicity causes neurocognitive impairment, especially in elderly patients. High-dose methotrexate (HD-MTX)-based induction chemotherapy with or without autologous stem cell transplantation (ASCT) or reduced-dose WBRT leads to durable disease control and less neurotoxicity. The optimal treatment has yet to be defined; however, HD-MTX-based induction chemotherapy is considered standard for newly diagnosed PCNSL. Ongoing randomized trials are addressing the roles of rituximab and consolidative treatment with ASCT or reduced-dose WBRT. Despite high tumor response rates with the initial treatment, many patients relapse with a very poor prognosis. The optimal treatment for refractory or relapsed PCNSL is poorly defined. The choice of salvage treatment depends on a patient's age, previous treatment and response, performance status, and comorbidities at the time of relapse. This review provides an overview of the clinical features, diagnosis, pathology, and management of PCNSL in immunocompetent patients, and it focuses on recent advances in treatment. Cancer 2017;123:4314-24. © 2017 American Cancer Society. © 2017 American Cancer Society.

Homogeneous Canine Chest Phantom Construction: A Tool for Image Quality Optimization.

PubMed

Pavan, Ana Luiza Menegatti; Rosa, Maria Eugênia Dela; Giacomini, Guilherme; Bacchim Neto, Fernando Antonio; Yamashita, Seizo; Vulcano, Luiz Carlos; Duarte, Sergio Barbosa; Miranda, José Ricardo de Arruda; de Pina, Diana Rodrigues

2016-01-01

Digital radiographic imaging is increasing in veterinary practice. The use of radiation demands responsibility to maintain high image quality. Low doses are necessary because workers are requested to restrain the animal. Optimizing digital systems is necessary to avoid unnecessary exposure, causing the phenomenon known as dose creep. Homogeneous phantoms are widely used to optimize image quality and dose. We developed an automatic computational methodology to classify and quantify tissues (i.e., lung tissue, adipose tissue, muscle tissue, and bone) in canine chest computed tomography exams. The thickness of each tissue was converted to simulator materials (i.e., Lucite, aluminum, and air). Dogs were separated into groups of 20 animals each according to weight. Mean weights were 6.5 ± 2.0 kg, 15.0 ± 5.0 kg, 32.0 ± 5.5 kg, and 50.0 ± 12.0 kg, for the small, medium, large, and giant groups, respectively. The one-way analysis of variance revealed significant differences in all simulator material thicknesses (p < 0.05) quantified between groups. As a result, four phantoms were constructed for dorsoventral and lateral views. In conclusion, the present methodology allows the development of phantoms of the canine chest and possibly other body regions and/or animals. The proposed phantom is a practical tool that may be employed in future work to optimize veterinary X-ray procedures.

Effect of crospovidone and hydroxypropyl cellulose on carbamazepine in high-dose tablet formulation.

PubMed

Flicker, Felicia; Betz, Gabriele

2012-06-01

The aim of this study was to develop a high-dose tablet formulation of the poorly soluble carbamazepine (CBZ) with sufficient tablet hardness and immediate drug release. A further aim was to investigate the influence of various commercial CBZ raw materials on the optimized tablet formulation. Hydroxypropyl cellulose (HPC-SL) was selected as a dry binder and crospovidone (CrosPVP) as a superdisintegrant. A direct compacted tablet formulation of 70% CBZ was optimized by a 3² full factorial design with two input variables, HPC (0--10%) and CrosPVP (0--5%). Response variables included disintegration time, amount of drug released at 15 and 60 min, and tablet hardness, all analyzed according to USP 31. Increasing HPC-SL together with CrosPVP not only increased tablet hardness but also reduced disintegration time. Optimal condition was achieved in the range of 5--9% HPC and 3--5% CrosPVP, where tablet properties were at least 70 N tablet hardness, less than 1 min disintegration, and within the USP requirements for drug release. Testing the optimized formulation with four different commercial CBZ samples, their variability was still observed. Nonetheless, all formulations conformed to the USP specifications. With the excipients CrosPVP and HPC-SL an immediate release tablet formulation was successfully formulated for high-dose CBZ of various commercial sources.

Homogeneous Canine Chest Phantom Construction: A Tool for Image Quality Optimization

PubMed Central

2016-01-01

Digital radiographic imaging is increasing in veterinary practice. The use of radiation demands responsibility to maintain high image quality. Low doses are necessary because workers are requested to restrain the animal. Optimizing digital systems is necessary to avoid unnecessary exposure, causing the phenomenon known as dose creep. Homogeneous phantoms are widely used to optimize image quality and dose. We developed an automatic computational methodology to classify and quantify tissues (i.e., lung tissue, adipose tissue, muscle tissue, and bone) in canine chest computed tomography exams. The thickness of each tissue was converted to simulator materials (i.e., Lucite, aluminum, and air). Dogs were separated into groups of 20 animals each according to weight. Mean weights were 6.5 ± 2.0 kg, 15.0 ± 5.0 kg, 32.0 ± 5.5 kg, and 50.0 ± 12.0 kg, for the small, medium, large, and giant groups, respectively. The one-way analysis of variance revealed significant differences in all simulator material thicknesses (p < 0.05) quantified between groups. As a result, four phantoms were constructed for dorsoventral and lateral views. In conclusion, the present methodology allows the development of phantoms of the canine chest and possibly other body regions and/or animals. The proposed phantom is a practical tool that may be employed in future work to optimize veterinary X-ray procedures. PMID:27101001

Exposures involving perturbations of the EM field have non-linear effects on radiation response and can alter the expression of radiation induced bystander effects

NASA Astrophysics Data System (ADS)

Mothersill, Carmel; Seymour, Colin

2012-07-01

Our recent data suggest there is a physical component to the bystander signal induced by radiation exposure and that alternative medicine techniques such as Reiki and acupuncture or exposures to weak EM fields alter the response of cells to direct irradiation and either altered bystander signal production or altered the response of cells receiving bystander signals. Our proposed mechanism to explain these findings is that perturbation of electromagnetic (EM) fields is central to the induction of low radiation dose responses especially non-targeted bystander effects. In this presentation we review the alternative medicine data and other data sets from our laboratory which test our hypothesis that perturbation of bio-fields will modulate radiation response in the low dose region. The other data sets include exposure to MRI, shielding using lead and or Faraday cages, the use of physical barriers to bystander signal transmission and the use of membrane channel blockers. The data taken together strongly suggest that EM field perturbation can modulate low dose response and that in fact the EM field rather than the targeted deposition of ionizing energy in the DNA may be the key determinant of dose response in a cell or organism The results also lead us to suspect that at least when chemical transmission is blocked, bystander signals can be transmitted by other means. Our recent experiments suggest light signals and volatiles are not likely. We conclude that alternative medicine and other techniques involving electromagnetic perturbations can modify the response of cells to low doses of ionizing radiation and can induce bystander effects similar to those seen in medium transfer experiments. In addition to the obvious implications for mechanistic studies of low dose effects, this could perhaps provide a novel target to exploit in space radiation protection and in optimizing therapeutic gain during radiotherapy.

Testing Moderating Detection Systems with {sup 252}Cf-Based Reference Neutron Fields

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

Hertel, Nolan E.; Sweezy, Jeremy; Sauber, Jeremiah S.

Calibration measurements were carried out on a probe designed to measure ambient dose equivalent in accordance with ICRP Pub 60 recommendations. It consists of a cylindrical {sup 3}He proportional counter surrounded by a 25-cm-diameter spherical polyethylene moderator. Its neutron response is optimized for dose rate measurements of neutrons between thermal energies and 20 MeV. The instrument was used to measure the dose rate in four separate neutron fields: unmoderated {sup 252}Cf, D{sub 2}O-moderated {sup 252}Cf, polyethylene-moderated {sup 252}Cf, and WEP neutron howitzer with {sup 252}Cf at its center. Dose equivalent measurements were performed at source-detector centerline distances from 50 tomore » 200 cm. The ratio of air-scatter- and room-return-corrected ambient dose equivalent rates to ambient dose equivalent rates calculated with the code MCNP are tabulated.« less

Equalizing access to pandemic influenza vaccines through optimal allocation to public health distribution points.

PubMed

Huang, Hsin-Chan; Singh, Bismark; Morton, David P; Johnson, Gregory P; Clements, Bruce; Meyers, Lauren Ancel

2017-01-01

Vaccines are arguably the most important means of pandemic influenza mitigation. However, as during the 2009 H1N1 pandemic, mass immunization with an effective vaccine may not begin until a pandemic is well underway. In the U.S., state-level public health agencies are responsible for quickly and fairly allocating vaccines as they become available to populations prioritized to receive vaccines. Allocation decisions can be ethically and logistically complex, given several vaccine types in limited and uncertain supply and given competing priority groups with distinct risk profiles and vaccine acceptabilities. We introduce a model for optimizing statewide allocation of multiple vaccine types to multiple priority groups, maximizing equal access. We assume a large fraction of available vaccines are distributed to healthcare providers based on their requests, and then optimize county-level allocation of the remaining doses to achieve equity. We have applied the model to the state of Texas, and incorporated it in a Web-based decision-support tool for the Texas Department of State Health Services (DSHS). Based on vaccine quantities delivered to registered healthcare providers in response to their requests during the 2009 H1N1 pandemic, we find that a relatively small cache of discretionary doses (DSHS reserved 6.8% in 2009) suffices to achieve equity across all counties in Texas.

Greater activation of peripheral T follicular helper cells following high dose influenza vaccine in older adults forecasts seroconversion.

PubMed

Pilkinton, Mark A; Nicholas, Katherine J; Warren, Christian M; Smith, Rita M; Yoder, Sandra M; Talbot, H Keipp; Kalams, Spyros A

2017-01-05

Influenza related morbidity and mortality disproportionately impacts older adults. The serologic response to vaccine is diminished in older adults; however, high dose inactivated influenza vaccine (HD IIV) has shown improved rates of seroconversion compared to standard dose (SD IIV). We hypothesize this may be due to the superior ability of high dose vaccine to activate T follicular helper (Tfh) cells and provide B cell dependent T cell help. We measured peripheral Tfh (pTfh) activation in 50 community dwelling adults 65years or older who were randomly assigned to receive either the HD IIV or SD IIV. The HD vaccination elicited significantly higher levels of ICOS expression on pTfh cells, at day 7 compared to SD vaccination (p=0.02). The magnitude of the increase in ICOS+ pTfh cells from baseline to day 7 was predictive of seroconversion for both influenza A and B vaccination. Strong Tfh activation in response to influenza vaccination forecasts successful seroconversion in older adults, and HD IIV elicits greater Tfh activation than SD IIV. Future vaccine studies should focus on ways to further optimize the Tfh response. Copyright © 2016 Elsevier Ltd. All rights reserved.

Radiobiological evaluation of the influence of dwell time modulation restriction in HIPO optimized HDR prostate brachytherapy implants.

PubMed

Mavroidis, Panayiotis; Katsilieri, Zaira; Kefala, Vasiliki; Milickovic, Natasa; Papanikolaou, Nikos; Karabis, Andreas; Zamboglou, Nikolaos; Baltas, Dimos

2010-09-01

One of the issues that a planner is often facing in HDR brachytherapy is the selective existence of high dose volumes around some few dominating dwell positions. If there is no information available about its necessity (e.g. location of a GTV), then it is reasonable to investigate whether this can be avoided. This effect can be eliminated by limiting the free modulation of the dwell times. HIPO, an inverse treatment plan optimization algorithm, offers this option. In treatment plan optimization there are various methods that try to regularize the variation of dose non-uniformity using purely dosimetric measures. However, although these methods can help in finding a good dose distribution they do not provide any information regarding the expected treatment outcome as described by radiobiology based indices. The quality of 12 clinical HDR brachytherapy implants for prostate utilizing HIPO and modulation restriction (MR) has been compared to alternative plans with HIPO and free modulation (without MR). All common dose-volume indices for the prostate and the organs at risk have been considered together with radiobiological measures. The clinical effectiveness of the different dose distributions was investigated by calculating the response probabilities of the tumors and organs-at-risk (OARs) involved in these prostate cancer cases. The radiobiological models used are the Poisson and the relative seriality models. Furthermore, the complication-free tumor control probability, P + and the biologically effective uniform dose ([Formula: see text]) were used for treatment plan evaluation and comparison. Our results demonstrate that HIPO with a modulation restriction value of 0.1-0.2 delivers high quality plans which are practically equivalent to those achieved with free modulation regarding the clinically used dosimetric indices. In the comparison, many of the dosimetric and radiobiological indices showed significantly different results. The modulation restricted clinical plans demonstrated a lower total dwell time by a mean of 1.4% that was proved to be statistically significant ( p = 0.002). The HIPO with MR treatment plans produced a higher P + by 0.5%, which stemmed from a better sparing of the OARs by 1.0%. Both the dosimetric and radiobiological comparison shows that the modulation restricted optimization gives on average similar results with the optimization without modulation restriction in the examined clinical cases. Concluding, based on our results, it appears that the applied dwell time regularization technique is expected to introduce a minor improvement in the effectiveness of the optimized HDR dose distributions.

Radiobiological evaluation of the influence of dwell time modulation restriction in HIPO optimized HDR prostate brachytherapy implants

PubMed Central

Katsilieri, Zaira; Kefala, Vasiliki; Milickovic, Natasa; Papanikolaou, Nikos; Karabis, Andreas; Zamboglou, Nikolaos; Baltas, Dimos

2010-01-01

Purpose One of the issues that a planner is often facing in HDR brachytherapy is the selective existence of high dose volumes around some few dominating dwell positions. If there is no information available about its necessity (e.g. location of a GTV), then it is reasonable to investigate whether this can be avoided. This effect can be eliminated by limiting the free modulation of the dwell times. HIPO, an inverse treatment plan optimization algorithm, offers this option. In treatment plan optimization there are various methods that try to regularize the variation of dose non-uniformity using purely dosimetric measures. However, although these methods can help in finding a good dose distribution they do not provide any information regarding the expected treatment outcome as described by radiobiology based indices. Material and methods The quality of 12 clinical HDR brachytherapy implants for prostate utilizing HIPO and modulation restriction (MR) has been compared to alternative plans with HIPO and free modulation (without MR). All common dose-volume indices for the prostate and the organs at risk have been considered together with radiobiological measures. The clinical effectiveness of the different dose distributions was investigated by calculating the response probabilities of the tumors and organs-at-risk (OARs) involved in these prostate cancer cases. The radiobiological models used are the Poisson and the relative seriality models. Furthermore, the complication-free tumor control probability, P+ and the biologically effective uniform dose (D¯¯) were used for treatment plan evaluation and comparison. Results Our results demonstrate that HIPO with a modulation restriction value of 0.1-0.2 delivers high quality plans which are practically equivalent to those achieved with free modulation regarding the clinically used dosimetric indices. In the comparison, many of the dosimetric and radiobiological indices showed significantly different results. The modulation restricted clinical plans demonstrated a lower total dwell time by a mean of 1.4% that was proved to be statistically significant (p = 0.002). The HIPO with MR treatment plans produced a higher P+ by 0.5%, which stemmed from a better sparing of the OARs by 1.0%. Conclusions Both the dosimetric and radiobiological comparison shows that the modulation restricted optimization gives on average similar results with the optimization without modulation restriction in the examined clinical cases. Concluding, based on our results, it appears that the applied dwell time regularization technique is expected to introduce a minor improvement in the effectiveness of the optimized HDR dose distributions. PMID:27853473

A single-blind cross over study investigating the efficacy of standard and controlled release levodopa in combination with entacapone in the treatment of end-of-dose effect in people with Parkinson's disease.

PubMed

Iansek, R; Danoudis, M

2011-08-01

To determine the efficacy of standard levodopa combined with controlled release levodopa and entacapone in controlling end-of-dose symptoms in Parkinson's disease. A single-blind cross over design was used to compare the duration of action for three pharmacological combinations: standard levodopa (L/DDC); standard levodopa combined with entacapone (L/DDC/E); and standard levodopa combined with controlled release levodopa (CR) and entacapone (L/DDC/CR/E). Thirty two participants with wearing-off symptoms and inadequate symptom control with L/DDC/E had their optimum dose of L/DDC determined at base line. Entacapone was added to the optimal L/DDC dose and duration of action determined. Levodopa CR dosage was adjusted to match the optimal L/DDC dose for each participant. All participants were then trialed on L/DDC/CR/E and duration of response calculated. Timed Up and Go (TUG) times and magnitude of extra movements were recorded hourly throughout the day over several days to determine the optimum interval between doses for each combination. The UPDRS (Sections 2 and 3), PDQ39 and fatigue scale, the PDF-16, were recorded at base line and when dosage intervals had stabilized on L/DDC/CR/E. Duration of response was greatest with L/DDC/CR/E compared to L/DDC/E (p < 0.001) and number of daily doses were less on L/DDC/CR/E compared to L/DDC/E (p < 0.001). UPDRS, PDQ39 and fatigue scores also improved on L/DDC/CR/E compared to L/DDC (p < 0.001). Dyskinesia increased on L/DDC/CR/E (p = 0.001) however magnitude was mild. Combining standard levodopa and levodopa CR preparations with entacapone is an additional treatment strategy to manage motor fluctuations in advanced PD. Copyright © 2011 Elsevier Ltd. All rights reserved.

The Effect of Ingested Glucose Dose on the Suppression of Endogenous Glucose Production in Humans.

PubMed

Kowalski, Greg M; Moore, Samantha M; Hamley, Steven; Selathurai, Ahrathy; Bruce, Clinton R

2017-09-01

Insulin clamp studies have shown that the suppressive actions of insulin on endogenous glucose production (EGP) are markedly more sensitive than for stimulating glucose disposal ( R d ). However, clamp conditions do not adequately mimic postprandial physiological responses. Here, using the variable infusion dual-tracer approach, we used a threefold range of ingested glucose doses (25, 50, and 75 g) to investigate how physiological changes in plasma insulin influence EGP in healthy subjects. Remarkably, the glucose responses were similar for all doses tested, yet there was a dose-dependent increase in insulin secretion and plasma insulin levels. Nonetheless, EGP was suppressed with the same rapidity and magnitude (∼55%) across all doses. The progressive hyperinsulinemia, however, caused a dose-dependent increase in the estimated rates of R d , which likely accounts for the lack of a dose effect on plasma glucose excursions. This suggests that after glucose ingestion, the body preferentially permits a transient and optimal degree of postprandial hyperglycemia to efficiently enhance insulin-induced changes in glucose fluxes, thereby minimizing the demand for insulin secretion. This may represent an evolutionarily conserved mechanism that not only reduces the secretory burden on β-cells but also avoids the potential negative consequences of excessive insulin release into the systemic arterial circulation. © 2017 by the American Diabetes Association.

Clinical knowledge-based inverse treatment planning

NASA Astrophysics Data System (ADS)

Yang, Yong; Xing, Lei

2004-11-01

Clinical IMRT treatment plans are currently made using dose-based optimization algorithms, which do not consider the nonlinear dose-volume effects for tumours and normal structures. The choice of structure specific importance factors represents an additional degree of freedom of the system and makes rigorous optimization intractable. The purpose of this work is to circumvent the two problems by developing a biologically more sensible yet clinically practical inverse planning framework. To implement this, the dose-volume status of a structure was characterized by using the effective volume in the voxel domain. A new objective function was constructed with the incorporation of the volumetric information of the system so that the figure of merit of a given IMRT plan depends not only on the dose deviation from the desired distribution but also the dose-volume status of the involved organs. The conventional importance factor of an organ was written into a product of two components: (i) a generic importance that parametrizes the relative importance of the organs in the ideal situation when the goals for all the organs are met; (ii) a dose-dependent factor that quantifies our level of clinical/dosimetric satisfaction for a given plan. The generic importance can be determined a priori, and in most circumstances, does not need adjustment, whereas the second one, which is responsible for the intractable behaviour of the trade-off seen in conventional inverse planning, was determined automatically. An inverse planning module based on the proposed formalism was implemented and applied to a prostate case and a head-neck case. A comparison with the conventional inverse planning technique indicated that, for the same target dose coverage, the critical structure sparing was substantially improved for both cases. The incorporation of clinical knowledge allows us to obtain better IMRT plans and makes it possible to auto-select the importance factors, greatly facilitating the inverse planning process. The new formalism proposed also reveals the relationship between different inverse planning schemes and gives important insight into the problem of therapeutic plan optimization. In particular, we show that the EUD-based optimization is a special case of the general inverse planning formalism described in this paper.

WE-AB-303-06: Combining DAO with MV + KV Optimization to Improve Skin Dose Sparing with Real-Time Fluoroscopy

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

Grelewicz, Z; Wiersma, R

Purpose: Real-time fluoroscopy may allow for improved patient positioning and tumor tracking, particularly in the treatment of lung tumors. In order to mitigate the effects of the imaging dose, previous studies have demonstrated the effect of including both imaging dose and imaging constraints into the inverse treatment planning object function. That method of combined MV+kV optimization may Result in plans with treatment beams chosen to allow for more gentle imaging beam-on times. Direct-aperture optimization (DAO) is also known to produce treatment plans with fluence maps more conducive to lower beam-on times. Therefore, in this work we demonstrate the feasibility ofmore » a combination of DAO and MV+kV optimization for further optimized real-time kV imaging. Methods: Therapeutic and imaging beams were modeled in the EGSnrc Monte Carlo environment, and applied to a patient model for a previously treated lung patient to provide dose influence matrices from DOSXYZnrc. An MV + kV IMRT DAO treatment planning system was developed to compare DAO treatment plans with and without MV+kV optimization. The objective function was optimized using simulated annealing. In order to allow for comparisons between different cases of the stochastically optimized plans, the optimization was repeated twenty times. Results: Across twenty optimizations, combined MV+kV IMRT resulted in an average of 12.8% reduction in peak skin dose. Both non-optimized and MV+kV optimized imaging beams delivered, on average, mean dose of approximately 1 cGy per fraction to the target, with peak doses to target of approximately 6 cGy per fraction. Conclusion: When using DAO, MV+kV optimization is shown to Result in improvements to plan quality in terms of skin dose, when compared to the case of MV optimization with non-optimized kV imaging. The combination of DAO and MV+kV optimization may allow for real-time imaging without excessive imaging dose. Financial support for the work has been provided in part by NIH Grant T32 EB002103, ACS RSG-13-313-01-CCE, and NIH S10 RR021039 and P30 CA14599 grants. The contents of this submission do not necessarily represent the official views of any of the supporting organizations.« less

GPU-based ultra-fast dose calculation using a finite size pencil beam model.

PubMed

Gu, Xuejun; Choi, Dongju; Men, Chunhua; Pan, Hubert; Majumdar, Amitava; Jiang, Steve B

2009-10-21

Online adaptive radiation therapy (ART) is an attractive concept that promises the ability to deliver an optimal treatment in response to the inter-fraction variability in patient anatomy. However, it has yet to be realized due to technical limitations. Fast dose deposit coefficient calculation is a critical component of the online planning process that is required for plan optimization of intensity-modulated radiation therapy (IMRT). Computer graphics processing units (GPUs) are well suited to provide the requisite fast performance for the data-parallel nature of dose calculation. In this work, we develop a dose calculation engine based on a finite-size pencil beam (FSPB) algorithm and a GPU parallel computing framework. The developed framework can accommodate any FSPB model. We test our implementation in the case of a water phantom and the case of a prostate cancer patient with varying beamlet and voxel sizes. All testing scenarios achieved speedup ranging from 200 to 400 times when using a NVIDIA Tesla C1060 card in comparison with a 2.27 GHz Intel Xeon CPU. The computational time for calculating dose deposition coefficients for a nine-field prostate IMRT plan with this new framework is less than 1 s. This indicates that the GPU-based FSPB algorithm is well suited for online re-planning for adaptive radiotherapy.

Optimization for high-dose-rate brachytherapy of cervical cancer with adaptive simulated annealing and gradient descent.

PubMed

Yao, Rui; Templeton, Alistair K; Liao, Yixiang; Turian, Julius V; Kiel, Krystyna D; Chu, James C H

2014-01-01

To validate an in-house optimization program that uses adaptive simulated annealing (ASA) and gradient descent (GD) algorithms and investigate features of physical dose and generalized equivalent uniform dose (gEUD)-based objective functions in high-dose-rate (HDR) brachytherapy for cervical cancer. Eight Syed/Neblett template-based cervical cancer HDR interstitial brachytherapy cases were used for this study. Brachytherapy treatment plans were first generated using inverse planning simulated annealing (IPSA). Using the same dwell positions designated in IPSA, plans were then optimized with both physical dose and gEUD-based objective functions, using both ASA and GD algorithms. Comparisons were made between plans both qualitatively and based on dose-volume parameters, evaluating each optimization method and objective function. A hybrid objective function was also designed and implemented in the in-house program. The ASA plans are higher on bladder V75% and D2cc (p=0.034) and lower on rectum V75% and D2cc (p=0.034) than the IPSA plans. The ASA and GD plans are not significantly different. The gEUD-based plans have higher homogeneity index (p=0.034), lower overdose index (p=0.005), and lower rectum gEUD and normal tissue complication probability (p=0.005) than the physical dose-based plans. The hybrid function can produce a plan with dosimetric parameters between the physical dose-based and gEUD-based plans. The optimized plans with the same objective value and dose-volume histogram could have different dose distributions. Our optimization program based on ASA and GD algorithms is flexible on objective functions, optimization parameters, and can generate optimized plans comparable with IPSA. Copyright © 2014 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

TU-EF-204-09: A Preliminary Method of Risk-Informed Optimization of Tube Current Modulation for Dose Reduction in CT

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

Gao, Y; Liu, B; Kalra, M

Purpose: X-rays from CT scans can increase cancer risk to patients. Lifetime Attributable Risk of Cancer Incidence for adult patients has been investigated and shown to decrease as patient age. However, a new risk model shows an increasing risk trend for several radiosensitive organs for middle age patients. This study investigates the feasibility of a general method for optimizing tube current modulation (TCM) functions to minimize risk by reducing radiation dose to radiosensitive organs of patients. Methods: Organ-based TCM has been investigated in literature for eye lens dose and breast dose. Adopting the concept in organ-based TCM, this study seeksmore » to find an optimized tube current for minimal total risk to breasts and lungs by reducing dose to these organs. The contributions of each CT view to organ dose are determined through simulations of CT scan view-by-view using a GPU-based fast Monte Carlo code, ARCHER. A Linear Programming problem is established for tube current optimization, with Monte Carlo results as weighting factors at each view. A pre-determined dose is used as upper dose boundary, and tube current of each view is optimized to minimize the total risk. Results: An optimized tube current is found to minimize the total risk of lungs and breasts: compared to fixed current, the risk is reduced by 13%, with breast dose reduced by 38% and lung dose reduced by 7%. The average tube current is maintained during optimization to maintain image quality. In addition, dose to other organs in chest region is slightly affected, with relative change in dose smaller than 10%. Conclusion: Optimized tube current plans can be generated to minimize cancer risk to lungs and breasts while maintaining image quality. In the future, various risk models and greater number of projections per rotation will be simulated on phantoms of different gender and age. National Institutes of Health R01EB015478.« less

Evidence-Based Design of Fixed-Dose Combinations: Principles and Application to Pediatric Anti-Tuberculosis Therapy.

PubMed

Svensson, Elin M; Yngman, Gunnar; Denti, Paolo; McIlleron, Helen; Kjellsson, Maria C; Karlsson, Mats O

2018-05-01

Fixed-dose combination formulations where several drugs are included in one tablet are important for the implementation of many long-term multidrug therapies. The selection of optimal dose ratios and tablet content of a fixed-dose combination and the design of individualized dosing regimens is a complex task, requiring multiple simultaneous considerations. In this work, a methodology for the rational design of a fixed-dose combination was developed and applied to the case of a three-drug pediatric anti-tuberculosis formulation individualized on body weight. The optimization methodology synthesizes information about the intended use population, the pharmacokinetic properties of the drugs, therapeutic targets, and practical constraints. A utility function is included to penalize deviations from the targets; a sequential estimation procedure was developed for stable estimation of break-points for individualized dosing. The suggested optimized pediatric anti-tuberculosis fixed-dose combination was compared with the recently launched World Health Organization-endorsed formulation. The optimized fixed-dose combination included 15, 36, and 16% higher amounts of rifampicin, isoniazid, and pyrazinamide, respectively. The optimized fixed-dose combination is expected to result in overall less deviation from the therapeutic targets based on adult exposure and substantially fewer children with underexposure (below half the target). The development of this design tool can aid the implementation of evidence-based formulations, integrating available knowledge and practical considerations, to optimize drug exposures and thereby treatment outcomes.

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

Quantifying the importance of pMHC valency, total pMHC dose and frequency on nanoparticle therapeutic efficacy.

PubMed

Sugarman, Jordan; Tsai, Sue; Santamaria, Pere; Khadra, Anmar

2013-05-01

Nanoparticles (NPs) coated with β-cell-specific peptide major histocompatibility complex (pMHC) class I molecules can effectively restore normoglycemia in spontaneously diabetic nonobese diabetic mice. They do so by expanding pools of cognate memory autoreactive regulatory CD8+ T cells that arise from naive low-avidity T-cell precursors to therapeutic levels. Here we develop our previously constructed mathematical model to explore the effects of compound design parameters (NP dose and pMHC valency) on therapeutic efficacy with the underlying hypothesis that the functional correlates of the therapeutic response (expansion of autoregulatory T cells and deletion of autoantigen-loaded antigen-presenting cells by these T cells) are biphasic. We show, using bifurcation analysis, that the model exhibits a 'resonance'-like behavior for a given range of NP dose in which bistability between the healthy state (possessing zero level of effector T-cell population) and autoimmune state (possessing elevated level of the same population) disappears. A heterogeneous population of model mice subjected to several treatment protocols under these new conditions is conducted to quantify both the average percentage of autoregulatory T cells in responsive and nonresponsive model mice, and the average valency-dependent minimal optimal dose needed for effective therapy. Our results reveal that a moderate increase (≥1.6-fold) in the NP-dependent expansion rate of autoregulatory T-cell population leads to a significant increase in the efficacy and the area corresponding to the effective treatment regimen, provided that NP dose ≥8 μg. We expect the model developed here to generalize to other autoimmune diseases and serve as a computational tool to understand and optimize pMHC-NP-based therapies.

Serum 25-hydroxyvitamin D response to vitamin D3 supplementation 50,000 IU monthly in youth with HIV-1 infection

USDA-ARS?s Scientific Manuscript database

Context: Vitamin D deficiency and insufficiency occur frequently in youth with HIV infection, particularly among those receiving the antiretroviral drug efavirenz. Optimal vitamin D dosing for treatment is unclear. Objective: Measure change in 25-hydroxy vitamin D (25-OHD) concentration from basel...

MO-G-18A-01: Radiation Dose Reducing Strategies in CT, Fluoroscopy and Radiography

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

Mahesh, M; Gingold, E; Jones, A

2014-06-15

Advances in medical x-ray imaging have provided significant benefits to patient care. According to NCRP 160, there are more than 400 million x-ray procedures performed annually in the United States alone that contributes to nearly half of all the radiation exposure to the US population. Similar growth trends in medical x-ray imaging are observed worldwide. Apparent increase in number of medical x-ray imaging procedures, new protocols and the associated radiation dose and risk has drawn considerable attention. This has led to a number of technological innovations such as tube current modulation, iterative reconstruction algorithms, dose alerts, dose displays, flat panelmore » digital detectors, high efficient digital detectors, storage phosphor radiography, variable filters, etc. that are enabling users to acquire medical x-ray images at a much lower radiation dose. Along with these, there are number of radiation dose optimization strategies that users can adapt to effectively lower radiation dose in medical x-ray procedures. The main objectives of this SAM course are to provide information and how to implement the various radiation dose optimization strategies in CT, Fluoroscopy and Radiography. Learning Objectives: To update impact of technological advances on dose optimization in medical imaging. To identify radiation optimization strategies in computed tomography. To describe strategies for configuring fluoroscopic equipment that yields optimal images at reasonable radiation dose. To assess ways to configure digital radiography systems and recommend ways to improve image quality at optimal dose.« less

Investigation of Cr(VI) adsorption onto chemically treated Helianthus annuus: optimization using response surface methodology.

PubMed

Jain, Monika; Garg, V K; Kadirvelu, K

2011-01-01

In the present study, chemically treated Helianthus annuus flowers (SHC) were used to optimize the removal efficiency for Cr(VI) by applying Response Surface Methodological approach. The surface structure of SHC was analyzed by Scanning Electron Microscopy (SEM) coupled with Energy Dispersive X-ray Analysis (EDX). Batch mode experiments were also carried out to assess the adsorption equilibrium in aqueous solution. The adsorption capacity (qe) was found to be 7.2 mg/g. The effect of three parameters, that is pH of the solution (2.0-7.0), initial concentration (10-70 mg/L) and adsorbent dose (0.05-0.5 g/100 mL) was studied for the removal of Cr(VI) by SHC. Box-Behnken model was used as an experimental design. The optimum pH, adsorbent dose and initial Cr(VI) concentration were found to be 2.0, 5.0 g/L and 40 mg/L, respectively. Under these conditions, removal efficiency of Cr(VI) was found to be 90.8%. Copyright © 2010 Elsevier Ltd. All rights reserved.

Intermittent Metronomic Drug Schedule Is Essential for Activating Antitumor Innate Immunity and Tumor Xenograft Regression12

PubMed Central

Chen, Chong-Sheng; Doloff, Joshua C; Waxman, David J

2014-01-01

Metronomic chemotherapy using cyclophosphamide (CPA) is widely associated with antiangiogenesis; however, recent studies implicate other immune-based mechanisms, including antitumor innate immunity, which can induce major tumor regression in implanted brain tumor models. This study demonstrates the critical importance of drug schedule: CPA induced a potent antitumor innate immune response and tumor regression when administered intermittently on a 6-day repeating metronomic schedule but not with the same total exposure to activated CPA administered on an every 3-day schedule or using a daily oral regimen that serves as the basis for many clinical trials of metronomic chemotherapy. Notably, the more frequent metronomic CPA schedules abrogated the antitumor innate immune and therapeutic responses. Further, the innate immune response and antitumor activity both displayed an unusually steep dose-response curve and were not accompanied by antiangiogenesis. The strong recruitment of innate immune cells by the 6-day repeating CPA schedule was not sustained, and tumor regression was abolished, by a moderate (25%) reduction in CPA dose. Moreover, an ∼20% increase in CPA dose eliminated the partial tumor regression and weak innate immune cell recruitment seen in a subset of the every 6-day treated tumors. Thus, metronomic drug treatment must be at a sufficiently high dose but also sufficiently well spaced in time to induce strong sustained antitumor immune cell recruitment. Many current clinical metronomic chemotherapeutic protocols employ oral daily low-dose schedules that do not meet these requirements, suggesting that they may benefit from optimization designed to maximize antitumor immune responses. PMID:24563621

Low-dose cyclophosphamide administered as daily or single dose enhances the antitumor effects of a therapeutic HPV vaccine

PubMed Central

Peng, Shiwen; Lyford-Pike, Sofia; Akpeng, Belinda; Wu, Annie; Hung, Chien-Fu; Hannaman, Drew; Saunders, John R.; Wu, T.-C.

2012-01-01

Although therapeutic HPV vaccines are able to elicit systemic HPV-specific immunity, clinical responses have not always correlated with levels of vaccine-induced CD8+ T cells in human clinical trials. This observed discrepancy may be attributable to an immunosuppressive tumor microenvironment in which the CD8+ T cells are recruited. Regulatory T cells (Tregs) are cells that can dampen cytotoxic CD8+ T-cell function. Cyclophosphamide (CTX) is a systemic chemotherapeutic agent, which can eradicate immune cells, including inhibitory Tregs. The optimal dose and schedule of CTX administration in combination with immunotherapy to eliminate the Treg population without adversely affecting vaccine-induced T-cell responses is unknown. Therefore, we investigated various dosing and administration schedules of CTX in combination with a therapeutic HPV vaccine in a preclinical tumor model. HPV tumor-bearing mice received either a single preconditioning dose or a daily dose of CTX in combination with the pNGVL4a-CRT/E7(detox) DNA vaccine. Both single and daily dosing of CTX in combination with vaccine had a synergistic anti-tumor effect as compared to monotherapy alone. The potent antitumor responses were attributed to the reduction in Treg frequency and increased infiltration of HPV16 E7-specific CD8+ T cells, which led to higher ratios of CD8+/Treg and CD8+/CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs). There was an observed trend toward decreased vaccine-induced CD8+ T-cell frequency with daily dosing of CTX. We recommend a single, preconditioning dose of CTX prior to vaccination due to its efficacy, ease of administration, and reduced cumulative adverse effect on vaccine-induced T cells. PMID:23011589

A Bayesian Dose-finding Design for Oncology Clinical Trials of Combinational Biological Agents

PubMed Central

Cai, Chunyan; Yuan, Ying; Ji, Yuan

2013-01-01

Treating patients with novel biological agents is becoming a leading trend in oncology. Unlike cytotoxic agents, for which efficacy and toxicity monotonically increase with dose, biological agents may exhibit non-monotonic patterns in their dose-response relationships. Using a trial with two biological agents as an example, we propose a dose-finding design to identify the biologically optimal dose combination (BODC), which is defined as the dose combination of the two agents with the highest efficacy and tolerable toxicity. A change-point model is used to reflect the fact that the dose-toxicity surface of the combinational agents may plateau at higher dose levels, and a flexible logistic model is proposed to accommodate the possible non-monotonic pattern for the dose-efficacy relationship. During the trial, we continuously update the posterior estimates of toxicity and efficacy and assign patients to the most appropriate dose combination. We propose a novel dose-finding algorithm to encourage sufficient exploration of untried dose combinations in the two-dimensional space. Extensive simulation studies show that the proposed design has desirable operating characteristics in identifying the BODC under various patterns of dose-toxicity and dose-efficacy relationships. PMID:24511160

Nanoscale Fe/Ag particles activated persulfate: optimization using response surface methodology.

PubMed

Silveira, Jefferson E; Barreto-Rodrigues, Marcio; Cardoso, Tais O; Pliego, Gema; Munoz, Macarena; Zazo, Juan A; Casas, José A

2017-05-01

This work studied the bimetallic nanoparticles Fe-Ag (nZVI-Ag) activated persulfate (PS) in aqueous solution using response surface methodology. The Box-Behnken design (BBD) was employed to optimize three parameters (nZVI-Ag dose, reaction temperature, and PS concentration) using 4-chlorophenol (4-CP) as the target pollutant. The synthesis of nZVI-Ag particles was carried out through a reduction of FeCl 2 with NaBH 4 followed by reductive deposition of Ag. The catalyst was characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM) and Brunauer-Emmett-Teller (BET) surface area. The BBD was considered a satisfactory model to optimize the process. Confirmatory tests were carried out using predicted and experimental values under the optimal conditions (50 mg L -1 nZVI-Ag, 21 mM PS at 57 °C) and the complete removal of 4-CP achieved experimentally was successfully predicted by the model, whereas the mineralization degree predicted (90%) was slightly overestimated against the measured data (83%).

SU-E-T-175: Clinical Evaluations of Monte Carlo-Based Inverse Treatment Plan Optimization for Intensity Modulated Radiotherapy

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

Chi, Y; Li, Y; Tian, Z

2015-06-15

Purpose: Pencil-beam or superposition-convolution type dose calculation algorithms are routinely used in inverse plan optimization for intensity modulated radiation therapy (IMRT). However, due to their limited accuracy in some challenging cases, e.g. lung, the resulting dose may lose its optimality after being recomputed using an accurate algorithm, e.g. Monte Carlo (MC). It is the objective of this study to evaluate the feasibility and advantages of a new method to include MC in the treatment planning process. Methods: We developed a scheme to iteratively perform MC-based beamlet dose calculations and plan optimization. In the MC stage, a GPU-based dose engine wasmore » used and the particle number sampled from a beamlet was proportional to its optimized fluence from the previous step. We tested this scheme in four lung cancer IMRT cases. For each case, the original plan dose, plan dose re-computed by MC, and dose optimized by our scheme were obtained. Clinically relevant dosimetric quantities in these three plans were compared. Results: Although the original plan achieved a satisfactory PDV dose coverage, after re-computing doses using MC method, it was found that the PTV D95% were reduced by 4.60%–6.67%. After re-optimizing these cases with our scheme, the PTV coverage was improved to the same level as in the original plan, while the critical OAR coverages were maintained to clinically acceptable levels. Regarding the computation time, it took on average 144 sec per case using only one GPU card, including both MC-based beamlet dose calculation and treatment plan optimization. Conclusion: The achieved dosimetric gains and high computational efficiency indicate the feasibility and advantages of the proposed MC-based IMRT optimization method. Comprehensive validations in more patient cases are in progress.« less

SU-E-T-503: IMRT Optimization Using Monte Carlo Dose Engine: The Effect of Statistical Uncertainty.

PubMed

Tian, Z; Jia, X; Graves, Y; Uribe-Sanchez, A; Jiang, S

2012-06-01

With the development of ultra-fast GPU-based Monte Carlo (MC) dose engine, it becomes clinically realistic to compute the dose-deposition coefficients (DDC) for IMRT optimization using MC simulation. However, it is still time-consuming if we want to compute DDC with small statistical uncertainty. This work studies the effects of the statistical error in DDC matrix on IMRT optimization. The MC-computed DDC matrices are simulated here by adding statistical uncertainties at a desired level to the ones generated with a finite-size pencil beam algorithm. A statistical uncertainty model for MC dose calculation is employed. We adopt a penalty-based quadratic optimization model and gradient descent method to optimize fluence map and then recalculate the corresponding actual dose distribution using the noise-free DDC matrix. The impacts of DDC noise are assessed in terms of the deviation of the resulted dose distributions. We have also used a stochastic perturbation theory to theoretically estimate the statistical errors of dose distributions on a simplified optimization model. A head-and-neck case is used to investigate the perturbation to IMRT plan due to MC's statistical uncertainty. The relative errors of the final dose distributions of the optimized IMRT are found to be much smaller than those in the DDC matrix, which is consistent with our theoretical estimation. When history number is decreased from 108 to 106, the dose-volume-histograms are still very similar to the error-free DVHs while the error in DDC is about 3.8%. The results illustrate that the statistical errors in the DDC matrix have a relatively small effect on IMRT optimization in dose domain. This indicates we can use relatively small number of histories to obtain the DDC matrix with MC simulation within a reasonable amount of time, without considerably compromising the accuracy of the optimized treatment plan. This work is supported by Varian Medical Systems through a Master Research Agreement. © 2012 American Association of Physicists in Medicine.

Psychophysical and Vasomotor Responses of the Oral Tissues: A Nicotine Dose-Response and Menthol Interaction Study.

PubMed

Arendt Nielsen, Thomas; Nielsen, Bruno Provstgaard; Wang, Kelun; Arendt-Nielsen, Lars; Boudreau, Shellie A

2016-05-01

This study implemented an intra-oral test-platform to assess the sensory, psychophysical, and vasomotor responses to nicotine and menthol, alone or in combination. Two double-blinded, placebo-controlled, randomized, cross-over studies, including healthy nonsmoking participants were performed. Study I: A dose-response relationship (N = 20) between 0, 2, and 4 mg nicotine gum. Study II: An interaction response (N = 22) to 30 mg menthol and 4 mg nicotine alone or in combination. Heart rate, blood pressure, tactile and thermosensory thresholds, intra-oral blood flow and temperature, pain/irritation intensities/locations, McGill Pain Questionnaire, and taste experience were assessed before, during or after the completion of a standardized chewing regime. A dose-response elevation in heart rate was attenuated when nicotine was combined with menthol. Blood flow, temperature, and warm-detection thresholds, as assessed on the tongue, similarly increased for all gums. Pain intensity and taste experiences were similar between nicotine doses. Nicotine attenuated the sweet, cooling, and freshening sensation of menthol. Within the first 4 minutes, menthol reduced the intensity but not the area of nicotine-induced pain and irritation. The 4-mg nicotine dose led to a continued increase in the intensity and area of irritation in the throat post-chewing. Moreover, one-half of participants responded to menthol as an irritant, and these individuals demonstrated larger areas of nicotine-induced irritation in the throat post-chewing. The intra-oral test platform provides a basis to optimize the assessment of nicotine-related taste and sensory experiences and can be used in future studies for profiling nicotine gum. © The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

4D Optimization of Scanned Ion Beam Tracking Therapy for Moving Tumors

PubMed Central

Eley, John Gordon; Newhauser, Wayne David; Lüchtenborg, Robert; Graeff, Christian; Bert, Christoph

2014-01-01

Motion mitigation strategies are needed to fully realize the theoretical advantages of scanned ion beam therapy for patients with moving tumors. The purpose of this study was to determine whether a new four-dimensional (4D) optimization approach for scanned-ion-beam tracking could reduce dose to avoidance volumes near a moving target while maintaining target dose coverage, compared to an existing 3D-optimized beam tracking approach. We tested these approaches computationally using a simple 4D geometrical phantom and a complex anatomic phantom, that is, a 4D computed tomogram of the thorax of a lung cancer patient. We also validated our findings using measurements of carbon-ion beams with a motorized film phantom. Relative to 3D-optimized beam tracking, 4D-optimized beam tracking reduced the maximum predicted dose to avoidance volumes by 53% in the simple phantom and by 13% in the thorax phantom. 4D-optimized beam tracking provided similar target dose homogeneity in the simple phantom (standard deviation of target dose was 0.4% versus 0.3%) and dramatically superior homogeneity in the thorax phantom (D5-D95 was 1.9% versus 38.7%). Measurements demonstrated that delivery of 4D-optimized beam tracking was technically feasible and confirmed a 42% decrease in maximum film exposure in the avoidance region compared with 3D-optimized beam tracking. In conclusion, we found that 4D-optimized beam tracking can reduce the maximum dose to avoidance volumes near a moving target while maintaining target dose coverage, compared with 3D-optimized beam tracking. PMID:24889215

4D optimization of scanned ion beam tracking therapy for moving tumors

NASA Astrophysics Data System (ADS)

Eley, John Gordon; Newhauser, Wayne David; Lüchtenborg, Robert; Graeff, Christian; Bert, Christoph

2014-07-01

Motion mitigation strategies are needed to fully realize the theoretical advantages of scanned ion beam therapy for patients with moving tumors. The purpose of this study was to determine whether a new four-dimensional (4D) optimization approach for scanned-ion-beam tracking could reduce dose to avoidance volumes near a moving target while maintaining target dose coverage, compared to an existing 3D-optimized beam tracking approach. We tested these approaches computationally using a simple 4D geometrical phantom and a complex anatomic phantom, that is, a 4D computed tomogram of the thorax of a lung cancer patient. We also validated our findings using measurements of carbon-ion beams with a motorized film phantom. Relative to 3D-optimized beam tracking, 4D-optimized beam tracking reduced the maximum predicted dose to avoidance volumes by 53% in the simple phantom and by 13% in the thorax phantom. 4D-optimized beam tracking provided similar target dose homogeneity in the simple phantom (standard deviation of target dose was 0.4% versus 0.3%) and dramatically superior homogeneity in the thorax phantom (D5-D95 was 1.9% versus 38.7%). Measurements demonstrated that delivery of 4D-optimized beam tracking was technically feasible and confirmed a 42% decrease in maximum film exposure in the avoidance region compared with 3D-optimized beam tracking. In conclusion, we found that 4D-optimized beam tracking can reduce the maximum dose to avoidance volumes near a moving target while maintaining target dose coverage, compared with 3D-optimized beam tracking.

Hard beta and gamma emissions of 124I. Impact on occupational dose in PET/CT.

PubMed

Kemerink, G J; Franssen, R; Visser, M G W; Urbach, C J A; Halders, S G E A; Frantzen, M J; Brans, B; Teule, G J J; Mottaghy, F M

2011-01-01

The hard beta and gamma radiation of 124I can cause high doses to PET/CT workers. In this study we tried to quantify this occupational exposure and to optimize radioprotection. Thin MCP-Ns thermoluminescent dosimeters suitable for measuring beta and gamma radiation were used for extremity dosimetry, active personal dosimeters for whole-body dosimetry. Extremity doses were determined during dispensing of 124I and oral administration of the activity to the patient, the body dose during all phases of the PET/CT procedure. In addition, dose rates of vials and syringes as used in clinical practice were measured. The procedure for dispensing 124I was optimized using newly developed shielding. Skin dose rates up to 100 mSv/min were measured when in contact with the manufacturer's vial containing 370 MBq of 124I. For an unshielded 5 ml syringe the positron skin dose was about seven times the gamma dose. Before optimization of the preparation of 124I, using an already reasonably safe technique, the highest mean skin dose caused by handling 370 MBq was 1.9 mSv (max. 4.4 mSv). After optimization the skin dose was below 0.2 mSv. The highly energetic positrons emitted by 124I can cause high skin doses if radioprotection is poor. Under optimized conditions occupational doses are acceptable. Education of workers is of paramount importance.

Optimization of equivalent uniform dose using the L-curve criterion.

PubMed

Chvetsov, Alexei V; Dempsey, James F; Palta, Jatinder R

2007-10-07

Optimization of equivalent uniform dose (EUD) in inverse planning for intensity-modulated radiation therapy (IMRT) prevents variation in radiobiological effect between different radiotherapy treatment plans, which is due to variation in the pattern of dose nonuniformity. For instance, the survival fraction of clonogens would be consistent with the prescription when the optimized EUD is equal to the prescribed EUD. One of the problems in the practical implementation of this approach is that the spatial dose distribution in EUD-based inverse planning would be underdetermined because an unlimited number of nonuniform dose distributions can be computed for a prescribed value of EUD. Together with ill-posedness of the underlying integral equation, this may significantly increase the dose nonuniformity. To optimize EUD and keep dose nonuniformity within reasonable limits, we implemented into an EUD-based objective function an additional criterion which ensures the smoothness of beam intensity functions. This approach is similar to the variational regularization technique which was previously studied for the dose-based least-squares optimization. We show that the variational regularization together with the L-curve criterion for the regularization parameter can significantly reduce dose nonuniformity in EUD-based inverse planning.

Prospective estimation of organ dose in CT under tube current modulation

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

Tian, Xiaoyu, E-mail: xt3@duke.edu; Li, Xiang; Segars, W. Paul

Purpose: Computed tomography (CT) has been widely used worldwide as a tool for medical diagnosis and imaging. However, despite its significant clinical benefits, CT radiation dose at the population level has become a subject of public attention and concern. In this light, optimizing radiation dose has become a core responsibility for the CT community. As a fundamental step to manage and optimize dose, it may be beneficial to have accurate and prospective knowledge about the radiation dose for an individual patient. In this study, the authors developed a framework to prospectively estimate organ dose for chest and abdominopelvic CT examsmore » under tube current modulation (TCM). Methods: The organ dose is mainly dependent on two key factors: patient anatomy and irradiation field. A prediction process was developed to accurately model both factors. To model the anatomical diversity and complexity in the patient population, the authors used a previously developed library of computational phantoms with broad distributions of sizes, ages, and genders. A selected clinical patient, represented by a computational phantom in the study, was optimally matched with another computational phantom in the library to obtain a representation of the patient’s anatomy. To model the irradiation field, a previously validated Monte Carlo program was used to model CT scanner systems. The tube current profiles were modeled using a ray-tracing program as previously reported that theoretically emulated the variability of modulation profiles from major CT machine manufacturers Li et al., [Phys. Med. Biol. 59, 4525–4548 (2014)]. The prediction of organ dose was achieved using the following process: (1) CTDI{sub vol}-normalized-organ dose coefficients (h{sub organ}) for fixed tube current were first estimated as the prediction basis for the computational phantoms; (2) each computation phantom, regarded as a clinical patient, was optimally matched with one computational phantom in the library; (3) to account for the effect of the TCM scheme, a weighted organ-specific CTDI{sub vol} [denoted as (CTDI{sub vol}){sub organ,weighted}] was computed for each organ based on the TCM profile and the anatomy of the “matched” phantom; (4) the organ dose was predicted by multiplying the weighted organ-specific CTDI{sub vol} with the organ dose coefficients (h{sub organ}). To quantify the prediction accuracy, each predicted organ dose was compared with the corresponding organ dose simulated from the Monte Carlo program with the TCM profile explicitly modeled. Results: The predicted organ dose showed good agreements with the simulated organ dose across all organs and modulation profiles. The average percentage error in organ dose estimation was generally within 20% across all organs and modulation profiles, except for organs located in the pelvic and shoulder regions. For an average CTDI{sub vol} of a CT exam of 10 mGy, the average error at full modulation strength (α = 1) across all organs was 0.91 mGy for chest exams, and 0.82 mGy for abdominopelvic exams. Conclusions: This study developed a quantitative model to predict organ dose for clinical chest and abdominopelvic scans. Such information may aid in the design of optimized CT protocols in relation to a targeted level of image quality.« less

SU-F-BRD-07: Fast Monte Carlo-Based Biological Optimization of Proton Therapy Treatment Plans for Thyroid Tumors

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

Wan Chan Tseung, H; Ma, J; Ma, D

2015-06-15

Purpose: To demonstrate the feasibility of fast Monte Carlo (MC) based biological planning for the treatment of thyroid tumors in spot-scanning proton therapy. Methods: Recently, we developed a fast and accurate GPU-based MC simulation of proton transport that was benchmarked against Geant4.9.6 and used as the dose calculation engine in a clinically-applicable GPU-accelerated IMPT optimizer. Besides dose, it can simultaneously score the dose-averaged LET (LETd), which makes fast biological dose (BD) estimates possible. To convert from LETd to BD, we used a linear relation based on cellular irradiation data. Given a thyroid patient with a 93cc tumor volume, we createdmore » a 2-field IMPT plan in Eclipse (Varian Medical Systems). This plan was re-calculated with our MC to obtain the BD distribution. A second 5-field plan was made with our in-house optimizer, using pre-generated MC dose and LETd maps. Constraints were placed to maintain the target dose to within 25% of the prescription, while maximizing the BD. The plan optimization and calculation of dose and LETd maps were performed on a GPU cluster. The conventional IMPT and biologically-optimized plans were compared. Results: The mean target physical and biological doses from our biologically-optimized plan were, respectively, 5% and 14% higher than those from the MC re-calculation of the IMPT plan. Dose sparing to critical structures in our plan was also improved. The biological optimization, including the initial dose and LETd map calculations, can be completed in a clinically viable time (∼30 minutes) on a cluster of 25 GPUs. Conclusion: Taking advantage of GPU acceleration, we created a MC-based, biologically optimized treatment plan for a thyroid patient. Compared to a standard IMPT plan, a 5% increase in the target’s physical dose resulted in ∼3 times as much increase in the BD. Biological planning was thus effective in escalating the target BD.« less

BaSO4:Eu as an energy independent thermoluminescent radiation dosimeter for gamma rays and C6+ ion beam

NASA Astrophysics Data System (ADS)

Sharma, Kanika; Bahl, Shaila; Singh, Birendra; Kumar, Pratik; Lochab, S. P.; Pandey, Anant

2018-04-01

BaSO4:Eu nanophosphor is delicately optimized by varying the concentration of the impurity element and compared to the commercially available thermoluminescent dosimeter (TLD) LiF:Mg,Ti (TLD-100) and by extension also to CaSO4:Dy (TLD-900) so as to achieve its maximum thermoluminescence (TL) sensitivity. Further, the energy dependence property of this barite nanophosphor is also explored at length by exposing the phosphor with 1.25 MeV of Co-60, 0.662 MeV of Cs-137, 85 MeV and 65 MeV of Carbon ion beams. Various batches of the phosphor at hand (with impurity concentrations being 0.05, 0.10, 0.20, 0.50 and 1.00 mol%) are prepared by the chemical co-precipitation method out of which BaSO4:Eu with 0.20 mol% Eu exhibits the maximum TL sensitivity. Further, the optimized nanophosphor exhibits a whopping 28.52 times higher TL sensitivity than the commercially available TLD-100 and 1.426 times higher sensitivity than TLD-900, a noteworthy linear response curve for an exceptionally wide range of doses i.e. 10 Gy to 2 kGy and a simple glow curve structure. Furthermore, when the newly optimized nanophosphor is exposed with two different energies of gamma radiations, namely 1.25 MeV of Co-60 (dose range- 10-300 Gy) and 0.662 MeV of Cs-137 (dose range- 1-300 Gy), it is observed that the shape and structure of the glow curves remain remarkably similar for different energies of radiation while the TL response curve shows little to no variation. When exposed to different energies of carbon ion beam BaSO4:Eu displays energy independence at lower doses i.e. from 6.059 to 14.497 kGy. Finally, even though energy independence is lost at higher doses, the material shows high sensitivity to higher energy (85 MeV) of carbon beam compared to the lower energy (65 MeV of C6+) and saturation is apparent only after 121.199 kGy. Therefore the present nanophosphor displays potential as an energy independent TLD.

Definitions and outlook targeting x-ray exposure of patients in diagnostic imaging

NASA Astrophysics Data System (ADS)

Regulla, Dieter F.

2011-03-01

Computer tomography (CT) is vital and currently irreplaceable in diagnostic radiology. But CT operates with ionizing radiation which may cause cancer or non-cancer diseases in humans. The degree of radiation impact depends on the dose administered by an investigation. And this is the core issue: Even CT exams executed lege artis, administer doses to patients which by magnitude are far beyond the level of hitherto known doses of conventional film-screen techniques. Patients undergoing one or multiple CT examinations, digital angiographies or interventions will be exposed to effective doses between roughly several mSv and several 100 mSv depending on type and frequency of the diagnostic investigations. From the radiation protection point of view, there is therefore the worldwide problem of formulating firm rules for the control of these high-dose investigations, as dose limits can not be established for reasons of the medical benefit. This makes the difference compared with radiation protection for occupationally exposed persons. What remains is "software", namely "justification" and "optimization". Justification requires balancing the interests between the health benefit and the potential harm of an exam which has to be responsibly executed by the physician himself; therefore the radiologists' associations are in the duty to prepare practicable rules for justification. Optimization again needs a cooperative solution, and that is the establishment of reference doses for diagnostic examinations, to be checked by the technical service of the producers' companies. Experts and authorities have been aware of the high-dose dilemma in diagnostic imaging since long. It is time for the reflection of active solutions and their implementation into practice.

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

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.

Dosing study of massage for chronic neck pain: protocol for the dose response evaluation and analysis of massage [DREAM] trial

PubMed Central

2012-01-01

Background Despite the growing popularity of massage, its effectiveness for treating neck pain remains unclear, largely because of the poor quality of research. A major deficiency of previous studies has been their use of low “doses” of massage that massage therapists consider inadequate. Unfortunately, the number of minutes per massage session, sessions per week, or weeks of treatment necessary for massage to have beneficial or optimal effects are not known. This study is designed to address these gaps in our knowledge by determining, for persons with chronic neck pain: 1) the optimal combination of number of treatments per week and length of individual treatment session, and 2) the optimal number of weeks of treatment. Methods/design In this study, 228 persons with chronic non-specific neck pain will be recruited from primary health care clinics in a large health care system in the Seattle area. Participants will be randomized to a wait list control group or 4 weeks of treatment with one of 5 different dosing combinations (2 or 3 30-min treatments per week or 1, 2, or 3 60-min treatments per week). At the end of this 4-week primary treatment period, participants initially receiving each of the 5 dosing combinations will be randomized to a secondary treatment period of either no additional treatment or 6 weekly 60-min massages. The primary outcomes, neck-related dysfunction and pain, will be assessed by blinded telephone interviewers 5, 12, and 26 weeks post-randomization. To better characterize the trajectory of treatment effects, these interview data will be supplemented with outcomes data collected by internet questionnaire at 10, 16, 20 and 39 weeks. Comparisons of outcomes for the 6 groups during the primary treatment period will identify the optimal weekly dose, while comparisons of outcomes during the secondary treatment period will determine if 10 weeks of treatment is superior to 4 weeks. Discussion A broad dosing schedule was included in this trial. If adherence to any of these doses is poor, those doses will be discontinued. Trial registration This trial is registered in ClinicalTrials.gov, with the ID number of NCT01122836 PMID:22985134

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

Li, Heng, E-mail: hengli@mdanderson.org; Zhu, X. Ronald; Zhang, Xiaodong

Purpose: To develop and validate a novel delivery strategy for reducing the respiratory motion–induced dose uncertainty of spot-scanning proton therapy. Methods and Materials: The spot delivery sequence was optimized to reduce dose uncertainty. The effectiveness of the delivery sequence optimization was evaluated using measurements and patient simulation. One hundred ninety-one 2-dimensional measurements using different delivery sequences of a single-layer uniform pattern were obtained with a detector array on a 1-dimensional moving platform. Intensity modulated proton therapy plans were generated for 10 lung cancer patients, and dose uncertainties for different delivery sequences were evaluated by simulation. Results: Without delivery sequence optimization,more » the maximum absolute dose error can be up to 97.2% in a single measurement, whereas the optimized delivery sequence results in a maximum absolute dose error of ≤11.8%. In patient simulation, the optimized delivery sequence reduces the mean of fractional maximum absolute dose error compared with the regular delivery sequence by 3.3% to 10.6% (32.5-68.0% relative reduction) for different patients. Conclusions: Optimizing the delivery sequence can reduce dose uncertainty due to respiratory motion in spot-scanning proton therapy, assuming the 4-dimensional CT is a true representation of the patients' breathing patterns.« less

Robust optimization in lung treatment plans accounting for geometric uncertainty.

PubMed

Zhang, Xin; Rong, Yi; Morrill, Steven; Fang, Jian; Narayanasamy, Ganesh; Galhardo, Edvaldo; Maraboyina, Sanjay; Croft, Christopher; Xia, Fen; Penagaricano, Jose

2018-05-01

Robust optimization generates scenario-based plans by a minimax optimization method to find optimal scenario for the trade-off between target coverage robustness and organ-at-risk (OAR) sparing. In this study, 20 lung cancer patients with tumors located at various anatomical regions within the lungs were selected and robust optimization photon treatment plans including intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) plans were generated. The plan robustness was analyzed using perturbed doses with setup error boundary of ±3 mm in anterior/posterior (AP), ±3 mm in left/right (LR), and ±5 mm in inferior/superior (IS) directions from isocenter. Perturbed doses for D 99 , D 98 , and D 95 were computed from six shifted isocenter plans to evaluate plan robustness. Dosimetric study was performed to compare the internal target volume-based robust optimization plans (ITV-IMRT and ITV-VMAT) and conventional PTV margin-based plans (PTV-IMRT and PTV-VMAT). The dosimetric comparison parameters were: ITV target mean dose (D mean ), R 95 (D 95 /D prescription ), Paddick's conformity index (CI), homogeneity index (HI), monitor unit (MU), and OAR doses including lung (D mean , V 20 Gy and V 15 Gy ), chest wall, heart, esophagus, and maximum cord doses. A comparison of optimization results showed the robust optimization plan had better ITV dose coverage, better CI, worse HI, and lower OAR doses than conventional PTV margin-based plans. Plan robustness evaluation showed that the perturbed doses of D 99 , D 98 , and D 95 were all satisfied at least 99% of the ITV to received 95% of prescription doses. It was also observed that PTV margin-based plans had higher MU than robust optimization plans. The results also showed robust optimization can generate plans that offer increased OAR sparing, especially for normal lungs and OARs near or abutting the target. Weak correlation was found between normal lung dose and target size, and no other correlation was observed in this study. © 2018 University of Arkansas for Medical Sciences. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

Effect of Aptensio XR (Methylphenidate HCl Extended-Release) Capsules on Sleep in Children with Attention-Deficit/Hyperactivity Disorder.

PubMed

Owens, Judith; Weiss, Margaret; Nordbrock, Earl; Mattingly, Greg; Wigal, Sharon; Greenhill, Laurence L; Chang, Wei-Wei; Childress, Ann; Kupper, Robert J; Adjei, Akwete

2016-12-01

To evaluate measures of sleep (exploratory endpoints) in two pivotal studies of a multilayer bead extended-release methylphenidate (MPH-MLR) treatment of attention-deficit/hyperactivity disorder in children. Study 1 evaluated the time course of response to MPH-MLR (n = 26) patients in an analog classroom setting through four phases: screening (≤28 days), open label (OL) dose optimization (4 weeks), double-blind (DB) crossover (2 weeks; placebo vs. optimized dose), and follow-up call. Study 2 was a forced-dose parallel evaluation of MPH-MLR (n = 230) in four phases: screening (≤28 days), DB (1 week; placebo or MPH-MLR 10, 15, 20, or 40 mg/day), OL dose optimization (11 weeks), and follow-up call. Sleep was evaluated by parents using the Children's or Adolescent Sleep Habits Questionnaire (CSHQ or ASHQ) during the DB and OL phases. DB analysis: Study 1 (crossover), analysis of variance; Study 2, analysis of covariance. OL analysis: paired t-test. DB: treatments were significantly different in Study 1 only for CSHQ Sleep Onset Delay (MPH-MLR, 1.90 vs. placebo, 1.34; p = 0.0046, placebo was better), and Study 2 for CSHQ Parasomnias (treatment, p = 0.0295), but no MPH-MLR treatment was different from placebo (pairwise MPH-MLR treatment to placebo, all p ≥ 0.170). OL: CSHQ total and Bedtime Resistance, Sleep Duration, Sleep Anxiety, Night Wakings, Parasomnias, and Sleep-disordered Breathing subscales decreased (improved, Study 1) significant only for CSHQ Night Wakings (p < 0.05); in Study 2 CSHQ total and Bedtime Resistance, Sleep Duration, Night Wakings, Parasomnias, and Daytime Sleepiness, and ASHQ total, Bedtime, Sleep Behavior, and Morning Waking all significantly improved (p < 0.05). In both studies, there was minimal negative impact of MPH-MLR on sleep during the brief DB phase and none during the longer duration OL phase. Some measures of sleep improved with optimized MPH-MLR dose.

Expected treatment dose construction and adaptive inverse planning optimization: Implementation for offline head and neck cancer adaptive radiotherapy

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

Yan Di; Liang Jian

Purpose: To construct expected treatment dose for adaptive inverse planning optimization, and evaluate it on head and neck (h and n) cancer adaptive treatment modification. Methods: Adaptive inverse planning engine was developed and integrated in our in-house adaptive treatment control system. The adaptive inverse planning engine includes an expected treatment dose constructed using the daily cone beam (CB) CT images in its objective and constrains. Feasibility of the adaptive inverse planning optimization was evaluated retrospectively using daily CBCT images obtained from the image guided IMRT treatment of 19 h and n cancer patients. Adaptive treatment modification strategies with respect tomore » the time and the number of adaptive inverse planning optimization during the treatment course were evaluated using the cumulative treatment dose in organs of interest constructed using all daily CBCT images. Results: Expected treatment dose was constructed to include both the delivered dose, to date, and the estimated dose for the remaining treatment during the adaptive treatment course. It was used in treatment evaluation, as well as in constructing the objective and constraints for adaptive inverse planning optimization. The optimization engine is feasible to perform planning optimization based on preassigned treatment modification schedule. Compared to the conventional IMRT, the adaptive treatment for h and n cancer illustrated clear dose-volume improvement for all critical normal organs. The dose-volume reductions of right and left parotid glands, spine cord, brain stem and mandible were (17 {+-} 6)%, (14 {+-} 6)%, (11 {+-} 6)%, (12 {+-} 8)%, and (5 {+-} 3)% respectively with the single adaptive modification performed after the second treatment week; (24 {+-} 6)%, (22 {+-} 8)%, (21 {+-} 5)%, (19 {+-} 8)%, and (10 {+-} 6)% with three weekly modifications; and (28 {+-} 5)%, (25 {+-} 9)%, (26 {+-} 5)%, (24 {+-} 8)%, and (15 {+-} 9)% with five weekly modifications. Conclusions: Adaptive treatment modification can be implemented including the expected treatment dose in the adaptive inverse planning optimization. The retrospective evaluation results demonstrate that utilizing the weekly adaptive inverse planning optimization, the dose distribution of h and n cancer treatment can be largely improved.« less

Growth hormone regimens in Australia: analysis of the first 3 years of treatment for idiopathic growth hormone deficiency and idiopathic short stature.

PubMed

Hughes, Ian P; Harris, Mark; Choong, Catherine S; Ambler, Geoff; Cutfield, Wayne; Hofman, Paul; Cowell, Chris T; Werther, George; Cotterill, Andrew; Davies, Peter S W

2012-07-01

To investigate response to growth hormone (GH) in the first, second and third years of treatment for all idiopathic GH-deficient (GHD) and idiopathic short stature (ISS) patients in Australia. Eligibility for subsidized GH treatment in Australia is determined on auxological criteria for the indication of Short Stature and Slow Growth (SSSG), which includes ISS (SSSG-ISS). The biochemical GHD (BGHD, peak GH < 10 mU/l) and SSSG indications are treated similarly: starting dose of 4·5 mg/m(2)/week with provision for incremental dosing. Some ISS patients were specifically diagnosed with familial short stature (SSSG-FSS). Responses for each year of treatment for BGHD, SSSG-ISS and SSSG-FSS cohorts were compared in relation to influencing variables and with international benchmarks. The effect of incremental dosing was assessed. Australian BGHD, SSSG-ISS and SSSG-FSS patients who had completed 1, 2, or 3 years of treatment and were currently receiving GH. Growth hormone dose, change in height-standard deviation score (ΔSDS) and growth velocity (GV). First-year response was 2-3 times greater than that in subsequent years: ΔSDS(1st year) = 0·92, 0·50 and 0·46 for BGHD, SSSG-ISS and SSSG-FSS, respectively. Responses were similar to international reports and inversely related to age at commencement of GH. First-year GV-for-age for BGHD patients was similar to international standards for idiopathic GHD. However, girls had an inferior response to boys when treatment commenced at <6 years of age. First-year GV-for-age for SSSG-ISS/FSS patients was less than ISS standards. Dose increments attenuated the first- to second-year decline in response to BGHD but marginally improved the responses for SSSG-ISS/FSS. The Australian auxology-based GH programme produces comparable responses to international programmes. A lower starting dose is offset by the initiation of treatment at younger ages. Incremental dosing does not appear optimal. A first-year dose of 6·4-6·9 mg/m(2)/week for GHD and 8·9 mg/m(2)/week for ISS with early commencement of GH treatment may be most efficacious. © 2012 Blackwell Publishing Ltd.

The Addition of an Immunosuppressant After Loss of Response to Anti-TNFα Monotherapy in Inflammatory Bowel Disease: A 2-Year Study.

PubMed

Macaluso, Fabio Salvatore; Sapienza, Chiara; Ventimiglia, Marco; Renna, Sara; Rizzuto, Giulia; Orlando, Rosalba; Di Pisa, Marta; Affronti, Marco; Orlando, Emanuele; Cottone, Mario; Orlando, Ambrogio

2018-01-18

The addition of an immunosuppressant (IM) after loss of response to anti-TNFα monotherapy is an emerging strategy of therapeutic optimization in patients with inflammatory bowel disease (IBD). However, few clinical data have been reported to date. We aimed to evaluate the efficacy and safety of this selective combination therapy in patients with IBD. All consecutive patients with loss of response to anti-TNFα monotherapy despite an intensive dose optimization who added an IM from October 2014 to October 2016 were entered into a prospective database. Among 630 patients treated with anti-TNFα agents during the study period, 46 (7.3%) added an IM. A total of 31 patients (67.4%) were treated with an intravenous anti-TNFα (infliximab, as originator or biosimilar), while 15 (32.6%) were treated with a subcutaneous anti-TNFα agent (10 adalimumab and 5 golimumab). The mean duration of follow-up was 12.8 ± 7.3 months. Twenty-one patients (45.7%) remained on combination therapy at the end of follow-up: 15 (32.6%) maintained a steroid-free remission, and 6 (13.0%) achieved a clinical response. In patients who experienced treatment success, the median value of C-reactive protein decreased from baseline to the end of follow-up (13.2 vs 3.0, P = 0.01; normal values <5 mg/L). Adverse events leading to treatment discontinuation were reported in 8 out of 46 patients (17.4%). In the largest cohort on this argument reported to date, the addition of an IM was an effective and safe optimization strategy after loss of response to anti-TNFα monotherapy. Low doses of IM were sufficient to achieve a clinical response. © 2018 Crohn’s & Colitis Foundation of America. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Experimental Design for Multi-drug Combination Studies Using Signaling Networks

PubMed Central

Huang, Hengzhen; Fang, Hong-Bin; Tan, Ming T.

2017-01-01

Summary Combinations of multiple drugs are an important approach to maximize the chance for therapeutic success by inhibiting multiple pathways/targets. Analytic methods for studying drug combinations have received increasing attention because major advances in biomedical research have made available large number of potential agents for testing. The preclinical experiment on multi-drug combinations plays a key role in (especially cancer) drug development because of the complex nature of the disease, the need to reduce development time and costs. Despite recent progresses in statistical methods for assessing drug interaction, there is an acute lack of methods for designing experiments on multi-drug combinations. The number of combinations grows exponentially with the number of drugs and dose-levels and it quickly precludes laboratory testing. Utilizing experimental dose-response data of single drugs and a few combinations along with pathway/network information to obtain an estimate of the functional structure of the dose-response relationship in silico, we propose an optimal design that allows exploration of the dose-effect surface with the smallest possible sample size in this paper. The simulation studies show our proposed methods perform well. PMID:28960231

Radiobiological description of the LET dependence of the cell survival of oxic and anoxic cells irradiated by carbon ions.

PubMed

Antonovic, L; Brahme, A; Furusawa, Y; Toma-Dasu, I

2013-01-01

Light-ion radiation therapy against hypoxic tumors is highly curative due to reduced dependence on the presence of oxygen in the tumor at elevated linear energy transfer (LET) towards the Bragg peak. Clinical ion beams using spread-out Bragg peak (SOBP) are characterized by a wide spectrum of LET values. Accurate treatment optimization requires a method that can account for influence of the variation in response for a broad range of tumor hypoxia, absorbed doses and LETs. This paper presents a parameterization of the Repairable Conditionally-Repairable (RCR) cell survival model that can describe the survival of oxic and hypoxic cells over a wide range of LET values, and investigates the relationship between hypoxic radiation resistance and LET. The biological response model was tested by fitting cell survival data under oxic and anoxic conditions for V79 cells irradiated with LETs within the range of 30-500 keV/µm. The model provides good agreement with experimental cell survival data for the range of LET investigated, confirming the robustness of the parameterization method. This new version of the RCR model is suitable for describing the biological response of mixed populations of oxic and hypoxic cells and at the same time taking into account the distribution of doses and LETs in the incident beam and its variation with depth in tissue. The model offers a versatile tool for the selection of LET and dose required in the optimization of the therapeutic effect, without severely affecting normal tissue in realistic tumors presenting highly heterogeneous oxic and hypoxic regions.

Alternating sequential chemotherapy with high-dose ifosfamide and doxorubicin/cyclophosphamide for adult non-small round cell soft tissue sarcomas.

PubMed

Kawai, Akira; Umeda, Toru; Wada, Takuro; Ihara, Koichiro; Isu, Kazuo; Abe, Satoshi; Ishii, Takeshi; Sugiura, Hideshi; Araki, Nobuhito; Ozaki, Toshifumi; Yabe, Hiroo; Hasegawa, Tadashi; Tsugane, Shoichiro; Beppu, Yasuo

2005-05-01

Doxorubicin and ifosfamide are the two most active agents used to treat soft tissue sarcomas. However, because of their overlapping side effects, concurrent administration to achieve optimal doses of each agent is difficult. We therefore conducted a Phase II trial to investigate the efficacy and feasibility of a novel alternating sequential chemotherapy regimen consisting of high dose ifosfamide and doxorubicin/cyclophosphamide in advanced adult non-small round cell soft tissue sarcomas. Adult patients with non-small round cell soft tissue sarcomas were enrolled. The treatment consisted of four sequential courses of chemotherapy that was planned for every 3 weeks. Cycles 1 and 3 consisted of ifosfamide (14 g/m(2)), and cycles 2 and 4 consisted of doxorubicin (60 mg/m(2)) and cyclophosphamide (1200 mg/m(2)). Forty-two patients (median age 47 years) were enrolled. Of the 36 assessable patients, 1 complete response and 16 partial responses were observed, for a response rate of 47.2%. Responses were observed in 57% of patients who had received no previous chemotherapy and 13% of those who had previously undergone chemotherapy. Grade 3-4 neutropenia was observed during 70% of all cycles. Sequential administration of high-dose ifosfamide and doxorubicin/cyclophosphamide has promising activity with manageable side effects in patients with advanced adult non-small round cell soft tissue sarcomas.

An Exploratory Study of Responses to Low-Dose Lithium in African Americans and Hispanics

PubMed Central

Arnold, Jodi Gonzalez; Salcedo, Stephanie; Ketter, Terrence A.; Calabrese, Joseph R.; Rabideau, Dustin J.; Nierenberg, Andrew A.; Bazan, Melissa; Leon, Andrew C.; Friedman, Edward S.; Iosifescu, Dan; Sylvia, Louisa G.; Ostacher, Michael; Thase, Michael; Reilly-Harrington, Noreen A.; Bowden, Charles L.

2015-01-01

Objectives Few prospective studies examine the impact of ethnicity or race on outcomes with lithium for bipolar disorder. This exploratory study examines differences in lithium response and treatment outcomes in Hispanics, African Americans, and non-Hispanic Whites with bipolar disorder in the Lithium Treatment Moderate Dose Use Study (LiTMUS). Methods LiTMUS was a six-site randomized controlled trial of low-dose lithium added to optimized treatment (OPT; personalized, evidence-based pharmacotherapy) versus OPT alone in outpatients with bipolar disorder. Of 283 participants, 47 African Americans, 39 Hispanics, and 175 non-Hispanic whites were examined. We predicted minority groups would have more negative medication attitudes and higher attrition rates, but better clinical outcomes. Results African Americans in the lithium group improved more on depression and life functioning compared to whites over the 6 month study. African Americans in the OPT only group had marginal improvement on depression symptoms. For Hispanics, satisfaction with life did not significantly improve in the OPT only group, in contrast to whites and African Americans who improved over time on all measures. Attitudes toward medications did not differ across ethnic/racial groups. Conclusions African Americans show some greater improvements with lithium than non-Hispanic whites, and Hispanics showed more consistent improvements in the lithium group. The impact of low-dose lithium should be studied in a larger sample as there may be particular benefit for African Americans and Hispanics. Given that the control group (regardless of ethnicity/race) had significant improvements, optimized treatment may be beneficial for any ethnic group. PMID:25827507

Current practices in the management of adverse events associated with targeted therapies for advanced renal cell carcinoma: a national survey of oncologists.

PubMed

Ruiz, Janelle Nicole; Belum, Viswanath Reddy; Creel, Patricia; Cohn, Allen; Ewer, Michael; Lacouture, Mario E

2014-10-01

Oncologists treating patients with targeted therapies encounter adverse events (AEs) that pose management challenges, lead to dosing inconsistencies, and impact patient quality of life. Oncologists' practices and attitudes in the management of targeted therapy-related AEs in patients with renal cell carcinoma (RCC) are poorly understood. We sought to identify unmet needs associated with AE management and understand oncologists' treatment optimization strategies. A 24-item online survey was administered in August 2012 to 119 US oncologists treating patients with advanced RCC. The survey solicited responses regarding demographics, practice settings, AE management practice patterns and beliefs, treatment barriers, and patient education. Respondents indicated that between 25% and 50% of patients require dose modification/discontinuation because of AEs. The greatest barrier to optimizing treatment for RCC is the unpredictability of patient responses to treatment (43%). Most respondents (78%) discuss AE management with patients, but only a minority of them proactively reach out to patients (46%). Most practitioners (70%) refer patients to nononcology specialists when faced with unfamiliar AEs, although finding interested physicians (43%) and time constraints (40%) were the most commonly cited barriers to consulting with other specialties. Results suggest that many patients require dose modification/discontinuation because of AEs and that nononcologists are a frequently utilized resource to manage these events. There is a need for predictive drug toxicity markers to establish counseling and prevention, along with opportunities for increased education on supportive care techniques to maintain health-related quality of life and consistent dosing. Copyright © 2014 Elsevier Inc. All rights reserved.

Optimization of dual-energy CT acquisitions for proton therapy using projection-based decomposition.

PubMed

Vilches-Freixas, Gloria; Létang, Jean Michel; Ducros, Nicolas; Rit, Simon

2017-09-01

Dual-energy computed tomography (DECT) has been presented as a valid alternative to single-energy CT to reduce the uncertainty of the conversion of patient CT numbers to proton stopping power ratio (SPR) of tissues relative to water. The aim of this work was to optimize DECT acquisition protocols from simulations of X-ray images for the treatment planning of proton therapy using a projection-based dual-energy decomposition algorithm. We have investigated the effect of various voltages and tin filtration combinations on the SPR map accuracy and precision, and the influence of the dose allocation between the low-energy (LE) and the high-energy (HE) acquisitions. For all spectra combinations, virtual CT projections of the Gammex phantom were simulated with a realistic energy-integrating detector response model. Two situations were simulated: an ideal case without noise (infinite dose) and a realistic situation with Poisson noise corresponding to a 20 mGy total central dose. To determine the optimal dose balance, the proportion of LE-dose with respect to the total dose was varied from 10% to 90% while keeping the central dose constant, for four dual-energy spectra. SPR images were derived using a two-step projection-based decomposition approach. The ranges of 70 MeV, 90 MeV, and 100 MeV proton beams onto the adult female (AF) reference computational phantom of the ICRP were analytically determined from the reconstructed SPR maps. The energy separation between the incident spectra had a strong impact on the SPR precision. Maximizing the incident energy gap reduced image noise. However, the energy gap was not a good metric to evaluate the accuracy of the SPR. In terms of SPR accuracy, a large variability of the optimal spectra was observed when studying each phantom material separately. The SPR accuracy was almost flat in the 30-70% LE-dose range, while the precision showed a minimum slightly shifted in favor of lower LE-dose. Photon noise in the SPR images (20 mGy dose) had lower impact on the proton range accuracy as comparable results were obtained for the noiseless situation (infinite dose). Root-mean-square range errors averaged over all irradiation angles associated to dual-energy imaging were comprised between 0.50 mm and 0.72 mm for the noiseless situation and between 0.51 mm and 0.77 mm for the realistic scenario. The impact of the dual-energy spectra and the dose allocation between energy levels on the SPR accuracy and precision determined through a projection-based dual-energy algorithm were evaluated to guide the choice of spectra for dual-energy CT for proton therapy. The dose balance between energy levels was not found to be sensitive for the SPR estimation. The optimal pair of dual-energy spectra was material dependent but on a heterogeneous anthropomorphic phantom, there was no significant difference in range accuracy and the choice of spectra could be driven by the precision, i.e., the energy gap. © 2017 American Association of Physicists in Medicine.

Epigallocatechin-3-gallate enhances key enzymatic activities of hepatic thioredoxin and glutathione systems in selenium-optimal mice but activates hepatic Nrf2 responses in selenium-deficient mice.

PubMed

Dong, Ruixia; Wang, Dongxu; Wang, Xiaoxiao; Zhang, Ke; Chen, Pingping; Yang, Chung S; Zhang, Jinsong

2016-12-01

Selenium participates in the antioxidant defense mainly through a class of selenoproteins, including thioredoxin reductase. Epigallocatechin-3-gallate (EGCG) is the most abundant and biologically active catechin in green tea. Depending upon the dose and biological systems, EGCG may function either as an antioxidant or as an inducer of antioxidant defense via its pro-oxidant action or other unidentified mechanisms. By manipulating the selenium status, the present study investigated the interactions of EGCG with antioxidant defense systems including the thioredoxin system comprising of thioredoxin and thioredoxin reductase, the glutathione system comprising of glutathione and glutathione reductase coupled with glutaredoxin, and the Nrf2 system. In selenium-optimal mice, EGCG increased hepatic activities of thioredoxin reductase, glutathione reductase and glutaredoxin. These effects of EGCG appeared to be not due to overt pro-oxidant action because melatonin, a powerful antioxidant, did not influence the increase. However, in selenium-deficient mice, with low basal levels of thioredoxin reductase 1, the same dose of EGCG did not elevate the above-mentioned enzymes; intriguingly EGCG in turn activated hepatic Nrf2 response, leading to increased heme oxygenase 1 and NAD(P)H:quinone oxidoreductase 1 protein levels and thioredoxin activity. Overall, the present work reveals that EGCG is a robust inducer of the Nrf2 system only in selenium-deficient conditions. Under normal physiological conditions, in selenium-optimal mice, thioredoxin and glutathione systems serve as the first line defense systems against the stress induced by high doses of EGCG, sparing the activation of the Nrf2 system. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Review of Hybrid (Deterministic/Monte Carlo) Radiation Transport Methods, Codes, and Applications at Oak Ridge National Laboratory

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

Wagner, John C; Peplow, Douglas E.; Mosher, Scott W

2011-01-01

This paper provides a review of the hybrid (Monte Carlo/deterministic) radiation transport methods and codes used at the Oak Ridge National Laboratory and examples of their application for increasing the efficiency of real-world, fixed-source Monte Carlo analyses. The two principal hybrid methods are (1) Consistent Adjoint Driven Importance Sampling (CADIS) for optimization of a localized detector (tally) region (e.g., flux, dose, or reaction rate at a particular location) and (2) Forward Weighted CADIS (FW-CADIS) for optimizing distributions (e.g., mesh tallies over all or part of the problem space) or multiple localized detector regions (e.g., simultaneous optimization of two or moremore » localized tally regions). The two methods have been implemented and automated in both the MAVRIC sequence of SCALE 6 and ADVANTG, a code that works with the MCNP code. As implemented, the methods utilize the results of approximate, fast-running 3-D discrete ordinates transport calculations (with the Denovo code) to generate consistent space- and energy-dependent source and transport (weight windows) biasing parameters. These methods and codes have been applied to many relevant and challenging problems, including calculations of PWR ex-core thermal detector response, dose rates throughout an entire PWR facility, site boundary dose from arrays of commercial spent fuel storage casks, radiation fields for criticality accident alarm system placement, and detector response for special nuclear material detection scenarios and nuclear well-logging tools. Substantial computational speed-ups, generally O(102-4), have been realized for all applications to date. This paper provides a brief review of the methods, their implementation, results of their application, and current development activities, as well as a considerable list of references for readers seeking more information about the methods and/or their applications.« less

A pharmacodynamic comparison of prasugrel vs. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: results of the Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 Trial

PubMed Central

Angiolillo, Dominick J.; Badimon, Juan Jose; Saucedo, Jorge F.; Frelinger, Andrew L.; Michelson, Alan D.; Jakubowski, Joseph A.; Zhu, Baojin; Ojeh, Clement K.; Baker, Brian A.; Effron, Mark B.

2011-01-01

Aims Patients with diabetes mellitus (DM) have increased platelet reactivity and reduced platelet response to clopidogrel compared with patients without DM. Prasugrel, a more potent antiplatelet agent, is associated with greater reductions in ischaemic events compared with clopidogrel, particularly in patients with DM. The aim of this study was to perform serial pharmacodynamic assessments of prasugrel with high-dose clopidogrel in patients with DM. Methods and results Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 was a prospective, randomized, double-blind, crossover study in patients with type 2 DM and coronary artery disease (CAD). Patients (n= 35) were randomly assigned to either prasugrel 60 mg loading dose (LD)/10 mg maintenance dose (MD) or clopidogrel 600 mg LD/150 mg MD over two 1-week treatment periods separated by a 2-week washout period. Platelet function was assessed by VerifyNow® P2Y12 assay, light transmission aggregometry, and vasodilator-stimulated phosphoprotein phosphorylation at 0, 1, 4, and 24 h and 7 days. Greater platelet inhibition by VerifyNow® P2Y12 was achieved by prasugrel compared with clopidogrel at 4 h post-LD (least squares mean, 89.3 vs. 27.7%, P< 0.0001; primary endpoint). The difference in platelet inhibition between prasugrel and clopidogrel was significant from 1 h through 7 days (P < 0.0001). Similar results were obtained using all other platelet function measures. Prasugrel resulted in fewer poor responders at all time points irrespective of definition used. Conclusion In patients with type 2 DM and CAD, standard-dose prasugrel is associated with greater platelet inhibition and better response profiles during both the loading and maintenance periods when compared with double-dose clopidogrel. Clinical trial identifier: www.clinicaltrials.gov—NCT00642174 PMID:21252171

Massage Therapy for Osteoarthritis of the Knee: A Randomized Dose-Finding Trial

PubMed Central

Perlman, Adam I.; Ali, Ather; Njike, Valentine Yanchou; Hom, David; Davidi, Anna; Gould-Fogerite, Susan; Milak, Carl; Katz, David L.

2012-01-01

Background In a previous trial of massage for osteoarthritis (OA) of the knee, we demonstrated feasibility, safety and possible efficacy, with benefits that persisted at least 8 weeks beyond treatment termination. Methods We performed a RCT to identify the optimal dose of massage within an 8-week treatment regimen and to further examine durability of response. Participants were 125 adults with OA of the knee, randomized to one of four 8-week regimens of a standardized Swedish massage regimen (30 or 60 min weekly or biweekly) or to a Usual Care control. Outcomes included the Western Ontario and McMaster Universities Arthritis Index (WOMAC), visual analog pain scale, range of motion, and time to walk 50 feet, assessed at baseline, 8-, 16-, and 24-weeks. Results WOMAC Global scores improved significantly (24.0 points, 95% CI ranged from 15.3–32.7) in the 60-minute massage groups compared to Usual Care (6.3 points, 95% CI 0.1–12.8) at the primary endpoint of 8-weeks. WOMAC subscales of pain and functionality, as well as the visual analog pain scale also demonstrated significant improvements in the 60-minute doses compared to usual care. No significant differences were seen in range of motion at 8-weeks, and no significant effects were seen in any outcome measure at 24-weeks compared to usual care. A dose-response curve based on WOMAC Global scores shows increasing effect with greater total time of massage, but with a plateau at the 60-minute/week dose. Conclusion Given the superior convenience of a once-weekly protocol, cost savings, and consistency with a typical real-world massage protocol, the 60-minute once weekly dose was determined to be optimal, establishing a standard for future trials. Trial Registration ClinicalTrials.gov NCT00970008 PMID:22347369

External beam radiotherapy for palliation of painful bone metastases: pooled data bioeffect dose response analysis of dose fractionation

NASA Astrophysics Data System (ADS)

Naveen, T.; Supe, Sanjay S.; Ganesh, K. M.; Samuel, Jacob

2009-01-01

Bone metastases develop in up to 70% of newly diagnosed cancer patients and result in immobility, anxiety, and depression, severely diminishing the patients quality of life. Radiotherapy is a frequently used modality for bone metastasis and has been shown to be effective in reducing metastatic bone pain and in some instances, causing tumor shrinkage or growth inhibition. There is controversy surrounding the optimal fractionation schedule and total dose of external beam radiotherapy, despite many randomized trials and overviews addressing the issue. This study was undertaken to apply BED to clinical fractionation data of radiotherapeutic management of bone metastases in order to arrive at optimum BED values for acceptable level of response rate. A computerised literature search was conducted to identify all prospective clinical studies that addressed the issue of fractionation for the treatment of bone metastasis. The results of these studies were pooled together to form the database for the analysis. A total of 4111 number of patients received radiation dose ranging from 4 to 40.5 Gy in 1 to 15 fractions with dose per fraction ranging from 2 to 10 Gy. Single fraction treatments were delivered in 2013 patients and the dose varied from 4 to 10 Gy. Multifraction treatments were delivered in 2098 patients and the dose varied from 15 to 40.5 Gy. The biological effective dose (BED) was evaluated for each fractionation schedule using the linear quadratic model and an α/β value of 10 Gy. Response rate increased significantly beyond a BED value of 14.4 Gy (p < 0.01). Based on our analysis and indications from the literature about higher retreatment and fracture rate of single fraction treatments, minimum BED value of 14.4 Gy is recommended.

SU-E-T-368: Evaluating Dosimetric Outcome of Modulated Photon Radiotherapy (XMRT) Optimization for Head and Neck Patients

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

McGeachy, P; Villarreal-Barajas, JE; Khan, R

2015-06-15

Purpose: The dosimetric outcome of optimized treatment plans obtained by modulating the photon beamlet energy and fluence on a small cohort of four Head and Neck (H and N) patients was investigated. This novel optimization technique is denoted XMRT for modulated photon radiotherapy. The dosimetric plans from XMRT for H and N treatment were compared to conventional, 6 MV intensity modulated radiotherapy (IMRT) optimization plans. Methods: An arrangement of two non-coplanar and five coplanar beams was used for all four H and N patients. Both XMRT and IMRT were subject to the same optimization algorithm, with XMRT optimization allowing bothmore » 6 and 18 MV beamlets while IMRT was restricted to 6 MV only. The optimization algorithm was based on a linear programming approach with partial-volume constraints implemented via the conditional value-at-risk method. H and N constraints were based off of those mentioned in the Radiation Therapy Oncology Group 1016 protocol. XMRT and IMRT solutions were assessed using metrics suggested by International Commission on Radiation Units and Measurements report 83. The Gurobi solver was used in conjunction with the CVX package to solve each optimization problem. Dose calculations and analysis were done in CERR using Monte Carlo dose calculation with VMC{sub ++}. Results: Both XMRT and IMRT solutions met all clinical criteria. Trade-offs were observed between improved dose uniformity to the primary target volume (PTV1) and increased dose to some of the surrounding healthy organs for XMRT compared to IMRT. On average, IMRT improved dose to the contralateral parotid gland and spinal cord while XMRT improved dose to the brainstem and mandible. Conclusion: Bi-energy XMRT optimization for H and N patients provides benefits in terms of improved dose uniformity to the primary target and reduced dose to some healthy structures, at the expense of increased dose to other healthy structures when compared with IMRT.« less

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

Stewart, J; Lindsay, P; University of Toronto, Toronto

Purpose: Recent progress in small animal radiotherapy systems has provided the foundation for delivering the heterogeneous, millimeter scale dose distributions demanded by preclinical radiobiology investigations. Despite advances in preclinical dose planning, delivery of highly heterogeneous dose distributions is constrained by the fixed collimation systems and large x-ray focal spot common in small animal radiotherapy systems. This work proposes a dual focal spot dose optimization and delivery method with a large x-ray focal spot used to deliver homogeneous dose regions and a small focal spot to paint spatially heterogeneous dose regions. Methods: Two-dimensional dose kernels were measured for a 1 mmmore » circular collimator with radiochromic film at 10 mm depth in a solid water phantom for the small and large x-ray focal spots on a recently developed small animal microirradiator. These kernels were used in an optimization framework which segmented a desired dose distribution into low- and high-spatial frequency regions for delivery by the large and small focal spot, respectively. For each region, the method determined an optimal set of stage positions and beam-on times. The method was demonstrated by optimizing a bullseye pattern consisting of 0.75 mm radius circular target and 0.5 and 1.0 mm wide rings alternating between 0 and 2 Gy. Results: Compared to a large focal spot technique, the dual focal spot technique improved the optimized dose distribution: 69.2% of the optimized dose was within 0.5 Gy of the intended dose for the large focal spot, compared to 80.6% for the dual focal spot method. The dual focal spot design required 14.0 minutes of optimization, and will require 178.3 minutes for automated delivery. Conclusion: The dual focal spot optimization and delivery framework is a novel option for delivering conformal and heterogeneous dose distributions at the preclinical level and provides a new experimental option for unique radiobiological investigations. Funding Support: this work is supported by funding the National Sciences and Engineering Research Council of Canada, and a Mitacs-accelerate fellowship. Conflict of Interest: Dr. Lindsay and Dr. Jaffray are listed as inventors of the small animal microirradiator described herein. This system has been licensed for commercial development.« less

Impact of a phenytoin loading dose program in the emergency department.

PubMed

Brancaccio, Adam; Giuliano, Christopher; McNorton, Kelly; Delgado, George

2014-11-01

The use of a combined physician-and pharmacist-directed phenytoin loading dose program in an emergency department (ED) was evaluated. This single-center, observational, preimplementation-postimplementation study evaluated adult patients who received a phenytoin loading dose in the ED. The primary outcome compared the proportion of optimal phenytoin loading doses in the preimplementation and postimplementation groups. The postimplementation group was further stratified into pharmacist- and prescriber-dosing groups. Other outcomes evaluated included the numbers of appropriate serum phenytoin concentrations measured, adverse drug reactions (ADRs), and recurrence of seizures within 24 hours of loading dose administration in the preimplementation and postimplementation groups. There was no difference in the proportion of optimal phenytoin loading doses between the preimplementation and postimplementation groups (50% versus 62%, respectively; p=0.19). When stratified by individual groups, the rate of optimal phenytoin loading doses increased by 64% in the postimplementation pharmacist group (50% versus 82%, p=0.007), while the rate in the prescriber-dosing group remained relatively unchanged (50% versus 49%, p=0.91). The number of appropriate serum phenytoin concentrations significantly improved in the postimplementation versus preimplementation group (65% versus 40%, p=0.025). Rates of ADRs and recurrence of seizures did not differ across the study groups. No change in the percentage of optimal phenytoin loading doses in the ED was observed after implementation of a combined pharmacist- and physician- dosing program. When stratified into pharmacist or prescriber dosing, the pharmacist-led dosing program significantly improved the proportion of patients who received optimal phenytoin loading doses. Copyright © 2014 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

MO-E-18A-01: Imaging: Best Practices In Pediatric Imaging

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

Willis, C; Strauss, K; MacDougall, R

This imaging educational program will focus on solutions to common pediatric imaging challenges. The speakers will present collective knowledge on best practices in pediatric imaging from their experience at dedicated children's hospitals. Areas of focus will include general radiography, the use of manual and automatic dose management in computed tomography, and enterprise-wide radiation dose management in the pediatric practice. The educational program will begin with a discussion of the complexities of exposure factor control in pediatric projection radiography. Following this introduction will be two lectures addressing the challenges of computed tomography (CT) protocol optimization in the pediatric population. The firstmore » will address manual CT protocol design in order to establish a managed radiation dose for any pediatric exam on any CT scanner. The second CT lecture will focus on the intricacies of automatic dose modulation in pediatric imaging with an emphasis on getting reliable results in algorithmbased technique selection. The fourth and final lecture will address the key elements needed to developing a comprehensive radiation dose management program for the pediatric environment with particular attention paid to new regulations and obligations of practicing medical physicists. Learning Objectives: To understand how general radiographic techniques can be optimized using exposure indices in order to improve pediatric radiography. To learn how to establish diagnostic dose reference levels for pediatric patients as a function of the type of examination, patient size, and individual design characteristics of the CT scanner. To learn how to predict the patient's radiation dose prior to the exam and manually adjust technique factors if necessary to match the patient's dose to the department's established dose reference levels. To learn how to utilize manufacturer-provided automatic dose modulation technology to consistently achieve patient doses within the department's established size-based diagnostic reference range. To understand the key components of an enterprise-wide pediatric dose management program that integrates the expanding responsibilities of medial physicists in the new era of dose monitoring.« less

SU-E-T-549: A Combinatorial Optimization Approach to Treatment Planning with Non-Uniform Fractions in Intensity Modulated Proton Therapy

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

Papp, D; Unkelbach, J

2014-06-01

Purpose: Non-uniform fractionation, i.e. delivering distinct dose distributions in two subsequent fractions, can potentially improve outcomes by increasing biological dose to the target without increasing dose to healthy tissues. This is possible if both fractions deliver a similar dose to normal tissues (exploit the fractionation effect) but high single fraction doses to subvolumes of the target (hypofractionation). Optimization of such treatment plans can be formulated using biological equivalent dose (BED), but leads to intractable nonconvex optimization problems. We introduce a novel optimization approach to address this challenge. Methods: We first optimize a reference IMPT plan using standard techniques that deliversmore » a homogeneous target dose in both fractions. The method then divides the pencil beams into two sets, which are assigned to either fraction one or fraction two. The total intensity of each pencil beam, and therefore the physical dose, remains unchanged compared to the reference plan. The objectives are to maximize the mean BED in the target and to minimize the mean BED in normal tissues, which is a quadratic function of the pencil beam weights. The optimal reassignment of pencil beams to one of the two fractions is formulated as a binary quadratic optimization problem. A near-optimal solution to this problem can be obtained by convex relaxation and randomized rounding. Results: The method is demonstrated for a large arteriovenous malformation (AVM) case treated in two fractions. The algorithm yields a treatment plan, which delivers a high dose to parts of the AVM in one of the fractions, but similar doses in both fractions to the normal brain tissue adjacent to the AVM. Using the approach, the mean BED in the target was increased by approximately 10% compared to what would have been possible with a uniform reference plan for the same normal tissue mean BED.« less

Obtaining the Optimal Dose in Alcohol Dependence Studies

PubMed Central

Wages, Nolan A.; Liu, Lei; O’Quigley, John; Johnson, Bankole A.

2012-01-01

In alcohol dependence studies, the treatment effect at different dose levels remains to be ascertained. Establishing this effect would aid us in identifying the best dose that has satisfactory efficacy while minimizing the rate of adverse events. We advocate the use of dose-finding methodology that has been successfully implemented in the cancer and HIV settings to identify the optimal dose in a cost-effective way. Specifically, we describe the continual reassessment method (CRM), an adaptive design proposed for cancer trials to reconcile the needs of dose-finding experiments with the ethical demands of established medical practice. We are applying adaptive designs for identifying the optimal dose of medications for the first time in the context of pharmacotherapy research in alcoholism. We provide an example of a topiramate trial as an illustration of how adaptive designs can be used to locate the optimal dose in alcohol treatment trials. It is believed that the introduction of adaptive design methods will enable the development of medications for the treatment of alcohol dependence to be accelerated. PMID:23189064

SU-G-TeP3-11: Radiobiological-Cum-Dosimetric Quality Assurance of Complex Radiotherapy Plans

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

Paudel, N; Narayanasamy, G; Zhang, X

2016-06-15

Purpose: Dosimetric gamma-analysis used for QA of complex radiotherapy plans tests the dosimetric equivalence of a delivered plan with the treatment planning system (TPS) optimized plan. It does not examine whether a dosimetric difference results in any radiobiological difference. This study introduces a method to test the radiobiological and dosimetric equivalence between a delivered and the TPS optimized plan. Methods: Six head and neck and seven lung cancer VMAT or IMRT plans optimized for patient treatment were calculated and delivered to an ArcCheck phantom. ArcCheck measured dose distributions were compared with the TPS calculated dose distributions using a 2-D gamma-analysis.more » Dose volume histograms (DVHs) for various patient structures were obtained by using measured data in 3DVH software and compared against the TPS calculated DVHs using 3-D gamma analysis. DVH data were used in the Poisson model to calculate tumor control probability (TCP) for the treatment targets and in the sigmoid dose response model to calculate normal tissue complication probability (NTCP) for the normal structures. Results: Two-D and three-D gamma passing rates among six H&N patient plans differed by 0 to 2.7% and among seven lung plans by 0.1 to 4.5%. Average ± SD TCPs based on measurement and TPS were 0.665±0.018 and 0.674±0.044 for H&N, and 0.791±0.027 and 0.733±0.031 for lung plans, respectively. Differences in NTCPs were usually negligible. The differences in dosimetric results, TCPs and NTCPs were insignificant. Conclusion: The 2-D and 3-D gamma-analysis based agreement between measured and planned dose distributions may indicate their dosimetric equivalence. Small and insignificant differences in TCPs and NTCPs based on measured and planned dose distributions indicate the radiobiological equivalence between the measured and optimized plans. However, patient plans showing larger differences between 2-D and 3-D gamma-analysis can help us make a more definite conclusion through our ongoing research with a larger number of patients.« less

Evaluation of an intragastric challenge model for Shigella dysenteriae 1 in rhesus monkeys (Macaca mulatta) for the pre-clinical assessment of Shigella vaccine formulations

PubMed Central

Islam, Dilara; Ruamsap, Nattaya; Khantapura, Patchariya; Aksomboon, Ajchara; Srijan, Apichai; Wongstitwilairoong, Boonchai; Bodhidatta, Ladaporn; Gettayacamin, Montip; Venkatesan, Malabi M; Mason, Carl J

2014-01-01

Shigellosis is a worldwide disease, characterized by abdominal pain, fever, vomiting, and the passage of blood- and mucus-streaked stools. Rhesus monkeys and other primates are the only animals that are naturally susceptible to shigellosis. A suitable animal model is required for the pre-clinical evaluation of vaccines candidates. In this study, the minimal dose of Shigella dysenteriae1 1617 strain required to produce dysentery in four of five (80% attack rate) monkeys using an escalating dose range for three groups [2 × 108, 2 × 109 and 2 × 1010 colony forming unit (CFU)] was determined. In addition, the monkeys were re-infected. The identified optimal challenge dose was 2 × 109 CFU; this dose elicited 60% protection in monkeys when they were re-challenged with a one log higher dose (2 × 1010 CFU). The challenge dose, 2 × 1010 CFU, produced severe dysentery in all monkeys, with one monkey dying within 24 h, elicited 100% protection when re-challenged with the same dose. All monkeys exhibited immune responses. This study concludes that the rhesus monkey model closely mimics the disease and immune response seen in humans and is a suitable animal model for the pre-clinical evaluation of Shigella vaccine candidates. Prior infection with the 1617 strain can protect monkeys against subsequent re-challenges with homologous strains. PMID:24028276

Safety and immunogenicity of a monovalent MF59®-adjuvanted A/H1N1 vaccine in HIV-infected children and young adults.

PubMed

Palma, Paolo; Romiti, Maria Luisa; Bernardi, Stefania; Pontrelli, Giuseppe; Mora, Nadia; Santilli, Veronica; Tchidjou, Hyppolite Kuekou; Aquilani, Angela; Cotugno, Nicola; Alghisi, Federico; Lucidi, Vincenzina; Rossi, Paolo; Douagi, Iyadh

2012-03-01

This Phase IV study evaluated the safety and immunogenicity of a two-dose, MF59®-adjuvanted (Novartis Vaccines, Marburg, Germany), monovalent, A/H1N1 pandemic influenza vaccination schedule in Human Immunodeficiency Virus (HIV) positive children and young adults. A total of 83 children infected with HIV-1, and 37 non-immunocompromised, age-matched controls were enrolled. All participants received two vaccine doses administered three weeks apart. Antibody responses were assessed by haemagglutination assay at baseline, three weeks after each vaccine dose, and six months after immunization. Vaccines were evaluated according to European influenza vaccine licensure criteria. The investigational vaccine was well tolerated. After the first vaccine dose, seroconversion rates were significantly lower in HIV-positive patients (60%) than controls (82%), with GMTs of 419 and 600, respectively. No significant differences in seroconversion rates were observed between the two study groups in response to the second vaccine dose. Persisting antibody titers were similar for both HIV-positive and non-infected controls, six months after immunization. One dose of MF59-adjuvanted vaccine was sufficient to provide adequate levels of seroprotection against A/H1N1 influenza disease in HIV-positive children. However, a two-dose vaccination schedule may be optimal for this population. Copyright © 2011 The International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

Effect of Neoadjuvant Radiation Dose on Surgical and Oncological Outcome in Locally Advanced Esophageal Cancer.

PubMed

Van Daele, E; Ceelen, W; Boterberg, T; Varinl, O; Van Nieuwenhove, Y; Putte, D Van de; Geboes, K; Pattyn, P

2015-01-01

Neoadjuvant chemoradiation (CRT) confers a survival benefit in locally advanced esophageal cancer. The optimal dose of radiotherapy remains undefined. From a prospective database, we identified patients who received CRT followed by Ivor Lewis esophagectomy. Surgical complications, pathological response, and oncological outcome were compared between patients who received a radiotherapy (RT) dose of 36 Gy (group1) versus a dose of > 40 Gy (group 1). 147 patients were evaluated: 109 received 36 Gy, while 38 received 41-50Gy. Mean age was 61 ± 9 years (84% male). Median hospital stay was 16 days. Anastomotic leakage occurred in 4.0%. Pulmonary complications occurred in 41.8%, neither being influenced by RT dose. Complete resection (R0) was achieved in 95% (group 1) and 100% (group 2), P = 0.3. Pathological complete response (pCR) was observed in 19% (group 1) and 37% (group 1), P = 0.04. Local recurrence developed in 9% in group 1, and 3% in group 2 (P = 0.3), but regional recurrence developed significantly higher in the low dose group (18% vs 3%, P < 0.001). Metastatic recurrence occurred in 48% in group 1 and 13% in group 1 (P < 0.001). In patients with locally advanced esophageal cancer a higher RT dose does not affect surgical outcome, enhances pCR rate, and reduces the locoregional and metastatic recurrence risk.

Effect of sub-optimal doses of fluoxetine plus estradiol on antidepressant-like behavior and hippocampal neurogenesis in ovariectomized rats.

PubMed

Vega-Rivera, Nelly M; Fernández-Guasti, Alonso; Ramírez-Rodríguez, Gerardo; Estrada-Camarena, Erika

2015-07-01

Estrogens and antidepressants synergize to reduce depressive symptoms and stimulate neurogenesis and neuroplastic events. The aim of this study was to explore whether the antidepressant-like effect induced by the combination of low doses of estradiol (E2) and fluoxetine (FLX) involves changes in cell proliferation, early survival, morphology and dendrite complexity of hippocampal new-immature neurons. The antidepressant-like effects of E2 and/or FLX were evaluated by the forced swimming test (FST), cell proliferation was determined with the endogenous marker Ki67, survival of newborn cells was established with bromo-deoxiuridine (BrdU) and immature neurons were ascertained by doublecortin (DCX) labeling while their dendrite complexity was evaluated with Sholl analysis. Ovariectomized Wistar rats were randomly assigned to one of the following groups: Vehicle (saline/14 days+Oil/-8h before FST); E2 (saline/14 days + E2 2.5 or 10 μg/rat; -8 h before FST); FLX (1.25 or 10 mg/kg for 14 days + oil -8h before FST), and FLX plus E2 (FLX 1.25 mg/kg for 14 days + E2 2.5 μg/rat -8 h before FST). The combination of sub-threshold doses of FLX plus E2 produced antidepressant-like actions similar to those induced by FLX or E2 given independently at optimal doses. Only FLX at an optimal dose and the combination of FLX plus E2 increased cell proliferation, the number of DCX-labeled immature neurons and the complexity of their dendritic tree, suggesting that these events may be responsible for their antidepressant-like effect. Copyright © 2015 Elsevier Ltd. All rights reserved.

TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules.

PubMed

Liu, Qian; Sun, Jessica D; Wang, Jingli; Ahluwalia, Dharmendra; Baker, Amanda F; Cranmer, Lee D; Ferraro, Damien; Wang, Yan; Duan, Jian-Xin; Ammons, W Steve; Curd, John G; Matteucci, Mark D; Hart, Charles P

2012-06-01

Subregional hypoxia is a common feature of tumors and is recognized as a limiting factor for the success of radiotherapy and chemotherapy. TH-302, a hypoxia-activated prodrug selectively targeting hypoxic regions of solid tumors, delivers a cytotoxic warhead to the tumor, while maintaining relatively low systemic toxicity. The antitumor activity, different dosing sequences, and dosing regimens of TH-302 in combination with commonly used conventional chemotherapeutics were investigated in human tumor xenograft models. Seven chemotherapeutic drugs (docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide) were tested in combination with TH-302 in eleven human xenograft models, including non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, fibrosarcoma, melanoma, and pancreatic cancer. The antitumor activity of docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide was increased when combined with TH-302 in nine out of eleven models tested. Administration of TH-302 2-8 h prior to the other chemotherapeutics yielded superior efficacy versus other sequences tested. Simultaneous administration of TH-302 and chemotherapeutics increased toxicity versus schedules with dosing separations. In a dosing optimization study, TH-302 administered daily at 50 mg/kg intraperitoneally for 5 days per week in the H460 NSCLC model showed the optimal response with minimal toxicity. TH-302 enhances the activity of a wide range of conventional anti-neoplastic agents in a broad panel of in vivo xenograft models. These data highlight in vivo effects of schedule and order of drug administration in regimen efficacy and toxicity and have relevance to the design of human regimens incorporating TH-302.

TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules

PubMed Central

Liu, Qian; Sun, Jessica D.; Wang, Jingli; Ahluwalia, Dharmendra; Baker, Amanda F.; Cranmer, Lee D.; Ferraro, Damien; Wang, Yan; Duan, Jian-Xin; Ammons, W. Steve; Curd, John G.; Matteucci, Mark D.

2014-01-01

Purpose Subregional hypoxia is a common feature of tumors and is recognized as a limiting factor for the success of radiotherapy and chemotherapy. TH-302, a hypoxia-activated prodrug selectively targeting hypoxic regions of solid tumors, delivers a cytotoxic warhead to the tumor, while maintaining relatively low systemic toxicity. The antitumor activity, different dosing sequences, and dosing regimens of TH-302 in combination with commonly used conventional chemotherapeutics were investigated in human tumor xenograft models. Methods Seven chemotherapeutic drugs (docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide) were tested in combination with TH-302 in eleven human xenograft models, including non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, fibrosarcoma, melanoma, and pancreatic cancer. Results The antitumor activity of docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide was increased when combined with TH-302 in nine out of eleven models tested. Administration of TH-302 2–8 h prior to the other chemotherapeutics yielded superior efficacy versus other sequences tested. Simultaneous administration of TH-302 and chemotherapeutics increased toxicity versus schedules with dosing separations. In a dosing optimization study, TH-302 administered daily at 50 mg/kg intraperitoneally for 5 days per week in the H460 NSCLC model showed the optimal response with minimal toxicity. Conclusions TH-302 enhances the activity of a wide range of conventional anti-neoplastic agents in a broad panel of in vivo xenograft models. These data highlight in vivo effects of schedule and order of drug administration in regimen efficacy and toxicity and have relevance to the design of human regimens incorporating TH-302. PMID:22382881

DNA methyltransferase mediates dose-dependent stimulation of neural stem cell proliferation by folate.

PubMed

Li, Wen; Yu, Min; Luo, Suhui; Liu, Huan; Gao, Yuxia; Wilson, John X; Huang, Guowei

2013-07-01

The proliferative response of neural stem cells (NSCs) to folate may play a critical role in the development, function and repair of the central nervous system. It is important to determine the dose-dependent effects of folate in NSC cultures that are potential sources of transplantable cells for therapies for neurodegenerative diseases. To determine the optimal concentration and mechanism of action of folate for stimulation of NSC proliferation in vitro, NSCs were exposed to folic acid or 5-methyltetrahydrofolate (5-MTHF) (0-200 μmol/L) for 24, 48 or 72 h. Immunocytochemistry and methyl thiazolyl tetrazolium assay showed that the optimal concentration of folic acid for NSC proliferation was 20-40 μmol/L. Stimulation of NSC proliferation by folic acid was associated with DNA methyltransferase (DNMT) activation and was attenuated by the DNMT inhibitor zebularine, which implies that folate dose-dependently stimulates NSC proliferation through a DNMT-dependent mechanism. Based on these new findings and previously published evidence, we have identified a mechanism by which folate stimulates NSC growth. Copyright © 2013 Elsevier Inc. All rights reserved.

Drug interactions: volatile anesthetics and opioids.

PubMed

Glass, P S; Gan, T J; Howell, S; Ginsberg, B

1997-09-01

Multiple drugs are used to provide anesthesia. Volatile anesthetics are commonly combined with opioids. Several studies have demonstrated that small doses of opioid (i.e., within the analgesic range) result in a marked reduction in minimum alveolar concentration (MAC) of the volatile anesthetic that will prevent purposeful movement in 50% of patients at skin incision). Further increases in opioid dose provide only a further small reduction in MAC. Thus, a ceiling effect of the opioid is observed at a MAC value of the volatile anesthetic equal to its MAC awake. Recovery from anesthesia when an opioid is combined with a volatile anesthetic is dependent on the rate of decrease of both drugs to their respective concentrations that are associated with adequate spontaneous ventilation and awakening. Through an understanding of the pharmacodynamic interaction of volatile anesthetics with opioids and the pharmacokinetic processes responsible for the recovery from drug effect, optimal dosing schemes can thus be developed. A review of these pharmacodynamic and pharmacokinetic principles that will allow clinicians to administer drugs to provide a more optimal anesthetic is provided.

Detector photon response and absorbed dose and their applications to rapid triage techniques

NASA Astrophysics Data System (ADS)

Voss, Shannon Prentice

As radiation specialists, one of our primary objectives in the Navy is protecting people and the environment from the effects of ionizing and non-ionizing radiation. Focusing on radiological dispersal devices (RDD) will provide increased personnel protection as well as optimize emergency response assets for the general public. An attack involving an RDD has been of particular concern because it is intended to spread contamination over a wide area and cause massive panic within the general population. A rapid method of triage will be necessary to segregate the unexposed and slightly exposed from those needing immediate medical treatment. Because of the aerosol dispersal of the radioactive material, inhalation of the radioactive material may be the primary exposure route. The primary radionuclides likely to be used in a RDD attack are Co-60, Cs-137, Ir-192, Sr-90 and Am-241. Through the use of a MAX phantom along with a few Simulink MATLAB programs, a good anthropomorphic phantom was created for use in MCNPX simulations that would provide organ doses from internally deposited radionuclides. Ludlum model 44-9 and 44-2 detectors were used to verify the simulated dose from the MCNPX code. Based on the results, acute dose rate limits were developed for emergency response personnel that would assist in patient triage.

SU-E-T-422: Fast Analytical Beamlet Optimization for Volumetric Intensity-Modulated Arc Therapy

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

Chan, Kenny S K; Lee, Louis K Y; Xing, L

2015-06-15

Purpose: To implement a fast optimization algorithm on CPU/GPU heterogeneous computing platform and to obtain an optimal fluence for a given target dose distribution from the pre-calculated beamlets in an analytical approach. Methods: The 2D target dose distribution was modeled as an n-dimensional vector and estimated by a linear combination of independent basis vectors. The basis set was composed of the pre-calculated beamlet dose distributions at every 6 degrees of gantry angle and the cost function was set as the magnitude square of the vector difference between the target and the estimated dose distribution. The optimal weighting of the basis,more » which corresponds to the optimal fluence, was obtained analytically by the least square method. Those basis vectors with a positive weighting were selected for entering into the next level of optimization. Totally, 7 levels of optimization were implemented in the study.Ten head-and-neck and ten prostate carcinoma cases were selected for the study and mapped to a round water phantom with a diameter of 20cm. The Matlab computation was performed in a heterogeneous programming environment with Intel i7 CPU and NVIDIA Geforce 840M GPU. Results: In all selected cases, the estimated dose distribution was in a good agreement with the given target dose distribution and their correlation coefficients were found to be in the range of 0.9992 to 0.9997. Their root-mean-square error was monotonically decreasing and converging after 7 cycles of optimization. The computation took only about 10 seconds and the optimal fluence maps at each gantry angle throughout an arc were quickly obtained. Conclusion: An analytical approach is derived for finding the optimal fluence for a given target dose distribution and a fast optimization algorithm implemented on the CPU/GPU heterogeneous computing environment greatly reduces the optimization time.« less

Anatomical robust optimization to account for nasal cavity filling variation during intensity-modulated proton therapy: a comparison with conventional and adaptive planning strategies

NASA Astrophysics Data System (ADS)

van de Water, Steven; Albertini, Francesca; Weber, Damien C.; Heijmen, Ben J. M.; Hoogeman, Mischa S.; Lomax, Antony J.

2018-01-01

The aim of this study is to develop an anatomical robust optimization method for intensity-modulated proton therapy (IMPT) that accounts for interfraction variations in nasal cavity filling, and to compare it with conventional single-field uniform dose (SFUD) optimization and online plan adaptation. We included CT data of five patients with tumors in the sinonasal region. Using the planning CT, we generated for each patient 25 ‘synthetic’ CTs with varying nasal cavity filling. The robust optimization method available in our treatment planning system ‘Erasmus-iCycle’ was extended to also account for anatomical uncertainties by including (synthetic) CTs with varying patient anatomy as error scenarios in the inverse optimization. For each patient, we generated treatment plans using anatomical robust optimization and, for benchmarking, using SFUD optimization and online plan adaptation. Clinical target volume (CTV) and organ-at-risk (OAR) doses were assessed by recalculating the treatment plans on the synthetic CTs, evaluating dose distributions individually and accumulated over an entire fractionated 50 GyRBE treatment, assuming each synthetic CT to correspond to a 2 GyRBE fraction. Treatment plans were also evaluated using actual repeat CTs. Anatomical robust optimization resulted in adequate CTV doses (V95%  ⩾  98% and V107%  ⩽  2%) if at least three synthetic CTs were included in addition to the planning CT. These CTV requirements were also fulfilled for online plan adaptation, but not for the SFUD approach, even when applying a margin of 5 mm. Compared with anatomical robust optimization, OAR dose parameters for the accumulated dose distributions were on average 5.9 GyRBE (20%) higher when using SFUD optimization and on average 3.6 GyRBE (18%) lower for online plan adaptation. In conclusion, anatomical robust optimization effectively accounted for changes in nasal cavity filling during IMPT, providing substantially improved CTV and OAR doses compared with conventional SFUD optimization. OAR doses can be further reduced by using online plan adaptation.

A gEUD-based inverse planning technique for HDR prostate brachytherapy: Feasibility study

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

Giantsoudi, D.; Department of Radiation Oncology, Francis H. Burr Proton Therapy Center, Boston, Massachusetts 02114; Baltas, D.

2013-04-15

Purpose: The purpose of this work was to study the feasibility of a new inverse planning technique based on the generalized equivalent uniform dose for image-guided high dose rate (HDR) prostate cancer brachytherapy in comparison to conventional dose-volume based optimization. Methods: The quality of 12 clinical HDR brachytherapy implants for prostate utilizing HIPO (Hybrid Inverse Planning Optimization) is compared with alternative plans, which were produced through inverse planning using the generalized equivalent uniform dose (gEUD). All the common dose-volume indices for the prostate and the organs at risk were considered together with radiobiological measures. The clinical effectiveness of the differentmore » dose distributions was investigated by comparing dose volume histogram and gEUD evaluators. Results: Our results demonstrate the feasibility of gEUD-based inverse planning in HDR brachytherapy implants for prostate. A statistically significant decrease in D{sub 10} or/and final gEUD values for the organs at risk (urethra, bladder, and rectum) was found while improving dose homogeneity or dose conformity of the target volume. Conclusions: Following the promising results of gEUD-based optimization in intensity modulated radiation therapy treatment optimization, as reported in the literature, the implementation of a similar model in HDR brachytherapy treatment plan optimization is suggested by this study. The potential of improved sparing of organs at risk was shown for various gEUD-based optimization parameter protocols, which indicates the ability of this method to adapt to the user's preferences.« less

Influence of Exercise Intensity for Improving Depressed Mood in Depression: A Dose-Response Study.

PubMed

Meyer, Jacob D; Koltyn, Kelli F; Stegner, Aaron J; Kim, Jee-Seon; Cook, Dane B

2016-07-01

Exercise effectively improves mood in major depressive disorder (MDD), but the optimal exercise stimulus to improve depressed mood is unknown. To determine the dose-response relationship of acute exercise intensity with depressed mood responses to exercise in MDD. We hypothesized that the acute response to exercise would differ between light, moderate, and hard intensity exercise with higher intensities yielding more beneficial responses. Once weekly, 24 women (age: 38.6±14.0) diagnosed with MDD underwent a 30-minute session at one of three steady-state exercise intensities (light, moderate, hard; rating of perceived exertion 11, 13 or 15) or quiet rest on a stationary bicycle. Depressed mood was evaluated with the Profile of Mood States before, 10 and 30 minutes post-exercise. Exercise reduced depressed mood 10 and 30 minutes following exercise, but this effect was not influenced by exercise intensity. Participants not currently taking antidepressants (n=10) had higher baseline depression scores, but did not demonstrate a different antidepressant response to exercise compared to those taking antidepressants. To acutely improve depressed mood, exercise of any intensity significantly improved feelings of depression with no differential effect following light, moderate, or hard exercise. Pharmacological antidepressant usage did not limit the mood-enhancing effect of acute exercise. Acute exercise should be used as a symptom management tool to improve mood in depression, with even light exercise an effective recommendation. These results need to be replicated and extended to other components of exercise prescription (e.g., duration, frequency, mode) to optimize exercise guidelines for improving depression. Copyright © 2016. Published by Elsevier Ltd.

Evaluation of a 15-week CHOP protocol for the treatment of canine multicentric lymphoma.

PubMed

Burton, J H; Garrett-Mayer, E; Thamm, D H

2013-12-01

Dose intense CHOP protocols have been shown to improve outcome for people with non-Hodgkin's lymphoma, but evaluation of dose intense CHOP protocols for canine lymphoma is currently limited. The hypothesis of this retrospective study was that a 15-week dose intense CHOP protocol would have shorter treatment duration with similar efficacy to other doxorubicin-based multidrug protocols. Thirty-one client owned dogs with multicentric lymphoma were treated with a 15-week CHOP chemotherapy protocol with an overall response rate of 100% and a median progression-free interval (PFI) of 140 days [95% confidence interval (CI) 91-335 days]. Dogs that had two or more treatment delays had significantly prolonged PFI and overall survival in multivariate analysis. Dose intensity did not correlate with patient outcome. Dogs experiencing multiple treatment delays secondary to adverse events may receive their individual maximally tolerated dose while dogs with no adverse events may be underdosed. Future studies should focus on individual patient dose optimization. © 2012 Blackwell Publishing Ltd.

Feasibility of dose enhancement assessment: Preliminary results by means of Gd-infused polymer gel dosimeter and Monte Carlo study.

PubMed

Santibáñez, M; Guillen, Y; Chacón, D; Figueroa, R G; Valente, M

2018-04-11

This work reports the experimental development of an integral Gd-infused dosimeter suitable for Gd dose enhancement assessment along with Monte Carlo simulations applied to determine the dose enhancement by radioactive and X-ray sources of interest in conventional and electronic brachytherapy. In this context, capability to elaborate a stable and reliable Gd-infused dosimeter was the first goal aimed at direct and accurate measurements of dose enhancement due to Gd presence. Dose-response was characterized for standard and Gd-infused PAGAT polymer gel dosimeters by means of optical transmission/absorbance. The developed Gd-infused PAGAT dosimeters demonstrated to be stable presenting similar dose-response as standard PAGAT within a linear trend up to 13 Gy along with good post-irradiation readout stability verified at 24 and 48 h. Additionally, dose enhancement was evaluated for Gd-infused PAGAT dosimeters by means of Monte Carlo (PENELOPE) simulations considering scenarios for isotopic and X-ray generator sources. The obtained results demonstrated the feasibility of obtaining a maximum enhancement around of (14 ± 1)% for 192 Ir source and an average enhancement of (70 ± 13)% for 241 Am. However, dose enhancement up to (267 ± 18)% may be achieved if suitable filtering is added to the 241 Am source. On the other hand, optimized X-ray spectra may attain dose enhancements up to (253 ± 22) %, which constitutes a promising future alternative for replacing radioactive sources by implementing electronic brachytherapy achieving high dose levels. Copyright © 2018. Published by Elsevier Ltd.

Dose, timing, schedule, and the choice of targeted epitope alter the efficacy of anti-CD22 immunotherapy in mice bearing human lymphoma xenografts.

PubMed

O'Donnell, Robert T; Ma, Yunpeng; McKnight, Hayes C; Pearson, David; Tuscano, Joseph M

2009-12-01

CD22 is a cell-surface adhesion molecule on most B-cell NHL, so it is a promising target for immunotherapy. HB22.7 is an anti-CD22 mAb that binds the two NH(2)-terminal immunoglobulin domains and specifically blocks the interaction of CD22 with its ligand. CD22-blocking mAbs induce apoptosis in neoplastic B-cells and are functionally distinguishable from other anti-CD22 mAbs. This study assessed the optimal dose, route, schedule, and the targeted CD22 epitope. Raji NHL-bearing nude mice were studied. A non-blocking anti-CD22 mAb (HB22.27) was used as a control. HB22.27 had minimal effect, whereas HB22.7 improved survival and shrank tumors substantially. HB22.7 doses greater than 1.4 mg/week did not further increase efficacy (or toxicity). Tumors less than 200 mm(3) had a higher response rate than did larger tumors. Various schedules of HB22.7 administration were tested; one dose every other week was more effective than more or less frequent dosing. Pharmacokinetic studies revealed that the half-life of HB22.7 was 28 days; this correlated with the time needed to re-populate cell-surface CD22 after treatment with HB22.7. Immuno-PET showed that NHL was rapidly and specifically targeted by copper-64-labeled-HB22.7. This study provided data as to an optimal dose, route, schedule and interval between doses of HB22.7.

The reverse remodeling response to sacubitril/valsartan therapy in heart failure with reduced ejection fraction.

PubMed

Martens, Pieter; Beliën, Hanne; Dupont, Matthias; Vandervoort, Pieter; Mullens, Wilfried

2018-05-17

Major classes of medical therapy for heart failure with reduced ejection fraction (HFrEF) induce reverse remodeling. The revere remodeling response to sacubitril/valsartan remains unstudied. We performed a single-center, prospective assessor-blinded study to determine the reverse remodeling response of sacubitril/valsartan therapy in HFrEF patients with a class I indication (New York heart Association [NYHA]-class II-IV, Left ventricular ejection fraction [LVEF] < 35%, optimal dose with Renin-Angiotensin-System-Blocker [RAS-blocker]). Doses of sacubitril/valsartan were optimized to individual tolerance. Echocardiographic images were assessed offline by 2 investigators blinded to both the clinical data and timing of echocardiograms. One-hundred-twenty-five HFrEF patients (66 ± 10 years) were prospectively included. The amount of RAS-blocker before and after switch to sacubitril/valsartan was similar(P = .290), indicating individual optimal dosing of sacubitril/valsartan. Over a median(IQR) follow-up of 118(77-160) days after initiation of sacubitril/valsartan, LVEF improved (29.6 ± 6% vs 34.8 ± 6%; P < .001) and Left ventricular end-systolic (LVESV) and end-diastolic volume (LVEDV) decreased (LVESV; 147 ± 57 mL vs 129 ± 55 mL; P < .001 and LVEDV; 206 ± 71 mL vs197 ± 72 mL; P = .027). Volumetric remodeling was associated with a reduction in the degree of mitral regurgitation (1.59 ± 1.0 vs 1.11 ± 0.8; P < .001; [scale from 0-4]). Metrics of diastolic function improved; including a drop in the E/A-wave ratio (1.75 ± 1.13 vs 1.38 ± 0.88; P = .002) and diastolic filling time (% of cycle length) prolonged (48 ± 9% vs 52 ± 1%; P = .005). The percent of patients with a restrictive mitral filling pattern dropped from 47% to 23% (P = .004). A dose-dependent effect was noted for changes in LVEF (P < .001) and LVESV (P = .031), with higher doses of sacubitril/valsartan leading to more reverse remodeling. Switching therapy in eligible HFrEF patients from a RAS-blocker to sacubitril/valsartan induces beneficial reverse remodeling of both metrics of systolic as diastolic function. © 2018 John Wiley & Sons Ltd.

Sex differences in the response of children with ADHD to once-daily formulations of methylphenidate.

PubMed

Sonuga-Barke, Edmund J S; Coghill, David; Markowitz, John S; Swanson, James M; Vandenberghe, Mieke; Hatch, Simon J

2007-06-01

Studies of sex differences in methylphenidate response by children with attention-deficit/hyperactivity disorder have lacked methodological rigor and statistical power. This paper reports an examination of sex differences based on further analysis of data from a comparison of two once-daily methylphenidate formulations (the COMACS study), which addresses these shortcomings. Children (184: 48 females; mean [SD] age, 9.58 [1.83] years) entered a double-blind, crossover trial of Concerta, MetadateCD/Equasym XL, or placebo. Attention-deficit/hyperactivity disorder symptoms were recorded at seven time points across the school day on the seventh day of treatment, using a laboratory classroom setting. More females had comorbid anxiety disorder. Males and females did not differ with regard to other characteristics. Observed sex differences in pharmacodynamic symptom profiles persisted after controlling for placebo and time 0 hours attention-deficit/hyperactivity disorder scores and the presence of an anxiety disorder. Females had a statistically superior response at 1.5 hours post-dosing and an inferior response at the 12-hour time point relative to their male counterparts, no matter which methylphenidate formulation was being assessed. Dose titration of once-daily formulations of methylphenidate should ideally be based on systematic evidence of response at different periods across the day. The responses of female patients may require additional assessments later in the day to determine the optimal dose.

Multiscale benchmarking of drug delivery vectors.

PubMed

Summers, Huw D; Ware, Matthew J; Majithia, Ravish; Meissner, Kenith E; Godin, Biana; Rees, Paul

2016-10-01

Cross-system comparisons of drug delivery vectors are essential to ensure optimal design. An in-vitro experimental protocol is presented that separates the role of the delivery vector from that of its cargo in determining the cell response, thus allowing quantitative comparison of different systems. The technique is validated through benchmarking of the dose-response of human fibroblast cells exposed to the cationic molecule, polyethylene imine (PEI); delivered as a free molecule and as a cargo on the surface of CdSe nanoparticles and Silica microparticles. The exposure metrics are converted to a delivered dose with the transport properties of the different scale systems characterized by a delivery time, τ. The benchmarking highlights an agglomeration of the free PEI molecules into micron sized clusters and identifies the metric determining cell death as the total number of PEI molecules presented to cells, determined by the delivery vector dose and the surface density of the cargo. Copyright © 2016 Elsevier Inc. All rights reserved.

Universal field matching in craniospinal irradiation by a background-dose gradient-optimized method.

PubMed

Traneus, Erik; Bizzocchi, Nicola; Fellin, Francesco; Rombi, Barbara; Farace, Paolo

2018-01-01

The gradient-optimized methods are overcoming the traditional feathering methods to plan field junctions in craniospinal irradiation. In this note, a new gradient-optimized technique, based on the use of a background dose, is described. Treatment planning was performed by RayStation (RaySearch Laboratories, Stockholm, Sweden) on the CT scans of a pediatric patient. Both proton (by pencil beam scanning) and photon (by volumetric modulated arc therapy) treatments were planned with three isocenters. An 'in silico' ideal background dose was created first to cover the upper-spinal target and to produce a perfect dose gradient along the upper and lower junction regions. Using it as background, the cranial and the lower-spinal beams were planned by inverse optimization to obtain dose coverage of their relevant targets and of the junction volumes. Finally, the upper-spinal beam was inversely planned after removal of the background dose and with the previously optimized beams switched on. In both proton and photon plans, the optimized cranial and the lower-spinal beams produced a perfect linear gradient in the junction regions, complementary to that produced by the optimized upper-spinal beam. The final dose distributions showed a homogeneous coverage of the targets. Our simple technique allowed to obtain high-quality gradients in the junction region. Such technique universally works for photons as well as protons and could be applicable to the TPSs that allow to manage a background dose. © 2017 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

Efficacy of robust optimization plan with partial-arc VMAT for photon volumetric-modulated arc therapy: A phantom study.

PubMed

Miura, Hideharu; Ozawa, Shuichi; Nagata, Yasushi

2017-09-01

This study investigated position dependence in planning target volume (PTV)-based and robust optimization plans using full-arc and partial-arc volumetric modulated arc therapy (VMAT). The gantry angles at the periphery, intermediate, and center CTV positions were 181°-180° (full-arc VMAT) and 181°-360° (partial-arc VMAT). A PTV-based optimization plan was defined by 5 mm margin expansion of the CTV to a PTV volume, on which the dose constraints were applied. The robust optimization plan consisted of a directly optimized dose to the CTV under a maximum-uncertainties setup of 5 mm. The prescription dose was normalized to the CTV D 99% (the minimum relative dose that covers 99% of the volume of the CTV) as an original plan. The isocenter was rigidly shifted at 1 mm intervals in the anterior-posterior (A-P), superior-inferior (S-I), and right-left (R-L) directions from the original position to the maximum-uncertainties setup of 5 mm in the original plan, yielding recalculated dose distributions. It was found that for the intermediate and center positions, the uncertainties in the D 99% doses to the CTV for all directions did not significantly differ when comparing the PTV-based and robust optimization plans (P > 0.05). For the periphery position, uncertainties in the D 99% doses to the CTV in the R-L direction for the robust optimization plan were found to be lower than those in the PTV-based optimization plan (P < 0.05). Our study demonstrated that a robust optimization plan's efficacy using partial-arc VMAT depends on the periphery CTV position. © 2017 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

TU-EF-304-07: Monte Carlo-Based Inverse Treatment Plan Optimization for Intensity Modulated Proton Therapy

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

Li, Y; UT Southwestern Medical Center, Dallas, TX; Tian, Z

2015-06-15

Purpose: Intensity-modulated proton therapy (IMPT) is increasingly used in proton therapy. For IMPT optimization, Monte Carlo (MC) is desired for spots dose calculations because of its high accuracy, especially in cases with a high level of heterogeneity. It is also preferred in biological optimization problems due to the capability of computing quantities related to biological effects. However, MC simulation is typically too slow to be used for this purpose. Although GPU-based MC engines have become available, the achieved efficiency is still not ideal. The purpose of this work is to develop a new optimization scheme to include GPU-based MC intomore » IMPT. Methods: A conventional approach using MC in IMPT simply calls the MC dose engine repeatedly for each spot dose calculations. However, this is not the optimal approach, because of the unnecessary computations on some spots that turned out to have very small weights after solving the optimization problem. GPU-memory writing conflict occurring at a small beam size also reduces computational efficiency. To solve these problems, we developed a new framework that iteratively performs MC dose calculations and plan optimizations. At each dose calculation step, the particles were sampled from different spots altogether with Metropolis algorithm, such that the particle number is proportional to the latest optimized spot intensity. Simultaneously transporting particles from multiple spots also mitigated the memory writing conflict problem. Results: We have validated the proposed MC-based optimization schemes in one prostate case. The total computation time of our method was ∼5–6 min on one NVIDIA GPU card, including both spot dose calculation and plan optimization, whereas a conventional method naively using the same GPU-based MC engine were ∼3 times slower. Conclusion: A fast GPU-based MC dose calculation method along with a novel optimization workflow is developed. The high efficiency makes it attractive for clinical usages.« less

SU-F-T-428: An Optimization-Based Commissioning Tool for Finite Size Pencil Beam Dose Calculations

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

Li, Y; Tian, Z; Song, T

Purpose: Finite size pencil beam (FSPB) algorithms are commonly used to pre-calculate the beamlet dose distribution for IMRT treatment planning. FSPB commissioning, which usually requires fine tuning of the FSPB kernel parameters, is crucial to the dose calculation accuracy and hence the plan quality. Yet due to the large number of beamlets, FSPB commissioning could be very tedious. This abstract reports an optimization-based FSPB commissioning tool we have developed in MatLab to facilitate the commissioning. Methods: A FSPB dose kernel generally contains two types of parameters: the profile parameters determining the dose kernel shape, and a 2D scaling factors accountingmore » for the longitudinal and off-axis corrections. The former were fitted using the penumbra of a reference broad beam’s dose profile with Levenberg-Marquardt algorithm. Since the dose distribution of a broad beam is simply a linear superposition of the dose kernel of each beamlet calculated with the fitted profile parameters and scaled using the scaling factors, these factors could be determined by solving an optimization problem which minimizes the discrepancies between the calculated dose of broad beams and the reference dose. Results: We have commissioned a FSPB algorithm for three linac photon beams (6MV, 15MV and 6MVFFF). Dose of four field sizes (6*6cm2, 10*10cm2, 15*15cm2 and 20*20cm2) were calculated and compared with the reference dose exported from Eclipse TPS system. For depth dose curves, the differences are less than 1% of maximum dose after maximum dose depth for most cases. For lateral dose profiles, the differences are less than 2% of central dose at inner-beam regions. The differences of the output factors are within 1% for all the three beams. Conclusion: We have developed an optimization-based commissioning tool for FSPB algorithms to facilitate the commissioning, providing sufficient accuracy of beamlet dose calculation for IMRT optimization.« less

Clinical Response of Pelvic and Para-aortic Lymphadenopathy to a Radiation Boost in the Definitive Management of Locally Advanced Cervical Cancer

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

Rash, Dominique L.; Lee, Yongsook C.; Kashefi, Amir

Purpose: Optimal treatment with radiation for metastatic lymphadenopathy in locally advanced cervical cancer remains controversial. We investigated the clinical dose response threshold for pelvic and para-aortic lymph node boost using radiographic imaging and clinical outcomes. Methods and Materials: Between 2007 and 2011, 68 patients were treated for locally advanced cervical cancer; 40 patients had clinically involved pelvic and/or para-aortic lymph nodes. Computed tomography (CT) or 18F-labeled fluorodeoxyglucose-positron emission tomography scans obtained pre- and postchemoradiation for 18 patients were reviewed to assess therapeutic radiographic response of individual lymph nodes. External beam boost doses to involved nodes were compared to treatment response,more » assessed by change in size of lymph nodes by short axis and change in standard uptake value (SUV). Patterns of failure, time to recurrence, overall survival (OS), and disease-free survival (DFS) were determined. Results: Sixty-four lymph nodes suspicious for metastatic involvement were identified. Radiation boost doses ranged from 0 to 15 Gy, with a mean total dose of 52.3 Gy. Pelvic lymph nodes were treated with a slightly higher dose than para-aortic lymph nodes: mean 55.3 Gy versus 51.7 Gy, respectively. There was no correlation between dose delivered and change in size of lymph nodes along the short axis. All lymph nodes underwent a decrease in SUV with a complete resolution of abnormal uptake observed in 68%. Decrease in SUV was significantly greater for lymph nodes treated with ≥54 Gy compared to those treated with <54 Gy (P=.006). Median follow-up was 18.7 months. At 2 years, OS and DFS for the entire cohort were 78% and 50%, respectively. Locoregional control at 2 years was 84%. Conclusions: A biologic response, as measured by the change in SUV for metastatic lymph nodes, was observed at a dose threshold of 54 Gy. We recommend that involved lymph nodes be treated to this minimum dose.« less

Bluetongue Disabled Infectious Single Animal (DISA) vaccine: Studies on the optimal route and dose in sheep.

PubMed

van Rijn, Piet A; Daus, Franz J; Maris-Veldhuis, Mieke A; Feenstra, Femke; van Gennip, René G P

2017-01-05

Bluetongue (BT) is a disease of ruminants caused by bluetongue virus (BTV) transmitted by biting midges of the Culicoides genus. Outbreaks have been controlled successfully by vaccination, however, currently available BT vaccines have several shortcomings. Recently, we have developed BT Disabled Infectious Single Animal (DISA) vaccines based on live-attenuated BTV without expression of dispensable non-structural NS3/NS3a protein. DISA vaccines are non-pathogenic replicating vaccines, do not cause viremia, enable DIVA and are highly protective. NS3/NS3a protein is involved in virus release, cytopathogenic effect and suppression of Interferon-I induction, suggesting that the vaccination route can be of importance. A standardized dose of DISA vaccine for serotype 8 has successfully been tested by subcutaneous vaccination. We show that 10 and 100times dilutions of this previously tested dose did not reduce the VP7 humoral response. Further, the vaccination route of DISA vaccine strongly determined the induction of VP7 directed antibodies (Abs). Intravenous vaccination induced high and prolonged humoral response but is not practical in field situations. VP7 seroconversion was stronger by intramuscular vaccination than by subcutaneous vaccination. For both vaccination routes and for two different DISA vaccine backbones, IgM Abs were rapidly induced but declined after 14days post vaccination (dpv), whereas the IgG response was slower. Interestingly, intramuscular vaccination resulted in an initial peak followed by a decline up to 21dpv and then increased again. This second increase is a steady and continuous increase of IgG Abs. These results indicate that intramuscular vaccination is the optimal route. The protective dose of DISA vaccine has not been determined yet, but it is expected to be significantly lower than of currently used BT vaccines. Therefore, in addition to the advantages of improved safety and DIVA compatibility, the novel DISA vaccines will be cost-competitive to commercially available live attenuated and inactivated vaccines for Bluetongue. Copyright © 2016 Elsevier Ltd. All rights reserved.

Enhanced protection against Ebola virus mediated by an improved adenovirus-based vaccine.

PubMed

Richardson, Jason S; Yao, Michel K; Tran, Kaylie N; Croyle, Maria A; Strong, James E; Feldmann, Heinz; Kobinger, Gary P

2009-01-01

The Ebola virus is transmitted by direct contact with bodily fluids of infected individuals, eliciting death rates as high as 90% among infected humans. Currently, replication defective adenovirus-based Ebola vaccine is being studied in a phase I clinical trial. Another Ebola vaccine, based on an attenuated vesicular stomatitis virus has shown efficacy in post-exposure treatment of nonhuman primates to Ebola infection. In this report, we modified the common recombinant adenovirus serotype 5-based Ebola vaccine expressing the wild-type ZEBOV glycoprotein sequence from a CMV promoter (Ad-CMVZGP). The immune response elicited by this improved expression cassette vector (Ad-CAGoptZGP) and its ability to afford protection against lethal ZEBOV challenge in mice was compared to the standard Ad-CMVZGP vector. Ad-CMVZGP was previously shown to protect mice, guinea pigs and nonhuman primates from an otherwise lethal challenge of Zaire ebolavirus. The antigenic expression cassette of this vector was improved through codon optimization, inclusion of a consensus Kozak sequence and reconfiguration of a CAG promoter (Ad-CAGoptZGP). Expression of GP from Ad-CAGoptZGP was substantially higher than from Ad-CMVZGP. Ad-CAGoptZGP significantly improved T and B cell responses at doses 10 to 100-fold lower than that needed with Ad-CMVZGP. Additionally, Ad-CAGoptZGP afforded full protections in mice against lethal challenge at a dose 100 times lower than the dose required for Ad-CMVZGP. Finally, Ad-CAGoptZGP induced full protection to mice when given 30 minutes post-challenge. We describe an improved adenovirus-based Ebola vaccine capable of affording post-exposure protection against lethal challenge in mice. The molecular modifications of the new improved vaccine also translated in the induction of significantly enhanced immune responses and complete protection at a dose 100 times lower than with the previous generation adenovirus-based Ebola vaccine. Understanding and improving the molecular components of adenovirus-based vaccines can produce potent, optimized product, useful for vaccination and post-exposure therapy.

Optimization of the beam shaping assembly in the D-D neutron generators-based BNCT using the response matrix method.

PubMed

Kasesaz, Y; Khalafi, H; Rahmani, F

2013-12-01

Optimization of the Beam Shaping Assembly (BSA) has been performed using the MCNP4C Monte Carlo code to shape the 2.45 MeV neutrons that are produced in the D-D neutron generator. Optimal design of the BSA has been chosen by considering in-air figures of merit (FOM) which consists of 70 cm Fluental as a moderator, 30 cm Pb as a reflector, 2mm (6)Li as a thermal neutron filter and 2mm Pb as a gamma filter. The neutron beam can be evaluated by in-phantom parameters, from which therapeutic gain can be derived. Direct evaluation of both set of FOMs (in-air and in-phantom) is very time consuming. In this paper a Response Matrix (RM) method has been suggested to reduce the computing time. This method is based on considering the neutron spectrum at the beam exit and calculating contribution of various dose components in phantom to calculate the Response Matrix. Results show good agreement between direct calculation and the RM method. Copyright © 2013 Elsevier Ltd. All rights reserved.

Outcomes of Optimized over Standard Protocol of Rabbit Antithymocyte Globulin for Severe Aplastic Anemia: A Single-Center Experience

PubMed Central

Ge, Meili; Shao, Yingqi; Huang, Jinbo; Huang, Zhendong; Zhang, Jing; Nie, Neng; Zheng, Yizhou

2013-01-01

Background Previous reports showed that outcome of rabbit antithymocyte globulin (rATG) was not satisfactory as the first-line therapy for severe aplastic anemia (SAA). We explored a modifying schedule of administration of rATG. Design and Methods Outcomes of a cohort of 175 SAA patients, including 51 patients administered with standard protocol (3.55 mg/kg/d for 5 days) and 124 cases with optimized protocol (1.97 mg/kg/d for 9 days) of rATG plus cyclosporine (CSA), were analyzed retrospectively. Results Of all 175 patients, response rates at 3 and 6 months were 36.6% and 56.0%, respectively. 51 cases received standard protocol had poor responses at 3 (25.5%) and 6 months (41.2%). However, 124 patients received optimized protocol had better responses at 3 (41.1%, P = 0.14) and 6 (62.1%, P = 0.01). Higher incidences of infection (57.1% versus 37.9%, P = 0.02) and early mortality (17.9% versus 0.8%, P<0.001) occurred in patients received standard protocol compared with optimized protocol. The 5-year overall survival in favor of the optimized over standard rATG protocol (76.0% versus. 50.3%, P<0.001) was observed. By multivariate analysis, optimized protocol (RR = 2.21, P = 0.04), response at 3 months (RR = 10.31, P = 0.03) and shorter interval (<23 days) between diagnosis and initial dose of rATG (RR = 5.35, P = 0.002) were independent favorable predictors of overall survival. Conclusions Optimized instead of standard rATG protocol in combination with CSA remained efficacious as a first-line immunosuppressive regimen for SAA. PMID:23554855

Quality assurance for high dose rate brachytherapy treatment planning optimization: using a simple optimization to verify a complex optimization

NASA Astrophysics Data System (ADS)

Deufel, Christopher L.; Furutani, Keith M.

2014-02-01

As dose optimization for high dose rate brachytherapy becomes more complex, it becomes increasingly important to have a means of verifying that optimization results are reasonable. A method is presented for using a simple optimization as quality assurance for the more complex optimization algorithms typically found in commercial brachytherapy treatment planning systems. Quality assurance tests may be performed during commissioning, at regular intervals, and/or on a patient specific basis. A simple optimization method is provided that optimizes conformal target coverage using an exact, variance-based, algebraic approach. Metrics such as dose volume histogram, conformality index, and total reference air kerma agree closely between simple and complex optimizations for breast, cervix, prostate, and planar applicators. The simple optimization is shown to be a sensitive measure for identifying failures in a commercial treatment planning system that are possibly due to operator error or weaknesses in planning system optimization algorithms. Results from the simple optimization are surprisingly similar to the results from a more complex, commercial optimization for several clinical applications. This suggests that there are only modest gains to be made from making brachytherapy optimization more complex. The improvements expected from sophisticated linear optimizations, such as PARETO methods, will largely be in making systems more user friendly and efficient, rather than in finding dramatically better source strength distributions.

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.

Digital radiography: optimization of image quality and dose using multi-frequency software.

PubMed

Precht, H; Gerke, O; Rosendahl, K; Tingberg, A; Waaler, D

2012-09-01

New developments in processing of digital radiographs (DR), including multi-frequency processing (MFP), allow optimization of image quality and radiation dose. This is particularly promising in children as they are believed to be more sensitive to ionizing radiation than adults. To examine whether the use of MFP software reduces the radiation dose without compromising quality at DR of the femur in 5-year-old-equivalent anthropomorphic and technical phantoms. A total of 110 images of an anthropomorphic phantom were imaged on a DR system (Canon DR with CXDI-50 C detector and MLT[S] software) and analyzed by three pediatric radiologists using Visual Grading Analysis. In addition, 3,500 images taken of a technical contrast-detail phantom (CDRAD 2.0) provide an objective image-quality assessment. Optimal image-quality was maintained at a dose reduction of 61% with MLT(S) optimized images. Even for images of diagnostic quality, MLT(S) provided a dose reduction of 88% as compared to the reference image. Software impact on image quality was found significant for dose (mAs), dynamic range dark region and frequency band. By optimizing image processing parameters, a significant dose reduction is possible without significant loss of image quality.

A comprehensive formulation for volumetric modulated arc therapy planning

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

Nguyen, Dan; Lyu, Qihui; Ruan, Dan

2016-07-15

Purpose: Volumetric modulated arc therapy (VMAT) is a widely employed radiation therapy technique, showing comparable dosimetry to static beam intensity modulated radiation therapy (IMRT) with reduced monitor units and treatment time. However, the current VMAT optimization has various greedy heuristics employed for an empirical solution, which jeopardizes plan consistency and quality. The authors introduce a novel direct aperture optimization method for VMAT to overcome these limitations. Methods: The comprehensive VMAT (comVMAT) planning was formulated as an optimization problem with an L2-norm fidelity term to penalize the difference between the optimized dose and the prescribed dose, as well as an anisotropicmore » total variation term to promote piecewise continuity in the fluence maps, preparing it for direct aperture optimization. A level set function was used to describe the aperture shapes and the difference between aperture shapes at adjacent angles was penalized to control MLC motion range. A proximal-class optimization solver was adopted to solve the large scale optimization problem, and an alternating optimization strategy was implemented to solve the fluence intensity and aperture shapes simultaneously. Single arc comVMAT plans, utilizing 180 beams with 2° angular resolution, were generated for a glioblastoma multiforme case, a lung (LNG) case, and two head and neck cases—one with three PTVs (H&N{sub 3PTV}) and one with foue PTVs (H&N{sub 4PTV})—to test the efficacy. The plans were optimized using an alternating optimization strategy. The plans were compared against the clinical VMAT (clnVMAT) plans utilizing two overlapping coplanar arcs for treatment. Results: The optimization of the comVMAT plans had converged within 600 iterations of the block minimization algorithm. comVMAT plans were able to consistently reduce the dose to all organs-at-risk (OARs) as compared to the clnVMAT plans. On average, comVMAT plans reduced the max and mean OAR dose by 6.59% and 7.45%, respectively, of the prescription dose. Reductions in max dose and mean dose were as high as 14.5 Gy in the LNG case and 15.3 Gy in the H&N{sub 3PTV} case. PTV coverages measured by D95, D98, and D99 were within 0.25% of the prescription dose. By comprehensively optimizing all beams, the comVMAT optimizer gained the freedom to allow some selected beams to deliver higher intensities, yielding a dose distribution that resembles a static beam IMRT plan with beam orientation optimization. Conclusions: The novel nongreedy VMAT approach simultaneously optimizes all beams in an arc and then directly generates deliverable apertures. The single arc VMAT approach thus fully utilizes the digital Linac’s capability in dose rate and gantry rotation speed modulation. In practice, the new single VMAT algorithm generates plans superior to existing VMAT algorithms utilizing two arcs.« less

A phase I dose-finding study of 5-azacytidine in combination with sodium phenylbutyrate in patients with refractory solid tumors.

PubMed

Lin, Jianqing; Gilbert, Jill; Rudek, Michelle A; Zwiebel, James A; Gore, Steve; Jiemjit, Anchalee; Zhao, Ming; Baker, Sharyn D; Ambinder, Richard F; Herman, James G; Donehower, Ross C; Carducci, Michael A

2009-10-01

This was a phase I trial to determine the minimal effective dose and optimal dose schedule for 5-azacytidine (5-AC) in combination with sodium phenylbutyrate in patients with refractory solid tumors. The pharmacokinetics, pharmacodynamics, and antineoplastic effects were also studied. Three dosing regimens were studied in 27 patients with advanced solid tumors, and toxicity was recorded. The pharmacokinetics of the combination of drugs was evaluated. Repeat tumor biopsies and peripheral blood mononuclear cells (PBMC) were analyzed to evaluate epigenetic changes in response to therapy. EBV titers were evaluated as a surrogate measure for gene re-expression of epigenetic modulation in PBMC. The three dose regimens of 5-AC and phenylbutyrate were generally well tolerated and safe. A total of 48 cycles was administrated to 27 patients. The most common toxicities were bone marrow suppression-related neutropenia and anemia, which were minor. The clinical response rate was disappointing for the combination of agents. One patient showed stable disease for 5 months whereas 26 patients showed progressive disease as the best tumor response. The administration of phenylbutyrate and 5-AC did not seem to alter the pharmacokinetics of either drug. Although there were individual cases of targeted DNA methyltransferase activity and histone H3/4 acetylation changes from paired biopsy or PBMC, no conclusive statement can be made based on these limited correlative studies. The combination of 5-AC and phenylbutyrate across three dose schedules was generally well tolerated and safe, yet lacked any real evidence for clinical benefit.

Use of a channelized Hotelling observer to assess CT image quality and optimize dose reduction for iteratively reconstructed images.

PubMed

Favazza, Christopher P; Ferrero, Andrea; Yu, Lifeng; Leng, Shuai; McMillan, Kyle L; McCollough, Cynthia H

2017-07-01

The use of iterative reconstruction (IR) algorithms in CT generally decreases image noise and enables dose reduction. However, the amount of dose reduction possible using IR without sacrificing diagnostic performance is difficult to assess with conventional image quality metrics. Through this investigation, achievable dose reduction using a commercially available IR algorithm without loss of low contrast spatial resolution was determined with a channelized Hotelling observer (CHO) model and used to optimize a clinical abdomen/pelvis exam protocol. A phantom containing 21 low contrast disks-three different contrast levels and seven different diameters-was imaged at different dose levels. Images were created with filtered backprojection (FBP) and IR. The CHO was tasked with detecting the low contrast disks. CHO performance indicated dose could be reduced by 22% to 25% without compromising low contrast detectability (as compared to full-dose FBP images) whereas 50% or more dose reduction significantly reduced detection performance. Importantly, default settings for the scanner and protocol investigated reduced dose by upward of 75%. Subsequently, CHO-based protocol changes to the default protocol yielded images of higher quality and doses more consistent with values from a larger, dose-optimized scanner fleet. CHO assessment provided objective data to successfully optimize a clinical CT acquisition protocol.

Clinical applications of advanced rotational radiation therapy

NASA Astrophysics Data System (ADS)

Nalichowski, Adrian

Purpose: With a fast adoption of emerging technologies, it is critical to fully test and understand its limits and capabilities. In this work we investigate new graphic processing unit (GPU) based treatment planning algorithm and its applications in helical tomotherapy dose delivery. We explore the limits of the system by applying it to challenging clinical cases of total marrow irradiation (TMI) and stereotactic radiosurgery (SRS). We also analyze the feasibility of alternative fractionation schemes for total body irradiation (TBI) and TMI based on reported historical data on lung dose and interstitial pneumonitis (IP) incidence rates. Methods and Materials: An anthropomorphic phantom was used to create TMI plans using the new GPU based treatment planning system and the existing CPU cluster based system. Optimization parameters were selected based on clinically used values for field width, modulation factor and pitch. Treatment plans were also created on Eclipse treatment planning system (Varian Medical Systems Inc, Palo Alto, CA) using volumetric modulated arc therapy (VMAT) for dose delivery on IX treatment unit. A retrospective review was performed of 42 publications that reported IP rates along with lung dose, fractionation regimen, dose rate and chemotherapy. The analysis consisted of nearly thirty two hundred patients and 34 unique radiation regimens. Multivariate logistic regression was performed to determine parameters associated with IP and establish does response function. Results: The results showed very good dosimetric agreement between the GPU and CPU calculated plans. The results from SBRT study show that GPU planning system can maintain 90% target coverage while meeting all the constraints of RTOG 0631 protocol. Beam on time for Tomotherapy and flattening filter free RapidArc was much faster than for Vero or Cyberknife. Retrospective data analysis showed that lung dose and Cyclophosphomide (Cy) are both predictors of IP in TBI/TMI treatments. The dose rate was not found to be an independent risk factor for IP. The model failed to establish accurate dose response function, but the discrete data indicated a radiation dose threshold of 7.6Gy (EQD2_repair) and 120 mg/kg of Cy below which no IP cases were reported. Conclusion: The TomoTherapy GPU based dose engine is capable of calculating TMI treatment plans with plan quality nearly identical to plans calculated using the traditional CPU/cluster based system, while significantly reducing the time required for optimization and dose calculation. The new system was able to achieve more uniform dose distribution throughout the target volume and steeper dose fall off, resulting in superior OAR sparing when compared to Eclipse treatment planning system for VMAT delivery. The machine optimization parameters tested for TMI cases provide a comprehensive overview of the capabilities of the treatment planning station and associated helical delivery system. The new system also proved to be dosimetrically compatible with other leading modalities for treatments of small and complicated target volumes and was even superior when treatment delivery times were compared. These finding demonstrate that the advanced treatment planning and delivery system from TomoTherapy is well suitable for treatments of complicated cases such as TMI and SRS and it's often dosimetrically and/or logistically superior to other modalities. The new planning system can easily meet the constraint of threshold lung dose established in this study. The results presented here on the capabilities of Tomotherapy and on the identified lung dose threshold provide an opportunity to explore alternative fractionation schemes without sacrificing target coverage or lung toxicity. (Abstract shortened by ProQuest.).

Optimal dose selection of N-methyl-N-nitrosourea for the rat comet assay to evaluate DNA damage in organs with different susceptibility to cytotoxicity.

PubMed

Kitamoto, Sachiko; Matsuyama, Ryoko; Uematsu, Yasuaki; Ogata, Keiko; Ota, Mika; Yamada, Toru; Miyata, Kaori; Funabashi, Hitoshi; Saito, Koichi

2015-07-01

The in vivo rodent alkaline comet assay (comet assay) is a promising technique to evaluate DNA damage in vivo. However, there is no agreement on a method to evaluate DNA damage in organs where cytotoxicity is observed. As a part of the Japanese Center for the Validation of Alternative Methods (JaCVAM)-initiative international validation study of the comet assay, we examined DNA damage in the liver, stomach, and bone marrow of rats given three oral doses of N-methyl-N-nitrosourea (MNU) up to the maximum tolerated dose based on systemic toxicity. MNU significantly increased the % tail DNA in all the organs. Histopathological analysis showed no cytotoxic effect on the liver, indicating clearly that MNU has a genotoxic potential in the liver. In the stomach, however, the cytotoxic effects were very severe at systemically non-toxic doses. Low-dose MNU significantly increased the % tail DNA even at a non-cytotoxic dose, indicating that MNU has a genotoxic potential also in the stomach. Part of the DNA damage at cytotoxic doses was considered to be a secondary effect of severe cell damage. In the bone marrow, both the % tail DNA and incidence of micronucleated polychromatic erythrocytes significantly increased at non-hematotoxic doses, which were different from the non-cytotoxic doses for liver and stomach. These findings indicate that an optimal dose for detecting DNA damage may vary among organs and that careful attention is required to select an optimum dose for the comet assay based on systemic toxicity such as mortality and clinical observations. The present study shows that when serious cytotoxicity is suggested by increased % hedgehogs in the comet assay, histopathological examination should be included for the evaluation of a positive response. Copyright © 2015 Elsevier B.V. All rights reserved.

Extracting the normal lung dose-response curve from clinical DVH data: a possible role for low dose hyper-radiosensitivity, increased radioresistance

NASA Astrophysics Data System (ADS)

Gordon, J. J.; Snyder, K.; Zhong, H.; Barton, K.; Sun, Z.; Chetty, I. J.; Matuszak, M.; Ten Haken, R. K.

2015-09-01

In conventionally fractionated radiation therapy for lung cancer, radiation pneumonitis’ (RP) dependence on the normal lung dose-volume histogram (DVH) is not well understood. Complication models alternatively make RP a function of a summary statistic, such as mean lung dose (MLD). This work searches over damage profiles, which quantify sub-volume damage as a function of dose. Profiles that achieve best RP predictive accuracy on a clinical dataset are hypothesized to approximate DVH dependence. Step function damage rate profiles R(D) are generated, having discrete steps at several dose points. A range of profiles is sampled by varying the step heights and dose point locations. Normal lung damage is the integral of R(D) with the cumulative DVH. Each profile is used in conjunction with a damage cutoff to predict grade 2 plus (G2+) RP for DVHs from a University of Michigan clinical trial dataset consisting of 89 CFRT patients, of which 17 were diagnosed with G2+ RP. Optimal profiles achieve a modest increase in predictive accuracy—erroneous RP predictions are reduced from 11 (using MLD) to 8. A novel result is that optimal profiles have a similar distinctive shape: enhanced damage contribution from low doses (<20 Gy), a flat contribution from doses in the range ~20-40 Gy, then a further enhanced contribution from doses above 40 Gy. These features resemble the hyper-radiosensitivity / increased radioresistance (HRS/IRR) observed in some cell survival curves, which can be modeled using Joiner’s induced repair model. A novel search strategy is employed, which has the potential to estimate RP dependence on the normal lung DVH. When applied to a clinical dataset, identified profiles share a characteristic shape, which resembles HRS/IRR. This suggests that normal lung may have enhanced sensitivity to low doses, and that this sensitivity can affect RP risk.

Fluence map optimization (FMO) with dose-volume constraints in IMRT using the geometric distance sorting method.

PubMed

Lan, Yihua; Li, Cunhua; Ren, Haozheng; Zhang, Yong; Min, Zhifang

2012-10-21

A new heuristic algorithm based on the so-called geometric distance sorting technique is proposed for solving the fluence map optimization with dose-volume constraints which is one of the most essential tasks for inverse planning in IMRT. The framework of the proposed method is basically an iterative process which begins with a simple linear constrained quadratic optimization model without considering any dose-volume constraints, and then the dose constraints for the voxels violating the dose-volume constraints are gradually added into the quadratic optimization model step by step until all the dose-volume constraints are satisfied. In each iteration step, an interior point method is adopted to solve each new linear constrained quadratic programming. For choosing the proper candidate voxels for the current dose constraint adding, a so-called geometric distance defined in the transformed standard quadratic form of the fluence map optimization model was used to guide the selection of the voxels. The new geometric distance sorting technique can mostly reduce the unexpected increase of the objective function value caused inevitably by the constraint adding. It can be regarded as an upgrading to the traditional dose sorting technique. The geometry explanation for the proposed method is also given and a proposition is proved to support our heuristic idea. In addition, a smart constraint adding/deleting strategy is designed to ensure a stable iteration convergence. The new algorithm is tested on four cases including head-neck, a prostate, a lung and an oropharyngeal, and compared with the algorithm based on the traditional dose sorting technique. Experimental results showed that the proposed method is more suitable for guiding the selection of new constraints than the traditional dose sorting method, especially for the cases whose target regions are in non-convex shapes. It is a more efficient optimization technique to some extent for choosing constraints than the dose sorting method. By integrating a smart constraint adding/deleting scheme within the iteration framework, the new technique builds up an improved algorithm for solving the fluence map optimization with dose-volume constraints.

SU-E-T-618: Dosimetric Comparison of Manual and Beam Angle Optimization of Gantry Angles in IMRT for Cervical Cancer

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

Lin, X; Sun, T; Liu, T

2014-06-01

Purpose: To evaluate the dosimetric characteristics of intensity-modulated radiotherapy (IMRT) treatment plan with beam angle optimization. Methods: Ten post-operation patients with cervical cancer were included in this analysis. Two IMRT plans using seven beams were designed in each patient. A standard coplanar equi-space beam angles were used in the first plan (plan 1), whereas the selection of beam angle was optimized by beam angle optimization algorithm in Varian Eclipse treatment planning system for the same number of beams in the second plan (plan 2). Two plans were designed for each patient with the same dose-volume constraints and prescription dose. Allmore » plans were normalized to the mean dose to PTV. The dose distribution in the target, the dose to the organs at risk and total MU were compared. Results: For conformity and homogeneity in PTV, no statistically differences were observed in the two plans. For the mean dose in bladder, plan 2 were significantly lower than plan 1(p<0.05). No statistically significant differences were observed between two plans for the mean doses in rectum, left and right femur heads. Compared with plan1, the average monitor units reduced 16% in plan 2. Conclusion: The IMRT plan based on beam angle optimization for cervical cancer could reduce the dose delivered to bladder and also reduce MU. Therefore there were some dosimetric advantages in the IMRT plan with beam angle optimization for cervical cancer.« less

Accuracy of rapid radiographic film calibration for intensity‐modulated radiation therapy verification

PubMed Central

Kulasekere, Ravi; Moran, Jean M.; Fraass, Benedick A.; Roberson, Peter L.

2006-01-01

A single calibration film method was evaluated for use with intensity‐modulated radiation therapy film quality assurance measurements. The single‐film method has the potential advantages of exposure simplicity, less media consumption, and improved processor quality control. Potential disadvantages include cross contamination of film exposure, implementation effort to document delivered dose, and added complication of film response analysis. Film response differences were measured between standard and single‐film calibration methods. Additional measurements were performed to help trace causes for the observed discrepancies. Kodak X‐OmatV (XV) film was found to have greater response variability than extended dose range (EDR) film. We found it advisable for XV film to relate the film response calibration for the single‐film method to a user‐defined optimal calibration geometry. Using a single calibration film exposed at the time of experiment, the total uncertainty of film response was estimated to be <2% (1%) for XV (EDR) film at 50 (100) cGy and higher, respectively. PACS numbers: 87.53.‐j, 87.53.Dq PMID:17533325

The effect of microdosimetric 12C6+ heavy ion irradiation and Mg2+ on canthaxanthin production in a novel strain of Dietzia natronolimnaea.

PubMed

Zhou, Xiang; Xie, Jia-Rong; Tao, Lei; Xin, Zhi-Jun; Zhao, Feng-Wu; Lu, Xi-Hong; Zhao, Mei-Rong; Wang, Liang; Liang, Jian-Ping

2013-09-28

Dietzia natronolimnaea is one of the most important bacterial bioresources for high efficiency canthaxanthin production. It produces the robust and stable pigment canthaxanthin, which is of special interest for the development of integrated biorefineries. Mutagenesis employing 12C6+ irradiation is a novel technique commonly used to improve microorganism productivity. This study presents a promising route to obtaining the highest feasible levels of biomass dry weight (BDW), and total canthaxanthin by using a microdosimetric model of 12C6+ irradiation mutation in combination with the optimization of nutrient medium components. This work characterized the rate of both lethal and non-lethal dose mutations for 12C6+ irradiation and the microdosimetric kinetic model using the model organism, D. natronolimnaea svgcc1.2736. Irradiation with 12C6+ ions resulted in enhanced production of canthaxanthin, and is therefore an effective method for strain improvement of D. natronolimnaea svgcc1.2736. Based on these results an optimal dose of 0.5-4.5 Gy, Linear energy transfer (LET) of 80 keV μm-1and energy of 60 MeV u-1 for 12C6+ irradiation are ideal for optimum and specific production of canthaxanthin in the bacterium. Second-order empirical calculations displaying high R-squared (0.996) values between the responses and independent variables were derived from validation experiments using response surface methodology. The highest canthaxanthin yield (8.14 mg) was obtained with an optimized growth medium containing 21.5 g L-1 D-glucose, 23.5 g L-1 mannose and 25 ppm Mg2+ in 1 L with an irradiation dose of 4.5 Gy. The microdosimetric 12C6+ irradiation model was an effective mutagenic technique for the strain improvement of D. natronolimnaea svgcc1.2736 specifically for enhanced canthaxanthin production. At the very least, random mutagenesis methods using 12C6+ions can be used as a first step in a combined approach with long-term continuous fermentation processes. Central composite design-response surface methodologies (CCD-RSM) were carried out to optimize the conditions for canthaxanthin yield. It was discovered D-glucose, Mg2+ and mannose have significant influence on canthaxanthin biosynthesis and growth of the mutant strain.

Feasibility of online IMPT adaptation using fast, automatic and robust dose restoration

NASA Astrophysics Data System (ADS)

Bernatowicz, Kinga; Geets, Xavier; Barragan, Ana; Janssens, Guillaume; Souris, Kevin; Sterpin, Edmond

2018-04-01

Intensity-modulated proton therapy (IMPT) offers excellent dose conformity and healthy tissue sparing, but it can be substantially compromised in the presence of anatomical changes. A major dosimetric effect is caused by density changes, which alter the planned proton range in the patient. Three different methods, which automatically restore an IMPT plan dose on a daily CT image were implemented and compared: (1) simple dose restoration (DR) using optimization objectives of the initial plan, (2) voxel-wise dose restoration (vDR), and (3) isodose volume dose restoration (iDR). Dose restorations were calculated for three different clinical cases, selected to test different capabilities of the restoration methods: large range adaptation, complex dose distributions and robust re-optimization. All dose restorations were obtained in less than 5 min, without manual adjustments of the optimization settings. The evaluation of initial plans on repeated CTs showed large dose distortions, which were substantially reduced after restoration. In general, all dose restoration methods improved DVH-based scores in propagated target volumes and OARs. Analysis of local dose differences showed that, although all dose restorations performed similarly in high dose regions, iDR restored the initial dose with higher precision and accuracy in the whole patient anatomy. Median dose errors decreased from 13.55 Gy in distorted plan to 9.75 Gy (vDR), 6.2 Gy (DR) and 4.3 Gy (iDR). High quality dose restoration is essential to minimize or eventually by-pass the physician approval of the restored plan, as long as dose stability can be assumed. Motion (as well as setup and range uncertainties) can be taken into account by including robust optimization in the dose restoration. Restoring clinically-approved dose distribution on repeated CTs does not require new ROI segmentation and is compatible with an online adaptive workflow.

Multiple anatomy optimization of accumulated dose

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

Watkins, W. Tyler, E-mail: watkinswt@virginia.edu; Siebers, Jeffrey V.; Moore, Joseph A.

Purpose: To investigate the potential advantages of multiple anatomy optimization (MAO) for lung cancer radiation therapy compared to the internal target volume (ITV) approach. Methods: MAO aims to optimize a single fluence to be delivered under free-breathing conditions such that the accumulated dose meets the plan objectives, where accumulated dose is defined as the sum of deformably mapped doses computed on each phase of a single four dimensional computed tomography (4DCT) dataset. Phantom and patient simulation studies were carried out to investigate potential advantages of MAO compared to ITV planning. Through simulated delivery of the ITV- and MAO-plans, target dosemore » variations were also investigated. Results: By optimizing the accumulated dose, MAO shows the potential to ensure dose to the moving target meets plan objectives while simultaneously reducing dose to organs at risk (OARs) compared with ITV planning. While consistently superior to the ITV approach, MAO resulted in equivalent OAR dosimetry at planning objective dose levels to within 2% volume in 14/30 plans and to within 3% volume in 19/30 plans for each lung V20, esophagus V25, and heart V30. Despite large variations in per-fraction respiratory phase weights in simulated deliveries at high dose rates (e.g., treating 4/10 phases during single fraction beams) the cumulative clinical target volume (CTV) dose after 30 fractions and per-fraction dose were constant independent of planning technique. In one case considered, however, per-phase CTV dose varied from 74% to 117% of prescription implying the level of ITV-dose heterogeneity may not be appropriate with conventional, free-breathing delivery. Conclusions: MAO incorporates 4DCT information in an optimized dose distribution and can achieve a superior plan in terms of accumulated dose to the moving target and OAR sparing compared to ITV-plans. An appropriate level of dose heterogeneity in MAO plans must be further investigated.« less

The pharmacogenetics and pharmacodynamics of clopidogrel response: an analysis from the PRINC (Plavix Response in Coronary Intervention) trial.

PubMed

Gladding, Patrick; Webster, Mark; Zeng, Irene; Farrell, Helen; Stewart, Jim; Ruygrok, Peter; Ormiston, John; El-Jack, Seif; Armstrong, Guy; Kay, Patrick; Scott, Douglas; Gunes, Arzu; Dahl, Marja-Liisa

2008-12-01

This study assessed the effect of pharmacogenetics on the antiplatelet effect of clopidogrel. Variability in clopidogrel response might be influenced by polymorphisms in genes coding for drug metabolism enzymes (cytochrome P450 [CYP] family), transport proteins (P-glycoprotein) and/or target proteins for the drug (adenosine diphosphate-receptor P2Y12). Sixty patients undergoing elective percutaneous coronary intervention in the randomized PRINC (Plavix Response in Coronary Intervention) trial had platelet function measured using the VerifyNow P2Y12 analyzer after a 600-mg or split 1,200-mg loading dose and after a 75- or 150-mg daily maintenance dosage. Polymerase chain reaction-based genotyping evaluated polymorphisms in the CYP2C19, CYP2C9, CYP3A4, CYP3A5, ABCB1, P2Y12, and CES genes. CYP2C19*1*1 carriers had greater platelet inhibition 2 h after a 600-mg dose (median: 23%, range: 0% to 66%), compared with platelet inhibition in CYP2C19*2 or *4 carriers (10%, 0% to 56%, p = 0.029) and CYP2C19*17 carriers (9%, 0% to 98%, p = 0.026). CYP2C19*2 or *4 carriers had greater platelet inhibition with the higher loading dose than with the lower dose at 4 h (37%, 8% to 87% vs. 14%, 0% to 22%, p = 0.002) and responded better with the higher maintenance dose regimen (51%, 15% to 86% vs. 14%, 0% to 67%, p = 0.042). Carriers of the CYP2C19*2 and *4 alleles showed reduced platelet inhibition after a clopidogrel 600-mg loading dose but responded to higher loading and maintenance dose regimens. Genotyping for the relevant gene polymorphisms may help to individualize and optimize clopidogrel treatment. (Australia New Zealand Clinical Trials Registry; ACTRN12606000129583).

EUD-based biological optimization for carbon ion therapy

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

Brüningk, Sarah C., E-mail: sarah.brueningk@icr.ac.uk; Kamp, Florian; Wilkens, Jan J.

2015-11-15

Purpose: Treatment planning for carbon ion therapy requires an accurate modeling of the biological response of each tissue to estimate the clinical outcome of a treatment. The relative biological effectiveness (RBE) accounts for this biological response on a cellular level but does not refer to the actual impact on the organ as a whole. For photon therapy, the concept of equivalent uniform dose (EUD) represents a simple model to take the organ response into account, yet so far no formulation of EUD has been reported that is suitable to carbon ion therapy. The authors introduce the concept of an equivalentmore » uniform effect (EUE) that is directly applicable to both ion and photon therapies and exemplarily implemented it as a basis for biological treatment plan optimization for carbon ion therapy. Methods: In addition to a classical EUD concept, which calculates a generalized mean over the RBE-weighted dose distribution, the authors propose the EUE to simplify the optimization process of carbon ion therapy plans. The EUE is defined as the biologically equivalent uniform effect that yields the same probability of injury as the inhomogeneous effect distribution in an organ. Its mathematical formulation is based on the generalized mean effect using an effect-volume parameter to account for different organ architectures and is thus independent of a reference radiation. For both EUD concepts, quadratic and logistic objective functions are implemented into a research treatment planning system. A flexible implementation allows choosing for each structure between biological effect constraints per voxel and EUD constraints per structure. Exemplary treatment plans are calculated for a head-and-neck patient for multiple combinations of objective functions and optimization parameters. Results: Treatment plans optimized using an EUE-based objective function were comparable to those optimized with an RBE-weighted EUD-based approach. In agreement with previous results from photon therapy, the optimization by biological objective functions resulted in slightly superior treatment plans in terms of final EUD for the organs at risk (OARs) compared to voxel-based optimization approaches. This observation was made independent of the underlying objective function metric. An absolute gain in OAR sparing was observed for quadratic objective functions, whereas intersecting DVHs were found for logistic approaches. Even for considerable under- or overestimations of the used effect- or dose–volume parameters during the optimization, treatment plans were obtained that were of similar quality as the results of a voxel-based optimization. Conclusions: EUD-based optimization with either of the presented concepts can successfully be applied to treatment plan optimization. This makes EUE-based optimization for carbon ion therapy a useful tool to optimize more specifically in the sense of biological outcome while voxel-to-voxel variations of the biological effectiveness are still properly accounted for. This may be advantageous in terms of computational cost during treatment plan optimization but also enables a straight forward comparison of different fractionation schemes or treatment modalities.« less

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure-FLT3 Relationship.

PubMed

Liu, Tao; Ivaturi, Vijay; Sabato, Philip; Gobburu, Jogarao V S; Greer, Jacqueline M; Wright, John J; Smith, B Douglas; Pratz, Keith W; Rudek, Michelle A

2018-04-27

Sorafenib administered at the approved dose continuously is not tolerated long-term in patients with acute myeloid leukemia (AML). The purpose of this study was to optimize the dosing regimen by characterizing the sorafenib exposure-response relationship in patients with AML. A one-compartment model with a transit absorption compartment and enterohepatic recirculation described the exposure. The relationship between sorafenib exposure and target modulation of kinase targets (FMS-like tyrosine kinase 3 (FLT3)-ITD and extracellular signal-regulated kinase (ERK)) were described by an inhibitory maximum effect (E max ) model. Sorafenib could inhibit FLT3-ITD activity by 100% with an IC 50 of 69.3 ng/mL and ERK activity by 84% with an IC 50 of 85.7 ng/mL (both adjusted for metabolite potency). Different dosing regimens utilizing 200 or 400 mg at varying frequencies were simulated based on the exposure-response relationship. Simulations demonstrate that a 200 mg twice daily (b.i.d.) dosing regimen showed similar FLT3-ITD and ERK inhibitory activity compared with 400 mg b.i.d. and is recommended in further clinical trials in patients with AML. © 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Combination therapy for type 2 diabetes: repaglinide plus rosiglitazone.

PubMed

Raskin, P; McGill, J; Saad, M F; Cappleman, J M; Kaye, W; Khutoryansky, N; Hale, P M

2004-04-01

This 24-week, randomized, multicentre, open-label, parallel-group clinical trial compared efficacy and safety of repaglinide monotherapy, rosiglitazone monotherapy, and combination therapy (repaglinide plus rosiglitazone) in Type 2 diabetes after unsatisfactory response to sulphonylurea or metformin monotherapy. Enrolled patients (n = 252) were adults having Type 2 diabetes for at least 1 year, with HbA(1c) values > 7.0% after previous monotherapy (sulphonylurea or metformin, >/= 50% maximal dose). Prior therapy was withdrawn for 2 weeks, followed by randomization to repaglinide, rosiglitazone, or repaglinide/rosiglitazone. Study treatments were initiated with a 12-week dose optimization period (doses optimized according to labelling), followed by a 12-week maintenance period. Efficacy endpoints were changes in HbA(1c) values (primary) or fasting plasma glucose values (secondary). Baseline HbA(1c) values were comparable (9.3% for repaglinide, 9.0% for rosiglitazone, 9.1% for combination). Mean changes in HbA(1c) values at the end of treatment were greater for repaglinide/rosiglitazone therapy (-1.43%) than for repaglinide (-0.17%) or rosiglitazone (-0.56%) monotherapy. Reductions of fasting plasma glucose values were also greater for combination therapy (-5.2 mmol/l, -94 mg/dl) than for repaglinide monotherapy (-3.0 mmol/l, -54 mg/dl) or rosiglitazone monotherapy (-3.7 mmol/l, -67 mg/dl). Minor hypoglycaemic events occurred in 9% of combination therapy patients, vs. 6% for repaglinide and 2% for rosiglitazone. Individual weight gains for combination therapy were correlated to HbA(1c) response. The combination therapy regimen was well tolerated. In patients previously showing unsatisfactory response to oral monotherapy, glycaemic reductions were greater for the repaglinide/rosiglitazone combination regimen than for use of either repaglinide or rosiglitazone alone.

Application of response surface methodology for optimization of biosorption of fluoride from groundwater using Shorea robusta flower petal

NASA Astrophysics Data System (ADS)

Biswas, G.; Kumari, M.; Adhikari, K.; Dutta, S.

2017-12-01

Fluoride pollution in groundwater is a major concern in rural areas. The flower petal of Shorea robusta, commonly known as sal tree, is used in the present study both in its native form and Ca-impregnated activated form to eradicate excess fluoride from simulated wastewater. Response surface methodology (RSM) was used for experimental designing and analyzing optimum condition for carbonization vis-à-vis calcium impregnation for preparation of adsorbent. During carbonization, temperature, time and weight ratio of calcium chloride to sal flower petal (SFP) have been considered as input factors and percentage removal of fluoride as response. Optimum condition for carbonization has been obtained as temperature, 500 °C; time, 1 h and weight ratio, 2.5 and the sample prepared has been termed as calcium-impregnated carbonized sal flower petal (CCSFP). Optimum condition as analyzed by one-factor-at-a-time (OFAT) method is initial fluoride concentration, 2.91 mg/L; pH 3 and adsorbent dose, 4 g/L. CCSFP shows maximum removal of 98.5% at this condition. RSM has also been used for finding out optimum condition for defluoridation considering initial concentration, pH and adsorbent dose as input parameters. The optimum condition as analyzed by RSM is: initial concentration, 5 mg/L; pH 3.5 and adsorbent dose, 2 g/L. Kinetic and equilibrium data follow Ho pseudo-second-order kinetic model and Freundlich isotherm model, respectively. Adsorption capacity of CCSFP has been found to be 5.465 mg/g. At optimized condition, CCSFP has been found to remove fluoride (80.4%) efficiently from groundwater collected from Bankura district in West Bengal, a fluoride-contaminated province in India.

Comparison of linear and nonlinear programming approaches for "worst case dose" and "minmax" robust optimization of intensity-modulated proton therapy dose distributions.

PubMed

Zaghian, Maryam; Cao, Wenhua; Liu, Wei; Kardar, Laleh; Randeniya, Sharmalee; Mohan, Radhe; Lim, Gino

2017-03-01

Robust optimization of intensity-modulated proton therapy (IMPT) takes uncertainties into account during spot weight optimization and leads to dose distributions that are resilient to uncertainties. Previous studies demonstrated benefits of linear programming (LP) for IMPT in terms of delivery efficiency by considerably reducing the number of spots required for the same quality of plans. However, a reduction in the number of spots may lead to loss of robustness. The purpose of this study was to evaluate and compare the performance in terms of plan quality and robustness of two robust optimization approaches using LP and nonlinear programming (NLP) models. The so-called "worst case dose" and "minmax" robust optimization approaches and conventional planning target volume (PTV)-based optimization approach were applied to designing IMPT plans for five patients: two with prostate cancer, one with skull-based cancer, and two with head and neck cancer. For each approach, both LP and NLP models were used. Thus, for each case, six sets of IMPT plans were generated and assessed: LP-PTV-based, NLP-PTV-based, LP-worst case dose, NLP-worst case dose, LP-minmax, and NLP-minmax. The four robust optimization methods behaved differently from patient to patient, and no method emerged as superior to the others in terms of nominal plan quality and robustness against uncertainties. The plans generated using LP-based robust optimization were more robust regarding patient setup and range uncertainties than were those generated using NLP-based robust optimization for the prostate cancer patients. However, the robustness of plans generated using NLP-based methods was superior for the skull-based and head and neck cancer patients. Overall, LP-based methods were suitable for the less challenging cancer cases in which all uncertainty scenarios were able to satisfy tight dose constraints, while NLP performed better in more difficult cases in which most uncertainty scenarios were hard to meet tight dose limits. For robust optimization, the worst case dose approach was less sensitive to uncertainties than was the minmax approach for the prostate and skull-based cancer patients, whereas the minmax approach was superior for the head and neck cancer patients. The robustness of the IMPT plans was remarkably better after robust optimization than after PTV-based optimization, and the NLP-PTV-based optimization outperformed the LP-PTV-based optimization regarding robustness of clinical target volume coverage. In addition, plans generated using LP-based methods had notably fewer scanning spots than did those generated using NLP-based methods. © 2017 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose-escalation and dose-expansion phase 1 study.

PubMed

Cassier, Philippe A; Italiano, Antoine; Gomez-Roca, Carlos A; Le Tourneau, Christophe; Toulmonde, Maud; Cannarile, Michael A; Ries, Carola; Brillouet, Anne; Müller, Claudia; Jegg, Anna-Maria; Bröske, Ann-Marie; Dembowski, Markus; Bray-French, Katharine; Freilinger, Christine; Meneses-Lorente, Georgina; Baehner, Monika; Harding, Ross; Ratnayake, Jayantha; Abiraj, Keelara; Gass, Nathalie; Noh, Karen; Christen, Randolph D; Ukarma, Lidia; Bompas, Emmanuelle; Delord, Jean-Pierre; Blay, Jean-Yves; Rüttinger, Dominik

2015-08-01

Diffuse-type tenosynovial giant cell tumour (dt-GCT) of the soft tissue (alternatively known as pigmented villonodular synovitis), an orphan disease with unmet medical need, is characterised by an overexpression of colony-stimulating factor 1 (CSF1), and is usually caused by a chromosomal translocation involving CSF1. CSF1 receptor (CSF1R) activation leads to the recruitment of CSF1R-expressing cells of the mononuclear phagocyte lineage that constitute the tumor mass in dt-GCT. Emactuzumab (RG7155) is a novel monoclonal antibody that inhibits CSF1R activation. We have assessed the safety, tolerability and activity of emactuzumab in patients with Dt-GCT of the soft tissue. In this phase 1, first-in-human dose-escalation and dose-expansion study, eligible patients were aged 18 years or older with dt-GCT of the soft tissue with locally advanced disease or resectable tumours requiring extensive surgery, an Eastern Cooperative Oncology Group performance status of 1 or less, measurable disease according to Response Evaluation Criteria In Solid Tumors version 1.1, and adequate end-organ function. Patients with GCT of the bone were not eligible. Patients received intravenous emactuzumab at 900 mg, 1350 mg, or 2000 mg every 2 weeks in the dose-escalation phase and at the optimal biological dose in a dose-expansion phase. The primary objective was to evaluate the safety and tolerability of emactuzumab, and to determine the maximum tolerated dose or optimal biological dose. All treated patients were included in the analyses. Expansion cohorts are currently ongoing. This study is registered with ClinicalTrials.gov, number NCT01494688. Between July 26, 2012, and Oct 21, 2013, 12 patients were enrolled in the dose-escalation phase. No dose-limiting toxicities were noted in the dose-escalation cohort; on the basis of pharmacokinetic, pharmacodynamic, and safety information, we chose a dose of 1000 mg every 2 week for the dose-expansion cohort, into which 17 patients were enrolled. Owing to different cutoff dates for safety and efficacy readouts, the safety population comprised 25 patients. Common adverse events after emactuzumab treatment were facial oedema (16 [64%] of 25 patients), asthenia (14 [56%]), and pruritus (14 [56%]). Five serious adverse events (periorbital oedema, lupus erythematosus [occurring twice], erythema, and dermohypodermitis all experienced by one [4%] patient each) were reported in five patients. Three of the five serious adverse events-periorbital oedema (one [4%]), lupus erythematosus (one [4%]), and dermohypodermitis (one [4%])-were assessed as grade 3. Two other grade 3 events were reported: mucositis (one [4%]) and fatigue (one [4%]). 24 (86%) of 28 patients achieved an objective response; two (7%) patients achieved a complete response. Further study of dt-GCT is warranted and different possibilities, such as an international collaboration with cooperative groups to assure appropriate recruitment in this rare disease, are currently being assessed. F Hoffmann-La Roche. Copyright © 2015 Elsevier Ltd. All rights reserved.

Dose algorithm for EXTRAD 4100S extremity dosimeter for use at Sandia National Laboratories.

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

Potter, Charles Augustus

An updated algorithm for the EXTRAD 4100S extremity dosimeter has been derived. This algorithm optimizes the binning of dosimeter element ratios and uses a quadratic function to determine the response factors for low response ratios. This results in lower systematic bias across all test categories and eliminates the need for the 'red strap' algorithm that was used for high energy beta/gamma emitting radionuclides. The Radiation Protection Dosimetry Program (RPDP) at Sandia National Laboratories uses the Thermo Fisher EXTRAD 4100S extremity dosimeter, shown in Fig 1.1 to determine shallow dose to the extremities of potentially exposed individuals. This dosimeter consists ofmore » two LiF TLD elements or 'chipstrates', one of TLD-700 ({sup 7}Li) and one of TLD-100 (natural Li) separated by a tin filter. Following readout and background subtraction, the ratio of the responses of the two elements is determined defining the penetrability of the incident radiation. While this penetrability approximates the incident energy of the radiation, X-rays and beta particles exist in energy distributions that make determination of dose conversion factors less straightforward in their determination.« less

Extended release amoxicillin/clavulanate: optimizing a product for respiratory infections based on pharmacodynamic principles.

PubMed

Jacobs, Michael R

2005-06-01

Acute bacterial respiratory tract infections cause a great deal of human morbidity and mortality. Treatment guidelines for these infections include macrolides, doxycycline, beta-lactams and beta-lactam/beta-lactamase inhibitor combinations such as amoxicillin/clavulanic acid to provide coverage for the common respiratory pathogens, including penicillin and macrolide nonsusceptible Streptococcus pneumoniae, as well as beta-lactamase-producing Haemophilus influenzae and Moraxella catarrhalis. In response to recent guidelines recommending higher dose amoxicillin to extend coverage to a higher percentage of S. pneumoniae, a new formulation of amoxicillin/clavulanic acid was developed. This formulation includes a higher amoxicillin dose, with part of the amoxicillin dose being in an extended release formulation, without increasing the clavulanate dose, for twice-daily oral treatment of these infections. Clinical studies of community-acquired pneumonia and acute rhinosinusitis have shown that the new formulation is well tolerated and highly efficacious, with clinical outcomes equivalent to comparators.

SCCT guidelines on radiation dose and dose-optimization strategies in cardiovascular CT

PubMed Central

Halliburton, Sandra S.; Abbara, Suhny; Chen, Marcus Y.; Gentry, Ralph; Mahesh, Mahadevappa; Raff, Gilbert L.; Shaw, Leslee J.; Hausleiter, Jörg

2012-01-01

Over the last few years, computed tomography (CT) has developed into a standard clinical test for a variety of cardiovascular conditions. The emergence of cardiovascular CT during a period of dramatic increase in radiation exposure to the population from medical procedures and heightened concern about the subsequent potential cancer risk has led to intense scrutiny of the radiation burden of this new technique. This has hastened the development and implementation of dose reduction tools and prompted closer monitoring of patient dose. In an effort to aid the cardiovascular CT community in incorporating patient-centered radiation dose optimization and monitoring strategies into standard practice, the Society of Cardiovascular Computed Tomography has produced a guideline document to review available data and provide recommendations regarding interpretation of radiation dose indices and predictors of risk, appropriate use of scanner acquisition modes and settings, development of algorithms for dose optimization, and establishment of procedures for dose monitoring. PMID:21723512

Peroxidase activity as an indicator of exposure of wetland seedlings to metals

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

Sutton, H.D.; Klaine, S.J.

1995-12-31

The enzyme peroxidase has been found to increase quantitatively in several aquatic plant species in response to increasing exposure to various contaminants. In this study, a number of wetland species are tested for their usefulness as bioindicators of metal exposure using the peroxidase assay. Woody species tested include Liquidambar styraciflua (sweetgum), Fraxinus pennsylvanica (green ash), and Cephalanthus occidentalis (buttonbush), while herbaceous species include Saururus cernuus (lizard`s tail) and Sparganium americanum (bur-reed). The assay has been optimized for all of these species. In all cases the pH optimum has been found to be either 5.5 or 6.0 and the substrate optimummore » is 2.8 or 1.4mM hydrogen peroxide. There is considerable variation in baseline peroxidase activity among the species when tested under their optimal assay conditions. These species are being dosed with copper, nickel, and cadmium in order to determine whether a response elicited. Seedlings will be dosed using both petri dish culture conditions and test tubes filled with vermiculite and sand combinations. The peroxidase response will be compared to germination and root elongation endpoints. Lettuce (Lactuca saliva) and radish (Raphanus sativus) are being tested alongside the wetland species as reference organisms for which background data is available. The wetland species tested in the present study have rarely if ever been used in toxicological studies.« less

Evaluation of an intragastric challenge model for Shigella dysenteriae 1 in rhesus monkeys (Macaca mulatta) for the pre-clinical assessment of Shigella vaccine formulations.

PubMed

Islam, Dilara; Ruamsap, Nattaya; Khantapura, Patchariya; Aksomboon, Ajchara; Srijan, Apichai; Wongstitwilairoong, Boonchai; Bodhidatta, Ladaporn; Gettayacamin, Montip; Venkatesan, Malabi M; Mason, Carl J

2014-06-01

Shigellosis is a worldwide disease, characterized by abdominal pain, fever, vomiting, and the passage of blood- and mucus-streaked stools. Rhesus monkeys and other primates are the only animals that are naturally susceptible to shigellosis. A suitable animal model is required for the pre-clinical evaluation of vaccines candidates. In this study, the minimal dose of Shigella dysenteriae1 1617 strain required to produce dysentery in four of five (80% attack rate) monkeys using an escalating dose range for three groups [2 × 10(8) , 2 × 10(9) and 2 × 10(10) colony forming unit (CFU)] was determined. In addition, the monkeys were re-infected. The identified optimal challenge dose was 2 × 10(9) CFU; this dose elicited 60% protection in monkeys when they were re-challenged with a one log higher dose (2 × 10(10) CFU). The challenge dose, 2 × 10(10) CFU, produced severe dysentery in all monkeys, with one monkey dying within 24 h, elicited 100% protection when re-challenged with the same dose. All monkeys exhibited immune responses. This study concludes that the rhesus monkey model closely mimics the disease and immune response seen in humans and is a suitable animal model for the pre-clinical evaluation of Shigella vaccine candidates. Prior infection with the 1617 strain can protect monkeys against subsequent re-challenges with homologous strains. © 2013 The Authors. APMIS published by John Wiley & Sons Ltd.

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

Gorissen, BL; Giantsoudi, D; Unkelbach, J

Purpose: Cell survival experiments suggest that the relative biological effectiveness (RBE) of proton beams depends on linear energy transfer (LET), leading to higher RBE near the end of range. With intensity-modulated proton therapy (IMPT), multiple treatment plans that differ in the dose contribution per field may yield a similar physical dose distribution, but the RBE-weighted dose distribution may be disparate. RBE models currently do not have the required predictive power to be included in an optimization model due to the variations in experimental data. We propose an LET-based planning method that guides IMPT optimization models towards plans with reduced RBE-weightedmore » dose in surrounding organs at risk (OARs) compared to inverse planning based on physical dose alone. Methods: Optimization models for physical dose are extended with a term for dose times LET (doseLET). Monte Carlo code is used to generate the physical dose and doseLET distribution of each individual pencil beam. The method is demonstrated for an atypical meningioma patient where the target volume abuts the brainstem and partially overlaps with the optic nerve. Results: A reference plan optimized based on physical dose alone yields high doseLET values in parts of the brainstem and optic nerve. Minimizing doseLET in these critical structures as an additional planning goal reduces the risk of high RBE-weighted dose. The resulting treatment plan avoids the distal fall-off of the Bragg peaks for shaping the dose distribution in front of critical stuctures. The maximum dose in the OARs evaluated with RBE models from literature is reduced by 8–14\\% with our method compared to conventional planning. Conclusion: LET-based inverse planning for IMPT offers the ability to reduce the RBE-weighted dose in OARs without sacrificing target dose. This project was in part supported by NCI - U19 CA 21239.« less

What is the optimal radiation dose for non-operable esophageal cancer? Dissecting the evidence in a meta-analysis.

PubMed

Chen, Yong; Zhu, Hui-Ping; Wang, Tao; Sun, Chang-Jiang; Ge, Xiao-Lin; Min, Ling-Feng; Zhang, Xian-Wen; Jia, Qing-Qing; Yu, Jie; Yang, Jian-Qi; Allgayer, Heike; Abba, Mohammed L; Zhang, Xi-Zhi; Sun, Xin-Chen

2017-10-24

The standard radiation dose 50.4 Gy with concurrent chemotherapy for localized inoperable esophageal cancer as supported by INT-0123 trail is now being challenged since a radiation dose above 50 Gy has been successfully administered with an observable dose-response relationship and insignificant untoward effects. Therefore, to ascertain the treatment benefits of different radiation doses, we performed a meta-analysis with 18 relative publications. According to our findings, a dose between 50 and 70 Gy appears optimal and patients who received ≥ 60 Gy radiation had a significantly better prognosis (pooled HR = 0.78, P = 0.004) as compared with < 60 Gy, especially in Asian countries (pooled HR = 0.75, P = 0.003). However, contradictory results of treatment benefit for ≥ 60 Gy were observed in two studies from Western countries, and the pooled treatment benefit of ≥ 60 Gy radiation was inconclusive (pooled HR = 0.86, P = 0.64). There was a marginal benefit in locoregional control in those treated with high dose (> 50.4/51 Gy) radiation when compared with those treated with low dose (≤ 50.4/51 Gy) radiation (pooled OR = 0.71, P = 0.06). Patients that received ≥ 60 Gy radiation had better locoregional control (OR = 0.29, P = 0.001), and for distant metastasis control, neither the > 50.4 Gy nor the ≥ 60 Gy treated group had any treatment benefit as compared to the groups that received ≤ 50.4 Gy and < 60 Gy group respectively. Taken together, a dose range of 50 to 70 Gy radiation with CCRT is recommended for non-operable EC patients. A dose of ≥ 60 Gy appears to be better in improving overall survival and locoregional control, especially in Asian countries, while the benefit of ≥ 60 Gy radiation in Western countries still remains controversial.

SU-E-T-488: An Iso-Dose Curve Based Interactive IMRT Optimization System for Physician-Driven Plan Tuning

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

Shi, F; Tian, Z; Jia, X

Purpose: In treatment plan optimization for Intensity Modulated Radiation Therapy (IMRT), after a plan is initially developed by a dosimetrist, the attending physician evaluates its quality and often would like to improve it. As opposed to having the dosimetrist implement the improvements, it is desirable to have the physician directly and efficiently modify the plan for a more streamlined and effective workflow. In this project, we developed an interactive optimization system for physicians to conveniently and efficiently fine-tune iso-dose curves. Methods: An interactive interface is developed under C++/Qt. The physician first examines iso-dose lines. S/he then picks an iso-dose curvemore » to be improved and drags it to a more desired configuration using a computer mouse or touchpad. Once the mouse is released, a voxel-based optimization engine is launched. The weighting factors corresponding to voxels between the iso-dose lines before and after the dragging are modified. The underlying algorithm then takes these factors as input to re-optimize the plan in near real-time on a GPU platform, yielding a new plan best matching the physician's desire. The re-optimized DVHs and iso-dose curves are then updated for the next iteration of modifications. This process is repeated until a physician satisfactory plan is achieved. Results: We have tested this system for a series of IMRT plans. Results indicate that our system provides the physicians an intuitive and efficient tool to edit the iso-dose curves according to their preference. The input information is used to guide plan re-optimization, which is achieved in near real-time using our GPU-based optimization engine. Typically, a satisfactory plan can be developed by a physician in a few minutes using this tool. Conclusion: With our system, physicians are able to manipulate iso-dose curves according to their preferences. Preliminary results demonstrate the feasibility and effectiveness of this tool.« less

SU-F-P-61: Does It Matter Not to Use Optimization Points at the Apex for Vaginal Cylinder HDR Brachytherapy Planning?

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

Kim, Y

2016-06-15

Purpose: To test the impact of the use of apex optimization points for new vaginal cylinder (VC) applicators. Methods: New “ClickFit” single channel VC applicators (Varian) that have a different top thicknesses but the same diameters as the old VC applicators (2.3 cm diameter, 2.6 cm, 3.0 cm, and 3.5 cm) were compared using phantom studies. Old VC applicator plans without apex optimization points were also compared to the plans with the optimization points. The apex doses were monitored at 5 mm depth doses (8 points) where a prescription dose (Rx) of 6Gy was prescribed. VC surface doses (8 points)more » were also analyzed. Results: The new VC applicator plans without apex optimization points presented significantly lower 5mm depth doses than Rx (on average −31 ± 7%, p <0.00001) due to their thicker VC tops (3.4 ± 1.1 mm thicker with the range of 1.2 to 4.4 mm) than the old VC applicators. Old VC applicator plans also showed a statistically significant reduction (p <0.00001) due to Ir-192 source anisotropic effect at the apex region but the % reduction over Rx was only −7 ± 9%. However, by adding apex optimization points to the new VC applicator plans, the plans improved 5 mm depth doses (−7 ± 9% over Rx) that were not statistically different from old VC plans (p = 0.923), along with apex VC surface doses (−22 ± 10% over old VC versus −46 ± 7% without using apex optimization points). Conclusion: The use of apex optimization points are important in order to avoid significant additional cold doses (−24 ± 2%) at the prescription depth (5 mm) of apex, especially for the new VC applicators that have thicker tops.« less

Phase 1b study of the mammalian target of rapamycin inhibitor sirolimus in combination with nanoparticle albumin-bound paclitaxel in patients with advanced solid tumors.

PubMed

Abu-Khalaf, Maysa M; Baumgart, Megan A; Gettinger, Scott N; Doddamane, Indukala; Tuck, David P; Hou, Shihe; Chen, Nianhang; Sullivan, Catherine; Lezon-Geyda, Kimberly; Zelterman, Daniel; Hatzis, Christos; Deshpande, Hari; Digiovanna, Michael P; Azodi, Masoud; Schwartz, Peter E; Harris, Lyndsay N

2015-06-01

The optimal weekly oral dose of sirolimus and intravenous nanoparticle albumin-bound paclitaxel (nab-paclitaxel) were evaluated. A phase 1b study was performed to evaluate escalating doses of oral sirolimus (5-60 mg) on days 2, 9, and 16 with intravenous nab-paclitaxel (100 mg/m(2) ) on days 1, 8, and 15 in a 28-day cycle. A run-in treatment of nab-paclitaxel (day -14) and sirolimus (day -7) was administered for pharmacokinetic and pharmacodynamic assessments. Clinical trial endpoints included dose-limiting toxicities (DLTs), maximum tolerated doses, and response rates. Pharmacodynamics included immunohistochemistry for phosphatase and tensin homolog, mammalian target of rapamycin (mTOR), AKT, phosphorylated AKT, S6K1, and phosphorylated S6K1; exploratory gene expression analysis; and [(18) F]fludeoxyglucose (FDG) positron emission tomography. Twenty-three patients with advanced solid tumors were treated. Fifteen patients had prior taxane therapy. Twenty-two patients were evaluable for responses. One patient had a complete response, and 5 patients had a partial response (3 confirmed). DLTs were seen in 1 patient each at 10 (grade 3 dyspnea/hypoxia) and 40 mg (grade 4 leukopenia/neutropenia) and in 2 patients at 60 mg (grade 3 fatigue and grade 4 pericardial effusion). Patients with higher expression of posttreatment AKT and a greater decline in FDG activity were more likely to have a treatment response or stable disease. Sirolimus showed an acceptable safety profile at a weekly dose of 40 mg with weekly intravenous nab-paclitaxel at 100 mg/m(2) on days 1, 8, and 15 every 28 days. The posttreatment AKT score and changes in FDG activity may have roles as early predictors of responses to mTOR inhibitors. © 2015 American Cancer Society.

Reanalysis of cancer mortality in Japanese A-bomb survivors exposed to low doses of radiation: bootstrap and simulation methods

PubMed Central

2009-01-01

Background The International Commission on Radiological Protection (ICRP) recommended annual occupational dose limit is 20 mSv. Cancer mortality in Japanese A-bomb survivors exposed to less than 20 mSv external radiation in 1945 was analysed previously, using a latency model with non-linear dose response. Questions were raised regarding statistical inference with this model. Methods Cancers with over 100 deaths in the 0 - 20 mSv subcohort of the 1950-1990 Life Span Study are analysed with Poisson regression models incorporating latency, allowing linear and non-linear dose response. Bootstrap percentile and Bias-corrected accelerated (BCa) methods and simulation of the Likelihood Ratio Test lead to Confidence Intervals for Excess Relative Risk (ERR) and tests against the linear model. Results The linear model shows significant large, positive values of ERR for liver and urinary cancers at latencies from 37 - 43 years. Dose response below 20 mSv is strongly non-linear at the optimal latencies for the stomach (11.89 years), liver (36.9), lung (13.6), leukaemia (23.66), and pancreas (11.86) and across broad latency ranges. Confidence Intervals for ERR are comparable using Bootstrap and Likelihood Ratio Test methods and BCa 95% Confidence Intervals are strictly positive across latency ranges for all 5 cancers. Similar risk estimates for 10 mSv (lagged dose) are obtained from the 0 - 20 mSv and 5 - 500 mSv data for the stomach, liver, lung and leukaemia. Dose response for the latter 3 cancers is significantly non-linear in the 5 - 500 mSv range. Conclusion Liver and urinary cancer mortality risk is significantly raised using a latency model with linear dose response. A non-linear model is strongly superior for the stomach, liver, lung, pancreas and leukaemia. Bootstrap and Likelihood-based confidence intervals are broadly comparable and ERR is strictly positive by bootstrap methods for all 5 cancers. Except for the pancreas, similar estimates of latency and risk from 10 mSv are obtained from the 0 - 20 mSv and 5 - 500 mSv subcohorts. Large and significant cancer risks for Japanese survivors exposed to less than 20 mSv external radiation from the atomic bombs in 1945 cast doubt on the ICRP recommended annual occupational dose limit. PMID:20003238

TL and OSL dose response of LiF:Mg,Ti and Al2O3:C dosimeters using a PMMA phantom for IMRT technique quality assurance.

PubMed

Matsushima, Luciana C; Veneziani, Glauco R; Sakuraba, Roberto K; Cruz, José C; Campos, Letícia L

2015-06-01

The principle of IMRT is to treat a patient from a number of different directions (or continuous arcs) with beams of nonuniform fluences, which have been optimized to deliver a high dose to the target volume and an acceptably low dose to the surrounding normal structures (Khan, 2010). This study intends to provide information to the physicist regarding the application of different dosimeters type, phantoms and analysis technique for Intensity Modulated Radiation Therapy (IMRT) dose distributions evaluation. The measures were performed using dosimeters of LiF:Mg,Ti and Al2O3:C evaluated by techniques of thermoluminescent (TL) and Optically Stimulated Luminescence (OSL). A polymethylmethacrylate (PMMA) phantom with five cavities, two principal target volumes considered like tumours to be treated and other three cavities to measure the scattered radiation dose was developed to carried out the measures. Copyright © 2015 Elsevier Ltd. All rights reserved.

Accurate dosimetry with GafChromic EBT film of a 6 MV photon beam in water: what level is achievable?

PubMed

van Battum, L J; Hoffmans, D; Piersma, H; Heukelom, S

2008-02-01

This paper focuses on the accuracy, in absolute dose measurements, with GafChromicTM EBT film achievable in water for a 6 MV photon beam up to a dose of 2.3 Gy. Motivation is to get an absolute dose detection system to measure up dose distributions in a (water) phantom, to check dose calculations. An Epson 1680 color (red green blue) transmission flatbed scanner has been used as film scanning system, where the response in the red color channel has been extracted and used for the analyses. The influence of the flatbed film scanner on the film based dose detection process was investigated. The scan procedure has been optimized; i.e. for instance a lateral correction curve was derived to correct the scan value, up to 10%, as a function of optical density and lateral position. Sensitometric curves of different film batches were evaluated in portrait and landscape scan mode. Between various batches important variations in sensitometric curve were observed. Energy dependence of the film is negligible, while a slight variation in dose response is observed for very large angles between film surface and incident photon beam. Improved accuracy in absolute dose detection can be obtained by repetition of a film measurement to tackle at least the inherent presence of film inhomogeneous construction. We state that the overall uncertainty is random in absolute EBT film dose detection and of the order of 1.3% (1 SD) under the condition that the film is scanned in a limited centered area on the scanner and at least two films have been applied. At last we advise to check a new film batch on its characteristics compared to available information, before using that batch for absolute dose measurements.

TU-EF-204-03: Task-Based KV and MAs Optimization for Radiation Dose Reduction in CT: From FBP to Statistical Model-Based Iterative Reconstruction (MBIR)

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

Gomez-Cardona, D; Li, K; Lubner, M G

Purpose: The introduction of the highly nonlinear MBIR algorithm to clinical CT systems has made CNR an invalid metric for kV optimization. The purpose of this work was to develop a task-based framework to unify kV and mAs optimization for both FBP- and MBIR-based CT systems. Methods: The kV-mAs optimization was formulated as a constrained minimization problem: to select kV and mAs to minimize dose under the constraint of maintaining the detection performance as clinically prescribed. To experimentally solve this optimization problem, exhaustive measurements of detectability index (d’) for a hepatic lesion detection task were performed at 15 different mAmore » levels and 4 kV levels using an anthropomorphic phantom. The measured d’ values were used to generate an iso-detectability map; similarly, dose levels recorded at different kV-mAs combinations were used to generate an iso-dose map. The iso-detectability map was overlaid on top of the iso-dose map so that for a prescribed detectability level d’, the optimal kV-mA can be determined from the crossing between the d’ contour and the dose contour that corresponds to the minimum dose. Results: Taking d’=16 as an example: the kV-mAs combinations on the measured iso-d’ line of MBIR are 80–150 (3.8), 100–140 (6.6), 120–150 (11.3), and 140–160 (17.2), where values in the parentheses are measured dose values. As a Result, the optimal kV was 80 and optimal mA was 150. In comparison, the optimal kV and mA for FBP were 100 and 500, which corresponded to a dose level of 24 mGy. Results of in vivo animal experiments were consistent with the phantom results. Conclusion: A new method to optimize kV and mAs selection has been developed. This method is applicable to both linear and nonlinear CT systems such as those using MBIR. Additional dose savings can be achieved by combining MBIR with this method. This work was partially supported by an NIH grant R01CA169331 and GE Healthcare. K. Li, D. Gomez-Cardona, M. G. Lubner: Nothing to disclose. P. J. Pickhardt: Co-founder, VirtuoCTC, LLC Stockholder, Cellectar Biosciences, Inc. G.-H. Chen: Research funded, GE Healthcare; Research funded, Siemens AX.« less

TH-AB-202-09: Direct-Aperture Optimization for Combined MV+kV Dose Planning in Fluoroscopic Real-Time Tumor-Tracking Radiation Therapy

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

Liu, X; Belcher, AH; Grelewicz, Z

Purpose: Real-time kV fluoroscopic tumor tracking has the benefit of direct tumor position monitoring. However, there is clinical concern over the excess kV imaging dose cost to the patient when imaging in continuous fluoroscopic mode. This work addresses this specific issue by proposing a combined MV+kV direct-aperture optimization (DAO) approach to integrate the kV imaging beam into a treatment planning such that the kV radiation is considered as a contributor to the overall dose delivery. Methods: The combined MV+kV DAO approach includes three algorithms. First, a projected Quasi-Newton algorithm (L-BFGS) is used to find optimized fluence with MV+kV dose formore » the best possible dose distribution. Then, Engel’s algorithm is applied to optimize the total number of monitor units and heuristically optimize the number of apertures. Finally, an aperture shape optimization (ASO) algorithm is applied to locally optimize the leaf positions of MLC. Results: Compared to conventional DAO MV plans with continuous kV fluoroscopic tracking, combined MV+kV DAO plan leads to a reduction in the total number of MV monitor units due to inclusion of kV dose as part of the PTV, and was also found to reduce the mean and maximum doses on the organs at risk (OAR). Compared to conventional DAO MV plan without kV tracking, the OAR dose in the combined MV+kV DAO plan was only slightly higher. DVH curves show that combined MV+kV DAO plan provided about the same PTV coverage as that in the conventional DAO plans without kV imaging. Conclusion: We report a combined MV+kV DAO approach that allows real time kV imager tumor tracking with only a trivial increasing on the OAR doses while providing the same coverage to PTV. The approach is suitable for clinic implementation.« less

Cellular stress responses, mitostress and carnitine insufficiencies as critical determinants in aging and neurodegenerative disorders: role of hormesis and vitagenes.

PubMed

Calabrese, Vittorio; Cornelius, Carolin; Stella, Anna Maria Giuffrida; Calabrese, Edward J

2010-12-01

The widely accepted oxidative stress theory of aging postulates that aging results from accumulation of oxidative damage. A prediction of this theory is that, among species, differential rates of aging may be apparent on the basis of intrinsic differences in oxidative damage accrual. Although widely accepted, there is a growing number of exceptions to this theory, most contingently related to genetic model organism investigations. Proteins are one of the prime targets for oxidative damage and cysteine residues are particularly sensitive to reversible and irreversible oxidation. The adaptation and survival of cells and organisms requires the ability to sense proteotoxic insults and to coordinate protective cellular stress response pathways and chaperone networks related to protein quality control and stability. The toxic effects that stem from the misassembly or aggregation of proteins or peptides, in any cell type, are collectively termed proteotoxicity. Despite the abundance and apparent capacity of chaperones and other components of homeostasis to restore folding equilibrium, the cell appears poorly adapted for chronic proteotoxic stress which increases in cancer, metabolic and neurodegenerative diseases. Pharmacological modulation of cellular stress response pathways has emerging implications for the treatment of human diseases, including neurodegenerative disorders, cardiovascular disease, and cancer. A critical key to successful medical intervention is getting the dose right. Achieving this goal can be extremely challenging due to human inter-individual variation as affected by age, gender, diet, exercise, genetic factors and health status. The nature of the dose response in and adjacent to the therapeutic zones, over the past decade has received considerable advances. The hormetic dose-response, challenging long-standing beliefs about the nature of the dose-response in a lowdose zone, has the potential to affect significantly the design of pre-clinical studies and clinical trials as well as strategies for optimal patient dosing in the treatment of numerous diseases. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing stress responses, including carnitines. This paper describes in mechanistic detail how hormetic dose responses are mediated for endogenous cellular defense pathways, including the possible signaling mechanisms by which the carnitine system, by interplaying metabolism, mitochondrial energetics and activation of critical vitagenes, modulates signal transduction cascades that confer cytoprotection against chronic degenerative damage associated to aging and neurodegenerative disorders.

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

Unkelbach, Jan, E-mail: junkelbach@mgh.harvard.edu; Botas, Pablo; Faculty of Physics, Ruprecht-Karls-Universität Heidelberg, Heidelberg

Purpose: We describe a treatment plan optimization method for intensity modulated proton therapy (IMPT) that avoids high values of linear energy transfer (LET) in critical structures located within or near the target volume while limiting degradation of the best possible physical dose distribution. Methods and Materials: To allow fast optimization based on dose and LET, a GPU-based Monte Carlo code was extended to provide dose-averaged LET in addition to dose for all pencil beams. After optimizing an initial IMPT plan based on physical dose, a prioritized optimization scheme is used to modify the LET distribution while constraining the physical dosemore » objectives to values close to the initial plan. The LET optimization step is performed based on objective functions evaluated for the product of LET and physical dose (LET×D). To first approximation, LET×D represents a measure of the additional biological dose that is caused by high LET. Results: The method is effective for treatments where serial critical structures with maximum dose constraints are located within or near the target. We report on 5 patients with intracranial tumors (high-grade meningiomas, base-of-skull chordomas, ependymomas) in whom the target volume overlaps with the brainstem and optic structures. In all cases, high LET×D in critical structures could be avoided while minimally compromising physical dose planning objectives. Conclusion: LET-based reoptimization of IMPT plans represents a pragmatic approach to bridge the gap between purely physical dose-based and relative biological effectiveness (RBE)-based planning. The method makes IMPT treatments safer by mitigating a potentially increased risk of side effects resulting from elevated RBE of proton beams near the end of range.« less

Oral oxybutynin for the treatment of hyperhidrosis: outcomes after one-year follow-up.

PubMed

Millán-Cayetano, José Francisco; Del Boz, Javier; Rivas-Ruiz, Francisco; Blázquez-Sánchez, Nuria; Hernández Ibáñez, Carlos; de Troya-Martín, Magdalena

2017-05-01

Although many treatments are available to address hyperhidrosis, the results are not always satisfactory. The aim of the study was to assess the effectiveness, optimal dosage regimen and long-term safety of oral oxybutynin in the treatment of hyperhidrosis. A retrospective review was performed on 110 patients who underwent treatment for hyperhidrosis between February 2007 and December 2013. Their response to treatment was evaluated using the hyperhidrosis disease severity scale at baseline, 3 and 12 months. Additionally, the safety and effectiveness of different up-dosing and fixed-dose regimens were compared. After 3 months of treatment, 87 of the 110 patients (79%) had responded (63%), which was considered excellent. After 12 months, 63 patients (62%) continued to respond, and the response was considered excellent in 50%. Nine patients were lost to follow up between month 3 and 12. In total, 77 and 70% of the patients who responded at 3 and 12 months, respectively, reported mild adverse events. No serious adverse events were observed. Treatment adherence was significantly higher among patients following the individualised up-dosing regimen. Oral oxybutynin may be an effective and safe option for the long-term treatment of hyperhidrosis. To improve treatment adherence, oxybutynin dosing regimens should be individualised on the basis of the patient's tolerance and response. © 2016 The Australasian College of Dermatologists.

Statistical model based iterative reconstruction in clinical CT systems. Part III. Task-based kV/mAs optimization for radiation dose reduction

PubMed Central

Li, Ke; Gomez-Cardona, Daniel; Hsieh, Jiang; Lubner, Meghan G.; Pickhardt, Perry J.; Chen, Guang-Hong

2015-01-01

Purpose: For a given imaging task and patient size, the optimal selection of x-ray tube potential (kV) and tube current-rotation time product (mAs) is pivotal in achieving the maximal radiation dose reduction while maintaining the needed diagnostic performance. Although contrast-to-noise (CNR)-based strategies can be used to optimize kV/mAs for computed tomography (CT) imaging systems employing the linear filtered backprojection (FBP) reconstruction method, a more general framework needs to be developed for systems using the nonlinear statistical model-based iterative reconstruction (MBIR) method. The purpose of this paper is to present such a unified framework for the optimization of kV/mAs selection for both FBP- and MBIR-based CT systems. Methods: The optimal selection of kV and mAs was formulated as a constrained optimization problem to minimize the objective function, Dose(kV,mAs), under the constraint that the achievable detectability index d′(kV,mAs) is not lower than the prescribed value of d℞′ for a given imaging task. Since it is difficult to analytically model the dependence of d′ on kV and mAs for the highly nonlinear MBIR method, this constrained optimization problem is solved with comprehensive measurements of Dose(kV,mAs) and d′(kV,mAs) at a variety of kV–mAs combinations, after which the overlay of the dose contours and d′ contours is used to graphically determine the optimal kV–mAs combination to achieve the lowest dose while maintaining the needed detectability for the given imaging task. As an example, d′ for a 17 mm hypoattenuating liver lesion detection task was experimentally measured with an anthropomorphic abdominal phantom at four tube potentials (80, 100, 120, and 140 kV) and fifteen mA levels (25 and 50–700) with a sampling interval of 50 mA at a fixed rotation time of 0.5 s, which corresponded to a dose (CTDIvol) range of [0.6, 70] mGy. Using the proposed method, the optimal kV and mA that minimized dose for the prescribed detectability level of d℞′=16 were determined. As another example, the optimal kV and mA for an 8 mm hyperattenuating liver lesion detection task were also measured using the developed framework. Both an in vivo animal and human subject study were used as demonstrations of how the developed framework can be applied to the clinical work flow. Results: For the first task, the optimal kV and mAs were measured to be 100 and 500, respectively, for FBP, which corresponded to a dose level of 24 mGy. In comparison, the optimal kV and mAs for MBIR were 80 and 150, respectively, which corresponded to a dose level of 4 mGy. The topographies of the iso-d′ map and the iso-CNR map were the same for FBP; thus, the use of d′- and CNR-based optimization methods generated the same results for FBP. However, the topographies of the iso-d′ and iso-CNR map were significantly different in MBIR; the CNR-based method overestimated the performance of MBIR, predicting an overly aggressive dose reduction factor. For the second task, the developed framework generated the following optimization results: for FBP, kV = 140, mA = 350, dose = 37.5 mGy; for MBIR, kV = 120, mA = 250, dose = 18.8 mGy. Again, the CNR-based method overestimated the performance of MBIR. Results of the preliminary in vivo studies were consistent with those of the phantom experiments. Conclusions: A unified and task-driven kV/mAs optimization framework has been developed in this work. The framework is applicable to both linear and nonlinear CT systems such as those using the MBIR method. As expected, the developed framework can be reduced to the conventional CNR-based kV/mAs optimization frameworks if the system is linear. For MBIR-based nonlinear CT systems, however, the developed task-based kV/mAs optimization framework is needed to achieve the maximal dose reduction while maintaining the desired diagnostic performance. PMID:26328971

A rapid non invasive L-DOPA-¹³C breath test for optimally suppressing extracerebral AADC enzyme activity - toward individualizing carbidopa therapy in Parkinson’s disease.

PubMed

Modak, Anil; Durso, Raymon; Josephs, Ephraim; Rosen, David

2012-01-01

Peripheral carbidopa (CD) levels directly impact on central dopamine (DA) production in Parkinson disease (PD) through extracerebral inhibition of dopa decarboxylase (AADC) resulting in an increase in levodopa (LD) bioavailability. Recent data suggests that higher CD doses than those presently used in PD treatment may result in improved clinical response. Optimizing CD doses in individual patients may, therefore, result in ideal individualized treatment. A single center, randomized, double-blind study was carried out recruiting 5 Parkinson’s disease (PD) patients already on LD/CD and 1 treatment näve PD patient using stable isotope labeled LD-1-¹³C as a substrate for a noninvasive breath test to evaluate individual AADC enzyme activity. Each patient was studied five times, receiving 200 mg LD-¹³C at each visit along with one of five randomized CD doses (0, 25, 50, 100 and 200 mg). The metabolite ¹³CO₂ in breath was measured for evaluating AADC enzyme activity and plasma metabolite levels for LD-¹³C and homovanillic acid (HVA) were measured for 4 hours. HVA in plasma and ¹³CO₂ in breath are metabolic products of LD. We found a significant positive correlation of ¹³CO₂ DOB AUC0-240 with serum HVA AUC0-240 following the oral dose of LD-1-¹³C for all 5 doses of CD (r² = 0.9378). With increasing inhibition of AADC enzyme activity with CD, we observed an increase in the plasma concentration of LD.We found an inverse correlation of the 13CO2 DOB AUC with serum LD-¹³C AUC. Our studies indicate the optimal dose of CD for maximal suppression of AADC enzyme activity can be determined for each individual from ¹³CO₂ generation in breath. The LD-breath test can be a useful noninvasive diagnostic tool for evaluation of AADC enzyme activity using the biomarker ¹³CO₂ in breath, a first step in personalizing CD doses for PD patients.

Response to the high-dose corticotrophin stimulation test depends on plasma adrenocotropin hormone levels in septic shock.

PubMed

Llompart-Pou, Juan Antonio; Raurich, Joan Maria; Ayestarán, Ignacio; Fernández-de-Castillo, Ana G; Pérez-Bárcena, Jon; Ibáñez, Jordi

2012-06-01

The use of the high-dose corticotrophin stimulation test (HDCST) as a guide to use low-dose steroid therapy in septic shock is controversial. The adrenocotropin hormone (ACTH) constitutes the immediate stimuli to produce cortisol. We evaluated the correlation of the response to the HDCST with plasma ACTH levels in patients with septic shock. This is a retrospective review of 102 patients with septic shock in which adrenal function was evaluated using the HDCST and plasma ACTH levels were measured. Patients with a δ cortisol of 9 μg/dL or less were considered as nonresponders or with subnormal response. The association between plasma ACTH levels and the response to the HDCST was investigated. Sixty-four patients (62.7%) had a subnormal response. Plasma ACTH levels were higher in patients with subnormal response (19.8 [11.7-31.4] vs 10.0 [7.0-21.2] pg/mL; P = .002). Patients in the highest quartile of plasma ACTH had lower δ cortisol (P = .014) and higher percentage of subnormal response (P = .005). The optimal cutoff point of plasma ACTH level with fewest false classifications was 10 pg/mL (sensitivity, 0.83 [95% confidence interval, 074-0.90] and specificity, 0.50 [95% confidence interval, 0.74-0.90]). Patients with septic shock with higher plasma ACTH values presented a subnormal response to the HDCST. The number of patients who failed to the HDCST was higher as plasma ACTH increased. Copyright © 2012 Elsevier Inc. All rights reserved.

Atomoxetine in patients with ADHD: A clinical and pharmacological review of the onset, trajectory, duration of response and implications for patients.

PubMed

Clemow, David B; Bushe, Chris J

2015-12-01

This article reviews data providing new insight into the trajectory of response and maintenance of response of atomoxetine in the treatment of child and adult attention-deficit hyperactivity disorder (ADHD). This nonsystematic review includes: onset of action and duration of effect, response rate, effect size, time to optimal response and norepinephrine transporter blockade biomarker data. Atomoxetine can have an onset of action within 1-2 weeks of starting treatment, but there is an incrementally increasing response for up to 24 weeks or longer. Responder rates and effect sizes are similar to methylphenidate. Upon treatment discontinuation, relapse rates are lower than expected. In adults, 50% maintain their response for at least 6 months after stopping atomoxetine, following 6 months of treatment. Single-dose atomoxetine can provide 24-hour efficacy, despite a 5-hour plasma half-life. Hypotheses can be generated relating to neuroadaptive changes, to explain these findings. Atomoxetine has a trajectory of response that is incremental over a long period of time, with a greater than expected maintenance of response. This has implications for physician atomoxetine dosing and efficacy assessment, patient education and outcomes, and for clinical trial design and assessment of comparative efficacy with stimulant medications. © The Author(s) 2015.

SU-E-T-625: Robustness Evaluation and Robust Optimization of IMPT Plans Based on Per-Voxel Standard Deviation of Dose Distributions.

PubMed

Liu, W; Mohan, R

2012-06-01

Proton dose distributions, IMPT in particular, are highly sensitive to setup and range uncertainties. We report a novel method, based on per-voxel standard deviation (SD) of dose distributions, to evaluate the robustness of proton plans and to robustly optimize IMPT plans to render them less sensitive to uncertainties. For each optimization iteration, nine dose distributions are computed - the nominal one, and one each for ± setup uncertainties along x, y and z axes and for ± range uncertainty. SD of dose in each voxel is used to create SD-volume histogram (SVH) for each structure. SVH may be considered a quantitative representation of the robustness of the dose distribution. For optimization, the desired robustness may be specified in terms of an SD-volume (SV) constraint on the CTV and incorporated as a term in the objective function. Results of optimization with and without this constraint were compared in terms of plan optimality and robustness using the so called'worst case' dose distributions; which are obtained by assigning the lowest among the nine doses to each voxel in the clinical target volume (CTV) and the highest to normal tissue voxels outside the CTV. The SVH curve and the area under it for each structure were used as quantitative measures of robustness. Penalty parameter of SV constraint may be varied to control the tradeoff between robustness and plan optimality. We applied these methods to one case each of H&N and lung. In both cases, we found that imposing SV constraint improved plan robustness but at the cost of normal tissue sparing. SVH-based optimization and evaluation is an effective tool for robustness evaluation and robust optimization of IMPT plans. Studies need to be conducted to test the methods for larger cohorts of patients and for other sites. This research is supported by National Cancer Institute (NCI) grant P01CA021239, the University Cancer Foundation via the Institutional Research Grant program at the University of Texas MD Anderson Cancer Center, and MD Anderson’s cancer center support grant CA016672. © 2012 American Association of Physicists in Medicine.

Robust optimization methods for cardiac sparing in tangential breast IMRT

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

Mahmoudzadeh, Houra, E-mail: houra@mie.utoronto.ca; Lee, Jenny; Chan, Timothy C. Y.

Purpose: In left-sided tangential breast intensity modulated radiation therapy (IMRT), the heart may enter the radiation field and receive excessive radiation while the patient is breathing. The patient’s breathing pattern is often irregular and unpredictable. We verify the clinical applicability of a heart-sparing robust optimization approach for breast IMRT. We compare robust optimized plans with clinical plans at free-breathing and clinical plans at deep inspiration breath-hold (DIBH) using active breathing control (ABC). Methods: Eight patients were included in the study with each patient simulated using 4D-CT. The 4D-CT image acquisition generated ten breathing phase datasets. An average scan was constructedmore » using all the phase datasets. Two of the eight patients were also imaged at breath-hold using ABC. The 4D-CT datasets were used to calculate the accumulated dose for robust optimized and clinical plans based on deformable registration. We generated a set of simulated breathing probability mass functions, which represent the fraction of time patients spend in different breathing phases. The robust optimization method was applied to each patient using a set of dose-influence matrices extracted from the 4D-CT data and a model of the breathing motion uncertainty. The goal of the optimization models was to minimize the dose to the heart while ensuring dose constraints on the target were achieved under breathing motion uncertainty. Results: Robust optimized plans were improved or equivalent to the clinical plans in terms of heart sparing for all patients studied. The robust method reduced the accumulated heart dose (D10cc) by up to 801 cGy compared to the clinical method while also improving the coverage of the accumulated whole breast target volume. On average, the robust method reduced the heart dose (D10cc) by 364 cGy and improved the optBreast dose (D99%) by 477 cGy. In addition, the robust method had smaller deviations from the planned dose to the accumulated dose. The deviation of the accumulated dose from the planned dose for the optBreast (D99%) was 12 cGy for robust versus 445 cGy for clinical. The deviation for the heart (D10cc) was 41 cGy for robust and 320 cGy for clinical. Conclusions: The robust optimization approach can reduce heart dose compared to the clinical method at free-breathing and can potentially reduce the need for breath-hold techniques.« less

Personalized versus standardized dosing strategies for the treatment of childhood amblyopia: study protocol for a randomized controlled trial.

PubMed

Moseley, Merrick J; Wallace, Michael P; Stephens, David A; Fielder, Alistair R; Smith, Laura C; Stewart, Catherine E

2015-04-25

Amblyopia is the commonest visual disorder of childhood in Western societies, affecting, predominantly, spatial visual function. Treatment typically requires a period of refractive correction ('optical treatment') followed by occlusion: covering the nonamblyopic eye with a fabric patch for varying daily durations. Recent studies have provided insight into the optimal amount of patching ('dose'), leading to the adoption of standardized dosing strategies, which, though an advance on previous ad-hoc regimens, take little account of individual patient characteristics. This trial compares the effectiveness of a standardized dosing strategy (that is, a fixed daily occlusion dose based on disease severity) with a personalized dosing strategy (derived from known treatment dose-response functions), in which an initially prescribed occlusion dose is modulated, in a systematic manner, dependent on treatment compliance. A total of 120 children aged between 3 and 8 years of age diagnosed with amblyopia in association with either anisometropia or strabismus, or both, will be randomized to receive either a standardized or a personalized occlusion dose regimen. To avoid confounding by the known benefits of refractive correction, participants will not be randomized until they have completed an optical treatment phase. The primary study objective is to determine whether, at trial endpoint, participants receiving a personalized dosing strategy require fewer hours of occlusion than those in receipt of a standardized dosing strategy. Secondary objectives are to quantify the relationship between observed changes in visual acuity (logMAR, logarithm of the Minimum Angle of Resolution) with age, amblyopia type, and severity of amblyopic visual acuity deficit. This is the first randomized controlled trial of occlusion therapy for amblyopia to compare a treatment arm representative of current best practice with an arm representative of an entirely novel treatment regimen based on statistical modelling of previous trial outcome data. Should the personalized dosing strategy demonstrate superiority over the standardized dosing strategy, then its adoption into routine practice could bring practical benefits in reducing the duration of treatment needed to achieve an optimal outcome. ISRCTN ISRCTN12292232.

Algorithms for the optimization of RBE-weighted dose in particle therapy.

PubMed

Horcicka, M; Meyer, C; Buschbacher, A; Durante, M; Krämer, M

2013-01-21

We report on various algorithms used for the nonlinear optimization of RBE-weighted dose in particle therapy. Concerning the dose calculation carbon ions are considered and biological effects are calculated by the Local Effect Model. Taking biological effects fully into account requires iterative methods to solve the optimization problem. We implemented several additional algorithms into GSI's treatment planning system TRiP98, like the BFGS-algorithm and the method of conjugated gradients, in order to investigate their computational performance. We modified textbook iteration procedures to improve the convergence speed. The performance of the algorithms is presented by convergence in terms of iterations and computation time. We found that the Fletcher-Reeves variant of the method of conjugated gradients is the algorithm with the best computational performance. With this algorithm we could speed up computation times by a factor of 4 compared to the method of steepest descent, which was used before. With our new methods it is possible to optimize complex treatment plans in a few minutes leading to good dose distributions. At the end we discuss future goals concerning dose optimization issues in particle therapy which might benefit from fast optimization solvers.

Algorithms for the optimization of RBE-weighted dose in particle therapy

NASA Astrophysics Data System (ADS)

Horcicka, M.; Meyer, C.; Buschbacher, A.; Durante, M.; Krämer, M.

2013-01-01

We report on various algorithms used for the nonlinear optimization of RBE-weighted dose in particle therapy. Concerning the dose calculation carbon ions are considered and biological effects are calculated by the Local Effect Model. Taking biological effects fully into account requires iterative methods to solve the optimization problem. We implemented several additional algorithms into GSI's treatment planning system TRiP98, like the BFGS-algorithm and the method of conjugated gradients, in order to investigate their computational performance. We modified textbook iteration procedures to improve the convergence speed. The performance of the algorithms is presented by convergence in terms of iterations and computation time. We found that the Fletcher-Reeves variant of the method of conjugated gradients is the algorithm with the best computational performance. With this algorithm we could speed up computation times by a factor of 4 compared to the method of steepest descent, which was used before. With our new methods it is possible to optimize complex treatment plans in a few minutes leading to good dose distributions. At the end we discuss future goals concerning dose optimization issues in particle therapy which might benefit from fast optimization solvers.

Dedicated high dose rate 192Ir brachytherapy radiation fields for in vitro cell exposures at variable source-target cell distances: killing of mammalian cells depends on temporal dose rate fluctuation

NASA Astrophysics Data System (ADS)

Veigel, Cornelia; Hartmann, Günther H.; Fritz, Peter; Debus, Jürgen; Weber, Klaus-Josef

2017-02-01

Afterloading brachytherapy is conducted by the stepwise movement of a radioactive source through surgically implanted applicator tubes where at predefined dwell positions calculated dwell times optimize spatial dose delivery with respect to a planned dose level. The temporal exposure pattern exhibits drastic fluctuations in dose rate at a given coordinate and within a single treatment session because of the discontinuous and repeated source movement into the target volume. This could potentially affect biological response. Therefore, mammalian cells were exposed as monolayers to a high dose rate 192Ir source by utilizing a dedicated irradiation device where the distance between a planar array of radioactive source positions and the plane of the cell monolayer could be varied from 2.5 mm to 40 mm, thus varying dose rate pattern for any chosen total dose. The Gammamed IIi afterloading system equipped with a nominal 370 GBq (10 Ci) 192-Ir source was used to irradiate V79 Chinese hamster lung fibroblasts from both confluent and from exponential growth phase with dose up to 12 Gy (at room temperature, total exposure not exceeding 1 h). For comparison, V79 cells were also exposed to 6 MV x-rays from a clinical linear accelerator (dose rate of 2.5 Gy min-1). As biological endpoint, cell survival was determined by standard colony forming assay. Dose measurements were conducted with a diamond detector (sensitive area 7.3 mm2), calibrated by means of 60Co radiation. Additionally, dose delivery was simulated by Monte Carlo calculations using the EGSnrc code system. The calculated secondary electron fluence spectra at the cell location did not indicate a significant change of radiation quality (i.e. higher linear energy transfer) at the lower distances. Clonogenic cell survival curves obtained after brachytherapy exhibited an altered biological response compared to x-rays which was characterized by a significant reduction of the survival curve shoulder when dose rate fluctuations were high. Therefore, also for the time scale of the present investigation, cellular effects of radiation are not invariant to the temporal pattern in dose rate. We propose that with high dose rate variation the cells activate less efficiently their DNA damage response than after continuous irradiation.

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

Lee, E; Yuan, F; Templeton, A

Purpose: The ultimate goal of radiotherapy treatment planning is to find a treatment that will yield a high tumor-control-probability(TCP) with an acceptable normal-tissue-complication probability(NTCP). Yet most treatment planning today is not based upon optimization of TCPs and NTCPs, but rather upon meeting physical dose and volume constraints defined by the planner. We design treatment plans that optimize TCP directly and contrast them with the clinical dose-based plans. PET image is incorporated to evaluate gain in TCP for dose escalation. Methods: We build a nonlinear mixed integer programming optimization model that maximizes TCP directly while satisfying the dose requirements on themore » targeted organ and healthy tissues. The solution strategy first fits the TCP function with a piecewise-linear approximation, then solves the problem that maximizes the piecewise linear approximation of TCP, and finally performs a local neighborhood search to improve the TCP value. To gauge the feasibility, characteristics, and potential benefit of PET-image guided dose escalation, initial validation consists of fifteen cervical cancer HDR patient cases. These patients have all received prior 45Gy of external radiation dose. For both escalated strategies, we consider 35Gy PTV-dose, and two variations (37Gy-boost to BTV vs 40Gy-boost) to PET-image-pockets. Results: TCP for standard clinical plans range from 59.4% - 63.6%. TCP for dose-based PET-guided escalated-dose-plan ranges from 63.8%–98.6% for all patients; whereas TCP-optimized plans achieves over 91% for all patients. There is marginal difference in TCP among those with 37Gy-boosted vs 40Gy-boosted. There is no increase in rectum and bladder dose among all plans. Conclusion: Optimizing TCP directly results in highly conformed treatment plans. The TCP-optimized plan is individualized based on the biological PET-image of the patients. The TCP-optimization framework is generalizable and has been applied successfully to other external-beam delivery modalities. A clinical trial is on-going to gauge the clinical significance. Partially supported by the National Science Foundation.« less

Humoral and cell-mediated immune responses after a booster dose of HBV vaccine in HIV-infected children, adolescents and young adults.

PubMed

Giacomet, Vania; Masetti, Michela; Nannini, Pilar; Forlanini, Federica; Clerici, Mario; Zuccotti, Gian Vincenzo; Trabattoni, Daria

2018-01-01

HBV vaccine induces protective antibodies only in 23-56% of HIV-infected children. The aim of our study is to evaluate the immunologic effects of a booster dose of HBV vaccine in HIV-infected youth. 53 young HIV-infected patients in whom HBV vaccination did not elicit protective Ab titers were enrolled. All patients were on ART with optimal immunological and viral response. All patients received a booster dose of HBV vaccine (HBVAXPRO 10 μg i.m.). HBV-specific Ab titer, viral load and CD4+ T cells were measured at baseline (T0), T1, T6 and T12 months. In a subgroup of 16 patients HBV-specific cell mediated immune responses were evaluated at baseline, at T1 and T6. The booster dose induced seroconversion in 51% of patients at T1, 57% at T6, and49% at T12; seroconversion rate was significantly correlated with CD4+T cells at T0 and to the CD4 nadir. The booster dose induced HBV-specific cell mediated immunity at T6 mainly in Responders (Rs): Effector Memory CD8+T cells, HBV-specific TNFα-, IFNγ-, granzyme secreting CD8+ T cells and IL2-secreting CD4+ T cells were significantly increased in Rs compared to T0. In Non Responders (NRs), HBV-specific IL2-secreting CD4+ T cells, Central and Effector Memory CD8+ T cells were the only parameters modified at T6. Seroconversion induced by a booster dose of vaccine correlates with the development of T cell immunological memory in HIV-infected patients who did not respond to the standard immunization. Alternate immunization schedules need to be considered in NRs.

MO-DE-204-02: Optimization of the Patient CT Dose in Europe

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

Tsapaki, V.

2016-06-15

The main topic of the session is to show how dose optimization is being implemented in various regions of the world, including Europe, Australia, North America and other regions. A multi-national study conducted under International Atomic Energy Agency (IAEA) across more than 50 less resourced countries gave insight into patient radiation doses and safety practices in CT, mammography, radiography and interventional procedures, both for children and adults. An important outcome was the capability development on dose assessment and management. An overview of recent European projects related to CT radiation dose and optimization both to adults and children will be presented.more » Existing data on DRLs together with a European methodology proposed on establishing and using DRLs for paediatric radiodiagnostic imaging and interventional radiology practices will be shown. Compared with much of Europe at least, many Australian imaging practices are relatively new to the task of diagnostic imaging dose optimisation. In 2008 the Australian Government prescribed a requirement to periodically compare patient radiation doses with diagnostic reference levels (DRLs), where DRLs have been established. Until recently, Australia had only established DRLs for computed tomography (CT). Regardless, both professional society and individual efforts to improved data collection and develop optimisation strategies across a range of modalities continues. Progress in this field, principally with respect to CT and interventional fluoroscopy will be presented. In the US, dose reduction and optimization efforts for computed tomography have been promoted and mandated by several organizations and accrediting entities. This presentation will cover the general motivation, implementation, and implications of such efforts. Learning Objectives: Understand importance of the dose optimization in Diagnostic Radiology. See how this goal is achieved in different regions of the World. Learn about the global trend in the dose optimization and future prospectives. M. Rehani, The work was a part of the work of IAEA where I was an employee and IAEA is a United Nations organization.« less

Dose optimization of total or partial skin electron irradiation by thermoluminescent dosimetry.

PubMed

Schüttrumpf, Lars; Neumaier, Klement; Maihoefer, Cornelius; Niyazi, Maximilian; Ganswindt, Ute; Li, Minglun; Lang, Peter; Reiner, Michael; Belka, Claus; Corradini, Stefanie

2018-05-01

Due to the complex surface of the human body, total or partial skin irradiation using large electron fields is challenging. The aim of the present study was to quantify the magnitude of dose optimization required after the application of standard fields. Total skin electron irradiation (TSEI) was applied using the Stanford technique with six dual-fields. Patients presenting with localized lesions were treated with partial skin electron irradiation (PSEI) using large electron fields, which were individually adapted. In order to verify and validate the dose distribution, in vivo dosimetry with thermoluminescent dosimeters (TLD) was performed during the first treatment fraction to detect potential dose heterogeneity and to allow for an individual dose optimization with adjustment of the monitor units (MU). Between 1984 and 2017, a total of 58 patients were treated: 31 patients received TSEI using 12 treatment fields, while 27 patients underwent PSEI and were treated with 4-8 treatment fields. After evaluation of the dosimetric results, an individual dose optimization was necessary in 21 patients. Of these, 7 patients received TSEI (7/31). Monitor units (MU) needed to be corrected by a mean value of 117 MU (±105, range 18-290) uniformly for all 12 treatment fields, corresponding to a mean relative change of 12% of the prescribed MU. In comparison, the other 14 patients received PSEI (14/27) and the mean adjustment of monitor units was 282 MU (±144, range 59-500) to single or multiple fields, corresponding to a mean relative change of 22% of the prescribed MU. A second dose optimization to obtain a satisfying dose at the prescription point was need in 5 patients. Thermoluminescent dosimetry allows an individual dose optimization in TSEI and PSEI to enable a reliable adjustment of the MUs to obtain the prescription dose. Especially in PSEI in vivo dosimetry is of fundamental importance.

Determining the Optimal Dose of Adenosine for Unmasking Dormant Pulmonary Vein Conduction Following Atrial Fibrillation Ablation: Electrophysiological and Hemodynamic Assessment. DORMANT-AF Study.

PubMed

Prabhu, Sandeep; Mackin, Vincent; McLellan, Alex J A; Phan, Tuong; McGlade, Desmond; Ling, Liang-Han; Peck, Kah Y; Voskoboinik, Alexandr; Pathik, Bupesh; Nalliah, Chrishan J; Wong, Geoff R; Azzopardi, Sonia M; Lee, Geoffrey; Mariani, Justin; Taylor, Andrew J; Kalman, Jonathan M; Kistler, Peter M

2017-01-01

ELECTROPHYSIOLOGICAL AND HEMODYNAMIC ASSESSMENT. The significance of adenosine induced dormant pulmonary vein (PV) conduction in atrial fibrillation (AF) ablation remains controversial. The optimal dose of adenosine to determine dormant PV conduction is yet to be systematically explored. ELECTROPHYSIOLOGICAL AND HEMODYNAMIC ASSESSMENT. Consecutive patients undergoing index AF ablation received 3 adenosine doses (12, 18, and 24 mg) in a randomized blinded order, immediately after pulmonary vein isolation (PVI). Electrophysiological (PR prolongation, AV block (AVB) and PV reconnection) and hemodynamic (BP) parameters were measured. A total, 339 doses (113/dose) assessed 191 PVs in 50 patients (66% male, 72% PAF, 52% hypertensive). Dormant PV conduction occurred in 28% of patients (16.5% [32] of PVs). All cases were associated with AVB (AVB: PV reconnection vs. no PV reconnection 100% vs. 83%, P = 0.007). AVB occurred more frequently at 24 mg versus 12 mg (92% vs. 82%, P = 0.019) but not versus 18 mg (91%, P = 0.62). AVB duration progressed between 12 mg (12.0 ± 8.9 seconds), 18 mg (16.1 ± 9.1 seconds, P = 0.001), and 24 mg (19.0 ± 9.3 seconds, P < 0.001) doses. MBP fell further at 24 mg (ΔMBP: 27 ± 12 mmHg) and 18 mg (26 ± 13 mmHg) doses compared to 12 mg (22 ± 10 mmHg vs., P < 0.001). A significant reduction in AVB in patients >110 kg (65% vs. 91% in 70-110 kg group, P < 0.001) in response to adenosine was seen. ELECTROPHYSIOLOGICAL AND HEMODYNAMIC ASSESSMENT. An adenosine dose producing AVB is required to unmask dormant PV conduction. AVB is significantly reduced in patients >110 kg. Weight and dosing variability may in part explain the conflicting results of studies evaluating the clinical utility of adenosine in PVI. © 2016 Wiley Periodicals, Inc.

The Impact of Monte Carlo Dose Calculations on Intensity-Modulated Radiation Therapy

NASA Astrophysics Data System (ADS)

Siebers, J. V.; Keall, P. J.; Mohan, R.

The effect of dose calculation accuracy for IMRT was studied by comparing different dose calculation algorithms. A head and neck IMRT plan was optimized using a superposition dose calculation algorithm. Dose was re-computed for the optimized plan using both Monte Carlo and pencil beam dose calculation algorithms to generate patient and phantom dose distributions. Tumor control probabilities (TCP) and normal tissue complication probabilities (NTCP) were computed to estimate the plan outcome. For the treatment plan studied, Monte Carlo best reproduces phantom dose measurements, the TCP was slightly lower than the superposition and pencil beam results, and the NTCP values differed little.

Monte Carlo calculations of electron beam quality conversion factors for several ion chamber types.

PubMed

Muir, B R; Rogers, D W O

2014-11-01

To provide a comprehensive investigation of electron beam reference dosimetry using Monte Carlo simulations of the response of 10 plane-parallel and 18 cylindrical ion chamber types. Specific emphasis is placed on the determination of the optimal shift of the chambers' effective point of measurement (EPOM) and beam quality conversion factors. The EGSnrc system is used for calculations of the absorbed dose to gas in ion chamber models and the absorbed dose to water as a function of depth in a water phantom on which cobalt-60 and several electron beam source models are incident. The optimal EPOM shifts of the ion chambers are determined by comparing calculations of R50 converted from I50 (calculated using ion chamber simulations in phantom) to R50 calculated using simulations of the absorbed dose to water vs depth in water. Beam quality conversion factors are determined as the calculated ratio of the absorbed dose to water to the absorbed dose to air in the ion chamber at the reference depth in a cobalt-60 beam to that in electron beams. For most plane-parallel chambers, the optimal EPOM shift is inside of the active cavity but different from the shift determined with water-equivalent scaling of the front window of the chamber. These optimal shifts for plane-parallel chambers also reduce the scatter of beam quality conversion factors, kQ, as a function of R50. The optimal shift of cylindrical chambers is found to be less than the 0.5 rcav recommended by current dosimetry protocols. In most cases, the values of the optimal shift are close to 0.3 rcav. Values of kecal are calculated and compared to those from the TG-51 protocol and differences are explained using accurate individual correction factors for a subset of ion chambers investigated. High-precision fits to beam quality conversion factors normalized to unity in a beam with R50 = 7.5 cm (kQ (')) are provided. These factors avoid the use of gradient correction factors as used in the TG-51 protocol although a chamber dependent optimal shift in the EPOM is required when using plane-parallel chambers while no shift is needed with cylindrical chambers. The sensitivity of these results to parameters used to model the ion chambers is discussed and the uncertainty related to the practical use of these results is evaluated. These results will prove useful as electron beam reference dosimetry protocols are being updated. The analysis of this work indicates that cylindrical ion chambers may be appropriate for use in low-energy electron beams but measurements are required to characterize their use in these beams.

Adaptive radiation therapy of prostate cancer

NASA Astrophysics Data System (ADS)

Wen, Ning

ART is a close-loop feedback algorithm which evaluates the organ deformation and motion right before the treatment and takes into account dose delivery variation daily to compensate for the difference between planned and delivered dose. It also has potential to allow further dose escalation and margin reduction to improve the clinical outcome. This retrospective study evaluated ART for prostate cancer treatment and radiobiological consequences. An IRB approved protocol has been used to evaluate actual dose delivery of patients with prostate cancer undergoing treatment with daily CBCT. The dose from CBCT was measured in phantom using TLD and ion chamber techniques in the pelvic scan setting. There were two major findings from the measurements of CBCT dose: (1) the lateral dose distribution was not symmetrical, with Lt Lat being ˜40% higher than Rt Lat and (2) AP skin dose varies with patient size, ranging 3.2--6.1 cGy for patient's AP separation of 20--33 cm (the larger the separation, the less the skin dose) but lateral skin doses depend little on separations. Dose was recalculated on each CBCT set under the same treatment plan. DIR was performed between SIM-CT and evaluated for each CT sets. Dose was reconstructed and accumulated to reflect the actual dose delivered to the patient. Then the adaptive plans were compared to the original plan to evaluate tumor control and normal tissue complication using radiobiological model. Different PTV margins were also studied to access margin reduction techniques. If the actual dose delivered to the PTV deviated significantly from the prescription dose for the given fractions or the OAR received higher dose than expected, the treatment plan would be re-optimized based on the previously delivered dose. The optimal schedule was compared based on the balance of PTV dose coverage and inhomogeneity, OAR dose constraints and labor involved. DIR was validated using fiducial marker position, visual comparison and UE. The mean and standard deviation of markers after rigid registration in L-R direction was 0 and 1 mm. But the mean was 2--4 mm in the A-P and S-I direction and standard deviation was about 2 mm. After DIR, the mean in all three directions became 0 and standard deviation was within sub millimeter. UE images were generated for each CT set and carefully reviewed in the prostate region. DIR provided accurate transformation matrix to be used for dose reconstruction. The delivered dose was evaluated with radiobiological models. TCP for the CTV was calculated to evaluate tumor control in different margin settings. TCP calculated from the reconstructed dose agreed within 5% of the value in the plan for all patients with three different margins. EUD and NTCP were calculated to evaluate reaction of rectum to radiation. Similar biological evaluation was performed for bladder. EUD of actual dose was 3%--9% higher than that of planned dose of patient 1--3, 11%--20% higher of patient 4--5. Smaller margins could not reduce late GU toxicity effectively since bladder complication was directly related to Dmax which was at the same magnitude in the bladder no matter which margin was applied. Re-optimization was performed at the 10th, 20th , 30th, and 40th fraction to evaluate the effectiveness to limit OAR dose while maintaining the target coverage. Reconstructed dose was added to dose from remaining fractions after optimization to show the total dose patient would receive. It showed that if the plan was re-optimized at 10th or 20th fraction, total dose to rectum and bladder were very similar to planned dose with minor deviations. If the plan was re-optimized at the 30th fraction, since there was a large deviation between reconstructed dose and planned dose to OAR, optimization could not limit the OAR dose to the original plan with only 12 fractions left. If the re-optimization was done at the 40th fraction, it was impossible to compensate in the last 2 fractions. Large deviations of total dose to bladder and rectum still existed while dose inhomogeneity to PTV was significantly increased due to hard constraints set in the optimization to reduce OAR dose. In summary, ART did not show improvements in TCP if the patient was setup with CBCT. However, EUD of rectum and bladder was increased significantly due to tissue deformation which varied daily. With the power of ART, margins added to the CTV could be further reduced to preserve critical organs surrounding the target. (Abstract shortened by UMI.)

Exploratory Study of 4D Versus 3D Robust Optimization in Intensity-Modulated Proton Therapy for Lung Cancer

PubMed Central

Liu, Wei; Schild, Steven E.; Chang, Joe Y.; Liao, Zhongxing; Chang, Yu-Hui; Wen, Zhifei; Shen, Jiajian; Stoker, Joshua B.; Ding, Xiaoning; Hu, Yanle; Sahoo, Narayan; Herman, Michael G.; Vargas, Carlos; Keole, Sameer; Wong, William; Bues, Martin

2015-01-01

Background To compare the impact of uncertainties and interplay effect on 3D and 4D robustly optimized intensity-modulated proton therapy (IMPT) plans for lung cancer in an exploratory methodology study. Methods IMPT plans were created for 11 non-randomly selected non-small-cell lung cancer (NSCLC) cases: 3D robustly optimized plans on average CTs with internal gross tumor volume density overridden to irradiate internal target volume, and 4D robustly optimized plans on 4D CTs to irradiate clinical target volume (CTV). Regular fractionation (66 Gy[RBE] in 33 fractions) were considered. In 4D optimization, the CTV of individual phases received non-uniform doses to achieve a uniform cumulative dose. The root-mean-square-dose volume histograms (RVH) measured the sensitivity of the dose to uncertainties, and the areas under the RVH curve (AUCs) were used to evaluate plan robustness. Dose evaluation software modeled time-dependent spot delivery to incorporate interplay effect with randomized starting phases of each field per fraction. Dose-volume histogram indices comparing CTV coverage, homogeneity, and normal tissue sparing were evaluated using Wilcoxon signed-rank test. Results 4D robust optimization plans led to smaller AUC for CTV (14.26 vs. 18.61 (p=0.001), better CTV coverage (Gy[RBE]) [D95% CTV: 60.6 vs 55.2 (p=0.001)], and better CTV homogeneity [D5%–D95% CTV: 10.3 vs 17.7 (p=0.002)] in the face of uncertainties. With interplay effect considered, 4D robust optimization produced plans with better target coverage [D95% CTV: 64.5 vs 63.8 (p=0.0068)], comparable target homogeneity, and comparable normal tissue protection. The benefits from 4D robust optimization were most obvious for the 2 typical stage III lung cancer patients. Conclusions Our exploratory methodology study showed that, compared to 3D robust optimization, 4D robust optimization produced significantly more robust and interplay-effect-resistant plans for targets with comparable dose distributions for normal tissues. A further study with a larger and more realistic patient population is warranted to generalize the conclusions. PMID:26725727

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.

Dosimetric comparison of helical tomotherapy treatment plans for total marrow irradiation created using GPU and CPU dose calculation engines.

PubMed

Nalichowski, Adrian; Burmeister, Jay

2013-07-01

To compare optimization characteristics, plan quality, and treatment delivery efficiency between total marrow irradiation (TMI) plans using the new TomoTherapy graphic processing unit (GPU) based dose engine and CPU/cluster based dose engine. Five TMI plans created on an anthropomorphic phantom were optimized and calculated with both dose engines. The planning treatment volume (PTV) included all the bones from head to mid femur except for upper extremities. Evaluated organs at risk (OAR) consisted of lung, liver, heart, kidneys, and brain. The following treatment parameters were used to generate the TMI plans: field widths of 2.5 and 5 cm, modulation factors of 2 and 2.5, and pitch of either 0.287 or 0.43. The optimization parameters were chosen based on the PTV and OAR priorities and the plans were optimized with a fixed number of iterations. The PTV constraint was selected to ensure that at least 95% of the PTV received the prescription dose. The plans were evaluated based on D80 and D50 (dose to 80% and 50% of the OAR volume, respectively) and hotspot volumes within the PTVs. Gamma indices (Γ) were also used to compare planar dose distributions between the two modalities. The optimization and dose calculation times were compared between the two systems. The treatment delivery times were also evaluated. The results showed very good dosimetric agreement between the GPU and CPU calculated plans for any of the evaluated planning parameters indicating that both systems converge on nearly identical plans. All D80 and D50 parameters varied by less than 3% of the prescription dose with an average difference of 0.8%. A gamma analysis Γ(3%, 3 mm) < 1 of the GPU plan resulted in over 90% of calculated voxels satisfying Γ < 1 criterion as compared to baseline CPU plan. The average number of voxels meeting the Γ < 1 criterion for all the plans was 97%. In terms of dose optimization/calculation efficiency, there was a 20-fold reduction in planning time with the new GPU system. The average optimization/dose calculation time utilizing the traditional CPU/cluster based system was 579 vs 26.8 min for the GPU based system. There was no difference in the calculated treatment delivery time per fraction. Beam-on time varied based on field width and pitch and ranged between 15 and 28 min. The TomoTherapy GPU based dose engine is capable of calculating TMI treatment plans with plan quality nearly identical to plans calculated using the traditional CPU/cluster based system, while significantly reducing the time required for optimization and dose calculation.

Investigation of the PAGAT polymer gel dosimeter using magnetic resonance imaging

NASA Astrophysics Data System (ADS)

Venning, A. J.; Hill, B.; Brindha, S.; Healy, B. J.; Baldock, C.

2005-08-01

Investigation of the normoxic PAGAT polymer gel dosimeter has been undertaken. The concentrations of the chemical components of the gel were varied and its response to ionizing radiation evaluated. Using MRI, the formulation to give the maximum change in the transverse relaxation rate R2 was determined to be 4.5% N, N'-methylene-bis-acrylamide (bis), 4.5% acrylamide (AA), 5% gelatine, 5 mM tetrakis (hydroxymethyl) phosphonium chloride (THPC), 0.01 mM hydroquinone (HQ) and 86% H2O. The optimal post-manufacture irradiation and post-irradiation imaging times were both determined to be 12 h. The R2-dose response was linear up to 7 Gy with R2-dose sensitivities of (0.183 ± 0.005) s-1 Gy-1, (0.182 ± 0.005) s-1 Gy-1 and (0.192 ± 0.005) s-1 Gy-1 when imaged at 12 h, 7 days and 24 days post-irradiation, respectively. The R2-dose sensitivities were within the range of previously published values for the hypoxic PAG formulations. For the imaging parameters used in this study the optimum dose resolution was achieved for low doses. The normalized R2 edge response showed a high degree of spatial stability over a 24 day period. This study has shown that the normoxic PAGAT polymer gel has the properties of a dosimetric tool, which can be used in clinical radiotherapy. The PAGAT polymer gel has been shown to have similar qualities to the PAG polymer gel, while offering the significant advantage of simplification of the manufacturing procedure.

Neuroprotective Dose Response in RCS Rats Implanted with Microphotodiode Arrays

PubMed Central

Pardue, Machelle T.; Kim, Moon K.; Walker, Tiffany A.; Faulkner, Amanda E.; Chow, Alan Y.; Ciavatta, Vincent T.

2012-01-01

Purpose Neuropreservation of retinal function and structure in RCS rats following implantation of a microphotodiode array (MPA) has been shown in previous studies(Pardue et al. 2005a; Pardue et al. 2005b). Since microphotodiodes produce electrical currents in proportion to the intensity of incident light, increased light exposure may result in greater neuroprotective effects. Our previous studies suggested that the frequency of light exposure to electroretinogram (ERG) flash stimuli might provide increased neuroprotection. Thus, in this study, we examined the dose response of subretinal electrical stimulation by exposing RCS rats implanted with MPAs to variable durations and combinations of two different lighting regimens: pulsing incandescent bulbs and xenon stimuli from an ERG Ganzfeld. While incandescent light regimens did not produce any significant differences in ERG function, we found significantly greater dark-adapted ERG b-wave amplitudes in RCS rats that received weekly versus biweekly ERGs over the course of 8 weeks of follow-up. These results suggest that subretinal electrical stimulation may be optimized to produce greater neuroprotective effects by dosing with periodic higher current. PMID:22183323

Patient specific optimization-based treatment planning for catheter-based ultrasound hyperthermia and thermal ablation

NASA Astrophysics Data System (ADS)

Prakash, Punit; Chen, Xin; Wootton, Jeffery; Pouliot, Jean; Hsu, I.-Chow; Diederich, Chris J.

2009-02-01

A 3D optimization-based thermal treatment planning platform has been developed for the application of catheter-based ultrasound hyperthermia in conjunction with high dose rate (HDR) brachytherapy for treating advanced pelvic tumors. Optimal selection of applied power levels to each independently controlled transducer segment can be used to conform and maximize therapeutic heating and thermal dose coverage to the target region, providing significant advantages over current hyperthermia technology and improving treatment response. Critical anatomic structures, clinical target outlines, and implant/applicator geometries were acquired from sequential multi-slice 2D images obtained from HDR treatment planning and used to reconstruct patient specific 3D biothermal models. A constrained optimization algorithm was devised and integrated within a finite element thermal solver to determine a priori the optimal applied power levels and the resulting 3D temperature distributions such that therapeutic heating is maximized within the target, while placing constraints on maximum tissue temperature and thermal exposure of surrounding non-targeted tissue. This optimizationbased treatment planning and modeling system was applied on representative cases of clinical implants for HDR treatment of cervix and prostate to evaluate the utility of this planning approach. The planning provided significant improvement in achievable temperature distributions for all cases, with substantial increase in T90 and thermal dose (CEM43T90) coverage to the hyperthermia target volume while decreasing maximum treatment temperature and reducing thermal dose exposure to surrounding non-targeted tissues and thermally sensitive rectum and bladder. This optimization based treatment planning platform with catheter-based ultrasound applicators is a useful tool that has potential to significantly improve the delivery of hyperthermia in conjunction with HDR brachytherapy. The planning platform has been extended to model thermal ablation, including the addition of temperature dependent attenuation, perfusion, and tissue damage. Pilot point control at the target boundaries was implemented to control power delivery to each transducer section, simulating an approach feasible for MR guided procedures. The computer model of thermal ablation was evaluated on representative patient anatomies to demonstrate the feasibility of using catheter-based ultrasound thermal ablation for treatment of benign prostate hyperplasia (BPH) and prostate cancer, and to assist in designing applicators and treatment delivery strategies.

2D convolution kernels of ionization chambers used for photon-beam dosimetry in magnetic fields: the advantage of small over large chamber dimensions

NASA Astrophysics Data System (ADS)

Khee Looe, Hui; Delfs, Björn; Poppinga, Daniela; Harder, Dietrich; Poppe, Björn

2018-04-01

This study aims at developing an optimization strategy for photon-beam dosimetry in magnetic fields using ionization chambers. Similar to the familiar case in the absence of a magnetic field, detectors should be selected under the criterion that their measured 2D signal profiles M(x,y) approximate the absorbed dose to water profiles D(x,y) as closely as possible. Since the conversion of D(x,y) into M(x,y) is known as the convolution with the ‘lateral dose response function’ K(x-ξ, y-η) of the detector, the ideal detector would be characterized by a vanishing magnetic field dependence of this convolution kernel (Looe et al 2017b Phys. Med. Biol. 62 5131–48). The idea of the present study is to find out, by Monte Carlo simulation of two commercial ionization chambers of different size, whether the smaller chamber dimensions would be instrumental to approach this aim. As typical examples, the lateral dose response functions in the presence and absence of a magnetic field have been Monte-Carlo modeled for the new commercial ionization chambers PTW 31021 (‘Semiflex 3D’, internal radius 2.4 mm) and PTW 31022 (‘PinPoint 3D’, internal radius 1.45 mm), which are both available with calibration factors. The Monte-Carlo model of the ionization chambers has been adjusted to account for the presence of the non-collecting part of the air volume near the guard ring. The Monte-Carlo results allow a comparison between the widths of the magnetic field dependent photon fluence response function K M(x-ξ, y-η) and of the lateral dose response function K(x-ξ, y-η) of the two chambers with the width of the dose deposition kernel K D(x-ξ, y-η). The simulated dose and chamber signal profiles show that in small photon fields and in the presence of a 1.5 T field the distortion of the chamber signal profile compared with the true dose profile is weakest for the smaller chamber. The dose responses of both chambers at large field size are shown to be altered by not more than 2% in magnetic fields up to 1.5 T for all three investigated chamber orientations.

Monte Carlo simulations and benchmark measurements on the response of TE(TE) and Mg(Ar) ionization chambers in photon, electron and neutron beams

NASA Astrophysics Data System (ADS)

Lin, Yi-Chun; Huang, Tseng-Te; Liu, Yuan-Hao; Chen, Wei-Lin; Chen, Yen-Fu; Wu, Shu-Wei; Nievaart, Sander; Jiang, Shiang-Huei

2015-06-01

The paired ionization chambers (ICs) technique is commonly employed to determine neutron and photon doses in radiology or radiotherapy neutron beams, where neutron dose shows very strong dependence on the accuracy of accompanying high energy photon dose. During the dose derivation, it is an important issue to evaluate the photon and electron response functions of two commercially available ionization chambers, denoted as TE(TE) and Mg(Ar), used in our reactor based epithermal neutron beam. Nowadays, most perturbation corrections for accurate dose determination and many treatment planning systems are based on the Monte Carlo technique. We used general purposed Monte Carlo codes, MCNP5, EGSnrc, FLUKA or GEANT4 for benchmark verifications among them and carefully measured values for a precise estimation of chamber current from absorbed dose rate of cavity gas. Also, energy dependent response functions of two chambers were calculated in a parallel beam with mono-energies from 20 keV to 20 MeV photons and electrons by using the optimal simple spherical and detailed IC models. The measurements were performed in the well-defined (a) four primary M-80, M-100, M120 and M150 X-ray calibration fields, (b) primary 60Co calibration beam, (c) 6 MV and 10 MV photon, (d) 6 MeV and 18 MeV electron LINACs in hospital and (e) BNCT clinical trials neutron beam. For the TE(TE) chamber, all codes were almost identical over the whole photon energy range. In the Mg(Ar) chamber, MCNP5 showed lower response than other codes for photon energy region below 0.1 MeV and presented similar response above 0.2 MeV (agreed within 5% in the simple spherical model). With the increase of electron energy, the response difference between MCNP5 and other codes became larger in both chambers. Compared with the measured currents, MCNP5 had the difference from the measurement data within 5% for the 60Co, 6 MV, 10 MV, 6 MeV and 18 MeV LINACs beams. But for the Mg(Ar) chamber, the derivations reached 7.8-16.5% below 120 kVp X-ray beams. In this study, we were especially interested in BNCT doses where low energy photon contribution is less to ignore, MCNP model is recognized as the most suitable to simulate wide photon-electron and neutron energy distributed responses of the paired ICs. Also, MCNP provides the best prediction of BNCT source adjustment by the detector's neutron and photon responses.

Discovery of ONO-7300243 from a Novel Class of Lysophosphatidic Acid Receptor 1 Antagonists: From Hit to Lead

PubMed Central

2016-01-01

Lysophosphatidic acid (LPA) evokes various physiological responses through a series of G protein-coupled receptors known as LPA1–6. A high throughput screen against LPA1 gave compound 7a as a hit. The subsequent optimization of 7a led to ONO-7300243 (17a) as a novel, potent LPA1 antagonist, which showed good efficacy in vivo. The oral dosing of 17a at 30 mg/kg led to reduced intraurethral pressure in rats. Notably, this compound was equal in potency to the α1 adrenoceptor antagonist tamsulosin, which is used in clinical practice to treat dysuria with benign prostatic hyperplasia (BPH). In contrast to tamsulosin, compound 17a had no impact on the mean blood pressure at this dose. These results suggest that LPA1 antagonists could be used to treat BPH without affecting the blood pressure. Herein, we report the hit-to-lead optimization of a unique series of LPA1 antagonists and their in vivo efficacy. PMID:27774128

Guaranteed epsilon-optimal treatment plans with the minimum number of beams for stereotactic body radiation therapy

NASA Astrophysics Data System (ADS)

Yarmand, Hamed; Winey, Brian; Craft, David

2013-09-01

Stereotactic body radiation therapy (SBRT) is characterized by delivering a high amount of dose in a short period of time. In SBRT the dose is delivered using open fields (e.g., beam’s-eye-view) known as ‘apertures’. Mathematical methods can be used for optimizing treatment planning for delivery of sufficient dose to the cancerous cells while keeping the dose to surrounding organs at risk (OARs) minimal. Two important elements of a treatment plan are quality and delivery time. Quality of a plan is measured based on the target coverage and dose to OARs. Delivery time heavily depends on the number of beams used in the plan as the setup times for different beam directions constitute a large portion of the delivery time. Therefore the ideal plan, in which all potential beams can be used, will be associated with a long impractical delivery time. We use the dose to OARs in the ideal plan to find the plan with the minimum number of beams which is guaranteed to be epsilon-optimal (i.e., a predetermined maximum deviation from the ideal plan is guaranteed). Since the treatment plan optimization is inherently a multi-criteria-optimization problem, the planner can navigate the ideal dose distribution Pareto surface and select a plan of desired target coverage versus OARs sparing, and then use the proposed technique to reduce the number of beams while guaranteeing epsilon-optimality. We use mixed integer programming (MIP) for optimization. To reduce the computation time for the resultant MIP, we use two heuristics: a beam elimination scheme and a family of heuristic cuts, known as ‘neighbor cuts’, based on the concept of ‘adjacent beams’. We show the effectiveness of the proposed technique on two clinical cases, a liver and a lung case. Based on our technique we propose an algorithm for fast generation of epsilon-optimal plans.

A GPU-accelerated and Monte Carlo-based intensity modulated proton therapy optimization system.

PubMed

Ma, Jiasen; Beltran, Chris; Seum Wan Chan Tseung, Hok; Herman, Michael G

2014-12-01

Conventional spot scanning intensity modulated proton therapy (IMPT) treatment planning systems (TPSs) optimize proton spot weights based on analytical dose calculations. These analytical dose calculations have been shown to have severe limitations in heterogeneous materials. Monte Carlo (MC) methods do not have these limitations; however, MC-based systems have been of limited clinical use due to the large number of beam spots in IMPT and the extremely long calculation time of traditional MC techniques. In this work, the authors present a clinically applicable IMPT TPS that utilizes a very fast MC calculation. An in-house graphics processing unit (GPU)-based MC dose calculation engine was employed to generate the dose influence map for each proton spot. With the MC generated influence map, a modified least-squares optimization method was used to achieve the desired dose volume histograms (DVHs). The intrinsic CT image resolution was adopted for voxelization in simulation and optimization to preserve spatial resolution. The optimizations were computed on a multi-GPU framework to mitigate the memory limitation issues for the large dose influence maps that resulted from maintaining the intrinsic CT resolution. The effects of tail cutoff and starting condition were studied and minimized in this work. For relatively large and complex three-field head and neck cases, i.e., >100,000 spots with a target volume of ∼ 1000 cm(3) and multiple surrounding critical structures, the optimization together with the initial MC dose influence map calculation was done in a clinically viable time frame (less than 30 min) on a GPU cluster consisting of 24 Nvidia GeForce GTX Titan cards. The in-house MC TPS plans were comparable to a commercial TPS plans based on DVH comparisons. A MC-based treatment planning system was developed. The treatment planning can be performed in a clinically viable time frame on a hardware system costing around 45,000 dollars. The fast calculation and optimization make the system easily expandable to robust and multicriteria optimization.

SU-G-TeP3-13: The Role of Nanoscale Energy Deposition in the Development of Gold Nanoparticle-Enhanced Radiotherapy

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

Kirkby, C; The University of Calgary, Calgary, AB; Koger, B

2016-06-15

Purpose: Gold nanoparticles (GNPs) can enhance radiotherapy effects. The high photoelectric cross section of gold relative to tissue, particularly at lower energies, leads to localized dose enhancement. However in a clinical context, photon energies must also be sufficient to reach a target volume at a given depth. These properties must be balanced to optimize such a therapy. Given that nanoscale energy deposition patterns around GNPs play a role in determining biological outcomes, in this work we seek to establish their role in this optimization process. Methods: The PENELOPE Monte Carlo code was used to generate spherical dose deposition kernels inmore » 1000 nm diameter spheres around 50 nm diameter GNPs in response to monoenergetic photons incident on the GNP. Induced “lesions” were estimated by either a local effect model (LEM) or a mean dose model (MDM). The ratio of these estimates was examined for a range of photon energies (10 keV to 2 MeV), for three sets of linear-quadratic parameters. Results: The models produce distinct differences in expected lesion values, the lower the alpha-beta ratio, the greater the difference. The ratio of expected lesion values remained constant within 5% for energies of 40 keV and above across all parameter sets and rose to a difference of 35% for lower energies only for the lowest alpha-beta ratio. Conclusion: Consistent with other work, these calculations suggest nanoscale energy deposition patterns matter in predicting biological response to GNP-enhanced radiotherapy. However the ratio of expected lesions between the different models is largely independent of energy, indicating that GNP-enhanced radiotherapy scenarios can be optimized in photon energy without consideration of the nanoscale patterns. Special attention may be warranted for energies of 20 keV or below and low alpha-beta ratios.« less

Review of Hybrid (Deterministic/Monte Carlo) Radiation Transport Methods, Codes, and Applications at Oak Ridge National Laboratory

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

Wagner, John C; Peplow, Douglas E.; Mosher, Scott W

2010-01-01

This paper provides a review of the hybrid (Monte Carlo/deterministic) radiation transport methods and codes used at the Oak Ridge National Laboratory and examples of their application for increasing the efficiency of real-world, fixed-source Monte Carlo analyses. The two principal hybrid methods are (1) Consistent Adjoint Driven Importance Sampling (CADIS) for optimization of a localized detector (tally) region (e.g., flux, dose, or reaction rate at a particular location) and (2) Forward Weighted CADIS (FW-CADIS) for optimizing distributions (e.g., mesh tallies over all or part of the problem space) or multiple localized detector regions (e.g., simultaneous optimization of two or moremore » localized tally regions). The two methods have been implemented and automated in both the MAVRIC sequence of SCALE 6 and ADVANTG, a code that works with the MCNP code. As implemented, the methods utilize the results of approximate, fast-running 3-D discrete ordinates transport calculations (with the Denovo code) to generate consistent space- and energy-dependent source and transport (weight windows) biasing parameters. These methods and codes have been applied to many relevant and challenging problems, including calculations of PWR ex-core thermal detector response, dose rates throughout an entire PWR facility, site boundary dose from arrays of commercial spent fuel storage casks, radiation fields for criticality accident alarm system placement, and detector response for special nuclear material detection scenarios and nuclear well-logging tools. Substantial computational speed-ups, generally O(10{sup 2-4}), have been realized for all applications to date. This paper provides a brief review of the methods, their implementation, results of their application, and current development activities, as well as a considerable list of references for readers seeking more information about the methods and/or their applications.« less

Development, validation, and implementation of a patient-specific Monte Carlo 3D internal dosimetry platform

NASA Astrophysics Data System (ADS)

Besemer, Abigail E.

Targeted radionuclide therapy is emerging as an attractive treatment option for a broad spectrum of tumor types because it has the potential to simultaneously eradicate both the primary tumor site as well as the metastatic disease throughout the body. Patient-specific absorbed dose calculations for radionuclide therapies are important for reducing the risk of normal tissue complications and optimizing tumor response. However, the only FDA approved software for internal dosimetry calculates doses based on the MIRD methodology which estimates mean organ doses using activity-to-dose scaling factors tabulated from standard phantom geometries. Despite the improved dosimetric accuracy afforded by direct Monte Carlo dosimetry methods these methods are not widely used in routine clinical practice because of the complexity of implementation, lack of relevant standard protocols, and longer dose calculation times. The main goal of this work was to develop a Monte Carlo internal dosimetry platform in order to (1) calculate patient-specific voxelized dose distributions in a clinically feasible time frame, (2) examine and quantify the dosimetric impact of various parameters and methodologies used in 3D internal dosimetry methods, and (3) develop a multi-criteria treatment planning optimization framework for multi-radiopharmaceutical combination therapies. This platform utilizes serial PET/CT or SPECT/CT images to calculate voxelized 3D internal dose distributions with the Monte Carlo code Geant4. Dosimetry can be computed for any diagnostic or therapeutic radiopharmaceutical and for both pre-clinical and clinical applications. In this work, the platform's dosimetry calculations were successfully validated against previously published reference doses values calculated in standard phantoms for a variety of radionuclides, over a wide range of photon and electron energies, and for many different organs and tumor sizes. Retrospective dosimetry was also calculated for various pre-clinical and clinical patients and large dosimetric differences resulted when using conventional organ-level methods and the patient-specific voxelized methods described in this work. The dosimetric impact of various steps in the 3D voxelized dosimetry process were evaluated including quantitative imaging acquisition, image coregistration, voxel resampling, ROI contouring, CT-based material segmentation, and pharmacokinetic fitting. Finally, a multi-objective treatment planning optimization framework was developed for multi-radiopharmaceutical combination therapies.

Optimal Design for the Precise Estimation of an Interaction Threshold: The Impact of Exposure to a Mixture of 18 Polyhalogenated Aromatic Hydrocarbons

PubMed Central

Yeatts, Sharon D.; Gennings, Chris; Crofton, Kevin M.

2014-01-01

Traditional additivity models provide little flexibility in modeling the dose–response relationships of the single agents in a mixture. While the flexible single chemical required (FSCR) methods allow greater flexibility, its implicit nature is an obstacle in the formation of the parameter covariance matrix, which forms the basis for many statistical optimality design criteria. The goal of this effort is to develop a method for constructing the parameter covariance matrix for the FSCR models, so that (local) alphabetic optimality criteria can be applied. Data from Crofton et al. are provided as motivation; in an experiment designed to determine the effect of 18 polyhalogenated aromatic hydrocarbons on serum total thyroxine (T4), the interaction among the chemicals was statistically significant. Gennings et al. fit the FSCR interaction threshold model to the data. The resulting estimate of the interaction threshold was positive and within the observed dose region, providing evidence of a dose-dependent interaction. However, the corresponding likelihood-ratio-based confidence interval was wide and included zero. In order to more precisely estimate the location of the interaction threshold, supplemental data are required. Using the available data as the first stage, the Ds-optimal second-stage design criterion was applied to minimize the variance of the hypothesized interaction threshold. Practical concerns associated with the resulting design are discussed and addressed using the penalized optimality criterion. Results demonstrate that the penalized Ds-optimal second-stage design can be used to more precisely define the interaction threshold while maintaining the characteristics deemed important in practice. PMID:22640366

Dose-response relationship of cardiorespiratory fitness adaptation to controlled endurance training in sedentary older adults.

PubMed

Huang, Guoyuan; Wang, Ru; Chen, Peijie; Huang, Sunny C; Donnelly, Joseph E; Mehlferber, Jon P

2016-03-01

The purpose of this investigation was to identify a quantitative dose-response relationship for enhancing maximal oxygen consumption (VO2max) in healthy sedentary older adults after controlled endurance training. This meta-analysis of controlled clinical trials included 1257 exercisers and 845 controls with a mean age of 67.45 ± 5.25 years. Effect sizes were calculated for training-induced VO2max changes. Different training regimens were analyzed and compared. The weighted net change of the mean VO2max values showed a significant increase of 3.78 ml/kg per min (95% confidence interval = 3.29 to 4.27; p < 0.0001) in response to aerobic training. Interstudy differences in VO2max changes were significantly related to exercise intensity, and explained approximately 11% of the variance of the VO2max responses. VO2max improved significantly at 35%-50% heart rate reserve (HRR) and continued improving at a greater rate with increasing "dose". The largest VO2max-improvement adaptation was achieved with a mean intensity of 66%-73% HRR. The magnitudes of the VO2max adaptation are identical to exercise at 57%-65% HRR and at 75%-80% HRR. Higher intensity doses more than 75-80% HRR did not lead to greater enhancement of VO2max improvements but, conversely, resulted in large declines. Our data provide quantitative insight into the magnitude of VO2max alterations as affected by exercise intensity, duration, frequency, and program length. The shapes of the dose-response curves are not simply linear, but with many similar trends and noteworthy characteristics. Aerobic training at a mean intensity of 66%-73% HRR with 40-50 min per session for 3-4 day/week for 30-40 weeks appears to be effective and optimal for maximum cardiorespiratory benefits in healthy sedentary older adults. © The European Society of Cardiology 2015.

Convex reformulation of biologically-based multi-criteria intensity-modulated radiation therapy optimization including fractionation effects

NASA Astrophysics Data System (ADS)

Hoffmann, Aswin L.; den Hertog, Dick; Siem, Alex Y. D.; Kaanders, Johannes H. A. M.; Huizenga, Henk

2008-11-01

Finding fluence maps for intensity-modulated radiation therapy (IMRT) can be formulated as a multi-criteria optimization problem for which Pareto optimal treatment plans exist. To account for the dose-per-fraction effect of fractionated IMRT, it is desirable to exploit radiobiological treatment plan evaluation criteria based on the linear-quadratic (LQ) cell survival model as a means to balance the radiation benefits and risks in terms of biologic response. Unfortunately, the LQ-model-based radiobiological criteria are nonconvex functions, which make the optimization problem hard to solve. We apply the framework proposed by Romeijn et al (2004 Phys. Med. Biol. 49 1991-2013) to find transformations of LQ-model-based radiobiological functions and establish conditions under which transformed functions result in equivalent convex criteria that do not change the set of Pareto optimal treatment plans. The functions analysed are: the LQ-Poisson-based model for tumour control probability (TCP) with and without inter-patient heterogeneity in radiation sensitivity, the LQ-Poisson-based relative seriality s-model for normal tissue complication probability (NTCP), the equivalent uniform dose (EUD) under the LQ-Poisson model and the fractionation-corrected Probit-based model for NTCP according to Lyman, Kutcher and Burman. These functions differ from those analysed before in that they cannot be decomposed into elementary EUD or generalized-EUD functions. In addition, we show that applying increasing and concave transformations to the convexified functions is beneficial for the piecewise approximation of the Pareto efficient frontier.

Is oral immunotherapy the cure for food allergies?

PubMed

Nowak-Wegrzyn, Anna; Fiocchi, Alessandro

2010-06-01

To review current evidence on food oral immunotherapy (OIT). Desensitized state, defined as the ingestion of a substantial amount of food in the home diet that protects from severe reactions to accidental exposures, can be achieved by approximately 50-75% of the children treated with OIT. The rate of permanent tolerance is unknown; the longer duration of OIT may result in permanent tolerance. Side effects are common both during the initial dose escalation and during home dosing. Most reactions are mild (oral pruritus, abdominal discomfort, and rashes) and decrease in frequency with the longer duration of OIT. Severe reactions treated with epinephrine have been reported during home dosing. Factors associated with increased risk of reactions to previously tolerated doses during home dosing include exercise, viral infection, dosing on empty stomach, menses, and asthma exacerbation. These preliminary data on OIT are encouraging. Additional studies must answer multiple questions including optimal dose, ideal duration of oral/sublingual immunotherapy, degree of protection, efficacy for different ages, severity and type of food allergy responsive to treatment and need for patient protection during home administration. Until these questions are answered in rigorous multicenter randomized and placebo-controlled trials, OIT remains an experimental approach with not sufficiently well established risk-to-benefit ratio.

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.

A phase I and pharmacokinetic study of lapatinib in combination with infusional 5-fluorouracil, leucovorin and irinotecan.

PubMed

Midgley, R S; Kerr, D J; Flaherty, K T; Stevenson, J P; Pratap, S E; Koch, K M; Smith, D A; Versola, M; Fleming, R A; Ward, C; O'Dwyer, P J; Middleton, M R

2007-12-01

This study determined the optimally tolerated regimen (OTR) of oral lapatinib administered in combination with infusional 5-fluorouracil (5-FU), leucovorin and irinotecan (FOLFIRI) and assessed the safety, tolerability and pharmacokinetics of the combination. Twenty-five patients were enrolled; 12 patients were treated at three dose levels to determine OTR; then 13 patients were treated at OTR to evaluate the pharmacokinetics of the combination. The 2-weekly OTR comprised lapatinib 1250 mg/day with irinotecan 108 mg/m(2) (day 1) and leucovorin 200 mg/m(2), 5-FU bolus 240 mg/m(2) and 5-FU infusion 360 mg/m(2) (days 1 and 2); doses of 5-FU and irinotecan represent a 40% reduction in dose compared to conventional FOLFIRI. Dose-limiting toxicities were grade 3 diarrhoea and grade 4 neutropenia. Co-administration of lapatinib increased the area under the plasma concentration-time curve of SN-38, the active metabolite of irinotecan, by an average of 41%; no other pharmacokinetic interactions were observed. Of 19 patients evaluable for disease response assessment, four patients had partial response and nine patients had stable disease. The combination of lapatinib and FOLFIRI is safe and demonstrates clinical activity; the documented PK interaction can effectively be compensated by lowering the doses of 5-FU and irinotecan. This regime may be further tested in a phase II trial.

Optimizing therapeutics in the management of patients with multiple sclerosis: a review of drug efficacy, dosing, and mechanisms of action

PubMed Central

Damal, Kavitha; Stoker, Emily; Foley, John F

2013-01-01

Multiple sclerosis (MS) is a debilitating neurological disorder that affects nearly 2 million adults, mostly in the prime of their youth. An environmental trigger, such as a viral infection, is hypothesized to initiate the abnormal behavior of host immune cells: to attack and damage the myelin sheath surrounding the neurons of the central nervous system. While several other pathways and disease triggers are still being investigated, it is nonetheless clear that MS is a heterogeneous disease with multifactorial etiologies that works independently or synergistically to initiate the aberrant immune responses to myelin. Although there are still no definitive markers to diagnose the disease or to cure the disease per se, research on management of MS has improved many fold over the past decade. New disease-modifying therapeutics are poised to decrease immune inflammatory responses and consequently decelerate the progression of MS disease activity, reduce the exacerbations of MS symptoms, and stabilize the physical and mental status of individuals. In this review, we describe the mechanism of action, optimal dosing, drug administration, safety, and efficacy of the disease-modifying therapeutics that are currently approved for MS therapy. We also briefly touch upon the new drugs currently under investigation, and discuss the future of MS therapeutics. PMID:24324326

Optimizing therapeutics in the management of patients with multiple sclerosis: a review of drug efficacy, dosing, and mechanisms of action.

PubMed

Damal, Kavitha; Stoker, Emily; Foley, John F

2013-01-01

Multiple sclerosis (MS) is a debilitating neurological disorder that affects nearly 2 million adults, mostly in the prime of their youth. An environmental trigger, such as a viral infection, is hypothesized to initiate the abnormal behavior of host immune cells: to attack and damage the myelin sheath surrounding the neurons of the central nervous system. While several other pathways and disease triggers are still being investigated, it is nonetheless clear that MS is a heterogeneous disease with multifactorial etiologies that works independently or synergistically to initiate the aberrant immune responses to myelin. Although there are still no definitive markers to diagnose the disease or to cure the disease per se, research on management of MS has improved many fold over the past decade. New disease-modifying therapeutics are poised to decrease immune inflammatory responses and consequently decelerate the progression of MS disease activity, reduce the exacerbations of MS symptoms, and stabilize the physical and mental status of individuals. In this review, we describe the mechanism of action, optimal dosing, drug administration, safety, and efficacy of the disease-modifying therapeutics that are currently approved for MS therapy. We also briefly touch upon the new drugs currently under investigation, and discuss the future of MS therapeutics.

Vitamin D: Immuno-modulation and tuberculosis treatment.

PubMed

Selvaraj, Paramasivam; Harishankar, Murugesan; Afsal, Kolloli

2015-05-01

Tuberculosis (TB) is a major global health problem and often coincides with vitamin D deficiency. High doses of vitamin D were widely used to treat TB during the pre-antibiotic era. Vitamin D exerts its action through vitamin D receptor (VDR), and VDR gene polymorphisms are associated with susceptibility or resistance to tuberculosis as well as sputum smear and culture conversion during anti-TB treatment. In-vitro studies have revealed that 1,25-dihydroxyvitamin D3 enhances innate immunity by increased expression of various antimicrobial peptides, including cathelicidin, and induction of autophagy of the infected cells thus restricts the intracellular growth of Mycobacterium tuberculosis in macrophages. On the other hand, vitamin D has been shown to suppress the pro-inflammatory cytokine response and enhance the anti-inflammatory response. Supplementation with vitamin D in concert with treatment for TB may be beneficial with respect to minimizing the excessive tissue damage that occurs during the active stage of tuberculosis disease. Several clinical trials have evaluated vitamin D supplementation as an adjunct therapy in the treatment for tuberculosis. However, results are conflicting, owing to variations in dose regimens and outcomes. Further investigations are needed to find the optimal concentration of vitamin D for supplementation with standard anti-TB drugs to optimize treatment, which could help to effectively manage both drug-sensitive and drug-resistant tuberculosis.

Mathematical optimization of high dose-rate brachytherapy—derivation of a linear penalty model from a dose-volume model

NASA Astrophysics Data System (ADS)

Morén, B.; Larsson, T.; Carlsson Tedgren, Å.

2018-03-01

High dose-rate brachytherapy is a method for cancer treatment where the radiation source is placed within the body, inside or close to a tumour. For dose planning, mathematical optimization techniques are being used in practice and the most common approach is to use a linear model which penalizes deviations from specified dose limits for the tumour and for nearby organs. This linear penalty model is easy to solve, but its weakness lies in the poor correlation of its objective value and the dose-volume objectives that are used clinically to evaluate dose distributions. Furthermore, the model contains parameters that have no clear clinical interpretation. Another approach for dose planning is to solve mixed-integer optimization models with explicit dose-volume constraints which include parameters that directly correspond to dose-volume objectives, and which are therefore tangible. The two mentioned models take the overall goals for dose planning into account in fundamentally different ways. We show that there is, however, a mathematical relationship between them by deriving a linear penalty model from a dose-volume model. This relationship has not been established before and improves the understanding of the linear penalty model. In particular, the parameters of the linear penalty model can be interpreted as dual variables in the dose-volume model.

High dose of plasmid IL-15 inhibits immune responses in an influenza non-human primates immunogenicity model

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

Yin Jiangmei; Dai Anlan; Laddy, Dominick J.

2009-10-10

Interleukin (IL)-15, is a cytokine that is important for the maintenance of long-lasting, high-avidity T cell response to invading pathogens and has, therefore, been used in vaccine and therapeutic platforms as an adjuvant. In addition to pure protein delivery, plasmids encoding the IL-15 gene have been utilized. However, it is critical to determine the appropriate dose to maximize the adjuvanting effects. We immunized rhesus macaques with different doses of IL-15 expressing plasmid in an influenza non-human primate immunogenicity model. We found that co-immunization of rhesus macaques with a Flu DNA-based vaccine and low doses of plasmid encoding macaque IL-15 enhancedmore » the production of IFN-gamma (0.5 mg) and the proliferation of CD4{sup +} and CD8{sup +} T cells, as well as T{sub CM} levels in proliferating CD8{sup +} T cells (0.25 mg). Whereas, high doses of IL-15 (4 mg) decrease the production of IFN-gamma and the proliferation of CD4{sup +} and CD8{sup +} T cells and T{sub CM} levels in the proliferating CD4{sup +} and CD8{sup +} T cells. In addition, the data of hemagglutination inhibition (HI) antibody titer suggest that although not significantly different, there appears to be a slight increase in antibodies at lower doses of IL-15. Importantly, however, the higher doses of IL-15 decrease the antibody levels significantly. This study demonstrates the importance of optimizing DNA-based cytokine adjuvants.« less

Is there a role for pharmacokinetic/pharmacodynamic-guided dosing for novel oral anticoagulants?

PubMed

Chan, Noel; Sager, Philip T; Lawrence, Jack; Ortel, Thomas's; Reilly, Paul; Berkowitz, Scott; Kubitza, Dagmar; Eikelboom, John; Florian, Jeffry; Stockbridge, Norman; Rose, Martin; Temple, Robert; Seltzer, Jonathan H

2018-05-01

The novel direct oral anticoagulants (NOACs) represent a major advance in oral anticoagulant therapy and are replacing vitamin K antagonists as the preferred options for many indications. Given in fixed doses without routine laboratory monitoring, they have been shown to be at least as effective in reducing thromboembolic stroke as dose-adjusted warfarin in phase 3 randomized trials and less likely to cause hemorrhagic stroke. Pharmacokinetic and/or pharmacodynamic subanalyses of the major NOAC trials in patients with atrial fibrillation have established relationships between clinical characteristics, and drug levels and/or pharmacodynamic responses with both efficacy and safety. Based on these analyses, pharmaceutical manufacturers and regulatory authorities have provided contraindications and dosing recommendations based on clinical characteristics that are associated with drug levels and/or pharmacodynamic responses, stroke reduction, and bleeding risk to optimize the risk-benefit profile of the NOACs in the real world. The current fixed-dosing strategy of NOACs has triggered discussions about the potential value of laboratory monitoring and dose adjustment in customizing drug exposure to further improve the safety and efficacy of the NOACs in patients with atrial fibrillation. As there is neither high-quality evidence nor consensus about the potential role of laboratory monitoring and dose adjustment for the NOACs, a Cardiac Research Safety Consortium "Think Tank" meeting was held at the American College of Cardiology Heart House in December 2015 to discussions these issues. This manuscript reports on the deliberations and the conclusions reached at that meeting. Copyright © 2017. Published by Elsevier Inc.

Physical activity and cancer risk: dose-response and cancer, all sites and site-specific.

PubMed

Thune, I; Furberg, A S

2001-06-01

The association between physical activity and overall and site-specific cancer risk is elaborated in relation to whether any observed dose-response association between physical activity and cancer can be interpreted in terms of how much physical activity (type, intensity, duration, frequency) is needed to influence site- and gender-specific cancer risk. Observational studies were reviewed that have examined the independent effect of the volume of occupational physical activity (OPA) and/or leisure time physical activity (LPA) on overall and site-specific cancer risk. The evidence of cohort and case-control studies suggests that both leisure time and occupational physical activity protect against overall cancer risk, with a graded dose-response association suggested in both sexes. Confounding effects such as diet, body weight, and parity are often included as a covariate in the analyses, with little influence on the observed associations. A crude graded inverse dose-response association was observed between physical activity and colon cancer in 48 studies including 40,674 colon/colorectal cancer cases for both sexes. A dose-response effect of physical activity on colon cancer risk was especially observed, when participation in activities of at least moderate activity (>4.5 MET) and demonstrated by activities expressed as MET-hours per week. An observed inverse association with a dose-response relationship between physical activity and breast cancer was also identified in the majority of the 41 studies including 108,031 breast cancer cases. The dose-response relationship was in particular observed in case-control studies and supported by observations in cohort studies when participation in activities of at least moderate activity (>4.5 MET) and demonstrated by activities expressed by MET-hours per week. This association between physical activity and breast cancer risk is possibly dependent on age at exposure, age at diagnosis, menopausal status and other effect modifiers, e.g., body mass index. Furthermore, data concerning carcinoma of other cancers (prostate, lung, endometrium, ovary, and testicular cancers) are required. A protective effect of physical activity on site-specific cancer risk with a dose-response association between physical activity and colon and pre- and postmenopausal breast cancer supported by identified biological mechanisms has been observed. The optimal permutation of type, intensity, duration, and frequency of physical activity across the lifespan is unclear, but it is gender, age, and site specific and supports moderate activity (>4.5 MET) more than light activities (<4.5 MET). The complicated nature of the physical activity variable, combined with lack of knowledge regarding possible biological mechanisms operating between physical activity and cancer, warrants further studies including controlled clinical randomized trials.

Real-time Tumor Oxygenation Changes After Single High-dose Radiation Therapy in Orthotopic and Subcutaneous Lung Cancer in Mice: Clinical Implication for Stereotactic Ablative Radiation Therapy Schedule Optimization

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

Song, Changhoon; Hong, Beom-Ju; Bok, Seoyeon

Purpose: To investigate the serial changes of tumor hypoxia in response to single high-dose irradiation by various clinical and preclinical methods to propose an optimal fractionation schedule for stereotactic ablative radiation therapy. Methods and Materials: Syngeneic Lewis lung carcinomas were grown either orthotopically or subcutaneously in C57BL/6 mice and irradiated with a single dose of 15 Gy to mimic stereotactic ablative radiation therapy used in the clinic. Serial [{sup 18}F]-misonidazole (F-MISO) positron emission tomography (PET) imaging, pimonidazole fluorescence-activated cell sorting analyses, hypoxia-responsive element-driven bioluminescence, and Hoechst 33342 perfusion were performed before irradiation (day −1), at 6 hours (day 0), and 2 (daymore » 2) and 6 (day 6) days after irradiation for both subcutaneous and orthotopic lung tumors. For F-MISO, the tumor/brain ratio was analyzed. Results: Hypoxic signals were too low to quantitate for orthotopic tumors using F-MISO PET or hypoxia-responsive element-driven bioluminescence imaging. In subcutaneous tumors, the maximum tumor/brain ratio was 2.87 ± 0.483 at day −1, 1.67 ± 0.116 at day 0, 2.92 ± 0.334 at day 2, and 2.13 ± 0.385 at day 6, indicating that tumor hypoxia was decreased immediately after irradiation and had returned to the pretreatment levels at day 2, followed by a slight decrease by day 6 after radiation. Pimonidazole analysis also revealed similar patterns. Using Hoechst 33342 vascular perfusion dye, CD31, and cleaved caspase 3 co-immunostaining, we found a rapid and transient vascular collapse, which might have resulted in poor intratumor perfusion of F-MISO PET tracer or pimonidazole delivered at day 0, leading to decreased hypoxic signals at day 0 by PET or pimonidazole analyses. Conclusions: We found tumor hypoxia levels decreased immediately after delivery of a single dose of 15 Gy and had returned to the pretreatment levels 2 days after irradiation and had decreased slightly by day 6. Our results indicate that single high-dose irradiation can produce a rapid, but reversible, vascular collapse in tumors.« less

Selective robust optimization: A new intensity-modulated proton therapy optimization strategy

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

Li, Yupeng; Niemela, Perttu; Siljamaki, Sami

2015-08-15

Purpose: To develop a new robust optimization strategy for intensity-modulated proton therapy as an important step in translating robust proton treatment planning from research to clinical applications. Methods: In selective robust optimization, a worst-case-based robust optimization algorithm is extended, and terms of the objective function are selectively computed from either the worst-case dose or the nominal dose. Two lung cancer cases and one head and neck cancer case were used to demonstrate the practical significance of the proposed robust planning strategy. The lung cancer cases had minimal tumor motion less than 5 mm, and, for the demonstration of the methodology,more » are assumed to be static. Results: Selective robust optimization achieved robust clinical target volume (CTV) coverage and at the same time increased nominal planning target volume coverage to 95.8%, compared to the 84.6% coverage achieved with CTV-based robust optimization in one of the lung cases. In the other lung case, the maximum dose in selective robust optimization was lowered from a dose of 131.3% in the CTV-based robust optimization to 113.6%. Selective robust optimization provided robust CTV coverage in the head and neck case, and at the same time improved controls over isodose distribution so that clinical requirements may be readily met. Conclusions: Selective robust optimization may provide the flexibility and capability necessary for meeting various clinical requirements in addition to achieving the required plan robustness in practical proton treatment planning settings.« less

Optimizing hydroxyurea therapy for sickle cell anemia.

PubMed

Ware, Russell E

2015-01-01

Hydroxyurea has proven efficacy in numerous clinical trials as a disease-modifying treatment for patients with sickle cell anemia (SCA) but is currently under-used in clinical practice. To improve the effectiveness of hydroxyurea therapy, efforts should be directed toward broadening the clinical treatment indications, optimizing the daily dosage, and emphasizing the benefits of early and extended treatment. Here, various issues related to hydroxyurea treatment are discussed, focusing on both published evidence and clinical experience. Specific guidance is provided regarding important but potentially unfamiliar aspects of hydroxyurea treatment for SCA, such as escalating to maximum tolerated dose, treating in the setting of cerebrovascular disease, switching from chronic transfusions to hydroxyurea, and using serial phlebotomy to alleviate iron overload. Future research directions to optimize hydroxyurea therapy are also discussed, including personalized dosing based on pharmacokinetic modeling, prediction of fetal hemoglobin responses based on pharmacogenomics, and the risks and benefits of hydroxyurea for non-SCA genotypes and during pregnancy/lactation. Another critical initiative is the introduction of hydroxyurea safely and effectively into global regions that have a high disease burden of SCA but limited resources, such as sub-Saharan Africa, the Caribbean, and India. Final considerations emphasize the long-term goal of optimizing hydroxyurea therapy, which is to help treatment become accepted as standard of care for all patients with SCA. © 2015 by The American Society of Hematology. All rights reserved.

Optimisation of Ethanol-Reflux Extraction of Saponins from Steamed Panax notoginseng by Response Surface Methodology and Evaluation of Hematopoiesis Effect.

PubMed

Hu, Yupiao; Cui, Xiuming; Zhang, Zejun; Chen, Lijuan; Zhang, Yiming; Wang, Chengxiao; Yang, Xiaoyan; Qu, Yuan; Xiong, Yin

2018-05-17

The present study aims to optimize the ethanol-reflux extraction conditions for extracting saponins from steamed Panax notoginseng (SPN). Four variables including the extraction time (0.5⁻2.5 h), ethanol concentration (50⁻90%), water to solid ratio (W/S, 8⁻16), and times of extraction (1⁻5) were investigated by using the Box-Behnken design response surface methodology (BBD-RSM). For each response, a second-order polynomial model with high R² values (>0.9690) was developed using multiple linear regression analysis and the optimum conditions to maximize the yield (31.96%), content (70.49 mg/g), and antioxidant activity (EC 50 value of 0.0421 mg/mL) for saponins extracted from SPN were obtained with a extraction time of 1.51 h, ethanol concentration of 60%, extraction done 3 times, and a W/S of 10. The experimental values were in good consistency with the predicted ones. In addition, the extracted SPN saponins could significantly increase the levels of blood routine parameters compared with the model group (p < 0.01) and there was no significant difference in the hematopoiesis effect between the SPN group and the SPN saponins group, of which the dose was 15 times lower than the former one. It is suggested that the SPN saponins extracted by the optimized method had similar functions of "blood tonifying" at a much lower dose.

Induction therapy with carboplatin/paclitaxel followed by concurrent carboplatin/paclitaxel and dose-escalating conformal radiotherapy in the treatment of locally advanced, unresectable non-small cell lung cancer: preliminary report of a phase I trial.

PubMed

Socinski, M A; Clark, J A; Halle, J; Steagall, A; Kaluzny, B; Rosenman, J G

1997-08-01

Locally advanced non-small cell lung cancer is optimally managed with chemotherapy and thoracic irradiation, although the most appropriate strategy is not yet defined. In this phase I trial, we use two 21-day cycles of induction chemotherapy with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) (225 mg/m2 over 3 hours) and carboplatin (area under the concentration-time curve = 6) followed by concurrent weekly paclitaxel (45 mg/m2/wk x 6) and carboplatin (area under the concentration-time curve = 2/wk x 6) and thoracic irradiation. Patients undergo three-dimensional treatment planning (conformal radiotherapy) to define the cancer target volume precisely. The phase I question being addressed in this study is the maximum tolerated radiation dose given concurrently with low-dose paclitaxel and carboplatin. The initial radiation dose is 60 Gy, with dose escalations to 66 Gy, 70 Gy, and 74 Gy being planned. Ten patients have been entered thus far (eight men and two women). Their median age is 67 years (range, 59 to 78 years), and none of the patients has had greater than 5% pretreatment weight loss. Seven of 10 are evaluable for response to induction carboplatin and paclitaxel, with a response rate of 57% (three partial responses and one minor response). Three patients had stable disease and none of the patients had evidence of progressive disease during induction chemotherapy. Three patients have completed all treatment at 60 Gy and one has completed all treatment at 66 Gy. Three of the four patients have had partial responses (75%), with the remaining patient having stable disease. Toxicity in the concurrent chemoradiotherapy portion of the trial thus far has consisted of grade 3 neutropenia in one patient and grade 4 lymphocytopenia in all four patients. No grade 3 or 4 nonhematologic toxicity has been seen. The trial data are not yet mature enough to report on survival. Accrual and treatment is continuing at the 66 Gy radiation dose level.

Automatic CT simulation optimization for radiation therapy: A general strategy.

PubMed

Li, Hua; Yu, Lifeng; Anastasio, Mark A; Chen, Hsin-Chen; Tan, Jun; Gay, Hiram; Michalski, Jeff M; Low, Daniel A; Mutic, Sasa

2014-03-01

In radiation therapy, x-ray computed tomography (CT) simulation protocol specifications should be driven by the treatment planning requirements in lieu of duplicating diagnostic CT screening protocols. The purpose of this study was to develop a general strategy that allows for automatically, prospectively, and objectively determining the optimal patient-specific CT simulation protocols based on radiation-therapy goals, namely, maintenance of contouring quality and integrity while minimizing patient CT simulation dose. The authors proposed a general prediction strategy that provides automatic optimal CT simulation protocol selection as a function of patient size and treatment planning task. The optimal protocol is the one that delivers the minimum dose required to provide a CT simulation scan that yields accurate contours. Accurate treatment plans depend on accurate contours in order to conform the dose to actual tumor and normal organ positions. An image quality index, defined to characterize how simulation scan quality affects contour delineation, was developed and used to benchmark the contouring accuracy and treatment plan quality within the predication strategy. A clinical workflow was developed to select the optimal CT simulation protocols incorporating patient size, target delineation, and radiation dose efficiency. An experimental study using an anthropomorphic pelvis phantom with added-bolus layers was used to demonstrate how the proposed prediction strategy could be implemented and how the optimal CT simulation protocols could be selected for prostate cancer patients based on patient size and treatment planning task. Clinical IMRT prostate treatment plans for seven CT scans with varied image quality indices were separately optimized and compared to verify the trace of target and organ dosimetry coverage. Based on the phantom study, the optimal image quality index for accurate manual prostate contouring was 4.4. The optimal tube potentials for patient sizes of 38, 43, 48, 53, and 58 cm were 120, 140, 140, 140, and 140 kVp, respectively, and the corresponding minimum CTDIvol for achieving the optimal image quality index 4.4 were 9.8, 32.2, 100.9, 241.4, and 274.1 mGy, respectively. For patients with lateral sizes of 43-58 cm, 120-kVp scan protocols yielded up to 165% greater radiation dose relative to 140-kVp protocols, and 140-kVp protocols always yielded a greater image quality index compared to the same dose-level 120-kVp protocols. The trace of target and organ dosimetry coverage and the γ passing rates of seven IMRT dose distribution pairs indicated the feasibility of the proposed image quality index for the predication strategy. A general strategy to predict the optimal CT simulation protocols in a flexible and quantitative way was developed that takes into account patient size, treatment planning task, and radiation dose. The experimental study indicated that the optimal CT simulation protocol and the corresponding radiation dose varied significantly for different patient sizes, contouring accuracy, and radiation treatment planning tasks.

SU-F-T-201: Acceleration of Dose Optimization Process Using Dual-Loop Optimization Technique for Spot Scanning Proton Therapy

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

Hirayama, S; Fujimoto, R

Purpose: The purpose was to demonstrate a developed acceleration technique of dose optimization and to investigate its applicability to the optimization process in a treatment planning system (TPS) for proton therapy. Methods: In the developed technique, the dose matrix is divided into two parts, main and halo, based on beam sizes. The boundary of the two parts is varied depending on the beam energy and water equivalent depth by utilizing the beam size as a singular threshold parameter. The optimization is executed with two levels of iterations. In the inner loop, doses from the main part are updated, whereas dosesmore » from the halo part remain constant. In the outer loop, the doses from the halo part are recalculated. We implemented this technique to the optimization process in the TPS and investigated the dependence on the target volume of the speedup effect and applicability to the worst-case optimization (WCO) in benchmarks. Results: We created irradiation plans for various cubic targets and measured the optimization time varying the target volume. The speedup effect was improved as the target volume increased, and the calculation speed increased by a factor of six for a 1000 cm3 target. An IMPT plan for the RTOG benchmark phantom was created in consideration of ±3.5% range uncertainties using the WCO. Beams were irradiated at 0, 45, and 315 degrees. The target’s prescribed dose and OAR’s Dmax were set to 3 Gy and 1.5 Gy, respectively. Using the developed technique, the calculation speed increased by a factor of 1.5. Meanwhile, no significant difference in the calculated DVHs was found before and after incorporating the technique into the WCO. Conclusion: The developed technique could be adapted to the TPS’s optimization. The technique was effective particularly for large target cases.« less

A selective phosphodiesterase 10A inhibitor reduces l-dopa-induced dyskinesias in parkinsonian monkeys.

PubMed

Beck, Goichi; Maehara, Shunsuke; Chang, Phat Ly; Papa, Stella M

2018-03-06

Phosphodiesterase 10A is a member of the phosphodiesterase family whose brain expression is restricted to the striatum. Phosphodiesterase 10A regulates cyclic adenosine monophosphate and cyclic guanosine monophosphate, which mediate responses to dopamine receptor activation, and the levels of these cyclic nucleotides are decreased in experimental models of l-dopa-induced dyskinesia. The elevation of cyclic adenosine monophosphate/cyclic guanosine monophosphate levels by phosphodiesterase 10A inhibition may thus be targeted to reduce l-dopa-induced dyskinesia. The present study was aimed at determining the potential antidyskinetic effects of phosphodiesterase 10A inhibitors in a primate model of Parkinson's disease (PD). The experiments performed in this model were also intended to provide translational data for the design of future clinical trials. Five MPTP-treated macaques with advanced parkinsonism and reproducible l-dopa-induced dyskinesia were used. MR1916, a selective phosphodiesterase 10A inhibitor, at doses 0.0015 to 0.05 mg/kg, subcutaneously, or its vehicle (control test) was coadministered with l-dopa methyl ester acutely (predetermined optimal and suboptimal subcutaneous doses) and oral l-dopa chronically as daily treatment for 5 weeks. Standardized scales were used to assess motor disability and l-dopa-induced dyskinesia by blinded examiners. Pharmacokinetics was also examined. MR1916 consistently reduced l-dopa-induced dyskinesia in acute tests of l-dopa optimal and suboptimal doses. Significant effects were present with every MR1916 dose tested, but the most effective was 0.015 mg/kg. None of the MR1916 doses tested affected the antiparkinsonian action of l-dopa at the optimal dose. The anti-l-dopa-induced dyskinesia effect of MR1916 (0.015 mg/kg, subcutaneously) was sustained with chronic administration, indicating that tolerance did not develop over the 5-week treatment. No adverse effects were observed after MR1916 administration acutely or chronically. Results show that regulation of striatal cyclic nucleotides by phosphodiesterase 10A inhibition could be a useful therapeutic approach for l-dopa-induced dyskinesia, and therefore data support further studies of selective phosphodiesterase 10A inhibitors for PD therapy. © 2018 International Parkinson and Movement Disorder Society. © 2018 International Parkinson and Movement Disorder Society.

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.

Dose-response association between leisure time physical activity and work ability: Cross-sectional study among 3000 workers.

PubMed

Calatayud, Joaquin; Jakobsen, Markus D; Sundstrup, Emil; Casaña, Jose; Andersen, Lars L

2015-12-01

Regular physical activity is important for longevity and health, but knowledge about the optimal dose of physical activity for maintaining good work ability is unknown. This study investigates the association between intensity and duration of physical activity during leisure time and work ability in relation to physical demands of the job. From the 2010 round of the Danish Work Environment Cohort Study, currently employed wage earners with physically demanding work (n = 2952) replied to questions about work, lifestyle and health. Excellent (100 points), very good (75 points), good (50 points), fair (25 points) and poor (0 points) work ability in relation to the physical demands of the job was experienced by 18%, 40%, 30%, 10% and 2% of the respondents, respectively. General linear models that controlled for gender, age, physical and psychosocial work factors, lifestyle and chronic disease showed that the duration of high-intensity physical activity during leisure was positively associated with work ability, in a dose-response fashion (p < 0.001). Those performing ⩾ 5 hours of high-intensity physical activity per week had on average 8 points higher work ability than those not performing such activities. The duration of low-intensity leisure-time physical activity was not associated with work ability (p = 0.5668). The duration of high-intensity physical activity during leisure time is associated in a dose-response fashion with work ability, in workers with physically demanding jobs. © 2015 the Nordic Societies of Public Health.

Investigation of endothelial function by pulse contour analysis: a protocol for drug administration and timing of pulse contour assessment

PubMed Central

Gordon, Sarah E; Cartwright, Neil; Griffiths, Mark J D

2009-01-01

AIMS Pulse contour analysis (PCA) obtained by finger photoplethysmography produces a digital volume pulse (DVP) including an inflection point in its down-slope. The reflection index (RI: ratio of the inflection point height over the maximal DVP) is responsive to vasodilatation. We aimed to optimize the drug dose and time interval for assessing endothelial function using PCA in healthy volunteers and patients with severe coronary artery disease. METHODS Time and dose to RI response relationships were constructed in 16 volunteers and nine patients to inhaled salbutamol (100–400 µg) or sublingual nitroglycerin (NTG; 25–400 µg). RESULTS For the volunteers, the time to maximum RI response to inhaled salbutamol and sublingual NTG was 10.73 ± 0.41 and 3.66 ± 0.21 min, respectively. A plateau in the RI response to salbutamol occurred between 5 and 15 min after inhalation and results were averaged over this period. A dose-dependent response was observed to inhaled salbutamol and sublingual NTG (P= 0.05 and P < 0.001 by repeated-measures anova, respectively) in healthy volunteers. By contrast, in patients with severe coronary artery disease inhaled salbutamol (100–400 µg) did not cause a significant change in RI. CONCLUSIONS In healthy volunteers the RI response to inhaled salbutamol (100–200 µg) averaged over 5–15 min after administration may be used to investigate endothelial function by PCA. The response to sublingual NTG (50 µg) should be determined at 4 min. This technique may not be suitable for the assessment of endothelial function in subjects with extensive coronary artery disease owing to the small responses observed and potential confounding effect of vasoactive medication. PMID:19843066

Agreement between gamma passing rates using computed tomography in radiotherapy and secondary cancer risk prediction from more advanced dose calculated models

PubMed Central

Balosso, Jacques

2017-01-01

Background During the past decades, in radiotherapy, the dose distributions were calculated using density correction methods with pencil beam as type ‘a’ algorithm. The objectives of this study are to assess and evaluate the impact of dose distribution shift on the predicted secondary cancer risk (SCR), using modern advanced dose calculation algorithms, point kernel, as type ‘b’, which consider change in lateral electrons transport. Methods Clinical examples of pediatric cranio-spinal irradiation patients were evaluated. For each case, two radiotherapy treatment plans with were generated using the same prescribed dose to the target resulting in different number of monitor units (MUs) per field. The dose distributions were calculated, respectively, using both algorithms types. A gamma index (γ) analysis was used to compare dose distribution in the lung. The organ equivalent dose (OED) has been calculated with three different models, the linear, the linear-exponential and the plateau dose response curves. The excess absolute risk ratio (EAR) was also evaluated as (EAR = OED type ‘b’ / OED type ‘a’). Results The γ analysis results indicated an acceptable dose distribution agreement of 95% with 3%/3 mm. Although, the γ-maps displayed dose displacement >1 mm around the healthy lungs. Compared to type ‘a’, the OED values from type ‘b’ dose distributions’ were about 8% to 16% higher, leading to an EAR ratio >1, ranged from 1.08 to 1.13 depending on SCR models. Conclusions The shift of dose calculation in radiotherapy, according to the algorithm, can significantly influence the SCR prediction and the plan optimization, since OEDs are calculated from DVH for a specific treatment. The agreement between dose distribution and SCR prediction depends on dose response models and epidemiological data. In addition, the γ passing rates of 3%/3 mm does not translate the difference, up to 15%, in the predictions of SCR resulting from alternative algorithms. Considering that modern algorithms are more accurate, showing more precisely the dose distributions, but that the prediction of absolute SCR is still very imprecise, only the EAR ratio could be used to rank radiotherapy plans. PMID:28811995

Scattering and absorption control in biocompatible fibers towards equalized photobiomodulation.

PubMed

George, J; Haghshenas, H; d'Hemecourt, D; Zhu, W; Zhang, L; Sorger, V

2017-03-01

Transparent tissue scaffolds enable illumination of growing tissue to accelerate cell proliferation and improve other cell functions through photobiomodulation. The biphasic dose response of cells exposed to photobiomodulating light dictates that the illumination be evenly distributed across the scaffold such that the cells are neither under nor over exposed to light. However, equalized illumination has not been sufficiently addressed. Here we analyze and experimentally demonstrate spatially equalizing illumination by three methods, namely: engineered surface scattering, reflection by a gold mirror, and traveling-waves in a ring mesh. Our results show that nearly equalized illumination is achievable by controlling the light scattering-to-loss ratio. This demonstration furthers opportunities for dose-optimized photobiomodulation in tissue regeneration.

Safety and immunogenicity of ricin vaccine, RVEc™, in a Phase 1 clinical trial.

PubMed

Pittman, Phillip R; Reisler, Ronald B; Lindsey, Changhong Y; Güereña, Fernando; Rivard, Robert; Clizbe, Denise P; Chambers, Matthew; Norris, Sarah; Smith, Leonard A

2015-12-16

Ricin is a potent toxin and potential bioterrorism weapon for which no specific licensed countermeasures are available. We report the safety and immunogenicity of the ricin vaccine RVEc™ in a Phase 1 (N=30) multiple-dose, open-label, non-placebo-controlled, dose-escalating (20, 50, and 100μg), single-center study. Each subject in the 20- and 50-μg dose groups (n=10 for each group) received three injections at 4-week intervals and was observed carefully for untoward effects of the vaccine; blood was drawn at predetermined intervals after each dose for up to 1 year. RVEc™ was safe and well tolerated at the 20- and 50-μg doses. The most common adverse events were pain at the injection site and headache. Of the 10 subjects who received a single 100-μg dose, two developed elevated creatine phosphokinase levels, which resolved without sequelae. No additional doses were administered to subjects in the 100-μg group. Immunogenicity of the vaccine was evaluated by measuring antibody response using the well standardized enzyme-linked immunosorbent assay (ELISA) and toxin neutralization assay (TNA). Of the subjects in the 20- and 50-μg dose groups, 100% achieved ELISA anti-ricin IgG titers of 1:500 to 1:121,500 and 50% produced neutralizing anti-ricin antibodies measurable by TNA. Four subjects in the 50-μg group received a single booster dose of RVEc™ 20-21 months after the initial dose. The single booster was safe and well tolerated, resulting in no serious adverse events, and significantly enhanced immunogenicity of the vaccine in human subjects. Each booster recipient developed a robust anamnestic response with ELISA anti-ricin IgG titers of 1:13,500 to 1:121,500 and neutralizing antibody titers of 1:400 to 1:3200. Future studies will attempt to optimize dose, scheduling, and route of administration. This study is registered at clinicaltrials.gov (NCT01317667 and NCT01846104). Published by Elsevier Ltd.

A Phase 2 randomized, observer-blind, placebo-controlled, dose-ranging trial of aluminum-adjuvanted respiratory syncytial virus F particle vaccine formulations in healthy women of childbearing age.

PubMed

August, Allison; Glenn, Gregory M; Kpamegan, Eloi; Hickman, Somia P; Jani, Dewal; Lu, Hanxin; Thomas, D Nigel; Wen, Judy; Piedra, Pedro A; Fries, Louis F

2017-06-27

Respiratory syncytial virus (RSV) causes significant morbidity and mortality in infants. We are developing an RSV fusion (F) protein nanoparticle vaccine for immunization of third trimester pregnant women to passively protect infants through transfer of RSV-specific maternal antibodies. The present trial was performed to assess the immunogenicity and safety of several formulations of RSV F vaccine in 1-dose or 2-dose schedules. Placebo, or vaccine with 60μg or 120μg RSV F protein and 0.2, 0.4, or 0.8mg aluminum, were administered intramuscularly on Days 0 and 28 to healthy women 18-35years old. Immunogenicity was assessed from Days 0 through 91 based on anti-F IgG and palivizumab-competitive antibody (PCA) by ELISA, and RSV A and B neutralizing antibodies by microneutralization (MN) assay. Solicited adverse events were collected through Day 7 and unsolicited adverse events through Day 91. All formulations were well-tolerated, with no treatment-related serious adverse events. Anti-F IgG and PCA responses were correlated and increased after both doses, while MN increased significantly only after the first dose, then plateaued. The timeliest and most robust antibody responses followed one dose of 120μg RSV F protein and 0.4mg aluminum, but persistence through 91days was modestly (∼25%) superior following two doses of 60μg RSV F protein and 0.8mg aluminum. Western blot analysis showed RSV infections in active vaccinees were reduced by 52% overall (p=0.009 overall) over the Day 0 through 90 period. RSV F nanoparticle vaccine formulations were well tolerated and immunogenic. The optimal combination of convenience and rapid response for immunization in the third trimester occurred with 120μg RSV F and 0.4mg aluminum, which achieved peak immune responses in 14days and sufficient persistence through 91days to allow for passive transfer of IgG antibodies to the fetus. NCT01960686. Copyright © 2017 Novavax. Published by Elsevier Ltd.. All rights reserved.

Impact of respiratory motion on worst-case scenario optimized intensity modulated proton therapy for lung cancers.

PubMed

Liu, Wei; Liao, Zhongxing; Schild, Steven E; Liu, Zhong; Li, Heng; Li, Yupeng; Park, Peter C; Li, Xiaoqiang; Stoker, Joshua; Shen, Jiajian; Keole, Sameer; Anand, Aman; Fatyga, Mirek; Dong, Lei; Sahoo, Narayan; Vora, Sujay; Wong, William; Zhu, X Ronald; Bues, Martin; Mohan, Radhe

2015-01-01

We compared conventionally optimized intensity modulated proton therapy (IMPT) treatment plans against worst-case scenario optimized treatment plans for lung cancer. The comparison of the 2 IMPT optimization strategies focused on the resulting plans' ability to retain dose objectives under the influence of patient setup, inherent proton range uncertainty, and dose perturbation caused by respiratory motion. For each of the 9 lung cancer cases, 2 treatment plans were created that accounted for treatment uncertainties in 2 different ways. The first used the conventional method: delivery of prescribed dose to the planning target volume that is geometrically expanded from the internal target volume (ITV). The second used a worst-case scenario optimization scheme that addressed setup and range uncertainties through beamlet optimization. The plan optimality and plan robustness were calculated and compared. Furthermore, the effects on dose distributions of changes in patient anatomy attributable to respiratory motion were investigated for both strategies by comparing the corresponding plan evaluation metrics at the end-inspiration and end-expiration phase and absolute differences between these phases. The mean plan evaluation metrics of the 2 groups were compared with 2-sided paired Student t tests. Without respiratory motion considered, we affirmed that worst-case scenario optimization is superior to planning target volume-based conventional optimization in terms of plan robustness and optimality. With respiratory motion considered, worst-case scenario optimization still achieved more robust dose distributions to respiratory motion for targets and comparable or even better plan optimality (D95% ITV, 96.6% vs 96.1% [P = .26]; D5%- D95% ITV, 10.0% vs 12.3% [P = .082]; D1% spinal cord, 31.8% vs 36.5% [P = .035]). Worst-case scenario optimization led to superior solutions for lung IMPT. Despite the fact that worst-case scenario optimization did not explicitly account for respiratory motion, it produced motion-resistant treatment plans. However, further research is needed to incorporate respiratory motion into IMPT robust optimization. Copyright © 2015 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

SU-E-T-452: Impact of Respiratory Motion On Robustly-Optimized Intensity-Modulated Proton Therapy to Treat Lung Cancers

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

Liu, W; Schild, S; Bues, M

Purpose: We compared conventionally optimized intensity-modulated proton therapy (IMPT) treatment plans against the worst-case robustly optimized treatment plans for lung cancer. The comparison of the two IMPT optimization strategies focused on the resulting plans' ability to retain dose objectives under the influence of patient set-up, inherent proton range uncertainty, and dose perturbation caused by respiratory motion. Methods: For each of the 9 lung cancer cases two treatment plans were created accounting for treatment uncertainties in two different ways: the first used the conventional Method: delivery of prescribed dose to the planning target volume (PTV) that is geometrically expanded from themore » internal target volume (ITV). The second employed the worst-case robust optimization scheme that addressed set-up and range uncertainties through beamlet optimization. The plan optimality and plan robustness were calculated and compared. Furthermore, the effects on dose distributions of the changes in patient anatomy due to respiratory motion was investigated for both strategies by comparing the corresponding plan evaluation metrics at the end-inspiration and end-expiration phase and absolute differences between these phases. The mean plan evaluation metrics of the two groups were compared using two-sided paired t-tests. Results: Without respiratory motion considered, we affirmed that worst-case robust optimization is superior to PTV-based conventional optimization in terms of plan robustness and optimality. With respiratory motion considered, robust optimization still leads to more robust dose distributions to respiratory motion for targets and comparable or even better plan optimality [D95% ITV: 96.6% versus 96.1% (p=0.26), D5% - D95% ITV: 10.0% versus 12.3% (p=0.082), D1% spinal cord: 31.8% versus 36.5% (p =0.035)]. Conclusion: Worst-case robust optimization led to superior solutions for lung IMPT. Despite of the fact that robust optimization did not explicitly account for respiratory motion it produced motion-resistant treatment plans. However, further research is needed to incorporate respiratory motion into IMPT robust optimization.« less

IMATINIB 800MG DAILY INDUCES DEEPER MOLECULAR RESPONSES THAN IMATINIB 400MG DAILY: RESULTS OF SWOG S0325, AN INTERGROUP RANDOMIZED PHASE II TRIAL IN NEWLY DIAGNOSED CHRONIC PHASE CHRONIC MYELOID LEUKAEMIA

PubMed Central

Deininger, Michael W.; Kopecky, Kenneth J.; Radich, Jerald P.; Kamel-Reid, Suzanne; Stock, Wendy; Paietta, Elisabeth; Emanuel, Peter D.; Tallman, Martin; Wadleigh, Martha; Larson, Richard A.; Lipton, Jeffrey H.; Slovak, Marilyn L.; Appelbaum, Frederick R.; Druker, Brian J.

2014-01-01

The standard dose of imatinib for newly diagnosed patients with chronic phase chronic myeloid leukemia (CP-CML) is 400mg daily (IM400), but the optimal dose is unknown. This randomized phase II study compared the rates of molecular, haematologic and cytogenetic response to IM400 vs. imatinib 400mg twice daily (IM800) in 153 adult patients with CP-CML. Dose adjustments for toxicity were flexible to maximize retention on study. Molecular response (MR) at 12 months was deeper in the IM800 arm (4-log reduction of BCR-ABL1 mRNA: 25% vs. 10% of patients, P=0.038; 3-log reduction: 53% vs. 35%, P=0.049). During the first 12 months BCR-ABL1 levels in the IM800 arm were an average 2.9-fold lower than in the IM400 arm (P=0.010). Complete haematologic response was similar, but complete cytogenetic response was higher with IM800 (85% vs. 67%, P=0.040). Grade 3–4 toxicities were more common for IM800 (58% vs. 31%, P=0.0007), and were most commonly haematologic. Few patients have relapsed, progressed or died, but progression-free (P=0.048) and relapse-free (P=0.031) survival were superior for IM800. In newly diagnosed CP-CML patients, IM800 induced deeper molecular responses than IM400, with a trend for improved progression-free and overall survival, but was associated with more severe toxicity. PMID:24383843

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.

Impact of Spot Size and Spacing on the Quality of Robustly Optimized Intensity Modulated Proton Therapy Plans for Lung Cancer.

PubMed

Liu, Chenbin; Schild, Steven E; Chang, Joe Y; Liao, Zhongxing; Korte, Shawn; Shen, Jiajian; Ding, Xiaoning; Hu, Yanle; Kang, Yixiu; Keole, Sameer R; Sio, Terence T; Wong, William W; Sahoo, Narayan; Bues, Martin; Liu, Wei

2018-06-01

To investigate how spot size and spacing affect plan quality, robustness, and interplay effects of robustly optimized intensity modulated proton therapy (IMPT) for lung cancer. Two robustly optimized IMPT plans were created for 10 lung cancer patients: first by a large-spot machine with in-air energy-dependent large spot size at isocenter (σ: 6-15 mm) and spacing (1.3 σ), and second by a small-spot machine with in-air energy-dependent small spot size (σ: 2-6 mm) and spacing (5 mm). Both plans were generated by optimizing radiation dose to internal target volume on averaged 4-dimensional computed tomography scans using an in-house-developed IMPT planning system. The dose-volume histograms band method was used to evaluate plan robustness. Dose evaluation software was developed to model time-dependent spot delivery to incorporate interplay effects with randomized starting phases for each field per fraction. Patient anatomy voxels were mapped phase-to-phase via deformable image registration, and doses were scored using in-house-developed software. Dose-volume histogram indices, including internal target volume dose coverage, homogeneity, and organs at risk (OARs) sparing, were compared using the Wilcoxon signed-rank test. Compared with the large-spot machine, the small-spot machine resulted in significantly lower heart and esophagus mean doses, with comparable target dose coverage, homogeneity, and protection of other OARs. Plan robustness was comparable for targets and most OARs. With interplay effects considered, significantly lower heart and esophagus mean doses with comparable target dose coverage and homogeneity were observed using smaller spots. Robust optimization with a small spot-machine significantly improves heart and esophagus sparing, with comparable plan robustness and interplay effects compared with robust optimization with a large-spot machine. A small-spot machine uses a larger number of spots to cover the same tumors compared with a large-spot machine, which gives the planning system more freedom to compensate for the higher sensitivity to uncertainties and interplay effects for lung cancer treatments. Copyright © 2018 Elsevier Inc. All rights reserved.

Cultivation of high-biomass crops on coal mine spoil banks: can microbial inoculation compensate for high doses of organic matter?

PubMed

Gryndler, Milan; Sudová, Radka; Püschel, David; Rydlová, Jana; Janousková, Martina; Vosátka, Miroslav

2008-09-01

Two greenhouse experiments were focused on the application of arbuscular mycorrhizal fungi (AMF) and plant growth promoting rhizobacteria (PGPR) in planting of high-biomass crops on reclaimed spoil banks. In the first experiment, we tested the effects of different organic amendments on growth of alfalfa and on the introduced microorganisms. While growth of plants was supported in substrate with compost amendment, mycorrhizal colonization was suppressed. Lignocellulose papermill waste had no negative effects on AMF, but did not positively affect growth of plants. The mixture of these two amendments was found to be optimal in both respects, plant growth and mycorrhizal development. Decreasing doses of this mixture amendment were used in the second experiment, where the effects of microbial inoculation (assumed to compensate for reduced doses of organic matter) on growth of two high-biomass crops, hemp and reed canarygrass, were studied. Plant growth response to microbial inoculation was either positive or negative, depending on the dose of the applied amendment and plant species.

Patient doses from CT examinations in Turkey.

PubMed

Ataç, Gökçe Kaan; Parmaksız, Aydın; İnal, Tolga; Bulur, Emine; Bulgurlu, Figen; Öncü, Tolga; Gündoğdu, Sadi

2015-01-01

We aimed to establish the first diagnostic reference levels (DRLs) for computed tomography (CT) examinations in adult and pediatric patients in Turkey and compare these with international DRLs. CT performance information and examination parameters (for head, chest, high-resolution CT of the chest [HRCT-chest], abdominal, and pelvic protocols) from 1607 hospitals were collected via a survey. Dose length products and effective doses for standard patient sizes were calculated from the reported volume CT dose index (CTDIvol). The median number of protocols reported from the 167 responding hospitals (10% response rate) was 102 across five different age groups. Third quartile CTDIvol values for adult pelvic and all pediatric body protocols were higher than the European Commission standards but were comparable to studies conducted in other countries. The radiation dose indicators for adult patients were similar to those reported in the literature, except for those associated with head protocols. CT protocol optimization is necessary for adult head and pediatric chest, HRCT-chest, abdominal, and pelvic protocols. The findings from this study are recommended for use as national DRLs in Turkey.

Feasibility and robustness of dose painting by numbers in proton therapy with contour-driven plan optimization

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

Barragán, A. M., E-mail: ana.barragan@uclouvain.be; Differding, S.; Lee, J. A.

Purpose: To prove the ability of protons to reproduce a dose gradient that matches a dose painting by numbers (DPBN) prescription in the presence of setup and range errors, by using contours and structure-based optimization in a commercial treatment planning system. Methods: For two patients with head and neck cancer, voxel-by-voxel prescription to the target volume (GTV{sub PET}) was calculated from {sup 18}FDG-PET images and approximated with several discrete prescription subcontours. Treatments were planned with proton pencil beam scanning. In order to determine the optimal plan parameters to approach the DPBN prescription, the effects of the scanning pattern, number ofmore » fields, number of subcontours, and use of range shifter were separately tested on each patient. Different constant scanning grids (i.e., spot spacing = Δx = Δy = 3.5, 4, and 5 mm) and uniform energy layer separation [4 and 5 mm WED (water equivalent distance)] were analyzed versus a dynamic and automatic selection of the spots grid. The number of subcontours was increased from 3 to 11 while the number of beams was set to 3, 5, or 7. Conventional PTV-based and robust clinical target volumes (CTV)-based optimization strategies were considered and their robustness against range and setup errors assessed. Because of the nonuniform prescription, ensuring robustness for coverage of GTV{sub PET} inevitably leads to overdosing, which was compared for both optimization schemes. Results: The optimal number of subcontours ranged from 5 to 7 for both patients. All considered scanning grids achieved accurate dose painting (1% average difference between the prescribed and planned doses). PTV-based plans led to nonrobust target coverage while robust-optimized plans improved it considerably (differences between worst-case CTV dose and the clinical constraint was up to 3 Gy for PTV-based plans and did not exceed 1 Gy for robust CTV-based plans). Also, only 15% of the points in the GTV{sub PET} (worst case) were above 5% of DPBN prescription for robust-optimized plans, while they were more than 50% for PTV plans. Low dose to organs at risk (OARs) could be achieved for both PTV and robust-optimized plans. Conclusions: DPBN in proton therapy is feasible with the use of a sufficient number subcontours, automatically generated scanning patterns, and no more than three beams are needed. Robust optimization ensured the required target coverage and minimal overdosing, while PTV-approach led to nonrobust plans with excessive overdose. Low dose to OARs can be achieved even in the presence of a high-dose escalation as in DPBN.« less

Comparison of different treatment planning optimization methods for vaginal HDR brachytherapy with multichannel applicators: A reduction of the high doses to the vaginal mucosa is possible.

PubMed

Carrara, Mauro; Cusumano, Davide; Giandini, Tommaso; Tenconi, Chiara; Mazzarella, Ester; Grisotto, Simone; Massari, Eleonora; Mazzeo, Davide; Cerrotta, Annamaria; Pappalardi, Brigida; Fallai, Carlo; Pignoli, Emanuele

2017-12-01

A direct planning approach with multi-channel vaginal cylinders (MVCs) used for HDR brachytherapy of vaginal cancers is particularly challenging. Purpose of this study was to compare the dosimetric performances of different forward and inverse methods used for the optimization of MVC-based vaginal treatments for endometrial cancer, with a particular attention to the definition of strategies useful to limit the high doses to the vaginal mucosa. Twelve postoperative vaginal HDR brachytherapy treatments performed with MVCs were considered. Plans were retrospectively optimized with three different methods: Dose Point Optimization followed by Graphical Optimization (DPO + GrO), Inverse Planning Simulated Annealing with two different class solutions as starting conditions (surflPSA and homogIPSA) and Hybrid Inverse Planning Optimization (HIPO). Several dosimetric parameters related to target coverage, hot spot extensions and sparing of organs at risk were analyzed to evaluate the quality of the achieved treatment plans. Dose homogeneity index (DHI), conformal index (COIN) and a further parameter quantifying the proportion of the central catheter loading with respect to the overall loading (i.e., the central catheter loading index: CCLI) were also quantified. The achieved PTV coverage parameters were highly correlated with each other but uncorrelated with the hot spot quantifiers. HomogIPSA and HIPO achieved higher DHIs and CCLIs and lower volumes of high doses than DPO + GrO and surflPSA. Within the investigated optimization methods, HIPO and homoglPSA showed the highest dose homogeneity to the target. In particular, homogIPSA resulted also the most effective in reducing hot spots to the vaginal mucosa. Copyright © 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Effect of 2',3'-didehydro-3'-deoxythymidine in an in vitro hollow-fiber pharmacodynamic model system correlates with results of dose-ranging clinical studies.

PubMed Central

Bilello, J A; Bauer, G; Dudley, M N; Cole, G A; Drusano, G L

1994-01-01

We sought to validate an in vitro system which could predict the minimal effect dose of antiretroviral agents. Mixtures of uninfected CEM cells and CEM cells chronically infected with human immunodeficiency virus (HIV) type 1 MN were exposed to 2',3'-didehydro-3'-deoxythymidine (D4T) in vitro in a hollow-fiber model which simulates the plasma concentration-time profile of D4T in patients. Drug concentration was adjusted to simulate continuous intravenous infusion, or an intravenous bolus administered twice daily. The effect of the dosing regimen was measured with viral infectivity, p24 antigen, and reverse transcriptase or PCR for unintegrated HIV DNA. Dose deescalation studies on a twice-daily dosing schedule predicted a minimum effect dose of 0.5 mg/kg of body weight per day which correlated with the results of a clinical trial. Antiviral effect was demonstrated to be independent of schedule for every 12-h dosing versus continuous infusion. Finally, at or near the minimal effect dose, efficacy appeared to depend on the viral load. The ability of this in vitro pharmacodynamic model to assess the response of HIV-infected cells to different doses and schedules of antiviral agents may be useful in the design of optimal dosing regimens for clinical trials but requires validation with other types of antiretroviral agents. PMID:8092842

Exploratory Study of 4D versus 3D Robust Optimization in Intensity Modulated Proton Therapy for Lung Cancer

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

Liu, Wei, E-mail: Liu.Wei@mayo.edu; Schild, Steven E.; Chang, Joe Y.

Purpose: The purpose of this study was to compare the impact of uncertainties and interplay on 3-dimensional (3D) and 4D robustly optimized intensity modulated proton therapy (IMPT) plans for lung cancer in an exploratory methodology study. Methods and Materials: IMPT plans were created for 11 nonrandomly selected non-small cell lung cancer (NSCLC) cases: 3D robustly optimized plans on average CTs with internal gross tumor volume density overridden to irradiate internal target volume, and 4D robustly optimized plans on 4D computed tomography (CT) to irradiate clinical target volume (CTV). Regular fractionation (66 Gy [relative biological effectiveness; RBE] in 33 fractions) was considered.more » In 4D optimization, the CTV of individual phases received nonuniform doses to achieve a uniform cumulative dose. The root-mean-square dose-volume histograms (RVH) measured the sensitivity of the dose to uncertainties, and the areas under the RVH curve (AUCs) were used to evaluate plan robustness. Dose evaluation software modeled time-dependent spot delivery to incorporate interplay effect with randomized starting phases of each field per fraction. Dose-volume histogram (DVH) indices comparing CTV coverage, homogeneity, and normal tissue sparing were evaluated using Wilcoxon signed rank test. Results: 4D robust optimization plans led to smaller AUC for CTV (14.26 vs 18.61, respectively; P=.001), better CTV coverage (Gy [RBE]) (D{sub 95%} CTV: 60.6 vs 55.2, respectively; P=.001), and better CTV homogeneity (D{sub 5%}-D{sub 95%} CTV: 10.3 vs 17.7, resspectively; P=.002) in the face of uncertainties. With interplay effect considered, 4D robust optimization produced plans with better target coverage (D{sub 95%} CTV: 64.5 vs 63.8, respectively; P=.0068), comparable target homogeneity, and comparable normal tissue protection. The benefits from 4D robust optimization were most obvious for the 2 typical stage III lung cancer patients. Conclusions: Our exploratory methodology study showed that, compared to 3D robust optimization, 4D robust optimization produced significantly more robust and interplay-effect-resistant plans for targets with comparable dose distributions for normal tissues. A further study with a larger and more realistic patient population is warranted to generalize the conclusions.« less

Design of shared unit-dose drug distribution network using multi-level particle swarm optimization.

PubMed

Chen, Linjie; Monteiro, Thibaud; Wang, Tao; Marcon, Eric

2018-03-01

Unit-dose drug distribution systems provide optimal choices in terms of medication security and efficiency for organizing the drug-use process in large hospitals. As small hospitals have to share such automatic systems for economic reasons, the structure of their logistic organization becomes a very sensitive issue. In the research reported here, we develop a generalized multi-level optimization method - multi-level particle swarm optimization (MLPSO) - to design a shared unit-dose drug distribution network. Structurally, the problem studied can be considered as a type of capacitated location-routing problem (CLRP) with new constraints related to specific production planning. This kind of problem implies that a multi-level optimization should be performed in order to minimize logistic operating costs. Our results show that with the proposed algorithm, a more suitable modeling framework, as well as computational time savings and better optimization performance are obtained than that reported in the literature on this subject.

Targeting the Tumor Microenvironment with Immunotherapy for Genitourinary Malignancies.

PubMed

Marciscano, Ariel E; Madan, Ravi A

2018-03-08

Bacillus Calmette-Guérin in urothelial carcinoma, high-dose interleukin-2 in renal cell carcinoma, and sipuleucel-T in prostate cancer serve as enduring examples that the host immune response can be harnessed to promote effective anti-tumor immunity in genitourinary malignancies. Recently, cancer immunotherapy with immune checkpoint inhibitors has transformed the prognostic landscape leading to durable responses in a subset of urothelial carcinoma and renal cell carcinoma patients with traditionally poor prognosis. Despite this success, many patients fail to respond to immune checkpoint inhibitors and progression/relapse remains common. Furthermore, modest clinical activity has been observed with ICIs as a monotherapy in advanced PCa. As such, novel treatment approaches are warranted and improved biomarkers for patient selection and treatment response are desperately needed. Future efforts should focus on exploring synergistic and rational combinations that safely and effectively boost response rates and survival in genitourinary malignancies. Specific areas of interest include (1) evaluating the optimal sequencing, disease burden, and timing of immuno-oncology agents with other anti-cancer therapeutics and (2) validating novel biomarkers of response to immunotherapy to optimize patient selection and to identify individuals most likely to benefit from immunotherapy across the heterogenous spectrum of genitourinary malignancies.

Inorganic mercury detection by valve closure response in the freshwater clam Corbicula fluminea: integration of time and water metal concentration changes.

PubMed

Tran, Damien; Fournier, Elodie; Durrieu, Gilles; Massabuau, Jean-Charles

2007-07-01

The objective of the present study was to monitor water-quality assessment by a biological method. Optimum dissolved inorganic mercury sensitivity in the freshwater bivalve Corbicula fluminea was estimated using a combined approach to determine their potentials and limits in detecting contaminants. Detection by bivalves is based on shell closure, a protective strategy when exposed to a water contaminant. To take the rate of spontaneous closures into account, stress associated with fixation by one valve in common valvometers was integrated, and the spontaneous rhythm was associated with daily activity. The response in conditions where the probability of spontaneous closing is the lowest was thus taken into account. To develop dose-response curves, impedance valvometry, in which lightweight impedance electrodes are applied to study free-ranging animals in low-stress conditions, also was used combined with a new analytical approach. The logistic regression dose-response curves take into account variations in both response time and metal concentration in water to significantly improve the methods aiming at determining the optimal sensitivity threshold response. This approach demonstrates that in C. fluminea, inorganic mercury concentrations under the range of 2.0 to 5.1 microg/L (95% confidence interval) cannot be detected within 5 h of addition.

Optimization of spatiotemporally fractionated radiotherapy treatments with bounds on the achievable benefit

NASA Astrophysics Data System (ADS)

Gaddy, Melissa R.; Yıldız, Sercan; Unkelbach, Jan; Papp, Dávid

2018-01-01

Spatiotemporal fractionation schemes, that is, treatments delivering different dose distributions in different fractions, can potentially lower treatment side effects without compromising tumor control. This can be achieved by hypofractionating parts of the tumor while delivering approximately uniformly fractionated doses to the surrounding tissue. Plan optimization for such treatments is based on biologically effective dose (BED); however, this leads to computationally challenging nonconvex optimization problems. Optimization methods that are in current use yield only locally optimal solutions, and it has hitherto been unclear whether these plans are close to the global optimum. We present an optimization framework to compute rigorous bounds on the maximum achievable normal tissue BED reduction for spatiotemporal plans. The approach is demonstrated on liver tumors, where the primary goal is to reduce mean liver BED without compromising any other treatment objective. The BED-based treatment plan optimization problems are formulated as quadratically constrained quadratic programming (QCQP) problems. First, a conventional, uniformly fractionated reference plan is computed using convex optimization. Then, a second, nonconvex, QCQP model is solved to local optimality to compute a spatiotemporally fractionated plan that minimizes mean liver BED, subject to the constraints that the plan is no worse than the reference plan with respect to all other planning goals. Finally, we derive a convex relaxation of the second model in the form of a semidefinite programming problem, which provides a rigorous lower bound on the lowest achievable mean liver BED. The method is presented on five cases with distinct geometries. The computed spatiotemporal plans achieve 12-35% mean liver BED reduction over the optimal uniformly fractionated plans. This reduction corresponds to 79-97% of the gap between the mean liver BED of the uniform reference plans and our lower bounds on the lowest achievable mean liver BED. The results indicate that spatiotemporal treatments can achieve substantial reductions in normal tissue dose and BED, and that local optimization techniques provide high-quality plans that are close to realizing the maximum potential normal tissue dose reduction.

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

MO-DE-204-01: Radiation Doses in Over 50 Developing Countries of Asia, Africa, Eastern European and Latin America

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

Rehani, M.

2016-06-15

The main topic of the session is to show how dose optimization is being implemented in various regions of the world, including Europe, Australia, North America and other regions. A multi-national study conducted under International Atomic Energy Agency (IAEA) across more than 50 less resourced countries gave insight into patient radiation doses and safety practices in CT, mammography, radiography and interventional procedures, both for children and adults. An important outcome was the capability development on dose assessment and management. An overview of recent European projects related to CT radiation dose and optimization both to adults and children will be presented.more » Existing data on DRLs together with a European methodology proposed on establishing and using DRLs for paediatric radiodiagnostic imaging and interventional radiology practices will be shown. Compared with much of Europe at least, many Australian imaging practices are relatively new to the task of diagnostic imaging dose optimisation. In 2008 the Australian Government prescribed a requirement to periodically compare patient radiation doses with diagnostic reference levels (DRLs), where DRLs have been established. Until recently, Australia had only established DRLs for computed tomography (CT). Regardless, both professional society and individual efforts to improved data collection and develop optimisation strategies across a range of modalities continues. Progress in this field, principally with respect to CT and interventional fluoroscopy will be presented. In the US, dose reduction and optimization efforts for computed tomography have been promoted and mandated by several organizations and accrediting entities. This presentation will cover the general motivation, implementation, and implications of such efforts. Learning Objectives: Understand importance of the dose optimization in Diagnostic Radiology. See how this goal is achieved in different regions of the World. Learn about the global trend in the dose optimization and future prospectives. M. Rehani, The work was a part of the work of IAEA where I was an employee and IAEA is a United Nations organization.« less

MO-DE-204-00: International Symposium: Patient Dose Reduction in Diagnostic Radiology

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

NONE

2016-06-15

The main topic of the session is to show how dose optimization is being implemented in various regions of the world, including Europe, Australia, North America and other regions. A multi-national study conducted under International Atomic Energy Agency (IAEA) across more than 50 less resourced countries gave insight into patient radiation doses and safety practices in CT, mammography, radiography and interventional procedures, both for children and adults. An important outcome was the capability development on dose assessment and management. An overview of recent European projects related to CT radiation dose and optimization both to adults and children will be presented.more » Existing data on DRLs together with a European methodology proposed on establishing and using DRLs for paediatric radiodiagnostic imaging and interventional radiology practices will be shown. Compared with much of Europe at least, many Australian imaging practices are relatively new to the task of diagnostic imaging dose optimisation. In 2008 the Australian Government prescribed a requirement to periodically compare patient radiation doses with diagnostic reference levels (DRLs), where DRLs have been established. Until recently, Australia had only established DRLs for computed tomography (CT). Regardless, both professional society and individual efforts to improved data collection and develop optimisation strategies across a range of modalities continues. Progress in this field, principally with respect to CT and interventional fluoroscopy will be presented. In the US, dose reduction and optimization efforts for computed tomography have been promoted and mandated by several organizations and accrediting entities. This presentation will cover the general motivation, implementation, and implications of such efforts. Learning Objectives: Understand importance of the dose optimization in Diagnostic Radiology. See how this goal is achieved in different regions of the World. Learn about the global trend in the dose optimization and future prospectives. M. Rehani, The work was a part of the work of IAEA where I was an employee and IAEA is a United Nations organization.« less

MO-DE-204-03: Radiology Dose Optimisation - An Australian Perspective

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

Schick, D.

2016-06-15

The main topic of the session is to show how dose optimization is being implemented in various regions of the world, including Europe, Australia, North America and other regions. A multi-national study conducted under International Atomic Energy Agency (IAEA) across more than 50 less resourced countries gave insight into patient radiation doses and safety practices in CT, mammography, radiography and interventional procedures, both for children and adults. An important outcome was the capability development on dose assessment and management. An overview of recent European projects related to CT radiation dose and optimization both to adults and children will be presented.more » Existing data on DRLs together with a European methodology proposed on establishing and using DRLs for paediatric radiodiagnostic imaging and interventional radiology practices will be shown. Compared with much of Europe at least, many Australian imaging practices are relatively new to the task of diagnostic imaging dose optimisation. In 2008 the Australian Government prescribed a requirement to periodically compare patient radiation doses with diagnostic reference levels (DRLs), where DRLs have been established. Until recently, Australia had only established DRLs for computed tomography (CT). Regardless, both professional society and individual efforts to improved data collection and develop optimisation strategies across a range of modalities continues. Progress in this field, principally with respect to CT and interventional fluoroscopy will be presented. In the US, dose reduction and optimization efforts for computed tomography have been promoted and mandated by several organizations and accrediting entities. This presentation will cover the general motivation, implementation, and implications of such efforts. Learning Objectives: Understand importance of the dose optimization in Diagnostic Radiology. See how this goal is achieved in different regions of the World. Learn about the global trend in the dose optimization and future prospectives. M. Rehani, The work was a part of the work of IAEA where I was an employee and IAEA is a United Nations organization.« less

Dosimetric evaluation of total marrow irradiation using 2 different planning systems

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

Nalichowski, Adrian, E-mail: nalichoa@karmanos.org; Eagle, Don G.; Burmeister, Jay

This study compared 2 different treatment planning systems (TPSs) for quality and efficiency of total marrow irradiation (TMI) plans. The TPSs used in this study were VOxel-Less Optimization (VoLO) (Accuray Inc, Sunnyvale, CA) using helical dose delivery on a Tomotherapy Hi-Art treatment unit and Eclipse (Varian Medical Systems Inc, Palo Alto, CA) using volumetric modulated arc therapy (VMAT) dose delivery on a Varian iX treatment unit. A total dose of 1200 cGy was prescribed to cover 95% of the planning target volume (PTV). The plans were optimized and calculated based on a single CT data and structure set using themore » Alderson Rando phantom (The Phantom Laboratory, Salem, NY) and physician contoured target and organ at risk (OAR) volumes. The OARs were lungs, heart, liver, kidneys, brain, and small bowel. The plans were evaluated based on plan quality, time to optimize the plan and calculate the dose, and beam on time. The resulting mean and maximum doses to the PTV were 1268 and 1465 cGy for VoLO and 1284 and 1541 cGy for Eclipse, respectively. For 5 of 6 OAR structures the VoLO system achieved lower mean and D10 doses ranging from 22% to 52% and 3% to 44%, respectively. Total computational time including only optimization and dose calculation were 0.9 hours for VoLO and 3.8 hours for Eclipse. These times do not include user-dependent target delineation and field setup. Both planning systems are capable of creating high-quality plans for total marrow irradiation. The VoLO planning system was able to achieve more uniform dose distribution throughout the target volume and steeper dose fall off, resulting in superior OAR sparing. VoLO's graphics processing unit (GPU)–based optimization and dose calculation algorithm also allowed much faster creation of TMI plans.« less

TU-AB-BRC-12: Optimized Parallel MonteCarlo Dose Calculations for Secondary MU Checks

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

French, S; Nazareth, D; Bellor, M

Purpose: Secondary MU checks are an important tool used during a physics review of a treatment plan. Commercial software packages offer varying degrees of theoretical dose calculation accuracy, depending on the modality involved. Dose calculations of VMAT plans are especially prone to error due to the large approximations involved. Monte Carlo (MC) methods are not commonly used due to their long run times. We investigated two methods to increase the computational efficiency of MC dose simulations with the BEAMnrc code. Distributed computing resources, along with optimized code compilation, will allow for accurate and efficient VMAT dose calculations. Methods: The BEAMnrcmore » package was installed on a high performance computing cluster accessible to our clinic. MATLAB and PYTHON scripts were developed to convert a clinical VMAT DICOM plan into BEAMnrc input files. The BEAMnrc installation was optimized by running the VMAT simulations through profiling tools which indicated the behavior of the constituent routines in the code, e.g. the bremsstrahlung splitting routine, and the specified random number generator. This information aided in determining the most efficient compiling parallel configuration for the specific CPU’s available on our cluster, resulting in the fastest VMAT simulation times. Our method was evaluated with calculations involving 10{sup 8} – 10{sup 9} particle histories which are sufficient to verify patient dose using VMAT. Results: Parallelization allowed the calculation of patient dose on the order of 10 – 15 hours with 100 parallel jobs. Due to the compiler optimization process, further speed increases of 23% were achieved when compared with the open-source compiler BEAMnrc packages. Conclusion: Analysis of the BEAMnrc code allowed us to optimize the compiler configuration for VMAT dose calculations. In future work, the optimized MC code, in conjunction with the parallel processing capabilities of BEAMnrc, will be applied to provide accurate and efficient secondary MU checks.« less

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

Dose in x-ray computed tomography

NASA Astrophysics Data System (ADS)

Kalender, Willi A.

2014-02-01

Radiation dose in x-ray computed tomography (CT) has become a topic of high interest due to the increasing numbers of CT examinations performed worldwide. This review aims to present an overview of current concepts for both scanner output metrics and for patient dosimetry and will comment on their strengths and weaknesses. Controversial issues such as the appropriateness of the CT dose index (CTDI) are discussed in detail. A review of approaches to patient dose assessment presently in practice, of the dose levels encountered and options for further dose optimization are also given and discussed. Patient dose assessment remains a topic for further improvement and for international consensus. All approaches presently in use are based on Monte Carlo (MC) simulations. Estimates for effective dose are established, but they are crude and not patient-specific; organ dose estimates are rarely available. Patient- and organ-specific dose estimates can be provided with adequate accuracy and independent of CTDI phantom measurements by fast MC simulations. Such information, in particular on 3D dose distributions, is important and helpful in optimization efforts. Dose optimization has been performed very successfully in recent years and even resulted in applications with effective dose values of below 1 mSv. In general, a trend towards lower dose values based on technical innovations has to be acknowledged. Effective dose values are down to clearly below 10 mSv on average, and there are a number of applications such as cardiac and pediatric CT which are performed routinely below 1 mSv on modern equipment.

Interference of plant volatiles on pheromone receptor neurons of male Grapholita molesta (Lepidoptera: Tortricidae).

PubMed

Ammagarahalli, Byrappa; Gemeno, César

2015-10-01

In moths, sex pheromone components are detected by pheromone-specific olfactory receptor neurons (ph-ORNs) housed in sensilla trichodea in the male antennae. In Grapholita molesta, ph-ORNs are highly sensitive and specific to the individual sex pheromone components, and thus help in the detection and discrimination of the unique conspecific pheromone blend. Plant odors interspersed with a sub-optimal pheromone dose are reported to increase male moth attraction. To determine if the behavioral synergism of pheromone and plant odors starts at the ph-ORN level, single sensillum recordings were performed on Z8-12:Ac and E8-12:Ac ph-ORNs (Z-ORNs and E-ORNs, respectively) stimulated with pheromone-plant volatile mixtures. First, biologically meaningful plant-volatile doses were determined by recording the response of plant-specific ORNs housed in sensilla auricillica and trichodea to several plant odorants. This exploration provided a first glance at plant ORNs in this species. Then, using these plant volatile doses, we found that the spontaneous activity of ph-ORNs was not affected by the stimulation with plant volatiles, but that a binary mixture of sex pheromone and plant odorants resulted in a small (about 15%), dose-independent, but statistically significant, reduction in the spike frequency of Z-ORNs with respect to stimulation with Z8-12:Ac alone. The response of E-ORNs to a combination of E8-12:Ac and plant volatiles was not different from E8-12:Ac alone. We argue that the small inhibition of Z-ORNs caused by physiologically realistic plant volatile doses is probably not fully responsible for the observed behavioral synergism of pheromone and plant odors. Copyright © 2015 Elsevier Ltd. All rights reserved.

A phantom-based JAFROC observer study of two CT reconstruction methods: the search for optimisation of lesion detection and effective dose

NASA Astrophysics Data System (ADS)

Thompson, John D.; Chakraborty, Dev P.; Szczepura, Katy; Vamvakas, Ioannis; Tootell, Andrew; Manning, David J.; Hogg, Peter

2015-03-01

Purpose: To investigate the dose saving potential of iterative reconstruction (IR) in a computed tomography (CT) examination of the thorax. Materials and Methods: An anthropomorphic chest phantom containing various configurations of simulated lesions (5, 8, 10 and 12mm; +100, -630 and -800 Hounsfield Units, HU) was imaged on a modern CT system over a tube current range (20, 40, 60 and 80mA). Images were reconstructed with (IR) and filtered back projection (FBP). An ATOM 701D (CIRS, Norfolk, VA) dosimetry phantom was used to measure organ dose. Effective dose was calculated. Eleven observers (15.11+/-8.75 years of experience) completed a free response study, localizing lesions in 544 single CT image slices. A modified jackknife alternative free-response receiver operating characteristic (JAFROC) analysis was completed to look for a significant effect of two factors: reconstruction method and tube current. Alpha was set at 0.05 to control the Type I error in this study. Results: For modified JAFROC analysis of reconstruction method there was no statistically significant difference in lesion detection performance between FBP and IR when figures-of-merit were averaged over tube current (F(1,10)=0.08, p = 0.789). For tube current analysis, significant differences were revealed between multiple pairs of tube current settings (F(3,10) = 16.96, p<0.001) when averaged over image reconstruction method. Conclusion: The free-response study suggests that lesion detection can be optimized at 40mA in this phantom model, a measured effective dose of 0.97mSv. In high-contrast regions the diagnostic value of IR, compared to FBP, is less clear.

SU-D-BRB-06: Treating Glioblastoma Multiforme (GBM) as a Chronic Disease: Implication of Temporal-Spatial Dose Fractionation Optimization Including Cancer Stem Cell Dynamics

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

Yu, V; Nguyen, D; Pajonk, F

Purpose: To explore the feasibility of improving GBM treatment outcome with temporal-spatial dose optimization of an ordinary differential equation (ODE) that models the differentiation and distinct radiosensitivity between cancer stem cells (CSC) and differentiated cancer cells (DCC). Methods: The ODE was formulated into a non-convex optimization problem with the objective to minimize remaining total cancer cells 500 days from the onset of radiotherapy when the total cancer cell number was 3.5×10{sup 7}, while maintaining normal tissue biological effective dose (BED) of 100Gy resulted from standard prescription of 2Gyx30. Assuming spatially separated CSC and DCC, optimization was also performed to exploremore » the potential benefit from dose-painting the two compartments. Dose escalation to a sub-cell-population in the GTV was also examined assuming that a 2 cm margin around the GTV allows sufficient dose drop-off to 100Gy BED. The recurrence time was determined as the time at which the total cancer cell number regrows to 10{sup 9} cells. Results: The recurrence time with variable fractional doses administered once per week, bi-week and month for one year were found to be 615, 593 and 570 days, superior to the standard-prescription recurrence time of 418 days. The optimal dose-fraction size progression for both uniform and dose-painting to the tumor is low and relatively constant in the beginning and gradually increases to more aggressive fractions at end of the treatment course. Dose escalation to BED of 200Gy to the whole tumor alongside with protracted weekly treatment was found to further delay recurrence to 733 days. Dose-painting of 200 and 500Gy BED to CSC on a year-long weekly schedule further extended recurrence to 736 and 1076 days, respectively. Conclusion: GBM treatment outcome can possibly be improved with a chronic treatment approach. Further dose escalation to the entire tumor or CSC targeted killing is needed to achieve total tumor control. This work is supported by the NSF Graduate Research Fellowship (DGE-1144087)« less

Inverse Planning Approach for 3-D MRI-Based Pulse-Dose Rate Intracavitary Brachytherapy in Cervix Cancer

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

Chajon, Enrique; Dumas, Isabelle; Touleimat, Mahmoud B.Sc.

2007-11-01

Purpose: The purpose of this study was to evaluate the inverse planning simulated annealing (IPSA) software for the optimization of dose distribution in patients with cervix carcinoma treated with MRI-based pulsed-dose rate intracavitary brachytherapy. Methods and Materials: Thirty patients treated with a technique using a customized vaginal mold were selected. Dose-volume parameters obtained using the IPSA method were compared with the classic manual optimization method (MOM). Target volumes and organs at risk were delineated according to the Gynecological Brachytherapy Group/European Society for Therapeutic Radiology and Oncology recommendations. Because the pulsed dose rate program was based on clinical experience with lowmore » dose rate, dwell time values were required to be as homogeneous as possible. To achieve this goal, different modifications of the IPSA program were applied. Results: The first dose distribution calculated by the IPSA algorithm proposed a heterogeneous distribution of dwell time positions. The mean D90, D100, and V100 calculated with both methods did not differ significantly when the constraints were applied. For the bladder, doses calculated at the ICRU reference point derived from the MOM differed significantly from the doses calculated by the IPSA method (mean, 58.4 vs. 55 Gy respectively; p = 0.0001). For the rectum, the doses calculated at the ICRU reference point were also significantly lower with the IPSA method. Conclusions: The inverse planning method provided fast and automatic solutions for the optimization of dose distribution. However, the straightforward use of IPSA generated significant heterogeneity in dwell time values. Caution is therefore recommended in the use of inverse optimization tools with clinical relevance study of new dosimetric rules.« less

Albumin treatment regimen for type 1 hepatorenal syndrome: a dose-response meta-analysis.

PubMed

Salerno, Francesco; Navickis, Roberta J; Wilkes, Mahlon M

2015-11-25

Recommended treatment for type 1 hepatorenal syndrome consists of albumin and vasoconstrictor. The optimal albumin dose remains poorly characterized. This meta-analysis aimed to determine the impact of albumin dose on treatment outcomes. Clinical studies of type 1 hepatorenal syndrome treatment with albumin and vasoconstrictor were sought. Search terms included: hepatorenal syndrome; albumin; vasoconstrictor; terlipressin; midodrine; octreotide; noradrenaline; and norepinephrine. A meta-analysis was performed of hepatorenal syndrome reversal and survival in relation to albumin dose. Nineteen clinical studies with 574 total patients were included, comprising 8 randomized controlled trials, 8 prospective studies and 3 retrospective studies. The pooled percentage of patients achieving hepatorenal syndrome reversal was 49.5% (95% confidence interval, 40.0-59.1%). Increments of 100 g in cumulative albumin dose were accompanied by significantly increased survival (hazard ratio, 1.15; 95% confidence interval, 1.02-1.31; p = 0.023). A non-significant increase of similar magnitude in hepatorenal syndrome reversal was also observed (odds ratio, 1.15; 95% confidence interval, 0.97-1.37; p = 0.10). Expected survival rates at 30 days among patients receiving cumulative albumin doses of 200, 400 and 600 g were 43.2% (95% confidence interval, 36.4-51.3%), 51.4% (95% confidence interval, 46.3-57.1%) and 59.0% (95% confidence interval, 51.9-67.2), respectively. Neither survival nor hepatorenal syndrome reversal was significantly affected by vasoconstrictor dose or type, treatment duration, age, baseline serum creatinine, bilirubin or albumin, baseline mean arterial pressure, or study design, size or time period. This meta-analysis suggests a dose-response relationship between infused albumin and survival in patients with type 1 hepatorenal syndrome. The meta-analysis provides the best current evidence on the potential role of albumin dose selection in improving outcomes of treatment for type 1 HRS and furnishes guidance for the design of future dose-ranging studies.

Dose-response relationship of a new Timothy grass pollen allergoid in comparison with a 6-grass pollen allergoid.

PubMed

Pfaar, O; Hohlfeld, J M; Al-Kadah, B; Hauswald, B; Homey, B; Hunzelmann, N; Schliemann, S; Velling, P; Worm, M; Klimek, L

2017-11-01

Subcutaneous allergen immunotherapy with grass pollen allergoids has been proven to be effective and safe in the treatment of patients with allergic rhinoconjunctivitis. Based on the extensive cross-reactivity among Pooideae species, it has been suggested that grass pollen extracts could be prepared from a single species, rather than from a multiple species mixture. To find the optimal dose of a Phleum pratense (P. pratense) allergoid preparation and compare its efficacy and safety to a 6-grass pollen allergoid preparation. In this double-blind, placebo-controlled study (EudraCT: 2011-000674-58), three doses of P. pratense allergoid (1800 therapeutic units (TU), standard-dose 6000 TU and 18 000 TU) were compared with placebo and the marketed 6-grass pollen allergoid (6000 TU). In a pre-seasonal dosing regimen, 102 patients were randomized to five treatment groups and received nine subcutaneous injections. The primary efficacy endpoint was the change in weal size (late-phase reaction [LPR]) in response to the intracutaneous testing (ICT) before and after treatment, comparing the active allergoids to placebo. Secondary outcomes were the change in Total Nasal Symptom Score (TNSS) assessed in the allergen exposure chamber (AEC), the changes in P. pratense-serum-specific IgG 4 and the incidence of adverse events (AEs). All three doses of the P. pratense and the 6-grass pollen allergoid preparations were significantly superior to placebo for the primary outcome, whereas there were no significant differences in the change in TNSS. Compared to the standard-dose, the high-dose of P. pratense did not produce any additional significant benefit, but showed a slight increase in AEs. Yet this increase in AEs was lower than for the 6-grass pollen preparation. The standard-dose of the new P. pratense allergoid was comparable to the marketed 6-grass pollen preparation at equal dose for the parameters measured. © 2017 The Authors. Clinical & Experimental Allergy Published by John Wiley & Sons Ltd.

On the development of a VIPARnd radiotherapy 3D polymer gel dosimeter

NASA Astrophysics Data System (ADS)

Kozicki, Marek; Jaszczak, Malwina; Maras, Piotr; Dudek, Mariusz; Cłapa, Marian

2017-02-01

This work presents an improvement of the VIPARnd (‘nd’ stands for ‘normoxic, double’, or VIP) polymer gel dosimeter. The gel composition was altered by increasing the concentration of the monomeric components, N-vinylpyrrolidone (NVP) and N,N‧-methylenebisacrylamide (MBA), in co-solvent solutions. The optimal composition (VIPARCT, where ‘CT’ stands for computed tomography, or VIC) comprised: 17% NVP, 8% MBA, 12% t-BuOH, 7.5% gelatine, 0.007% ascorbic acid, 0.0008% CuSO4  ×  5H2O and 0.02% hydroquinone. The following characteristics of VIC were achieved: (i) linear dose range of 0.9_30 Gy, (ii) saturation for radiation doses of over 50 Gy, (iii) threshold dose of about 0.5 Gy, (iv) dose sensitivity of 0.171 Gy-1 s-1, which is roughly 2.2 times higher than that of VIP (for nuclear magnetic resonance measurements). It was also found that VIC is dose- rate-independent, and its dose response does not alter if the radiation source is changed from electrons to photons for external beam radiotherapy. The gel responded similarly to irradiation with small changes in radiation energy but was sensitive to larger energy changes. The VIC gel retained temporal stability from 20 h until at least 10 d after irradiation, whereas spatial stability was retained from 20 h until at least 6 d after irradiation. The scheme adopted for VIC manufacturing yields repeatable gels in terms of radiation dose response. The VIC was also shown to perform better than VIP using x-ray computed tomography as a readout method; the dose sensitivity of VIC (0.397 HU Gy-1) was 1.5 times higher than that of VIP. Also, the dose resolution of VIC was better than that of VIP in the whole dose range examined.

MO-AB-BRA-01: A Global Level Set Based Formulation for Volumetric Modulated Arc Therapy

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

Nguyen, D; Lyu, Q; Ruan, D

2016-06-15

Purpose: The current clinical Volumetric Modulated Arc Therapy (VMAT) optimization is formulated as a non-convex problem and various greedy heuristics have been employed for an empirical solution, jeopardizing plan consistency and quality. We introduce a novel global direct aperture optimization method for VMAT to overcome these limitations. Methods: The global VMAT (gVMAT) planning was formulated as an optimization problem with an L2-norm fidelity term and an anisotropic total variation term. A level set function was used to describe the aperture shapes and adjacent aperture shapes were penalized to control MLC motion range. An alternating optimization strategy was implemented to solvemore » the fluence intensity and aperture shapes simultaneously. Single arc gVMAT plans, utilizing 180 beams with 2° angular resolution, were generated for a glioblastoma multiforme (GBM), lung (LNG), and 2 head and neck cases—one with 3 PTVs (H&N3PTV) and one with 4 PTVs (H&N4PTV). The plans were compared against the clinical VMAT (cVMAT) plans utilizing two overlapping coplanar arcs. Results: The optimization of the gVMAT plans had converged within 600 iterations. gVMAT reduced the average max and mean OAR dose by 6.59% and 7.45% of the prescription dose. Reductions in max dose and mean dose were as high as 14.5 Gy in the LNG case and 15.3 Gy in the H&N3PTV case. PTV coverages (D95, D98, D99) were within 0.25% of the prescription dose. By globally considering all beams, the gVMAT optimizer allowed some beams to deliver higher intensities, yielding a dose distribution that resembles a static beam IMRT plan with beam orientation optimization. Conclusions: The novel VMAT approach allows for the search of an optimal plan in the global solution space and generates deliverable apertures directly. The single arc VMAT approach fully utilizes the digital linacs’ capability in dose rate and gantry rotation speed modulation. Varian Medical Systems, NIH grant R01CA188300, NIH grant R43CA183390.« less

A two‐point scheme for optimal breast IMRT treatment planning

PubMed Central

2013-01-01

We propose an approach to determining optimal beam weights in breast/chest wall IMRT treatment plans. The goal is to decrease breathing effect and to maximize skin dose if the skin is included in the target or, otherwise, to minimize the skin dose. Two points in the target are utilized to calculate the optimal weights. The optimal plan (i.e., the plan with optimal beam weights) consists of high energy unblocked beams, low energy unblocked beams, and IMRT beams. Six breast and five chest wall cases were retrospectively planned with this scheme in Eclipse, including one breast case where CTV was contoured by the physician. Compared with 3D CRT plans composed of unblocked and field‐in‐field beams, the optimal plans demonstrated comparable or better dose uniformity, homogeneity, and conformity to the target, especially at beam junction when supraclavicular nodes are involved. Compared with nonoptimal plans (i.e., plans with nonoptimized weights), the optimal plans had better dose distributions at shallow depths close to the skin, especially in cases where breathing effect was taken into account. This was verified with experiments using a MapCHECK device attached to a motion simulation table (to mimic motion caused by breathing). PACS number: 87.55 de PMID:24257291

Antimicrobials used for surgical prophylaxis by equine veterinary practitioners in Australia.

PubMed

Hardefeldt, L Y; Browning, G F; Thursky, K; Gilkerson, J R; Billman-Jacobe, H; Stevenson, M A; Bailey, K E

2018-01-01

Antimicrobials are widely used in Australian veterinary practices, but no investigation into the classes of antimicrobials used, or the appropriateness of use in horses, has been conducted. The aim of the study was to describe antimicrobial use for surgical prophylaxis in equine practice in Australia. Cross-sectional questionnaire survey. An online questionnaire was used to document antimicrobial usage patterns. Information solicited in the questionnaire included demographic details of the respondents, the frequency with which antimicrobials were used for specific surgical conditions (including the dose, timing and duration of therapy) and practice antimicrobial use policies and sources of information about antimicrobials and their uses. A total of 337 members of the Australian veterinary profession completed the survey. Generally, the choice of antimicrobial was appropriate for the specified equine surgical condition, but the dose and duration of therapy varied greatly. While there was poor optimal compliance with British Equine Veterinary Association guidelines in all scenarios (range 1-15%), except removal of a nonulcerated dermal mass (42%), suboptimal compliance (compliant antimicrobial drug selection but inappropriate timing, dose or duration of therapy) was moderate for all scenarios (range 48-68%), except for an uninfected contaminated wound over the thorax, where both optimal and suboptimal compliance was very poor (1%). Veterinarians practicing at a university hospital had higher odds of compliance than general practice veterinarians (Odds ratio 3.2, 95% CI, 1.1-8.9, P = 0.03). Many survey responses were collected at conferences which may introduce selection bias, as veterinarians attending conferences may be more likely to have been exposed to contemporary antimicrobial prescribing recommendations. Antimicrobial use guidelines need to be developed and promoted to improve the responsible use of antimicrobials in equine practice in Australia. An emphasis should be placed on antimicrobial therapy for wounds and appropriate dosing for procaine penicillin. © 2017 EVJ Ltd.

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

Wan Chan Tseung, Hok Seum, E-mail: wanchantseung.hok@mayo.edu; Ma, Jiasen; Kreofsky, Cole R.

Purpose: Our aim is to demonstrate the feasibility of fast Monte Carlo (MC)–based inverse biological planning for the treatment of head and neck tumors in spot-scanning proton therapy. Methods and Materials: Recently, a fast and accurate graphics processor unit (GPU)–based MC simulation of proton transport was developed and used as the dose-calculation engine in a GPU-accelerated intensity modulated proton therapy (IMPT) optimizer. Besides dose, the MC can simultaneously score the dose-averaged linear energy transfer (LET{sub d}), which makes biological dose (BD) optimization possible. To convert from LET{sub d} to BD, a simple linear relation was assumed. By use of thismore » novel optimizer, inverse biological planning was applied to 4 patients, including 2 small and 1 large thyroid tumor targets, as well as 1 glioma case. To create these plans, constraints were placed to maintain the physical dose (PD) within 1.25 times the prescription while maximizing target BD. For comparison, conventional intensity modulated radiation therapy (IMRT) and IMPT plans were also created using Eclipse (Varian Medical Systems) in each case. The same critical-structure PD constraints were used for the IMRT, IMPT, and biologically optimized plans. The BD distributions for the IMPT plans were obtained through MC recalculations. Results: Compared with standard IMPT, the biologically optimal plans for patients with small tumor targets displayed a BD escalation that was around twice the PD increase. Dose sparing to critical structures was improved compared with both IMRT and IMPT. No significant BD increase could be achieved for the large thyroid tumor case and when the presence of critical structures mitigated the contribution of additional fields. The calculation of the biologically optimized plans can be completed in a clinically viable time (<30 minutes) on a small 24-GPU system. Conclusions: By exploiting GPU acceleration, MC-based, biologically optimized plans were created for small–tumor target patients. This optimizer will be used in an upcoming feasibility trial on LET{sub d} painting for radioresistant tumors.« less

Stochastic optimization of intensity modulated radiotherapy to account for uncertainties in patient sensitivity

NASA Astrophysics Data System (ADS)

Kåver, Gereon; Lind, Bengt K.; Löf, Johan; Liander, Anders; Brahme, Anders

1999-12-01

The aim of the present work is to better account for the known uncertainties in radiobiological response parameters when optimizing radiation therapy. The radiation sensitivity of a specific patient is usually unknown beyond the expectation value and possibly the standard deviation that may be derived from studies on groups of patients. Instead of trying to find the treatment with the highest possible probability of a desirable outcome for a patient of average sensitivity, it is more desirable to maximize the expectation value of the probability for the desirable outcome over the possible range of variation of the radiation sensitivity of the patient. Such a stochastic optimization will also have to consider the distribution function of the radiation sensitivity and the larger steepness of the response for the individual patient. The results of stochastic optimization are also compared with simpler methods such as using biological response `margins' to account for the range of sensitivity variation. By using stochastic optimization, the absolute gain will typically be of the order of a few per cent and the relative improvement compared with non-stochastic optimization is generally less than about 10 per cent. The extent of this gain varies with the level of interpatient variability as well as with the difficulty and complexity of the case studied. Although the dose changes are rather small (<5 Gy) there is a strong desire to make treatment plans more robust, and tolerant of the likely range of variation of the radiation sensitivity of each individual patient. When more accurate predictive assays of the radiation sensitivity for each patient become available, the need to consider the range of variations can be reduced considerably.

Optimizing dosing of oncology drugs.

PubMed

Minasian, L; Rosen, O; Auclair, D; Rahman, A; Pazdur, R; Schilsky, R L

2014-11-01

The purpose of this article is to acknowledge the challenges in optimizing the dosing of oncology drugs and to propose potential approaches to address these challenges in order to optimize effectiveness, minimize toxicity, and promote adherence in patients. These approaches could provide better opportunities to understand the sources of variability in drug exposure and clinical outcomes during the development and premarketing evaluation of investigational new drugs.

The association between cumulative adversity and mental health: considering dose and primary focus of adversity.

PubMed

Keinan, Giora; Shrira, Amit; Shmotkin, Dov

2012-09-01

The study addressed the dose-response model in the association of cumulative adversity with mental health. Data of 1,725 participants aged 50+ were drawn from the Israeli component of the Survey of Health, Ageing, and Retirement in Europe. Measures included an inventory of potentially traumatic events, distress (lifetime depression, depressive symptoms), and well-being (quality of life, optimism/hope). The maximal effect of cumulative trauma emerged in the contrast between 0-2 and 3+ events, where the higher number of events related to higher distress but also to higher well-being. While self-oriented adversity revealed no, or negative, association with well-being, other-oriented adversity revealed a positive association. The study suggests an experiential dose of cumulative adversity leading to a co-activation of distress and well-being. The source of this co-activation seems to be other-oriented adversity.

Optimizing oncology therapeutics through quantitative translational and clinical pharmacology: challenges and opportunities.

PubMed

Venkatakrishnan, K; Friberg, L E; Ouellet, D; Mettetal, J T; Stein, A; Trocóniz, I F; Bruno, R; Mehrotra, N; Gobburu, J; Mould, D R

2015-01-01

Despite advances in biomedical research that have deepened our understanding of cancer hallmarks, resulting in the discovery and development of targeted therapies, the success rates of oncology drug development remain low. Opportunities remain for objective dose selection informed by exposure-response understanding to optimize the benefit-risk balance of novel therapies for cancer patients. This review article discusses the principles and applications of modeling and simulation approaches across the lifecycle of development of oncology therapeutics. Illustrative examples are used to convey the value gained from integration of quantitative clinical pharmacology strategies from the preclinical-translational phase through confirmatory clinical evaluation of efficacy and safety. © 2014 American Society for Clinical Pharmacology and Therapeutics.

Dose-response of altitude training: how much altitude is enough?

PubMed

Levine, Benjamin D; Stray-Gundersen, James

2006-01-01

Altitude training continues to be a key adjunctive aid for the training of competitive athletes throughout the world. Over the past decade, evidence has accumulated from many groups of investigators that the "living high--training low" approach to altitude training provides the most robust and reliable performance enhancements. The success of this strategy depends on two key features: 1) living high enough, for enough hours per day, for a long enough period of time, to initiate and sustain an erythropoietic effect of high altitude; and 2) training low enough to allow maximal quality of high intensity workouts, requiring high rates of sustained oxidative flux. Because of the relatively limited access to environments where such a strategy can be practically applied, numerous devices have been developed to "bring the mountain to the athlete," which has raised the key issue of the appropriate "dose" of altitude required to stimulate an acclimatization response and performance enhancement. These include devices using molecular sieve technology to provide a normobaric hypoxic living or sleeping environment, approaches using very high altitudes (5,500m) for shorter periods of time during the day, and "intermittent hypoxic training" involving breathing very hypoxic gas mixtures for alternating 5 minutes periods over the course of 60-90 minutes. Unfortunately, objective testing of the strategies employing short term (less than 4 hours) normobaric or hypobaric hypoxia has failed to demonstrate an advantage of these techniques. Moreover individual variability of the response to even the best of living high--training low strategies has been great, and the mechanisms behind this variability remain obscure. Future research efforts will need to focus on defining the optimal dosing strategy for these devices, and determining the underlying mechanisms of the individual variability so as to enable the individualized "prescription" of altitude exposure to optimize the performance of each athlete.

Optimal effect-site concentration of remifentanil when combined with dexmedetomidine in patients undergoing cystoscopy

PubMed Central

Heo, Bongha; Kim, Minsun; Lee, Hyunjung; Park, Sanghee

2014-01-01

Background Cystoscopic procedure is a very common practice in the field of urology due to its ability to survey the bladder for a variety of indications. However, patients who undergo cystoscopy feel intense pain and discomfort. This study investigated the half maximal effective concentration (EC50) of remifentanil in preventing cystoscope insertion pain under sedation using dexmedetomidine. Methods The study was prospectively conducted on 18 male patients, aged 18 to 65. Remifentail infusion was initiated together with dexmedetomidine, and started at a dose of 2.4 ng/ml on the first patient. The effect-site concentration (Ce) of remifentanil for each subsequent patient was determined by the previous patient's response using Dixon's up-and-down method with an interval of 0.3 ng/ml. Patients received a loading dose of 1.0 µg/kg dexmedetomidine over 10 minutes, followed by a maintenance dose of 0.6 µg/kg/hr. After the patient's OAA/S score (Observer's Assessment of Alertness/Sedation scale) reached 3-4, and the Ce of remifentanil reached target concentration, the urologist was allowed to insert the cystoscope and the pain responses were observed. Results The effect-site concentration of remifentanil required to prevent cystoscope insertion pain in 50% of patients under sedation using dexmedetomidine was 1.30 ± 0.12 ng/ml by Dixon's up-and-down method. The logistic regression curve of the probability of response showed that the EC50 and EC95 values (95% confidence limits) of remifentanil were 1.33 ng/ml (1.12-1.52 ng/ml) and 1.58 ng/ml (1.44-2.48 ng/ml), respectively. Conclusions Cystoscopic procedure can be carried out successfully without any pain or adverse effects by optimal remifentanil effect-site concentration (EC50, 1.33 ng/ml; EC95, 1.58 ng/ ml) combined with sedation using dexmedetomidine. PMID:24567812

Humoral immune responses against gonadotropin releasing hormone elicited by immunization with phage-peptide constructs obtained via phage display.

PubMed

Samoylov, Alexandre; Cochran, Anna; Schemera, Bettina; Kutzler, Michelle; Donovan, Caitlin; Petrenko, Valery; Bartol, Frank; Samoylova, Tatiana

2015-12-20

Phage display is based on genetic engineering of phage coat proteins resulting in fusion peptides displayed on the surface of phage particles. The technology is widely used for generation of phages with novel characteristics for numerous applications in biomedicine and far beyond. The focus of this study was on development of phage-peptide constructs that stimulate production of antibodies against gonadotropin releasing hormone (GnRH). Phage-peptide constructs that elicit production of neutralizing GnRH antibodies can be used for anti-fertility and anti-cancer applications. Phage-GnRH constructs were generated via selection from a phage display library using several types of GnRH antibodies as selection targets. Such phage constructs were characterized for sequence similarities to GnRH peptide and frequency of their occurrence in the selection rounds. Five of the constructs with suitable characteristics were tested in mice as a single dose 5×10(11) virions (vir) vaccine and were found to be able to stimulate production of GnRH-specific antibodies, but not to suppress testosterone (indirect indicator of GnRH antibody neutralizing properties). Next, one of the constructs was tested at a higher dose of 2×10(12) vir per mouse in combination with a poly(lactide-co-glycolide) (PLGA)-based adjuvant. This resulted in multifold increase in GnRH antibody production and significant reduction of serum testosterone, indicating that antibodies produced in response to the phage-GnRH immunization possess neutralizing properties. To achieve optimal immune responses for desired applications, phage-GnRH constructs can be modified with respect to flanking sequences of GnRH-like peptides displayed on phage. Anticipated therapeutic effects also might be attained using optimized phage doses, a combination of several constructs in a single treatment, or application of adjuvants and advanced phage delivery systems. Copyright © 2015 Elsevier B.V. All rights reserved.

Effect of Admission Oral Diuretic Dose on Response to Continuous versus Bolus Intravenous Diuretics in Acute Heart Failure: An Analysis from DOSE-AHF

PubMed Central

Shah, Ravi V.; McNulty, Steven; O'Connor, Christopher M.; Felker, G. Michael; Braunwald, Eugene; Givertz, Michael M.

2014-01-01

Background Results from the Diuretic Optimization Strategies in Acute Heart Failure (DOSE-AHF) study suggest that an initial continuous infusion of loop diuretics is not superior to bolus dosing with regard to clinical endpoints in AHF. We hypothesized that outpatient furosemide dose was associated with congestion and poorer renal function, and explored the hypothesis that a continuous infusion may be more effective in patients on higher outpatient diuretic doses. Methods DOSE-AHF randomized 308 patients within 24 hours of admission to high vs. low initial intravenous diuretic dose given as either a continuous infusion or bolus. We compared baseline characteristics and assessed associations between mode of administration (bolus vs. continuous) and outcomes in patients receiving high-dose (≥120 mg furosemide equivalent, n=177) versus low-dose (<120 mg furosemide equivalent, n=131) outpatient diuretics. Results Patients on higher doses of furosemide were less frequently on renin-angiotensin system inhibitors (P=.01), and had worse renal function and more advanced symptoms. There was a significant interaction between outpatient dose and mode of therapy (P=0.01) with respect to net fluid loss at 72 hours after adjusting for creatinine and intensification strategy. Admission diuretic dose was associated with an increased risk of death or rehospitalization at 60 days (adjusted HR=1.08 per 20-mg increment in dose, 95% CI 1.01–1.16, P=.03). Conclusions In acute HF, patients on higher diuretic doses have greater disease severity, and may benefit from an initial bolus strategy. PMID:23194486

Clinical pharmacokinetics, safety, and preliminary efficacy evaluation of icotinib in patients with advanced non-small cell lung cancer.

PubMed

Liu, Dongyang; Zhang, Li; Wu, Yiwen; Jiang, Ji; Tan, Fenlai; Wang, Yingxiang; Liu, Yong; Hu, Pei

2015-09-01

To receive pharmacokinetics, safety, and anti-tumor activity of icotinib, a novel epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), in patients with advanced non-small-cell lung cancer (NSCLC). Patients (n=40) with advanced NSCLC were enrolled to receive escalating doses of icotinib, which was administrated on Day 1 followed by 28-day continuous dosing starting from Day 4. Four dosing regimens, 100mg b.i.d., 150 mg b.i.d., 125 mg t.i.d., and 200mg b.i.d. were studied. Pharmacokinetics (PK), safety, and efficacy of icotinib were evaluated. Icotinib was well tolerated in Chinese patients with refractory NSCLC. No toxicity with >3 grades were reported in more than 2 patients under any dose levels. One complete response (3%) and 9 partial responses (23%) were received. Total disease control rate could reach at 73% and median progress-free survival (range) was 154 (17-462) days. PK exposure of icotinib increased with increase of dose in NSCLC patients. Food was suggested to increase PK exposure by ∼30%. Mean t1/2β was within 5.31-8.07 h. No major metabolite (>10% plasma exposure of icotinib) was found in NSCLC patients. Icotinib with up to 400 mg/day exhibited good tolerance and preliminary antitumor activity in Chinese NSCLC patients. Pharmacokinetics of icotinib and 5 major metabolites were fully investigated in NSCLC patients. Optimized biologic dose (OBD) was finally recommended to be 125 mg t.i.d. for the later clinical study. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Optimization of inactivated H5N9 highly pathogenic avian influenza vaccine and inactivated Salmonella enterica serovar Typhimurium vaccine with antigen dose and prime-boost regimen in domestic ducks.

PubMed

Yuk, Seong-Su; To, Eredene-Ochir; Kwon, Jung-Hoon; Noh, Jin-Yong; Hong, Woo-Tack; Jeong, Jei-Hyun; Gwon, Gyeong-Bin; Song, Chang-Seon

2017-09-01

Owing to the increase in the number of diseases affecting ducks and the demand for food safety by consumers, vaccination has become one of the factors that influence duck meat productivity. The highly pathogenic avian influenza (HPAI) virus is one of the most prevalent and causes one of the most lethal diseases in domestic ducks, and Salmonella enterica serovar Typhimurium is a food-borne pathogen persistent in the domestic duck population. To better understand the optimal usage of HPAI and S. enterica serovar Typhimurium vaccines, we aimed to determine antigen dose, oil and gel adjuvant usage with prime-boost regimen, and vaccination age, inducing the best immune response in ducks, without an effect on body weight gain. In the case of the inactivated H5N9 vaccine, a single dose of vaccine was inadequate to induce proper antibody titer when administered to day-old ducks, which necessitates boost vaccination. Administration of the oil-adjuvanted H5N9 vaccine administration in day-old and 2-week-old ducks resulted in a lower body weight at the time of slaughtering, compared to that of gel-adjuvanted H5N9 vaccine. However, gel-adjuvanted H5N9 vaccine failed to induce proper immune response to an extent recommend by OIE-World Organization for Animal Health. In the case of the Salmonella enterica serovar Typhimurium vaccine, a moderate or low dose of vaccine was appropriate for day-old ducks receiving the gel prime-oil boost vaccination. Single vaccination with oil adjuvants affects the mean body weight of 7-week-old ducks, suggesting that the gel adjuvant is more suitable for meat production. We expect that the use of adjuvants in a prime-boost regimen and at antigen doses set in this study will be helpful to maximize body weight in the case of domestic duck production at the actual farm site. © 2017 Poultry Science Association Inc.

Clinical and Genetic Determinants of Warfarin Pharmacokinetics and Pharmacodynamics during Treatment Initiation

PubMed Central

Gong, Inna Y.; Schwarz, Ute I.; Crown, Natalie; Dresser, George K.; Lazo-Langner, Alejandro; Zou, GuangYong; Roden, Dan M.; Stein, C. Michael; Rodger, Marc; Wells, Philip S.; Kim, Richard B.; Tirona, Rommel G.

2011-01-01

Variable warfarin response during treatment initiation poses a significant challenge to providing optimal anticoagulation therapy. We investigated the determinants of initial warfarin response in a cohort of 167 patients. During the first nine days of treatment with pharmacogenetics-guided dosing, S-warfarin plasma levels and international normalized ratio were obtained to serve as inputs to a pharmacokinetic-pharmacodynamic (PK-PD) model. Individual PK (S-warfarin clearance) and PD (Imax) parameter values were estimated. Regression analysis demonstrated that CYP2C9 genotype, kidney function, and gender were independent determinants of S-warfarin clearance. The values for Imax were dependent on VKORC1 and CYP4F2 genotypes, vitamin K status (as measured by plasma concentrations of proteins induced by vitamin K absence, PIVKA-II) and weight. Importantly, indication for warfarin was a major independent determinant of Imax during initiation, where PD sensitivity was greater in atrial fibrillation than venous thromboembolism. To demonstrate the utility of the global PK-PD model, we compared the predicted initial anticoagulation responses with previously established warfarin dosing algorithms. These insights and modeling approaches have application to personalized warfarin therapy. PMID:22114699

By-product identification and phytotoxicity of biodegraded Direct Yellow 4 dye.

PubMed

Nouren, Shazia; Bhatti, Haq Nawaz; Iqbal, Munawar; Bibi, Ismat; Kamal, Shagufta; Sadaf, Sana; Sultan, Misbah; Kausar, Abida; Safa, Yusra

2017-02-01

Citrus limon peroxidase mediated decolourization of Direct Yellow 4 (DY4) was investigated. The process variables (pH, temperature, incubation time, enzyme dose, H 2 O 2 amount, dye concentration, co-metal ions and surfactants) were optimized for maximum degradation of dye. Maximum dye decolourization of 89.47% was achieved at pH 5.0, temperature 50 °C, enzyme dose 24 U/mL, H 2 O 2 concentration 0.25 mM and DY4 concentration 18.75 mg/L and incubation time 10 min. The co-metal ions and surfactants did not affect the dye decolourization significantly. Response surface analysis revealed that predicted values were in agreement with experimentally determined responses. The degradation products were identified by UPLC/MS analysis and degradation pathway was proposed. Besides, phytotoxicity assay revealed a considerable detoxification in response of biodegradation of DY4 dye. C. limon showed promising efficiency for DY4 degradation and could possibly be used for the remediation of textile effluents. Copyright © 2016 Elsevier Ltd. All rights reserved.

Development of radiochromic film for spatially quantitative dosimetric analysis of indirect ionizing radiation fields

NASA Astrophysics Data System (ADS)

Brady, Samuel Loren

Two types of radiochromic films (RCF) were characterized for this work: EBT and XRQA film. Both films were investigated for: radiation interaction with film structure; light interaction with film structure for optimal film readout (densitometry) sensitivity; range of absorbed dose measurements; dependence of film dose measurement response as a function of changing radiation energy; fractionation and dose rate effects on film measurement response; film response sensitivity to ambient factors; and stability of measured film response with time. EBT film was shown to have the following properties: near water equivalent atomic weight (Zeff); dynamic dose range of 10 -1-102 Gy; 3% change in optical density (OD) response for a single exposure level when exposed to radiation energies from (75-18,000) kV; and best digitized using transmission densitometry. XRQA film was shown to have: a Zeff of ˜25; a 12 fold increase in sensitivity at lower photon energies for a dynamic dose range of 10-3-100 Gy, a difference of 25% in OD response when comparing 120 kV to 320 kV, and best digitized using reflective densitometry. Both XRQA and EBT films were shown to have: a temporal stability (DeltaOD) of ˜1% for t > 24 hr post film exposure for up to ˜20 days; a change in dose response of ˜0.03 mGy hr-1 when exposed to fluorescent room lighting at standard room temperature and humidity levels; a negligible dose rate and fractionation effect when operated within the optimal dose ranges; and a light wavelength dependence with dose for film readout. The flat bed scanner was chosen as the primary film digitizer due to its availability, cost, OD range, functionality (transmission and reflection scanning), and digitization speed. As a cost verses functionality comparison, the intrinsic and operational limitations were determined for two flat bed scanners. The EPSON V700 and 10000XL exhibited equal spatial and OD accuracy. The combined precision of both the scanner light sources and CCD sensors measured < 2% and < 7% deviation in pixel light intensities for 50 consecutive scans, respectively. Both scanner light sources were shown to be uniform in transmission and reflection scan modes along the center axis of light source translation. Additionally, RCFs demonstrated a larger dynamic range in pixel light intensities, and to be less sensitive to off axis light inhomogeneity, when scanned in landscape mode (long axis of film parallel with axis of light source translation). The EPSON 10000XL demonstrated slightly better light source/CCD temporal stability and provided a capacity to scan larger film formats at the center of the scanner in landscape mode. However, the EPSON V700 only measured an overall difference in accuracy and precision by 2%, and though smaller in size, at the time of this work, was one sixth the cost of the 10000XL. A scan protocol was developed to maximize RCF digitization accuracy and precision, and a calibration fitting function was developed for RCF absolute dosimetry. The fitting function demonstrated a superior goodness of fit for both RCF types over a large range of absorbed dose levels as compared to the currently accepted function found in literature. The RCF dosimetry system was applied to three novel areas from which a benefit could be derived for 2D or 3D dosimetric information. The first area was for a 3D dosimetry of a pendant breast in 3D-CT mammography. The novel method of developing a volumetric image of the breast from a CT acquisition technique was empirically measured for its dosimetry and compared to standard dual field digital mammography. The second area was dose reduction in CT for pediatric and adult scan protocols. In this application, novel methodologies were developed to measure 3D organ dosimetry and characterize a dose reduction scan protocol for pediatric and adult body habitus. The third area was in the field of small animal irradiation for radiobiology purposes and cancer patient treatment verification. In every case, the RCF dosimetry system was verified for accuracy using a traditional PDD as the golden standard. When considering all areas of radiation energy applications, the RCF dosimetry system agreed to better than 7% of the golden standard, and in some cases within better than 1%. In many instances, this work provided vital dosimetric information that otherwise was not captured using the PDD in similar geometry. This work demonstrates the need for RCF to more accurately measure volumetric dose. (Abstract shortened by UMI.)

Speed and convergence properties of gradient algorithms for optimization of IMRT.

PubMed

Zhang, Xiaodong; Liu, Helen; Wang, Xiaochun; Dong, Lei; Wu, Qiuwen; Mohan, Radhe

2004-05-01

Gradient algorithms are the most commonly employed search methods in the routine optimization of IMRT plans. It is well known that local minima can exist for dose-volume-based and biology-based objective functions. The purpose of this paper is to compare the relative speed of different gradient algorithms, to investigate the strategies for accelerating the optimization process, to assess the validity of these strategies, and to study the convergence properties of these algorithms for dose-volume and biological objective functions. With these aims in mind, we implemented Newton's, conjugate gradient (CG), and the steepest decent (SD) algorithms for dose-volume- and EUD-based objective functions. Our implementation of Newton's algorithm approximates the second derivative matrix (Hessian) by its diagonal. The standard SD algorithm and the CG algorithm with "line minimization" were also implemented. In addition, we investigated the use of a variation of the CG algorithm, called the "scaled conjugate gradient" (SCG) algorithm. To accelerate the optimization process, we investigated the validity of the use of a "hybrid optimization" strategy, in which approximations to calculated dose distributions are used during most of the iterations. Published studies have indicated that getting trapped in local minima is not a significant problem. To investigate this issue further, we first obtained, by trial and error, and starting with uniform intensity distributions, the parameters of the dose-volume- or EUD-based objective functions which produced IMRT plans that satisfied the clinical requirements. Using the resulting optimized intensity distributions as the initial guess, we investigated the possibility of getting trapped in a local minimum. For most of the results presented, we used a lung cancer case. To illustrate the generality of our methods, the results for a prostate case are also presented. For both dose-volume and EUD based objective functions, Newton's method far outperforms other algorithms in terms of speed. The SCG algorithm, which avoids expensive "line minimization," can speed up the standard CG algorithm by at least a factor of 2. For the same initial conditions, all algorithms converge essentially to the same plan. However, we demonstrate that for any of the algorithms studied, starting with previously optimized intensity distributions as the initial guess but for different objective function parameters, the solution frequently gets trapped in local minima. We found that the initial intensity distribution obtained from IMRT optimization utilizing objective function parameters, which favor a specific anatomic structure, would lead to a local minimum corresponding to that structure. Our results indicate that from among the gradient algorithms tested, Newton's method appears to be the fastest by far. Different gradient algorithms have the same convergence properties for dose-volume- and EUD-based objective functions. The hybrid dose calculation strategy is valid and can significantly accelerate the optimization process. The degree of acceleration achieved depends on the type of optimization problem being addressed (e.g., IMRT optimization, intensity modulated beam configuration optimization, or objective function parameter optimization). Under special conditions, gradient algorithms will get trapped in local minima, and reoptimization, starting with the results of previous optimization, will lead to solutions that are generally not significantly different from the local minimum.

Is Dosing of Therapeutic Immunoglobulins Optimal? A Review of a Three-Decade Long Debate in Europe

PubMed Central

Kerr, Jacqueline; Quinti, Isabella; Eibl, Martha; Chapel, Helen; Späth, Peter J.; Sewell, W. A. Carrock; Salama, Abdulgabar; van Schaik, Ivo N.; Kuijpers, Taco W.; Peter, Hans-Hartmut

2014-01-01

The consumption of immunoglobulins (Ig) is increasing due to better recognition of antibody deficiencies, an aging population, and new indications. This review aims to examine the various dosing regimens and research developments in the established and in some of the relevant off-label indications in Europe. The background to the current regulatory settings in Europe is provided as a backdrop for the latest developments in primary and secondary immunodeficiencies and in immunomodulatory indications. In these heterogeneous areas, clinical trials encompassing different routes of administration, varying intervals, and infusion rates are paving the way toward more individualized therapy regimens. In primary antibody deficiencies, adjustments in dosing and intervals will depend on the clinical presentation, effective IgG trough levels and IgG metabolism. Ideally, individual pharmacokinetic profiles in conjunction with the clinical phenotype could lead to highly tailored treatment. In practice, incremental dosage increases are necessary to titrate the optimal dose for more severely ill patients. Higher intravenous doses in these patients also have beneficial immunomodulatory effects beyond mere IgG replacement. Better understanding of the pharmacokinetics of Ig therapy is leading to a move away from simplistic “per kg” dosing. Defective antibody production is common in many secondary immunodeficiencies irrespective of whether the causative factor was lymphoid malignancies (established indications), certain autoimmune disorders, immunosuppressive agents, or biologics. This antibody failure, as shown by test immunization, may be amenable to treatment with replacement Ig therapy. In certain immunomodulatory settings [e.g., idiopathic thrombocytopenic purpura (ITP)], selection of patients for Ig therapy may be enhanced by relevant biomarkers in order to exclude non-responders and thus obtain higher response rates. In this review, the developments in dosing of therapeutic immunoglobulins have been limited to high and some medium priority indications such as ITP, Kawasaki’ disease, Guillain–Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, myasthenia gravis, multifocal motor neuropathy, fetal alloimmune thrombocytopenia, fetal hemolytic anemia, and dermatological diseases. PMID:25566244

Treatment regimens of classical and newer taxanes.

PubMed

Joerger, Markus

2016-02-01

The classical taxanes (paclitaxel, docetaxel), the newer taxane cabazitaxel and the nanoparticle-bound nab-paclitaxel are among the most widely used anticancer drugs. The taxanes share the characteristics of extensive hepatic metabolism and biliary excretion, the need for dose adaptation in patients with liver dysfunction, and a substantial pharmacokinetic variability even after taking into account known covariates. Data from clinical studies suggest that optimal scheduling of the taxanes is dependent not only on the specific taxane compound, but also on the tumor type and line of treatment. Still, the optimal dosing regimen (weekly vs 3 weekly) and optimal dose of the taxanes are controversial, as is the value of pharmacological personalization of taxane dosing. In this article, an overview is given on the pharmacological properties of the taxanes, including metabolism, pharmacokinetics-pharmacodynamics and aspects in the clinical use of taxanes. The latter includes the ongoing debate on the most active and safe regimen, the recommended initial dose and the issue of therapeutic drug dosing.

Appropriate Use of Effective Dose in Radiation Protection and Risk Assessment.

PubMed

Fisher, Darrell R; Fahey, Frederic H

2017-08-01

Effective dose was introduced by the ICRP for the single, over-arching purpose of setting limits for radiation protection. Effective dose is a derived quantity or mathematical construct and not a physical, measurable quantity. The formula for calculating effective dose to a reference model incorporates terms to account for all radiation types, organ and tissue radiosensitivities, population groups, and multiple biological endpoints. The properties and appropriate applications of effective dose are not well understood by many within and outside the health physics profession; no other quantity in radiation protection has been more confusing or misunderstood. According to ICRP Publication 103, effective dose is to be used for "prospective dose assessment for planning and optimization in radiological protection, and retrospective demonstration of compliance for regulatory purposes." In practice, effective dose has been applied incorrectly to predict cancer risk among exposed persons. The concept of effective dose applies generally to reference models only and not to individual subjects. While conceived to represent a measure of cancer risk or heritable detrimental effects, effective dose is not predictive of future cancer risk. The formula for calculating effective dose incorporates committee-selected weighting factors for radiation quality and organ sensitivity; however, the organ weighting factors are averaged across all ages and both genders and thus do not apply to any specific individual or radiosensitive subpopulations such as children and young women. Further, it is not appropriate to apply effective dose to individual medical patients because patient-specific parameters may vary substantially from the assumptions used in generalized models. Also, effective dose is not applicable to therapeutic uses of radiation, as its mathematical underpinnings pertain only to observed late (stochastic) effects of radiation exposure and do not account for short-term adverse tissue reactions. The weighting factors incorporate substantial uncertainties, and linearity of the dose-response function at low dose is uncertain and highly disputed. Since effective dose is not predictive of future cancer incidence, it follows that effective dose should never be used to estimate future cancer risk from specific sources of radiation exposure. Instead, individual assessments of potential detriment should only be based on organ or tissue radiation absorbed dose, together with best scientific understanding of the corresponding dose-response relationships.

Intracoronary Adenosine: Dose-Response Relationship With Hyperemia.

PubMed

Adjedj, Julien; Toth, Gabor G; Johnson, Nils P; Pellicano, Mariano; Ferrara, Angela; Floré, Vincent; Di Gioia, Giuseppe; Barbato, Emanuele; Muller, Olivier; De Bruyne, Bernard

2015-09-01

The present study sought to establish the dosage of intracoronary (IC) adenosine associated with minimal side effects and above which no further increase in flow can be expected. Despite the widespread adoption of IC adenosine in clinical practice, no wide-ranging, dose-response study has been conducted. A recurring debate still exists regarding its optimal dose. In 30 patients, Doppler-derived flow velocity measurements were obtained in 10 right coronary arteries (RCAs) and 20 left coronary arteries (LCAs) free of stenoses >20% in diameter. Flow velocity was measured at baseline and after 8 ml bolus administrations of arterial blood, saline, contrast medium, and 9 escalating doses of adenosine (4 to 500 μg). The hyperemic value was expressed in percent of the maximum flow velocity reached in a given artery (Q/Qmax, %). Q/Qmax did not increase significantly beyond dosages of 60 μg for the RCA and 160 μg for LCA. Heart rate did not change, whereas mean arterial blood pressure decreased by a maximum of 7% (p < 0.05) after bolus injections of IC adenosine. The incidence of transient A-V blocks was 40% after injection of 100 μg in the RCA and was 15% after injection of 200 μg in the LCA. The duration of the plateau reached 12 ± 13 s after injection of 100 μg in the RCA and 21 ± 6 s after the injection of 200 μg in the LCA. A progressive prolongation of the time needed to return to baseline was observed. Hyperemic response after injection of 8 ml of contrast medium reached 65 ± 36% of that achieved after injection of 200 μg of adenosine. This wide-ranging, dose-response study indicates that an IC adenosine bolus injection of 100 μg in the RCA and 200 μg in the LCA induces maximum hyperemia while being associated with minimal side effects. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Evaluation and optimization of occupational eye lens dosimetry during positron emission tomography (PET) procedures.

PubMed

Guiu-Souto, Jacobo; Sánchez-García, Manuel; Vázquez-Vázquez, Rubén; Otero, Carlos; Luna, Victor; Mosquera, Javier; Busto, Ramón Lobato; Aguiar, Pablo; Ruibal, Álvaro; Pardo-Montero, Juan; Pombar-Cameán, Miguel

2016-06-01

The last recommendations of the International Commission on Radiological Protection for eye lens dose suggest an important reduction on the radiation limits associated with early and late tissue reactions. The aim of this work is to quantify and optimize the eye lens dose associated to nurse staff during positron emission tomography (PET) procedures. PET is one of the most important diagnostic methods of oncological and neurological cancer disease involving an important number of workers exposed to the high energy isotope F-18. We characterize the relevant stages as preparation and administration of monodose syringes in terms of occupational dose. A direct reading silicon dosimeter was used to measure the lens dose to staff. The highest dose of radiation was observed during preparation of the fluorodesoxyglucose (FDG) syringes. By optimizing a suitable vials' distribution of FDG we find an important reduction in occupational doses. Extrapolation of our data to other clinical scenarios indicates that, depending on the work load and/or syringes activity, safety limits of the dose might be exceeded.

Optimal iodine-131 dose for eliminating hyperthyroidism in Graves' disease

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

Nordyke, R.A.; Gilbert, F.I. Jr.

1991-03-01

Since hypothyroidism is commonplace after treatment of Graves' disease with radioiodine, the goal should be cure of hyperthyroidism rather than avoidance of hypothyroidism. To find the optimal dose to accomplish cure, we treated 605 patients with stepwise increasing doses of 3, 4, 5, 6, 8, and 10 mCi, analyzing the relationship of dose, age, sex, gland weight, and thyroidal uptake to cure. Estimates of cure at doses above 10 mCi were made from the literature. Cure was directly related to dose between 5 and 10 mCi. There was no significant relationship between cure and age (chi-square, p = 0.74), sexmore » (chi-square, p = 0.12), and 24-hr uptake if over 30% (chi-square for slope, p greater than 0.10). Cure and gland weight had an inverse relationship (chi-square for slope, 0.01 less than p less than 0.02). We concluded that the optimal 131I dose for curing hyperthyroidism is approximated by starting with 10 mCi and increasing it for unusually large glands or for special patient circumstances.« less

Predicting the optimal geometry of microneedles and their array for dermal vaccination using a computational model.

PubMed

Römgens, Anne M; Bader, Dan L; Bouwstra, Joke A; Oomens, Cees W J

2016-11-01

Microneedle arrays have been developed to deliver a range of biomolecules including vaccines into the skin. These microneedles have been designed with a wide range of geometries and arrangements within an array. However, little is known about the effect of the geometry on the potency of the induced immune response. The aim of this study was to develop a computational model to predict the optimal design of the microneedles and their arrangement within an array. The three-dimensional finite element model described the diffusion and kinetics in the skin following antigen delivery with a microneedle array. The results revealed an optimum distance between microneedles based on the number of activated antigen presenting cells, which was assumed to be related to the induced immune response. This optimum depends on the delivered dose. In addition, the microneedle length affects the number of cells that will be involved in either the epidermis or dermis. By contrast, the radius at the base of the microneedle and release rate only minimally influenced the number of cells that were activated. The model revealed the importance of various geometric parameters to enhance the induced immune response. The model can be developed further to determine the optimal design of an array by adjusting its various parameters to a specific situation.

Optimization of Treatment Geometry to Reduce Normal Brain Dose in Radiosurgery of Multiple Brain Metastases with Single-Isocenter Volumetric Modulated Arc Therapy.

PubMed

Wu, Qixue; Snyder, Karen Chin; Liu, Chang; Huang, Yimei; Zhao, Bo; Chetty, Indrin J; Wen, Ning

2016-09-30

Treatment of patients with multiple brain metastases using a single-isocenter volumetric modulated arc therapy (VMAT) has been shown to decrease treatment time with the tradeoff of larger low dose to the normal brain tissue. We have developed an efficient Projection Summing Optimization Algorithm to optimize the treatment geometry in order to reduce dose to normal brain tissue for radiosurgery of multiple metastases with single-isocenter VMAT. The algorithm: (a) measures coordinates of outer boundary points of each lesion to be treated using the Eclipse Scripting Application Programming Interface, (b) determines the rotations of couch, collimator, and gantry using three matrices about the cardinal axes, (c) projects the outer boundary points of the lesion on to Beam Eye View projection plane, (d) optimizes couch and collimator angles by selecting the least total unblocked area for each specific treatment arc, and (e) generates a treatment plan with the optimized angles. The results showed significant reduction in the mean dose and low dose volume to normal brain, while maintaining the similar treatment plan qualities on the thirteen patients treated previously. The algorithm has the flexibility with regard to the beam arrangements and can be integrated in the treatment planning system for clinical application directly.

Comprehensive optimization process of paranasal sinus radiography.

PubMed

Saarakkala, S; Nironen, K; Hermunen, H; Aarnio, J; Heikkinen, J O

2009-04-01

The optimization of radiological examinations is important in order to reduce unnecessary patient radiation exposure. To perform a comprehensive optimization process for paranasal sinus radiography at Mikkeli Central Hospital, Finland. Patients with suspicion of acute sinusitis were imaged with a Kodak computed radiography (CR) system (n=20) and with a Philips digital radiography (DR) system (n=30) using focus-detector distances (FDDs) of 110 cm, 150 cm, or 200 cm. Patients' radiation exposure was determined in terms of entrance surface dose and dose-area product. Furthermore, an anatomical phantom was used for the estimation of point doses inside the head. Clinical image quality was evaluated by an experienced radiologist, and physical image quality was evaluated from the digital radiography phantom. Patient doses were significantly lower and image quality better with the DR system compared to the CR system. The differences in patient dose and physical image quality were small with varying FDD. Clinical image quality of the DR system was lowest with FDD of 200 cm. Further, imaging with FDD of 150 cm was technically easier for the technologist to perform than with FDD of 110 cm. After optimization, it was recommended that the DR system with FDD of 150 cm should always be used at Mikkeli Central Hospital. We recommend this kind of comprehensive approach in all optimization processes of radiological examinations.

Optimal dose selection accounting for patient subpopulations in a randomized Phase II trial to maximize the success probability of a subsequent Phase III trial.

PubMed

Takahashi, Fumihiro; Morita, Satoshi

2018-02-08

Phase II clinical trials are conducted to determine the optimal dose of the study drug for use in Phase III clinical trials while also balancing efficacy and safety. In conducting these trials, it may be important to consider subpopulations of patients grouped by background factors such as drug metabolism and kidney and liver function. Determining the optimal dose, as well as maximizing the effectiveness of the study drug by analyzing patient subpopulations, requires a complex decision-making process. In extreme cases, drug development has to be terminated due to inadequate efficacy or severe toxicity. Such a decision may be based on a particular subpopulation. We propose a Bayesian utility approach (BUART) to randomized Phase II clinical trials which uses a first-order bivariate normal dynamic linear model for efficacy and safety in order to determine the optimal dose and study population in a subsequent Phase III clinical trial. We carried out a simulation study under a wide range of clinical scenarios to evaluate the performance of the proposed method in comparison with a conventional method separately analyzing efficacy and safety in each patient population. The proposed method showed more favorable operating characteristics in determining the optimal population and dose.

Sequential allergen desensitization of basophils is non-specific and may involve p38 MAPK.

PubMed

Witting Christensen, S K; Kortekaas Krohn, I; Thuraiaiyah, J; Skjold, T; Schmid, J M; Hoffmann, H J H

2014-10-01

Sequential allergen desensitization provides temporary tolerance for allergic patients. We adapted a clinical protocol to desensitize human blood basophils ex vivo and investigated the mechanism and allergen specificity. We included 28 adult, grass allergic subjects. The optimal, activating allergen concentration was determined by measuring activated CD63(+) CD193(+) SS(Low) basophils in a basophil activation test with 8 log-dilutions of grass allergen. Basophils in whole blood were desensitized by incubation with twofold to 2.5-fold increasing allergen doses in 10 steps starting at 1 : 1000 of the optimal dose. Involvement of p38 mitogen-activated protein kinase (MAPK) was assessed after 3 min of allergen stimulation (n = 7). Allergen specificity was investigated by desensitizing cells from multi-allergic subjects with grass allergen and challenging with optimal doses of grass, birch, recombinant house dust mite (rDer p2) allergen or anti-IgE (n = 10). Desensitization reduced the fraction of blood basophils responding to challenge with an optimal allergen dose from a median (IQR) 81.0% (66.3-88.8) to 35.4% (19.8-47.1, P < 0.0001). CD63 MFI expression was reduced from 68 248 (29 336-92 001) to 30 496 (14 046-46 179, P < 0.0001). Basophils from multi-allergic subjects were desensitized with grass allergen. Challenge with grass allergen resulted in 39.6% activation (15.8-58.3). An unrelated challenge (birch, rDer p2 or anti-IgE) resulted in 53.4% activation (30.8-66.8, P = 0.16 compared with grass). Desensitization reduced p38 MAPK phosphorylation from a median 48.1% (15.6-92.8) to 26.1% (7.4-71.2, P = 0.047) and correlated with decrease in CD63 upregulation (n = 7, r > 0.79, P < 0.05). Desensitization attenuated basophil response rapidly and non-specifically at a stage before p38 MAPK phosphorylation. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Long-term Outcomes of Infliximab Use for Pediatric Crohn Disease: A Canadian Multicenter Clinical Practice Experience.

PubMed

deBruyn, Jennifer C; Jacobson, Kevan; El-Matary, Wael; Carroll, Matthew; Wine, Eytan; Wrobel, Iwona; Van Woudenberg, Mariel; Huynh, Hien Q

2018-02-01

Data on long-term real-world outcomes of infliximab in pediatric Crohn disease are limited. The aim of the study was to evaluate infliximab optimization and durability in children with Crohn disease. We performed a retrospective review of children with Crohn disease who started infliximab from January 2008 to December 2012 in 4 Canadian tertiary care centers. A priori factors associated with optimization and discontinuation from loss of response were evaluated using logistic regression and Cox proportional hazards model, respectively. One hundred eighty children (54.4% boys) started infliximab; all completed induction. Median age at infliximab start was 14.3 years (Q1, Q3: 12.8, 15.9 years) and median time from diagnosis to infliximab start was 1.5 years (Q1, Q3: 0.6, 3.5 years). At last follow-up, 87.1% were maintained on infliximab (median duration follow-up 85.9 weeks [Q1, Q3: 43.8, 138.8 weeks]). Infliximab optimization occurred in 57.3% (dose escalation 15.2%, interval shortening 3.9%, both 38.2%), primarily due to loss of response. Younger age at diagnosis (<10 years old) and nonstricturing, nonpenetrating behavior were associated with optimization (odds ratio 6.5, 95% confidence interval [CI] 2.0-21.1 and odds ratio 2.1, 95% CI 1.0-4.2, respectively). The 1- and 2-year durability of infliximab (percentage in follow-up who were continuing on infliximab) were 95.5% (95% CI 90.4-98.3) and 91.0% (95% CI 82.4-96.3), respectively. Annual discontinuation due to loss of response occurred at 3.2% per year (95% CI 1.1-5.2). Children with Crohn disease maintain a durable response to infliximab. Optimization occurs frequently and allows for continued use. Younger age at diagnosis and nonstricturing, nonpenetrating behavior are associated with increased need for infliximab optimization.

Increasing the Vegetable Intake Dose Is Associated with a Rise in Plasma Carotenoids without Modifying Oxidative Stress or Inflammation in Overweight or Obese Postmenopausal Women123

PubMed Central

Crane, Tracy E.; Kubota, Chieri; West, Julie L.; Kroggel, Mark A.; Wertheim, Betsy C.; Thomson, Cynthia A.

2011-01-01

The optimal amount of vegetable consumption required to reduce chronic disease risk is widely debated. Intervention trials evaluating biological activity of vegetables at various doses are limited. We conducted a 3-dose, crossover feeding trial to test the hypothesis that vegetable intake is associated in a dose-dependent manner with increased plasma carotenoids and subsequently reduced oxidative stress and inflammation in 49 overweight, postmenopausal women. Participants were assigned in random order to 2 (130 g), 5 (287 g), and 10 (614 g) daily servings of fresh, greenhouse-grown vegetables for 3-wk intervals with a 4-wk washout period between treatments. Plasma total carotenoids significantly increased from 1.63 to 2.07 μmol/L with a dose of 2 vegetable servings, from 1.49 to 2.84 μmol/L with a dose of 5 vegetable servings, and from 1.40 to 4.42 μmol/L with a dose of 10 vegetable servings (pre-post paired ttests, all P < 0.001). The change during each feeding period increased with each dose level (P < 0.001). Urine concentrations of 8-isoprostane F2α, hexanoyl lysine, and serum high sensitivity C-reactive protein were not affected by any administered vegetable dose. In this variable-dose vegetable study, a dose-response for plasma carotenoids was demonstrated without significant change in oxidative stress and inflammation in overweight, postmenopausal women. PMID:21865569

SU-F-T-193: Evaluation of a GPU-Based Fast Monte Carlo Code for Proton Therapy Biological Optimization

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

Taleei, R; Qin, N; Jiang, S

2016-06-15

Purpose: Biological treatment plan optimization is of great interest for proton therapy. It requires extensive Monte Carlo (MC) simulations to compute physical dose and biological quantities. Recently, a gPMC package was developed for rapid MC dose calculations on a GPU platform. This work investigated its suitability for proton therapy biological optimization in terms of accuracy and efficiency. Methods: We performed simulations of a proton pencil beam with energies of 75, 150 and 225 MeV in a homogeneous water phantom using gPMC and FLUKA. Physical dose and energy spectra for each ion type on the central beam axis were scored. Relativemore » Biological Effectiveness (RBE) was calculated using repair-misrepair-fixation model. Microdosimetry calculations were performed using Monte Carlo Damage Simulation (MCDS). Results: Ranges computed by the two codes agreed within 1 mm. Physical dose difference was less than 2.5 % at the Bragg peak. RBE-weighted dose agreed within 5 % at the Bragg peak. Differences in microdosimetric quantities such as dose average lineal energy transfer and specific energy were < 10%. The simulation time per source particle with FLUKA was 0.0018 sec, while gPMC was ∼ 600 times faster. Conclusion: Physical dose computed by FLUKA and gPMC were in a good agreement. The RBE differences along the central axis were small, and RBE-weighted dose difference was found to be acceptable. The combined accuracy and efficiency makes gPMC suitable for proton therapy biological optimization.« less

Role of step size and max dwell time in anatomy based inverse optimization for prostate implants

PubMed Central

Manikandan, Arjunan; Sarkar, Biplab; Rajendran, Vivek Thirupathur; King, Paul R.; Sresty, N.V. Madhusudhana; Holla, Ragavendra; Kotur, Sachin; Nadendla, Sujatha

2013-01-01

In high dose rate (HDR) brachytherapy, the source dwell times and dwell positions are vital parameters in achieving a desirable implant dose distribution. Inverse treatment planning requires an optimal choice of these parameters to achieve the desired target coverage with the lowest achievable dose to the organs at risk (OAR). This study was designed to evaluate the optimum source step size and maximum source dwell time for prostate brachytherapy implants using an Ir-192 source. In total, one hundred inverse treatment plans were generated for the four patients included in this study. Twenty-five treatment plans were created for each patient by varying the step size and maximum source dwell time during anatomy-based, inverse-planned optimization. Other relevant treatment planning parameters were kept constant, including the dose constraints and source dwell positions. Each plan was evaluated for target coverage, urethral and rectal dose sparing, treatment time, relative target dose homogeneity, and nonuniformity ratio. The plans with 0.5 cm step size were seen to have clinically acceptable tumor coverage, minimal normal structure doses, and minimum treatment time as compared with the other step sizes. The target coverage for this step size is 87% of the prescription dose, while the urethral and maximum rectal doses were 107.3 and 68.7%, respectively. No appreciable difference in plan quality was observed with variation in maximum source dwell time. The step size plays a significant role in plan optimization for prostate implants. Our study supports use of a 0.5 cm step size for prostate implants. PMID:24049323

A novel role for autologous tumour cell vaccination in the immunotherapy of the poorly immunogenic B16-BL6 melanoma.

PubMed

Geiger, J D; Wagner, P D; Shu, S; Chang, A E

1992-06-01

The growth of immunogenic tumours stimulates the generation of tumour-sensitized, but not functional, pre-effector T cells in the draining lymph nodes. These pre-effector cells can mature into effector cells upon in-vitro stimulation with anti-CD3 and IL-2. In the current study, using a defined, poorly immunogenic tumour, B16-BL6 melanoma, the pre-effector cell response was not evident during progressive tumour growth but was elicited by vaccination with irradiated tumour cells admixed with Corynebacterium parvum. After anti-CD3/IL-2 activation, these cells were capable of mediating the regression of established pulmonary metastases. The efficacy of the vaccine depended on the doses of both tumour cells and the adjuvant. While higher numbers of tumour cells were more effective, an optimal dose (12.5 micrograms) of C. parvum was required. The dose of irradiation was not a critical factor. After vaccination, kinetic studies revealed that the pre-effector cell response was evident 4 days later and declined after 14 days. These observations illustrate the potential role of active immunization in the cellular therapy of cancer.

Safety and immunogenicity in human volunteers of a chloroform-methanol residue vaccine for Q fever.

PubMed Central

Fries, L F; Waag, D M; Williams, J C

1993-01-01

Current Q fever vaccines, consisting of Formalin-inactivated phase I whole Coxiella burnetii, are highly efficacious in preventing disease in high-risk settings but are associated with a risk of unacceptable local reactions in previously immune individuals and require cumbersome preliminary immunologic evaluation of potential vaccinees. A vaccine prepared from the residue of chloroform-methanol extraction of phase I Henzerling strain C. burnetii (CMR) has been shown to be less reactogenic but still immunogenic and protective in small animals and sheep. In a placebo-controlled trial, we immunized 35 healthy adults unscreened for markers of prior C. burnetii immunity with a single subcutaneous CMR dose of 30, 60, 120, or 240 micrograms. None of those receiving the 30- or 60-micrograms CMR dose and none of the placebo recipients experienced any adverse effects. Five of 15 120-micrograms dose CMR recipients complained of transient discomfort in the inoculated arm; erythema or induration of > or = 100 mm2 was noted in three and four, respectively, and two had malaise and low-grade fever (< 101 degrees F, orally). No 240-micrograms dose vaccinee reported limb discomfort, but 7 of 10 had erythema and/or induration of > or = 100 mm2 (P < 0.001 versus placebo). Two reported malaise, and one had low-grade fever. All adverse effects were self-limited. Serum immunoglobulin M responses were optimally detected with CMR antigen and occurred in 50, 60, 73, and 90% of recipients of the 30-, 60-, 120-, and 240-micrograms doses, respectively; results with phase I whole-cell antigen were similar. Serum immunoglobulin G responses were best detected with phase II antigen and were seen in 20, 20, and 40% of those receiving the 60-, 120-, and 240-micrograms doses, respectively. Peripheral blood T-cell proliferative responses to C. burnetii recall antigens were transient and of low magnitude but were seen with CMR antigen in 33% of 120-micrograms dose recipients and 40% of 240-micrograms dose recipients. Data from this study and those from comparative-efficacy trials in primates should provide the basis for field trials of the CMR vaccine. PMID:8454328

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

Nusrat, Humza; Pang, Geordi; Ahmad, Syed

Purpose: In radiotherapy, the amount of radiation delivered is determined by optimizing the amount of absorbed dose to the tumor. Dose does not always correlate well with the actual biological effects of radiation. This work seeks to validate the LET-dependence of doped plastic scintillators for use in a radiation beam quality (LET) detector. Methods: The LET spectrum ([Φ]) can be resolved knowing the measured signals of uniquely LET-dependent detectors, [S], and the response of each LET-dependent detector to specific LETs ([R]), through the relation [Φ]=[S][R]{sup −1}. Plastic scintillator response is intrinsically LET dependent and can be varied via doping. Initialmore » prototype consists of plastic scintillator and glass taper coupled to an optical fiber; components are housed in black acrylic, reducing effect of ambient light. In order to determine [R], the light response matrix, GEANT4.10.1 Monte Carlo (MC) was used. To validate MC, measurements were done using high energy electrons (9,12,15MeV) and orthovoltage x-rays (100,250kV); scintillator signal was normalized to dose measured simultaneously. Results: Stopping power was varied by changing particle type/energy; measurements indicated that as stopping power increased from 1.9 to 6.6MeV/cm, detector response increased by 263% (+/−29.2%) for 5%Pb-doped scintillator (155% in MC); 52% (+/−7.8%) increase observed when undoped scintillator was used (49% in MC). 5%Pb-doped discrepancy (100kV x-rays) is being investigated. Conclusions: This work validates that doping effects LET/energy response of scintillators; an effect that can be utilized for construction of an LET detector.« less

Hepatitis C treatment among racial and ethnic groups in the IDEAL trial.

PubMed

Muir, A J; Hu, K-Q; Gordon, S C; Koury, K; Boparai, N; Noviello, S; Albrecht, J K; Sulkowski, M S; McCone, J

2011-04-01

Previous studies of chronic hepatitis C virus (HCV) treatment have demonstrated variations in response among racial and ethnic groups including poorer efficacy rates among African American and Hispanic patients. The individualized dosing efficacy vs flat dosing to assess optimaL pegylated interferon therapy (IDEAL) trial enrolled 3070 patients from 118 United States centres to compare treatment with peginterferon (PEG-IFN) alfa-2a and ribavirin (RBV) and two doses of PEG-IFN alfa-2b and RBV. This analysis examines treatment response among the major racial and ethnic groups in the trial. Overall, sustained virologic response (SVR) rates were 44% for white, 22% for African American, 38% for Hispanic and 59% for Asian American patients. For patients with undetectable HCV RNA at treatment week 4, the positive predictive value of SVR was 86% for white, 92% for African American, 83% for Hispanic and 89% for Asian American patients. The positive predictive values of SVR in those with undetectable HCV RNA at treatment week 12 ranged from 72% to 81%. Multivariate regression analysis using baseline characteristics demonstrated that treatment regimen was not a predictor of SVR. Despite wide-ranging SVR rates among the different racial and ethnic groups, white and Hispanic patients had similar SVR rates. In all groups, treatment response was largely determined by antiviral activity in the first 12 weeks of treatment. Therefore, decisions regarding HCV treatment should consider the predictive value of the early on-treatment response, not just baseline characteristics, such as race and ethnicity. © 2010 Blackwell Publishing Ltd.

Design of a modulated orthovoltage stereotactic radiosurgery system.

PubMed

Fagerstrom, Jessica M; Bender, Edward T; Lawless, Michael J; Culberson, Wesley S

2017-07-01

To achieve stereotactic radiosurgery (SRS) dose distributions with sharp gradients using orthovoltage energy fluence modulation with inverse planning optimization techniques. A pencil beam model was used to calculate dose distributions from an orthovoltage unit at 250 kVp. Kernels for the model were derived using Monte Carlo methods. A Genetic Algorithm search heuristic was used to optimize the spatial distribution of added tungsten filtration to achieve dose distributions with sharp dose gradients. Optimizations were performed for depths of 2.5, 5.0, and 7.5 cm, with cone sizes of 5, 6, 8, and 10 mm. In addition to the beam profiles, 4π isocentric irradiation geometries were modeled to examine dose at 0.07 mm depth, a representative skin depth, for the low energy beams. Profiles from 4π irradiations of a constant target volume, assuming maximally conformal coverage, were compared. Finally, dose deposition in bone compared to tissue in this energy range was examined. Based on the results of the optimization, circularly symmetric tungsten filters were designed to modulate the orthovoltage beam across the apertures of SRS cone collimators. For each depth and cone size combination examined, the beam flatness and 80-20% and 90-10% penumbrae were calculated for both standard, open cone-collimated beams as well as for optimized, filtered beams. For all configurations tested, the modulated beam profiles had decreased penumbra widths and flatness statistics at depth. Profiles for the optimized, filtered orthovoltage beams also offered decreases in these metrics compared to measured linear accelerator cone-based SRS profiles. The dose at 0.07 mm depth in the 4π isocentric irradiation geometries was higher for the modulated beams compared to unmodulated beams; however, the modulated dose at 0.07 mm depth remained <0.025% of the central, maximum dose. The 4π profiles irradiating a constant target volume showed improved statistics for the modulated, filtered distribution compared to the standard, open cone-collimated distribution. Simulations of tissue and bone confirmed previously published results that a higher energy beam (≥ 200 keV) would be preferable, but the 250 kVp beam was chosen for this work because it is available for future measurements. A methodology has been described that may be used to optimize the spatial distribution of added filtration material in an orthovoltage SRS beam to result in dose distributions with decreased flatness and penumbra statistics compared to standard open cones. This work provides the mathematical foundation for a novel, orthovoltage energy fluence-modulated SRS system. © 2017 American Association of Physicists in Medicine.

The immunomodulatory effect of vitamin D in chickens is dose-dependent and influenced by calcium and phosphorus levels.

PubMed

Rodriguez-Lecompte, J C; Yitbarek, A; Cuperus, T; Echeverry, H; van Dijk, A

2016-11-01

Vitamin D requirement is estimated to be higher than recommended values for the first two weeks of a broiler chicken's life, and is heavily dependent on the concentrations of Ca and P in the diet. There are data indicating the beneficial effect of higher vitamin D levels on performance and overall health of the chickens. However, data on the role of higher vitamin D levels on the innate immune response of chickens are limited. Therefore, in the current study, we examined the effect of higher doses of vitamin D supplementation on the innate immune response in broiler chickens receiving optimal or calcium (Ca) and phosphorus (P) deficient diets. Three hundred Ross-308 male broiler chicks were randomly allocated into 60 cages with 5 birds per cage in a 3 × 2 factorial design with three levels of vitamin D and two levels of Ca/P with each experimental diet fed to 10 cages (10 replicates). Quantitative reverse transcription PCR (n = 5) was used to assess Toll-like receptor (TLR2b and 4), cytokine/chemokine (IL-12, IFN-γ, IL-10, IL-4, IL-13, IL-18, CxCLi2) and cathelicidin (CATH1, CATHB1, CATH3) transcription levels in peripheral blood mononuclear cells (PBMCs), spleen, and bursa of Fabricius. Vitamin D supplementation of the Ca and P deficient diet considerably augmented transcription of TLR2b, TLR4, CATH1, and CATHB1 and predominantly Th2 cytokines in spleen. Supplementation of the control diet with vitamin D downregulated TLR4 transcription, and dose-dependently increased CATH1, CATHB1, Th1, and Th2 cytokine transcription (Th2>Th1). All diets downregulated CATH3 transcription. In conclusion, vitamin D or its derivative 25-OH-D 3 both have a robust immunomodulatory property with a more favorable Th2 response, while at the same time enhancing observed Th2 cytokine responses under both optimal and lower Ca and P inclusion levels in the diets of broiler chickens. © 2016 Poultry Science Association Inc.

Patient Dose Management: Focus on Practical Actions

PubMed Central

2016-01-01

Medical radiation is a very important part of modern medicine, and should be only used when needed and optimized. Justification and optimization of radiation examinations must be performed. The first step of reduction of medical exposure is to know the radiation dose in currently performed examinations. This review covers radiation units, how various imaging modalities report dose, and the current status of radiation dose reports and legislation. Also, practical tips that can be applied to clinical practice are introduced. Afterwards, the importance of radiology exposure related education is emphasized and the current status of education for medical personal and the public is explained, and appropriate education strategies are suggested. Commonly asked radiation dose related example questions and answers are provided in detail to allow medical personnel to answer patients. Lastly, we talk about computerized programs that can be used in medical facilities for managing patient dose. While patient dose monitoring and management should be used to decrease and optimize overall radiation dose, it should not be used to assess individual cancer risk. One must always remember that medically justified examinations should always be performed, and unneeded examinations should be avoided in the first place. PMID:26908988

SU-F-19A-03: Dosimetric Advantages in Critical Structure Dose Sparing by Using a Multichannel Cylinder in High Dose Rate Brachytherapy to Treat Vaginal Cuff Cancer

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

Syh, J; Syh, J; Patel, B

2014-06-15

Purpose: The multichannel cylindrical vaginal applicator is a variation of traditional single channel cylindrical vaginal applicator. The multichannel applicator has additional peripheral channels that provide more flexibility in the planning process. The dosimetric advantage is to reduce dose to adjacent organ at risk (OAR) such as bladder and rectum while maintaining target coverage with the dose optimization from additional channels. Methods: Vaginal HDR brachytherapy plans are all CT based. CT images were acquired in 2 mm thickness to keep integrity of cylinder contouring. The CTV of 5mm Rind with prescribed treatment length was reconstructed from 5mm expansion of inserted cylinder.more » The goal was 95% of CTV covered by 95% of prescribed dose in both single channel planning (SCP)and multichannel planning (MCP) before proceeding any further optimization for dose reduction to critical structures with emphasis on D2cc and V2Gy . Results: This study demonstrated noticeable dose reduction to OAR was apparent in multichannel plans. The D2cc of the rectum and bladder were showing the reduced dose for multichannel versus single channel. The V2Gy of the rectum was 93.72% and 83.79% (p=0.007) for single channel and multichannel respectively (Figure 1 and Table 1). To assure adequate coverage to target while reducing the dose to the OAR without any compromise is the main goal in using multichannel vaginal applicator in HDR brachytherapy. Conclusion: Multichannel plans were optimized using anatomical based inverse optimization algorithm of inverse planning simulation annealing. The optimization solution of the algorithm was to improve the clinical target volume dose coverage while reducing the dose to critical organs such as bladder, rectum and bowels. The comparison between SCP and MCP demonstrated MCP is superior to SCP where the dwell positions were based on geometric array only. It concluded that MCP is preferable and is able to provide certain features superior to SCP.« less

Influence of molecular structure on the tolerogenicity of bacterial dextrans. I. The alpha1--6-linked epitope of dextran B512.

PubMed Central

Howard, J G; Vicari, G; Courtenay, B M

1975-01-01

Native dextran B512 is a near-linear glucose polymer with 96 per cent alpha1--6 and 4 per cent alpha1--3 linkages and a molecular weight (mol. wt) of 8 X 10(7). Sheep RBC sensitized with its O-stearoyl derivative (prepared by a modified method) have been used satisfactorily in direct PFC assays. B512 immunizes BALB/c mice optimally with doses of 1--10 mug and produces B-cell tolerance with 1 mg upwards. The specificity of the response determined by PFC inhibition analysis, is directed towards an alpha1--6-linked epitope. High dose tolerance is not preceded by immunity and is stable on cell transfer to irradiated recipients in which responsiveness becomes perceptible after 4--6 weeks. Progressive depolymerization of this polysaccharide reduces immunogenicity and tolerogenicity, both of which are extinguished when the mol. wt falls to 2 X 10(4). Optimal immunization with B512 is succeeded by partial tolerance (previously characterized by analogous levan experiments as a B-cell exhaustion process). The tolerance threshold dose of B512 is reduced 1000-fold during immunosuppression with cyclophosphamide. PFC inhibition studies supported the contention that tolerogenicity of polysaccharides is influenced by their overall binding capacities. A direct relationship between inhibitory and tolerogenic activities was found both with B512 fractions of varying mol. wt and with heterologous dextrans. The similarities between B512 and levan argue against the association of a highly branched structure with greater tolerogenicity. The effect of reducing the percentage of alpha1--6 linkages in dextrans suggests, however, that epitope density probably plays a contributory role in determining the outcome of interaction between polysaccharides and B cells. PMID:52612

SU-F-BRD-08: Guaranteed Epsilon-Optimal Treatment Plans with Minimum Number of Beams for SBRT Using RayStation

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

Yarmand, H; Winey, B; Craft, D

2014-06-15

Purpose: To efficiently find quality-guaranteed treatment plans with the minimum number of beams for stereotactic body radiation therapy using RayStation. Methods: For a pre-specified pool of candidate beams we use RayStation (a treatment planning software for clinical use) to identify the deliverable plan which uses all the beams with the minimum dose to organs at risk (OARs) and dose to the tumor and other structures in specified ranges. Then use the dose matrix information for the generated apertures from RayStation to solve a linear program to find the ideal plan with the same objective and constraints allowing use of allmore » beams. Finally we solve a mixed integer programming formulation of the beam angle optimization problem (BAO) with the objective of minimizing the number of beams while remaining in a predetermined epsilon-optimality of the ideal plan with respect to the dose to OARs. Since the treatment plan optimization is a multicriteria optimization problem, the planner can exploit the multicriteria optimization capability of RayStation to navigate the ideal dose distribution Pareto surface and select a plan of desired target coverage versus OARs sparing, and then use the proposed technique to reduce the number of beams while guaranteeing quality. For the numerical experiments two liver cases and one lung case with 33 non-coplanar beams are considered. Results: The ideal plan uses an impractically large number of beams. The proposed technique reduces the number of beams to the range of practical application (5 to 9 beams) while remaining in the epsilon-optimal range of 1% to 5% optimality gap. Conclusion: The proposed method can be integrated into a general algorithm for fast navigation of the ideal dose distribution Pareto surface and finding the treatment plan with the minimum number of beams, which corresponds to the delivery time, in epsilon-optimality range of the desired ideal plan. The project was supported by the Federal Share of program income earned by Massachusetts General Hospital on C06 CA059267, Proton Therapy Research and Treatment Center and partially by RaySearch Laboratories.« less

A novel adaptive needle insertion sequencing for robotic, single needle MR-guided high-dose-rate prostate brachytherapy

NASA Astrophysics Data System (ADS)

Borot de Battisti, M.; de Senneville, B. Denis; Hautvast, G.; Binnekamp, D.; Lagendijk, J. J. W.; Maenhout, M.; Moerland, M. A.

2017-05-01

MR-guided high-dose-rate (HDR) brachytherapy has gained increasing interest as a treatment for patients with localized prostate cancer because of the superior value of MRI for tumor and surrounding tissues localization. To enable needle insertion into the prostate with the patient in the MR bore, a single needle MR-compatible robotic system involving needle-by-needle dose delivery has been developed at our institution. Throughout the intervention, dose delivery may be impaired by: (1) sub-optimal needle positioning caused by e.g. needle bending, (2) intra-operative internal organ motion such as prostate rotations or swelling, or intra-procedural rectum or bladder filling. This may result in failure to reach clinical constraints. To assess the first aforementioned challenge, a recent study from our research group demonstrated that the deposited dose may be greatly improved by real-time adaptive planning with feedback on the actual needle positioning. However, the needle insertion sequence is left to the doctor and therefore, this may result in sub-optimal dose delivery. In this manuscript, a new method is proposed to determine and update automatically the needle insertion sequence. This strategy is based on the determination of the most sensitive needle track. The sensitivity of a needle track is defined as its impact on the dose distribution in case of sub-optimal positioning. A stochastic criterion is thus presented to determine each needle track sensitivity based on needle insertion simulations. To assess the proposed sequencing strategy, HDR prostate brachytherapy was simulated on 11 patients with varying number of needle insertions. Sub-optimal needle positioning was simulated at each insertion (modeled by typical random angulation errors). In 91% of the scenarios, the dose distribution improved when the needle was inserted into the most compared to the least sensitive needle track. The computation time for sequencing was less than 6 s per needle track. The proposed needle insertion sequencing can therefore assist in delivering an optimal dose in HDR prostate brachytherapy.

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

Kofler, J.

The main topic of the session is to show how dose optimization is being implemented in various regions of the world, including Europe, Australia, North America and other regions. A multi-national study conducted under International Atomic Energy Agency (IAEA) across more than 50 less resourced countries gave insight into patient radiation doses and safety practices in CT, mammography, radiography and interventional procedures, both for children and adults. An important outcome was the capability development on dose assessment and management. An overview of recent European projects related to CT radiation dose and optimization both to adults and children will be presented.more » Existing data on DRLs together with a European methodology proposed on establishing and using DRLs for paediatric radiodiagnostic imaging and interventional radiology practices will be shown. Compared with much of Europe at least, many Australian imaging practices are relatively new to the task of diagnostic imaging dose optimisation. In 2008 the Australian Government prescribed a requirement to periodically compare patient radiation doses with diagnostic reference levels (DRLs), where DRLs have been established. Until recently, Australia had only established DRLs for computed tomography (CT). Regardless, both professional society and individual efforts to improved data collection and develop optimisation strategies across a range of modalities continues. Progress in this field, principally with respect to CT and interventional fluoroscopy will be presented. In the US, dose reduction and optimization efforts for computed tomography have been promoted and mandated by several organizations and accrediting entities. This presentation will cover the general motivation, implementation, and implications of such efforts. Learning Objectives: Understand importance of the dose optimization in Diagnostic Radiology. See how this goal is achieved in different regions of the World. Learn about the global trend in the dose optimization and future prospectives. M. Rehani, The work was a part of the work of IAEA where I was an employee and IAEA is a United Nations organization.« 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

Novel Approaches for Visualizing and Analyzing Dose-Timing Data from Electronic Drug Monitors, or "How the 'Broken Window' Theory Pertains to ART Adherence".

PubMed

Gill, Christopher J; DeSilva, Mary Bachman; Hamer, Davidson H; Keyi, Xu; Wilson, Ira B; Sabin, Lora

2015-11-01

Adherence to antiretroviral medications is usually expressed in terms of the proportion of doses taken. However, the timing of doses taken may also be an important dimension to overall adherence. Little is known about whether patients who mistime doses are also more likely to skip doses. Using data from the completed Adherence for Life randomized controlled trial, we created visual and statistical models to capture and analyze dose timing data collected longitudinally with electronic drug monitors (EDM). From scatter plots depicting dose time versus calendar date, we identified dominant patterns of dose taking and calculated key features [slope of line over calendar date; residual mean standard error (RMSE)]. Each was assessed for its ability to categorize subjects with 'sub-optimal' (<95 % of doses taken) using area under the receiver operating characteristic (AROC) curve analysis. Sixty eight subjects contributed EDM data, with ~300 to 400 observations/subject. While regression line slopes did not predict 'sub-optimal' adherence (AROC 0.51, 95 % CI 0.26-0.75), the variability in dose timing (RMSE) was strongly predictive (AROC 0.79, 95 % CI 0.62-0.97). Compared with the lowest quartile of RMSE (minimal dose time variability), each successive quartile roughly doubled the odds of 'sub-optimal' adherence (OR 2.1, 95 % CI 1.3-3.4). Patterns of dose timing and mistiming are strongly related to overall adherence behavior. Notably, individuals who skip doses are more likely to mistime doses, with the degree of risk positively correlated with the extent of dose timing variability.

Advanced Variance Reduction Strategies for Optimizing Mesh Tallies in MAVRIC

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

Peplow, Douglas E.; Blakeman, Edward D; Wagner, John C

2007-01-01

More often than in the past, Monte Carlo methods are being used to compute fluxes or doses over large areas using mesh tallies (a set of region tallies defined on a mesh that overlays the geometry). For problems that demand that the uncertainty in each mesh cell be less than some set maximum, computation time is controlled by the cell with the largest uncertainty. This issue becomes quite troublesome in deep-penetration problems, and advanced variance reduction techniques are required to obtain reasonable uncertainties over large areas. The CADIS (Consistent Adjoint Driven Importance Sampling) methodology has been shown to very efficientlymore » optimize the calculation of a response (flux or dose) for a single point or a small region using weight windows and a biased source based on the adjoint of that response. This has been incorporated into codes such as ADVANTG (based on MCNP) and the new sequence MAVRIC, which will be available in the next release of SCALE. In an effort to compute lower uncertainties everywhere in the problem, Larsen's group has also developed several methods to help distribute particles more evenly, based on forward estimates of flux. This paper focuses on the use of a forward estimate to weight the placement of the source in the adjoint calculation used by CADIS, which we refer to as a forward-weighted CADIS (FW-CADIS).« less

Chitosan based grey wastewater treatment--a statistical design approach.

PubMed

Thirugnanasambandham, K; Sivakumar, V; Prakash Maran, J; Kandasamy, S

2014-01-01

In this present study, grey wastewater was treated under different operating conditions such as agitation time (1-3 min), pH (2.5-5.5), chitosan dose (0.3-0.6g/l) and settling time (10-20 min) using response surface methodology (RSM). Four factors with three levels Box-Behnken response surface design (BBD) were employed to optimize and investigate the effect of process variables on the responses such as turbidity, BOD and COD removal. The results were analyzed by Pareto analysis of variance (ANOVA) and second order polynomial models were developed in order to predict the responses. Under the optimum conditions, experimental values such as turbidity (96%), BOD (91%) and COD (73%) removals are closely agreed with predicted values. Copyright © 2013 Elsevier Ltd. All rights reserved.

Pharmacogenetic testing for clopidogrel using the rapid INFINITI analyzer: a dose-escalation study.

PubMed

Gladding, Patrick; White, Harvey; Voss, Jamie; Ormiston, John; Stewart, Jim; Ruygrok, Peter; Bvaldivia, Badi; Baak, Ruth; White, Catherine; Webster, Mark

2009-11-01

Our aim was to assess whether a higher clopidogrel maintenance dose has a greater antiplatelet effect in CYP2C19*2 allele carriers compared with noncarriers. Clopidogrel is a prodrug that is biotransformed by the cytochrome P450 enzymes CYP2C19, 2C9, and 3A4, 2B6, 1A2. The CYPC219*2 loss of function variant has been associated with a reduced antiplatelet response to clopidogrel and a 3-fold risk of stent thrombosis. Forty patients on standard maintenance dosage clopidogrel (75 mg), for 9.4 +/- 9.2 weeks, were enrolled into a dose escalation study. Platelet function was assessed at baseline and after 1 week of 150 mg once daily using the VerifyNow platelet function analyzer (Accumetrics Ltd., San Diego, California). Genomic DNA was hybridized to a BioFilmChip microarray on the INFINITI analyzer (AutoGenomics Inc., Carlsbad, California) and analyzed for the CYP19*2, *4, *17, and CYP2C9*2, *3 polymorphisms. Platelet inhibition increased over 1 week, mean +8.6 +/- 13.5% (p = 0.0003). Carriers of the CYP2C19*2 allele had significantly reduced platelet inhibition at baseline (median 18%, range 0% to 72%) compared with wildtype (wt) (median 59%, range 11% to 95%, p = 0.01) and at 1 week (p = 0.03). CYP2C19*2 allele carriers had an increase in platelet inhibition of (mean +9 +/- 11%, p = 0.03) and reduction in platelet reactivity (mean -26 +/- 38 platelet response unit, p = 0.04) with a higher dose. Together CYP2C19*2 and CYP2C9*3 loss of function carriers had a greater change in platelet inhibition with 150 mg daily than wt/wt (+10.9% vs. +0.7%, p = 0.04). Increasing the dose of clopidogrel in patients with nonresponder polymorphisms can increase antiplatelet response. Personalizing clopidogrel dosing using pharmacogenomics may be an effective method of optimizing treatment.

Introduction of a deformable x-ray CT polymer gel dosimetry system

NASA Astrophysics Data System (ADS)

Maynard, E.; Heath, E.; Hilts, M.; Jirasek, A.

2018-04-01

This study introduces the first 3D deformable dosimetry system based on x-ray computed tomography (CT) polymer gel dosimetry and establishes the setup reproducibility, deformation characteristics and dose response of the system. A N-isopropylacrylamide (NIPAM)-based gel formulation optimized for x-ray CT gel dosimetry was used, with a latex balloon serving as the deformable container and low-density polyethylene and polyvinyl alcohol providing additional oxygen barrier. Deformable gels were irradiated with a 6 MV calibration pattern to determine dosimetric response and a dosimetrically uniform plan to determine the spatial uniformity of the response. Wax beads were added to each gel as fiducial markers to track the deformation and setup of the gel dosimeters. From positions of the beads on CT images the setup reproducibility and the limits and reproducibility of gel deformation were determined. Comparison of gel measurements with Monte Carlo dose calculations found excellent dosimetric accuracy, comparable to that of an established non-deformable dosimetry system, with a mean dose discrepancy of 1.5% in the low-dose gradient region and a gamma pass rate of 97.9% using a 3%/3 mm criterion. The deformable dosimeter also showed good overall spatial dose uniformity throughout the dosimeter with some discrepancies within 20 mm of the edge of the container. Tracking of the beads within the dosimeter found that sub-millimetre setup accuracy is achievable with this system. The dosimeter was able to deform and relax when externally compressed by up to 30 mm without sustaining any permanent damage. Internal deformations in 3D produced average marker movements of up to 12 mm along the direction of compression. These deformations were also shown to be reproducible over 100 consecutive deformations. This work has established several important characteristics of a new deformable dosimetry system which shows promise for future clinical applications, including the validation of deformable dose accumulation algorithms.

TH-CD-202-08: Feasibility Study of Planning Phase Optimization Using Patient Geometry-Driven Information for Better Dose Sparing of Organ at Risks

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

Kang, S; Kim, D; Kim, T

2016-06-15

Purpose: To propose a simple and effective cost value function to search optimal planning phase (gating window) and demonstrated its feasibility for respiratory correlated radiation therapy. Methods: We acquired 4DCT of 10 phases for 10 lung patients who have tumor located near OARs such as esophagus, heart, and spinal cord (i.e., central lung cancer patients). A simplified mathematical optimization function was established by using overlap volume histogram (OVH) between the target and organ at risk (OAR) at each phase and the tolerance dose of selected OARs to achieve surrounding OARs dose-sparing. For all patients and all phases, delineation of themore » target volume and selected OARs (esophagus, heart, and spinal cord) was performed (by one observer to avoid inter-observer variation), then cost values were calculated for all phases. After the breathing phases were ranked according to cost value function, the relationship between score and dose distribution at highest and lowest cost value phases were evaluated by comparing the mean/max dose. Results: A simplified mathematical cost value function showed noticeable difference from phase to phase, implying it is possible to find optimal phases for gating window. The lowest cost value which may result in lower mean/max dose to OARs was distributed at various phases for all patients. The mean doses of the OARs significantly decreased about 10% with statistical significance for all 3 OARs at the phase with the lowest cost value. Also, the max doses of the OARs were decreased about 2∼5% at the phase with the lowest cost value compared to the phase with the highest cost value. Conclusion: It is demonstrated that optimal phases (in dose distribution perspective) for gating window could exist differently through each patient and the proposed cost value function can be a useful tool for determining such phases without performing dose optimization calculations. This research was supported by the Mid-career Researcher Program through NRF funded by the Ministry of Science, ICT & Future Planning of Korea (NRF-2014R1A2A1A10050270) and by the Radiation Technology R&D program through the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (No. 2013M2A2A7038291)« less

Clinical utility of therapeutic drug monitoring in biological disease modifying anti-rheumatic drug treatment of rheumatic disorders: a systematic narrative review.

PubMed

Van Herwaarden, Noortje; Van Den Bemt, Bart J F; Wientjes, Maike H M; Kramers, Cornelis; Den Broeder, Alfons A

2017-08-01

Biological Disease Modifying Anti-Rheumatic Drugs (bDMARDs) have improved the treatment outcomes of inflammatory rheumatic diseases including Rheumatoid Arthritis and spondyloarthropathies. Inter-individual variation exists in (maintenance of) response to bDMARDs. Therapeutic Drug Monitoring (TDM) of bDMARDs could potentially help in optimizing treatment for the individual patient. Areas covered: Evidence of clinical utility of TDM in bDMARD treatment is reviewed. Different clinical scenarios will be discussed, including: prediction of response after start of treatment, prediction of response to a next bDMARD in case of treatment failure of the first, prediction of successful dose reduction or discontinuation in case of low disease activity, prediction of response to dose-escalation in case of active disease and prediction of response to bDMARD in case of flare in disease activity. Expert opinion: The limited available evidence does often not report important outcomes for diagnostic studies, such as sensitivity and specificity. In most clinical relevant scenarios, predictive value of serum (anti-) drug levels is absent, therefore the use of TDM of bDMARDs cannot be advocated. Well-designed prospective studies should be done to further investigate the promising scenarios to determine the place of TDM in clinical practice.

Spatiotemporal radiotherapy planning using a global optimization approach

NASA Astrophysics Data System (ADS)

Adibi, Ali; Salari, Ehsan

2018-02-01

This paper aims at quantifying the extent of potential therapeutic gain, measured using biologically effective dose (BED), that can be achieved by altering the radiation dose distribution over treatment sessions in fractionated radiotherapy. To that end, a spatiotemporally integrated planning approach is developed, where the spatial and temporal dose modulations are optimized simultaneously. The concept of equivalent uniform BED (EUBED) is used to quantify and compare the clinical quality of spatiotemporally heterogeneous dose distributions in target and critical structures. This gives rise to a large-scale non-convex treatment-plan optimization problem, which is solved using global optimization techniques. The proposed spatiotemporal planning approach is tested on two stylized cancer cases resembling two different tumor sites and sensitivity analysis is performed for radio-biological and EUBED parameters. Numerical results validate that spatiotemporal plans are capable of delivering a larger BED to the target volume without increasing the BED in critical structures compared to conventional time-invariant plans. In particular, this additional gain is attributed to the irradiation of different regions of the target volume at different treatment sessions. Additionally, the trade-off between the potential therapeutic gain and the number of distinct dose distributions is quantified, which suggests a diminishing marginal gain as the number of dose distributions increases.

A detailed dosimetric comparison between manual and inverse plans in HDR intracavitary/interstitial cervical cancer brachytherapy.

PubMed

Trnková, Petra; Baltas, Dimos; Karabis, Andreas; Stock, Markus; Dimopoulos, Johannes; Georg, Dietmar; Pötter, Richard; Kirisits, Christian

2010-12-01

The purpose of this study was to compare two inverse planning algorithms for cervical cancer brachytherapy and a conventional manual treatment planning according to the MUW (Medical University of Vienna) protocol. For 20 patients, manually optimized, and, inversely optimized treatment plans with Hybrid Inverse treatment Planning and Optimization (HIPO) and with Inverse Planning Simulated Annealing (IPSA) were created. Dosimetric parameters, absolute volumes of normal tissue receiving reference doses, absolute loading times of tandem, ring and interstitial needles, Paddick and COIN conformity indices were evaluated. HIPO was able to achieve a similar dose distribution to manual planning with the restriction of high dose regions. It reduced the loading time of needles and the overall treatment time. The values of both conformity indices were the lowest. IPSA was able to achieve acceptable dosimetric results. However, it overloaded the needles. This resulted in high dose regions located in the normal tissue. The Paddick index for the volume of two times prescribed dose was outstandingly low. HIPO can produce clinically acceptable treatment plans with the elimination of high dose regions in normal tissue. Compared to IPSA, it is an inverse optimization method which takes into account current clinical experience gained from manual treatment planning.

A detailed dosimetric comparison between manual and inverse plans in HDR intracavitary/interstitial cervical cancer brachytherapy

PubMed Central

Baltas, Dimos; Karabis, Andreas; Stock, Markus; Dimopoulos, Johannes; Georg, Dietmar; Pötter, Richard; Kirisits, Christian

2011-01-01

Purpose The purpose of this study was to compare two inverse planning algorithms for cervical cancer brachytherapy and a conventional manual treatment planning according to the MUW (Medical University of Vienna) protocol. Material and methods For 20 patients, manually optimized, and, inversely optimized treatment plans with Hybrid Inverse treatment Planning and Optimization (HIPO) and with Inverse Planning Simulated Annealing (IPSA) were created. Dosimetric parameters, absolute volumes of normal tissue receiving reference doses, absolute loading times of tandem, ring and interstitial needles, Paddick and COIN conformity indices were evaluated. Results HIPO was able to achieve a similar dose distribution to manual planning with the restriction of high dose regions. It reduced the loading time of needles and the overall treatment time. The values of both conformity indices were the lowest. IPSA was able to achieve acceptable dosimetric results. However, it overloaded the needles. This resulted in high dose regions located in the normal tissue. The Paddick index for the volume of two times prescribed dose was outstandingly low. Conclusions HIPO can produce clinically acceptable treatment plans with the elimination of high dose regions in normal tissue. Compared to IPSA, it is an inverse optimization method which takes into account current clinical experience gained from manual treatment planning. PMID:27853479

Optimization of dose and image quality in adult and pediatric computed tomography scans

NASA Astrophysics Data System (ADS)

Chang, Kwo-Ping; Hsu, Tzu-Kun; Lin, Wei-Ting; Hsu, Wen-Lin

2017-11-01

Exploration to maximize CT image and reduce radiation dose was conducted while controlling for multiple factors. The kVp, mAs, and iteration reconstruction (IR), affect the CT image quality and radiation dose absorbed. The optimal protocols (kVp, mAs, IR) are derived by figure of merit (FOM) based on CT image quality (CNR) and CT dose index (CTDIvol). CT image quality metrics such as CT number accuracy, SNR, low contrast materials' CNR and line pair resolution were also analyzed as auxiliary assessments. CT protocols were carried out with an ACR accreditation phantom and a five-year-old pediatric head phantom. The threshold values of the adult CT scan parameters, 100 kVp and 150 mAs, were determined from the CT number test and line pairs in ACR phantom module 1and module 4 respectively. The findings of this study suggest that the optimal scanning parameters for adults be set at 100 kVp and 150-250 mAs. However, for improved low- contrast resolution, 120 kVp and 150-250 mAs are optimal. Optimal settings for pediatric head CT scan were 80 kVp/50 mAs, for maxillary sinus and brain stem, while 80 kVp /300 mAs for temporal bone. SNR is not reliable as the independent image parameter nor the metric for determining optimal CT scan parameters. The iteration reconstruction (IR) approach is strongly recommended for both adult and pediatric CT scanning as it markedly improves image quality without affecting radiation dose.

Impact of imaging approach on radiation dose and associated cancer risk in children undergoing cardiac catheterization

PubMed Central

Einstein, Andrew J.; Januzis, Natalie; Nguyen, Giao; Li, Jennifer S.; Fleming, Gregory A.; Yoshizumi, Terry K.

2016-01-01

Objectives To quantify the impact of image optimization on absorbed radiation dose and associated risk in children undergoing cardiac catheterization. Background Various imaging and fluoroscopy system technical parameters including camera magnification, source-to-image distance, collimation, anti-scatter grids, beam quality, and pulse rates, all affect radiation dose but have not been well studied in younger children. Methods We used anthropomorphic phantoms (ages: newborn and 5-years-old) to measure surface radiation exposure from various imaging approaches and estimated absorbed organ doses and effective doses (ED) using Monte Carlo simulations. Models developed in the National Academies’ Biological Effects of Ionizing Radiation VII report were used to compare an imaging protocol optimized for dose reduction versus suboptimal imaging (+20cm source-to-image-distance, +1 magnification setting, no collimation) on lifetime attributable risk (LAR) of cancer. Results For the newborn and 5-year-old phantoms respectively ED changes were as follows: +157% and +232% for an increase from 6-inch to 10-inch camera magnification; +61% and +59% for a 20cm increase in source-to-image-distance; −42% and −48% with addition of 1-inch periphery collimation; −31% and −46% with removal of the anti-scatter grid. Compared to an optimized protocol, suboptimal imaging increased ED by 2.75-fold (newborn) and 4-fold (5-year-old). Estimated cancer LAR from 30-minutes of postero-anterior fluoroscopy using optimized versus sub-optimal imaging respectively was: 0.42% versus 1.23% (newborn female), 0.20% vs 0.53% (newborn male), 0.47% versus 1.70% (5-year-old female) and 0.16% vs 0.69% (5-year-old male). Conclusions Radiation-related risks to children undergoing cardiac catheterization can be substantial but are markedly reduced with an optimized imaging approach. PMID:27315598

Vitamin C revisited.

PubMed

Oudemans-van Straaten, Heleen M; Spoelstra-de Man, Angelique Me; de Waard, Monique C

2014-08-06

This narrative review summarizes the role of vitamin C in mitigating oxidative injury-induced microcirculatory impairment and associated organ failure in ischemia/reperfusion or sepsis. Preclinical studies show that high-dose vitamin C can prevent or restore microcirculatory flow impairment by inhibiting activation of nicotinamide adenine dinucleotide phosphate-oxidase and inducible nitric oxide synthase, augmenting tetrahydrobiopterin, preventing uncoupling of oxidative phosphorylation, and decreasing the formation of superoxide and peroxynitrite, and by directly scavenging superoxide. Vitamin C can additionally restore vascular responsiveness to vasoconstrictors, preserve endothelial barrier by maintaining cyclic guanylate phosphatase and occludin phosphorylation and preventing apoptosis. Finally, high-dose vitamin C can augment antibacterial defense. These protective effects against overwhelming oxidative stress due to ischemia/reperfusion, sepsis or burn seems to mitigate organ injury and dysfunction, and promote recovery after cardiac revascularization and in critically ill patients, in the latter partially in combination with other antioxidants. Of note, several questions remain to be solved, including optimal dose, timing and combination of vitamin C with other antioxidants. The combination obviously offers a synergistic effect and seems reasonable during sustained critical illness. High-dose vitamin C, however, provides a cheap, strong and multifaceted antioxidant, especially robust for resuscitation of the circulation. Vitamin C given as early as possible after the injurious event, or before if feasible, seems most effective. The latter could be considered at the start of cardiac surgery, organ transplant or major gastrointestinal surgery. Preoperative supplementation should consider the inhibiting effect of vitamin C on ischemic preconditioning. In critically ill patients, future research should focus on the use of short-term high-dose intravenous vitamin C as a resuscitation drug, to intervene as early as possible in the oxidant cascade in order to optimize macrocirculation and microcirculation and limit cellular injury.


Intrathecal analgesia by bupivacaine is not enhanced by coadministration of morphine in patients with severe cancer-related pain: a randomized double-blind cross-over study.

PubMed

Reif, Ingalill; Wincent, Anders; Stiller, Carl-Olav

2017-06-01

The objective of this randomized double blind cross-over trial was to determine if patients with severe cancer-related pain and inadequate response to systemic opioids prefer intrathecal (IT) pain relief with a combination of bupivacaine and morphine or bupivacaine only. Adult patients with cancer-related pain (n = 23) scheduled for IT analgesia at the Pain Center at the Karo-linska University Hospital Solna, Stockholm, Sweden, were included. The optimal individual flow rate of IT bupivacaine (2 mg/mL) in addition to bolus doses was titrated and maintained for 4 days. Morphine (1 mg/mL) was added to bupivacaine either on day 2 or 4 according to a randomization protocol. Expression of pain relief preference for morphine instead of control (bupivacaine only) was the primary outcome. Secondary outcomes were difference in pain intensity, pain relief, total use of bupivacaine per 24 hours and number of requested bolus doses. Eight patients dropped out during the 4-day study period for reasons not related to the trial. IT bupivacaine significantly decreased median (interquartile range) pain intensity from 5 (3 - 7) at baseline (before catheter insertion) to 1 (0 - 1) (p = 0.0001; Wilcoxon test). Only 1 patient of 15 with 4-day data expressed any preference for morphine. The addition of IT morphine did not result in any significant change of pain intensity, pain relief score, total use of bupivacaine per 24 hours, or number of requested bolus doses. These results suggest that patients with cancer-related pain treated with high doses of systemic opioids, may start IT treatment with an optimal dose of IT bupivacaine without morphine.
.

Bridging the gap: a review of dose investigations in paediatric investigation plans

PubMed Central

Hampson, Lisa V; Herold, Ralf; Posch, Martin; Saperia, Julia; Whitehead, Anne

2014-01-01

Aims In the EU, development of new medicines for children should follow a prospectively agreed paediatric investigation plan (PIP). Finding the right dose for children is crucial but challenging due to the variability of pharmacokinetics across age groups and the limited sample sizes available. We examined strategies adopted in PIPs to support paediatric dosing recommendations to identify common assumptions underlying dose investigations and the attempts planned to verify them in children. Methods We extracted data from 73 PIP opinions recently adopted by the Paediatric Committee of the European Medicines Agency. These opinions represented 79 medicinal development programmes and comprised a total of 97 dose investigation studies. We identified the design of these dose investigation studies, recorded the analyses planned and determined the criteria used to define target doses. Results Most dose investigation studies are clinical trials (83 of 97) that evaluate a single dosing rule. Sample sizes used to investigate dose are highly variable across programmes, with smaller numbers used in younger children (< 2 years). Many studies (40 of 97) do not pre-specify a target dose criterion. Of those that do, most (33 of 57 studies) guide decisions using pharmacokinetic data alone. Conclusions Common assumptions underlying dose investigation strategies include dose proportionality and similar exposure−response relationships in adults and children. Few development programmes pre-specify steps to verify assumptions in children. There is scope for the use of Bayesian methods as a framework for synthesizing existing information to quantify prior uncertainty about assumptions. This process can inform the design of optimal drug development strategies. PMID:24720849

Adjoint sensitivity analysis of a tumor growth model and its application to spatiotemporal radiotherapy optimization.

PubMed

Fujarewicz, Krzysztof; Lakomiec, Krzysztof

2016-12-01

We investigate a spatial model of growth of a tumor and its sensitivity to radiotherapy. It is assumed that the radiation dose may vary in time and space, like in intensity modulated radiotherapy (IMRT). The change of the final state of the tumor depends on local differences in the radiation dose and varies with the time and the place of these local changes. This leads to the concept of a tumor's spatiotemporal sensitivity to radiation, which is a function of time and space. We show how adjoint sensitivity analysis may be applied to calculate the spatiotemporal sensitivity of the finite difference scheme resulting from the partial differential equation describing the tumor growth. We demonstrate results of this approach to the tumor proliferation, invasion and response to radiotherapy (PIRT) model and we compare the accuracy and the computational effort of the method to the simple forward finite difference sensitivity analysis. Furthermore, we use the spatiotemporal sensitivity during the gradient-based optimization of the spatiotemporal radiation protocol and present results for different parameters of the model.

Iodine-131 metaiodobenzylguanidine treatment for metastatic carcinoid. Results in 98 patients.

PubMed

Safford, Shawn D; Coleman, R Edward; Gockerman, Jon P; Moore, Joseph; Feldman, Jerome; Onaitis, Mark W; Tyler, Douglas S; Olson, John A

2004-11-01

Iodine-131 metaiodobenzylguanidine (131I-MIBG) is useful for imaging carcinoid tumors and recently has been applied to the palliative treatment of metastatic carcinoid in small studies. The authors now report their results on the therapeutic utility of high-dose 131I-MIBG treatment in a large group of patients with metastatic carcinoid tumors. The authors performed a retrospective review of 98 patients with metastatic carcinoid who were treated at their institution with 131I-MIBG over a 15-year period. Endpoints examined included the World Health Organization criteria for treatment response: symptoms, hormone (5-hydroxyindoleacetic acid [5-HIAA]) production, and clinical tumor response. Patients received a median dose of 401 +/- 202 millicuries (mCi) 131I-MIBG. The median survival after treatment was 2.3 years. Patients who experienced a symptomatic response had improved survival (5.76 years vs. 2.09 years; P < 0.01). For the 56 patients who had 5-HIAA levels monitored, the mean urine 5-HIAA levels decreased significantly after 131I-MIBG treatment (126 +/- 122 ng/mL vs. 91 +/- 125 ng/mL; P < 0.01); however, the patients with reduced 5-HIAA levels did not experience improved survival (4.11 years vs. 3.42 years; P = 0.2). Patients who received an initial 131I-MIBG dose > 400 mCi lived longer than patients who received < 400 mCi (4.69 years vs. 1.86 years; P = 0.05). Radiographic tumor response did not predict survival. Toxicity included pancytopenia, thrombocytopenia, nausea, and emesis. The current data support 131I-MIBG treatment in select patients with metastatic carcinoid who progress despite optimal medical management. Improved survival was predicted best by symptomatic response to 131I-MIBG treatment, but not by hormone or radiographic response.

Concurrent Monte Carlo transport and fluence optimization with fluence adjusting scalable transport Monte Carlo

PubMed Central

Svatos, M.; Zankowski, C.; Bednarz, B.

2016-01-01

Purpose: The future of radiation therapy will require advanced inverse planning solutions to support single-arc, multiple-arc, and “4π” delivery modes, which present unique challenges in finding an optimal treatment plan over a vast search space, while still preserving dosimetric accuracy. The successful clinical implementation of such methods would benefit from Monte Carlo (MC) based dose calculation methods, which can offer improvements in dosimetric accuracy when compared to deterministic methods. The standard method for MC based treatment planning optimization leverages the accuracy of the MC dose calculation and efficiency of well-developed optimization methods, by precalculating the fluence to dose relationship within a patient with MC methods and subsequently optimizing the fluence weights. However, the sequential nature of this implementation is computationally time consuming and memory intensive. Methods to reduce the overhead of the MC precalculation have been explored in the past, demonstrating promising reductions of computational time overhead, but with limited impact on the memory overhead due to the sequential nature of the dose calculation and fluence optimization. The authors propose an entirely new form of “concurrent” Monte Carlo treat plan optimization: a platform which optimizes the fluence during the dose calculation, reduces wasted computation time being spent on beamlets that weakly contribute to the final dose distribution, and requires only a low memory footprint to function. In this initial investigation, the authors explore the key theoretical and practical considerations of optimizing fluence in such a manner. Methods: The authors present a novel derivation and implementation of a gradient descent algorithm that allows for optimization during MC particle transport, based on highly stochastic information generated through particle transport of very few histories. A gradient rescaling and renormalization algorithm, and the concept of momentum from stochastic gradient descent were used to address obstacles unique to performing gradient descent fluence optimization during MC particle transport. The authors have applied their method to two simple geometrical phantoms, and one clinical patient geometry to examine the capability of this platform to generate conformal plans as well as assess its computational scaling and efficiency, respectively. Results: The authors obtain a reduction of at least 50% in total histories transported in their investigation compared to a theoretical unweighted beamlet calculation and subsequent fluence optimization method, and observe a roughly fixed optimization time overhead consisting of ∼10% of the total computation time in all cases. Finally, the authors demonstrate a negligible increase in memory overhead of ∼7–8 MB to allow for optimization of a clinical patient geometry surrounded by 36 beams using their platform. Conclusions: This study demonstrates a fluence optimization approach, which could significantly improve the development of next generation radiation therapy solutions while incurring minimal additional computational overhead. PMID:27277051

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

Li Yexiong, E-mail: yexiong@yahoo.com; Wang Hua; Jin Jing

Purpose: This study aims to evaluate the outcome and pattern of failure in a large cohort of patients with Stage I NK/T-cell lymphoma of the upper aerodigestive tract treated with radiotherapy alone. Methods and Materials: The pathological diagnosis was confirmed using standard criteria. All patients were treated with high-dose extended-field radiotherapy alone. The median dose was 50 Gy. The primary tumor was located in the nasal cavity (n = 80), Waldeyer ring (n = 5), or oral cavity (n = 2). Results: The overall response to radiotherapy was achieved in 85 of 87 (97.7%) patients, with a complete response ratemore » of 95.4% and a partial response rate of 2.3%. The 5-year overall survival, progression-free survival, and local control rates for all patients were 80%, 69%, and 93%, respectively. Twenty patients (23%) had disease progression or relapse. Of these, 15 patients (17%) developed systemic extranodal disseminations, whereas only 4 (5%) patients had local relapse and 4 (5%) patients had lymph node relapse. Conclusions: Our study suggests that high-dose extended-field radiotherapy alone is a curative therapy and shows favorable clinical outcome in patients with Stage I disease. With the high possibility of local control and primary failure of systemic dissemination, the integration of optimal radiotherapy with more effective systematic therapy is warranted to bring additional improvement to the outcome for these patients.« less

SU-F-T-35: Optimization of Bladder and Rectal Doses Using a Multi-Lumen Intracavitary Applicator for Gynecological Brachytherapy

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

Laoui, S; Dietrich, S; Sehgal, V

2016-06-15

Purpose: Radiation dose delivery for endometrial cancer using HDR techniques is limited by dose to bladder and rectum. A dosimetric study was performed using Varian Capri vaginal brachytherapy applicator to determine the optimal channel configuration which minimizes dose to bladder and rectum, while providing good target coverage. Methods: A total of 17 patients, 63 plans clinically delivered, and 252 simulated plans using Varian BrachyVision planning system were generated to investigate optimal channel configuration which results in minimum dose to bladder and rectum while providing adequate target coverage. The Capri applicator consists of 13 lumens arranged in two concentric rings, onemore » central lumen and six lumens per ring. Manual dose shaping is invariably required to lower the dose to critical organs. Three-dimensional plans were simulated for 4 channel arrangements, all 13 channels, channel 12 o’clock (close to bladder) and 6 o’clock (close to rectum) deactivated, central channel deactivated, and central channel in addition to 12 o’clock and 6 o’clock deactivated. A relationship between V100, the volume that receives the prescribed dose, and the amount of curie-seconds required to deliver it, was established. Results: Using all 13 channels results in maximum dose to bladder and rectum. Deactivating central channel in addition to 12 o’clock and 6 o’clock resulted in minimizing bladder and rectum doses but compromised target coverage. The relationship between V100, the volume that receives the prescribed dose, and the curie seconds was found to be linear. Conclusion: Deactivating channels 12 o’clock and 6 o’clock was shown to be the optimal configuration leading to minimum dose to bladder and rectum without compromising target coverage. The linear relationship between V100 and the curie- seconds can be used as a verification parameter.« less

Explicit optimization of plan quality measures in intensity-modulated radiation therapy treatment planning.

PubMed

Engberg, Lovisa; Forsgren, Anders; Eriksson, Kjell; Hårdemark, Björn

2017-06-01

To formulate convex planning objectives of treatment plan multicriteria optimization with explicit relationships to the dose-volume histogram (DVH) statistics used in plan quality evaluation. Conventional planning objectives are designed to minimize the violation of DVH statistics thresholds using penalty functions. Although successful in guiding the DVH curve towards these thresholds, conventional planning objectives offer limited control of the individual points on the DVH curve (doses-at-volume) used to evaluate plan quality. In this study, we abandon the usual penalty-function framework and propose planning objectives that more closely relate to DVH statistics. The proposed planning objectives are based on mean-tail-dose, resulting in convex optimization. We also demonstrate how to adapt a standard optimization method to the proposed formulation in order to obtain a substantial reduction in computational cost. We investigated the potential of the proposed planning objectives as tools for optimizing DVH statistics through juxtaposition with the conventional planning objectives on two patient cases. Sets of treatment plans with differently balanced planning objectives were generated using either the proposed or the conventional approach. Dominance in the sense of better distributed doses-at-volume was observed in plans optimized within the proposed framework. The initial computational study indicates that the DVH statistics are better optimized and more efficiently balanced using the proposed planning objectives than using the conventional approach. © 2017 American Association of Physicists in Medicine.

Trichinella spiralis: strong antibody response to a 49 kDa newborn larva antigen in infected rats.

PubMed

Salinas-Tobon, Maria Del Rosario; Navarrete-Leon, Anaid; Mendez-Loredo, Blanca Esther; Esquivel-Aguirre, Dalia; Martínez-Abrajan, Dulce Maria; Hernandez-Sanchez, Javier

2007-02-01

In this work, we analyzed the kinetics of anti-Trichinella spiralis newborn larva (NBL) antibodies (Ab) and the antigenic recognition pattern of NBL proteins and its dose effects. Wistar rats were infected with 0, 700, 2000, 4000 and 8000 muscle larvae (ML) and bled at different time intervals up to day 31 post infection (p.i.). Ab production was higher with 2000 ML dose and decreased with 8000, 4000 and 700 ML. Abs were not detected until day 10, peaked on day 14 for the 2000 ML dose and on day 19 for the other doses and thereafter declined slowly from 19 to 31 days p.i. In contrast, Abs to ML increased from day 10, peaked on day 19 and remained high until the end of the study. Abs bound strongly at least to three NBL components of 188, 205 and 49 kDa. NBL antigen of 188 and 205 kDa were recognized 10-26 days p.i. and that of 49 kDa from day 10 to day 31 p.i. A weak recognition towards antigens of 52, 54, 62 and 83 kDa was also observed during the infection. An early recognition of 31, 43, 45, 55, 68 and 85 kDa ML antigens was observed whereas the response to those of 43, 45, 48, 60, 64 and 97 kDa (described previously as TSL-1 antigens) occurred late in the infection. A follow-up of antigen recognition up to day 61 with the optimal immunization dose (2000 ML) evidenced a decline of Ab production to the 49 kDa NBL antigen 42 days p.i., which suggested antigenic differences with the previously reported 43 kDa ML antigen strongly recognized late in the infection. To analyze the stage-specificity of the 49 kDa NBL antigen, polyclonal antibodies (PoAb) were obtained in rats immunized with 49 kDa NBL antigen. PoAb reacted strongly with the 49 kDa NBL component in NBL total soluble extract but no reactivity was observed with soluble antigen of the other T. spiralis stages. Albeit with less intensity, the 49 kDa component was also recognized by PoAb together with other antigens of 53, 97 and 107 kDa, in NBL excretory-secretory products (NBL-ESP). Thus, our results reveal differences in the kinetics of anti-NBL and ML Ab responses. While anti-NBL Abs declined slowly from day 19 until the end of the experiment, Abs to ML antigen remained high in the same period. It is remarkable the optimal Ab response to NBL antigens with 2000 ML infective dose and the reduced number of NBL antigens identified throughout the experimental T. spiralis infection, standing out the immunodominant 49 kDa antigen. Interestingly, this antigen, which was prominently expressed in NBL somatic proteins, was also detected in NBL-ESP.

Research pressure instrumentation for NASA Space Shuttle main engine, modification no. 5

NASA Technical Reports Server (NTRS)

Anderson, P. J.; Nussbaum, P.; Gustafson, G.

1984-01-01

The objective of the research project described is to define and demonstrate methods to advance the state of the art of pressure sensors for the space shuttle main engine (SSME). Silicon piezoresistive technology was utilized in completing tasks: generation and testing of three transducer design concepts for solid state applications; silicon resistor characterization at cryogenic temperatures; experimental chip mounting characterization; frequency response optimization and prototype design and fabrication. Excellent silicon sensor performance was demonstrated at liquid nitrogen temperature. A silicon resistor ion implant dose was customized for SSME temperature requirements. A basic acoustic modeling software program was developed as a design tool to evaluate frequency response characteristics.

Investigation of effective decision criteria for multiobjective optimization in IMRT.

PubMed

Holdsworth, Clay; Stewart, Robert D; Kim, Minsun; Liao, Jay; Phillips, Mark H

2011-06-01

To investigate how using different sets of decision criteria impacts the quality of intensity modulated radiation therapy (IMRT) plans obtained by multiobjective optimization. A multiobjective optimization evolutionary algorithm (MOEA) was used to produce sets of IMRT plans. The MOEA consisted of two interacting algorithms: (i) a deterministic inverse planning optimization of beamlet intensities that minimizes a weighted sum of quadratic penalty objectives to generate IMRT plans and (ii) an evolutionary algorithm that selects the superior IMRT plans using decision criteria and uses those plans to determine the new weights and penalty objectives of each new plan. Plans resulting from the deterministic algorithm were evaluated by the evolutionary algorithm using a set of decision criteria for both targets and organs at risk (OARs). Decision criteria used included variation in the target dose distribution, mean dose, maximum dose, generalized equivalent uniform dose (gEUD), an equivalent uniform dose (EUD(alpha,beta) formula derived from the linear-quadratic survival model, and points on dose volume histograms (DVHs). In order to quantatively compare results from trials using different decision criteria, a neutral set of comparison metrics was used. For each set of decision criteria investigated, IMRT plans were calculated for four different cases: two simple prostate cases, one complex prostate Case, and one complex head and neck Case. When smaller numbers of decision criteria, more descriptive decision criteria, or less anti-correlated decision criteria were used to characterize plan quality during multiobjective optimization, dose to OARs and target dose variation were reduced in the final population of plans. Mean OAR dose and gEUD (a = 4) decision criteria were comparable. Using maximum dose decision criteria for OARs near targets resulted in inferior populations that focused solely on low target variance at the expense of high OAR dose. Target dose range, (D(max) - D(min)), decision criteria were found to be most effective for keeping targets uniform. Using target gEUD decision criteria resulted in much lower OAR doses but much higher target dose variation. EUD(alpha,beta) based decision criteria focused on a region of plan space that was a compromise between target and OAR objectives. None of these target decision criteria dominated plans using other criteria, but only focused on approaching a different area of the Pareto front. The choice of decision criteria implemented in the MOEA had a significant impact on the region explored and the rate of convergence toward the Pareto front. When more decision criteria, anticorrelated decision criteria, or decision criteria with insufficient information were implemented, inferior populations are resulted. When more informative decision criteria were used, such as gEUD, EUD(alpha,beta), target dose range, and mean dose, MOEA optimizations focused on approaching different regions of the Pareto front, but did not dominate each other. Using simple OAR decision criteria and target EUD(alpha,beta) decision criteria demonstrated the potential to generate IMRT plans that significantly reduce dose to OARs while achieving the same or better tumor control when clinical requirements on target dose variance can be met or relaxed.

Poster — Thur Eve — 35: The impact of intensity- and energy-modulated photon radiotherapy (XMRT) optimization on a variety of organ geometries

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

McGeachy, P.; Villarreal-Barajas, J. E.; Khan, R.

2014-08-15

We previously reported on a novel, modulated in both energy and intensity; photon radiotherapy (XMRT) optimization technique. The purpose of this investigation was to test this XMRT optimization against conventional intensity modulated radiotherapy (IMRT) optimization on four different organ test geometries. All geometries mimicked clinically relevant scenarios. Both IMRT and XMRT were based on a linear programming approach where the objective function was the mean dose to healthy organs and organ-specific linear dose-point constraints were used. For IMRT, the beam energy was fixed to 6 MV while XMRT optimized in terms of both 6 and 18 MV beams. All plansmore » consisted of a seven beam coplanar arrangement. All organ geometries were contoured on a 25cm diameter cylindrical water phantom in open source radiotherapy research software known as CERR. Solutions for both IMRT and XMRT were obtained for each geometry using a numerical solver Gurobi. Analyzing the quality of the solutions was done by comparing dose distributions and dose volume histograms calculated using CERR. For all four geometries, IMRT and XMRT solutions were comparable in terms of target coverage. For two of the geometries, IMRT provided an advantage in terms of reduced dose to the healthy structures. XMRT showed improved dose reduction to healthy organs for one geometry and a comparable dose distribution to IMRT for the remaining geometry. The inability to exploit the benefits of using multiple energies may be attributed to limited water phantom diameter and having the majority of the organs in close proximity to the transverse axis.« less

Optimized Orthovoltage Stereotactic Radiosurgery

NASA Astrophysics Data System (ADS)

Fagerstrom, Jessica M.

Because of its ability to treat intracranial targets effectively and noninvasively, stereotactic radiosurgery (SRS) is a prevalent treatment modality in modern radiation therapy. This work focused on SRS delivering rectangular function dose distributions, which are desirable for some targets such as those with functional tissue included within the target volume. In order to achieve such distributions, this work used fluence modulation and energies lower than those utilized in conventional SRS. In this work, the relationship between prescription isodose and dose gradients was examined for standard, unmodulated orthovoltage SRS dose distributions. Monte Carlo-generated energy deposition kernels were used to calculate 4pi, isocentric dose distributions for a polyenergetic orthovoltage spectrum, as well as monoenergetic orthovoltage beams. The relationship between dose gradients and prescription isodose was found to be field size and energy dependent, and values were found for prescription isodose that optimize dose gradients. Next, a pencil-beam model was used with a Genetic Algorithm search heuristic to optimize the spatial distribution of added tungsten filtration within apertures of cone collimators in a moderately filtered 250 kVp beam. Four cone sizes at three depths were examined with a Monte Carlo model to determine the effects of the optimized modulation compared to open cones, and the simulations found that the optimized cones were able to achieve both improved penumbra and flatness statistics at depth compared to the open cones. Prototypes of the filter designs calculated using mathematical optimization techniques and Monte Carlo simulations were then manufactured and inserted into custom built orthovoltage SRS cone collimators. A positioning system built in-house was used to place the collimator and filter assemblies temporarily in the 250 kVp beam line. Measurements were performed in water using radiochromic film scanned with both a standard white light flatbed scanner as well as a prototype laser densitometry system. Measured beam profiles showed that the modulated beams could more closely approach rectangular function dose profiles compared to the open cones. A methodology has been described and implemented to achieve optimized SRS delivery, including the development of working prototypes. Future work may include the construction of a full treatment platform.

HDL and CER-001 Inverse-Dose Dependent Inhibition of Atherosclerotic Plaque Formation in apoE-/- Mice: Evidence of ABCA1 Down-Regulation

PubMed Central

Tardy, Claudine; Goffinet, Marine; Boubekeur, Nadia; Cholez, Guy; Ackermann, Rose; Sy, Gavin; Keyserling, Constance; Lalwani, Narendra; Paolini, John F.; Dasseux, Jean-Louis; Barbaras, Ronald; Baron, Rudi

2015-01-01

Objective CER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and charged phospholipids that was designed to mimic the beneficial properties of nascent pre-ß HDL. In this study, we have evaluated the dose-dependent regulation of ABCA1 expression in vitro and in vivo in the presence of CER-001 and native HDL (HDL3). Methods and Results CER-001 induced cholesterol efflux from J774 macrophages in a dose-dependent manner similar to natural HDL. A strong down-regulation of the ATP-binding cassette A1 (ABCA1) transporter mRNA (- 50%) as well as the ABCA1 membrane protein expression (- 50%) was observed at higher doses of CER-001 and HDL3 compared to non-lipidated apoA-I. In vivo, in an apoE-/- mouse “flow cessation model,” in which the left carotid artery was ligatured to induce local inflammation, the inhibition of atherosclerotic plaque burden progression in response to a dose-range of every-other-day CER-001 or HDL in the presence of a high-fat diet for two weeks was assessed. We observed a U-shaped dose-response curve: inhibition of the plaque total cholesterol content increased with increasing doses of CER-001 or HDL3 up to a maximum inhibition (- 51%) at 5 mg/kg; however, as the dose was increased above this threshold, a progressively less pronounced inhibition of progression was observed, reaching a complete absence of inhibition of progression at doses of 20 mg/kg and over. ABCA1 protein expression in the same atherosclerotic plaque was decreased by-45% and-68% at 50 mg/kg for CER-001 and HDL respectively. Conversely, a-12% and 0% decrease in ABCA1 protein expression was observed at the 5 mg/kg dose for CER-001 and HDL respectively. Conclusions These data demonstrate that high doses of HDL and CER-001 are less effective at slowing progression of atherosclerotic plaque in apoE-/- mice compared to lower doses, following a U-shaped dose-response curve. A potential mechanism for this phenomenon is supported by the observation that high doses of HDL and CER-001 induce a rapid and strong down-regulation of ABCA1 both in vitro and in vivo. In conclusion, maximally efficient HDL- or CER-001-mediated cholesterol removal from atherosclerotic plaque is achieved by maximizing macrophage-mediated efflux from the plaque while minimizing dose-dependent down-regulation of ABCA1 expression. These observations may help define the optimal dose of HDL mimetics for testing in clinical trials of atherosclerotic burden regression. PMID:26335690

HDL and CER-001 Inverse-Dose Dependent Inhibition of Atherosclerotic Plaque Formation in apoE-/- Mice: Evidence of ABCA1 Down-Regulation.

PubMed

Tardy, Claudine; Goffinet, Marine; Boubekeur, Nadia; Cholez, Guy; Ackermann, Rose; Sy, Gavin; Keyserling, Constance; Lalwani, Narendra; Paolini, John F; Dasseux, Jean-Louis; Barbaras, Ronald; Baron, Rudi

2015-01-01

CER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and charged phospholipids that was designed to mimic the beneficial properties of nascent pre-ß HDL. In this study, we have evaluated the dose-dependent regulation of ABCA1 expression in vitro and in vivo in the presence of CER-001 and native HDL (HDL3). CER-001 induced cholesterol efflux from J774 macrophages in a dose-dependent manner similar to natural HDL. A strong down-regulation of the ATP-binding cassette A1 (ABCA1) transporter mRNA (- 50%) as well as the ABCA1 membrane protein expression (- 50%) was observed at higher doses of CER-001 and HDL3 compared to non-lipidated apoA-I. In vivo, in an apoE-/- mouse "flow cessation model," in which the left carotid artery was ligatured to induce local inflammation, the inhibition of atherosclerotic plaque burden progression in response to a dose-range of every-other-day CER-001 or HDL in the presence of a high-fat diet for two weeks was assessed. We observed a U-shaped dose-response curve: inhibition of the plaque total cholesterol content increased with increasing doses of CER-001 or HDL3 up to a maximum inhibition (- 51%) at 5 mg/kg; however, as the dose was increased above this threshold, a progressively less pronounced inhibition of progression was observed, reaching a complete absence of inhibition of progression at doses of 20 mg/kg and over. ABCA1 protein expression in the same atherosclerotic plaque was decreased by-45% and-68% at 50 mg/kg for CER-001 and HDL respectively. Conversely, a-12% and 0% decrease in ABCA1 protein expression was observed at the 5 mg/kg dose for CER-001 and HDL respectively. These data demonstrate that high doses of HDL and CER-001 are less effective at slowing progression of atherosclerotic plaque in apoE-/- mice compared to lower doses, following a U-shaped dose-response curve. A potential mechanism for this phenomenon is supported by the observation that high doses of HDL and CER-001 induce a rapid and strong down-regulation of ABCA1 both in vitro and in vivo. In conclusion, maximally efficient HDL- or CER-001-mediated cholesterol removal from atherosclerotic plaque is achieved by maximizing macrophage-mediated efflux from the plaque while minimizing dose-dependent down-regulation of ABCA1 expression. These observations may help define the optimal dose of HDL mimetics for testing in clinical trials of atherosclerotic burden regression.

Simultaneous optimization of photons and electrons for mixed beam radiotherapy

NASA Astrophysics Data System (ADS)

Mueller, S.; Fix, M. K.; Joosten, A.; Henzen, D.; Frei, D.; Volken, W.; Kueng, R.; Aebersold, D. M.; Stampanoni, M. F. M.; Manser, P.

2017-07-01

The aim of this work is to develop and investigate an inverse treatment planning process (TPP) for mixed beam radiotherapy (MBRT) capable of performing simultaneous optimization of photon and electron apertures. A simulated annealing based direct aperture optimization (DAO) is implemented to perform simultaneous optimization of photon and electron apertures, both shaped with the photon multileaf collimator (pMLC). Validated beam models are used as input for Monte Carlo dose calculations. Consideration of photon pMLC transmission during DAO and a weight re-optimization of the apertures after deliverable dose calculation are utilized to efficiently reduce the differences between optimized and deliverable dose distributions. The TPP for MBRT is evaluated for an academic situation with a superficial and an enlarged PTV in the depth, a left chest wall case including the internal mammary chain and a squamous cell carcinoma case. Deliverable dose distributions of MBRT plans are compared to those of modulated electron radiotherapy (MERT), photon IMRT and if available to those of clinical VMAT plans. The generated MBRT plans dosimetrically outperform the MERT, photon IMRT and VMAT plans for all investigated situations. For the clinical cases of the left chest wall and the squamous cell carcinoma, the MBRT plans cover the PTV similarly or more homogeneously than the VMAT plans, while OARs are spared considerably better with average reductions of the mean dose to parallel OARs and D 2% to serial OARs by 54% and 26%, respectively. Moreover, the low dose bath expressed as V 10% to normal tissue is substantially reduced by up to 45% compared to the VMAT plans. A TPP for MBRT including simultaneous optimization is successfully implemented and the dosimetric superiority of MBRT plans over MERT, photon IMRT and VMAT plans is demonstrated for academic and clinical situations including superficial targets with and without deep-seated part.

Simultaneous optimization of photons and electrons for mixed beam radiotherapy.

PubMed

Mueller, S; Fix, M K; Joosten, A; Henzen, D; Frei, D; Volken, W; Kueng, R; Aebersold, D M; Stampanoni, M F M; Manser, P

2017-06-26

The aim of this work is to develop and investigate an inverse treatment planning process (TPP) for mixed beam radiotherapy (MBRT) capable of performing simultaneous optimization of photon and electron apertures. A simulated annealing based direct aperture optimization (DAO) is implemented to perform simultaneous optimization of photon and electron apertures, both shaped with the photon multileaf collimator (pMLC). Validated beam models are used as input for Monte Carlo dose calculations. Consideration of photon pMLC transmission during DAO and a weight re-optimization of the apertures after deliverable dose calculation are utilized to efficiently reduce the differences between optimized and deliverable dose distributions. The TPP for MBRT is evaluated for an academic situation with a superficial and an enlarged PTV in the depth, a left chest wall case including the internal mammary chain and a squamous cell carcinoma case. Deliverable dose distributions of MBRT plans are compared to those of modulated electron radiotherapy (MERT), photon IMRT and if available to those of clinical VMAT plans. The generated MBRT plans dosimetrically outperform the MERT, photon IMRT and VMAT plans for all investigated situations. For the clinical cases of the left chest wall and the squamous cell carcinoma, the MBRT plans cover the PTV similarly or more homogeneously than the VMAT plans, while OARs are spared considerably better with average reductions of the mean dose to parallel OARs and D 2% to serial OARs by 54% and 26%, respectively. Moreover, the low dose bath expressed as V 10% to normal tissue is substantially reduced by up to 45% compared to the VMAT plans. A TPP for MBRT including simultaneous optimization is successfully implemented and the dosimetric superiority of MBRT plans over MERT, photon IMRT and VMAT plans is demonstrated for academic and clinical situations including superficial targets with and without deep-seated part.

Composite Resin Dosimeters: A New Concept and Design for a Fibrous Color Dosimeter.

PubMed

Kinashi, Kenji; Iwata, Takato; Tsuchida, Hayato; Sakai, Wataru; Tsutsumi, Naoto

2018-04-11

Polystyrene (PS)-based composite microfibers combined with a photochromic spiropyran dye, 1,3,3-trimethylindolino-6'-nitrobenzopyrylospiran (6-nitro BIPS), and a photostimulable phosphor, europium-doped barium fluorochloride (BaFCl:Eu 2+ ), were developed for the detection of X-ray exposure doses on the order of approximately 1 Gy. To produce the PS-based composite microfibers, we employed a forcespinning method that embeds a high concentration of phosphor in PS in a safe, inexpensive, and simple procedure. On the basis of the optimization of the forcespinning process, fibrous color dosimeters with a high radiation dose sensitivity of 1.2-4.4 Gy were fabricated. The color of the dosimeters was found to transition from white to blue in response to X-ray exposure. The optimized fibrous color dosimeter, made from a solution having a PS/6-nitro BIPS/BaFCl:Eu 2+ /C 2 Cl 4 ratio of 7.0/0.21/28.0/28.0 (wt %) and produced with a 290 mm distance between the needle and collectors, a 0.34 mm 23 G needle nozzle, and a spinneret rotational rate of 3000 rpm, exhibited sensitivity to a dose as low as 1.2 Gy. To realize practical applications, we manufactured the optimized fibrous color dosimeter into a clothlike color dosimeter. The clothlike color dosimeter was mounted on a stuffed bear, and its coloring behavior was demonstrated upon X-ray exposure. After exposure with X-ray, a blue colored and shaped in the form of the letter "[Formula: see text]" clearly appeared on the surface of the clothlike color dosimeter. The proposed fibrous color dosimeters having excellent workability will be an unprecedented dosimetry and contributed to all industries utilizing radiation dosimeters. This new fibrous "composite resin dosimeter" should be able to replace traditional, wearable, and individual radiation dose monitoring devices, such as film badges.

Pharmacokinetics and concentration-effect relationships of therapeutic monoclonal antibodies and fusion proteins.

PubMed

Ternant, David; Paintaud, Gilles

2005-09-01

Although monoclonal antibodies (mAbs) constitute a major advance in therapeutics, their pharmacokinetic (PK) and pharmacodynamic (PD) properties are not fully understood. Saturable mechanisms are thought to occur in distribution and elimination of mAbs, which are protected from degradation by the Brambell's receptor (FcRn). The binding of mAbs to their target antigen explains part of their nonlinear PK and PD properties. The interindividual variability in mAb PK can be explained by several factors, including immune response against the biodrug and differences in the number of antigenic sites. The concentration-effect relationships of mAbs are complex and dependent on their mechanism of action. Interindividual differences in mAb PD can be explained by factors such as genetics and clinical status. PK and concentration-effect studies are necessary to design optimal dosing regimens. Because of their above-mentioned characteristics, the interindividual variability in their dose-response relationships must be studied by PK-PD modelling.

Recommendations for Optimizing Tuberculosis Treatment: Therapeutic Drug Monitoring, Pharmacogenetics, and Nutritional Status Considerations

PubMed Central

Choi, Rihwa; Jeong, Byeong-Ho

2017-01-01

Although tuberculosis is largely a curable disease, it remains a major cause of morbidity and mortality worldwide. Although the standard 6-month treatment regimen is highly effective for drug-susceptible tuberculosis, the use of multiple drugs over long periods of time can cause frequent adverse drug reactions. In addition, some patients with drug-susceptible tuberculosis do not respond adequately to treatment and develop treatment failure and drug resistance. Response to tuberculosis treatment could be affected by multiple factors associated with the host-pathogen interaction including genetic factors and the nutritional status of the host. These factors should be considered for effective tuberculosis control. Therefore, therapeutic drug monitoring (TDM), which is individualized drug dosing guided by serum drug concentrations during treatment, and pharmacogenetics-based personalized dosing guidelines of anti-tuberculosis drugs could reduce the incidence of adverse drug reactions and increase the likelihood of successful treatment outcomes. Moreover, assessment and management of comorbid conditions including nutritional status could improve anti-tuberculosis treatment response. PMID:28028995

Protection of Chickens against Avian Influenza with Non-Replicating Adenovirus-Vectored Vaccine

PubMed Central

Toro, Haroldo; Tang, De-chu C.; Suarez, David L.; Shi, Z.

2009-01-01

Protective immunity against avian influenza (AI) virus was elicited in chickens by single-dose vaccination with a replication competent adenovirus (RCA) -free human adenovirus (Ad) vector encoding an H7 AI hemagglutinin (AdChNY94.H7). Chickens vaccinated in ovo with an Ad vector encoding an AI H5 (AdTW68.H5) previously described, which were subsequently vaccinated intramuscularly with AdChNY94.H7 post-hatch, responded with robust antibody titers against both the H5 and H7 AI proteins. Antibody responses to Ad vector in ovo vaccination follow a dose-response kinetic. The use of a synthetic AI H5 gene codon optimized to match the chicken cell tRNA pool was more potent than the cognate H5 gene. The use of Ad-vectored vaccines to increase resistance of chicken populations against multiple AI strains could reduce the risk of an avian-originating influenza pandemic in humans. PMID:18384919

Modeling and investigation of submerged fermentation process to produce extracellular polysaccharide using Lactobacillus confusus.

PubMed

Thirugnanasambandham, K; Sivakumar, V; Prakash Maran, J

2014-12-19

The main objective of the present study is to investigate and optimize the Submerged fermentation (SMF) process parameters such as addition of coconut water, NaCl dose, incubation time and temperature on the production of extracellular polysaccharide (EPS) and biomass production using Lactobacillus confuses. Response surface methodology (RSM) coupled with four factors three level Box-Behnken design (BBD) was employed to model the SMF process. RSM analysis indicated good correspondence between experimental and predicted values. Three dimentional (3D) response surface plots were used to study the interactive effects of process variables on SMF process. The optimum process conditions for the maximum production of EPS and biomass were found to be as follows; addition of coconut water of 40%, NaCl dose of 15%, incubation time of 24h and temperature of 35°C. Under these conditions, 10.57 g/L of EPS and 3.9 g/L of biomass were produced. Copyright © 2014 Elsevier Ltd. All rights reserved.

Recommendations for Optimizing Tuberculosis Treatment: Therapeutic Drug Monitoring, Pharmacogenetics, and Nutritional Status Considerations.

PubMed

Choi, Rihwa; Jeong, Byeong Ho; Koh, Won Jung; Lee, Soo Youn

2017-03-01

Although tuberculosis is largely a curable disease, it remains a major cause of morbidity and mortality worldwide. Although the standard 6-month treatment regimen is highly effective for drug-susceptible tuberculosis, the use of multiple drugs over long periods of time can cause frequent adverse drug reactions. In addition, some patients with drug-susceptible tuberculosis do not respond adequately to treatment and develop treatment failure and drug resistance. Response to tuberculosis treatment could be affected by multiple factors associated with the host-pathogen interaction including genetic factors and the nutritional status of the host. These factors should be considered for effective tuberculosis control. Therefore, therapeutic drug monitoring (TDM), which is individualized drug dosing guided by serum drug concentrations during treatment, and pharmacogenetics-based personalized dosing guidelines of anti-tuberculosis drugs could reduce the incidence of adverse drug reactions and increase the likelihood of successful treatment outcomes. Moreover, assessment and management of comorbid conditions including nutritional status could improve anti-tuberculosis treatment response.

WE-EF-BRA-07: High Performance Preclinical Irradiation Through Optimized Dual Focal Spot Dose Painting and Online Virtual Isocenter Radiation Field Targeting

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

Stewart, J; Princess Margaret Cancer Centre, University Health Network, Toronto, CA; Lindsay, P

Purpose: Advances in radiotherapy practice facilitated by collimation systems to shape radiation fields and image guidance to target these conformal beams have motivated proposals for more complex dose patterns to improve the therapeutic ratio. Recent progress in small animal radiotherapy platforms has provided the foundation to validate the efficacy of such interventions, but robustly delivering heterogeneous dose distributions at the scale and accuracy demanded by preclinical studies remains challenging. This work proposes a dual focal spot optimization method to paint spatially heterogeneous dose regions and an online virtual isocenter targeting method to accurately target the dose distributions. Methods: Two-dimensional dosemore » kernels were empirically measured for the 1 mm diameter circular collimator with radiochromic film in a solid water phantom for the small and large x-ray focal spots on the X-RAD 225Cx microirradiator. These kernels were used in an optimization framework which determined a set of animal stage positions, beam-on times, and focal spot settings to optimally deliver a given desired dose distribution. An online method was developed which defined a virtual treatment isocenter based on a single image projection of the collimated radiation field. The method was demonstrated by optimization of a 6 mm circular 2 Gy target adjoining a 4 mm semicircular avoidance region. Results: The dual focal spot technique improved the optimized dose distribution with the proportion of avoidance region receiving more than 0.5 Gy reduced by 40% compared to the large focal spot technique. Targeting tests performed by irradiating ball bearing targets on radiochromic film pieced revealed the online targeting method improved the three-dimensional accuracy from 0.48 mm to 0.15 mm. Conclusion: The dual focal spot optimization and online virtual isocenter targeting framework is a robust option for delivering dose at the preclinical level and provides a new experimental option for unique radiobiological investigations This work is supported, in part, by the Natural Sciences and Engineering Research Council of Canada and a Mitacs-Accelerate fellowship. P.E. Lindsay, and D.A. Jaffray are listed as inventors of the system described herein. This system has been licensed to Precision X-Ray Inc. for commercial development.« less

Quantitative Modeling of Microbial Population Responses to Chronic Irradiation Combined with Other Stressors

PubMed Central

Shuryak, Igor; Dadachova, Ekaterina

2016-01-01

Microbial population responses to combined effects of chronic irradiation and other stressors (chemical contaminants, other sub-optimal conditions) are important for ecosystem functioning and bioremediation in radionuclide-contaminated areas. Quantitative mathematical modeling can improve our understanding of these phenomena. To identify general patterns of microbial responses to multiple stressors in radioactive environments, we analyzed three data sets on: (1) bacteria isolated from soil contaminated by nuclear waste at the Hanford site (USA); (2) fungi isolated from the Chernobyl nuclear-power plant (Ukraine) buildings after the accident; (3) yeast subjected to continuous γ-irradiation in the laboratory, where radiation dose rate and cell removal rate were independently varied. We applied generalized linear mixed-effects models to describe the first two data sets, whereas the third data set was amenable to mechanistic modeling using differential equations. Machine learning and information-theoretic approaches were used to select the best-supported formalism(s) among biologically-plausible alternatives. Our analysis suggests the following: (1) Both radionuclides and co-occurring chemical contaminants (e.g. NO2) are important for explaining microbial responses to radioactive contamination. (2) Radionuclides may produce non-monotonic dose responses: stimulation of microbial growth at low concentrations vs. inhibition at higher ones. (3) The extinction-defining critical radiation dose rate is dramatically lowered by additional stressors. (4) Reproduction suppression by radiation can be more important for determining the critical dose rate, than radiation-induced cell mortality. In conclusion, the modeling approaches used here on three diverse data sets provide insight into explaining and predicting multi-stressor effects on microbial communities: (1) the most severe effects (e.g. extinction) on microbial populations may occur when unfavorable environmental conditions (e.g. fluctuations of temperature and/or nutrient levels) coincide with radioactive contamination; (2) an organism’s radioresistance and bioremediation efficiency in rich laboratory media may be insufficient to carry out radionuclide bioremediation in the field—robustness against multiple stressors is needed. PMID:26808049

A comprehensive study on the relationship between the image quality and imaging dose in low-dose cone beam CT

NASA Astrophysics Data System (ADS)

Yan, Hao; Cervino, Laura; Jia, Xun; Jiang, Steve B.

2012-04-01

While compressed sensing (CS)-based algorithms have been developed for the low-dose cone beam CT (CBCT) reconstruction, a clear understanding of the relationship between the image quality and imaging dose at low-dose levels is needed. In this paper, we qualitatively investigate this subject in a comprehensive manner with extensive experimental and simulation studies. The basic idea is to plot both the image quality and imaging dose together as functions of the number of projections and mAs per projection over the whole clinically relevant range. On this basis, a clear understanding of the tradeoff between the image quality and imaging dose can be achieved and optimal low-dose CBCT scan protocols can be developed to maximize the dose reduction while minimizing the image quality loss for various imaging tasks in image-guided radiation therapy (IGRT). Main findings of this work include (1) under the CS-based reconstruction framework, image quality has little degradation over a large range of dose variation. Image quality degradation becomes evident when the imaging dose (approximated with the x-ray tube load) is decreased below 100 total mAs. An imaging dose lower than 40 total mAs leads to a dramatic image degradation, and thus should be used cautiously. Optimal low-dose CBCT scan protocols likely fall in the dose range of 40-100 total mAs, depending on the specific IGRT applications. (2) Among different scan protocols at a constant low-dose level, the super sparse-view reconstruction with the projection number less than 50 is the most challenging case, even with strong regularization. Better image quality can be acquired with low mAs protocols. (3) The optimal scan protocol is the combination of a medium number of projections and a medium level of mAs/view. This is more evident when the dose is around 72.8 total mAs or below and when the ROI is a low-contrast or high-resolution object. Based on our results, the optimal number of projections is around 90 to 120. (4) The clinically acceptable lowest imaging dose level is task dependent. In our study, 72.8 mAs is a safe dose level for visualizing low-contrast objects, while 12.2 total mAs is sufficient for detecting high-contrast objects of diameter greater than 3 mm.

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

SU-F-J-105: Towards a Novel Treatment Planning Pipeline Delivering Pareto- Optimal Plans While Enabling Inter- and Intrafraction Plan Adaptation

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

Kontaxis, C; Bol, G; Lagendijk, J

2016-06-15

Purpose: To develop a new IMRT treatment planning methodology suitable for the new generation of MR-linear accelerator machines. The pipeline is able to deliver Pareto-optimal plans and can be utilized for conventional treatments as well as for inter- and intrafraction plan adaptation based on real-time MR-data. Methods: A Pareto-optimal plan is generated using the automated multicriterial optimization approach Erasmus-iCycle. The resulting dose distribution is used as input to the second part of the pipeline, an iterative process which generates deliverable segments that target the latest anatomical state and gradually converges to the prescribed dose. This process continues until a certainmore » percentage of the dose has been delivered. Under a conventional treatment, a Segment Weight Optimization (SWO) is then performed to ensure convergence to the prescribed dose. In the case of inter- and intrafraction adaptation, post-processing steps like SWO cannot be employed due to the changing anatomy. This is instead addressed by transferring the missing/excess dose to the input of the subsequent fraction. In this work, the resulting plans were delivered on a Delta4 phantom as a final Quality Assurance test. Results: A conventional static SWO IMRT plan was generated for two prostate cases. The sequencer faithfully reproduced the input dose for all volumes of interest. For the two cases the mean relative dose difference of the PTV between the ideal input and sequenced dose was 0.1% and −0.02% respectively. Both plans were delivered on a Delta4 phantom and passed the clinical Quality Assurance procedures by achieving 100% pass rate at a 3%/3mm gamma analysis. Conclusion: We have developed a new sequencing methodology capable of online plan adaptation. In this work, we extended the pipeline to support Pareto-optimal input and clinically validated that it can accurately achieve these ideal distributions, while its flexible design enables inter- and intrafraction plan adaptation. This research is financially supported by Elekta AB, Stockholm, Sweden.« less

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

Yang, Y. M., E-mail: ymingy@gmail.com; Bednarz, B.; Svatos, M.

Purpose: The future of radiation therapy will require advanced inverse planning solutions to support single-arc, multiple-arc, and “4π” delivery modes, which present unique challenges in finding an optimal treatment plan over a vast search space, while still preserving dosimetric accuracy. The successful clinical implementation of such methods would benefit from Monte Carlo (MC) based dose calculation methods, which can offer improvements in dosimetric accuracy when compared to deterministic methods. The standard method for MC based treatment planning optimization leverages the accuracy of the MC dose calculation and efficiency of well-developed optimization methods, by precalculating the fluence to dose relationship withinmore » a patient with MC methods and subsequently optimizing the fluence weights. However, the sequential nature of this implementation is computationally time consuming and memory intensive. Methods to reduce the overhead of the MC precalculation have been explored in the past, demonstrating promising reductions of computational time overhead, but with limited impact on the memory overhead due to the sequential nature of the dose calculation and fluence optimization. The authors propose an entirely new form of “concurrent” Monte Carlo treat plan optimization: a platform which optimizes the fluence during the dose calculation, reduces wasted computation time being spent on beamlets that weakly contribute to the final dose distribution, and requires only a low memory footprint to function. In this initial investigation, the authors explore the key theoretical and practical considerations of optimizing fluence in such a manner. Methods: The authors present a novel derivation and implementation of a gradient descent algorithm that allows for optimization during MC particle transport, based on highly stochastic information generated through particle transport of very few histories. A gradient rescaling and renormalization algorithm, and the concept of momentum from stochastic gradient descent were used to address obstacles unique to performing gradient descent fluence optimization during MC particle transport. The authors have applied their method to two simple geometrical phantoms, and one clinical patient geometry to examine the capability of this platform to generate conformal plans as well as assess its computational scaling and efficiency, respectively. Results: The authors obtain a reduction of at least 50% in total histories transported in their investigation compared to a theoretical unweighted beamlet calculation and subsequent fluence optimization method, and observe a roughly fixed optimization time overhead consisting of ∼10% of the total computation time in all cases. Finally, the authors demonstrate a negligible increase in memory overhead of ∼7–8 MB to allow for optimization of a clinical patient geometry surrounded by 36 beams using their platform. Conclusions: This study demonstrates a fluence optimization approach, which could significantly improve the development of next generation radiation therapy solutions while incurring minimal additional computational overhead.« less

Limiting the risk of cardiac toxicity with esophageal-sparing intensity modulated radiotherapy for locally advanced lung cancers.

PubMed

Woodford, Katrina; Panettieri, Vanessa; Ruben, Jeremy D; Senthi, Sashendra

2016-05-01

Intensity modulated radiotherapy (IMRT) is routinely utilized in the treatment of locally advanced non-small cell lung cancer (NSCLC). RTOG 0617 found that overall survival was impacted by increased low (5 Gy) and intermediate (30 Gy) cardiac doses. We evaluated the impact of esophageal-sparing IMRT on cardiac doses with and without the heart considered in the planning process and predicted toxicity compared to 3D-conventional radiotherapy (3DCRT). Ten consecutive patients with N2 Stage III NSCLC treated to 60 Gy in 30 fractions, between February 2012 and September 2014, were evaluated. For each patient, 3DCRT and esophageal-sparing IMRT plans were generated. IMRT plans were then created with and without the heart considered in the optimization process. To compare plans, the dose delivered to 95% and 99% of the target (D95% and D99%), and doses to the esophagus, lung and heart were compared by determining the volume receiving X dose (VXGy) and the normal tissue complication probability (NTCP) calculated. IMRT reduced maximum esophagus dose to below 60 Gy in all patients and produced significant reductions to V50Gy, V40Gy and esophageal NTCP. The cost of this reduction was a non-statistically, non-clinically significant increase in low dose (5 Gy) lung exposure that did not worsen lung NTCP. IMRT plans produced significant cardiac sparing, with the amount of improvement correlating to the amount of heart overlapping with the target. When included in plan optimization, for selected patients further sparing of the heart and improvement in heart NTCP was possible. Esophageal-sparing IMRT can significantly spare the heart even if it is not considered in the optimization process. Further sparing can be achieved if plan optimization constrains low and intermediate heart doses, without compromising lung doses.

Simultaneously optimizing dose and schedule of a new cytotoxic agent.

PubMed

Braun, Thomas M; Thall, Peter F; Nguyen, Hoang; de Lima, Marcos

2007-01-01

Traditionally, phase I clinical trial designs are based upon one predefined course of treatment while varying among patients the dose given at each administration. In actual medical practice, patients receive a schedule comprised of several courses of treatment, and some patients may receive one or more dose reductions or delays during treatment. Consequently, the overall risk of toxicity for each patient is a function of both actual schedule of treatment and the differing doses used at each adminstration. Our goal is to provide a practical phase I clinical trial design that more accurately reflects actual medical practice by accounting for both dose per administration and schedule. We propose an outcome-adaptive Bayesian design that simultaneously optimizes both dose and schedule in terms of the overall risk of toxicity, based on time-to-toxicity outcomes. We use computer simulation as a tool to calibrate design parameters. We describe a phase I trial in allogeneic bone marrow transplantation that was designed and is currently being conducted using our new method. Our computer simulations demonstrate that our method outperforms any method that searches for an optimal dose but does not allow schedule to vary, both in terms of the probability of identifying optimal (dose, schedule) combinations, and the numbers of patients assigned to those combinations in the trial. Our design requires greater sample sizes than those seen in traditional phase I studies due to the larger number of treatment combinations examined. Our design also assumes that the effects of multiple administrations are independent of each other and that the hazard of toxicity is the same for all administrations. Our design is the first for phase I clinical trials that is sufficiently flexible and practical to truly reflect clinical practice by varying both dose and the timing and number of administrations given to each patient.

A quantitative study of IMRT delivery effects in commercial planning systems for the case of oesophagus and prostate tumours.

PubMed

Seco, J; Clark, C H; Evans, P M; Webb, S

2006-05-01

This study focuses on understanding the impact of intensity-modulated radiotherapy (IMRT) delivery effects when applied to plans generated by commercial treatment-planning systems such as Pinnacle (ADAC Laboratories Inc.) and CadPlan/Helios (Varian Medical Systems). These commercial planning systems have had several version upgrades (with improvements in the optimization algorithm), but the IMRT delivery effects have not been incorporated into the optimization process. IMRT delivery effects include head-scatter fluence from IMRT fields, transmission through leaves and the effect of the rounded shape of the leaf ends. They are usually accounted for after optimization when leaf sequencing the "optimal" fluence profiles, to derive the delivered fluence profile. The study was divided into two main parts: (a) analysing the dose distribution within the planning-target volume (PTV), produced by each of the commercial treatment-planning systems, after the delivered fluence had been renormalized to deliver the correct dose to the PTV; and (b) studying the impact of the IMRT delivery technique on the surrounding critical organs such as the spinal cord, lungs, rectum, bladder etc. The study was performed for tumours of (i) the oesophagus and (ii) the prostate and pelvic nodes. An oesophagus case was planned with the Pinnacle planning system for IMRT delivery, via multiple-static fields (MSF) and compensators, using the Elekta SL25 with a multileaf collimator (MLC) component. A prostate and pelvic nodes IMRT plan was performed with the Cadplan/Helios system for a dynamic delivery (DMLC) using the Varian 120-leaf Millennium MLC. In these commercial planning systems, since IMRT delivery effects are not included into the optimization process, fluence renormalization is required such that the median delivered PTV dose equals the initial prescribed PTV dose. In preparing the optimum fluence profile for delivery, the PTV dose has been "smeared" by the IMRT delivery techniques. In the case of the oesophagus, the critical organ, spinal cord, received a greater dose than initially planned, due to the delivery effects. The increase in the spinal cord dose is of the order of 2-3 Gy. In the case of the prostate and pelvic nodes, the IMRT delivery effects led to an increase of approximately 2 Gy in the dose delivered to the secondary PTV, the pelvic nodes. In addition to this, the small bowel, rectum and bladder received an increased dose of the order of 2-3 Gy to 50% of their total volume. IMRT delivery techniques strongly influence the delivered dose distributions for the oesophagus and prostate/pelvic nodes tumour sites and these effects are not yet accounted for in the Pinnacle and the CadPlan/Helios planning systems. Currently, they must be taken into account during the optimization stage by altering the dose limits accepted during optimization so that the final (sequenced) dose is within the constraints.

A robust two-stage design identifying the optimal biological dose for phase I/II clinical trials.

PubMed

Zang, Yong; Lee, J Jack

2017-01-15

We propose a robust two-stage design to identify the optimal biological dose for phase I/II clinical trials evaluating both toxicity and efficacy outcomes. In the first stage of dose finding, we use the Bayesian model averaging continual reassessment method to monitor the toxicity outcomes and adopt an isotonic regression method based on the efficacy outcomes to guide dose escalation. When the first stage ends, we use the Dirichlet-multinomial distribution to jointly model the toxicity and efficacy outcomes and pick the candidate doses based on a three-dimensional volume ratio. The selected candidate doses are then seamlessly advanced to the second stage for dose validation. Both toxicity and efficacy outcomes are continuously monitored so that any overly toxic and/or less efficacious dose can be dropped from the study as the trial continues. When the phase I/II trial ends, we select the optimal biological dose as the dose obtaining the minimal value of the volume ratio within the candidate set. An advantage of the proposed design is that it does not impose a monotonically increasing assumption on the shape of the dose-efficacy curve. We conduct extensive simulation studies to examine the operating characteristics of the proposed design. The simulation results show that the proposed design has desirable operating characteristics across different shapes of the underlying true dose-toxicity and dose-efficacy curves. The software to implement the proposed design is available upon request. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Single line source with and without vaginal loading and the impact on target coverage and organ at risk doses for cervix cancer Stages IB, II, and IIIB: treatment planning simulation in patients treated with MRI-guided adaptive brachytherapy in a multicentre study (EMBRACE).

PubMed

Nkiwane, Karen S; Pötter, Richard; Tanderup, Kari; Federico, Mario; Lindegaard, Jacob C; Kirisits, Christian

2013-01-01

Three-dimensional evaluation and comparison of target and organs at risk (OARs) doses from two traditional standard source loading patterns in the frame of MRI-guided cervical cancer brachytherapy for various clinical scenarios based on patient data collected in a multicenter trial setting. Two nonoptimized three-dimensional MRI-based treatment plans, Plan 1 (tandem and vaginal loading) and Plan 2 (tandem loading only), were generated for 134 patients from seven centers participating in the EMBRACE study. Both plans were normalized to point A (Pt. A). Target and OAR doses were evaluated in terms of minimum dose to 90% of the high-risk clinical target volume (HRCTV D90) grouped by tumor stage and minimum dose to the most exposed 2cm³ of the OARs volume. An HRCTV D90 ≥ Pt. A was achieved in 82% and 44% of the patients with Plans 1 and 2, respectively. Median HRCTV D90 with Plans 1 and 2 was 120% and 90% of Pt. A dose, respectively. Both plans had optimal dose coverage in 88% of Stage IB tumors; however, the tandem-only plan resulted in about 50% of dose reduction to the vagina and rectum. For Stages IIB and IIIB, Plan 1 had on average 35% better target coverage but with significant doses to OARs. Standard tandem loading alone results in good target coverage in most Stage IB tumors without violating OAR dose constraints. For Stage IIB tumors, standard vaginal loading improves the therapeutic window, however needs optimization to fulfill the dose prescription for target and OAR. In Stage IIIB, even optimized vaginal loading often does not fulfill the needs for dose prescription. The significant dose variation across various clinical scenarios for both target and OARs indicates the need for image-guided brachytherapy for optimal dose adaptation both for limited and advanced diseases. Copyright © 2013 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Cerium nanoparticle effect on sensitivity of Fricke gel dosimeter: Initial investigation

NASA Astrophysics Data System (ADS)

Ebenezer Suman Babu, S.; Peace Balasingh, S. Timothy; Benedicta Pearlin, R.; Rabi Raja Singh, I.; Ravindran, B. Paul

2017-05-01

Fricke gel dosimeters (FXGs) have been the preferred dosimeters because of its ease in preparation and water and tissue equivalency. Visible changes happen three dimensionally in the dosimeter as the ferrous (Fe2+) ions change into ferric (Fe3+) ions upon irradiation and the measure of this change can be correlated to the dose absorbed. Nanoparticles are promising entities that can improve the sensitivity of the gel dosimeter. Cerium Oxide nanoparticle was investigated for possible enhancement of absorbed dose in the FXG. Various concentrations of the nanoparticle based gel dosimeters were prepared and irradiated for a clinical dose range of 0-3 Gy in a telegamma unit. The optimal concentration of 0.1 mM nanoparticle incorporated in the FXG enhances the radiation sensitivity of the unmodified FXG taken as reference without modifying the background absorbance prior to irradiation. The gel recipe consisted of 5% (wt) gelatin, 50 mM Sulphuric acid, 0.05 mM Xylenol Orange, 0.5 mM Ferrous Ammonium Sulphate and 0.1 mM Cerium (IV) Oxide nanoparticle (< 25 nm particle size) and triple distilled water. The FXGs with nanoparticle showed linear dose response in the dose range tested.

Using translational medicine to understand clinical differences between botulinum toxin formulations.

PubMed

Aoki, K R; Ranoux, D; Wissel, J

2006-12-01

When using botulinum toxin-based products, the physician must decide the optimal location and dose required to alleviate symptoms and improve the patient's quality of life. To deliver effective treatment, the physician needs to understand the importance of accurate target muscle selection and localization and the implications of each product's migration properties when diluted in different volumes. Pre-clinical mouse models of efficacy and safety have been utilized to compare local and distal muscle relaxation effects following defined intramuscular administration. Data from the model allow the products to be ranked based on their propensity for local efficacy versus their distal migration properties. Using standardized dilutions, the non-parallel dose-response curves for the various formulations demonstrate that they have different efficacy profiles. Distal effects were also noted at different treatment doses, which are reflected in the different safety and/or therapeutic margins. Based on these pre-clinical data, the safety and therapeutic margin rankings are ordered, largest to smallest, as BOTOX, Dysport and Myobloc. The results of subsequent clinical trials are variable and dose comparisons are inconclusive, thus supporting the regulatory position that the dose units of the individual preparations are unique and cannot be simply converted between products.

Optimizing treatment of hypothyroidism.

PubMed

Clarke, Nick; Kabadi, Udaya M

2004-01-01

Several thyroid hormone preparations are currently available, including levothyroxine sodium (thyroxine), liothyronine (triiodothyronine), and desiccated thyroid extract, as well as a combination of levothyroxine sodium and liothyronine. Levothyroxine sodium monotherapy at an appropriate daily dose provides uniform levels of both thyroxine and triiodothyronine in the circulation without diurnal variation. Therefore, it is the preparation of choice in most patients with hypothyroidism of both the primary and central types. A normal thyrotropin (TSH) level of 1-2 mU/L is considered the determinant of optimal daily levothyroxine sodium dose in patients with primary hypothyroidism, whereas normal thyroxine and triiodothyronine levels in the mid or upper normal range may denote optimal replacement in patients with central hypothyroidism. Optimal daily levothyroxine sodium dose may be determined according to serum TSH level at the time of diagnosis of primary hypothyroidism. Initial administration of close to the full calculated dose of levothyroxine sodium is appropriate for younger patients, reducing the need for follow-up visits and repeated laboratory testing for dose titration. In the elderly and in patients with a history of coronary artery disease (CAD), the well established approach of starting with a low dose and gradually titrating to the full calculated dose is always the best option. Levothyroxine sodium can and should be continued in patients receiving treatment for CAD. Even minor over-replacement during initial titration of levothyroxine sodium should be avoided, because of the risk of cardiac events. Chronic over-replacement may induce osteoporosis, particularly in postmenopausal women, and should also be avoided.

CT dose minimization using personalized protocol optimization and aggressive bowtie

NASA Astrophysics Data System (ADS)

Wang, Hui; Yin, Zhye; Jin, Yannan; Wu, Mingye; Yao, Yangyang; Tao, Kun; Kalra, Mannudeep K.; De Man, Bruno

2016-03-01

In this study, we propose to use patient-specific x-ray fluence control to reduce the radiation dose to sensitive organs while still achieving the desired image quality (IQ) in the region of interest (ROI). The mA modulation profile is optimized view by view, based on the sensitive organs and the ROI, which are obtained from an ultra-low-dose volumetric CT scout scan [1]. We use a clinical chest CT scan to demonstrate the feasibility of the proposed concept: the breast region is selected as the sensitive organ region while the cardiac region is selected as IQ ROI. Two groups of simulations are performed based on the clinical CT dataset: (1) a constant mA scan adjusted based on the patient attenuation (120 kVp, 300 mA), which serves as baseline; (2) an optimized scan with aggressive bowtie and ROI centering combined with patient-specific mA modulation. The results shows that the combination of the aggressive bowtie and the optimized mA modulation can result in 40% dose reduction in the breast region, while the IQ in the cardiac region is maintained. More generally, this paper demonstrates the general concept of using a 3D scout scan for optimal scan planning.

A pragmatic approach to determine the optimal kVp in cone beam CT: balancing contrast-to-noise ratio and radiation dose

PubMed Central

Silkosessak, O; Jacobs, R; Bogaerts, R; Bosmans, H; Panmekiate, S

2014-01-01

Objectives: To determine the optimal kVp setting for a particular cone beam CT (CBCT) device by maximizing technical image quality at a fixed radiation dose. Methods: The 3D Accuitomo 170 (J. Morita Mfg. Corp., Kyoto, Japan) CBCT was used. The radiation dose as a function of kVp was measured in a cylindrical polymethyl methacrylate (PMMA) phantom using a small-volume ion chamber. Contrast-to-noise ratio (CNR) was measured using a PMMA phantom containing four materials (air, aluminium, polytetrafluoroethylene and low-density polyethylene), which was scanned using 180 combinations of kVp/mA, ranging from 60/1 to 90/8. The CNR was measured for each material using PMMA as background material. The pure effect of kVp and mAs on the CNR values was analysed. Using a polynomial fit for CNR as a function of mA for each kVp value, the optimal kVp was determined at five dose levels. Results: Absorbed doses ranged between 0.034 mGy mAs−1 (14 × 10 cm, 60 kVp) and 0.108 mGy mAs−1 (14 × 10 cm, 90 kVp). The relation between kVp and dose was quasilinear (R2 > 0.99). The effect of mA and kVp on CNR could be modelled using a second-degree polynomial. At a fixed dose, there was a tendency for higher CNR values at increasing kVp values, especially at low dose levels. A dose reduction through mA was more efficient than an equivalent reduction through kVp in terms of image quality deterioration. Conclusions: For the investigated CBCT model, the most optimal contrast at a fixed dose was found at the highest available kVp setting. There is great potential for dose reduction through mA with a minimal loss in image quality. PMID:24708447

SU-E-I-57: Evaluation and Optimization of Effective-Dose Using Different Beam-Hardening Filters in Clinical Pediatric Shunt CT Protocol

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

Gill, K; Aldoohan, S; Collier, J

Purpose: Study image optimization and radiation dose reduction in pediatric shunt CT scanning protocol through the use of different beam-hardening filters Methods: A 64-slice CT scanner at OU Childrens Hospital has been used to evaluate CT image contrast-to-noise ratio (CNR) and measure effective-doses based on the concept of CT dose index (CTDIvol) using the pediatric head shunt scanning protocol. The routine axial pediatric head shunt scanning protocol that has been optimized for the intrinsic x-ray tube filter has been used to evaluate CNR by acquiring images using the ACR approved CT-phantom and radiation dose CTphantom, which was used to measuremore » CTDIvol. These results were set as reference points to study and evaluate the effects of adding different filtering materials (i.e. Tungsten, Tantalum, Titanium, Nickel and Copper filters) to the existing filter on image quality and radiation dose. To ensure optimal image quality, the scanner routine air calibration was run for each added filter. The image CNR was evaluated for different kVps and wide range of mAs values using above mentioned beam-hardening filters. These scanning protocols were run under axial as well as under helical techniques. The CTDIvol and the effective-dose were measured and calculated for all scanning protocols and added filtration, including the intrinsic x-ray tube filter. Results: Beam-hardening filter shapes energy spectrum, which reduces the dose by 27%. No noticeable changes in image low contrast detectability Conclusion: Effective-dose is very much dependent on the CTDIVol, which is further very much dependent on beam-hardening filters. Substantial reduction in effective-dose is realized using beam-hardening filters as compare to the intrinsic filter. This phantom study showed that significant radiation dose reduction could be achieved in CT pediatric shunt scanning protocols without compromising in diagnostic value of image quality.« less

Experimental verification of bremsstrahlung production and dosimetry predictions for 15.5 MeV electrons

NASA Astrophysics Data System (ADS)

Sanford, T. W. L.; Beutler, D. E.; Halbleib, J. A.; Knott, D. P.

1991-12-01

The radiation produced by a 15.5-MeV monoenergetic electron beam incident on optimized and nonoptimized bremsstrahlung targets is characterized using the ITS Monte Carlo code and measurements with equilibrated and nonequilibrated TLD dosimetry. Comparisons between calculations and measurements verify the calculations and demonstrate that the code can be used to predict both bremsstrahlung production and TLD response for radiation fields that are characteristic of those produced by pulsed simulators of gamma rays. The comparisons provide independent confirmation of the validity of the TLD calibration for photon fields characteristic of gamma-ray simulators. The empirical Martin equation, which is often used to calculate radiation dose from optimized bremsstrahlung targets, is examined, and its range of validity is established.

Clinical implementation of a knowledge based planning tool for prostate VMAT.

PubMed

Powis, Richard; Bird, Andrew; Brennan, Matthew; Hinks, Susan; Newman, Hannah; Reed, Katie; Sage, John; Webster, Gareth

2017-05-08

A knowledge based planning tool has been developed and implemented for prostate VMAT radiotherapy plans providing a target average rectum dose value based on previously achievable values for similar rectum/PTV overlap. The purpose of this planning tool is to highlight sub-optimal clinical plans and to improve plan quality and consistency. A historical cohort of 97 VMAT prostate plans was interrogated using a RayStation script and used to develop a local model for predicting optimum average rectum dose based on individual anatomy. A preliminary validation study was performed whereby historical plans identified as "optimal" and "sub-optimal" by the local model were replanned in a blinded study by four experienced planners and compared to the original clinical plan to assess whether any improvement in rectum dose was observed. The predictive model was then incorporated into a RayStation script and used as part of the clinical planning process. Planners were asked to use the script during planning to provide a patient specific prediction for optimum average rectum dose and to optimise the plan accordingly. Plans identified as "sub-optimal" in the validation study observed a statistically significant improvement in average rectum dose compared to the clinical plan when replanned whereas plans that were identified as "optimal" observed no improvement when replanned. This provided confidence that the local model can identify plans that were suboptimal in terms of rectal sparing. Clinical implementation of the knowledge based planning tool reduced the population-averaged mean rectum dose by 5.6Gy. There was a small but statistically significant increase in total MU and femoral head dose and a reduction in conformity index. These did not affect the clinical acceptability of the plans and no significant changes to other plan quality metrics were observed. The knowledge-based planning tool has enabled substantial reductions in population-averaged mean rectum dose for prostate VMAT patients. This suggests plans are improved when planners receive quantitative feedback on plan quality against historical data.

SU-E-T-214: Intensity Modulated Proton Therapy (IMPT) Based On Passively Scattered Protons and Multi-Leaf Collimation: Prototype TPS and Dosimetry Study

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

Sanchez-Parcerisa, D; Carabe-Fernandez, A

2014-06-01

Purpose. Intensity-modulated proton therapy is usually implemented with multi-field optimization of pencil-beam scanning (PBS) proton fields. However, at the view of the experience with photon-IMRT, proton facilities equipped with double-scattering (DS) delivery and multi-leaf collimation (MLC) could produce highly conformal dose distributions (and possibly eliminate the need for patient-specific compensators) with a clever use of their MLC field shaping, provided that an optimal inverse TPS is developed. Methods. A prototype TPS was developed in MATLAB. The dose calculation process was based on a fluence-dose algorithm on an adaptive divergent grid. A database of dose kernels was precalculated in order tomore » allow for fast variations of the field range and modulation during optimization. The inverse planning process was based on the adaptive simulated annealing approach, with direct aperture optimization of the MLC leaves. A dosimetry study was performed on a phantom formed by three concentrical semicylinders separated by 5 mm, of which the inner-most and outer-most were regarded as organs at risk (OARs), and the middle one as the PTV. We chose a concave target (which is not treatable with conventional DS fields) to show the potential of our technique. The optimizer was configured to minimize the mean dose to the OARs while keeping a good coverage of the target. Results. The plan produced by the prototype TPS achieved a conformity index of 1.34, with the mean doses to the OARs below 78% of the prescribed dose. This Result is hardly achievable with traditional conformal DS technique with compensators, and it compares to what can be obtained with PBS. Conclusion. It is certainly feasible to produce IMPT fields with MLC passive scattering fields. With a fully developed treatment planning system, the produced plans can be superior to traditional DS plans in terms of plan conformity and dose to organs at risk.« less

Low-dose computed tomography scans with automatic exposure control for patients of different ages undergoing cardiac PET/CT and SPECT/CT.

PubMed

Yang, Ching-Ching; Yang, Bang-Hung; Tu, Chun-Yuan; Wu, Tung-Hsin; Liu, Shu-Hsin

2017-06-01

This study aimed to evaluate the efficacy of automatic exposure control (AEC) in order to optimize low-dose computed tomography (CT) protocols for patients of different ages undergoing cardiac PET/CT and single-photon emission computed tomography/computed tomography (SPECT/CT). One PET/CT and one SPECT/CT were used to acquire CT images for four anthropomorphic phantoms representative of 1-year-old, 5-year-old and 10-year-old children and an adult. For the hybrid systems investigated in this study, the radiation dose and image quality of cardiac CT scans performed with AEC activated depend mainly on the selection of a predefined image quality index. Multiple linear regression methods were used to analyse image data from anthropomorphic phantom studies to investigate the effects of body size and predefined image quality index on CT radiation dose in cardiac PET/CT and SPECT/CT scans. The regression relationships have a coefficient of determination larger than 0.9, indicating a good fit to the data. According to the regression models, low-dose protocols using the AEC technique were optimized for patients of different ages. In comparison with the standard protocol with AEC activated for adult cardiac examinations used in our clinical routine practice, the optimized paediatric protocols in PET/CT allow 32.2, 63.7 and 79.2% CT dose reductions for anthropomorphic phantoms simulating 10-year-old, 5-year-old and 1-year-old children, respectively. The corresponding results for cardiac SPECT/CT are 8.4, 51.5 and 72.7%. AEC is a practical way to reduce CT radiation dose in cardiac PET/CT and SPECT/CT, but the AEC settings should be determined properly for optimal effect. Our results show that AEC does not eliminate the need for paediatric protocols and CT examinations using the AEC technique should be optimized for paediatric patients to reduce the radiation dose as low as reasonably achievable.

WE-AB-207B-07: Dose Cloud: Generating “Big Data” for Radiation Therapy Treatment Plan Optimization Research

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

Folkerts, MM; University of California San Diego, La Jolla, California; Long, T

Purpose: To provide a tool to generate large sets of realistic virtual patient geometries and beamlet doses for treatment optimization research. This tool enables countless studies exploring the fundamental interplay between patient geometry, objective functions, weight selections, and achievable dose distributions for various algorithms and modalities. Methods: Generating realistic virtual patient geometries requires a small set of real patient data. We developed a normalized patient shape model (PSM) which captures organ and target contours in a correspondence-preserving manner. Using PSM-processed data, we perform principal component analysis (PCA) to extract major modes of variation from the population. These PCA modes canmore » be shared without exposing patient information. The modes are re-combined with different weights to produce sets of realistic virtual patient contours. Because virtual patients lack imaging information, we developed a shape-based dose calculation (SBD) relying on the assumption that the region inside the body contour is water. SBD utilizes a 2D fluence-convolved scatter kernel, derived from Monte Carlo simulations, and can compute both full dose for a given set of fluence maps, or produce a dose matrix (dose per fluence pixel) for many modalities. Combining the shape model with SBD provides the data needed for treatment plan optimization research. Results: We used PSM to capture organ and target contours for 96 prostate cases, extracted the first 20 PCA modes, and generated 2048 virtual patient shapes by randomly sampling mode scores. Nearly half of the shapes were thrown out for failing anatomical checks, the remaining 1124 were used in computing dose matrices via SBD and a standard 7-beam protocol. As a proof of concept, and to generate data for later study, we performed fluence map optimization emphasizing PTV coverage. Conclusions: We successfully developed and tested a tool for creating customizable sets of virtual patients suitable for large-scale radiation therapy optimization research.« less

IMRT: Improvement in treatment planning efficiency using NTCP calculation independent of the dose-volume-histogram

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

Grigorov, Grigor N.; Chow, James C.L.; Grigorov, Lenko

2006-05-15

The normal tissue complication probability (NTCP) is a predictor of radiobiological effect for organs at risk (OAR). The calculation of the NTCP is based on the dose-volume-histogram (DVH) which is generated by the treatment planning system after calculation of the 3D dose distribution. Including the NTCP in the objective function for intensity modulated radiation therapy (IMRT) plan optimization would make the planning more effective in reducing the postradiation effects. However, doing so would lengthen the total planning time. The purpose of this work is to establish a method for NTCP determination, independent of a DVH calculation, as a quality assurancemore » check and also as a mean of improving the treatment planning efficiency. In the study, the CTs of ten randomly selected prostate patients were used. IMRT optimization was performed with a PINNACLE3 V 6.2b planning system, using planning target volume (PTV) with margins in the range of 2 to 10 mm. The DVH control points of the PTV and OAR were adapted from the prescriptions of Radiation Therapy Oncology Group protocol P-0126 for an escalated prescribed dose of 82 Gy. This paper presents a new model for the determination of the rectal NTCP ({sub R}NTCP). The method uses a special function, named GVN (from Gy, Volume, NTCP), which describes the {sub R}NTCP if 1 cm{sup 3} of the volume of intersection of the PTV and rectum (R{sub int}) is irradiated uniformly by a dose of 1 Gy. The function was 'geometrically' normalized using a prostate-prostate ratio (PPR) of the patients' prostates. A correction of the {sub R}NTCP for different prescribed doses, ranging from 70 to 82 Gy, was employed in our model. The argument of the normalized function is the R{sub int}, and parameters are the prescribed dose, prostate volume, PTV margin, and PPR. The {sub R}NTCPs of another group of patients were calculated by the new method and the resulting difference was <{+-}5% in comparison to the NTCP calculated by the PINNACLE3 software where Kutcher's dose-response model for NTCP calculation is adopted.« less

Performance traits and metabolic responses in goats (Capra hircus) supplemented with inorganic trivalent chromium.

PubMed

Haldar, Sudipto; Mondal, Souvik; Samanta, Saikat; Ghosh, Tapan Kumar

2009-11-01

The effects of supplemental chromium (Cr) as chromic chloride hexahydrate in incremental dose levels (0, 0.5, 1.0, and 1.5 mg/day for 240 days) on metabolism of nutrients and trace elements were determined in dwarf Bengal goats (Capra hircus, castrated males, average age 3 months, n = 24, initial mean body weight 6.4 +/- 0.22 kg). Live weight increased linearly (p < 0.05) with the level of supplemental Cr. Organic matter and crude protein digestibility, intake of total digestible nutrients, and retention of N (g/g N intake) increased (p < 0.05) in a dose-dependent linear manner. Serum cholesterol and tryacylglycerol concentrations changed inversely with the dose of supplemental Cr (p < 0.01). Supplemental Cr positively influenced retention of copper and iron (p < 0.05) causing linear increase (p < 0.01) in their serum concentrations. It was concluded that Cr supplementation may improve utilization of nutrients including the trace elements and may also elicit a hypolidemic effect in goats. However, further study with regards to optimization of dose is warranted.

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

Integrated beam orientation and scanning-spot optimization in intensity-modulated proton therapy for brain and unilateral head and neck tumors.

PubMed

Gu, Wenbo; O'Connor, Daniel; Nguyen, Dan; Yu, Victoria Y; Ruan, Dan; Dong, Lei; Sheng, Ke

2018-04-01

Intensity-Modulated Proton Therapy (IMPT) is the state-of-the-art method of delivering proton radiotherapy. Previous research has been mainly focused on optimization of scanning spots with manually selected beam angles. Due to the computational complexity, the potential benefit of simultaneously optimizing beam orientations and spot pattern could not be realized. In this study, we developed a novel integrated beam orientation optimization (BOO) and scanning-spot optimization algorithm for intensity-modulated proton therapy (IMPT). A brain chordoma and three unilateral head-and-neck patients with a maximal target size of 112.49 cm 3 were included in this study. A total number of 1162 noncoplanar candidate beams evenly distributed across 4π steradians were included in the optimization. For each candidate beam, the pencil-beam doses of all scanning spots covering the PTV and a margin were calculated. The beam angle selection and spot intensity optimization problem was formulated to include three terms: a dose fidelity term to penalize the deviation of PTV and OAR doses from ideal dose distribution; an L1-norm sparsity term to reduce the number of active spots and improve delivery efficiency; a group sparsity term to control the number of active beams between 2 and 4. For the group sparsity term, convex L2,1-norm and nonconvex L2,1/2-norm were tested. For the dose fidelity term, both quadratic function and linearized equivalent uniform dose (LEUD) cost function were implemented. The optimization problem was solved using the Fast Iterative Shrinkage-Thresholding Algorithm (FISTA). The IMPT BOO method was tested on three head-and-neck patients and one skull base chordoma patient. The results were compared with IMPT plans created using column generation selected beams or manually selected beams. The L2,1-norm plan selected spatially aggregated beams, indicating potential degeneracy using this norm. L2,1/2-norm was able to select spatially separated beams and achieve smaller deviation from the ideal dose. In the L2,1/2-norm plans, the [mean dose, maximum dose] of OAR were reduced by an average of [2.38%, 4.24%] and[2.32%, 3.76%] of the prescription dose for the quadratic and LEUD cost function, respectively, compared with the IMPT plan using manual beam selection while maintaining the same PTV coverage. The L2,1/2 group sparsity plans were dosimetrically superior to the column generation plans as well. Besides beam orientation selection, spot sparsification was observed. Generally, with the quadratic cost function, 30%~60% spots in the selected beams remained active. With the LEUD cost function, the percentages of active spots were in the range of 35%~85%.The BOO-IMPT run time was approximately 20 min. This work shows the first IMPT approach integrating noncoplanar BOO and scanning-spot optimization in a single mathematical framework. This method is computationally efficient, dosimetrically superior and produces delivery-friendly IMPT plans. © 2018 American Association of Physicists in Medicine.

Is patient size important in dose determination and optimization in cardiology?

NASA Astrophysics Data System (ADS)

Reay, J.; Chapple, C. L.; Kotre, C. J.

2003-12-01

Patient dose determination and optimization have become more topical in recent years with the implementation of the Medical Exposures Directive into national legislation, the Ionising Radiation (Medical Exposure) Regulations. This legislation incorporates a requirement for new equipment to provide a means of displaying a measure of patient exposure and introduces the concept of diagnostic reference levels. It is normally assumed that patient dose is governed largely by patient size; however, in cardiology, where procedures are often very complex, the significance of patient size is less well understood. This study considers over 9000 cardiology procedures, undertaken throughout the north of England, and investigates the relationship between patient size and dose. It uses simple linear regression to calculate both correlation coefficients and significance levels for data sorted by both room and individual clinician for the four most common examinations, left ventrical and/or coronary angiography, single vessel stent insertion and single vessel angioplasty. This paper concludes that the correlation between patient size and dose is weak for the procedures considered. It also illustrates the use of an existing method for removing the effect of patient size from dose survey data. This allows typical doses and, therefore, reference levels to be defined for the purposes of dose optimization.

LACK OF CORRELATION BETWEEN OPIOID DOSE ADJUSTMENT AND PAIN SCORE CHANGE IN A GROUP OF CHRONIC PAIN PATIENTS

PubMed Central

Chen, Lucy; Vo, Trang; Seefeld, Lindsey; Malarick, Charlene; Houghton, Mary; Ahmed, Shihab; Zhang, Yi; Cohen, Abigail; Retamozo, Cynthia; Hilaire, Kristen St.; Zhang, Vivian; Mao, Jianren

2013-01-01

Despite the increasing use of opioid analgesics for chronic pain management, it is unclear whether opioid dose escalation leads to better pain relief during chronic opioid therapy. In this study, we retrospectively analyzed clinical data collected from the Massachusetts General Hospital (MGH) Center for Pain Medicine over a 7-year period. We examined 1) the impact of opioid dose adjustment (increase or decrease) on clinical pain score, 2) gender and age differences in response to opioid therapy, and 3) the influence of clinical pain conditions on the opioid analgesic efficacy. A total of 109 subjects met the criteria for data collection. We found that neither opioid dose increase, nor decrease, correlated with point changes in clinical pain score in a subset of chronic pain patients over a prolonged course of opioid therapy (an average of 704 days). This lack of correlation was consistent regardless of the type of chronic pain including neuropathic, nociceptive, or mixed pain conditions. Neither gender nor age differences showed a significant influence on the clinical response to opioid therapy in these subjects. These results suggest that dose adjustment during opioid therapy may not necessarily alter long-term clinical pain score in a group of chronic pain patients and that individualized opioid therapy based on the clinical effectiveness should be considered to optimize the treatment outcome. Perspectives The study reports a relationship, or lack thereof, between opioid dose change and clinical pain score in a group of chronic pain patients. The study also calls for further investigation into the effectiveness of opioid therapy in the management of chronic non-malignant pain conditions. PMID:23452826

Immunohematopoietic modulation by oral β-1,3-glucan in mice infected with Listeria monocytogenes.

PubMed

Torello, Cristiane O; de Souza Queiroz, Julia; Oliveira, Sueli C; Queiroz, Mary L S

2010-12-01

In this study we demonstrated that the oral administration of β-1,3-glucan (Imunoglucan®) protects mice from a lethal dose of Listeria monocytogenes (LM) when administered prophylactically for 10 days at the doses of 150 and 300 mg/kg, with survival rates up to 40%. These doses also prevented the myelosuppression and the splenomegaly caused by a sublethal infection with LM, due to increased numbers of granulocyte-macrophage progenitors (CFU-GM) in the bone marrow. Investigation of the production of colony-stimulating factors revealed an increased colony-stimulating activity (CSA) in the serum of infected mice pre-treated with Imunoglucan®. The treatment also restored the reduced ability of stromal cells to display myeloid progenitors in long-term bone marrow cultures (LTBMC) and up-regulated IL-6 and IL-1α production by these cells in the infected mice, which was consistent with higher number of non-adherent cells. Additional studies to investigate the levels of interferon-gamma (INF-γ) in the supernatant of splenocyte cultures demonstrated a further increase in the level of this cytokine in infected-treated mice, compared to infected controls. In all cases, no differences were observed between the responses of the two optimal biologically effective doses. In contrast, no significant changes were produced by the treatment with the 50mg/kg dose. In addition, no changes were observed in normal mice treated with the three doses used. All together our results suggest that orally given Imunoglucan® indirectly modulates immune activity and probably disengages Listeria induced suppression of these responses by inducing a higher reserve of myeloid progenitors in the bone marrow in consequence of biologically active cytokine release (CSFs, IL-1α, IL-6, and INF-γ). Copyright © 2010 Elsevier B.V. All rights reserved.

Analysis of the antinociceptive interactions in two-drug combinations of gabapentin, oxcarbazepine and amitriptyline in streptozotocin-induced diabetic mice.

PubMed

Tomić, Maja A; Vucković, Sonja M; Stepanović-Petrović, Radica M; Micov, Ana M; Ugresić, Nenad D; Prostran, Milica S; Bosković, Bogdan

2010-02-25

Antiepileptic and antidepressant drugs are the primary treatments for pain relief in diabetic neuropathy. Combination therapy is a valid approach in pain treatment, where a reduction of doses could reduce side effects and still achieve optimal analgesia. We examined the effects of two-drug combinations of gabapentin, oxcarbazepine, and amitriptyline on nociception in diabetic mice and aimed to determine the type of interaction between components. The nociceptive responses in normal and diabetic mice were assessed by the tail-flick test. The testing was performed before and three weeks after the diabetes induction with streptozotocin (150mg/kg; i.p.), when the antinociceptive effects of gabapentin, oxcarbazepine, amitriptyline and their two-drug combinations were examined. Gabapentin (10-40mg/kg; p.o.) and oxcarbazepine (20-80mg/kg; p.o.) produced a significant, dose-dependent antinociception in diabetic mice while amitriptyline (5-60mg/kg; p.o.) produced weak antinociceptive effect. In normal mice, neither of the drugs produced antinociception. Gabapentin and oxcarbazepine, co-administered in fixed-dose fractions of the ED(50) to diabetic mice, induced significant, dose-dependent antinociception. Isobolographic analysis revealed synergistic interaction. Oxcarbazepine (10-60mg/kg; p.o.)+amitriptyline (5mg/kg; p.o.) and gabapentin (10-30mg/kg; p.o.)+amitriptyline (5mg/kg; p.o.) combinations significantly and dose-dependently reduced nociception in diabetic mice. Analysis of the log dose-response curves for oxcarbazepine or gabapentin in a presence of amitriptyline and oxcarbazepine or gabapentin applied alone, revealed a synergism in oxcarbazepine-amitriptyline and additivity in gabapentin-amitriptyline combination. These findings provide new information about the combination therapy of painful diabetic neuropathy and should be explored further in patients with diabetic neuropathy.

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