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Sample records for doses predict poorer

  1. Pretransplant renal dysfunction predicts poorer outcome in liver transplantation.

    PubMed

    Lafayette, R A; Paré, G; Schmid, C H; King, A J; Rohrer, R J; Nasraway, S A

    1997-09-01

    The postoperative courses of 115 liver transplant recipients were reviewed to monitor for outcomes of acute renal failure and mortality. An analysis of baseline (preoperative) variables with particular attention to baseline renal function was accomplished to establish predictive variables for a complicated postoperative course. Acute renal failure requiring dialysis occurred in 27 cases (23%) and was associated with a prolonged ICU stay, greater infectious complications, greater hospital charges and a high mortality rate (46 +/- 11% vs. 9 +/- 3%) as compared to patients who did not experience acute renal failure. Death occurred in 20 patients (17%) overall prior to discharge. In order to assess the contribution of renal function, the population was divided arbitrarily into two groups based on preoperative serum creatinine. Group 1 (n = 50) had a preoperative serum creatinine < 1.0 mg/dl (mean +/- SD = 2.2 +/- 0.2 mg/dl) and Group 2 (n = 65) had a preoperative serum creatinine < or = 1.0 mg/dl (0.7 +/- 0.1 mg/dl). The groups experienced similar operative courses. Group 1 patients experienced significantly longer ICU stays (18 +/- 3 vs. 10 +/- 2 days), higher rates of acute renal failure requiring dialysis (52 +/- 7 vs. 5 +/- 2%), higher hospital charges (231,454 +/- 17,088 vs. 178,755 +/- 14,744 $, US) and a greatly increased mortality rate (32 +/- 1 vs. 6 +/- 1%), as compared to Group 2 patients. A multifactorial regression analysis demonstrated that of all pretransplant factors analyzed, elevation in the serum creatinine was significantly associated and was the strongest predictor of both outcomes: acute renal failure requiring dialysis (ROC = 0.89) and death (ROC = 0.83). The presence or absence of hepatorenal syndrome did not influence the results of this analysis. This study demonstrates that cirrhotic patients with renal dysfunction, as indicated by an elevated serum creatinine, experience a poor surgical outcome following liver transplantation. These patients

  2. Somatic Complaints in Children with Anxiety Disorders and Their Unique Prediction of Poorer Academic Performance

    ERIC Educational Resources Information Center

    Hughes, Alicia A.; Lourea-Waddell, Brittany; Kendall, Philip C.

    2008-01-01

    The present study aimed to examine somatic complaints in children with anxiety disorders compared to non-anxious control children and whether somatic complaints predict poorer academic performance. The sample consisted of 108 children and adolescents (aged 8-14 years) assessed by a structured diagnostic interview: 69 with a principal (i.e., most…

  3. Sustain talk predicts poorer outcomes among mandated college student drinkers receiving a brief motivational intervention.

    PubMed

    Apodaca, Timothy R; Borsari, Brian; Jackson, Kristina M; Magill, Molly; Longabaugh, Richard; Mastroleo, Nadine R; Barnett, Nancy P

    2014-09-01

    Within-session client language that represents a movement toward behavior change (change talk) has been linked to better treatment outcomes in the literature on motivational interviewing (MI). There has been somewhat less study of the impact of client language against change (sustain talk) on outcomes following an MI session. This study examined the role of both client change talk and sustain talk, as well as therapist language, occurring during a brief motivational intervention (BMI) session with college students who had violated college alcohol policy (N = 92). Audiotapes of these sessions were coded using a therapy process coding system. A series of hierarchical regressions were used to examine the relationships among therapist MI-consistent and MI-inconsistent language, client change talk and sustain talk, as well as global measures of relational variables, and drinking outcomes. Contrary to prior research, sustain talk, but not change talk, predicted poorer alcohol use outcomes following the BMI at 3- and 12-month follow-up assessments. Higher levels of client self-exploration during the session also predicted improved drinking outcomes. Therapist measures of MI-consistent and MI-inconsistent language, and global measures of therapist acceptance and MI spirit were unrelated to client drinking outcomes. Results suggest that client sustain talk and self-exploration during the session play an important role in determining drinking outcomes among mandated college students receiving a BMI addressing alcohol use. PMID:25222170

  4. Increased marijuana use and gender predict poorer cognitive functioning in adolescents and emerging adults.

    PubMed

    Lisdahl, Krista M; Price, Jenessa S

    2012-07-01

    This study sought to characterize neuropsychological functioning in MJ-using adolescents and emerging adults (ages 18-26) and to investigate whether gender moderated these effects. Data were collected from 59 teens and emerging adults including MJ users (n = 23, 56% female) and controls (n = 35, 50% female) aged 18-26 (M = 21 years). Exclusionary criteria included independent Axis I disorders (besides SUD), and medical and neurologic disorders. After controlling for reading ability, gender, subclinical depressive symptoms, body mass index, and alcohol and other drug use, increased MJ use was associated with slower psychomotor speed/sequencing ability (p < .01), less efficient sustained attention (p < .05), and increased cognitive inhibition errors (p < .03). Gender significantly moderated the effects of MJ on psychomotor speed/sequencing ability (p < .003) in that males had a more robust negative relationship. The current study demonstrated that MJ exposure was associated with poorer psychomotor speed, sustained attention and cognitive inhibition in a dose-dependent manner in young adults, findings that are consistent with other samples of adolescent MJ users. Male MJ users demonstrated greater cognitive slowing than females. Future studies need to examine the neural substrates underlying with these cognitive deficits and whether cognitive rehabilitation or exercise interventions may serve as a viable treatments of cognitive deficits in emerging adult MJ users. PMID:22613255

  5. Casein Kinase 1 Epsilon Expression Predicts Poorer Prognosis in Low T-Stage Oral Cancer Patients

    PubMed Central

    Lin, Shu-Hui; Lin, Yueh-Min; Yeh, Chung-Min; Chen, Chih-Jung; Chen, Mei-Wen; Hung, Hsiao-Fang; Yeh, Kun-Tu; Yang, Shun-Fa

    2014-01-01

    Casein kinase 1 is a group of ubiquitous serine/threonine kinases that are involved in normal cellular functions and several pathological conditions, such as DNA repair, cell cycle progression, cytokinesis, differentiation, and apoptosis. Recent studies have indicated that casein kinase 1-epsilon (CK1ɛ) and casein kinase 1-delta (CK1δ) expression has a role in human cancers. We investigated the associations between CK1ɛ and CK1δ expression and the clinical parameters of oral cancer using immunohistochemical study methods on oral squamous cell carcinoma specimens. The results of our immunohistochemical analysis showed that the loss of CK1ɛ expression was greatly associated with a poor four-year survival rate in oral cancer patients (p = 0.002). A Kaplan-Meier analysis showed that patients who had a loss of CK1ɛ expression had a considerably poorer overall survival rate than patients who had positive CK1ɛ expressions (p = 0.022). A univariate analysis revealed that patients who had a loss of CK1ɛ expression had considerably poorer overall survival (OS) than patients who had positive expression (p = 0.024, hazard ratio (HR) = 1.7). In conclusion, our data indicated that the loss of cytoplasmic CK1ɛ expression is greatly associated with poor survival and might be an adverse survival factor. PMID:24557581

  6. Anhedonia Predicts Poorer Recovery among Youth with Selective Serotonin Reuptake Inhibitor Treatment-Resistant Depression

    ERIC Educational Resources Information Center

    McMakin, Dana L.; Olino, Thomas M.; Porta, Giovanna; Dietz, Laura J.; Emslie, Graham; Clarke, Gregory; Wagner, Karen Dineen; Asarnow, Joan R.; Ryan, Neal D.; Birmaher, Boris; Shamseddeen, Wael; Mayes, Taryn; Kennard, Betsy; Spirito, Anthony; Keller, Martin; Lynch, Frances L.; Dickerson, John F.; Brent, David A.

    2012-01-01

    Objective: To identify symptom dimensions of depression that predict recovery among selective serotonin reuptake inhibitor (SSRI) treatment-resistant adolescents undergoing second-step treatment. Method: The Treatment of Resistant Depression in Adolescents (TORDIA) trial included 334 SSRI treatment-resistant youth randomized to a medication…

  7. Peer Victimization, Depressive Symptoms, and High Salivary Cortisol Predict Poorer Memory in Children

    ERIC Educational Resources Information Center

    Vaillancourt, Tracy; Duku, Eric; Becker, Suzanna; Schmidt, Louis A.; Nicol, Jeffrey; Muir, Cameron; MacMillan, Harriet

    2011-01-01

    The predictive relations of peer victimization, depressive symptoms, and salivary cortisol on memory in 168 children aged 12 at Time 1 (T1) were examined using a longitudinal design in which data were collected on four occasions over a 2-year period. Results indicated that: (1) peer victimization, depressive symptoms, and evening cortisol were…

  8. Impulsiveness, overactivity, and poorer sustained attention improve by chronic treatment with low doses of l-amphetamine in an animal model of Attention-Deficit/Hyperactivity Disorder (ADHD)

    PubMed Central

    2011-01-01

    Background ADHD is currently defined as a cognitive/behavioral developmental disorder where all clinical criteria are behavioral. Overactivity, impulsiveness, and inattentiveness are presently regarded as the main clinical symptoms. There is no biological marker, but there is considerable evidence to suggest that ADHD behavior is associated with poor dopaminergic and noradrenergic modulation of neuronal circuits that involve the frontal lobes. The best validated animal model of ADHD, the Spontaneously Hypertensive Rat (SHR), shows pronounced overactivity, impulsiveness, and deficient sustained attention. The primary objective of the present research was to investigate behavioral effects of a range of doses of chronic l-amphetamine on ADHD-like symptoms in the SHR. Methods The present study tested the behavioral effects of 0.75 and 2.2 mg l-amphetamine base/kg i.p. in male SHRs and their controls, the Wistar Kyoto rat (WKY). ADHD-like behavior was tested with a visual discrimination task measuring overactivity, impulsiveness and inattentiveness. Results The striking impulsiveness, overactivity, and poorer sustained attention seen during baseline conditions in the SHR were improved by chronic treatment with l-amphetamine. The dose-response curves were, however, different for the different behaviors. Most significantly, the 0.75 mg/kg dose of l-amphetamine improved sustained attention without reducing overactivity and impulsiveness. The 2.2 mg/kg dose improved sustained attention as well as reduced SHR overactivity and impulsiveness. Discussion The effects of l-amphetamine to reduce the behavioral symptoms of ADHD in the SHR were maintained over the 14 days of daily dosing with no evidence of tolerance developing. PMID:21450079

  9. O10.08HIGH G-PROTEIN-COUPLED RECEPTORS 65 (GPR65) EXPRESSION PREDICTS A POORER SURGICAL OUTCOME OF GLIOBLASTOMA PATIENTS

    PubMed Central

    Xu, T.; Wang, H.; Yan, Y.; Qin, R.; Jiang, Y.; Lu, Y.; Li, W.; Xia, C.; Chen, J.

    2014-01-01

    OBJECTIVES: To investigate the expression and prognostic value of G-protein-coupled receptors 65 (GPR65, also known as T-cell death-associated gene 8, TDAG8) in glioblastoma patients. METHODS: We determined the expression of GPR65 using immunohistochemistry in tissue microarrays containing 102 GBM samples and 15 normal brain samples. Cumulative survival was calculated by the Kaplan-Meier method and analyzed by the log-rank test. Univariate and multivariate analyses were performed by the stepwise forward Cox regression model. RESULTS: GPR65 protein levels were significantly elevated in glioblastoma tissues compared with those of normal brain tissues for nearly 5 folds (P < 0.001). In addition to standard therapy, patients with high GPR65 protein expression had significantly shorter OS and PFS than those with low GPR65 expression (OS: 14.6 versus 22.6 months or 14.7 versus 22.6 months, p = 0.047 and 0.040, respectively; PFS: 12.5 versus 18.9 months or 12.8 versus 19.0 months, p = 0.089 and p = 0.085, respectively). In multivariate analysis, Cox regression model identified high GPR65 expression as an independent prognostic factor for OS and PFS (Hazard ration [HR] = 1.599 and 1.593; p = 0.037 and 0.034, respectively) of primary GBM patients. No adjuvant radiotherapy, small extent of resection were other three independent risk factors of poor prognosis in glioblastoma patients. CONCLUSION: High GPR65 expression occurs in a significant subset of glioblastoma patients and predicts a poorer outcome. The study identifies a potentially useful molecular marker for the categorization and targeted therapy of glioblastoma.

  10. Expression of FOXP1 in mucosa-associated lymphoid tissue lymphoma suggests a large tumor cell transformation and predicts a poorer prognosis in the positive thyroid patients.

    PubMed

    Jiang, Wei; Li, Lei; Tang, Yuan; Zhang, Wen-yan; Liu, Wei-ping; Li, Gan-di

    2012-12-01

    The forkhead box protein P1 (FOXP1) expression resulted from chromosome translocation was found in MALT lymphoma, and its nuclear expression in diffuse large B cell lymphoma has been believed to be a poor prognostic factor. In our study, FOXP1 expression was investigated in its relationship to the occurrence of large tumor cells, clinical features, and prognosis in a series of 115 MALT lymphomas divided into two groups with or without the large tumor cells. All cases were morphologically reviewed, and FOXP1 expression was detected both in mRNA and protein levels by real-time PCR, immunochemical staining, and Western blot hybridization. All available clinical data were collected. In the MALT lymphoma with large cells, FOXP1 expression was higher at both mRNA (P = 0.008) and protein (P = 0.000) levels than that in group without large cells, and most large tumor cells showed FOXP1 positivity. It was also found that cases beyond Ann Arbor stage I have a higher FOXP1 expression rate than cases in stage I (P = 0.01), moreover, FOXP1-positive group has more plasmacytic differentiation (P = 0.025), deeper filtrating depth in digestive tract (P = 0.039), and a higher Ki67 proliferation index (P = 0.022). However, no statistical significance was identified in the involved anatomic sites and prognosis. Our data demonstrated the close relationship between FOXP1 nuclear expression and the occurrence of large tumor cells in MALT lymphoma, which suggested the possibility of large cell transformation of FOXP1-positive cases. And FOXP1 positivity was associated with enhanced invasion and proliferation ability of tumor cells. In the thyroid cases, the FOXP1 positivity showed a poorer prognosis (P = 0.043), but the significance was not found in the overall survival analysis (P = 0.1123). PMID:22736042

  11. Absorbed dose measurements and predictions on LDEF

    NASA Technical Reports Server (NTRS)

    Frank, A. L.; Benton, E. V.; Armstrong, T. W.; Colborn, B. L.

    1993-01-01

    The overall radiation environment of the Long Duration Exposure Facility (LDEF) was determined in part through the use of thermoluminescent detectors (TLD's) which were included in several experiments. The results given are from four experiments (A0015 Biostack, M0004 Fiber Optics Data Link, P0004 Seeds in Space, and P0006 Linear Energy Transfer Spectrum Measurement) and represent a large fraction of existing absorbed dose data. The TLD's were located on the leading and the trailing edges and the Earth end of the spacecraft under various shielding depths (0.48 to 15.4 g/sq cm). The measured absorbed doses were found to reflect both directional dependence of incident trapped protons and shielding. At the leading edge, doses ranged from 2.10 to 2.58 Gy under shielding of 2.90 to 1.37 g/sq cm Al equivalent (M0004). At the trailing edge, doses varied from 3.04 to 4.49 Gy under shielding of 11.7 to 3.85 g/sq cm (A0015), doses varied from 2.91 to 6.64 Gy under shielding of 11.1 to 0.48 g/sq cm (P0004), and a dose range of 2.66 to 6.48 Gy was measured under shielding of 15.4 to 0.48 g/sq cm (P0006). At the Earth end of the spacecraft, doses from 2.41 to 3.93 Gy were found under shielding of 10.0 to 1.66 g/sq cm (A0015). The effect of the trapped proton anisotropy was such that the western side of LDEF received more than 2 times the dose of the eastern side at shielding depths of approximately 1 g/sq cm. Calculations utilizing a directional model of trapped proton spectra predict smaller doses than those measured, being about 50 percent of measured values at the trailing edge and Earth end, and about 80 percent near the leading edge.

  12. Why are older pensioners poorer?

    PubMed

    Johnson, P; Stears, G

    1998-08-01

    "We show that older [UK] male pensioners have substantially lower incomes than younger pensioners.... We find that cohort differences more than account for the lower incomes of older pensioners in the sense that the mean income of older pensioners is actually higher than the mean income of the same cohort of pensioners when they were younger. We explore a number of possible reasons for this and conclude that it is driven by differential mortality between richer and poorer pensioners. We show how this manifests itself in a long time series of cross-sectional datasets." PMID:12294901

  13. Prediction Of Patient Doses In Diagnostic Radiology

    NASA Astrophysics Data System (ADS)

    Wilson, Charles R.; Palmer, David W.

    1980-08-01

    X-ray spectra and outputs are computed based on three formulations of x-ray bremsstrahlung production by Kramers, Storm, and Birch and Marshall. Published, measured spectra compare favorable with Storm and Birch and Marshall. Measured outputs (mR/mAs at 100 cm) agree best with Storm. TLD measurements of x-ray exposure agree well with predictions made using Storm over a range of techniques. Rapid calculation of output for either single phase or three phase operation is possible using coefficients from a third order fit to the data based on Storm for 40 to 120 kV and 2 to 8 mm aluminum total filtration.

  14. PREDICTIVE BAYESIAN PATHOGEN DOSE-RESPONSE MODEL FORMS

    EPA Science Inventory

    The use of predictive Bayesian methods in dose-response assessment will be investigated. The predictive Bayesian approach offers an alternative to current approaches in that it does not require the selection of a specific confidence limit, yet provides an answer that is more cons...

  15. Prediction of the mortality dose-response relationship in man

    SciTech Connect

    Morris, M.D.; Jones, T.D.

    1987-01-01

    Based upon an extensive data base including 100 separate animal studies, an estimate of the mortality dose-response relationship due to continuous photon radiation is predicted for 70 kg man. The model used in this prediction exercise includes fixed terms accounting for effects of body weight and dose rate, and random terms accounting for inter- and intra-species variation and experimental error. Point predictions and 95% prediction intervals are given for the LD/sub 05/, LD/sub 10/, LD/sub 25/, LD/sub 50/, LD/sub 75/, LD/sub 90/, and LD/sub 95/, for dose rates ranging from 1 to 50 R/min. 6 refs., 5 tabs.

  16. Quantifying and Communicating Uncertainty in Preclinical Human Dose-Prediction

    PubMed Central

    Sundqvist, M; Lundahl, A; Någård, MB; Bredberg, U; Gennemark, P

    2015-01-01

    Human dose-prediction is fundamental for ranking lead-optimization compounds in drug discovery and to inform design of early clinical trials. This tutorial describes how uncertainty in such predictions can be quantified and efficiently communicated to facilitate decision-making. Using three drug-discovery case studies, we show how several uncertain pieces of input information can be integrated into one single uncomplicated plot with key predictions, including their uncertainties, for many compounds or for many scenarios, or both. PMID:26225248

  17. Experimental verification of a portal dose prediction model

    SciTech Connect

    Elmpt, W.J.C. van; Nijsten, S.M.J.J.G.; Mijnheer, B.J.; Minken, A.W.H.

    2005-09-15

    Electronic portal imaging devices (EPIDs) can be used to measure a two-dimensional (2D) dose distribution behind a patient, thus allowing dosimetric treatment verification. For this purpose we experimentally assessed the accuracy of a 2D portal dose prediction model based on pencil beam scatter kernels. A straightforward derivation of these pencil beam scatter kernels for portal dose prediction models is presented based on phantom measurements. The model is able to predict the 2D portal dose image (PDI) behind a patient, based on a PDI without the patient in the beam in combination with the radiological thickness of the patient, which requires in addition a PDI with the patient in the beam. To assess the accuracy of portal dose and radiological thickness values obtained with our model, various types of homogeneous as well as inhomogeneous phantoms were irradiated with a 6 MV photon beam. With our model we are able to predict a PDI with an accuracy better than 2% (mean difference) if the radiological thickness of the object in the beam is symmetrically situated around the isocenter. For other situations deviations up to 3% are observed for a homogeneous phantom with a radiological thickness of 17 cm and a 9 cm shift of the midplane-to-detector distance. The model can extract the radiological thickness within 7 mm (maximum difference) of the actual radiological thickness if the object is symmetrically distributed around the isocenter plane. This difference in radiological thickness is related to a primary portal dose difference of 3%. It can be concluded that our model can be used as an easy and accurate tool for the 2D verification of patient treatments by comparing predicted and measured PDIs. The model is also able to extract the primary portal dose with a high accuracy, which can be used as the input for a 3D dose reconstruction method based on back-projection.

  18. Radioactive Doses - Predicted and Actual - and Likely Health Effects.

    PubMed

    Nagataki, S; Takamura, N

    2016-04-01

    Five years have passed since the nuclear accident at Fukushima Daiichi Nuclear Power Stations on 11 March 2011. Here we refer to reports from international organisations as sources of predicted values obtained from environmental monitoring and dose estimation models, and reports from various institutes in Japan are used as sources of individual actual values. The World Health Organization, based on information available up to 11 September 2011 (and published in 2012), reported that characteristic effective doses in the first year after the accident, to all age groups, were estimated to be in the 10-50 mSv dose band in example locations in evacuation areas. Estimated characteristic thyroid doses to infants in Namie Town were within the 100-200 mSv dose band. A report from the United Nations Scientific Committee on the Effects of Atomic Radiation published in 2014 shows that the effective dose received by adults in evacuation areas during the first year after the accident was 1.1-13 mSv. The absorbed dose to the thyroid in evacuated settlements was 7.2-35 mSv in adults and 15-83 mSv in 1-year-old infants. Individual external radiation exposure in the initial 4 months after the accident, estimated by superimposing individual behaviour data on to a daily dose rate map, was less than 3 mSv in 93.9% of residents (maximum 15 mSv) in evacuation areas. Actual individual thyroid equivalent doses were less than 15 mSv in 98.8% of children (maximum 25 mSv) in evacuation areas. When uncertainty exists in dose estimation models, it may be sensible to err on the side of caution, and final estimated doses are often much greater than actual radiation doses. However, overestimation of the dose at the time of an accident has a great influence on the psychology of residents. More than 100 000 residents have not returned to the evacuation areas 5 years after the Fukushima accident because of the social and mental effects during the initial period of the disaster. Estimates of

  19. Predicting Pneumonitis Risk: A Dosimetric Alternative to Mean Lung Dose

    SciTech Connect

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

    2013-02-01

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

  20. Dosing Algorithms to Predict Warfarin Maintenance Dose in Caucasians and African Americans

    PubMed Central

    Schelleman, Hedi; Chen, Jinbo; Chen, Zhen; Christie, Jason; Newcomb, Craig W.; Brensinger, Colleen M.; Price, Maureen; Whitehead, Alexander S.; Kealey, Carmel; Thorn, Caroline F.; Samaha, Frederick F.; Kimmel, Stephen E

    2008-01-01

    Objectives The objective of this study was to determine whether clinical, environmental, and genetic factors can be used to develop dosing algorithms for Caucasians and African Americans that perform better than giving empirical 5 mg/day. Methods From April 2002 through December 2005, 259 warfarin initiators were prospectively followed until they reached maintenance dose. Results The Caucasian algorithm included 11 variables (R2=0.43). This model (51% within 1 mg) performed better compared with 5 mg/day (29% within 5±1 mg). The African American algorithm included 10 variables (R2=0.28). This model predicted 37% of doses within 1 mg of the observed dose; a small improvement compared with 5 mg/day (34%). These results were similar to the results we obtained from testing other (published) algorithms. Conclusions The dosing algorithms in Caucasians explained <45% of the variability and the algorithms in African Americans performed only marginally better than giving 5 mg empirically. PMID:18596683

  1. Genetic Risk Score Modelling for Disease Progression in New-Onset Type 1 Diabetes Patients: Increased Genetic Load of Islet-Expressed and Cytokine-Regulated Candidate Genes Predicts Poorer Glycemic Control.

    PubMed

    Brorsson, Caroline A; Nielsen, Lotte B; Andersen, Marie Louise; Kaur, Simranjeet; Bergholdt, Regine; Hansen, Lars; Mortensen, Henrik B; Pociot, Flemming; Størling, Joachim

    2016-01-01

    Genome-wide association studies (GWAS) have identified over 40 type 1 diabetes risk loci. The clinical impact of these loci on β-cell function during disease progression is unknown. We aimed at testing whether a genetic risk score could predict glycemic control and residual β-cell function in type 1 diabetes (T1D). As gene expression may represent an intermediate phenotype between genetic variation and disease, we hypothesized that genes within T1D loci which are expressed in islets and transcriptionally regulated by proinflammatory cytokines would be the best predictors of disease progression. Two-thirds of 46 GWAS candidate genes examined were expressed in human islets, and 11 of these significantly changed expression levels following exposure to proinflammatory cytokines (IL-1β + IFNγ + TNFα) for 48 h. Using the GWAS single nucleotide polymorphisms (SNPs) from each locus, we constructed a genetic risk score based on the cumulative number of risk alleles carried in children with newly diagnosed T1D. With each additional risk allele carried, HbA1c levels increased significantly within first year after diagnosis. Network and gene ontology (GO) analyses revealed that several of the 11 candidate genes have overlapping biological functions and interact in a common network. Our results may help predict disease progression in newly diagnosed children with T1D which can be exploited for optimizing treatment. PMID:26904692

  2. Quantity and Quality of Inhaled Dose Predicts Immunopathology in Tuberculosis

    PubMed Central

    Fennelly, Kevin P.; Jones-López, Edward C.

    2015-01-01

    Experimental animal models of tuberculosis (TB) have convincingly demonstrated that inhaled dose predicts immunopathology and survival. In contrast, the importance of inhaled dose has generally not been appreciated in TB epidemiology, clinical science, or the practice of TB control. Infectiousness of TB patients has traditionally been assessed using microscopy for acid-fast bacilli in the sputum, which should be considered only a risk factor. We have recently demonstrated that cough aerosol cultures from index cases with pulmonary TB are the best predictors of new infection among household contacts. We suggest that cough aerosols of M. tuberculosis are the best surrogates of inhaled dose, and we hypothesize that the quantity of cough aerosols is associated with TB infection versus disease. Although several factors affect the quality of infectious aerosols, we propose that the particle size distribution of cough aerosols is an important predictor of primary upper airway disease and cervical lymphadenitis and of immune responses in exposed hosts. We hypothesize that large droplet aerosols (>5 μ) containing M. tuberculosis deposit in the upper airway and can induce immune responses without establishing infection. We suggest that this may partially explain the large proportion of humans who never develop TB disease in spite of having immunological evidence of M. tuberculosis infection (e.g., positive tuberculin skin test or interferon gamma release assay). If these hypotheses are proven true, they would alter the current paradigm of latent TB infection and reactivation, further demonstrating the need for better biomarkers or methods of assessing TB infection and the risk of developing disease. PMID:26175730

  3. HOW RELIABLE IS 24 HOUR SERUM LITHIUM LEVEL AFTER A TEST DOSE OF LITHIUM IN PREDICTING OPTIMAL LITHIUM DOSE?

    PubMed Central

    Kuruvilla, K.; Shaji, K.S.

    1989-01-01

    SUMMARY 57% of a group of 35 patients treated with Lithium Carbonate at dosages predicted by the nomogram suggested by Cooper et al (1973) failed to reach therapeutic levels of serum lithium. This finding casts serious doubts on the usefulness of the claim by Cooper et al (1973 & 1976) that 24 hour serum lithium level after a test dose of 600 mg. lithium can predict the daily lithium dose. PMID:21927360

  4. Three-dimensional dose prediction based on two-dimensional verification measurements for IMRT.

    PubMed

    Sumida, Iori; Yamaguchi, Hajime; Kizaki, Hisao; Aboshi, Keiko; Yamada, Yuji; Yoshioka, Yasuo; Ogawa, Kazuhiko

    2014-01-01

    Dose verifications for intensity-modulated radiation therapy (IMRT) are generally performed once before treatment. A 39-fraction treatment course for prostate cancer delivers a dose prescription of 78 Gy in eight weeks. Any changes in multileaf collimator leaf position over the treatment course may affect the dosimetry. To evaluate the magnitude of deviations from the predicted dose over an entire treatment course with MLC leaf calibrations performed every two weeks, we tracked weekly changes in relative dose error distributions measured with two-dimensional (2D) beam-by-beam analysis. We compared the dosimetric results from 20 consecutive patient-specific IMRT quality assurance (QA) tests using beam-by-beam analysis and a 2D diode detector array to the dose plans calculated by the treatment planning system (TPS). We added back the resulting relative dose error measured weekly into the original dose grid for each beam. To validate the prediction method, the predicted doses and dose distributions were compared to the measurements using an ionization chamber and film. The predicted doses were in good agreement, within 2% of the measured doses, and the predicted dose distributions also presented good agreement with the measured distributions. Dose verification results measured once as a pretreatment QA test were not completely stable, as results of weekly beam-by-beam analysis showed some variation. Because dosimetric errors throughout the treatment course were averaged, the overall dosimetric impact to patients was small. PMID:25207574

  5. Detailed dose distribution prediction of Cf-252 brachytherapy source with boron loading dose enhancement.

    PubMed

    Ghassoun, J; Mostacci, D; Molinari, V; Jehouani, A

    2010-02-01

    The purpose of this work is to evaluate the dose rate distribution and to determine the boron effect on dose rate distribution for (252)Cf brachytherapy source. This study was carried out using a Monte Carlo simulation. To validate the Monte Carlo computer code, the dosimetric parameters were determined following the updated TG-43 formalism and compared with current literature data. The validated computer code was then applied to evaluate the neutron and photon dose distribution and to illustrate the boron loading effect. PMID:19889549

  6. TH-A-9A-01: Active Optical Flow Model: Predicting Voxel-Level Dose Prediction in Spine SBRT

    SciTech Connect

    Liu, J; Wu, Q.J.; Yin, F; Kirkpatrick, J; Cabrera, A; Ge, Y

    2014-06-15

    Purpose: To predict voxel-level dose distribution and enable effective evaluation of cord dose sparing in spine SBRT. Methods: We present an active optical flow model (AOFM) to statistically describe cord dose variations and train a predictive model to represent correlations between AOFM and PTV contours. Thirty clinically accepted spine SBRT plans are evenly divided into training and testing datasets. The development of predictive model consists of 1) collecting a sequence of dose maps including PTV and OAR (spinal cord) as well as a set of associated PTV contours adjacent to OAR from the training dataset, 2) classifying data into five groups based on PTV's locations relative to OAR, two “Top”s, “Left”, “Right”, and “Bottom”, 3) randomly selecting a dose map as the reference in each group and applying rigid registration and optical flow deformation to match all other maps to the reference, 4) building AOFM by importing optical flow vectors and dose values into the principal component analysis (PCA), 5) applying another PCA to features of PTV and OAR contours to generate an active shape model (ASM), and 6) computing a linear regression model of correlations between AOFM and ASM.When predicting dose distribution of a new case in the testing dataset, the PTV is first assigned to a group based on its contour characteristics. Contour features are then transformed into ASM's principal coordinates of the selected group. Finally, voxel-level dose distribution is determined by mapping from the ASM space to the AOFM space using the predictive model. Results: The DVHs predicted by the AOFM-based model and those in clinical plans are comparable in training and testing datasets. At 2% volume the dose difference between predicted and clinical plans is 4.2±4.4% and 3.3±3.5% in the training and testing datasets, respectively. Conclusion: The AOFM is effective in predicting voxel-level dose distribution for spine SBRT. Partially supported by NIH/NCI under grant

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

    NASA Technical Reports Server (NTRS)

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

    2001-01-01

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

  8. An Interactive Point Kernel Program For Photon Dose Rate Prediction of Cylindrical Source/Shield Arrangements.

    Energy Science and Technology Software Center (ESTSC)

    1990-10-26

    Version 00 The program ZYLIND is an interactive point kernel program for photon dose rate prediction of a homogeneous cylindrical source shielded by cylindrical (radial) or plane (axial) layered shields.

  9. Imprecision in predicted dose from /sup 137/Cs resulting from biological variability

    SciTech Connect

    Dunning, D.E. Jr.; Schwarz, G.

    1981-01-01

    The variability of observed values of human metabolic and physiological characteristics which influence estimates of dose from ingestion of a unit of Cesium-137 activity, and the subsequent predicted total-body dose commitment is analyzed. The analysis is based on extensive literature review and statistical comparison of parameter variability, correlation and reliability. (PSB)

  10. Contextual Atlas Regression Forests: Multiple-Atlas-Based Automated Dose Prediction in Radiation Therapy.

    PubMed

    McIntosh, Chris; Purdie, Thomas G

    2016-04-01

    Radiation therapy is an integral part of cancer treatment, but to date it remains highly manual. Plans are created through optimization of dose volume objectives that specify intent to minimize, maximize, or achieve a prescribed dose level to clinical targets and organs. Optimization is NP-hard, requiring highly iterative and manual initialization procedures. We present a proof-of-concept for a method to automatically infer the radiation dose directly from the patient's treatment planning image based on a database of previous patients with corresponding clinical treatment plans. Our method uses regression forests augmented with density estimation over the most informative features to learn an automatic atlas-selection metric that is tailored to dose prediction. We validate our approach on 276 patients from 3 clinical treatment plan sites (whole breast, breast cavity, and prostate), with an overall dose prediction accuracies of 78.68%, 64.76%, 86.83% under the Gamma metric. PMID:26660888

  11. Can radiation therapy treatment planning system accurately predict surface doses in postmastectomy radiation therapy patients?

    SciTech Connect

    Wong, Sharon; Back, Michael; Tan, Poh Wee; Lee, Khai Mun; Baggarley, Shaun; Lu, Jaide Jay

    2012-07-01

    Skin doses have been an important factor in the dose prescription for breast radiotherapy. Recent advances in radiotherapy treatment techniques, such as intensity-modulated radiation therapy (IMRT) and new treatment schemes such as hypofractionated breast therapy have made the precise determination of the surface dose necessary. Detailed information of the dose at various depths of the skin is also critical in designing new treatment strategies. The purpose of this work was to assess the accuracy of surface dose calculation by a clinically used treatment planning system and those measured by thermoluminescence dosimeters (TLDs) in a customized chest wall phantom. This study involved the construction of a chest wall phantom for skin dose assessment. Seven TLDs were distributed throughout each right chest wall phantom to give adequate representation of measured radiation doses. Point doses from the CMS Xio Registered-Sign treatment planning system (TPS) were calculated for each relevant TLD positions and results correlated. There were no significant difference between measured absorbed dose by TLD and calculated doses by the TPS (p > 0.05 (1-tailed). Dose accuracy of up to 2.21% was found. The deviations from the calculated absorbed doses were overall larger (3.4%) when wedges and bolus were used. 3D radiotherapy TPS is a useful and accurate tool to assess the accuracy of surface dose. Our studies have shown that radiation treatment accuracy expressed as a comparison between calculated doses (by TPS) and measured doses (by TLD dosimetry) can be accurately predicted for tangential treatment of the chest wall after mastectomy.

  12. Even Poorer Nations Not Immune to High Blood Pressure

    MedlinePlus

    ... 160306.html Even Poorer Nations Not Immune to High Blood Pressure Researchers cite aging populations, diet, inactivity and lack ... 2016 (HealthDay News) -- For the first time ever, high blood pressure rates are higher in low- and middle-income ...

  13. Novel Radiobiological Gamma Index for Evaluation of 3-Dimensional Predicted Dose Distribution

    SciTech Connect

    Sumida, Iori; Yamaguchi, Hajime; Kizaki, Hisao; Aboshi, Keiko; Tsujii, Mari; Yoshikawa, Nobuhiko; Yamada, Yuji; Suzuki, Osamu; Seo, Yuji; Isohashi, Fumiaki; Yoshioka, Yasuo; Ogawa, Kazuhiko

    2015-07-15

    Purpose: To propose a gamma index-based dose evaluation index that integrates the radiobiological parameters of tumor control (TCP) and normal tissue complication probabilities (NTCP). Methods and Materials: Fifteen prostate and head and neck (H&N) cancer patients received intensity modulated radiation therapy. Before treatment, patient-specific quality assurance was conducted via beam-by-beam analysis, and beam-specific dose error distributions were generated. The predicted 3-dimensional (3D) dose distribution was calculated by back-projection of relative dose error distribution per beam. A 3D gamma analysis of different organs (prostate: clinical [CTV] and planned target volumes [PTV], rectum, bladder, femoral heads; H&N: gross tumor volume [GTV], CTV, spinal cord, brain stem, both parotids) was performed using predicted and planned dose distributions under 2%/2 mm tolerance and physical gamma passing rate was calculated. TCP and NTCP values were calculated for voxels with physical gamma indices (PGI) >1. We propose a new radiobiological gamma index (RGI) to quantify the radiobiological effects of TCP and NTCP and calculate radiobiological gamma passing rates. Results: The mean RGI gamma passing rates for prostate cases were significantly different compared with those of PGI (P<.03–.001). The mean RGI gamma passing rates for H&N cases (except for GTV) were significantly different compared with those of PGI (P<.001). Differences in gamma passing rates between PGI and RGI were due to dose differences between the planned and predicted dose distributions. Radiobiological gamma distribution was visualized to identify areas where the dose was radiobiologically important. Conclusions: RGI was proposed to integrate radiobiological effects into PGI. This index would assist physicians and medical physicists not only in physical evaluations of treatment delivery accuracy, but also in clinical evaluations of predicted dose distribution.

  14. Islet Oxygen Consumption Rate (OCR) Dose Predicts Insulin Independence in Clinical Islet Autotransplantation

    PubMed Central

    Papas, Klearchos K.; Bellin, Melena D.; Sutherland, David E. R.; Suszynski, Thomas M.; Kitzmann, Jennifer P.; Avgoustiniatos, Efstathios S.; Gruessner, Angelika C.; Mueller, Kathryn R.; Beilman, Gregory J.; Balamurugan, Appakalai N.; Loganathan, Gopalakrishnan; Colton, Clark K.; Koulmanda, Maria; Weir, Gordon C.; Wilhelm, Josh J.; Qian, Dajun; Niland, Joyce C.; Hering, Bernhard J.

    2015-01-01

    Background Reliable in vitro islet quality assessment assays that can be performed routinely, prospectively, and are able to predict clinical transplant outcomes are needed. In this paper we present data on the utility of an assay based on cellular oxygen consumption rate (OCR) in predicting clinical islet autotransplant (IAT) insulin independence (II). IAT is an attractive model for evaluating characterization assays regarding their utility in predicting II due to an absence of confounding factors such as immune rejection and immunosuppressant toxicity. Methods Membrane integrity staining (FDA/PI), OCR normalized to DNA (OCR/DNA), islet equivalent (IE) and OCR (viable IE) normalized to recipient body weight (IE dose and OCR dose), and OCR/DNA normalized to islet size index (ISI) were used to characterize autoislet preparations (n = 35). Correlation between pre-IAT islet product characteristics and II was determined using receiver operating characteristic analysis. Results Preparations that resulted in II had significantly higher OCR dose and IE dose (p<0.001). These islet characterization methods were highly correlated with II at 6–12 months post-IAT (area-under-the-curve (AUC) = 0.94 for IE dose and 0.96 for OCR dose). FDA/PI (AUC = 0.49) and OCR/DNA (AUC = 0.58) did not correlate with II. OCR/DNA/ISI may have some utility in predicting outcome (AUC = 0.72). Conclusions Commonly used assays to determine whether a clinical islet preparation is of high quality prior to transplantation are greatly lacking in sensitivity and specificity. While IE dose is highly predictive, it does not take into account islet cell quality. OCR dose, which takes into consideration both islet cell quality and quantity, may enable a more accurate and prospective evaluation of clinical islet preparations. PMID:26258815

  15. Use of dose-dependent absorption into target tissues to more accurately predict cancer risk at low oral doses of hexavalent chromium.

    PubMed

    Haney, J

    2015-02-01

    The mouse dose at the lowest water concentration used in the National Toxicology Program hexavalent chromium (CrVI) drinking water study (NTP, 2008) is about 74,500 times higher than the approximate human dose corresponding to the 35-city geometric mean reported in EWG (2010) and over 1000 times higher than that based on the highest reported tap water concentration. With experimental and environmental doses differing greatly, it is a regulatory challenge to extrapolate high-dose results to environmental doses orders of magnitude lower in a meaningful and toxicologically predictive manner. This seems particularly true for the low-dose extrapolation of results for oral CrVI-induced carcinogenesis since dose-dependent differences in the dose fraction absorbed by mouse target tissues are apparent (Kirman et al., 2012). These data can be used for a straightforward adjustment of the USEPA (2010) draft oral slope factor (SFo) to be more predictive of risk at environmentally-relevant doses. More specifically, the evaluation of observed and modeled differences in the fraction of dose absorbed by target tissues at the point-of-departure for the draft SFo calculation versus lower doses suggests that the draft SFo be divided by a dose-specific adjustment factor of at least an order of magnitude to be less over-predictive of risk at more environmentally-relevant doses. PMID:25445295

  16. A polymorphism in the VKORC1-regulator calumenin predicts higher warfarin doses in African-Americans

    PubMed Central

    Voora, D; Koboldt, DC; King, CR; Lenzini, PA; Eby, CS; Porche-Sorbet, R; Deych, E; Crankshaw, M; Milligan, PE; McLeod, HL; Patel, SR; Cavallari, LH; Ridker, PM; Grice, GR; Miller, RD; Gage, BF

    2010-01-01

    Background Warfarin demonstrates wide interindividual variability that is partly mediated by variants in CYP2C9 and VKORC1. Whether variants in CALU (vitamin K reductase regulator) influence warfarin dose is unknown. Methods and Results We resequenced CALU regions in a discovery cohort of dose-outliers: patients with high(>90th percentile, n=55) or low(<10th percentile, n=53) dose requirements(after accounting for known genetic and nongenetic variables). One CALU variant, rs339097, was associated with high-doses(p=0.01). We validated this variant as a predictor of higher warfarin doses in two replication cohorts: 1)496 patients of mixed ethnicity, 2)194 African-American patients. The G allele of rs339097(African-American and Caucasian allele frequency 0.14 and 0.002, respectively), was associated with a 14.5%(SD±7%) greater therapeutic dose(p=0.03) in the first replication cohort and a higher than predicted dose in the second replication cohort(allele frequency=0.14, one-sided p=0.03). Conclusions CALU rs339097 A>G is associated with higher warfarin dose requirements independent of known genetic and nongenetic predictors of warfarin dose in African-Americans. PMID:20200517

  17. Predictive factors in eradicating hepatitis C virus using a relatively small dose of interferon.

    PubMed

    Fukuda, M; Chayama, K; Tsubota, A; Kobayashi, M; Hashimoto, M; Miyano, Y; Koike, H; Kobayashi, M; Koida, I; Arase, Y; Saitoh, S; Murashima, N; Ikeda, K; Kumada, H

    1998-04-01

    Interferon (IFN) can reduce hepatitis C virus load and even eliminate the virus in 30-40% of patients. Several predictive factors for eradication of the virus have been reported and a higher dose of IFN tends to result in elimination of the virus. However, a small dose of IFN sometimes is as effective as a large dose in eradicating the virus. The predictive factors for such a response are not well established. We retrospectively analysed 50 patients with chronic hepatitis C who were treated with relatively small amounts of IFN (equal or less than 252 million units). Eleven patients were responders (elimination of hepatitis C virus (HCV) and normalization of alanine amino transferase (ALT) for at least 6 months), but the remaining 39 were non-responders. Multivariate analysis showed that the pretreatment viral load and total dose of IFN per kilogram of bodyweight were significant predictive factors of response to therapy. We also assessed the amino acid substitutions in the IFN sensitivity determining region (ISDR), NS5A codon 2209-2248, of HCV in serum samples obtained from 31 patients with HCV genotype 1b. The presence of more than one amino acid substitution in the ISDR tended to correlate with HCV genotype 1b elimination. As IFN is expensive and has a number of serious side effects, our study suggests that the optimal dose of IFN may vary from one patient to another and that more stringent criteria should be used to select the optimal dose for therapy. PMID:9641307

  18. Slow sluggish cognitive tempo symptoms are associated with poorer academic performance in children with ADHD.

    PubMed

    Tamm, Leanne; Garner, Annie A; Loren, Richard E A; Epstein, Jeffery N; Vaughn, Aaron J; Ciesielski, Heather A; Becker, Stephen P

    2016-08-30

    Sluggish cognitive tempo (SCT) symptoms may confer risk for academic impairment in attention-deficit/hyperactivity disorder (ADHD). We investigated SCT in relation to academic performance and impairment in 252 children (ages 6-12, 67% boys) with ADHD. Parents and teachers completed SCT and academic impairment ratings, and achievement in reading, math, and spelling was assessed. Simultaneous regressions controlling for IQ, ADHD, and comorbidities were conducted. Total SCT predicted parent-rated impairments in writing, mathematics, and overall school but not reading. Parent-rated SCT Slow predicted poorer reading and spelling, but not math achievement. Teacher-rated SCT Slow predicted poorer spelling and math, but not reading achievement. Parent-rated SCT Slow predicted greater academic impairment ratings across all domains, whereas teacher-rated SCT Slow predicted greater impairment in writing only. Age and gender did not moderate these relationships with the exception of math impairment; SCT slow predicted math impairment for younger but not older children. Parent and teacher SCT Sleepy and Daydreamy ratings were not significant predictors. SCT Slow appears to be uniquely related to academic problems in ADHD, and may be important to assess and potentially target in intervention. More work is needed to better understand the nature of SCT Slow symptoms in relation to inattention and amotivation. PMID:27294799

  19. Incorporation of gantry angle correction for 3D dose prediction in intensity-modulated radiation therapy

    PubMed Central

    Sumida, Iori; Yamaguchi, Hajime; Kizaki, Hisao; Aboshi, Keiko; Tsujii, Mari; Yamada, Yuji; Yagi, Masashi; Ogawa, Kazuhiko

    2015-01-01

    Pretreatment dose verification with beam-by-beam analysis for intensity-modulated radiation therapy (IMRT) is commonly performed with a gantry angle of 0° using a 2D diode detector array. Any changes in multileaf collimator (MLC) position between the actual treatment gantry angle and 0° may result in deviations from the planned dose. We evaluated the effects of MLC positioning errors between the actual treatment gantry angles and nominal gantry angles. A gantry angle correction (GAC) factor was generated by performing a non-gap test at various gantry angles using an electronic portal imaging device (EPID). To convert pixel intensity to dose at the MLC abutment positions, a non-gap test was performed using an EPID and a film at 0° gantry angle. We then assessed the correlations between pixel intensities and doses. Beam-by-beam analyses for 15 prostate IMRT cases as patient-specific quality assurance were performed with a 2D diode detector array at 0° gantry angle to determine the relative dose error for each beam. The resulting relative dose error with or without GAC was added back to the original dose grid for each beam. We compared the predicted dose distributions with or without GAC for film measurements to validate GAC effects. A gamma pass rate with a tolerance of 2%/2 mm was used to evaluate these dose distributions. The gamma pass rate with GAC was higher than that without GAC (P = 0.01). The predicted dose distribution improved with GAC, although the dosimetric effect to a patient was minimal. PMID:25742866

  20. Predicting astronaut radiation doses from major solar particle events using artificial intelligence

    NASA Astrophysics Data System (ADS)

    Tehrani, Nazila H.

    1998-06-01

    Space radiation is an important issue for manned space flight. For long missions outside of the Earth's magnetosphere, there are two major sources of exposure. Large Solar Particle Events (SPEs) consisting of numerous energetic protons and other heavy ions emitted by the Sun, and the Galactic Cosmic Rays (GCRs) that constitute an isotropic radiation field of low flux and high energy. In deep-space missions both SPEs and GCRs can be hazardous to the space crew. SPEs can provide an acute dose, which is a large dose over a short period of time. The acute doses from a large SPE that could be received by an astronaut with shielding as thick as a spacesuit maybe as large as 500 cGy. GCRs will not provide acute doses, but may increase the lifetime risk of cancer from prolonged exposures in a range of 40-50 cSv/yr. In this research, we are using artificial intelligence to model the dose-time profiles during a major solar particle event. Artificial neural networks are reliable approximators for nonlinear functions. In this study we design a dynamic network. This network has the ability to update its dose predictions as new input dose data is received while the event is occurring. To accomplish this temporal behavior of the system we use an innovative Sliding Time-Delay Neural Network (STDNN). By using a STDNN one can predict doses received from large SPEs while the event is happening. The parametric fits and actual calculated doses for the skin, eye and bone marrow are used. The parametric data set obtained by fitting the Weibull functional forms to the calculated dose points has been divided into two subsets. The STDNN has been trained using some of these parametric events. The other subset of parametric data and the actual doses are used for testing with the resulting weights and biases of the first set. This is done to show that the network can generalize. Results of this testing indicate that the STDNN is capable of predicting doses from events that it has not seen

  1. On the accuracy of dose prediction near metal fixation devices for spine SBRT.

    PubMed

    Cheng, Zhangkai J; Bromley, Regina M; Oborn, Brad; Carolan, Martin; Booth, Jeremy T

    2016-01-01

    The metallic fixations used in surgical procedures to support the spine mechani-cally usually consist of high-density materials. Radiation therapy to palliate spinal cord compression can include prophylactic inclusion of potential tumor around the site of such fixation devices. Determination of the correct density and shape of the spine fixation device has a direct effect on the dose calculation of the radiation field. Even with the application of modern computed tomography (CT), under- or overestimation of dose, both immediately next to the device and in the surround-ing tissues, can occur due to inaccuracies in the dose prediction algorithm. In this study, two commercially available dose prediction algorithms (Eclipse AAA and ACUROS), EGSnrc Monte Carlo, and GAFchromic film measurements were com-pared for a clinical spine SBRT case to determine their accuracy. An open six-field plan and a clinical nine-field IMRT plan were applied to a phantom containing a metal spine fixation device. Dose difference and gamma analysis were performed in and around the tumor region adjacent to the fixation device. Dose calculation inconsistency was observed in the open field plan. However, in the IMRT plan, the dose perturbation effect was not observed beyond 5 mm. Our results suggest that the dose effect of the metal fixation device to the spinal cord and the tumor volume is not observable, and all dose calculation algorithms evaluated can provide clinically acceptable accuracy in the case of spinal SBRT, with the tolerance of 95% for gamma criteria of 3%/3 mm. PMID:27167252

  2. Predicting standard-dose PET image from low-dose PET and multimodal MR images using mapping-based sparse representation.

    PubMed

    Wang, Yan; Zhang, Pei; An, Le; Ma, Guangkai; Kang, Jiayin; Shi, Feng; Wu, Xi; Zhou, Jiliu; Lalush, David S; Lin, Weili; Shen, Dinggang

    2016-01-21

    Positron emission tomography (PET) has been widely used in clinical diagnosis for diseases and disorders. To obtain high-quality PET images requires a standard-dose radionuclide (tracer) injection into the human body, which inevitably increases risk of radiation exposure. One possible solution to this problem is to predict the standard-dose PET image from its low-dose counterpart and its corresponding multimodal magnetic resonance (MR) images. Inspired by the success of patch-based sparse representation (SR) in super-resolution image reconstruction, we propose a mapping-based SR (m-SR) framework for standard-dose PET image prediction. Compared with the conventional patch-based SR, our method uses a mapping strategy to ensure that the sparse coefficients, estimated from the multimodal MR images and low-dose PET image, can be applied directly to the prediction of standard-dose PET image. As the mapping between multimodal MR images (or low-dose PET image) and standard-dose PET images can be particularly complex, one step of mapping is often insufficient. To this end, an incremental refinement framework is therefore proposed. Specifically, the predicted standard-dose PET image is further mapped to the target standard-dose PET image, and then the SR is performed again to predict a new standard-dose PET image. This procedure can be repeated for prediction refinement of the iterations. Also, a patch selection based dictionary construction method is further used to speed up the prediction process. The proposed method is validated on a human brain dataset. The experimental results show that our method can outperform benchmark methods in both qualitative and quantitative measures. PMID:26732849

  3. Predicting standard-dose PET image from low-dose PET and multimodal MR images using mapping-based sparse representation

    NASA Astrophysics Data System (ADS)

    Wang, Yan; Zhang, Pei; An, Le; Ma, Guangkai; Kang, Jiayin; Shi, Feng; Wu, Xi; Zhou, Jiliu; Lalush, David S.; Lin, Weili; Shen, Dinggang

    2016-01-01

    Positron emission tomography (PET) has been widely used in clinical diagnosis for diseases and disorders. To obtain high-quality PET images requires a standard-dose radionuclide (tracer) injection into the human body, which inevitably increases risk of radiation exposure. One possible solution to this problem is to predict the standard-dose PET image from its low-dose counterpart and its corresponding multimodal magnetic resonance (MR) images. Inspired by the success of patch-based sparse representation (SR) in super-resolution image reconstruction, we propose a mapping-based SR (m-SR) framework for standard-dose PET image prediction. Compared with the conventional patch-based SR, our method uses a mapping strategy to ensure that the sparse coefficients, estimated from the multimodal MR images and low-dose PET image, can be applied directly to the prediction of standard-dose PET image. As the mapping between multimodal MR images (or low-dose PET image) and standard-dose PET images can be particularly complex, one step of mapping is often insufficient. To this end, an incremental refinement framework is therefore proposed. Specifically, the predicted standard-dose PET image is further mapped to the target standard-dose PET image, and then the SR is performed again to predict a new standard-dose PET image. This procedure can be repeated for prediction refinement of the iterations. Also, a patch selection based dictionary construction method is further used to speed up the prediction process. The proposed method is validated on a human brain dataset. The experimental results show that our method can outperform benchmark methods in both qualitative and quantitative measures.

  4. Portal dose image prediction for in vivo treatment verification completely based on EPID measurements

    SciTech Connect

    Zijtveld, Mathilda van; Dirkx, Maarten; Breuers, Marcel; Boer, Hans; Heijmen, Ben de

    2009-03-15

    A high dosimetric accuracy is required for radiotherapy treatments where IMRT in combination with narrow treatment margins is applied to achieve optimally conformal dose distributions. In order to routinely verify the in vivo fluence delivery (i.e., during the actual patient treatment), our method for predicting portal dose images with a patient in the beam was validated. A unique feature of this method is that it is fully based on calibration measurements with an EPID. The portal dose image (PDI) behind a patient is dependent on the transmission of primary radiation through the patient and a contribution of scattered radiation from the patient. To derive both components, the patient geometry as observed in the planning CT scan is converted into an equivalent homogeneous phantom. A limited set of EPID measurements is required to derive the input parameters of this model. The accuracy of the in vivo PDI prediction was verified using measurements behind phantoms and four prostate cancer patients treated with IMRT. Behind homogeneous slab phantoms, the local differences between measured and predicted PDIs were within 2% inside the field, while behind a lung and a pelvic phantom, the agreement was within 3% or within 3 mm in regions with steep gradients. Outside the fields, the PDIs agreed within 2% of the global dose maximum. Evaluation of the in vivo PDI measurements behind patients showed that, on average, 87% of the pixels inside the field fulfilled the 3% local dose and 3 mm distance-to-agreement criteria. For half of the failing pixels the differences occurred due to changes in patient geometry with respect to the planning CT or due to beam attenuation by the treatment couch that was not accounted for. A fully EPID-based method for predicting portal dose images using the planning CT scan has been implemented and validated for phantoms and clinical patients.

  5. Monitor units are not predictive of neutron dose for high-energy IMRT

    PubMed Central

    2012-01-01

    Background Due to the substantial increase in beam-on time of high energy intensity-modulated radiotherapy (>10 MV) techniques to deliver the same target dose compared to conventional treatment techniques, an increased dose of scatter radiation, including neutrons, is delivered to the patient. As a consequence, an increase in second malignancies may be expected in the future with the application of intensity-modulated radiotherapy. It is commonly assumed that the neutron dose equivalent scales with the number of monitor units. Methods Measurements of neutron dose equivalent were performed for an open and an intensity-modulated field at four positions: inside and outside of the treatment field at 0.2 cm and 15 cm depth, respectively. Results It was shown that the neutron dose equivalent, which a patient receives during an intensity-modulated radiotherapy treatment, does not scale with the ratio of applied monitor units relative to an open field irradiation. Outside the treatment volume at larger depth 35% less neutron dose equivalent is delivered than expected. Conclusions The predicted increase of second cancer induction rates from intensity-modulated treatment techniques can be overestimated when the neutron dose is simply scaled with monitor units. PMID:22883384

  6. Prediction of in-phantom dose distribution using in-air neutron beam characteristics for BNCS

    SciTech Connect

    Verbeke, Jerome M.

    1999-12-14

    A monoenergetic neutron beam simulation study is carried out to determine the optimal neutron energy range for treatment of rheumatoid arthritis using radiation synovectomy. The goal of the treatment is the ablation of diseased synovial membranes in joints, such as knees and fingers. This study focuses on human knee joints. Two figures-of-merit are used to measure the neutron beam quality, the ratio of the synovium absorbed dose to the skin absorbed dose, and the ratio of the synovium absorbed dose to the bone absorbed dose. It was found that (a) thermal neutron beams are optimal for treatment, (b) similar absorbed dose rates and therapeutic ratios are obtained with monodirectional and isotropic neutron beams. Computation of the dose distribution in a human knee requires the simulation of particle transport from the neutron source to the knee phantom through the moderator. A method was developed to predict the dose distribution in a knee phantom from any neutron and photon beam spectra incident on the knee. This method was revealed to be reasonably accurate and enabled one to reduce by a factor of 10 the particle transport simulation time by modeling the moderator only.

  7. Clinical implementation of dose-volume histogram predictions for organs-at-risk in IMRT planning

    NASA Astrophysics Data System (ADS)

    Moore, K. L.; Appenzoller, L. M.; Tan, J.; Michalski, J. M.; Thorstad, W. L.; Mutic, S.

    2014-03-01

    True quality control (QC) of the planning process requires quantitative assessments of treatment plan quality itself, and QC in IMRT has been stymied by intra-patient anatomical variability and inherently complex three-dimensional dose distributions. In this work we describe the development of an automated system to reduce clinical IMRT planning variability and improve plan quality using mathematical models that predict achievable OAR DVHs based on individual patient anatomy. These models rely on the correlation of expected dose to the minimum distance from a voxel to the PTV surface, whereby a three-parameter probability distribution function (PDF) was used to model iso-distance OAR subvolume dose distributions. DVH models were obtained by fitting the evolution of the PDF with distance. Initial validation on clinical cohorts of 40 prostate and 24 head-and-neck plans demonstrated highly accurate model-based predictions for achievable DVHs in rectum, bladder, and parotid glands. By quantifying the integrated difference between candidate DVHs and predicted DVHs, the models correctly identified plans with under-spared OARs, validated by replanning all cases and correlating any realized improvements against the predicted gains. Clinical implementation of these predictive models was demonstrated in the PINNACLE treatment planning system by use of existing margin expansion utilities and the scripting functionality inherent to the system. To maintain independence from specific planning software, a system was developed in MATLAB to directly process DICOM-RT data. Both model training and patient-specific analyses were demonstrated with significant computational accelerations from parallelization.

  8. Per-beam, planar IMRT QA passing rates do not predict clinically relevant patient dose errors

    SciTech Connect

    Nelms, Benjamin E.; Zhen Heming; Tome, Wolfgang A.

    2011-02-15

    Purpose: The purpose of this work is to determine the statistical correlation between per-beam, planar IMRT QA passing rates and several clinically relevant, anatomy-based dose errors for per-patient IMRT QA. The intent is to assess the predictive power of a common conventional IMRT QA performance metric, the Gamma passing rate per beam. Methods: Ninety-six unique data sets were created by inducing four types of dose errors in 24 clinical head and neck IMRT plans, each planned with 6 MV Varian 120-leaf MLC linear accelerators using a commercial treatment planning system and step-and-shoot delivery. The error-free beams/plans were used as ''simulated measurements'' (for generating the IMRT QA dose planes and the anatomy dose metrics) to compare to the corresponding data calculated by the error-induced plans. The degree of the induced errors was tuned to mimic IMRT QA passing rates that are commonly achieved using conventional methods. Results: Analysis of clinical metrics (parotid mean doses, spinal cord max and D1cc, CTV D95, and larynx mean) vs IMRT QA Gamma analysis (3%/3 mm, 2/2, 1/1) showed that in all cases, there were only weak to moderate correlations (range of Pearson's r-values: -0.295 to 0.653). Moreover, the moderate correlations actually had positive Pearson's r-values (i.e., clinically relevant metric differences increased with increasing IMRT QA passing rate), indicating that some of the largest anatomy-based dose differences occurred in the cases of high IMRT QA passing rates, which may be called ''false negatives.'' The results also show numerous instances of false positives or cases where low IMRT QA passing rates do not imply large errors in anatomy dose metrics. In none of the cases was there correlation consistent with high predictive power of planar IMRT passing rates, i.e., in none of the cases did high IMRT QA Gamma passing rates predict low errors in anatomy dose metrics or vice versa. Conclusions: There is a lack of correlation between

  9. Dynamic interactions between hydrogeological and exposure parameters in daily dose prediction under uncertainty and temporal variability.

    PubMed

    Kumar, Vikas; de Barros, Felipe P J; Schuhmacher, Marta; Fernàndez-Garcia, Daniel; Sanchez-Vila, Xavier

    2013-12-15

    We study the time dependent interaction between hydrogeological and exposure parameters in daily dose predictions due to exposure of humans to groundwater contamination. Dose predictions are treated stochastically to account for an incomplete hydrogeological and geochemical field characterization, and an incomplete knowledge of the physiological response. We used a nested Monte Carlo framework to account for uncertainty and variability arising from both hydrogeological and exposure variables. Our interest is in the temporal dynamics of the total dose and their effects on parametric uncertainty reduction. We illustrate the approach to a HCH (lindane) pollution problem at the Ebro River, Spain. The temporal distribution of lindane in the river water can have a strong impact in the evaluation of risk. The total dose displays a non-linear effect on different population cohorts, indicating the need to account for population variability. We then expand the concept of Comparative Information Yield Curves developed earlier (see de Barros et al. [29]) to evaluate parametric uncertainty reduction under temporally variable exposure dose. Results show that the importance of parametric uncertainty reduction varies according to the temporal dynamics of the lindane plume. The approach could be used for any chemical to aid decision makers to better allocate resources towards reducing uncertainty. PMID:24011618

  10. Heliocentric Potential (HCP) Prediction Model for Nowscast of Aviation Radiation Dose

    NASA Astrophysics Data System (ADS)

    Hwang, Junga; Kim, Kyung-Chan; Dokgo, Kyunghwan; Choi, Enjin; Kim, Hang-Pyo

    2015-03-01

    It is well known that the space radiation dose over the polar route should be carefully considered especially when the space weather shows sudden disturbances such as CME and flares. The National Meteorological Satellite Center (NMSC) and Korea Astronomy and Space Science Institute (KASI) recently established a basis for a space radiation service for the public by developing a space radiation prediction model and heliocentric potential (HCP) prediction model. The HCP value is used as a critical input value of the CARI-6 and CARI-6M programs, which estimate the aviation route dose. The CARI-6/6M is the most widely used and confidential program that is officially provided by the U.S. Federal Aviation Administration (FAA). The HCP value is given one month late in the FAA official webpage, making it difficult to obtain real-time information on the aviation route dose. In order to overcome this limitation regarding time delay, we developed a HCP prediction model based on the sunspot number variation. In this paper, we focus on the purpose and process of our HCP prediction model development. Finally, we find the highest correlation coefficient of 0.9 between the monthly sunspot number and the HCP value with an eight month time shift.

  11. Analytic IMRT dose calculations utilizing Monte Carlo to predict MLC fluence modulation

    PubMed Central

    Mihaylov, I. B.; Lerma, F. A.; Wu, Y.; Siebers, J. V.

    2007-01-01

    A hybrid dose-computation method is designed which accurately accounts for multileaf collimator (MLC)-induced intensity modulation in intensity modulated radiation therapy (IMRT) dose calculations. The method employs Monte Carlo (MC) modeling to determine the fluence modulation caused by the delivery of dynamic or multisegmental (step-and-shoot) MLC fields, and a conventional dose-computation algorithm to estimate the delivered dose to a phantom or a patient. Thus, it determines the IMRT fluence prediction accuracy achievable by analytic methods in the limit that the analytic method includes all details of the MLC leaf transport and scatter. The hybrid method is validated and benchmarked by comparison with in-phantom film dose measurements, as well as dose calculations from two in-house, and two commercial treatment planning system analytic fluence estimation methods. All computation methods utilize the same dose algorithm to calculate dose to a phantom, varying only in the estimation of the MLC modulation of the incident photon energy fluence. Gamma analysis, with respect to measured two-dimensional (2D) dose planes, is used to benchmark each algorithm’s performance. The analyzed fields include static and dynamic test patterns, as well as fields from ten DMLC IMRT treatment plans (79 fields) and five SMLC treatment plans (29 fields). The test fields (fully closed MLC, picket fence, sliding windows of different size, and leaf-tip profiles) cover the extremes of MLC usage during IMRT, while the patient fields represent realistic clinical conditions. Of the methods tested, the hybrid method most accurately reproduces measurements. For the hybrid method, 79 of 79 DMLC field calculations have γ ≤1 (3% /3 mm) for more than 95% of the points (per field) while for SMLC fields, 27 of 29 pass the same criteria. The analytic energy fluence estimation methods show inferior pass rates, with 76 of 79 DMLC and 24 of 29 SMLC fields having more than 95% of the test points

  12. Inclusion of the treatment couch in portal dose image prediction for high precision EPID dosimetry

    SciTech Connect

    Ali, Ali Sid Ahmed M.; Dirkx, Maarten L. P.; Breuers, Marcel G. J.; Heijmen, Ben J. M.

    2011-01-15

    Purpose: When comparing predicted portal dose images (PDIs) to PDIs acquired by an EPID during treatment delivery, differences are often observed. These differences may be partially attributed to beam attenuation by parts of the treatment couch not taken into account in the PDI prediction. In order to improve the agreement, a model for the treatment couch was derived and included in the PDI prediction. Methods: A CT scan was used to model the couch top. The model for the couch top base was derived by iteratively matching the predicted and measured PDIs for gantry angles of 0 deg., 45 deg., and 90 deg. For PDI prediction, the modeled treatment couch was added to the CT scan of a patient or phantom by using the recorded couch positions from the record and verify system. To validate the couch model, PDI measurements were performed for a range of couch positions and gantry angles, both with and without an anatomical phantom in the beam. Results: After including the couch model in the PDI prediction for beams passing through the couch without phantom, the mean local dose differences between measured and predicted PDIs were reduced from up to 5.5% to less than 1.0% at each gantry angle. Similar results were obtained for measurements with a lung phantom on the couch. Although the couch model was originally derived by using a 6 MV photon beam, the results showed that it is also applicable for a 10 MV beam. Conclusions: A model of the treatment couch was derived and included in the PDI prediction, yielding a substantially improved agreement between measured and predicted PDIs, which makes interpretation of the observed deviations more straightforward.

  13. A two-dimensional matrix correction for off-axis portal dose prediction errors

    SciTech Connect

    Bailey, Daniel W.; Kumaraswamy, Lalith; Bakhtiari, Mohammad; Podgorsak, Matthew B.

    2013-05-15

    Purpose: This study presents a follow-up to a modified calibration procedure for portal dosimetry published by Bailey et al. ['An effective correction algorithm for off-axis portal dosimetry errors,' Med. Phys. 36, 4089-4094 (2009)]. A commercial portal dose prediction system exhibits disagreement of up to 15% (calibrated units) between measured and predicted images as off-axis distance increases. The previous modified calibration procedure accounts for these off-axis effects in most regions of the detecting surface, but is limited by the simplistic assumption of radial symmetry. Methods: We find that a two-dimensional (2D) matrix correction, applied to each calibrated image, accounts for off-axis prediction errors in all regions of the detecting surface, including those still problematic after the radial correction is performed. The correction matrix is calculated by quantitative comparison of predicted and measured images that span the entire detecting surface. The correction matrix was verified for dose-linearity, and its effectiveness was verified on a number of test fields. The 2D correction was employed to retrospectively examine 22 off-axis, asymmetric electronic-compensation breast fields, five intensity-modulated brain fields (moderate-high modulation) manipulated for far off-axis delivery, and 29 intensity-modulated clinical fields of varying complexity in the central portion of the detecting surface. Results: Employing the matrix correction to the off-axis test fields and clinical fields, predicted vs measured portal dose agreement improves by up to 15%, producing up to 10% better agreement than the radial correction in some areas of the detecting surface. Gamma evaluation analyses (3 mm, 3% global, 10% dose threshold) of predicted vs measured portal dose images demonstrate pass rate improvement of up to 75% with the matrix correction, producing pass rates that are up to 30% higher than those resulting from the radial correction technique alone. As in

  14. Importance of predicting the dose temporal profile for large solar energetic particle events

    NASA Astrophysics Data System (ADS)

    Neal, John S.; Nichols, Theodore F.; Townsend, Lawrence W.

    2008-09-01

    It has been proposed that proton intensities on the stream-limited plateau present a minimal radiation hazard to astronauts, and hazardous intensities occur upon coronal-mass-ejection-driven shock arrival at the spacecraft. Forecasts then need only predict the arrival time and severity of the shock prior to its arrival at the spacecraft. We evaluated dose to the bone marrow, eye, and skin for the largest events since 1996, in terms of the >10 MeV proton flux, prior to and after shock arrival. Doses at shock arrival were compared to the space-permissible exposure limits (SPELs), and for five of the seven events, limits were exceeded for aluminum shielding thicknesses up to 3 g cm-2 prior to the arrival of the shocks. The 30-d SPELs have been exceeded as early as 9 h after event initiation, but more generally, sometime between 20 and 50 h after event initiation. These results suggest that one cannot simply predict the arrival time and intensity of a shock if exceeding the 30-d SPELs is to be avoided. Similarly, waiting for the shock to arrive at a sentinel spacecraft such as the Advanced Composition Explorer to provide a 1-h warning of shock intensity may not prevent one from exceeding the 30-d SPELs. In order to predict when 30-d SPELs will be exceeded for a given event, one must forecast the dose temporal profile associated with that event.

  15. Tumor angiogenesis as prognostic and predictive marker for chemotherapy dose-intensification efficacy in high-risk breast cancer patients within the WSG AM-01 trial.

    PubMed

    Gluz, Oleg; Wild, Peter; Liedtke, Cornelia; Kates, Ronald; Mendrik, Heiko; Ehm, Elisabeth; Artinger, Verena; Diallo-Danebrock, Raihanatou; Ting, Evelyn; Mohrmann, Svjetlana; Poremba, Christopher; Harbeck, Nadia; Nitz, Ulrike; Hartmann, Arndt; Gaumann, Andreas

    2011-04-01

    The goal of this analysis was to characterize the survival impact of angiogenesis in the patients with high-risk breast cancer, particularly the predictive impact on benefit from dose intensification of adjuvant chemotherapy. Formalin-fixed tissue sample of 152 patients treated as part of the WSG AM-01 trial by either high-dose or conventional dose-dense chemotherapy were analyzed. Angiogenic activity was measured using microvessel count and vascular surface area (VSA) determined by the expression of vascular markers CD31 (n = 128) and CD105/endoglin (n = 130). Protein molecular breast cancer subclasses were analyzed by k-means clustering (k = 5). The univariate impact of factors on event-free (EFS) and overall survival (OS) was tested by log-rank statistics and quantified by univariate Cox analysis. Multivariate survival analysis included factors significant in univariate analysis, as well as interactions was performed for EFS. Both VSA/CD31 (P = 0.004) and VSA/CD105 (P = 0.003) were significantly higher among cases with increased Ki-67. A significant association with molecular subtypes was also found for VSA/CD105: in patients with basal-like/Her-2 subtypes, mean was 1.72 versus 1.24 in patients with other subtypes (P < 0.001). Elevated VSA/CD105 was associated with both significantly decreased EFS (P = 0.01) and OS (P = 0.02). Increased tumor size and positive Her-2 status were also prognostic for poorer EFS. The benefit of dose intensification for EFS was seen in those low-VSA/CD105 patients. The result was evident both in univariate and in multivariate survival analysis including all factors that were significant at the univariate level. Expression of angiogenesis markers may mirror or confer resistance to chemotherapy in the patients with breast cancer, particularly within the context of dose intensified chemotherapy. Highly angiogenic tumors may not derive sufficient benefit from dose intensification of chemotherapy alone. Our findings may serve as a

  16. [HEALTH PREDICTION INDICES OBTAINED WITH LOW-DOSE COMPUTER TOMOGRAPHY SCANS].

    PubMed

    Matkevich, E i; Sinitsyn, V e; Ivanov LV

    2015-01-01

    Purpose of the investigation was to make prognostic estimations of reductions in somatic morbidity and temporal disability, and tumor pathology using low-dose computer tomography (CT) scans and to compare with standard protocols. Mean effective radiation doses were determined based on the results of 1627 diagnostic CT investigations made in 2012-2014 at the Treatment and Rehabilitation Center of the Russian Ministry of Health. Low-dose CT scans of the head and thoracic, abdominal and small pelvis organs were obtained on a GE Discovery CT750 HD, and with the help of the ASIR and MBIR algorithms of iterative reconstruction. In comparison with a standard dose, a single CT scan with a dose reduced by 10-12 mSv predicts a decrease in total morbidity by 0.84-5.52% and temporal disability by 0.55-1.65% per 100 employees over a year; total risk of tumors and genetic effects reduced in 5 to 10 times, which may be equal to 40-90 cases per 100,000 of 30 y.o. males. PMID:26934792

  17. Cellular response of the rat brain to single doses of 137Cs γ rays does not predict its response to prolonged ‘biologically equivalent’ fractionated doses

    PubMed Central

    Greene-Schloesser, Dana M.; Kooshki, Mitra; Payne, Valerie; D’Agostino, Ralph B.; Wheeler, Kenneth T.; Metheny-Barlow, Linda J.; Robbins, Mike E.

    2014-01-01

    Purpose To determine if the brain’s response to single doses predicts its response to ‘biologically equivalent’ fractionated doses. Methods Young adult male Fischer 344 rats were whole-brain irradiated with either single 11, 14, or 16.5 Gy doses of 137Cs γ rays or their ‘biologically equivalent’ 20, 30, or 40 Gy fractionated doses (fWBI) delivered in 5 Gy fractions, twice/week for 2, 3, or 4 weeks, respectively. At 2 months post-irradiation, cellular markers of inflammation (total, activated, and newborn microglia) and neurogenesis (newborn neurons) were measured in 40 µm sections of the dentate gyrus (DG). Results Although the total number of microglia in the DG/hilus was not significantly different (p > 0.7) in unirradiated, single dose, and fWBI rats, single doses produced a significant (p < 0.003) increase in the percent-activated microglia; fWBI did not (p > 0.1). Additionally, single doses produced a significant (p < 0.002) dose-dependent increase in surviving newborn microglia; fWBI did not (p < 0.8). Although total proliferation in the DG was reduced equally by single and fWBI doses, single doses produced a significant dose-dependent (p < 0.02) decrease in surviving newborn neurons; fWBI did not (p > 0.6). Conclusions These data demonstrate that the rat brain’s cellular response to single doses often does not predict its cellular response to ‘biologically equivalent’ fWBI doses. PMID:24937374

  18. Geometric dose prediction model for hemithoracic intensity-modulated radiation therapy in mesothelioma patients with two intact lungs.

    PubMed

    Kuo, LiCheng; Yorke, Ellen D; Dumane, Vishruta A; Foster, Amanda; Zhang, Zhigang; Mechalakos, James G; Wu, Abraham J; Rosenzweig, Kenneth E; Rimner, Andreas

    2016-01-01

    The presence of two intact lungs makes it challenging to reach a tumoricidal dose with hemithoracic pleural intensity-modulated radiation therapy (IMRT) in patients with malignant pleural mesothelioma (MPM) who underwent pleurectomy/decor-tications or have unresectable disease. We developed an anatomy-based model to predict attainable prescription dose before starting optimization. Fifty-six clinically delivered IMRT plans were analyzed regarding correlation of prescription dose and individual and total lung volumes, planning target volume (PTV), ipsilateral normal lung volume and ratios: contralateral/ipsilateral lung (CIVR); contralateral lung/PTV (CPVR); ipsilateral lung /PTV (IPVR); ipsilateral normal lung /total lung (INTLVR); ipsilateral normal lung/PTV (INLPVR). Spearman's rank correlation and Fisher's exact test were used. Correlation between mean ipsilateral lung dose (MILD) and these volume ratios and between prescription dose and single lung mean doses were studied. The prediction models were validated in 23 subsequent MPM patients. CIVR showed the strongest correlation with dose (R = 0.603, p < 0.001) and accurately predicted prescription dose in the validation cases. INLPVR and MILD as well as MILD and prescription dose were significantly correlated (R = -0.784, p < 0.001 and R = 0.554, p < 0.001, respectively) in the training and validation cases. Parameters obtainable directly from planning scan anatomy predict achievable prescription doses for hemithoracic IMRT treatment of MPM patients with two intact lungs. PMID:27167294

  19. Significance of certain rustler aquifer parameters for predicting long-term radiation doses from WIPP

    SciTech Connect

    Wofsy, C

    1980-09-01

    This report considers some aspects of the radionuclide transport modeling presented in documents published by the US Department of Energy (DOE) regarding the Waste Isolation Pilot Plant (WIPP) nuclear waste repository proposed for development in Southeastern New Mexico. The radionuclide transport modeling is used to predict worst possible consequences of a WIPP repository breach event in which waste enters groundwater. The aim of this report is to determine whether plausible changes in the parameters used by DOE to describe the flow of groundwater near the WIPP site could result in: (a) significantly faster radionuclide movement in groundwater; and (b) significantly higher concentrations of radionuclides in Pecos River water and correspondingly higher radiation doses than predicted by DOE. The conclusion reached is that while plausible changes in hydrologic conditions and waste-rock interactions might result in a significant reduction in the time it takes for radionuclides to reach the Pecos River, the shorter travel times do not result in significant increases in the estimated concentrations of radionuclides in the Pecos River nor in the radiation doses associated with the use of such water. Other ways in which parameter changes might affect these concentrations and doses are mentioned in the Conclusions section of the report, but are not the subject of this analysis.

  20. Factors for Predicting Rectal Dose of High-Dose-Rate Intracavitary Brachytherapy After Pelvic Irradiation in Patients With Cervical Cancer: A Retrospective Study With Radiography-Based Dosimetry

    SciTech Connect

    Huang Engyen; Wang Chongjong; Lan Jenhong; Chen Huichun; Fang Fumin; Hsu, H.-C.; Huang Yujie; Wang Changyu; Wang Yuming

    2010-02-01

    Purpose: To evaluate the predictive factors for rectal dose of the first fraction of high-dose-rate intracavitary brachytherapy (HDR-ICBT) in patients with cervical cancer. Methods and Materials: From March 1993 through February 2008, 946 patients undergoing pelvic irradiation and HDR-ICBT were analyzed. Examination under anesthesia (EUA) at the first implantation of the applicator was usually performed in the early period. Rectal point was determined radiographically according to the 38th Report of the International Commission of Radiation Units and Measurements (ICRU). The ICRU rectal dose (PRD) as a percentage of point A dose was calculated; multiple linear regression models were used to predict PRD. Results: Factors influencing successful rectal dose calculation were EUA (p < 0.001) and absence of diabetes (p = 0.047). Age (p < 0.001), body weight (p = 0.002), diabetes (p = 0.020), and EUA (p < 0.001) were independent factors for the PRD. The predictive equation derived from the regression model was PRD (%) = 57.002 + 0.443 x age (years) - 0.257 x body weight (kg) + 6.028 x diabetes (no: 0; yes: 1) - 8.325 x EUA (no: 0; yes: 1) Conclusion: Rectal dose at the first fraction of HDR-ICBT is positively influenced by age and diabetes, and negatively correlated with EUA and body weight. A small fraction size at point A may be considered in patients with a potentially high rectal dose to reduce the biologically effective dose if the ICRU rectal dose has not been immediately obtained in the first fraction of HDR-ICBT.

  1. Dose-distance metric that predicts late rectal bleeding in patients receiving radical prostate external-beam radiotherapy

    NASA Astrophysics Data System (ADS)

    Lee, Richard; Chan, Elisa K.; Kosztyla, Robert; Liu, Mitchell; Moiseenko, Vitali

    2012-12-01

    The relationship between rectal dose distribution and the incidence of late rectal complications following external-beam radiotherapy has been previously studied using dose-volume histograms or dose-surface histograms. However, they do not account for the spatial dose distribution. This study proposes a metric based on both surface dose and distance that can predict the incidence of rectal bleeding in prostate cancer patients treated with radical radiotherapy. One hundred and forty-four patients treated with radical radiotherapy for prostate cancer were prospectively followed to record the incidence of grade ≥2 rectal bleeding. Radiotherapy plans were used to evaluate a dose-distance metric that accounts for the dose and its spatial distribution on the rectal surface, characterized by a logistic weighting function with slope a and inflection point d0. This was compared to the effective dose obtained from dose-surface histograms, characterized by the parameter n which describes sensitivity to hot spots. The log-rank test was used to determine statistically significant (p < 0.05) cut-off values for the dose-distance metric and effective dose that predict for the occurrence of rectal bleeding. For the dose-distance metric, only d0 = 25 and 30 mm combined with a > 5 led to statistical significant cut-offs. For the effective dose metric, only values of n in the range 0.07-0.35 led to statistically significant cut-offs. The proposed dose-distance metric is a predictor of rectal bleeding in prostate cancer patients treated with radiotherapy. Both the dose-distance metric and the effective dose metric indicate that the incidence of grade ≥2 rectal bleeding is sensitive to localized damage to the rectal surface.

  2. Absorbed Dose Determination Using Experimental and Analytical Predictions of X-Ray Spectra

    NASA Technical Reports Server (NTRS)

    Edwards, D. L.; Carruth, Ralph (Technical Monitor)

    2001-01-01

    Electron beam welding in a vacuum is a technology that NASA is investigating as a joining technique for manufacture of space structures. This investigation characterizes the x-ray environment due to operation of an in-vacuum electron beam welding tool and provides recommendations for adequate shielding for astronauts performing the in-vacuum electron beam welding. NASA, in a joint venture with the Russian Space Agency, was scheduled to perform a series of welding in space experiments on board the U.S. Space Shuttle. This series of experiments was named the international space welding experiment (ISWE). The hardware associated with the ISWE was leased to NASA by the Paton Welding Institute (PWI) in Ukraine for ground-based welding experiments in preparation for flight. Two ground tests were scheduled, using the ISWE electron beam welding tool, to characterize the radiation exposure to an astronaut during the operation of the ISWE. These radiation exposure tests used thermoluminescence dosimeters (TLD's) shielded with material currently used by astronauts during extravehicular activities to measure the radiation dose. The TLD's were exposed to x-ray radiation generated by operation of the ISWE in-vacuum electron beam welding tool. This investigation was the first known application of TLD's to measure absorbed dose from x rays of energy less than 10 keV. The ISWE hardware was returned to Ukraine before the issue of adequate shielding for the astronauts was completely verified. Therefore, alternate experimental and analytical methods were developed to measure and predict the x-ray spectral and intensity distribution generated by ISWE electron beam impact with metal. These x-ray spectra were normalized to an equivalent ISWE exposure, then used to calculate the absorbed radiation dose to astronauts. These absorbed dose values were compared to TLD measurements obtained during actual operation of the ISWE in-vacuum electron beam welding tool. The calculated absorbed dose

  3. BIODOSE: a code for predicting the dose to man from radionuclides released from underground nuclear waste repositories

    SciTech Connect

    Bonner, N.A.; Ng, Y.C.

    1980-03-01

    The BIODOSE computer program simulates the environmental transport of radionuclides released to surface water and predicts the resulting dosage to humans. This report describes the program and discusses its use in the evaluation of nuclear waste repositories. The methods used to estimate dose are examined critically, and the most important parameters in each stage of the calculations are identified as an aid in planning for measurements in the field. Dose predictions from releases of nuclear waste to a large northwestern river (the baseline river) are presented to point out the nuclides, compartments and pathways that contribute most to the hazard as a function of waste storage time. Predictions for five other water systems are presented to identify the most important system parameters that determine the concentrations of individual nuclides in compartments and the resultant dose. The uncertainties in the biological parameters for dose prediction are identified, and changes in current values are suggested. Various ways of reporting dose estimates for radiological safety assessments are discussed. Additional work needed to improve the dose predictions from BIODOSE and specific areas and steps to improve our capabilities to assess the environmental transport of nuclides released from nuclear waste repositories and the resultant dose to man are suggested.

  4. Method for the prediction of the effective dose equivalent to the crew of the International Space Station

    NASA Astrophysics Data System (ADS)

    El-Jaby, Samy; Tomi, Leena; Sihver, Lembit; Sato, Tatsuhiko; Richardson, Richard B.; Lewis, Brent J.

    2014-03-01

    This paper describes a methodology for assessing the pre-mission exposure of space crew aboard the International Space Station (ISS) in terms of an effective dose equivalent. In this approach, the PHITS Monte Carlo code was used to assess the particle transport of galactic cosmic radiation (GCR) and trapped radiation for solar maximum and minimum conditions through an aluminum shield thickness. From these predicted spectra, and using fluence-to-dose conversion factors, a scaling ratio of the effective dose equivalent rate to the ICRU ambient dose equivalent rate at a 10 mm depth was determined. Only contributions from secondary neutrons, protons, and alpha particles were considered in this analysis. Measurements made with a tissue equivalent proportional counter (TEPC) located at Service Module panel 327, as captured through a semi-empirical correlation in the ISSCREM code, where then scaled using this conversion factor for prediction of the effective dose equivalent. This analysis shows that at this location within the service module, the total effective dose equivalent is 10-30% less than the total TEPC dose equivalent. Approximately 75-85% of the effective dose equivalent is derived from the GCR. This methodology provides an opportunity for pre-flight predictions of the effective dose equivalent and therefore offers a means to assess the health risks of radiation exposure on ISS flight crew.

  5. Error prediction of LiF-TLD used for gamma dose measurement for BNCT.

    PubMed

    Liu, H M; Liu, Y H

    2011-12-01

    To predict the neutron influence on various (6)LiF concentration in the LiF-TLD, the Monte Carlo code MCNP was adopted to simulate the energy deposition on a TLD chip with dimensions of 3.2×3.2×0.9 mm. By assuming that the TL response is proportional to the energy deposition on it, the percentage error of LiF-TLD used for gamma dose measurement in mixed (n, γ) fields can be written as: %Error=R(n)/R(g)×100%. Where R(n) and R(g) are the TL responses resulted from neutron and gamma, respectively. Taking the water phantom irradiated with the BNCT facility at the Tsing Hua Open-pool Reactor (THOR) as an example, the (6)LiF concentration for TLD-700 is 0.007%, the magnitude of the neutron flux is ~1×10(9) n/cm(2)/s, the neutron energy is ~4×10(-7) MeV (cadmium cut-off energy), the gamma dose rate is ~3 Gy/h, thus the percentage error can be predicted as 38%. PMID:21489808

  6. Poorer Prognosis With Ethylenediaminetetraacetic Acid-dependent Pseudothrombocytopenia

    PubMed Central

    Ohashi-Fukuda, Naoko; Inokuchi, Ryota; Sato, Hajime; Nakamura, Kensuke; Iwagami, Masao; Wada, Tomoki; Jona, Masahiro; Hisasue, Takashi; Nakajima, Susumu; Yahagi, Naoki

    2015-01-01

    Abstract In ethylenediaminetetraacetic acid (EDTA)-dependent pseudothrombocytopenia (PTCP), automated platelet counts are lower than actual counts because of EDTA-induced aggregation. Factors contributing to the incidence of EDTA-PTCP are unknown, and no study has assessed the prognosis of EDTA-PTCP patients. This retrospective study assessed characteristics in EDTA-PTCP patients and matched controls to determine differences in prognosis. A retrospective case–control study was designed. From the University of Tokyo Hospital database, we identified patients diagnosed with EDTA-PTCP between 2009 and 2012, and performed 1:2 case:control matching for age and sex. A control group of sex- and age-matched patients was selected at random from the same database. We investigated differences in the frequency of complications, medication history, and blood transfusion history between the groups at the time of blood collection. Prognosis was evaluated using multivariate Cox regression analysis adjusting for age, sex, autoimmune disease, liver disease, and malignant tumor. We identified 104 EDTA-PTCP patients and 208 matched controls. The median age was 69.0 years (interquartile range: 54–76), with men comprising 51%. EDTA-PTCP patients had a higher frequency of malignant tumor and a lower frequency of hypertension and diabetes than controls. After adjustment for background factors, prognosis of EDTA-PTCP patients was significantly poorer than controls (hazard ratio, 11.8; 95% confidence intervals, 2.62–53.54). In conclusion, EDTA-PTCP patients had higher mortality, and EDTA-PTCP may need to be recognized as an indicator of worse prognosis. PMID:25881844

  7. Incorporating system latency associated with real-time target tracking radiotherapy in the dose prediction step

    NASA Astrophysics Data System (ADS)

    Roland, Teboh; Mavroidis, Panayiotis; Shi, Chengyu; Papanikolaou, Nikos

    2010-05-01

    System latency introduces geometric errors in the course of real-time target tracking radiotherapy. This effect can be minimized, for example by the use of predictive filters, but cannot be completely avoided. In this work, we present a convolution technique that can incorporate the effect as part of the treatment planning process. The method can be applied independently or in conjunction with the predictive filters to compensate for residual latency effects. The implementation was performed on TrackBeam (Initia Ltd, Israel), a prototype real-time target tracking system assembled and evaluated at our Cancer Institute. For the experimental system settings examined, a Gaussian distribution attributable to the TrackBeam latency was derived with σ = 3.7 mm. The TrackBeam latency, expressed as an average response time, was deduced to be 172 ms. Phantom investigations were further performed to verify the convolution technique. In addition, patient studies involving 4DCT volumes of previously treated lung cancer patients were performed to incorporate the latency effect in the dose prediction step. This also enabled us to effectively quantify the dosimetric and radiobiological impact of the TrackBeam and other higher latency effects on the clinical outcome of a real-time target tracking delivery.

  8. Post-radioembolization yttrium-90 PET/CT - part 2: dose-response and tumor predictive dosimetry for resin microspheres

    PubMed Central

    2013-01-01

    Background Coincidence imaging of low-abundance yttrium-90 (90Y) internal pair production by positron emission tomography with integrated computed tomography (PET/CT) achieves high-resolution imaging of post-radioembolization microsphere biodistribution. Part 2 analyzes tumor and non-target tissue dose-response by 90Y PET quantification and evaluates the accuracy of tumor 99mTc macroaggregated albumin (MAA) single-photon emission computed tomography with integrated CT (SPECT/CT) predictive dosimetry. Methods Retrospective dose quantification of 90Y resin microspheres was performed on the same 23-patient data set in part 1. Phantom studies were performed to assure quantitative accuracy of our time-of-flight lutetium-yttrium-oxyorthosilicate system. Dose-responses were analyzed using 90Y dose-volume histograms (DVHs) by PET voxel dosimetry or mean absorbed doses by Medical Internal Radiation Dose macrodosimetry, correlated to follow-up imaging or clinical findings. Intended tumor mean doses by predictive dosimetry were compared to doses by 90Y PET. Results Phantom studies demonstrated near-perfect detector linearity and high tumor quantitative accuracy. For hepatocellular carcinomas, complete responses were generally achieved at D70 > 100 Gy (D70, minimum dose to 70% tumor volume), whereas incomplete responses were generally at D70 < 100 Gy; smaller tumors (<80 cm3) achieved D70 > 100 Gy more easily than larger tumors. There was complete response in a cholangiocarcinoma at D70 90 Gy and partial response in an adrenal gastrointestinal stromal tumor metastasis at D70 53 Gy. In two patients, a mean dose of 18 Gy to the stomach was asymptomatic, 49 Gy caused gastritis, 65 Gy caused ulceration, and 53 Gy caused duodenitis. In one patient, a bilateral kidney mean dose of 9 Gy (V20 8%) did not cause clinically relevant nephrotoxicity. Under near-ideal dosimetric conditions, there was excellent correlation between intended tumor mean doses by predictive dosimetry and those

  9. Prediction of dose and field mapping around a shielded plutonium fuel fabrication glovebox

    SciTech Connect

    Strode, J.N.; Soldat, K.L.; Brackenbush, L.W.

    1984-04-25

    Westinghouse Hanford Company, as the Department of Energy's (DOE) prime contractor for the operation of the Hanford Engineering Development Laboratory (HEDL), is responsible for the development of the Secure Automated Fabrication (SAF) Line which is to be installed in the recently constructed Fuels and Materials Examination Facility (FMEF). The SAF Line will fabricate mixed-oxide (MOX) fuel pins for the Fast Flux Test Facility (FFTF) at an annual throughput rate of six (6) metric tons (MT) of MOX. The SAF Line will also demonstrate the automated manufacture of fuel pins on a production-scale. This paper describes some of the techniques used to reduce personnel exposure on the SAF Line, as well as the prediction and field mapping of doses from a shielded fuel fabrication glovebox. Tables are also presented from which exposure rate estimates can be made for plutonium recovered from fuels having different isotopic compositions as a result of varied burnup.

  10. Optimal dosing of cancer chemotherapy using model predictive control and moving horizon state/parameter estimation.

    PubMed

    Chen, Tao; Kirkby, Norman F; Jena, Raj

    2012-12-01

    Model predictive control (MPC), originally developed in the community of industrial process control, is a potentially effective approach to optimal scheduling of cancer therapy. The basis of MPC is usually a state-space model (a system of ordinary differential equations), whereby existing studies usually assume that the entire states can be directly measured. This paper aims to demonstrate that when the system states are not fully measurable, in conjunction with model parameter discrepancy, MPC is still a useful method for cancer treatment. This aim is achieved through the application of moving horizon estimation (MHE), an optimisation-based method to jointly estimate the system states and parameters. The effectiveness of the MPC-MHE scheme is illustrated through scheduling the dose of tamoxifen for simulated tumour-bearing patients, and the impact of estimation horizon and magnitude of parameter discrepancy is also investigated. PMID:22739208

  11. Predicting physical stability in pressurized metered dose inhalers via dwell and instantaneous force colloidal probe microscopy.

    PubMed

    D'Sa, Dexter; Chan, Hak-Kim; Chrzanowski, Wojciech

    2014-09-01

    Colloidal probe microscopy (CPM) is a quantitative predictive tool, which can offer insight into particle behavior in suspension pressurized metered dose inhalers (pMDIs). Although CPM instantaneous force measurements, which involve immediate retraction of the probe upon sample contact, can provide information on inter-particle attractive forces, they lack the ability to appropriately imitate all critical particle pMDI interactions (e.g., particle re-dispersion after prolonged pMDI storage). In this paper, two novel dwell force techniques - indentation and deflection dwell - were employed to mimic long-term particle interactions present in pMDIs, using particles of various internal structures and a model liquid propellant (2H,3H perfluoropentane) as a model system. Dwell measurements involve particle contact for an extended period of time. In deflection dwell mode the probe is held at a specific position, while in indentation dwell mode the probe is forced into the sample with a constant force for the entirety of the contact time. To evaluate the applicability of CPM to predict actual pMDI physical stability, inter-particle force measurements were compared with qualitative and quantitative bulk pMDI measurement techniques (visual quality and light scattering). Measured instantaneous attractive (snap-in) and adhesive (max-pull) forces decreased as a function of increasing surface area, while adhesive forces measured by indentation dwell decreased as a function of dwell contact time for particles containing voids. Instantaneous force measurements provided information on the likelihood of floccule formation, which was predictive of partitioning rates, while indentation dwell force measurements were predictive of formulation re-dispersibility after prolonged storage. Dwell force measurements provide additional information on particle behavior within a pMDI not obtainable via instantaneous measurements. PMID:25058596

  12. Sludge reduction at low ozone doses: predictive effects and full-scale study.

    PubMed

    Romero, P; Coello, M D; Aragón, C A; Eusebi, A L

    2015-01-01

    The activated sludge process is the most widely used wastewater treatment. The main drawback of this technology is the excess sludge production (ESP). The ozonation of sludge of the recirculation line is used to reduce the ESP. In this study, ozonation was applied on a fraction of sludge of the recirculation line in a full-scale plant (50,000 population equivalent) at a lower-specific ozone dose (SOD) compared to previous studies. The results of batch tests to predict the main effect of the technology on the biomass activities are reported. Specifically, tests at 0.7-5 g O₃/kg MLVSS (mixed liquor volatile suspended solids) doses were made to evaluate the changes of the nitrification and denitrification rates, the population of phosphate-accumulating organisms and the gravitational properties. A certain reduction of the impact of ozonation on the kinetic parameters of sludge for values of SOD over 2 g O₃/kg MLVSS was found. The present study highlights also the use of the ratio of ozonated biomass to total biomass as an important operative parameter for ozonation in full-scale plants. Reduction in ESP in the wastewater treatment plant was equal to 10% as dry solids applying a SOD from 1.03 to 1.63 g O₃/kg MLVSS. An analysis of the economic cost of the technique is also reported. PMID:25633941

  13. PREDICTING THE RISKS OF NEUROTOXIC VOLATILE ORGANIC COMPOUNDS BASED ON TARGET TISSUE DOSE.

    EPA Science Inventory

    Quantitative exposure-dose-response models relate the external exposure of a substance to the dose in the target tissue, and then relate the target tissue dose to production of adverse outcomes. We developed exposure-dose-response models to describe the affects of acute exposure...

  14. Late Fecal Incontinence After High-Dose Radiotherapy for Prostate Cancer: Better Prediction Using Longitudinal Definitions

    SciTech Connect

    Fiorino, Claudio; Rancati, Tiziana; Fellin, Gianni; Vavassori, Vittorio; Cagna, Emanuela; Casanova Borca, Valeria; Girelli, Giuseppe; Menegotti, Loris; Monti, Angelo Filippo; Tortoreto, Francesca; Delle Canne, Stefania; Valdagni, Riccardo

    2012-05-01

    Purpose: To model late fecal incontinence after high-dose prostate cancer radiotherapy (RT) in patients accrued in the AIROPROS (prostate working group of the Italian Association of Radiation Oncology) 0102 trial using different endpoint definitions. Methods and Materials: The self-reported questionnaires (before RT, 1 month after RT, and every 6 months for {<=}3 years after RT) of 586 patients were available. The peak incontinence (P{sub I}NC) and two longitudinal definitions (chronic incontinence [C{sub I}NC], defined as the persistence of Grade 1 or greater incontinence after any Grade 2-3 event; and mean incontinence score [M{sub I}NC], defined as the average score during the 3-year period after RT) were considered. The correlation between the clinical/dosimetric parameters (including rectal dose-volume histograms) and P{sub I}NC (Grade 2 or greater), C{sub I}NC, and M{sub I}NC of {>=}1 were investigated using multivariate logistic analyses. Receiver operating characteristic curves and the area under the curve were used to assess the predictive value of the different multivariate models. Results: Of the 586 patients, 36 with a Grade 1 or greater incontinence score before RT were not included in the present analysis. Of the 550 included patients, 197 (35.8%) had at least one control with a Grade 1 or greater incontinence score (M{sub I}NC >0). Of these 197 patients, 37 (6.7%), 22 (4.0%), and 17 (3.1%) were scored as having P{sub I}NC, M{sub I}NC {>=}1, and C{sub I}NC, respectively. On multivariate analysis, Grade 2 or greater acute incontinence was the only predictor of P{sub I}NC (odds ratio [OR], 5.9; p = .0009). Grade 3 acute incontinence was predictive of C{sub I}NC (OR, 9.4; p = .02), and percentage of the rectal volume receiving >40 Gy of {>=}80% was predictive of a M{sub I}NC of {>=}1 (OR, 3.8; p = .008) and of C{sub I}NC (OR, 3.6; p = .03). Previous bowel disease, previous abdominal/pelvic surgery, and the use of antihypertensive (protective factor

  15. The prediction of radiation-induced liver dysfunction using a local dose and regional venous perfusion model

    SciTech Connect

    Cao Yue; Platt, Joel F.; Francis, Isaac R; Balter, James M.; Pan, Charlie; Normolle, Daniel; Ben-Josef, Edgar; Haken, Randall K. ten; Lawrence, Theodore S.

    2007-02-15

    We have shown that high dose conformal radiation combined with chemotherapy appears to prolong the survival of patients with unresectable intrahepatic cancers. The ability to safely deliver higher doses is primarily limited by the development of radiation-induced liver disease, characterized by venous occlusion. In this study, we investigated whether portal venous perfusion measured prior to the end of radiation therapy (RT) together with dose could predict liver venous perfusion dysfunction after treatment. Ten patients with unresectable intrahepatic cancer participated in an IRB-approved computer tomography (CT) perfusion study. Hepatic arterial and portal vein perfusion distributions were estimated by using dynamic contrast enhanced CT and the single compartmental model. Scans were obtained at four time points: prior to treatment, after 15 and 30 fractions of 1.5 Gy treatments, and one month following the completion of RT. Multivariant linear regression was used to determine covariances among the first three time point measurements plus dose for prediction of the post RT measurement. The reduction in the regional venous perfusion one month following RT was predicted by the local accumulated dose and the change in the regional venous perfusion after {approx}30 fractions (F=90.6,p<0.000 01). Each Gy produced an approximately 1.2% of reduction in the venous perfusion. This local dose and venous perfusion model has the potential to predict individual sensitivity to radiation. This is the first step toward developing a method to deliver higher and potentially more curative radiation doses to the patients who can safely receive these higher doses.

  16. Prediction of maintenance dose required to attain a desired drug concentration at steady-state from a single determination of concentration after an initial dose.

    PubMed

    Slattery, J T; Gibaldi, M; Koup, J R

    1980-01-01

    Strong correlations have been reported between drug concentrations at steady-state and a single drug concentration determined sometime after an initial dose for lithium, nortriptyline, imipramine, desipramine, choramphenicol and theophylline. The mathematical basis of these relationships suggests that a one point method for predicting steady-state drug concentrations and individual dosing requirements should be widely applicable to most drugs and should be valid for patients having a wide range of drug half-lives. A method is presented for evaluating the optimum time of blood sampling to determine a drug concentration in serum of plasma that best correlates with steady-state levels and for defining the range of drug half-lives beyond which the predictive approach is likely to give poor results. PMID:7398172

  17. Development and verification of an analytical algorithm to predict absorbed dose distributions in ocular proton therapy using Monte Carlo simulations

    NASA Astrophysics Data System (ADS)

    Koch, Nicholas C.; Newhauser, Wayne D.

    2010-02-01

    Proton beam radiotherapy is an effective and non-invasive treatment for uveal melanoma. Recent research efforts have focused on improving the dosimetric accuracy of treatment planning and overcoming the present limitation of relative analytical dose calculations. Monte Carlo algorithms have been shown to accurately predict dose per monitor unit (D/MU) values, but this has yet to be shown for analytical algorithms dedicated to ocular proton therapy, which are typically less computationally expensive than Monte Carlo algorithms. The objective of this study was to determine if an analytical method could predict absolute dose distributions and D/MU values for a variety of treatment fields like those used in ocular proton therapy. To accomplish this objective, we used a previously validated Monte Carlo model of an ocular nozzle to develop an analytical algorithm to predict three-dimensional distributions of D/MU values from pristine Bragg peaks and therapeutically useful spread-out Bragg peaks (SOBPs). Results demonstrated generally good agreement between the analytical and Monte Carlo absolute dose calculations. While agreement in the proximal region decreased for beams with less penetrating Bragg peaks compared with the open-beam condition, the difference was shown to be largely attributable to edge-scattered protons. A method for including this effect in any future analytical algorithm was proposed. Comparisons of D/MU values showed typical agreement to within 0.5%. We conclude that analytical algorithms can be employed to accurately predict absolute proton dose distributions delivered by an ocular nozzle.

  18. Poorer verbal working memory for a second language selectively impacts academic achievement in university medical students.

    PubMed

    Mann, Collette; Canny, Benedict J; Reser, David H; Rajan, Ramesh

    2013-01-01

    Working memory (WM) is often poorer for a second language (L2). In low noise conditions, people listening to a language other than their first language (L1) may have similar auditory perception skills for that L2 as native listeners, but do worse in high noise conditions, and this has been attributed to the poorer WM for L2. Given that WM is critical for academic success in children and young adults, these speech in noise effects have implications for academic performance where the language of instruction is L2 for a student. We used a well-established Speech-in-Noise task as a verbal WM (vWM) test, and developed a model correlating vWM and measures of English proficiency and/or usage to scholastic outcomes in a multi-faceted assessment medical education program. Significant differences in Speech-Noise Ratio (SNR50) values were observed between medical undergraduates who had learned English before or after five years of age, with the latter group doing worse in the ability to extract whole connected speech in the presence of background multi-talker babble (Student-t tests, p < 0.001). Significant negative correlations were observed between the SNR50 and seven of the nine variables of English usage, learning styles, stress, and musical abilities in a questionnaire administered to the students previously. The remaining two variables, Perceived Stress Scale (PSS) and the Age of Acquisition of English (AoAoE) were significantly positively correlated with the SNR50, showing that those with a poorer capacity to discriminate simple English sentences from noise had learnt English later in life and had higher levels of stress - all characteristics of the international students. Local students exhibited significantly lower SNR50 scores and were significantly younger when they first learnt English. No significant correlation was detected between the SNR50 and the students' Visual/Verbal Learning Style (r = -0.023). Standard multiple regression was carried out to assess

  19. Poorer verbal working memory for a second language selectively impacts academic achievement in university medical students

    PubMed Central

    Canny, Benedict J.; Reser, David H.; Rajan, Ramesh

    2013-01-01

    Working memory (WM) is often poorer for a second language (L2). In low noise conditions, people listening to a language other than their first language (L1) may have similar auditory perception skills for that L2 as native listeners, but do worse in high noise conditions, and this has been attributed to the poorer WM for L2. Given that WM is critical for academic success in children and young adults, these speech in noise effects have implications for academic performance where the language of instruction is L2 for a student. We used a well-established Speech-in-Noise task as a verbal WM (vWM) test, and developed a model correlating vWM and measures of English proficiency and/or usage to scholastic outcomes in a multi-faceted assessment medical education program. Significant differences in Speech-Noise Ratio (SNR50 ) values were observed between medical undergraduates who had learned English before or after five years of age, with the latter group doing worse in the ability to extract whole connected speech in the presence of background multi-talker babble (Student-t tests, p < 0.001). Significant negative correlations were observed between the SNR50 and seven of the nine variables of English usage, learning styles, stress, and musical abilities in a questionnaire administered to the students previously. The remaining two variables, Perceived Stress Scale (PSS) and the Age of Acquisition of English (AoAoE) were significantly positively correlated with the SNR50 , showing that those with a poorer capacity to discriminate simple English sentences from noise had learnt English later in life and had higher levels of stress – all characteristics of the international students. Local students exhibited significantly lower SNR50 scores and were significantly younger when they first learnt English. No significant correlation was detected between the SNR50 and the students’ Visual/Verbal Learning Style (r = −0.023). Standard multiple regression was carried out to

  20. Predictive factors of head and neck squamous cell carcinoma patient tolerance to high-dose cisplatin in concurrent chemoradiotherapy

    PubMed Central

    NAKANO, KENJI; SATO, YASUYOSHI; TOSHIYASU, TAKASHI; SATO, YUKIKO; INAGAKI, LINA; TOMOMATSU, JUNICHI; SASAKI, TORU; SHIMBASHI, WATARU; FUKUSHIMA, HIROFUMI; YONEKAWA, HIROYUKI; MITANI, HIROKI; KAWABATA, KAZUYOSHI; TAKAHASHI, SHUNJI

    2016-01-01

    Although high-dose cisplatin is the standard regimen of concurrent chemoradiotherapy (CCRT) for locally advanced head and neck squamous cell carcinoma (HNSCC), varying levels of patient tolerance towards cisplatin have been reported, and the predictive factors of cisplatin tolerance remain to be elucidated. The present study retrospectively reviewed newly diagnosed HNSCC patients who received CCRT. Cisplatin (80 mg/m2) was administered every 3 weeks. The proportion of high-dose cisplatin-tolerant patients (cumulative cisplatin dose, ≥200 mg/m2) was determined, and the predictive factors of cisplatin tolerance were analyzed in a logistic regression analysis. Between June 2006 and March 2013, a total of 159 patients were treated with CCRT. The median follow-up time was 36.7 months. A total of 73 patients (46%) tolerated a cumulative cisplatin dose ≥200 mg/m2; male gender [odds ratio (OR), 25.00; P=0.005] and high body surface area (BSA) (>1.80 m2; OR, 2.21; P=0.032) were significantly predictive of high-dose cisplatin tolerance. The high-dose cisplatin-tolerant patients had a significantly higher complete response (CR) rate (82 vs. 67%, P=0.045); however, there were no significant between-group differences in the 3-year OS (79.5 vs. 81.2%, P=0.59) or PFS (70.4 vs. 44.6%, P=0.076) by cisplatin tolerance. In clinical practice, approximately one-half of the patients tolerated high-dose cisplatin in CCRT. Male gender and high BSA could be predictive of cisplatin tolerance. PMID:26893880

  1. LINKING DERMAL MODELING AND LOADING DATA TO PREDICT LONG-TERM DOSES FROM INTERMITTENT DERMAL CONTACT

    EPA Science Inventory

    In this paper we assess dermal exposure and dose resulting from intermittent contact with residue-contaminated surfaces. These estimates require an understanding of (1) the quantitative relationship between exposure and absorbed dose; (2) the impact of intermittent exposure on ...

  2. Bladder (ICRU) dose point does not predict urinary acute toxicity in adjuvant isolated vaginal vault high-dose-rate brachytherapy for intermediate-risk endometrial cancer

    PubMed Central

    Aiza, Antonio; Gomes, Maria José Leite; Chen, Michael Jenwei; Pellizzon, Antonio Cassio de Assis; Mansur, David B.; Baiocchi, Glauco

    2015-01-01

    Purpose High-dose-rate brachytherapy (HDR-BT) alone is an adjuvant treatment option for stage I intermediaterisk endometrial cancer after complete surgical resection. The aim of this study was to determine the value of the dose reported to ICRU bladder point in predicting acute urinary toxicity. Oncologic results are also presented. Material and methods One hundred twenty-six patients were treated with postoperative HDR-BT 24 Gy (4 × 6 Gy) per ICRU guidelines for dose reporting. Cox analysis was used to identify variables that affected local control. The mean bladder point dose was examined for its ability to predict acute urinary toxicity. Results Two patients (1.6%) developed grade 1 gastrointestinal toxicity and 12 patients (9.5%) developed grades 1-2 urinary toxicity. No grade 3 or greater toxicity was observed. The mean bladder point dose was 46.9% (11.256 Gy) and 49.8% (11.952 Gy) for the asymptomatic and symptomatic groups, respectively (p = 0.69). After a median follow-up of 36.8 months, the 3-year local failure and 5-year cancer-specific and overall survival rates were 2.1%, 100%, and 94.6%, respectively. No pelvic failure was seen in this cohort. Age over 60 years (p = 0.48), lymphatic invasion (p = 0.77), FIGO histological grade (p = 0.76), isthmus invasion (p = 0.68), and applicator type (cylinder × ovoid) (p = 0.82) did not significantly affect local control. Conclusions In this retrospective study, ICRU bladder point did not correlate with urinary toxicity. Four fractions of 6 Gy HDR-BT effected satisfactory local control, with acceptable urinary and gastrointestinal toxicity. PMID:26622241

  3. Sarcopenia Predicts Early Dose-Limiting Toxicities and Pharmacokinetics of Sorafenib in Patients with Hepatocellular Carcinoma

    PubMed Central

    Mir, Olivier; Coriat, Romain; Blanchet, Benoit; Durand, Jean-Philippe; Boudou-Rouquette, Pascaline; Michels, Judith; Ropert, Stanislas; Vidal, Michel; Pol, Stanislas; Chaussade, Stanislas; Goldwasser, François

    2012-01-01

    Background Sorafenib induces frequent dose limiting toxicities (DLT) in patients with advanced hepatocellular carcinoma (HCC). Sarcopenia has been associated with poor performance status and shortened survival in cancer patients. Patients and Methods The characteristics of Child Pugh A cirrhotic patients with HCC receiving sorafenib in our institution were retrospectively analyzed. Sorafenib plasma concentrations were determined at each visit. Toxicities were recorded during the first month of treatment, and sarcopenia was determined from baseline CT-scans. Results Forty patients (30 males) were included. Eleven (27.5%) were sarcopenic. Eighteen patients (45%) experienced a DLT during the first month of treatment. Sarcopenic patients experienced significantly more DLTs than non-sarcopenic patients did (82% versus 31%, p = 0.005). Grade 3 diarrhea was significantly more frequent in sarcopenic patients than in non-sarcopenic patients (45.5% versus 6.9%, p = 0.01), but not grade 3 hand foot syndrome reaction (9% versus 17.2%, p = 1). On day 28, median sorafenib AUC (n = 17) was significantly higher in sarcopenic patients (102.4 mg/l.h versus 53.7 mg/l.h, p = 0.013). Conclusions Among cirrhotic Child Pugh A patients with advanced HCC, sarcopenia predicts sorafenib exposure and the occurrence of DLT within the first month of treatment. PMID:22666367

  4. Dose-response curve slope helps predict therapeutic potency and breadth of HIV broadly neutralizing antibodies.

    PubMed

    Webb, Nicholas E; Montefiori, David C; Lee, Benhur

    2015-01-01

    A new generation of HIV broadly neutralizing antibodies (bnAbs) with remarkable potency, breadth and epitope diversity has rejuvenated interest in immunotherapeutic strategies. Potencies defined by in vitro IC50 and IC80 values (50 and 80% inhibitory concentrations) figure prominently into the selection of clinical candidates; however, much higher therapeutic levels will be required to reduce multiple logs of virus and impede escape. Here we predict bnAb potency at therapeutic levels by analysing dose-response curve slopes, and show that slope is independent of IC50/IC80 and specifically relates to bnAb epitope class. With few exceptions, CD4-binding site and V3-glycan bnAbs exhibit slopes >1, indicative of higher expected therapeutic effectiveness, whereas V2-glycan, gp41 membrane-proximal external region (MPER) and gp120-gp41 bnAbs exhibit less favourable slopes <1. Our results indicate that slope is one major predictor of both potency and breadth for bnAbs at clinically relevant concentrations, and may better coordinate the relationship between bnAb epitope structure and therapeutic expectations. PMID:26416571

  5. Critical Combinations of Radiation Dose and Volume Predict IQ and Academic Achievement Scores after Craniospinal Irradiation in Children with Medulloblastoma

    PubMed Central

    Merchant, Thomas E.; Schreiber, Jane E.; Wu, Shengjie; Lukose, Renin; Xiong, Xiaoping; Gajjar, Amar

    2016-01-01

    Purpose To prospectively follow children treated with craniospinal irradiation to determine critical combinations of radiation dose and volume that would predict for cognitive effects. Methods and Materials Between 1996 and 2003, 58 patients (median age 8.14 years, range 3.99–20.11 years) with medulloblastoma received risk-adapted CSI followed by dose-intense chemotherapy and were followed longitudinally with multiple cognitive evaluations (through 5 years post-treatment) that included IQ (estimated-EIQ, full-scale, verbal and performance) and academic achievement (math, reading, spelling) tests. CSI consisted of 23.4Gy for average-risk patients (non-metastatic) and 36–39.6Gy for high-risk patients (metastatic or residual disease > 1.5cm2). The primary site was treated using conformal or intensity-modulated radiation therapy using a 2cm clinical target volume margin. The effect of clinical variables and radiation dose to different brain volumes were modeled to estimate cognitive scores after treatment. Results A decline with time for all test scores was observed for the entire cohort. Sex, race and CSF shunt status had a significant impact on baseline scores. Age and mean radiation dose to specific brain volumes, including the temporal lobes and hippocampi, had a significant impact on longitudinal scores. Dichotomized dose distributions at 25Gy, 35Gy, 45Gy and 55Gy were modeled to show the impact of the high-dose volume on longitudinal test scores. The 50% risk of a below-normal cognitive test score was calculated according to mean dose and dose intervals between 25Gy and 55Gy at 10Gy increments according to brain volume and age. Conclusions The ability to predict cognitive outcomes in children with medulloblastoma using dose-effects models for different brain sub-volumes will improve treatment planning, guide intervention, and help estimate the value of newer methods of irradiation. PMID:25160611

  6. Optimal dose reduction in computed tomography methodologies predicted from real-time dosimetry

    NASA Astrophysics Data System (ADS)

    Tien, Christopher Jason

    Over the past two decades, computed tomography (CT) has become an increasingly common and useful medical imaging technique. CT is a noninvasive imaging modality with three-dimensional volumetric viewing abilities, all in sub-millimeter resolution. Recent national scrutiny on radiation dose from medical exams has spearheaded an initiative to reduce dose in CT. This work concentrates on dose reduction of individual exams through two recently-innovated dose reduction techniques: organ dose modulation (ODM) and tube current modulation (TCM). ODM and TCM tailor the phase and amplitude of x-ray current, respectively, used by the CT scanner during the scan. These techniques are unique because they can be used to achieve patient dose reduction without any appreciable loss in image quality. This work details the development of the tools and methods featuring real-time dosimetry which were used to provide pioneering measurements of ODM or TCM in dose reduction for CT.

  7. Development of Dose-Response Models to Predict the Relationship for Human Toxoplasma gondii Infection Associated with Meat Consumption.

    PubMed

    Guo, Miao; Mishra, Abhinav; Buchanan, Robert L; Dubey, Jitender P; Hill, Dolores E; Gamble, H Ray; Jones, Jeffrey L; Du, Xianzhi; Pradhan, Abani K

    2016-05-01

    Toxoplasma gondii is a protozoan parasite that is responsible for approximately 24% of deaths attributed to foodborne pathogens in the United States. It is thought that a substantial portion of human T. gondii infections is acquired through the consumption of meats. The dose-response relationship for human exposures to T. gondii-infected meat is unknown because no human data are available. The goal of this study was to develop and validate dose-response models based on animal studies, and to compute scaling factors so that animal-derived models can predict T. gondii infection in humans. Relevant studies in literature were collected and appropriate studies were selected based on animal species, stage, genotype of T. gondii, and route of infection. Data were pooled and fitted to four sigmoidal-shaped mathematical models, and model parameters were estimated using maximum likelihood estimation. Data from a mouse study were selected to develop the dose-response relationship. Exponential and beta-Poisson models, which predicted similar responses, were selected as reasonable dose-response models based on their simplicity, biological plausibility, and goodness fit. A confidence interval of the parameter was determined by constructing 10,000 bootstrap samples. Scaling factors were computed by matching the predicted infection cases with the epidemiological data. Mouse-derived models were validated against data for the dose-infection relationship in rats. A human dose-response model was developed as P (d) = 1-exp (-0.0015 × 0.005 × d) or P (d) = 1-(1 + d × 0.003 / 582.414)(-1.479) . Both models predict the human response after consuming T. gondii-infected meats, and provide an enhanced risk characterization in a quantitative microbial risk assessment model for this pathogen. PMID:26477997

  8. Prediction of In-Phantom Dose Distribution Using In-Air Neutron Beam Characteristics for Boron Neutron Capture Synovectomy

    SciTech Connect

    Verbeke, Jerome M.; Chen, Allen S.; Vujic, Jasmina L.; Leung, Ka-Ngo

    2000-08-15

    A monoenergetic neutron beam simulation study was carried out to determine the optimal neutron energy range for treatment of rheumatoid arthritis using radiation synovectomy. The goal of the treatment is the ablation of diseased synovial membranes in joints such as knees and fingers. This study focuses on human knee joints. Two figures of merit are used to measure the neutron beam quality, the ratio of the synovium-absorbed dose to the skin-absorbed dose, and the ratio of the synovium-absorbed dose to the bone-absorbed dose. It was found that (a) thermal neutron beams are optimal for treatment and that (b) similar absorbed dose rates and therapeutic ratios are obtained with monodirectional and isotropic neutron beams. Computation of the dose distribution in a human knee requires the simulation of particle transport from the neutron source to the knee phantom through the moderator. A method was developed to predict the dose distribution in a knee phantom from any neutron and photon beam spectra incident on the knee. This method was revealed to be reasonably accurate and enabled one to reduce the particle transport simulation time by a factor of 10 by modeling the moderator only.

  9. Low dose dobutamine stress echocardiography predicts the improvement of left ventricular systolic function in dilated cardiomyopathy

    PubMed Central

    Kitaoka, H; Takata, J; Yabe, T; Hitomi, N; Furuno, T; Doi, Y

    1999-01-01

    OBJECTIVE—To determine whether dobutamine stress echocardiography can predict the improvement of left ventricular systolic function in patients with dilated cardiomyopathy (DCM).
METHODS—Myocardial contractile reserve, as assessed by dobutamine stress echocardiography, was determined in 18 patients with DCM (mean (SD) age 53 (13) years, left ventricular ejection fraction (LVEF) 28 (10)%) and compared with changes in LVEF during a follow up period of 15 (8) months. The LVEF and regional left ventricular wall motion score (0, normal to 4, dyskinesis) of 12 segments in short axis and four chamber views were analysed before and after dobutamine infusion (5-20 µg/kg/min).
RESULTS—During a follow up period of 15 (8) months, a significant improvement in LVEF (> 20%) was found in seven patients but not in the remaining 11. Baseline haemodynamic findings were similar in both groups. Patients with an improvement in follow up LVEF showed a greater change in wall motion score from baseline during dobutamine infusion than patients with no improvement (at rest, 1.7 (0.4) v 1.9 (0.2), NS; dobutamine 10 µg/kg/min, 0.6 (0.4) v 1.2 (0.4), p < 0.05). The percentage change in LVEF during dobutamine infusion was also significantly greater in patients who showed improvement than in those who did not. The change in LVEF during the follow up period (follow up LVEF/baseline LVEF) correlated well with the change in LVEF during dobutamine stress (LVEF at rest/LVEF at dobutamine 10 µg/kg/min; r = 0.74, p < 0.001).
CONCLUSIONS—Changes in left ventricular systolic performance during low dose dobutamine stress echocardiography are a useful marker to predict the outcome of left ventricular systolic function in patients with DCM.


Keywords: dilated cardiomyopathy; dobutamine stress echocardiography; contractile reserve PMID:10212172

  10. Predicted and observed therapeutic dose exceedances of ionizable pharmaceuticals in fish plasma from urban coastal systems.

    PubMed

    Scott, W Casan; Du, Bowen; Haddad, Samuel P; Breed, Christopher S; Saari, Gavin N; Kelly, Martin; Broach, Linda; Chambliss, C Kevin; Brooks, Bryan W

    2016-04-01

    Instream flows of the rapidly urbanizing watersheds and estuaries of the Gulf of Mexico in Texas (USA) are increasingly dominated by reclaimed waters. Though ionizable pharmaceuticals have received increasing attention in freshwaters, many research questions remain unanswered, particularly in tidally influenced urban coastal systems, which experience significant spatiotemporal variability in pH that influences bioavailability and bioaccumulation. The authors coupled fish plasma modeling of therapeutic hazard values with field monitoring of water chemistry variability and pharmaceutical occurrence to examine whether therapeutic hazards to fish existed within these urban coastal ecosystems and whether therapeutic hazards differed within and among coastal locations and seasons. Spatial and temporal fluctuations in pH within study sites altered the probability of encountering pharmaceutical hazards to fish. Significant water quality differences were consistently observed among traditional parameters and pharmaceuticals collected from surface and bottom waters, which are rarely sampled during routine surface water quality assessments. The authors then compared modeling predictions of fish plasma concentrations of pharmaceuticals to measured plasma levels from various field-collected fish species. Diphenhydramine and diltiazem were observed in plasma of multiple species, and diltiazem exceeded human therapeutic doses in largemouth bass, catfish, and mullet inhabiting these urban estuaries. Though the present study only examined a small number of target analytes, which represent a microcosm of the exposome of these fish, coastal systems are anticipated to be more strongly influenced by continued urbanization, altered instream flows, and population growth in the future. Unfortunately, aquatic toxicology information for diltiazem and many other pharmaceuticals is not available for marine and estuarine organisms, but such field observations suggest that potential adverse

  11. Incorporating single-side sparing in models for predicting parotid dose sparing in head and neck IMRT

    SciTech Connect

    Yuan, Lulin Wu, Q. Jackie; Yin, Fang-Fang; Yoo, David; Jiang, Yuliang; Ge, Yaorong

    2014-02-15

    Purpose: Sparing of single-side parotid gland is a common practice in head-and-neck (HN) intensity modulated radiation therapy (IMRT) planning. It is a special case of dose sparing tradeoff between different organs-at-risk. The authors describe an improved mathematical model for predicting achievable dose sparing in parotid glands in HN IMRT planning that incorporates single-side sparing considerations based on patient anatomy and learning from prior plan data. Methods: Among 68 HN cases analyzed retrospectively, 35 cases had physician prescribed single-side parotid sparing preferences. The single-side sparing model was trained with cases which had single-side sparing preferences, while the standard model was trained with the remainder of cases. A receiver operating characteristics (ROC) analysis was performed to determine the best criterion that separates the two case groups using the physician's single-side sparing prescription as ground truth. The final predictive model (combined model) takes into account the single-side sparing by switching between the standard and single-side sparing models according to the single-side sparing criterion. The models were tested with 20 additional cases. The significance of the improvement of prediction accuracy by the combined model over the standard model was evaluated using the Wilcoxon rank-sum test. Results: Using the ROC analysis, the best single-side sparing criterion is (1) the predicted median dose of one parotid is higher than 24 Gy; and (2) that of the other is higher than 7 Gy. This criterion gives a true positive rate of 0.82 and a false positive rate of 0.19, respectively. For the bilateral sparing cases, the combined and the standard models performed equally well, with the median of the prediction errors for parotid median dose being 0.34 Gy by both models (p = 0.81). For the single-side sparing cases, the standard model overestimates the median dose by 7.8 Gy on average, while the predictions by the combined

  12. High-dimensional pharmacogenetic prediction of a continuous trait using machine learning techniques with application to warfarin dose prediction in African Americans

    PubMed Central

    Cosgun, Erdal; Limdi, Nita A.; Duarte, Christine W.

    2011-01-01

    Motivation: With complex traits and diseases having potential genetic contributions of thousands of genetic factors, and with current genotyping arrays consisting of millions of single nucleotide polymorphisms (SNPs), powerful high-dimensional statistical techniques are needed to comprehensively model the genetic variance. Machine learning techniques have many advantages including lack of parametric assumptions, and high power and flexibility. Results: We have applied three machine learning approaches: Random Forest Regression (RFR), Boosted Regression Tree (BRT) and Support Vector Regression (SVR) to the prediction of warfarin maintenance dose in a cohort of African Americans. We have developed a multi-step approach that selects SNPs, builds prediction models with different subsets of selected SNPs along with known associated genetic and environmental variables and tests the discovered models in a cross-validation framework. Preliminary results indicate that our modeling approach gives much higher accuracy than previous models for warfarin dose prediction. A model size of 200 SNPs (in addition to the known genetic and environmental variables) gives the best accuracy. The R2 between the predicted and actual square root of warfarin dose in this model was on average 66.4% for RFR, 57.8% for SVR and 56.9% for BRT. Thus RFR had the best accuracy, but all three techniques achieved better performance than the current published R2 of 43% in a sample of mixed ethnicity, and 27% in an African American sample. In summary, machine learning approaches for high-dimensional pharmacogenetic prediction, and for prediction of clinical continuous traits of interest, hold great promise and warrant further research. Contact: cduarte@uab.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:21450715

  13. Pharmacokinetic-Pharmacodynamic Model for Gentamicin and Its Adaptive Resistance with Predictions of Dosing Schedules in Newborn Infants

    PubMed Central

    Nielsen, Elisabet I.; Cars, Otto; Friberg, Lena E.

    2012-01-01

    Gentamicin is commonly used in the management of neonatal infections. Development of adaptive resistance is typical for aminoglycosides and reduces the antibacterial effect. There is, however, a lack of understanding of how this phenomenon influences the effect of different dosing schedules. The aim was to develop a pharmacokinetic-pharmacodynamic (PKPD) model that describes the time course of the bactericidal activity of gentamicin and its adaptive resistance and to investigate different dosing schedules in preterm and term newborn infants based on the developed model. In vitro time-kill curve experiments were conducted on a strain of Escherichia coli (MIC of 2 mg/liter). The gentamicin exposure was either constant (0.125 to 16 mg/liter) or dynamic (simulated concentration-time profiles in a kinetic system with peak concentrations of 2.0, 3.9, 7.8, and 16 mg/liter given as single doses or as repeated doses every 6, 12, or 24 h). Semimechanistic PKPD models were fitted to the bacterial counts in the NONMEM (nonlinear mixed effects modeling) program. A model with compartments for growing and resting bacteria, with a function allowing the maximal bacterial killing of gentamicin to reduce with exposure, characterized both the fast bactericidal effect and the adaptive resistance. Despite a lower peak concentration, preterm neonates were predicted to have a higher bacterial killing effect than term neonates for the same per-kg dose because of gentamicin's longer half-life. The model supported an extended dosing interval of gentamicin in preterm neonates, and for all neonates, dosing intervals of 36 to 48 h were as effective as a 24-h dosing interval for the same total dose. PMID:22037853

  14. Pharmacokinetic-pharmacodynamic model for gentamicin and its adaptive resistance with predictions of dosing schedules in newborn infants.

    PubMed

    Mohamed, Ami F; Nielsen, Elisabet I; Cars, Otto; Friberg, Lena E

    2012-01-01

    Gentamicin is commonly used in the management of neonatal infections. Development of adaptive resistance is typical for aminoglycosides and reduces the antibacterial effect. There is, however, a lack of understanding of how this phenomenon influences the effect of different dosing schedules. The aim was to develop a pharmacokinetic-pharmacodynamic (PKPD) model that describes the time course of the bactericidal activity of gentamicin and its adaptive resistance and to investigate different dosing schedules in preterm and term newborn infants based on the developed model. In vitro time-kill curve experiments were conducted on a strain of Escherichia coli (MIC of 2 mg/liter). The gentamicin exposure was either constant (0.125 to 16 mg/liter) or dynamic (simulated concentration-time profiles in a kinetic system with peak concentrations of 2.0, 3.9, 7.8, and 16 mg/liter given as single doses or as repeated doses every 6, 12, or 24 h). Semimechanistic PKPD models were fitted to the bacterial counts in the NONMEM (nonlinear mixed effects modeling) program. A model with compartments for growing and resting bacteria, with a function allowing the maximal bacterial killing of gentamicin to reduce with exposure, characterized both the fast bactericidal effect and the adaptive resistance. Despite a lower peak concentration, preterm neonates were predicted to have a higher bacterial killing effect than term neonates for the same per-kg dose because of gentamicin's longer half-life. The model supported an extended dosing interval of gentamicin in preterm neonates, and for all neonates, dosing intervals of 36 to 48 h were as effective as a 24-h dosing interval for the same total dose. PMID:22037853

  15. Age-related differences in sequential modulations of poorer-strategy effects.

    PubMed

    Lemaire, Patrick; Hinault, Thomas

    2014-01-01

    To determine how younger and older adults modulate execution of strategies across successive trials, we asked participants to accomplish a computational estimation task (i.e., provide approximate products to two-digit multiplication problems like 38 × 74). For each problem, they were cued to execute a better versus a poorer strategy. Their performance revealed sequential modulations of poorer-strategy effects (i.e., longer solution times and larger error rates when asked to execute a poorer than a better strategy). That is, poorer-strategy effects were smaller on current problems after using a poorer strategy on preceding problems than after using a better strategy. Moreover, sequential modulations of these poorer-strategy effects were smaller in older than in younger adults, especially older adults with low-cognitive control skills (as measured by conflict adaptation effects in the Simon task). Our findings suggest that these sequential modulations may result from executive control mechanisms, the efficiency of which is known to decrease in older adults. These findings have important implications regarding mechanisms underlying strategy execution and aging effects on strategic variations. PMID:24217137

  16. Prediction of lethal/effective concentration/dose in the presence of multiple auxiliary covariates and components of variance

    USGS Publications Warehouse

    Gutreuter, S.; Boogaard, M.A.

    2007-01-01

    Predictors of the percentile lethal/effective concentration/dose are commonly used measures of efficacy and toxicity. Typically such quantal-response predictors (e.g., the exposure required to kill 50% of some population) are estimated from simple bioassays wherein organisms are exposed to a gradient of several concentrations of a single agent. The toxicity of an agent may be influenced by auxiliary covariates, however, and more complicated experimental designs may introduce multiple variance components. Prediction methods lag examples of those cases. A conventional two-stage approach consists of multiple bivariate predictions of, say, medial lethal concentration followed by regression of those predictions on the auxiliary covariates. We propose a more effective and parsimonious class of generalized nonlinear mixed-effects models for prediction of lethal/effective dose/concentration from auxiliary covariates. We demonstrate examples using data from a study regarding the effects of pH and additions of variable quantities 2???,5???-dichloro-4???- nitrosalicylanilide (niclosamide) on the toxicity of 3-trifluoromethyl-4- nitrophenol to larval sea lamprey (Petromyzon marinus). The new models yielded unbiased predictions and root-mean-squared errors (RMSEs) of prediction for the exposure required to kill 50 and 99.9% of some population that were 29 to 82% smaller, respectively, than those from the conventional two-stage procedure. The model class is flexible and easily implemented using commonly available software. ?? 2007 SETAC.

  17. Early childhood attention deficit hyperactivity disorder predicts poorer response to acute lithium therapy in adolescent mania.

    PubMed

    Strober, M; DeAntonio, M; Schmidt-Lackner, S; Freeman, R; Lampert, C; Diamond, J

    1998-11-01

    We compared the response to acute lithium therapy in 30 adolescents, 13-17 years of age, with mania and a prior history of early childhood attention deficit hyperactivity disorder (ADHD) to a sex- and age-matched control group of adolescent manics without premorbid psychiatric illness. Response to treatment was assessed daily over the course of 28 days using measures of global clinical improvement and severity ratings on the Bech-Rafaelsen Mania Scale (BRMS). BRMS scores decreased by a mean of 24.3 in the subgroup without prior ADHD compared to 16.7 in patients with ADHD (P = 0.0005). The average percent drop in BRMS scores over the study period in these two subgroups was 80.6% and 57.7%, respectively (P = 0.0005). Time to onset of sustained global clinical improvement was also assessed using Kaplan-Meier survival methods and possible covariates of time to improvement were tested in a Cox proportional hazards model. Median time to onset of sustained improvement was lengthened significantly in patients with early ADHD (23 days) compared to those without it (17 days; log rank chi2 = 7.2, P = 0.007). The results suggest that early childhood ADHD defines an important source of heterogeneity in bipolar illness with developmental, clinical, and neuropharmacogenetic implications. PMID:10743847

  18. Greater emotional arousal predicts poorer long-term memory of communication skills in couples

    PubMed Central

    Baucom, Brian R.; Weusthoff, Sarah; Atkins, David; Hahlweg, Kurt

    2012-01-01

    Many studies have examined the importance of learning skills in behaviorally based couple interventions but none have examined predictors of long-term memory for skills. Associations between emotional arousal and long-term recall of communication skills delivered to couples during a behaviorally based relationship distress prevention program were examined in a sample of 49 German couples. Fundamental frequency (f0), a vocal measure of encoded emotional arousal, was measured during pre-treatment couple conflict. Higher levels of f0 were linked to fewer skills remembered 11 years after completing the program, and women remembered more skills than men. Implications of results for behaviorally based couple interventions are discussed. PMID:22542535

  19. Higher Levels of Psychopathy Predict Poorer Motor Control: Implications for Understanding the Psychopathy Construct

    PubMed Central

    Robinson, Michael D.; Bresin, Konrad

    2014-01-01

    A review of the literature suggests that higher levels of psychopathy may be linked to less effective behavioral control. However, several commentators have urged caution in making statements of this type in the absence of direct evidence. In two studies (total N = 142), moment-to-moment accuracy in a motor control task was examined as a function of dimensional variations in psychopathy in an undergraduate population. As hypothesized, motor control was distinctively worse at higher levels of psychopathy relative to lower levels, both as a function of primary and secondary psychopathy and particularly their shared variance. These novel findings provide support for the idea that motor control systematically varies by psychopathy, in a basic manner, consistent with views of psychopathy emphasizing lesser control. PMID:25419045

  20. Prediction of Optimal Reversal Dose of Sugammadex after Rocuronium Administration in Adult Surgical Patients

    PubMed Central

    Iwasaki, Hiroshi

    2014-01-01

    The objective of this study was to determine the point after sugammadex administration at which sufficient or insufficient dose could be determined, using first twitch height of train-of-four (T1 height) or train-of-four ratio (TOFR) as indicators. Groups A and B received 1 mg/kg and 0.5 mg/kg of sugammadex, respectively, as a first dose when the second twitch reappeared in train-of-four stimulation, and Groups C and D received 1 mg/kg and 0.5 mg/kg of sugammadex, respectively, as the first dose at posttetanic counts 1–3. Five minutes after the first dose, an additional 1 mg/kg of sugammadex was administered and changes in T1 height and TOFR were observed. Patients were divided into a recovered group and a partly recovered group, based on percentage changes in T1 height after additional dosing. T1 height and TOFR during the 5 min after first dose were then compared. In the recovered group, TOFR exceeded 90% in all patients at 3 min after sugammadex administration. In the partly recovered group, none of the patients had a TOFR above 90% at 3 min after sugammadex administration. An additional dose of sugammadex can be considered unnecessary if the train-of-four ratio is ≥90% at 3 min after sugammadex administration. This trial is registered with UMIN000007245. PMID:24672542

  1. Dose-Volume Parameters Predict for the Development of Chest Wall Pain After Stereotactic Body Radiation for Lung Cancer

    SciTech Connect

    Mutter, Robert W.; Liu Fan; Abreu, Andres; Yorke, Ellen; Jackson, Andrew; Rosenzweig, Kenneth E.

    2012-04-01

    Purpose: Chest wall (CW) pain has recently been recognized as an important adverse effect of stereotactic body radiation therapy (SBRT) for non-small-cell lung cancer (NSCLC). We developed a dose-volume model to predict the development of this toxicity. Methods and Materials: A total of 126 patients with primary, clinically node-negative NSCLC received three to five fractions of SBRT to doses of 40-60 Gy and were prospectively followed. The dose-absolute volume histograms of two different definitions of the CW as an organ at risk (CW3cm and CW2cm) were examined for all 126 patients. Results: With a median follow-up of 16 months, the 2-year estimated actuarial incidence of Grade {>=} 2 CW pain was 39%. The median time to onset of Grade {>=} 2 CW pain (National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0) was 9 months. There was no predictive advantage for biologically corrected dose over physical dose. Neither fraction number (p = 0.07) nor prescription dose (p = 0.07) were significantly correlated with the development of Grade {>=} 2 CW pain. Cox Proportional Hazards analysis identified significant correlation with a broad range of dose-volume combinations, with the CW volume receiving 30 Gy (V30) as one of the strongest predictors (p < 0.001). CW2cm consistently enabled better prediction of CW toxicity. When a physical dose of 30 Gy was received by more than 70 cm{sup 3} of CW2cm, there was a significant correlation with Grade {>=} 2 CW pain (p = 0.004). Conclusions: CW toxicity after SBRT is common and long-term follow-up is needed to identify affected patients. A volume of CW {>=} 70 cm{sup 3} receiving 30 Gy is significantly correlated with Grade {>=} 2 CW pain. We are currently applying this constraint at our institution for patients receiving thoracic SBRT. An actuarial atlas of our data is provided as an electronic supplement to facilitate data-sharing and meta-analysis relating to CW pain.

  2. Bridging the gap between in vitro and in vivo: Dose and schedule predictions for the ATR inhibitor AZD6738.

    PubMed

    Checkley, Stephen; MacCallum, Linda; Yates, James; Jasper, Paul; Luo, Haobin; Tolsma, John; Bendtsen, Claus

    2015-01-01

    Understanding the therapeutic effect of drug dose and scheduling is critical to inform the design and implementation of clinical trials. The increasing complexity of both mono, and particularly combination therapies presents a substantial challenge in the clinical stages of drug development for oncology. Using a systems pharmacology approach, we have extended an existing PK-PD model of tumor growth with a mechanistic model of the cell cycle, enabling simulation of mono and combination treatment with the ATR inhibitor AZD6738 and ionizing radiation. Using AZD6738, we have developed multi-parametric cell based assays measuring DNA damage and cell cycle transition, providing quantitative data suitable for model calibration. Our in vitro calibrated cell cycle model is predictive of tumor growth observed in in vivo mouse xenograft studies. The model is being used for phase I clinical trial designs for AZD6738, with the aim of improving patient care through quantitative dose and scheduling prediction. PMID:26310312

  3. Bridging the gap between in vitro and in vivo: Dose and schedule predictions for the ATR inhibitor AZD6738

    PubMed Central

    Checkley, Stephen; MacCallum, Linda; Yates, James; Jasper, Paul; Luo, Haobin; Tolsma, John; Bendtsen, Claus

    2015-01-01

    Understanding the therapeutic effect of drug dose and scheduling is critical to inform the design and implementation of clinical trials. The increasing complexity of both mono, and particularly combination therapies presents a substantial challenge in the clinical stages of drug development for oncology. Using a systems pharmacology approach, we have extended an existing PK-PD model of tumor growth with a mechanistic model of the cell cycle, enabling simulation of mono and combination treatment with the ATR inhibitor AZD6738 and ionizing radiation. Using AZD6738, we have developed multi-parametric cell based assays measuring DNA damage and cell cycle transition, providing quantitative data suitable for model calibration. Our in vitro calibrated cell cycle model is predictive of tumor growth observed in in vivo mouse xenograft studies. The model is being used for phase I clinical trial designs for AZD6738, with the aim of improving patient care through quantitative dose and scheduling prediction. PMID:26310312

  4. On the Sensitivity of α/β Prediction to Dose Calculation Methodology in Prostate Brachytherapy

    SciTech Connect

    Afsharpour, Hossein; Walsh, Sean; Collins Fekete, Charles-Antoine; Vigneault, Eric; Verhaegen, Frank; Beaulieu, Luc

    2014-02-01

    Purpose: To study the relationship between the accuracy of the dose calculation in brachytherapy and the estimations of the radiosensitivity parameter, α/β, for prostate cancer. Methods and Materials: In this study, Monte Carlo methods and more specifically the code ALGEBRA was used to produce accurate dose calculations in the case of prostate brachytherapy. Equivalent uniform biologically effective dose was calculated for these dose distributions and was used in an iso-effectiveness relationship with external beam radiation therapy. Results: By considering different levels of detail in the calculations, the estimation for the α/β parameter varied from 1.9 to 6.3 Gy, compared with a value of 3.0 Gy suggested by the American Association of Physicists in Medicine Task Group 137. Conclusions: Large variations of the α/β show the sensitivity of this parameter to dose calculation modality. The use of accurate dose calculation engines is critical for better evaluating the biological outcomes of treatments.

  5. Predicting terrestrial gamma dose rate based on geological and soil information: case study of Perak state, Malaysia.

    PubMed

    Ramli, A T; Apriantoro, N H; Heryansyah, A; Basri, N A; Sanusi, M S M; Abu Hanifah, N Z H

    2016-03-01

    An extensive terrestrial gamma radiation dose (TGRD) rate survey has been conducted in Perak State, Peninsular Malaysia. The survey has been carried out taking into account geological and soil information, involving 2930 in situ surveys. Based on geological and soil information collected during TGRD rate measurements, TGRD rates have been predicted in Perak State using a statistical regression analysis which would be helpful to focus surveys in areas that are difficult to access. An equation was formulated according to a linear relationship between TGRD rates, geological contexts and soil types. The comparison of in situ measurements and predicted TGRD dose rates was tabulated and showed good agreement with the linear regression equation. The TGRD rates in the study area ranged from 38 nGy h(-1) to 1039 nGy h(-1) with a mean value of 224  ±  138 nGy h(-1). This value is higher than the world average as reported in UNSCEAR 2000. The TGRD rates contribute an average dose rate of 1.37 mSv per year. An isodose map for the study area was developed using a Kriging method based on predicted and in situ TGRD rate values. PMID:26583298

  6. Benchmarking B-Cell Epitope Prediction with Quantitative Dose-Response Data on Antipeptide Antibodies: Towards Novel Pharmaceutical Product Development

    PubMed Central

    Caoili, Salvador Eugenio C.

    2014-01-01

    B-cell epitope prediction can enable novel pharmaceutical product development. However, a mechanistically framed consensus has yet to emerge on benchmarking such prediction, thus presenting an opportunity to establish standards of practice that circumvent epistemic inconsistencies of casting the epitope prediction task as a binary-classification problem. As an alternative to conventional dichotomous qualitative benchmark data, quantitative dose-response data on antibody-mediated biological effects are more meaningful from an information-theoretic perspective in the sense that such effects may be expressed as probabilities (e.g., of functional inhibition by antibody) for which the Shannon information entropy (SIE) can be evaluated as a measure of informativeness. Accordingly, half-maximal biological effects (e.g., at median inhibitory concentrations of antibody) correspond to maximally informative data while undetectable and maximal biological effects correspond to minimally informative data. This applies to benchmarking B-cell epitope prediction for the design of peptide-based immunogens that elicit antipeptide antibodies with functionally relevant cross-reactivity. Presently, the Immune Epitope Database (IEDB) contains relatively few quantitative dose-response data on such cross-reactivity. Only a small fraction of these IEDB data is maximally informative, and many more of them are minimally informative (i.e., with zero SIE). Nevertheless, the numerous qualitative data in IEDB suggest how to overcome the paucity of informative benchmark data. PMID:24949474

  7. Subjective relative deprivation is associated with poorer physical and mental health.

    PubMed

    Mishra, Sandeep; Carleton, R Nicholas

    2015-12-01

    Substantial epidemiological evidence has shown that income inequality and objective measures of relative deprivation are associated with poorer health outcomes. However, surprisingly little research has examined whether subjective feelings of relative deprivation are similarly linked with poorer health outcomes. The relative deprivation hypothesis suggests that inequality affects health at the individual level through negative consequences of social comparison. We directly examined the relationship between subjective feelings of personal relative deprivation and self-reported physical and mental health in a diverse community sample (n = 328). Results demonstrated that subjective feelings of personal relative deprivation are associated with significantly poorer physical and mental health. These relationships held even when accounting for covariates that have been previously associated with both relative deprivation and health. These results further support the link between relative deprivation and health outcomes and suggest that addressing root causes of relative deprivation may lead to greater individual health. PMID:26575605

  8. Global forecast model to predict the daily dose of the solar erythemally effective UV radiation.

    PubMed

    Schmalwieser, Alois W; Schauberger, Günther; Janouch, Michal; Nunez, Manuel; Koskela, Tapani; Berger, Daniel; Karamanian, Gabriel

    2005-01-01

    A worldwide forecast of the erythemally effective ultraviolet (UV) radiation is presented. The forecast was established to inform the public about the expected amount of erythemally effective UV radiation for the next day. Besides the irradiance, the daily dose is forecasted to enable people to choose the appropriate sun protection tools. Following the UV Index as the measure of global erythemally effective irradiance, the daily dose is expressed in units of UV Index hours. In this study, we have validated the model and the forecast against measurements from broadband UV radiometers of the Robertson-Berger type. The measurements were made at four continents ranging from the northern polar circle (67.4 degrees N) to the Antarctic coast (61.1 degrees S). As additional quality criteria the frequency of underestimation was taken into account because the forecast is a tool of radiation protection and made to avoid overexposure. A value closer than one minimal erythemal dose for the most sensitive skin type 1 to the observed value was counted as hit and greater deviations as underestimation or overestimation. The Austrian forecast model underestimates the daily dose in 3.7% of all cases, whereas 1.7% results from the model and 2.0% from the assumed total ozone content. The hit rate could be found in the order of 40%. PMID:15453822

  9. Prediction of the location and size of the stomach using patient characteristics for retrospective radiation dose estimation following radiotherapy

    NASA Astrophysics Data System (ADS)

    Lamart, Stephanie; Imran, Rebecca; Simon, Steven L.; Doi, Kazutaka; Morton, Lindsay M.; Curtis, Rochelle E.; Lee, Choonik; Drozdovitch, Vladimir; Maass-Moreno, Roberto; Chen, Clara C.; Whatley, Millie; Miller, Donald L.; Pacak, Karel; Lee, Choonsik

    2013-12-01

    Following cancer radiotherapy, reconstruction of doses to organs, other than the target organ, is of interest for retrospective health risk studies. Reliable estimation of doses to organs that may be partially within or fully outside the treatment field requires reliable knowledge of the location and size of the organs, e.g., the stomach, which is at risk from abdominal irradiation. The stomach location and size are known to be highly variable between individuals, but have been little studied. Moreover, for treatments conducted years ago, medical images of patients are usually not available in medical records to locate the stomach. In light of the poor information available to locate the stomach in historical dose reconstructions, the purpose of this work was to investigate the variability of stomach location and size among adult male patients and to develop prediction models for the stomach location and size using predictor variables generally available in medical records of radiotherapy patients treated in the past. To collect data on stomach size and position, we segmented the contours of the stomach and of the skeleton on contemporary computed tomography (CT) images for 30 male patients in supine position. The location and size of the stomach was found to depend on body mass index (BMI), ponderal index (PI), and age. For example, the anteroposterior dimension of the stomach was found to increase with increasing BMI (≈0.25 cm kg-1 m2) whereas its craniocaudal dimension decreased with increasing PI (≈-3.3 cm kg-1 m3) and its transverse dimension increased with increasing PI (≈2.5 cm kg-1 m3). Using the prediction models, we generated three-dimensional computational stomach models from a deformable hybrid phantom for three patients of different BMI. Based on a typical radiotherapy treatment, we simulated radiotherapy treatments on the predicted stomach models and on the CT images of the corresponding patients. Those dose calculations demonstrated good

  10. The calculation of radial dose from heavy ions: predictions of biological action cross sections

    NASA Technical Reports Server (NTRS)

    Katz, R.; Cucinotta, F. A.; Zhang, C. X.; Wilson, J. W. (Principal Investigator)

    1996-01-01

    The track structure model of heavy ion cross sections was developed by Katz and co-workers in the 1960s. In this model the action cross section is evaluated by mapping the dose-response of a detector to gamma rays (modeled from biological target theory) onto the radial dose distribution from delta rays about the path of the ion. This is taken to yield the radial distribution of probability for a "hit" (an interaction leading to an observable end-point). Radial integration of the probability yields the cross section. When different response from ions of different Z having the same stopping power is observed this model may be indicated. Since the 1960s there have been several developments in the computation of the radial dose distribution, in the measurement of these distributions, and in new radiobiological data against which to test the model. The earliest model, by Butts and Katz made use of simplified delta ray distribution functions, of simplified electron range-energy relations, and neglected angular distributions. Nevertheless it made possible the calculation of cross sections for the inactivation of enzymes and viruses, and allowed extension to tracks in nuclear emulsions and other detectors and to biological cells. It set the pattern for models of observable effects in the matter through which the ion passed. Here we outline subsequent calculations of radial dose which make use of improved knowledge of the electron emission spectrum, the electron range-energy relation, the angular distribution, and some considerations of molecular excitation, of particular interest both close to the path of the ion and the outer limits of electron penetration. These are applied to the modeling of action cross sections for the inactivation of several strains of E-coli and B. subtilis spores where extensive measurements in the "thin-down" region have been made with heavy ion beams. Such calculations serve to test the radial dose calculations at the outer limit of electron

  11. Predicting Radiosensitivity with Gamma-H2AX Foci Assay after Single High-Dose-Rate and Pulsed Dose-Rate Ionizing Irradiation.

    PubMed

    van Oorschot, Bregje; Hovingh, Suzanne; Dekker, Annelot; Stalpers, Lukas J; Franken, Nicolaas A P

    2016-02-01

    Gamma-H2AX foci detection is the standard method to quantify DNA double-strand break (DSB) induction and repair. In this study, we investigated the induction and decay of γ-H2AX foci of different tumor cell lines and fibroblasts with known mutations in DNA damage repair genes, including ATM, LigIV, DNA-PKcs, Rad51 and Rad54. A radiation dose of 2.4 Gy was used for either an acute single high-dose-rate (sHDR) exposure or a pulsed dose-rate (pDR) exposure over 24 h. The number of γ-H2AX foci was determined at 30 min and 24 h after sHDR irradiation and directly after pDR irradiation. In a similar manner, γ-H2AX foci were also examined in lymphocytes of patients with differences in normal tissue toxicity after a total radiation dose of 1 Gy. In an initial count of the number of foci 30 min after sHDR irradiation, repair-proficient cell types could not be distinguished from repair-deficient cell types. However at 24 h postirradiation, while we observed a large decrease in foci numbers in NHEJ-proficient cells, the amount of γ-H2AX foci in cell types with mutated NHEJ repair remained at high levels. Except for IRS-1SF cells, HR-deficient cell types eventually did show a moderate decrease in foci number over time, albeit to a lesser extent than their corresponding parentals or repair-proficient control cells. In addition, analysis of γ-H2AX foci after sHDR exposure of patients with different sensitivity status clearly showed individual differences in radiation response. Radiosensitive patients could be distinguished from the more radioresistant patients with γ-H2AX foci decay ratios (initial number of foci divided by residual number of foci). Significantly higher decay ratios were observed in patients without toxicities, indicating more proficient repair compared to patients with radiation-induced side effects. After pDR irradiation, no consistent correlation could be found between foci number and radiosensitivity. In conclusion, γ-H2AX formation is a rapid and

  12. Multivariate analysis of factors predicting prostate dose in intensity-modulated radiotherapy

    SciTech Connect

    Tomita, Tsuneyuki; Nakamura, Mitsuhiro; Hirose, Yoshinori; Kitsuda, Kenji; Notogawa, Takuya; Miki, Katsuhito; Nakamura, Kiyonao; Ishigaki, Takashi

    2014-01-01

    We conducted a multivariate analysis to determine relationships between prostate radiation dose and the state of surrounding organs, including organ volumes and the internal angle of the levator ani muscle (LAM), based on cone-beam computed tomography (CBCT) images after bone matching. We analyzed 270 CBCT data sets from 30 consecutive patients receiving intensity-modulated radiation therapy for prostate cancer. With patients in the supine position on a couch with the HipFix system, data for center of mass (COM) displacement of the prostate and the state of individual organs were acquired and compared between planning CT and CBCT scans. Dose distributions were then recalculated based on CBCT images. The relative effects of factors on the variance in COM, dose covering 95% of the prostate volume (D{sub 95%}), and percentage of prostate volume covered by the 100% isodose line (V{sub 100%}) were evaluated by a backward stepwise multiple regression analysis. COM displacement in the anterior-posterior direction (COM{sub AP}) correlated significantly with the rectum volume (δVr) and the internal LAM angle (δθ; R = 0.63). Weak correlations were seen for COM in the left-right (R = 0.18) and superior-inferior directions (R = 0.31). Strong correlations between COM{sub AP} and prostate D{sub 95%} and V{sub 100%} were observed (R ≥ 0.69). Additionally, the change ratios in δVr and δθ remained as predictors of prostate D{sub 95%} and V{sub 100%}. This study shows statistically that maintaining the same rectum volume and LAM state for both the planning CT simulation and treatment is important to ensure the correct prostate dose in the supine position with bone matching.

  13. Children's Executive Functions: Are They Poorer after Very Early Brain Insult

    ERIC Educational Resources Information Center

    Anderson, Vicki; Spencer-Smith, Megan; Coleman, Lee; Anderson, Peter; Williams, Jackie; Greenham, Mardee; Leventer, Richard J.; Jacobs, Rani

    2010-01-01

    Traditionally early brain insult (EBI) has been considered to have better outcome than later injury, consistent with the notion that the young brain is flexible and able to reorganize. Recent research findings question this view, suggesting that EBI might lead to poorer outcome than brain insult at any other age. Exploring this early vulnerability…

  14. Middle Schools and Poorer Neighbourhoods: Between Effectiveness and the Law, Ethics and Culture Model

    ERIC Educational Resources Information Center

    Acosta, Felicitas

    2006-01-01

    This article presents a series of reflections based on a study of two schools of secondary level in the city of Buenos Aires. The purpose is to identify reasons why some schools in poorer areas obtain higher levels of success for their pupils. The conceptual basis is one of cultural analysis, permitting a contextual and situational perspective…

  15. Deprivation amplification revisited; or, is it always true that poorer places have poorer access to resources for healthy diets and physical activity?

    PubMed Central

    Macintyre, Sally

    2007-01-01

    Background It has commonly been suggested (including by this author) that individual or household deprivation (for example, low income) is amplified by area level deprivation (for example, lack of affordable nutritious food or facilities for physical activity in the neighbourhood). Discussion The idea of deprivation amplification has some intuitive attractiveness and helps divert attention away from purely individual determinants of diet and physical activity, and towards health promoting or health damaging features of the physical and social environment. Such environmental features may be modifiable, and environmental changes may help promote healthier behaviors. However, recent empirical examination of the distribution of facilities and resources shows that location does not always disadvantage poorer neighbourhoods. This suggests that we need: a) to ensure that theories and policies are based on up-to-date empirical evidence on the socio-economic distribution of neighbourhood resources, and b) to engage in further research on the relative importance of, and interactions between, individual and environmental factors in shaping behavior. Summary In this debate paper I suggest that it may not always be true that poorer neighbourhoods are more likely to lack health promoting resources, and to be exposed to more health damaging resources. The spatial distribution of environmental resources by area socioeconomic status may vary between types of resource, countries, and time periods. It may also be that the presence or absence of resources is less important than their quality, their social meaning, or local perceptions of their accessibility and relevance. PMID:17683624

  16. Dose to Larynx Predicts for Swallowing Complications After Intensity-Modulated Radiotherapy

    SciTech Connect

    Caglar, Hale B.; Tishler, Roy B.; Burke, Elaine; Li Yi; Goguen, Laura; Norris, Carl M.; Allen, Aaron M.

    2008-11-15

    Purpose: To evaluate early swallowing after intensity-modulated radiotherapy for head and neck squamous cell carcinoma and determine factors correlating with aspiration and/or stricture. Methods and Materials: Consecutive patients treated with intensity-modulated radiotherapy with or without chemotherapy between September 2004 and August 2006 at the Dana Farber Cancer Institute/Brigham and Women's Hospital were evaluated with institutional review board approval. Patients underwent swallowing evaluation after completion of therapy; including video swallow studies. The clinical- and treatment-related variables were examined for correlation with aspiration or strictures, as well as doses to the larynx, pharyngeal constrictor muscles, and cervical esophagus. The correlation was assessed with logistic regression analysis. Results: A total of 96 patients were evaluated. Their median age was 55 years, and 79 (82%) were men. The primary site of cancer was the oropharynx in 43, hypopharynx/larynx in 17, oral cavity in 13, nasopharynx in 11, maxillary sinus in 2, and unknown primary in 10. Of the 96 patients, 85% underwent definitive RT and 15% postoperative RT. Also, 28 patients underwent induction chemotherapy followed by concurrent chemotherapy, 59 received concurrent chemotherapy, and 9 patients underwent RT alone. The median follow-up was 10 months. Of the 96 patients, 31 (32%) had clinically significant aspiration and 36 (37%) developed a stricture. The radiation dose-volume metrics, including the volume of the larynx receiving {>=}50 Gy (p = 0.04 and p = 0.03, respectively) and volume of the inferior constrictor receiving {>=}50 Gy (p = 0.05 and p = 0.02, respectively) were significantly associated with both aspiration and stricture. The mean larynx dose correlated with aspiration (p = 0.003). Smoking history was the only clinical factor to correlate with stricture (p = 0.05) but not aspiration. Conclusion: Aspiration and stricture are common side effects after

  17. Calculation and Prediction of the Effect of Respiratory Motion on Whole Breast Radiation Therapy Dose Distributions

    SciTech Connect

    Cao Junsheng; Roeske, John C.; Chmura, Steve J.; Salama, Joseph K.; Shoushtari, Asal N.; Boyer, Arthur L.; Martel, Mary K.

    2009-07-01

    The standard treatment technique used for whole-breast irradiation can result in undesirable dose distributions in the treatment site, leading to skin reaction/fibrosis and pulmonary and cardiac toxicities. Hence, the technique has evolved from conventional wedged technique (CWT) to segment intensity-modulated radiation therapy (SIMRT) and beamlet IMRT (IMRT). However, these newer techniques feature more highly modulated dose distributions that may be affected by respiration. The purpose of this work was to conduct a simple study of the clinical impact of respiratory motion on breast radiotherapy dose distributions for the three treatment planning techniques. The ultimate goal was to determine which patients would benefit most from the use of motion management. Eight patients with early-stage breast cancer underwent a free-breathing (FB) computed tomography (CT) simulation, with medial and lateral markers placed on the skin. Two additional CT scans were obtained at the end of inspiration (EI) and the end of expiration (EE). The FB-CT scan was used to develop treatment plans using each technique. Each plan was then applied to EI and EE-CT scans. Compared with the FB CT scan, the medial markers moved up to 1.8 cm in the anterior-superior direction at the end of inspiration (EI-scan), and on average 8 mm. The CWT and SIMRT techniques were not 'sensitive' to respiratory motion, because the % clinical target volume (CTV) receiving 95% of the prescription dose (V{sub 95%}) remained constant for both techniques. For patients that had large respiratory motion indicated by marker movement >0.6 cm, differences in coverage of the CTV at the V100% between FB and EI for beamlet IMRT plans were on the order of >10% and up to 18%. A linear model was developed to relate the dosimetric coverage difference introduced by respiration with the motion information. With this model, the dosimetric coverage difference introduced by respiratory motion could be evaluated during patient CT

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

    PubMed

    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

  19. 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

  20. Prediction of powdered activated carbon doses for 2-MIB removal in drinking water treatment using a simplified HSDM approach.

    PubMed

    Yu, Jianwei; Yang, Fong-Chen; Hung, Wei-Nung; Liu, Chia-Ling; Yang, Min; Lin, Tsair-Fuh

    2016-08-01

    The addition of powdered activated carbon (PAC) is an effective measure to cope with seasonal taste and odor (T&O) problems caused by 2-methylisoborneol (2-MIB) and trans-1, 10-dimethyl-trans-9-decalol (geosmin) in drinking water. Some T&O problems are episodic in nature, and generally require rapid responses. This paper proposed a simplified approach for the application of the homogenous surface diffusion model (HSDM) to predict the appropriate PAC doses for the removal of 2-MIB. Equilibrium and kinetic experiments were performed for 2-MIB adsorption onto five PACs in three source waters. The simplified HSDM approach was compared with the experimental data, by assigning the Freundlich 1/n value in the range of 0.1-1.0 and obtaining the Freundlich equilibrium parameter K value through a 6-hr adsorption kinetic test. The model describes the kinetic adsorption data very well for all of the tested PACs in different source waters. The results were validated using the data obtained from one full scale water treatment plant, and the differences between the predicted and observed results were within 10% range. This simplified HSDM approach may be applied for the rapid determination of PAC doses for water treatment plants when faced with 2-MIB episodes in source waters. PMID:27186686

  1. Sarcopenia and body mass index predict sunitinib-induced early dose-limiting toxicities in renal cancer patients

    PubMed Central

    Huillard, O; Mir, O; Peyromaure, M; Tlemsani, C; Giroux, J; Boudou-Rouquette, P; Ropert, S; Delongchamps, N Barry; Zerbib, M; Goldwasser, F

    2013-01-01

    Background: Little is known on factors predicting sunitinib toxicity. Recently, the condition of low muscle mass, named sarcopenia, was identified as a significant predictor of toxicity in metastatic renal cell cancer (mRCC) patients treated with sorafenib. We investigated whether sarcopenia could predict early dose-limiting toxicities (DLTs) occurrence in mRCC patients treated with sunitinib. Methods: Consecutive mRCC patients treated with sunitinib were retrospectively reviewed. A DLT was defined as any toxicity leading to dose reduction or treatment discontinuation. Body composition was evaluated using CT scan obtained within 1 month before treatment initiation. Results: Among 61 patients eligible for analysis, 52.5% were sarcopenic and 32.8% had both sarcopenia and a body mass index (BMI)<25 kg m−2. Eighteen patients (29.5%) experienced a DLT during the first cycle. Sarcopenic patients with a BMI<25 kg m−2 experienced more DLTs (P=0.01; odds ratio=4.1; 95% CI: (1.3–13.3)), more cumulative grade 2 or 3 toxicities (P=0.008), more grade 3 toxicities (P=0.04) and more acute vascular toxicities (P=0.009). Conclusion: Patients with sarcopenia and a BMI<25 kg m−2 experienced significantly more DLTs during the first cycle of treatment. PMID:23462722

  2. Perineural Invasion Predicts Increased Recurrence, Metastasis, and Death From Prostate Cancer Following Treatment With Dose-Escalated Radiation Therapy

    SciTech Connect

    Feng, Felix Y.; Qian Yushen; Stenmark, Matthew H.; Halverson, Schuyler; Blas, Kevin; Vance, Sean; Sandler, Howard M.; Hamstra, Daniel A.

    2011-11-15

    Purpose: To assess the prognostic value of perineural invasion (PNI) for patients treated with dose-escalated external-beam radiation therapy for prostate cancer. Methods and Materials: Outcomes were analyzed for 651 men treated for prostate cancer with EBRT to a minimum dose {>=}75 Gy. We assessed the impact of PNI as well as pretreatment and treatment-related factors on freedom from biochemical failure (FFBF), freedom from metastasis (FFM), cause-specific survival (CSS), and overall survival. Results: PNI was present in 34% of specimens at biopsy and was significantly associated with higher Gleason score (GS), T stage, and prostate-specific antigen level. On univariate and multivariate analysis, the presence of PNI was associated with worse FFBF (hazard ratio = 1.7, p <0.006), FFM (hazard ratio = 1.8, p <0.03), and CSS (HR = 1.4, p <0.05) compared with absence of PNI; there was no difference in overall survival. Seven-year rates of FFBF, FFM, and CCS were 64% vs. 80%, 84% vs. 92%, and 91% vs. 95% for those patients with and without PNI, respectively. On recursive partitioning analysis, PNI predicted for worse FFM and CSS in patients with GS 8-10, with FFM of 67% vs. 89% (p <0.02), and CSS of 69% vs. 91%, (p <0.04) at 7 years for those with and without PNI, respectively. Conclusions: The presence of PNI in the prostate biopsy predicts worse clinical outcome for patients treated with dose-escalated external-beam radiation therapy. Particularly in patients with GS 8-10 disease, the presence of PNI suggests an increased risk of metastasis and prostate cancer death.

  3. Strengths and limitations of using repeat-dose toxicity studies to predict effects on fertility.

    PubMed

    Dent, M P

    2007-08-01

    The upcoming European chemicals legislation REACH (Registration, Evaluation, and Authorisation of Chemicals) will require the risk assessment of many thousands of chemicals. It is therefore necessary to develop intelligent testing strategies to ensure that chemicals of concern are identified whilst minimising the testing of chemicals using animals. Xenobiotics may perturb the reproductive cycle, and for this reason several reproductive studies are recommended under REACH. One of the endpoints assessed in this battery of tests is mating performance and fertility. Animal tests that address this endpoint use a relatively large number of animals and are also costly in terms of resource, time, and money. If it can be shown that data from non-reproductive studies such as in-vitro or repeat-dose toxicity tests are capable of generating reliable alerts for effects on fertility then some animal testing may be avoided. Available rat sub-chronic and fertility data for 44 chemicals that have been classified by the European Union as toxic to fertility were therefore analysed for concordance of effects. Because it was considered appropriate to read across data for some chemicals these data sets were considered relevant for 73 of the 102 chemicals currently classified as toxic to reproduction (fertility) under this system. For all but 5 of these chemicals it was considered that a well-performed sub-chronic toxicity study would have detected pathology in the male, and in some cases, the female reproductive tract. Three showed evidence of direct interaction with oestrogen or androgen receptors (linuron, nonylphenol, and fenarimol). The remaining chemicals (quinomethionate and azafenidin) act by modes of action that do not require direct interaction with steroid receptors. However, both these materials caused in-utero deaths in pre-natal developmental toxicity studies, and the relatively low NOAELs and the nature of the hazard identified in the sub-chronic tests provides an alert

  4. Prediction of imipramine serum levels in enuretic children by a Bayesian method: comparison with two other conventional dosing methods.

    PubMed

    Fernández de Gatta, M M; Tamayo, M; García, M J; Amador, D; Rey, F; Gutiérrez, J R; Domínguez-Gil Hurlé, A

    1989-11-01

    The aim of the present study was to characterize the kinetic behavior of imipramine (IMI) and desipramine in enuretic children and to evaluate the performance of different methods for dosage prediction based on individual and/or population data. The study was carried out in 135 enuretic children (93 boys) ranging in age between 5 and 13 years undergoing treatment with IMI in variable single doses (25-75 mg/day) administered at night. Sampling time was one-half the dosage interval at steady state. The number of data available for each patient varied (1-4) and was essentially limited by clinical criteria. Pharmacokinetic calculations were performed using a simple proportional relationship (method 1) and a multiple nonlinear regression program (MULTI 2 BAYES) with two different options: using the ordinary least-squares method (method 2) and the least-squares method based on the Bayesian algorithm (method 3). The results obtained point to a coefficient of variation for the level/dose ratio of the drug (58%) that is significantly lower than that of the metabolite (101.4%). The forecasting capacity of method 1 is deficient both regarding accuracy [mean prediction error (MPE) = -5.48 +/- 69.15] and precision (root mean squared error = 46.42 +/- 51.39). The standard deviation of the MPE (69) makes the method unacceptable from the clinical point of view. The more information that is available concerning the serum levels, the greater are the accuracy and precision of methods (2 and 3). With the Bayesian method, less information on drug serum levels is needed to achieve clinically acceptable predictions. PMID:2595743

  5. Isothermal calorimetry: a predictive tool to model drug-propellant interactions in pressurized metered dose systems.

    PubMed

    Ooi, Jesslynn; Gaisford, Simon; Boyd, Ben J; Young, Paul M; Traini, Daniela

    2014-01-30

    The purpose of this work was to evaluate gas perfusion isothermal calorimetry (ITC) as a method to characterize the physicochemical changes of active pharmaceutical ingredients (APIs) intended to be formulated in pressurized metered dose inhalers (pMDIs) after exposure to a model propellant. Spray dried samples of beclomethasone dipropionate (BDP) and salbutamol sulphate (SS) were exposed to controlled quantities of 2H,3H-decafluoropentane (HPFP) to determine whether ITC could be used as a suitable analytical method for gathering data on the behavioural properties of the powders in real time. The crystallization kinetics of BDP and the physiochemical properties of SS were successfully characterized using ITC and supported by a variety of other analytical techniques. Correlations between real and model propellant systems were also established using hydrofluoroalkane (HFA-227) propellant. In summary, ITC was found to be suitable for gathering data on the crystallization kinetics of BDP and SS. In a wider context, this work will have implications on the use of ITC for stability testing of APIs in HFA-based pMDIs. PMID:24325938

  6. Poorer Financial and Health Literacy Among Community-Dwelling Older Adults With Mild Cognitive Impairment

    PubMed Central

    Han, S. Duke; Boyle, Patricia A.; James, Bryan D.; Yu, Lei; Bennett, David A.

    2015-01-01

    Objective Literacy is an important determinant of financial and health outcomes in old age, and cognitive decline has been linked with lower literacy. We tested the hypothesis that mild cognitive impairment (MCI) is associated with poorer financial and health literacy. Method Participants (n = 730) from the Rush Memory and Aging Project were given a clinical evaluation and an assessment of total, financial, and health literacy. Regression was used to examine whether MCI was associated with lower literacy. In secondary analyses, we investigated the association of particular cognitive systems with literacy. Results MCI was associated with lower total, financial, and health literacy. An interaction was observed such that higher education reduced the effect of MCI on total and financial literacy. Multiple cognitive systems were associated with literacy in participants with MCI, and semantic memory accounted for the most variance. Discussion Persons with MCI exhibit poorer financial and health literacy, and education mitigates this effect. PMID:25903976

  7. Assessment of uncertainties in radiation-induced cancer risk predictions at clinically relevant doses

    SciTech Connect

    Nguyen, J.; Moteabbed, M.; Paganetti, H.

    2015-01-15

    Purpose: Theoretical dose–response models offer the possibility to assess second cancer induction risks after external beam therapy. The parameters used in these models are determined with limited data from epidemiological studies. Risk estimations are thus associated with considerable uncertainties. This study aims at illustrating uncertainties when predicting the risk for organ-specific second cancers in the primary radiation field illustrated by choosing selected treatment plans for brain cancer patients. Methods: A widely used risk model was considered in this study. The uncertainties of the model parameters were estimated with reported data of second cancer incidences for various organs. Standard error propagation was then subsequently applied to assess the uncertainty in the risk model. Next, second cancer risks of five pediatric patients treated for cancer in the head and neck regions were calculated. For each case, treatment plans for proton and photon therapy were designed to estimate the uncertainties (a) in the lifetime attributable risk (LAR) for a given treatment modality and (b) when comparing risks of two different treatment modalities. Results: Uncertainties in excess of 100% of the risk were found for almost all organs considered. When applied to treatment plans, the calculated LAR values have uncertainties of the same magnitude. A comparison between cancer risks of different treatment modalities, however, does allow statistically significant conclusions. In the studied cases, the patient averaged LAR ratio of proton and photon treatments was 0.35, 0.56, and 0.59 for brain carcinoma, brain sarcoma, and bone sarcoma, respectively. Their corresponding uncertainties were estimated to be potentially below 5%, depending on uncertainties in dosimetry. Conclusions: The uncertainty in the dose–response curve in cancer risk models makes it currently impractical to predict the risk for an individual external beam treatment. On the other hand, the ratio

  8. Assessment of uncertainties in radiation-induced cancer risk predictions at clinically relevant doses

    PubMed Central

    Nguyen, J.; Moteabbed, M.; Paganetti, H.

    2015-01-01

    Purpose: Theoretical dose–response models offer the possibility to assess second cancer induction risks after external beam therapy. The parameters used in these models are determined with limited data from epidemiological studies. Risk estimations are thus associated with considerable uncertainties. This study aims at illustrating uncertainties when predicting the risk for organ-specific second cancers in the primary radiation field illustrated by choosing selected treatment plans for brain cancer patients. Methods: A widely used risk model was considered in this study. The uncertainties of the model parameters were estimated with reported data of second cancer incidences for various organs. Standard error propagation was then subsequently applied to assess the uncertainty in the risk model. Next, second cancer risks of five pediatric patients treated for cancer in the head and neck regions were calculated. For each case, treatment plans for proton and photon therapy were designed to estimate the uncertainties (a) in the lifetime attributable risk (LAR) for a given treatment modality and (b) when comparing risks of two different treatment modalities. Results: Uncertainties in excess of 100% of the risk were found for almost all organs considered. When applied to treatment plans, the calculated LAR values have uncertainties of the same magnitude. A comparison between cancer risks of different treatment modalities, however, does allow statistically significant conclusions. In the studied cases, the patient averaged LAR ratio of proton and photon treatments was 0.35, 0.56, and 0.59 for brain carcinoma, brain sarcoma, and bone sarcoma, respectively. Their corresponding uncertainties were estimated to be potentially below 5%, depending on uncertainties in dosimetry. Conclusions: The uncertainty in the dose–response curve in cancer risk models makes it currently impractical to predict the risk for an individual external beam treatment. On the other hand, the ratio

  9. Altered tract-specific white matter microstructure is related to poorer cognitive performance: The Rotterdam Study.

    PubMed

    Cremers, Lotte G M; de Groot, Marius; Hofman, Albert; Krestin, Gabriel P; van der Lugt, Aad; Niessen, Wiro J; Vernooij, Meike W; Ikram, M Arfan

    2016-03-01

    White matter microstructural integrity has been related to cognition. Yet, the potential role of specific white matter tracts on top of a global white matter effect remains unclear, especially when considering specific cognitive domains. Therefore, we determined the tract-specific effect of white matter microstructure on global cognition and specific cognitive domains. In 4400 nondemented and stroke-free participants (mean age 63.7 years, 55.5% women), we obtained diffusion magnetic resonance imaging parameters (fractional anisotropy and mean diffusivity) in 14 white matter tracts using probabilistic tractography and assessed cognitive performance with a cognitive test battery. Tract-specific white matter microstructure in all supratentorial tracts was associated with poorer global cognition. Lower fractional anisotropy in association tracts, primarily the inferior fronto-occipital fasciculus, and higher mean diffusivity in projection tracts, in particular the posterior thalamic radiation, most strongly related to poorer cognition. Altered white matter microstructure related to poorer information processing speed, executive functioning, and motor speed, but not to memory. Tract-specific microstructural changes may aid in better understanding the mechanism of cognitive impairment and neurodegenerative diseases. PMID:26923407

  10. Improved tumour response prediction with equivalent uniform dose in pre-clinical study using direct intratumoural infusion of liposome-encapsulated 186Re radionuclides

    NASA Astrophysics Data System (ADS)

    Hrycushko, Brian A.; Ware, Steve; Li, Shihong; Bao, Ande

    2011-09-01

    Crucial to all cancer therapy modalities is a strong correlation between treatment and effect. Predictability of therapy success/failure allows for the optimization of treatment protocol and aids in the decision of whether additional treatment is necessary to prevent tumour progression. This work evaluated the relationship between cancer treatment and effect for intratumoural infusions of liposome-encapsulated 186Re to head and neck squamous cell carcinoma xenografts of nude rats. Absorbed dose calculations using a dose-point kernel convolution technique showed significant intratumoural dose heterogeneity due to the short range of the beta-particle emissions. The use of three separate tumour infusion locations improved dose homogeneity compared to a single infusion location as a result of a more uniform radioactivity distribution. An improved dose-response correlation was obtained when using effective uniform dose (EUD) calculations based on a generic set of radiobiological parameters (R2 = 0.84) than when using average tumour absorbed dose (R2 = 0.22). Varying radiobiological parameter values over ranges commonly used for all types of tumours showed little effect on EUD calculations, which suggests that individualized parameter use is of little significance as long as the intratumoural dose heterogeneity is taken into consideration in the dose-response relationship. The improved predictability achieved when using EUD calculations for this cancer therapy modality may be useful for treatment planning and evaluation.

  11. Dosimetric verification of IMAT delivery with a conventional EPID system and a commercial portal dose image prediction tool

    SciTech Connect

    Iori, Mauro; Cagni, Elisabetta; Paiusco, Marta; Munro, Peter; Nahum, Alan E.

    2010-01-15

    Purpose: The electronic portal imaging device (EPID) is a system for checking the patient setup; as a result of its integration with the linear accelerator and software customized for dosimetry, it is increasingly used for verification of the delivery of fixed-field intensity-modulated radiation therapy (IMRT). In order to extend such an approach to intensity-modulated arc therapy (IMAT), the combined use of an EPID system and a portal dose image prediction (PDIP) tool has been investigated. Methods: The dosimetric behavior of an EPID system, mechanically reinforced to maintain its positional stability during the accelerator gantry rotation, has been studied to assess its ability to measure portal dose distributions for IMAT treatment beams. In addition, the PDIP tool of a commercial treatment planning system, commonly used for static IMRT dosimetry, has been validated for simulating the PDIs of IMAT treatment fields. The method has been applied to the delivery verification of 23 treatment fields that were measured in their dual mode of IMRT and IMAT modalities. Results: The EPID system has proved to be appropriate for measuring the PDIs of IMAT fields; additionally the PDIP tool was able to simulate these accurately. The results are quite similar to those obtained for static IMRT treatment verification, although it was necessary to investigate the dependence of the EPID signal and of the accelerator monitor chamber response on variable dose rate. Conclusions: Our initial tests indicate that the EPID system, together with the PDIP tool, is a suitable device for the verification of IMAT plan delivery; however, additional tests are necessary to confirm these results.

  12. Standard-Fractionated Radiotherapy for Optic Nerve Sheath Meningioma: Visual Outcome Is Predicted by Mean Eye Dose

    SciTech Connect

    Abouaf, Lucie; Girard, Nicolas; Lefort, Thibaud; D'hombres, Anne; Tilikete, Caroline; Vighetto, Alain; Mornex, Francoise

    2012-03-01

    Purpose: Radiotherapy has shown its efficacy in controlling optic nerve sheath meningiomas (ONSM) tumor growth while allowing visual acuity to improve or stabilize. However, radiation-induced toxicity may ultimately jeopardize the functional benefit. The purpose of this study was to identify predictive factors of poor visual outcome in patients receiving radiotherapy for ONSM. Methods and Materials: We conducted an extensive analysis of 10 patients with ONSM with regard to clinical, radiologic, and dosimetric aspects. All patients were treated with conformal radiotherapy and subsequently underwent biannual neuroophthalmologic and imaging assessments. Pretreatment and posttreatment values of visual acuity and visual field were compared with Wilcoxon's signed rank test. Results: Visual acuity values significantly improved after radiotherapy. After a median follow-up time of 51 months, 6 patients had improved visual acuity, 4 patients had improved visual field, 1 patient was in stable condition, and 1 patient had deteriorated visual acuity and visual field. Tumor control rate was 100% at magnetic resonance imaging assessment. Visual acuity deterioration after radiotherapy was related to radiation-induced retinopathy in 2 patients and radiation-induced mature cataract in 1 patient. Study of radiotherapy parameters showed that the mean eye dose was significantly higher in those 3 patients who had deteriorated vision. Conclusions: Our study confirms that radiotherapy is efficient in treating ONSM. Long-term visual outcome may be compromised by radiation-induced side effects. Mean eye dose has to be considered as a limiting constraint in treatment planning.

  13. A novel method for patient exit and entrance dose prediction based on water equivalent path length measured with an amorphous silicon electronic portal imaging device.

    PubMed

    Kavuma, Awusi; Glegg, Martin; Metwaly, Mohamed; Currie, Garry; Elliott, Alex

    2010-01-21

    In vivo dosimetry is one of the quality assurance tools used in radiotherapy to monitor the dose delivered to the patient. Electronic portal imaging device (EPID) images for a set of solid water phantoms of varying thicknesses were acquired and the data fitted onto a quadratic equation, which relates the reduction in photon beam intensity to the attenuation coefficient and material thickness at a reference condition. The quadratic model is used to convert the measured grey scale value into water equivalent path length (EPL) at each pixel for any material imaged by the detector. For any other non-reference conditions, scatter, field size and MU variation effects on the image were corrected by relative measurements using an ionization chamber and an EPID. The 2D EPL is linked to the percentage exit dose table, for different thicknesses and field sizes, thereby converting the plane pixel values at each point into a 2D dose map. The off-axis ratio is corrected using envelope and boundary profiles generated from the treatment planning system (TPS). The method requires field size, monitor unit and source-to-surface distance (SSD) as clinical input parameters to predict the exit dose, which is then used to determine the entrance dose. The measured pixel dose maps were compared with calculated doses from TPS for both entrance and exit depth of phantom. The gamma index at 3% dose difference (DD) and 3 mm distance to agreement (DTA) resulted in an average of 97% passing for the square fields of 5, 10, 15 and 20 cm. The exit dose EPID dose distributions predicted by the algorithm were in better agreement with TPS-calculated doses than phantom entrance dose distributions. PMID:20019398

  14. A novel method for patient exit and entrance dose prediction based on water equivalent path length measured with an amorphous silicon electronic portal imaging device

    NASA Astrophysics Data System (ADS)

    Kavuma, Awusi; Glegg, Martin; Metwaly, Mohamed; Currie, Garry; Elliott, Alex

    2010-01-01

    In vivo dosimetry is one of the quality assurance tools used in radiotherapy to monitor the dose delivered to the patient. Electronic portal imaging device (EPID) images for a set of solid water phantoms of varying thicknesses were acquired and the data fitted onto a quadratic equation, which relates the reduction in photon beam intensity to the attenuation coefficient and material thickness at a reference condition. The quadratic model is used to convert the measured grey scale value into water equivalent path length (EPL) at each pixel for any material imaged by the detector. For any other non-reference conditions, scatter, field size and MU variation effects on the image were corrected by relative measurements using an ionization chamber and an EPID. The 2D EPL is linked to the percentage exit dose table, for different thicknesses and field sizes, thereby converting the plane pixel values at each point into a 2D dose map. The off-axis ratio is corrected using envelope and boundary profiles generated from the treatment planning system (TPS). The method requires field size, monitor unit and source-to-surface distance (SSD) as clinical input parameters to predict the exit dose, which is then used to determine the entrance dose. The measured pixel dose maps were compared with calculated doses from TPS for both entrance and exit depth of phantom. The gamma index at 3% dose difference (DD) and 3 mm distance to agreement (DTA) resulted in an average of 97% passing for the square fields of 5, 10, 15 and 20 cm. The exit dose EPID dose distributions predicted by the algorithm were in better agreement with TPS-calculated doses than phantom entrance dose distributions.

  15. Predictive factors for erectile dysfunction in men with prostate cancer after brachytherapy: Is dose to the penile bulb important?

    SciTech Connect

    Macdonald, A. Graham . E-mail: gmacdonald@easynet.co.uk; Keyes, Mira; Kruk, Alexandra; Duncan, Graeme; Moravan, Veronika; Morris, W. James

    2005-09-01

    Purpose: To determine predictive factors for postimplant erectile dysfunction (ED) in a cohort of patients, according to prospectively collected data; specifically, to assess the impact of penile bulb volume and D50 and D95 (dose covering 50% and 95% of the penile bulb volume, respectively) on ED. Methods and Materials: Three hundred forty-two patients were identified who were potent before implant and who had at least 2 years' follow-up. Patient, tumor, treatment, and dosimetric data were collected on all patients. Postimplant ED was defined according to both physician-documented and patient-documented outcome data. Binary logistic regression analysis was used to create multivariable models of predictors for ED at 1, 2, and 3 years after implant. Results: Physician-documented rates of ED were 57%, 48%, and 38% at 1, 2, and 3 years after implant, respectively. Patient-documented rates of ED were 70% and 66% at 1 and 2 years, respectively. Multivariable analyses revealed age and degree of preimplant erectile function to be consistently significant predictors of ED. Use of hormones was significant at the 1-year physician-documented ED endpoint but not thereafter, in keeping with the time course of testosterone recovery. Penile bulb volume, D50, and D95 were not found to be predictive for ED at any time point, in contrast to previous studies. In addition, planning ultrasound target volume, number of needles, and institutional case sequence number were significant predictors of ED at various time points, consistent with a traumatic etiology of ED. Conclusions: We found no evidence to support penile bulb dosimetry as an independent predictive factor for ED after implant, using physician-documented or patient-documented outcomes.

  16. Severity of mild cognitive impairment in early Parkinson's disease contributes to poorer quality of life

    PubMed Central

    Lawson, Rachael A.; Yarnall, Alison J.; Duncan, Gordon W.; Khoo, Tien K.; Breen, David P.; Barker, Roger A.; Collerton, Daniel; Taylor, John-Paul; Burn, David J.

    2014-01-01

    Background Poor quality of life (QoL) is a feature of people with Parkinson's disease (PD) who develop dementia. The relationship between mild cognitive impairment in PD (PD-MCI) and QoL is less clear. To address this, we studied the impact of varying severities of cognitive impairment on QoL in a cohort of non-demented patients with early PD. Method Patients with newly diagnosed PD (n = 219) and age and sex matched healthy controls (n = 99) completed a schedule of neuropsychological tests, in addition to scales assessing QoL (PDQ-39), depression, sleep, neuropsychiatric symptoms and a clinical examination. The Movement Disorder Society criteria were used to define and classify PD-MCI. Results Participants with PD-MCI were significantly older than those with normal cognition, had more severe motor symptoms, scored higher for depression and had poorer quality of life. Logistic regression showed that mild cognitive impairment, independent of other factors, was an indicator of poorer QoL. Using cognitive performance 2.0 standard deviations (SD) below normative data as a cut-off to define PD-MCI, there was a significant difference in QoL scores between patients with PD-MCI and those classified as having normal cognition. Subjects with less severe mild cognitive impairment did not exhibit significant differences in QoL. Conclusions PD-MCI is a significant, independent factor contributing to poorer QoL in patients with newly diagnosed PD. Those classified with greatest impairment (2.0 SD below normal values) have lower QoL. This has implications for clinical practice and future interventions targeting cognitive impairments. PMID:25074728

  17. Modeling of Salivary Production Recovery After Radiotherapy Using Mixed Models: Determination of Optimal Dose Constraint for IMRT Planning and Construction of Convenient Tools to Predict Salivary Function

    SciTech Connect

    Ortholan, Cecile Chamorey, Emmanuel Phar; Benezery, Karen; Thariat, Juliette; Dassonville, Olivier; Poissonnet, Gilles; Bozec, Alexandre; Follana, Philippe; Peyrade, Frederique; Sudaka, Anne; Gerard, Jean Pierre; Bensadoun, Rene Jean

    2009-01-01

    Purpose: The mathematical relationship between the dose to the parotid glands and salivary gland production needs to be elucidated. This study, which included data from patients included in a French prospective study assessing the benefit of intensity-modulated radiotherapy (RT), sought to elaborate a convenient and original model of salivary recovery. Methods and Materials: Between January 2001 and December 2004, 44 patients were included (35 with oropharyngeal and 9 with nasopharyngeal cancer). Of the 44 patients, 24 were treated with intensity-modulated RT, 17 with three-dimensional conformal RT, and 2 with two-dimensional RT. Stimulated salivary production was collected for {<=}24 months after RT. The data of salivary production, time of follow-up, and dose to parotid gland were modeled using a mixed model. Several models were developed to assess the best-fitting variable for the dose level to the parotid gland. Results: Models developed with the dose to the contralateral parotid fit the data slightly better than those with the dose to both parotids, suggesting that contralateral and ipsilateral parotid glands are not functionally equivalent even with the same dose level to the glands. The best predictive dose-value variable for salivary flow recovery was the volume of the contralateral parotid gland receiving >40 Gy. Conclusion: The results of this study show that the recommendation of a dose constraint for intensity-modulated RT planning should be established at the volume of the contralateral parotid gland receiving >40 Gy rather than the mean dose. For complete salivary production recovery after 24 months, the volume of the contralateral parotid gland receiving >40 Gy should be <33%. Our results permitted us to establish two convenient tools to predict the saliva production recovery function according to the dose received by the contralateral parotid gland.

  18. Do poorer people have poorer access to local resources and facilities? The distribution of local resources by area deprivation in Glasgow, Scotland.

    PubMed

    Macintyre, Sally; Macdonald, Laura; Ellaway, Anne

    2008-09-01

    It has commonly been suggested that in modern cities individual or household deprivation (for example, low income or education) is amplified by area level deprivation (for example, lack of jobs or good schools), in ways which damage the health of the poorest and increase health inequalities. The aim of this study was to determine the location of a range of resources and exposures by deprivation in a UK city. We examined the location of 42 resources in Glasgow City, Scotland, in 2005-2006, by quintile of small area deprivation. Measures included number per 1000 population, network distance to nearest resource, and percentage of data zones containing at least one of each type of resource. Twelve resources had higher density in, and/or were closer to or more common in, more deprived neighbourhoods: public nurseries, public primary schools, police stations, pharmacies, credit unions, post offices, bus stops, bingo halls, public swimming pools, public sports centres, outdoor play areas, and vacant and derelict land/buildings. Sixteen had higher density in, and/or were closer to, or more common in, more affluent neighbourhoods: public secondary schools, private schools, banks, building societies, museums/art galleries, railway stations, subway stations, tennis courts, bowling greens, private health clubs, private swimming pools, colleges, A & E hospitals, parks, waste disposal sites, and tourist attractions. Private nurseries, Universities, fire stations, general, dental and ophthalmic practices, pawn brokers, ATMs, supermarkets, fast food chains, cafes, public libraries, golf courses, and cinemas showed no clear pattern by deprivation. Thus it appears that in the early 21st century access to resources does not always disadvantage poorer neighbourhoods in the UK. We conclude that we need to ensure that theories and policies are based on up-to-date and context-specific empirical evidence on the distribution of neighbourhood resources, and to engage in further research on

  19. Do poorer people have poorer access to local resources and facilities? The distribution of local resources by area deprivation in Glasgow, Scotland☆

    PubMed Central

    Macintyre, Sally; Macdonald, Laura; Ellaway, Anne

    2008-01-01

    It has commonly been suggested that in modern cities individual or household deprivation (for example, low income or education) is amplified by area level deprivation (for example, lack of jobs or good schools), in ways which damage the health of the poorest and increase health inequalities. The aim of this study was to determine the location of a range of resources and exposures by deprivation in a UK city. We examined the location of 42 resources in Glasgow City, Scotland, in 2005–2006, by quintile of small area deprivation. Measures included number per 1000 population, network distance to nearest resource, and percentage of data zones containing at least one of each type of resource. Twelve resources had higher density in, and/or were closer to or more common in, more deprived neighbourhoods: public nurseries, public primary schools, police stations, pharmacies, credit unions, post offices, bus stops, bingo halls, public swimming pools, public sports centres, outdoor play areas, and vacant and derelict land/buildings. Sixteen had higher density in, and/or were closer to, or more common in, more affluent neighbourhoods: public secondary schools, private schools, banks, building societies, museums/art galleries, railway stations, subway stations, tennis courts, bowling greens, private health clubs, private swimming pools, colleges, A & E hospitals, parks, waste disposal sites, and tourist attractions. Private nurseries, Universities, fire stations, general, dental and ophthalmic practices, pawn brokers, ATMs, supermarkets, fast food chains, cafes, public libraries, golf courses, and cinemas showed no clear pattern by deprivation. Thus it appears that in the early 21st century access to resources does not always disadvantage poorer neighbourhoods in the UK. We conclude that we need to ensure that theories and policies are based on up-to-date and context-specific empirical evidence on the distribution of neighbourhood resources, and to engage in further research

  20. Predictive value of phase I trials for safety in later trials and final approved dose: analysis of 61 approved cancer drugs.

    PubMed

    Jardim, Denis L; Hess, Kenneth R; Lorusso, Patricia; Kurzrock, Razelle; Hong, David S

    2014-01-15

    Phase I trials use a small number of patients to define a maximum tolerated dose (MTD) and the safety of new agents. We compared data from phase I and registration trials to determine whether early trials predicted later safety and final dose. We searched the U.S. Food and Drug Administration (FDA) website for drugs approved in nonpediatric cancers (January 1990-October 2012). The recommended phase II dose (R2PD) and toxicities from phase I were compared with doses and safety in later trials. In 62 of 85 (73%) matched trials, the dose from the later trial was within 20% of the RP2D. In a multivariable analysis, phase I trials of targeted agents were less predictive of the final approved dose (OR, 0.2 for adopting ± 20% of the RP2D for targeted vs. other classes; P = 0.025). Of the 530 clinically relevant toxicities in later trials, 70% (n = 374) were described in phase I. A significant relationship (P = 0.0032) between increasing the number of patients in phase I (up to 60) and the ability to describe future clinically relevant toxicities was observed. Among 28,505 patients in later trials, the death rate that was related to drug was 1.41%. In conclusion, dosing based on phase I trials was associated with a low toxicity-related death rate in later trials. The ability to predict relevant toxicities correlates with the number of patients on the initial phase I trial. The final dose approved was within 20% of the RP2D in 73% of assessed trials. PMID:24190980

  1. Prediction of Acute Radiation Mucositis using an Oral Mucosal Dose Surface Model in Carbon Ion Radiotherapy for Head and Neck Tumors

    PubMed Central

    Musha, Atsushi; Shimada, Hirofumi; Shirai, Katsuyuki; Saitoh, Jun-ichi; Yokoo, Satoshi; Chikamatsu, Kazuaki; Ohno, Tatsuya; Nakano, Takashi

    2015-01-01

    Purpose To evaluate the dose-response relationship for development of acute radiation mucositis (ARM) using an oral mucosal dose surface model (OMDS-model) in carbon ion radiotherapy (C-ion RT) for head and neck tumors. Methods Thirty-nine patients receiving C-ion RT for head and neck cancer were evaluated for ARM (once per week for 6 weeks) according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, and the Radiation Therapy Oncology Group (RTOG) scoring systems. The irradiation schedule typically used was 64 Gy [relative biological effectiveness (RBE)] in 16 fractions for 4 weeks. Maximum point doses in the palate and tongue were compared with ARM in each patient. Results The location of the ARM coincided with the high-dose area in the OMDS-model. There was a clear dose-response relationship between maximum point dose and ARM grade assessed using the RTOG criteria but not the CTCAE. The threshold doses for grade 2–3 ARM in the palate and tongue were 43.0 Gy(RBE) and 54.3 Gy(RBE), respectively. Conclusions The OMDS-model was useful for predicting the location and severity of ARM. Maximum point doses in the model correlated well with grade 2–3 ARM. PMID:26512725

  2. Higher infused lymphocyte dose predicts higher lymphocyte recovery, which in turn, predicts superior overall survival following autologous hematopoietic stem cell transplantation for multiple myeloma.

    PubMed

    Hiwase, Devendra K; Hiwase, Smita; Bailey, Michael; Bollard, Geraldine; Schwarer, Anthony P

    2008-01-01

    Autologous stem cell transplantation (ASCT) is the standard of care for patients with multiple myeloma (MM) younger than 70 years. However, despite this aggressive therapy most patients will still die of progressive disease. Recent reports have suggested that lymphocyte recovery is an important predictor of relapse or progressive disease in a number of hematologic malignancies including MM. We have conducted retrospective analysis of factors that could predict overall (OS) and progression free survival (PFS) in patients with MM who had ASCT. One hundred nineteen patients with multiple myeloma underwent ASCT. The median OS and PFS were 64 and 32 months, respectively. Univariate and multivariate analysis using Cox proportional hazards regression model showed that absolute lymphocyte count on day 30 following ASCT (ALC-30), international staging system (ISS) stage at diagnosis, and age at diagnosis significantly influenced OS and PFS following ASCT. OS (96 versus 48 months, P = .04) and PFS (43 versus 29 months, P = .03) following ASCT were higher in patients with ALC-30 >or=1.0 x 10(9)/L compared to patients ALC-30 <1.0 x 10(9)/L. Higher ALC-60, ALC-100, ALC-180, and ALC-365 did not predict superior OS and PFS. Patients with early-stage disease had significantly higher OS (ISS stages I, II, and III: 96, 53, and 29 months, respectively; P = .0023) and PFS (ISS stages I, II, and III: 55.5, 31, and 12 months, respectively; P = .027) compared to patients with advanced-stage disease at diagnosis. On univariate analysis, the type of initial chemotherapy (melphalan, VAD, PCAB), lymphocyte count on day of leukapheresis, and the lymphocyte dose infused (LY-DO) significantly influenced lymphocyte recovery following ASCT. Patients who received higher lymphocyte dose (LY-DO) >or=0.2 x 10(9)/kg had higher median ALC-15 (0.25 versus 0.19 x 10(9)/L; P = .3), ALC-30 (1.20 versus 0.99 x 10(9)/L; P = .08), ALC-60 (1.90 versus 1.01 x 10(9)/L; P = .013), ALC-100 (1.58 versus 1.03 x 10

  3. A photobleaching-based PDT dose metric predicts PDT efficacy over certain BPD concentration ranges in a three-dimensional model of ovarian cancer

    NASA Astrophysics Data System (ADS)

    Anbil, S.; Rizvi, I.; Celli, J. P.; Alagic, N.; Hasan, T.

    2013-03-01

    Photodynamic therapy (PDT) dosimetry is an active area of study that is motivated by the need to reliably predict treatment outcomes. Implicit dosimetric parameters, such as photosensitizer (PS) photobleaching, may indicate PDT efficacy and could establish a framework to provide patient-customized PDT. Here, tumor destruction and benzoporphryin-derivative (BPD) photobleaching are characterized by systematically varying BPD-light combinations to achieve fixed PDT doses (M * J * cm-2) in a three-dimensional (3D) model of micrometastatic ovarian cancer (OvCa). It is observed that the BPD-light parameters used to construct a given PDT dose significantly impact nodule viability and BPD photobleaching. As a result, PDT dose, when measured by the product of BPD concentration and fluence, does not reliably predict overall efficacy. A PDT dose metric that incorporates a term for BPD photobleaching more robustly predicts PDT efficacy at low concentrations of BPD. These results suggest that PDT dose metrics that are informed by implicit approaches to dosimetry could improve the reliability of PDT-based regimens and provide opportunities for patient-specific treatment planning.

  4. Predictive dose-based estimation of systemic exposure multiples in mouse and monkey relative to human for antisense oligonucleotides with 2'-o-(2-methoxyethyl) modifications.

    PubMed

    Yu, Rosie Z; Grundy, John S; Henry, Scott P; Kim, Tae-Won; Norris, Daniel A; Burkey, Jennifer; Wang, Yanfeng; Vick, Andrew; Geary, Richard S

    2015-01-01

    Evaluation of species differences and systemic exposure multiples (or ratios) in toxicological animal species versus human is an ongoing exercise during the course of drug development. The systemic exposure ratios are best estimated by directly comparing area under the plasma concentration-time curves (AUCs), and sometimes by comparing the dose administered, with the dose being adjusted either by body surface area (BSA) or body weight (BW). In this study, the association between AUC ratio and the administered dose ratio from animals to human were studied using a retrospective data-driven approach. The dataset included nine antisense oligonucleotides (ASOs) with 2'-O-(2-methoxyethyl) modifications, evaluated in two animal species (mouse and monkey) following single and repeated parenteral administrations. We found that plasma AUCs were similar between ASOs within the same species, and are predictable to human exposure using a single animal species, either mouse or monkey. Between monkey and human, the plasma exposure ratio can be predicted directly based on BW-adjusted dose ratios, whereas between mouse and human, the exposure ratio would be nearly fivefold lower in mouse compared to human based on BW-adjusted dose values. Thus, multiplying a factor of 5 for the mouse BW-adjusted dose would likely provide a reasonable AUC exposure estimate in human at steady-state. PMID:25602582

  5. Predictive Dose-Based Estimation of Systemic Exposure Multiples in Mouse and Monkey Relative to Human for Antisense Oligonucleotides With 2′-O-(2-Methoxyethyl) Modifications

    PubMed Central

    Yu, Rosie Z; Grundy, John S; Henry, Scott P; Kim, Tae-Won; Norris, Daniel A; Burkey, Jennifer; Wang, Yanfeng; Vick, Andrew; Geary, Richard S

    2015-01-01

    Evaluation of species differences and systemic exposure multiples (or ratios) in toxicological animal species versus human is an ongoing exercise during the course of drug development. The systemic exposure ratios are best estimated by directly comparing area under the plasma concentration-time curves (AUCs), and sometimes by comparing the dose administered, with the dose being adjusted either by body surface area (BSA) or body weight (BW). In this study, the association between AUC ratio and the administered dose ratio from animals to human were studied using a retrospective data-driven approach. The dataset included nine antisense oligonucleotides (ASOs) with 2′-O-(2-methoxyethyl) modifications, evaluated in two animal species (mouse and monkey) following single and repeated parenteral administrations. We found that plasma AUCs were similar between ASOs within the same species, and are predictable to human exposure using a single animal species, either mouse or monkey. Between monkey and human, the plasma exposure ratio can be predicted directly based on BW-adjusted dose ratios, whereas between mouse and human, the exposure ratio would be nearly fivefold lower in mouse compared to human based on BW-adjusted dose values. Thus, multiplying a factor of 5 for the mouse BW-adjusted dose would likely provide a reasonable AUC exposure estimate in human at steady-state. PMID:25602582

  6. Postoperative Nomogram Predicting the 9-Year Probability of Prostate Cancer Recurrence After Permanent Prostate Brachytherapy Using Radiation Dose as a Prognostic Variable

    SciTech Connect

    Potters, Louis; Roach, Mack; Davis, Brian J.; Stock, Richard G.; Ciezki, Jay P.; Zelefsky, Michael J.; Stone, Nelson N.; Fearn, Paul A.; Yu Changhong; Shinohara, Katsuto; Kattan, Michael W.

    2010-03-15

    Purpose: To report a multi-institutional outcomes study on permanent prostate brachytherapy (PPB) to 9 years that includes postimplant dosimetry, to develop a postimplant nomogram predicting biochemical freedom from recurrence. Methods and Materials: Cox regression analysis was used to model the clinical information for 5,931 patients who underwent PPB for clinically localized prostate cancer from six centers. The model was validated against the dataset using bootstrapping. Disease progression was determined using the Phoenix definition. The biological equivalent dose was calculated from the minimum dose to 90% of the prostate volume (D90) and external-beam radiotherapy dose using an alpha/beta of 2. Results: The 9-year biochemical freedom from recurrence probability for the modeling set was 77% (95% confidence interval, 73-81%). In the model, prostate-specific antigen, Gleason sum, isotope, external beam radiation, year of treatment, and D90 were associated with recurrence (each p < 0.05), whereas clinical stage was not. The concordance index of the model was 0.710. Conclusion: A predictive model for a postimplant nomogram for prostate cancer recurrence at 9-years after PPB has been developed and validated from a large multi-institutional database. This study also demonstrates the significance of implant dosimetry for predicting outcome. Unique to predictive models, these nomograms may be used a priori to calculate a D90 that likely achieves a desired outcome with further validation. Thus, a personalized dose prescription can potentially be calculated for each patient.

  7. Dexterous Manipulation Is Poorer at Older Ages and Is Dissociated From Decline of Hand Strength

    PubMed Central

    Dayanidhi, Sudarshan

    2014-01-01

    Background. The ability to dynamically control fingertip force vector magnitude and direction is critical for dexterous manipulation. We quantified the dynamic control of fingertip forces to examine how dexterous manipulation declines with age. Methods. The strength–dexterity (SD) test measures fingertip forces during compression of a slender spring prone to instability and buckling. The greatest sustained compression (designed to be under 3 N), and force dynamics therein, have been shown to be simple and quick measures of dynamic dexterous manipulation ability. We measured pinch strength and strength–dexterity test in a cross-sectional population of 98 people from 18 to 89 years of age. Results. Dexterous manipulation ability is poorer at older ages, beginning in middle age (p < .001), with greater decline past 65 years of age. Fingertip force dynamics during spring compression and stabilization show a deterioration of neuromuscular control with age. Importantly, this novel detection of decline in dynamic manipulation ability is not correlated with, and thus cannot be entirely explained by, the known decline in pinch strength. We also measured standardized tests of dexterity in participants older than 45, and discuss how the strength–dexterity test uniquely captures features of sensorimotor capabilities for dexterous manipulation in this adult population. Conclusions. Starting in middle age, changes in the functional interactions among sensory, motor, and neural capabilities result in measurably poorer dynamic dexterous manipulation. This deterioration of neuromuscular control motivates and enables future studies to understand the physiological bases for this functional decline so critical to activities of daily living and quality of life. PMID:24610868

  8. More missing teeth are associated with poorer general health in the rural Korean elderly.

    PubMed

    Lee, Hee-Kyung; Lee, Kyung-Dong; Merchant, Anwar T; Lee, Sung-Kook; Song, Keun-Bae; Lee, Sang Gyu; Choi, Youn-Hee

    2010-01-01

    The aim was to investigate the association between missing teeth and general health conditions in elderly Korean people. This cross-sectional study was conducted as a part of a health-screening program supported by the National Health Insurance Corporation of Korea in a local region of Sungju-gun, Gyeongsangbuk-do from 2000 to 2006. The participants were 3611 in number (1494 males and 2117 females) aged 60 years and over. The outcome variable was the number of missing teeth in the mouth determined by dental examination; general medical examination included blood pressure, body height and weight to compute body mass index (BMI). Laboratory investigations included aspartate transaminase (AST), hemoglobin (HB), fasting plasma glucose (FPG), and total cholesterol (CHOL). Demographic factors and smoking status were obtained from questionnaires by an interviewer. Multiple regression models were used as a statistical analysis. The subjects were classified into three groups according to the number of missing teeth (<8, 8-18, and >18). In unadjusted analyses individuals with more missing teeth, had poorer general health status (higher blood pressure, higher levels of AST, FPG, and CHOL, and higher BMI in females). In multiple regression models with the number of missing teeth as an outcome, systolic blood pressure, CHOL, FPG, and HB in males were statistically significant after adjusting for age and smoking. In females, systolic blood pressure, CHOL, FPG, and BMI were positively associated with the number of missing teeth. The number of missing teeth was positively related to poorer general health status such as blood pressure, FPG, CHOL, after adjusting for age and smoking in the rural elderly in Korea. PMID:19230988

  9. Higher sleep variability is associated with poorer glycaemic control in patients with type 1 diabetes.

    PubMed

    Chontong, Sasipas; Saetung, Sunee; Reutrakul, Sirimon

    2016-08-01

    Sleep disturbances have been linked to insulin resistance and poor glycaemic control in patients with type 2 diabetes. However, the data are limited in type 1 diabetes. Recently, varying day-to-day sleep schedules, i.e. sleep variability, have been associated with adverse metabolic profile in healthy individuals. This study explored whether sleep variability affects glycaemic control and insulin requirement in type 1 diabetes. Forty-one adult patients with type 1 diabetes wore an actigraphy for 5 nights. Standard deviation of sleep duration, efficiency and mid-sleep time were sleep variability parameters. Sleep apnoea risk and self-reported sleep quality were assessed by the Berlin questionnaire and Pittsburgh Sleep Quality Index. Haemoglobin A1c, diabetes complications and insulin regimen were obtained from medical records. After adjusting for neuropathic symptoms, sleep apnoea risk and poor self-reported sleep quality, higher sleep variability was significantly associated with poorer glycaemic control (standard deviation of sleep duration, B = 0.100, P = 0.004; and standard deviation of mid-sleep time, B = 0.068, P = 0.04). In addition, standard deviations of sleep duration and mid-sleep time were highly correlated, suggesting that participants changed their sleep duration along with sleep timing. After adjusting for covariates, the standard deviation of sleep duration (P = 0.009) and standard deviation of mid-sleep time (P = 0.012) were associated with higher insulin requirement. In summary, higher sleep variability, which likely reflects sleep deprivation alternating with sleep compensation along with shifts in their circadian timing, was associated with poorer glycaemic control and higher insulin requirement in patients with type 1 diabetes. Increased sleep regularity may improve metabolic control in type 1 diabetes. PMID:26912272

  10. Prediction of nonresponsiveness to medium-dose intravenous immunoglobulin (1 g/kg) treatment: an effective and safe schedule of acute treatment for Kawasaki disease

    PubMed Central

    Moon, Kyung Pil; Kim, Beom Joon; Lee, Kyu Jin; Oh, Jin Hee; Han, Ji Whan; Lee, Kyung Yil

    2016-01-01

    Purpose Medium-dose (1 g/kg) intravenous immunoglobulin (IVIG) is effective in the majority of patients with Kawasaki disease (KD) but some patients who do not respond to medium-dose IVIG are at high risk for the development of coronary artery lesions (CALs). The purpose of this study was to identify the clinical predictors associated with unresponsiveness to medium-dose IVIG and the development of CALs. Methods A retrospective study was performed in 91 children with KD who were treated with medium-dose IVIG at our institution from January 2004 to December 2013. We classified the patients into responders (group 1; n=68) and nonresponders (group 2; n=23). We compared demographic, laboratory, and echocardiographic data between the 2 groups. Results Multivariate logistic regression analysis identified 6 variables as predictors for resistance to medium-dose IVIG. We generated a predictive scoring system assigning 1 point each for percentage of neutrophils ≥65%, C-reactive protein≥100 mg/L, aspartate aminotransferase≥100 IU/L, and alanine aminotransferase≥100 IU/L, as well as 2 points for less than 5 days of illness, and serum sodium level≤136 mmol/L. Using a cutoff point of ≥4 with this scoring system, we could predict nonresponsiveness to medium-dose IVIG with 74% sensitivity and 71% specificity. Conclusion If a patient has a low-risk score in this system, medium-dose IVIG can be recommended as the initial treatment. Through this process, we can minimize the adverse effects of high-dose IVIG and incidence of CALs. PMID:27186228

  11. A Semiphysiologically Based Pharmacokinetic Modeling Approach to Predict the Dose-Exposure Relationship of an Antiparasitic Prodrug/Active Metabolite Pair

    PubMed Central

    Yan, Grace Zhixia; Generaux, Claudia N.; Yoon, Miyoung; Goldsmith, Rachel B.; Tidwell, Richard R.; Hall, James E.; Olson, Carol A.; Clewell, Harvey J.; Brouwer, Kim L. R.

    2012-01-01

    Dose selection during antiparasitic drug development in animal models and humans traditionally has relied on correlations between plasma concentrations obtained at or below maximally tolerated doses that are efficacious. The objective of this study was to improve the understanding of the relationship between dose and plasma/tissue exposure of the model antiparasitic agent, pafuramidine, using a semiphysiologically based pharmacokinetic (semi-PBPK) modeling approach. Preclinical and clinical data generated during the development of pafuramidine, a prodrug of the active metabolite, furamidine, were used. A whole-body semi-PBPK model for rats was developed based on a whole-liver PBPK model using rat isolated perfused liver data. A whole-body semi-PBPK model for humans was developed on the basis of the whole-body rat model. Scaling factors were calculated using metabolic and transport clearance data generated from rat and human sandwich-cultured hepatocytes. Both whole-body models described pafuramidine and furamidine disposition in plasma and predicted furamidine tissue (liver and kidney) exposure and excretion profiles (biliary and renal). The whole-body models predicted that the intestine contributes significantly (30–40%) to presystemic furamidine formation in both rats and humans. The predicted terminal elimination half-life of furamidine in plasma was 3- to 4-fold longer than that of pafuramidine in rats (170 versus 47 h) and humans (64 versus 19 h). The dose-plasma/tissue exposure relationship for the prodrug/active metabolite pair was determined using the whole-body models. The human model proposed a dose regimen of pafuramidine (40 mg once daily) based on a predefined efficacy-safety index. A similar approach could be used to guide dose-ranging studies in humans for next-in-class compounds. PMID:21953913

  12. Prediction of Therapy Tumor-Absorbed Dose Estimates in I-131 Radioimmunotherapy Using Tracer Data Via a Mixed-Model Fit to Time Activity

    PubMed Central

    Koral, Kenneth F.; Avram, Anca M.; Kaminski, Mark S.; Dewaraja, Yuni K.

    2012-01-01

    Abstract Background For individualized treatment planning in radioimmunotherapy (RIT), correlations must be established between tracer-predicted and therapy-delivered absorbed doses. The focus of this work was to investigate this correlation for tumors. Methods The study analyzed 57 tumors in 19 follicular lymphoma patients treated with I-131 tositumomab and imaged with SPECT/CT multiple times after tracer and therapy administrations. Instead of the typical least-squares fit to a single tumor's measured time-activity data, estimation was accomplished via a biexponential mixed model in which the curves from multiple subjects were jointly estimated. The tumor-absorbed dose estimates were determined by patient-specific Monte Carlo calculation. Results The mixed model gave realistic tumor time-activity fits that showed the expected uptake and clearance phases even with noisy data or missing time points. Correlation between tracer and therapy tumor-residence times (r=0.98; p<0.0001) and correlation between tracer-predicted and therapy-delivered mean tumor-absorbed doses (r=0.86; p<0.0001) were very high. The predicted and delivered absorbed doses were within±25% (or within±75 cGy) for 80% of tumors. Conclusions The mixed-model approach is feasible for fitting tumor time-activity data in RIT treatment planning when individual least-squares fitting is not possible due to inadequate sampling points. The good correlation between predicted and delivered tumor doses demonstrates the potential of using a pretherapy tracer study for tumor dosimetry-based treatment planning in RIT. PMID:22947086

  13. SU-D-201-02: Prediction of Delivered Dose Based On a Joint Histogram of CT and FDG PET Images

    SciTech Connect

    Park, M; Choi, Y; Cho, A; Hwang, S; Cha, J; Lee, N; Yun, M

    2015-06-15

    Purpose: To investigate whether pre-treatment images can be used in predicting microsphere distribution in tumors. When intra-arterial radioembolization using Y90 microspheres was performed, the microspheres were often delivered non-uniformly within the tumor, which could lead to an inefficient therapy. Therefore, it is important to estimate the distribution of microspheres. Methods: Early arterial phase CT and FDG PET images were acquired for patients with primary liver cancer prior to radioembolization (RE) using Y90 microspheres. Tumor volume was delineated on CT images and fused with FDG PET images. From each voxel (3.9×3.9×3.3 mm3) in the tumor, the Hounsfield unit (HU) from the CT and SUV values from the FDG PET were harvested. We binned both HU and SUV into 11 bins and then calculated a normalized joint-histogram in an 11×11 array.Patients also underwent a post-treatment Y90 PET imaging. Radiation dose for the tumor was estimated using convolution of the Y90 distribution with a dose-point kernel. We also calculated a fraction of the tumor volume that received a radiation dose great than 100Gy. Results: Averaged over 40 patients, 55% of tumor volume received a dose greater than 100Gy (range : 1.1 – 100%). The width of the joint histogram was narrower for patients with a high dose. For patients with a low dose, the width was wider and a larger fraction of tumor volume had low HU. Conclusion: We have shown the pattern of joint histogram of the HU and SUV depends on delivered dose. The patterns can predict the efficacy of uniform intra-arterial delivery of Y90 microspheres.

  14. Code System for Real-Time Prediction of Radiation Dose to the Public Due to an Accidental Release from a Nuclear Power Plant.

    Energy Science and Technology Software Center (ESTSC)

    1987-01-20

    Version 00 The suite of computer codes, SPEEDI, predicts the dose to the public from a plume released from a nuclear power plant. The main codes comprising SPEEDI are: WIND04, PRWDA, and CIDE. WIND04 calculates three-dimensional mass-conservative windfields. PRWDA calculates concentration distributions, and CIDE estimates the external and internal doses. These models can take into account the spatial and temporal variation of wind, variable topography, deposition and variable source intensity for use in real-time assessment.more » We recommend that you also review the emergency response supporting system CCC-661/ EXPRESS documentation.« less

  15. The Observed Variance Between Predicted and Measured Radiation Dose in Breast and Prostate Patients Utilizing an In Vivo Dosimeter

    SciTech Connect

    Scarantino, Charles W. Prestidge, Bradley R.; Anscher, Mitchel S.; Ferree, Carolyn R.; Kearns, William T.; Black, Robert D.; Bolick, Natasha G.; Beyer, Gloria P.

    2008-10-01

    Purpose: Report the results of using a permanently implantable dosimeter in radiation therapy: determine specific adverse events, degree of migration, and acquire dose measurements during treatment to determine difference between expected and measured dose. Methods and Materials: The Dose Verification System is a wireless, permanently implantable metal-oxide semiconductor field-effect transistor dosimeter using a bidirectional antenna for power and data transfer. The study cohort includes 36 breast (33 patients received two devices) and 29 prostate (21 patients received two devices) cancer patients. A total of 1,783 and 1,749 daily dose measurements were obtained on breast and prostate patients, respectively. The measurements were compared with the planned expected dose. Biweekly computed tomography scans were obtained to evaluate migration and the National Cancer Institute's Common Toxicity Criteria, version 3, was used to evaluate adverse events. Results: Only Grade I/II adverse events of pain and bleeding were noted. There were only four instances of dosimeter migration of >5 mm from known factors. A deviation of {>=}7% in cumulative dose was noted in 7 of 36 (19%) for breast cancer patients. In prostate cancer patients, a {>=}7% deviation was noted in 6 of 29 (21%) and 8 of 19 (42%) during initial and boost irradiation, respectively. The two patterns of dose deviation were random and systematic. Some causes for these differences could involve organ movement, patient movement, or treatment plan considerations. Conclusions: The Dose Verification System was not associated with significant adverse events or migration. The dosimeter can measure dose in situ on a daily basis. The accuracy and utility of the dose verification system complements current image-guided radiation therapy and intensity-modulated radiation therapy techniques.

  16. From active shape model to active optical flow model: a shape-based approach to predicting voxel-level dose distributions in spine SBRT

    NASA Astrophysics Data System (ADS)

    Liu, Jianfei; Wu, Q. Jackie; Kirkpatrick, John P.; Yin, Fang-Fang; Yuan, Lulin; Ge, Yaorong

    2015-03-01

    Prediction of achievable dose distribution in spine stereotactic body radiation therapy (SBRT) can help in designing high-quality treatment plans to maximally protect spinal cords and to effectively control tumours. Dose distributions at spinal cords are primarily affected by the shapes of adjacent planning target volume (PTV) contours. In this work, we estimate such contour effects and predict dose distributions by exploring active optical flow model (AOFM) and active shape model (ASM). We first collect a sequence of dose sub-images and PTV contours near spinal cords from fifteen SBRT plans in the training dataset. The data collection is then classified into five groups according to the PTV locations in relation to spinal cords. In each group, we randomly choose a dose sub-image as the reference and register all other sub-images to the reference using an optical flow method. AOFM is then constructed by importing optical flow vectors and dose values into the principal component analysis (PCA). Similarly, we build ASM by using PCA on PTV contour points. The correlation between ASM and AOFM is estimated via a stepwise multiple regression model. When predicting dose distribution of a new case, the group is first determined based on the PTV contour. The prediction model of the selected group is used to estimate dose distributions by mapping the PTV contours from the ASM space to the AOFM space. This method was validated on fifteen SBRT plans in the testing dataset. Analysis of dose-volume histograms revealed that the important D2%, D5%, D10% and D0.1cc dosimetric parameters of spinal cords between the prediction and the clinical plans were 11.7  ±  1.7 Gy versus 11.8  ±  1.7 Gy (p = 0.95), 10.9  ±  1.7 Gy versus 11.1  ±  1.9 Gy (p = 0.8295), 10.2  ±  1.6 Gy versus 10.1  ±  1.7 (p = 0.9036) and 11.2  ±  2.0 Gy versus 11.1  ±  2.2 Gy (p = 0.5208), respectively. Here, the ‘cord’ is the spinal cord proper (not the

  17. Temporal Lobe Reactions After Carbon Ion Radiation Therapy: Comparison of Relative Biological Effectiveness–Weighted Tolerance Doses Predicted by Local Effect Models I and IV

    SciTech Connect

    Gillmann, Clarissa; Jäkel, Oliver; Schlampp, Ingmar; Karger, Christian P.

    2014-04-01

    Purpose: To compare the relative biological effectiveness (RBE)–weighted tolerance doses for temporal lobe reactions after carbon ion radiation therapy using 2 different versions of the local effect model (LEM I vs LEM IV) for the same patient collective under identical conditions. Methods and Materials: In a previous study, 59 patients were investigated, of whom 10 experienced temporal lobe reactions (TLR) after carbon ion radiation therapy for low-grade skull-base chordoma and chondrosarcoma at Helmholtzzentrum für Schwerionenforschung (GSI) in Darmstadt, Germany in 2002 and 2003. TLR were detected as visible contrast enhancements on T1-weighted MRI images within a median follow-up time of 2.5 years. Although the derived RBE-weighted temporal lobe doses were based on the clinically applied LEM I, we have now recalculated the RBE-weighted dose distributions using LEM IV and derived dose-response curves with Dmax,V-1 cm³ (the RBE-weighted maximum dose in the remaining temporal lobe volume, excluding the volume of 1 cm³ with the highest dose) as an independent dosimetric variable. The resulting RBE-weighted tolerance doses were compared with those of the previous study to assess the clinical impact of LEM IV relative to LEM I. Results: The dose-response curve of LEM IV is shifted toward higher values compared to that of LEM I. The RBE-weighted tolerance dose for a 5% complication probability (TD{sub 5}) increases from 68.8 ± 3.3 to 78.3 ± 4.3 Gy (RBE) for LEM IV as compared to LEM I. Conclusions: LEM IV predicts a clinically significant increase of the RBE-weighted tolerance doses for the temporal lobe as compared to the currently applied LEM I. The limited available photon data do not allow a final conclusion as to whether RBE predictions of LEM I or LEM IV better fit better clinical experience in photon therapy. The decision about a future clinical application of LEM IV therefore requires additional analysis of temporal lobe reactions in a

  18. Increased attrition of leukocyte telomere length in young adults is associated with poorer cognitive function in midlife.

    PubMed

    Cohen-Manheim, Irit; Doniger, Glen Michael; Sinnreich, Ronit; Simon, Ely Samuel; Pinchas, Ronit; Aviv, Abraham; Kark, Jeremy David

    2016-02-01

    Evidence for an association of leukocyte telomere length (LTL) with cognitive function, predominantly in older adults, is inconsistent. No report has examined the association of LTL dynamics (age-specific LTL and its attrition rate) with cognitive function. We aimed to examine the association of LTL dynamics over 13 years in young adulthood with cognitive function in midlife. 497 individuals who had LTL measured at ages 28-32 and 41-46 years were assessed at ages 48-52 for global cognitive function and its five specific component domains with a NeuroTrax computerized test battery. Multivariable regression and logistic models were applied for cognition treated as a continuous and categorical variable, respectively. We found that LTL attrition (adjusted for sex, baseline LTL and potential confounders including socioeconomic variables) was inversely associated with global cognition (standardized β = -.119, p = .004) and its component domains: information processing speed (β = -.102, p = .024), visual-spatial function (β = -.102, p = .017) and memory (β = -.093, p = .045), but less so for the attention and executive domains. The multivariable-adjusted odds ratio for low global cognition comparing the upper versus lower thirds of LTL attrition was 2.12 (95 % CI 1.11-4.08, p for trend = .023). There was no association of baseline or follow-up LTL with cognition. No effect modification was evident for sex, smoking or inflammatory markers. In conclusion, faster LTL attrition in young adulthood was associated with poorer global and domain-specific cognitive function in midlife, suggesting that more rapid LTL attrition may be predictive of cognitive aging in healthy young adults. PMID:26076919

  19. Nevirapine exposure with WHO pediatric weight band dosing: enhanced therapeutic concentrations predicted based on extensive international pharmacokinetic experience.

    PubMed

    Nikanjam, Mina; Kabamba, Desiré; Cressey, Tim R; Burger, David; Aweeka, Francesca T; Acosta, Edward P; Spector, Stephen A; Capparelli, Edmund V

    2012-10-01

    Nevirapine (NVP) is a nonnucleoside reverse transcriptase inhibitor (NNRTI) used worldwide as part of combination antiretroviral therapy in infants and children to treat HIV infection. Dosing based on either weight or body surface area has been approved by the U.S. Food and Drug Administration (FDA) but can be difficult to implement in resource-limited settings. The World Health Organization (WHO) has developed simplified weight band dosing for NVP, but it has not been critically evaluated. NVP pharmacokinetic data were combined from eight pediatric clinical trials (Pediatric AIDS Clinical Trials Group [PACTG] studies 245, 356, 366, 377, 403, 1056, and 1069 and Children with HIV in Africa Pharmacokinetics and Adherence of Simple Antiretroviral Regimens [CHAPAS]) representing subjects from multiple continents and across the pediatric age continuum. A population pharmacokinetic model was developed to characterize developmental changes in NVP disposition, identify potential sources of NVP pharmacokinetic variability, and assess various pediatric dosing strategies and their impact on NVP exposure. Age, CYP2B6 genotype, and ritonavir were independent predictors of oral NVP clearance. The Triomune fixed-dose tablet was an independent predictor of bioavailability compared to the liquid and other tablet formulations. Monte Carlo simulations of the final model were used to assess WHO weight band dosing recommendations. The final pharmacokinetic model indicated that WHO weight band dosing is likely to result in a percentage of children with NVP exposure within the target range similar to that obtained with FDA dosing. Weight band dosing of NVP proposed by the WHO has the potential to provide a simple and effective dosing strategy for resource limited settings. PMID:22869579

  20. Elevated intraindividual variability in methamphetamine dependence is associated with poorer everyday functioning.

    PubMed

    Morgan, Erin E; Doyle, Katie L; Minassian, Arpi; Henry, Brook L; Perry, William; Marcotte, Thomas D; Woods, Steven Paul; Grant, Igor

    2014-12-15

    Methamphetamine (MA) dependence is associated with executive dysfunction, but no studies have evaluated MA-related elevations in neurocognitive intraindividual variability (IIV), an expression of cognitive dyscontrol linked to poor daily functioning in populations with frontal systems injury. We examined IIV during a vigilance task in a well-characterized sample of 35 MA-dependent (MA+) and 55 non-MA using comparison participants (MA-) as part of a larger neuropsychological battery that included self-report and performance-based measures of everyday functioning. A mixed model ANOVA was conducted while controlling for covariates, including factors that differed between the groups (e.g., education) and those with conceptual relevance to IIV: mean reaction time, global cognitive performance, and HIV-infection (which was comparable across groups; p=0.32). This analysis revealed significantly elevated IIV among MA+ relative to MA- individuals that was comparable in magnitude across all trial blocks of the vigilance task. Within the MA group, elevated IIV was associated with executive dysfunction, psychomotor slowing, and recency of MA use, as well as poorer automobile driving simulator performance, worse laboratory-based functional skills, and more cognitive complaints. MA-users are vulnerable to IIV elevation, likely due to cognitive dyscontrol, which may increase their risk of real-world problems. PMID:25081313

  1. High expression of RUNX1 is associated with poorer outcomes in cytogenetically normal acute myeloid leukemia.

    PubMed

    Fu, Lin; Fu, Huaping; Tian, Lei; Xu, Keman; Hu, Kai; Wang, Jing; Wang, Jijun; Jing, Hongmei; Shi, Jinlong; Ke, Xiaoyan

    2016-03-29

    Depending on its expression level, RUNX1 can act as a tumor promoter or suppressor in hematological malignancies. The clinical impact of RUNX1 expression in cytogenetically normal acute myeloid leukemia (CN-AML) remained unknown, however. We evaluated the prognostic significance of RUNX1 expression using several public microarray datasets. In the testing group (n = 157), high RUNX1 expression (RUNX1high) was associated with poorer overall survival (OS; P = 0.0025) and event-free survival (EFS; P = 0.0025) than low RUNX1 expression (RUNX1low). In addition, the prognostic significance of RUNX1 was confirmed using European Leukemia Net (ELN) genetic categories and multivariable analysis, which was further validated using a second independent CN-AML cohort (n = 162, OS; P = 0.03953). To better understand the mechanisms of RUNX1, we investigated genome-wide gene/microRNAs expression signatures and cell signaling pathways associated with RUNX1 expression status. Several known oncogenes/oncogenic microRNAs and cell signaling pathways were all up-regulated, while some anti-oncogenes and molecules of immune activation were down-regulated in RUNX1high CN-AML patients. These findings suggest RUNX1high is a prognostic biomarker of unfavorable outcome in CN-AML, which is supported by the distinctive gene/microRNA signatures and cell signaling pathways. PMID:26910834

  2. High expression of RUNX1 is associated with poorer outcomes in cytogenetically normal acute myeloid leukemia

    PubMed Central

    Xu, Keman; Hu, Kai; Wang, Jing; Wang, Jijun; Jing, Hongmei; Shi, Jinlong; Ke, Xiaoyan

    2016-01-01

    Depending on its expression level, RUNX1 can act as a tumor promoter or suppressor in hematological malignancies. The clinical impact of RUNX1 expression in cytogenetically normal acute myeloid leukemia (CN-AML) remained unknown, however. We evaluated the prognostic significance of RUNX1 expression using several public microarray datasets. In the testing group (n = 157), high RUNX1 expression (RUNX1high) was associated with poorer overall survival (OS; P = 0.0025) and event-free survival (EFS; P = 0.0025) than low RUNX1 expression (RUNX1low). In addition, the prognostic significance of RUNX1 was confirmed using European Leukemia Net (ELN) genetic categories and multivariable analysis, which was further validated using a second independent CN-AML cohort (n = 162, OS; P = 0.03953). To better understand the mechanisms of RUNX1, we investigated genome-wide gene/microRNAs expression signatures and cell signaling pathways associated with RUNX1 expression status. Several known oncogenes/oncogenic microRNAs and cell signaling pathways were all up-regulated, while some anti-oncogenes and molecules of immune activation were down-regulated in RUNX1high CN-AML patients. These findings suggest RUNX1high is a prognostic biomarker of unfavorable outcome in CN-AML, which is supported by the distinctive gene/microRNA signatures and cell signaling pathways. PMID:26910834

  3. Elevated intraindividual variability in methamphetamine dependence is associated with poorer everyday functioning

    PubMed Central

    Morgan, Erin E.; Doyle, Katie L.; Minassian, Arpi; Henry, Brook; Perry, William; Marcotte, Thomas D.; Woods, Steven Paul; Grant, Igor

    2014-01-01

    Methamphetamine (MA) dependence is associated with executive dysfunction, but no studies have evaluated MA-related elevations in neurocognitive intraindividual variability (IIV), an expression of cognitive dyscontrol linked to poor daily functioning in populations with frontal systems injury. We examined IIV during a vigilance task in a well-characterized sample of 35 MA-dependent (MA+) and 55 non-MA using comparison participants (MA−) as part of a larger neuropsychological battery that included self-report and performance-based measures of everyday functioning. A mixed model ANOVA was conducted while controlling for covariates, including factors that differed between the groups (e.g., education) and those with conceptual relevance to IIV: mean reaction time, global cognitive performance, and HIV-infection (which was comparable across groups; p = .32). This analysis revealed significantly elevated IIV among MA+ relative to MA− individuals that was comparable in magnitude across all trial blocks of the vigilance task. Within the MA group, elevated IIV was associated with executive dysfunction, psychomotor slowing, and recency of MA use, as well as poorer automobile driving simulator performance, worse laboratory-based functional skills, and more cognitive complaints. MA-users are vulnerable to IIV elevation, likely due to cognitive dyscontrol, which may increase their risk of real-world problems. PMID:25081313

  4. Liver cirrhosis leads to poorer survival in patients with end-stage renal disease

    PubMed Central

    Kim, Ae Jin; Lim, Hye Jin; Ro, Han; Jung, Ji Yong; Lee, Hyun Hee; Chung, Wookyung; Chang, Jae Hyun

    2016-01-01

    Background/Aims: Liver cirrhosis (LC) is an important problem in patients withend-stage renal disease (ESRD). Few studies have investigated the inf luence ofLC on mortality in patients with ESRD. This study investigated the associationbetween LC and mortality among patients with ESRD and compare mortality betweentwo dialysis modalities. Methods: Adult patients (≥ 18 years of age) starting dialysis for ESRD were enrolledin the present study from 2000 to 2011. We analyzed 1,069 patients withESRD; of these, 742 patients were undergoing hemodialysis (HD) and 327 patientswere undergoing peritoneal dialysis (PD). Results: The prevalence of LC was 44 of 1,069 patients (4.1%). The cumulative 1-,3-, and 5-year survival rates of noncirrhotic patients were 93%, 83%, and 73%, respectively,whereas the equivalent survival rates of cirrhotic patients were 90%,68%, and 48%, respectively (p = 0.011). After adjustment, LC was an independentrisk factor for death in patients with ESRD. No difference in mortality associatedwith LC was found between the HD and PD subgroups. Conclusions: Of the patients with ESRD, cirrhotic patients had poorer survivalthan noncirrhotic patients. Among patients with ESRD and LC, survival of patientsundergoing PD may be comparable with that of patients undergoing HD. PMID:27017394

  5. Predictive Models for Regional Hepatic Function Based upon 99mTc-IDA SPECT and Local Radiation Dose for Physiological Adaptive RT

    PubMed Central

    Wang, Hesheng; Feng, Mary; Frey, Kirk A.; Ten Haken, Randall K.; Lawrence, Theodore S.; Cao, Yue

    2013-01-01

    Purpose High dose radiation therapy (RT) for intrahepatic cancer is limited by the development of liver injury. This study investigated whether regional hepatic function assessed prior to and during the course of RT using 99mTc-labeled immindodiacetic acid (IDA) SPECT could predict regional liver function reserve after RT. Methods and Materials Fourteen patients treated with RT for intrahepatic cancers underwent dynamic 99mTc-IDA SPECT scans prior to RT, during, and one month after completion of RT. Indocyanine green (ICG) tests (a measure of overall liver function) were performed within 1 day of each scan. 3D volumetric hepatic extraction fraction (HEF) images of the liver were estimated by deconvolution analysis. After co-registration of the CT/SPECT and the treatment planning CT, HEF dose-response functions during and post-RT were generated. The volumetric mean of the HEFs in the whole liver was correlated with ICG clearance time. Three models, Dose, Priori and Adaptive models, were developed using multivariate linear regression to assess whether the regional HEFs measured before and during RT helped predict regional hepatic function post-RT. Results The mean of the volumetric liver HEFs was significantly correlated with ICG clearance half-life time (r = −0.80, p<0.0001), for all time points. Linear correlations between local doses and regional HEFs one month post-RT were significant in 12 patients. In the priori model, regional HEF post-RT was predicted by the planned dose and regional HEF assessed prior to RT (R=0.71, p<0.0001). In the adaptive model, regional HEF post-RT was predicted by regional HEF re-assessed during RT and the remaining planned local dose (R=0.83, p<0.0001). Conclusions 99mTc-IDA SPECT obtained during RT could be used to assess regional hepatic function and helped predict post-RT regional liver function reserve. This could support individualized adaptive radiation treatment strategies to maximize tumor control and minimize the risk of

  6. Human respiratory tract cancer risks of inhaled formaldehyde: dose-response predictions derived from biologically-motivated computational modeling of a combined rodent and human dataset.

    PubMed

    Conolly, Rory B; Kimbell, Julia S; Janszen, Derek; Schlosser, Paul M; Kalisak, Darin; Preston, Julian; Miller, Frederick J

    2004-11-01

    Formaldehyde inhalation at 6 ppm and above causes nasal squamous cell carcinoma (SCC) in F344 rats. The quantitative implications of the rat tumors for human cancer risk are of interest, since epidemiological studies have provided only equivocal evidence that formaldehyde is a human carcinogen. Conolly et al. (Toxicol. Sci. 75, 432-447, 2003) analyzed the rat tumor dose-response assuming that both DNA-reactive and cytotoxic effects of formaldehyde contribute to SCC development. The key elements of their approach were: (1) use of a three-dimensional computer reconstruction of the rat nasal passages and computational fluid dynamics (CFD) modeling to predict regional dosimetry of formaldehyde; (2) association of the flux of formaldehyde into the nasal mucosa, as predicted by the CFD model, with formation of DNA-protein cross-links (DPX) and with cytolethality/regenerative cellular proliferation (CRCP); and (3) use of a two-stage clonal growth model to link DPX and CRCP with tumor formation. With this structure, the prediction of the tumor dose response was extremely sensitive to cell kinetics. The raw dose-response data for CRCP are J-shaped, and use of these data led to a predicted J-shaped dose response for tumors, notwithstanding a concurrent low-dose-linear, directly mutagenic effect of formaldehyde mediated by DPX. In the present work the modeling approach used by Conolly et al. (ibid.) was extended to humans. Regional dosimetry predictions for the entire respiratory tract were obtained by merging a three-dimensional CFD model for the human nose with a one-dimensional typical path model for the lower respiratory tract. In other respects, the human model was structurally identical to the rat model. The predicted human dose response for DPX was obtained by scale-up of a computational model for DPX calibrated against rat and rhesus monkey data. The rat dose response for CRCP was used "as is" for the human model, since no preferable alternative was identified. Three

  7. High Graft CD8 Cell Dose Predicts Improved Survival and Enables Better Donor Selection in Allogeneic Stem-Cell Transplantation With Reduced-Intensity Conditioning

    PubMed Central

    Reshef, Ran; Huffman, Austin P.; Gao, Amy; Luskin, Marlise R.; Frey, Noelle V.; Gill, Saar I.; Hexner, Elizabeth O.; Kambayashi, Taku; Loren, Alison W.; Luger, Selina M.; Mangan, James K.; Nasta, Sunita D.; Richman, Lee P.; Sell, Mary; Stadtmauer, Edward A.; Vonderheide, Robert H.; Mick, Rosemarie; Porter, David L.

    2015-01-01

    Purpose To characterize the impact of graft T-cell composition on outcomes of reduced-intensity conditioned (RIC) allogeneic hematopoietic stem-cell transplantation (alloHSCT) in adults with hematologic malignancies. Patients and Methods We evaluated associations between graft T-cell doses and outcomes in 200 patients who underwent RIC alloHSCT with a peripheral blood stem-cell graft. We then studied 21 alloHSCT donors to identify predictors of optimal graft T-cell content. Results Higher CD8 cell doses were associated with a lower risk for relapse (adjusted hazard ratio [aHR], 0.43; P = .009) and improved relapse-free survival (aHR, 0.50; P = .006) and overall survival (aHR, 0.57; P = .04) without a significant increase in graft-versus-host disease or nonrelapse mortality. A cutoff level of 0.72 × 108 CD8 cells per kilogram optimally segregated patients receiving CD8hi and CD8lo grafts with differing overall survival (P = .007). Donor age inversely correlated with graft CD8 dose. Consequently, older donors were unlikely to provide a CD8hi graft, whereas approximately half of younger donors provided CD8hi grafts. Compared with recipients of older sibling donor grafts (consistently containing CD8lo doses), survival was significantly better for recipients of younger unrelated donor grafts with CD8hi doses (P = .03), but not for recipients of younger unrelated donor CD8lo grafts (P = .28). In addition, graft CD8 content could be predicted by measuring the proportion of CD8 cells in a screening blood sample from stem-cell donors. Conclusion Higher graft CD8 dose, which was restricted to young donors, predicted better survival in patients undergoing RIC alloHSCT. PMID:26056179

  8. TH-E-BRF-03: A Multivariate Interaction Model for Assessment of Hippocampal Vascular Dose-Response and Early Prediction of Radiation-Induced Neurocognitive Dysfunction

    SciTech Connect

    Farjam, R; Pramanik, P; Srinivasan, A; Chapman, C; Tsien, C; Lawrence, T; Cao, Y

    2014-06-15

    Purpose: Vascular injury could be a cause of hippocampal dysfunction leading to late neurocognitive decline in patients receiving brain radiotherapy (RT). Hence, our aim was to develop a multivariate interaction model for characterization of hippocampal vascular dose-response and early prediction of radiation-induced late neurocognitive impairments. Methods: 27 patients (17 males and 10 females, age 31–80 years) were enrolled in an IRB-approved prospective longitudinal study. All patients were diagnosed with a low-grade glioma or benign tumor and treated by 3-D conformal or intensity-modulated RT with a median dose of 54 Gy (50.4–59.4 Gy in 1.8− Gy fractions). Six DCE-MRI scans were performed from pre-RT to 18 months post-RT. DCE data were fitted to the modified Toft model to obtain the transfer constant of gadolinium influx from the intravascular space into the extravascular extracellular space, Ktrans, and the fraction of blood plasma volume, Vp. The hippocampus vascular property alterations after starting RT were characterized by changes in the hippocampal mean values of, μh(Ktrans)τ and μh(Vp)τ. The dose-response, Δμh(Ktrans/Vp)pre->τ, was modeled using a multivariate linear regression considering integrations of doses with age, sex, hippocampal laterality and presence of tumor/edema near a hippocampus. Finally, the early vascular dose-response in hippocampus was correlated with neurocognitive decline 6 and 18 months post-RT. Results: The μh(Ktrans) increased significantly from pre-RT to 1 month post-RT (p<0.0004). The multivariate model showed that the dose effect on Δμh(Ktrans)pre->1M post-RT was interacted with sex (p<0.0007) and age (p<0.00004), with the dose-response more pronounced in older females. Also, the vascular dose-response in the left hippocampus of females was significantly correlated with memory function decline at 6 (r = − 0.95, p<0.0006) and 18 (r = −0.88, p<0.02) months post-RT. Conclusion: The hippocampal vascular

  9. Critical Combinations of Radiation Dose and Volume Predict Intelligence Quotient and Academic Achievement Scores After Craniospinal Irradiation in Children With Medulloblastoma

    SciTech Connect

    Merchant, Thomas E.; Schreiber, Jane E.; Wu, Shengjie; Lukose, Renin; Xiong, Xiaoping; Gajjar, Amar

    2014-11-01

    Purpose: To prospectively follow children treated with craniospinal irradiation to determine critical combinations of radiation dose and volume that would predict for cognitive effects. Methods and Materials: Between 1996 and 2003, 58 patients (median age 8.14 years, range 3.99-20.11 years) with medulloblastoma received risk-adapted craniospinal irradiation followed by dose-intense chemotherapy and were followed longitudinally with multiple cognitive evaluations (through 5 years after treatment) that included intelligence quotient (estimated intelligence quotient, full-scale, verbal, and performance) and academic achievement (math, reading, spelling) tests. Craniospinal irradiation consisted of 23.4 Gy for average-risk patients (nonmetastatic) and 36-39.6 Gy for high-risk patients (metastatic or residual disease >1.5 cm{sup 2}). The primary site was treated using conformal or intensity modulated radiation therapy using a 2-cm clinical target volume margin. The effect of clinical variables and radiation dose to different brain volumes were modeled to estimate cognitive scores after treatment. Results: A decline with time for all test scores was observed for the entire cohort. Sex, race, and cerebrospinal fluid shunt status had a significant impact on baseline scores. Age and mean radiation dose to specific brain volumes, including the temporal lobes and hippocampi, had a significant impact on longitudinal scores. Dichotomized dose distributions at 25 Gy, 35 Gy, 45 Gy, and 55 Gy were modeled to show the impact of the high-dose volume on longitudinal test scores. The 50% risk of a below-normal cognitive test score was calculated according to mean dose and dose intervals between 25 Gy and 55 Gy at 10-Gy increments according to brain volume and age. Conclusions: The ability to predict cognitive outcomes in children with medulloblastoma using dose-effects models for different brain subvolumes will improve treatment planning, guide intervention, and help

  10. Cognitive Results of CANTAB Tests and Their Change Due to the First Dose of Donepezil May Predict Treatment Efficacy in Alzheimer Disease

    PubMed Central

    Kuzmickienė, Jurgita; Kaubrys, Gintaras

    2015-01-01

    Background Ability to predict the efficacy of treatment in Alzheimer disease (AD) may be very useful in clinical practice. Cognitive predictors should be investigated alongside with the demographic, genetic, and other predictors of treatment efficacy. The aim of this study was to establish whether the baseline measures of CANTAB tests and their changes due to the first donepezil dose are able to predict the efficacy of treatment after 4 months of therapy. We also compared the predictive value of cognitive, clinical, and demographic predictors of treatment efficacy in AD. Material/Methods Seventy-two AD patients (62 treatment-naïve and 10 donepezil-treated) and 30 controls were enrolled in this prospective, randomized, rater-blinded, follow-up study. Treatment-naïve AD patients were randomized to 2 groups to take the first donepezil dose after the first or second CANTAB testing, separated by 4 hours. Follow-up Test 3 was performed 4 months after the initial assessment. Results The groups were similar in age, education, gender, Hachinski index, and depression. General Regression Models (GRM) have shown that cognitive changes after the first dose of donepezil in PAL (t-values for regression coefficients from 3.43 to 6.44), PRMd (t=4.33), SWM (t=5.85) test scores, and baseline results of PAL (t=2.57–2.86), PRM (t=3.08), and CRT (t=3.42) tests were significant predictors of long-term donepezil efficacy in AD (p<0.05). Conclusions The cognitive changes produced by the first donepezil dose in CANTAB PAL, PRM, and SWM test measures are able to predict the long-term efficacy of donepezil in AD. Baseline PAL, PRM, and CRT test results were significant predictors. PMID:26656642

  11. Newborn Event-Related Potentials Predict Poorer Pre-Reading Skills in Children at Risk for Dyslexia

    ERIC Educational Resources Information Center

    Guttorm, Tomi K.; Leppanen, Paavo H. T.; Hamalainen, Jarmo A.; Eklund, Kenneth M.; Lyytinen, Heikki J.

    2010-01-01

    Earlier results from the Jyvaskyla Longitudinal Study of Dyslexia showed that newborn event-related potentials (ERPs) of children with and without familial risk for dyslexia were associated with receptive language and verbal memory skills between 2.5 and 5 years of age. We further examined whether these ERPs (responses to synthetic consonant-vowel…

  12. Fluconazole dosing predictions in critically-ill patients receiving prolonged intermittent renal replacement therapy: a Monte Carlo simulation approach.

    PubMed

    Gharibian, Katherine N; Mueller, Bruce A

    2016-07-01

    Fluconazole is a renally-eliminated antifungal commonly used to treat Candida species infections. In critically-ill patients receiving prolonged intermittent renal replacement therapy (PIRRT), limited pharmacokinetic (PK) data are available to guide fluconazole dosing. We used previously-published fluconazole clearance data and PK data of critically-ill patients with acute kidney injury to develop a PK model with the goal of determining a therapeutic dosing regimen for critically-ill patients receiving PIRRT. Monte Carlo simulations were performed to create a virtual cohort of patients receiving different fluconazole dosing regimens. Plasma drug concentration-time profiles were evaluated on the probability of attaining a mean 24-hour area under the drug concentration-time curve to minimum inhibitory concentration ratio (AUC24h : MIC) of 100 during the initial 48 hours of antifungal therapy. At the susceptibility breakpoint of Candida albicans (2 mg/L), 93 - 96% of simulated subjects receiving PIRRT attained the pharmacodynamic target with a fluconazole 800-mg loading dose plus 400 mg twice daily (q12h or pre and post PIRRT) regimen. Monte Carlo simulations of a PK model of PIRRT provided a basis for the development of an informed fluconazole dosing recommendation when PK data was limited. This finding should be validated in the clinical setting. PMID:27251341

  13. Initial misdiagnosis of melanoma located on the foot is associated with poorer prognosis.

    PubMed

    Sondermann, Wiebke; Zimmer, Lisa; Schadendorf, Dirk; Roesch, Alexander; Klode, Joachim; Dissemond, Joachim

    2016-07-01

    Acral melanoma has been reported to be associated with poorer outcomes than melanoma occurring on other cutaneous sites. It has been suggested that part of this disparity in outcomes may be related to delay in diagnosis. Therefore, we have analyzed the rate of misdiagnoses in patients with melanoma located on the foot and have characterized the influence on the clinical course and survival of the patients. A prospective, computerized melanoma database at the Skin Cancer Center of the University Hospital Essen, Germany was used to identify patients with histologically confirmed melanoma located on the foot between 2002 and July 2013 for subsequent analysis. A cohort of 151 patients diagnosed with primary melanoma located on the foot was identified. One hundred seven patients qualified for subsequent analysis. Forty-two patients were male (39.3%) and 65 (60.7%) were female; the mean age at first diagnosis was 61.6 years (median 66 years). The youngest patient was 19 years, the oldest 88 years old.Of the 107 patients analyzed, 32 (30%) were initially misdiagnosed. Misdiagnoses included chronic wounds, nevi, hematoma, fungal infections, warts, and paronychia. Misdiagnosis caused a median delay in diagnosis of 9 months. The 5-year disease-free survival rate (47.8% vs 72.7%) and the 5-year overall survival rate (63.5% vs 88.4%) were statistically significant lower in the misdiagnosis cohort.The awareness of potentially overlooked melanoma located on the foot has to increase among physicians.To improve early detection and, thus, the prognosis of patients with melanoma located on the foot, taking a biopsy from any suspicious lesion should be taken into consideration as soon as possible. PMID:27442685

  14. Dry Eye Disease Patients with Xerostomia Report Higher Symptom Load and Have Poorer Meibum Expressibility

    PubMed Central

    Eidet, Jon R.; Utheim, Tor P.; Ræder, Sten; Lagali, Neil S.; Messelt, Edvard B.; Dartt, Darlene A.

    2016-01-01

    The purpose of the study was to investigate if xerostomia (dry mouth) is associated with symptoms and signs of dry eye disease (DED). At the Norwegian Dry Eye Clinic, patients with symptomatic DED with different etiologies were consecutively included in the study. The patients underwent a comprehensive ophthalmological work-up and completed self-questionnaires on symptoms of ocular dryness (Ocular Surface Disease Index [OSDI] and McMonnies Dry Eye Questionnaire) and the Sjögren’s syndrome (SS) questionnaire (SSQ). Three hundred and eighteen patients (52% women and 48% men) with DED were included. Patient demographics were: 0 to 19 years (1%), 20 to 39 (25%), 40 to 59 (34%), 60 to 79 (35%) and 80 to 99 (5%). Xerostomia, defined as “daily symptoms of dry mouth the last three months” (as presented in SSQ) was reported by 23% of the patients. Female sex was more common among patients with xerostomia (81%) than among non-xerostomia patients (44%; P<0.001). Patients with xerostomia (60 ± 15 years) were older than those without xerostomia (51 ± 17; P<0.001). The use of prescription drugs was more prevalent among xerostomia patients (65%) than among non-xerostomia patients (35%; P<0.021; adjusted for age and sex). Patients with xerostomia had a higher OSDI score (19.0 ± 10.0) than those without xerostomia (12.9 ± 8.0; P<0.001). Moreover, xerostomia patients had more pathological meibum expressibility (0.9 ± 0.7) than those without xerostomia (0.7 ± 0.8; P = 0.046). Comparisons of OSDI and ocular signs were performed after controlling for the effects of sex, age and the number of systemic prescription drugs used. In conclusion, xerostomia patients demonstrated a higher DED symptom load and had poorer meibum expressibility than non-xerostomia patients. PMID:27148875

  15. Poorer prognosis with ethylenediaminetetraacetic acid-dependent pseudothrombocytopenia: a single-center case-control study.

    PubMed

    Ohashi-Fukuda, Naoko; Inokuchi, Ryota; Sato, Hajime; Nakamura, Kensuke; Iwagami, Masao; Wada, Tomoki; Jona, Masahiro; Hisasue, Takashi; Nakajima, Susumu; Yahagi, Naoki

    2015-04-01

    In ethylenediaminetetraacetic acid (EDTA)-dependent pseudothrombocytopenia (PTCP), automated platelet counts are lower than actual counts because of EDTA-induced aggregation. Factors contributing to the incidence of EDTA-PTCP are unknown, and no study has assessed the prognosis of EDTA-PTCP patients. This retrospective study assessed characteristics in EDTA-PTCP patients and matched controls to determine differences in prognosis. A retrospective case-control study was designed. From the University of Tokyo Hospital database, we identified patients diagnosed with EDTA-PTCP between 2009 and 2012, and performed 1:2 case:control matching for age and sex. A control group of sex- and age-matched patients was selected at random from the same database. We investigated differences in the frequency of complications, medication history, and blood transfusion history between the groups at the time of blood collection. Prognosis was evaluated using multivariate Cox regression analysis adjusting for age, sex, autoimmune disease, liver disease, and malignant tumor. We identified 104 EDTA-PTCP patients and 208 matched controls. The median age was 69.0 years (interquartile range: 54-76), with men comprising 51%. EDTA-PTCP patients had a higher frequency of malignant tumor and a lower frequency of hypertension and diabetes than controls. After adjustment for background factors, prognosis of EDTA-PTCP patients was significantly poorer than controls (hazard ratio, 11.8; 95% confidence intervals, 2.62-53.54). In conclusion, EDTA-PTCP patients had higher mortality, and EDTA-PTCP may need to be recognized as an indicator of worse prognosis. PMID:25881844

  16. Hyper-responsiveness to acute stress, emotional problems and poorer memory in former preterm children.

    PubMed

    Quesada, Andrea A; Tristão, Rosana M; Pratesi, Riccardo; Wolf, Oliver T

    2014-09-01

    The prevalence of preterm birth (PTB) is high worldwide, especially in developing countries like Brazil. PTB is marked by a stressful environment in intra- as well as extrauterine life, which can affect neurodevelopment and hormonal and physiological systems and lead to long-term negative outcomes. Nevertheless, little is known about PTB and related outcomes later on in childhood. Thus, the goals of the current study were threefold: (1) comparing cortisol and alpha-amylase (sAA) profiles, including cortisol awakening response (CAR), between preterm and full-term children; (2) evaluating whether preterm children are more responsive to acute stress and (3) assessing their memory skills and emotional and behavioral profiles. Basal cortisol and sAA profiles, including CAR of 30 preterm children, aged 6 to 10 years, were evaluated. Further, we assessed memory functions using the Wide Range Assessment of Memory and Learning, and we screened behavior/emotion using the Strengths and Difficulties Questionnaire. The results of preterm children were compared to an age- and sex-matched control group. One week later, participants were exposed to a standardized laboratory stressor [Trier Social Stress Test for Children (TSST-C)], in which cortisol and sAA were measured at baseline, 1, 10 and 25 min after stressor exposure. Preterm children had higher cortisol concentrations at awakening, a flattened CAR and an exaggerated response to TSST-C compared to full-term children. These alterations were more pronounced in girls. In addition, preterm children were characterized by more emotional problems and poorer memory performance. Our findings illustrate the long-lasting and in part sex-dependent effects of PTB on the hypothalamic-pituitary-adrenal (HPA) axis, internalizing behavior and memory. The findings are in line with the idea that early adversity alters the set-point of the HPA axis, thereby creating a more vulnerable phenotype. PMID:25089937

  17. Dry Eye Disease Patients with Xerostomia Report Higher Symptom Load and Have Poorer Meibum Expressibility.

    PubMed

    Fostad, Ida G; Eidet, Jon R; Utheim, Tor P; Ræder, Sten; Lagali, Neil S; Messelt, Edvard B; Dartt, Darlene A

    2016-01-01

    The purpose of the study was to investigate if xerostomia (dry mouth) is associated with symptoms and signs of dry eye disease (DED). At the Norwegian Dry Eye Clinic, patients with symptomatic DED with different etiologies were consecutively included in the study. The patients underwent a comprehensive ophthalmological work-up and completed self-questionnaires on symptoms of ocular dryness (Ocular Surface Disease Index [OSDI] and McMonnies Dry Eye Questionnaire) and the Sjögren's syndrome (SS) questionnaire (SSQ). Three hundred and eighteen patients (52% women and 48% men) with DED were included. Patient demographics were: 0 to 19 years (1%), 20 to 39 (25%), 40 to 59 (34%), 60 to 79 (35%) and 80 to 99 (5%). Xerostomia, defined as "daily symptoms of dry mouth the last three months" (as presented in SSQ) was reported by 23% of the patients. Female sex was more common among patients with xerostomia (81%) than among non-xerostomia patients (44%; P<0.001). Patients with xerostomia (60 ± 15 years) were older than those without xerostomia (51 ± 17; P<0.001). The use of prescription drugs was more prevalent among xerostomia patients (65%) than among non-xerostomia patients (35%; P<0.021; adjusted for age and sex). Patients with xerostomia had a higher OSDI score (19.0 ± 10.0) than those without xerostomia (12.9 ± 8.0; P<0.001). Moreover, xerostomia patients had more pathological meibum expressibility (0.9 ± 0.7) than those without xerostomia (0.7 ± 0.8; P = 0.046). Comparisons of OSDI and ocular signs were performed after controlling for the effects of sex, age and the number of systemic prescription drugs used. In conclusion, xerostomia patients demonstrated a higher DED symptom load and had poorer meibum expressibility than non-xerostomia patients. PMID:27148875

  18. SU-F-BRD-16: Under Dose Regions Recalculated by Monte Carlo Cannot Predict the Local Failure for NSCLC Patients Treated with SBRT

    SciTech Connect

    Liu, H; Cherian, S; Stephans, K; Videtic, G; Qi, P; Xia, P; Zhuang, T

    2014-06-15

    Purpose: To investigate whether Monte Carlo (MC) recalculated dose distributions can predict the geometric location of the recurrence for nonsmall cell lung cancer (NSCLC) patients treated with stereotactic body radiotherapy (SBRT). Methods: Thirty NSCLC patients with local recurrence were retrospectively selected for this study. The recurred gross target volumes (rGTV) were delineated on the follow-up CT/PET images and then rigidly transferred via imaging fusion to the original planning CTs. Failure pattern was defined according to the overlap between the rGTV and planning GTV (pGTV) as: (a) in-field failure (≥80%), (b) marginal failure (20%–80%), and (c) out-of-field failure (≤20%). All clinical plans were calculated initially with pencil beam (PB) with or without heterogeneity correction dependent of protocols. These plans were recalculated with MC with heterogeneity correction. Because of non-uniform dose distributions in the rGTVs, the rGTVs were further divided into four regions: inside the pGTV (GTVin), inside the PTV (PTVin), outside the pGTV (GTVout), and outside the PTV (PTVout). The mean doses to these regions were reported and analyzed separately. Results: Among 30 patients, 10 patients had infield recurrences, 15 marginal and 5 out-of-field failures. With MC calculations, D95 and D99 of the PTV were reduced by (10.6 ± 7.4)% and (11.7 ± 7.9)%. The average MC calculated mean doses of GTVin, GTVout, PTVin and PTVout were 48.2 ± 5.3 Gy, 48.2 ± 5.5 Gy, 46.3 ± 6.2 Gy and 46.6 ± 5.6 Gy, respectively. No significant dose differences between GTVin and GTVout (p=0.65), PTVin and PTVout (p=0.19) were observed, using the paired students t-test. Conclusion: Although the PB calculations underestimated the tumor target doses, the geometric location of the recurrence did not correlate with the mean doses of subsections of the recurrent GTV. Under dose regions recalculated by MC cannot predict the local failure for NSCLC patients treated with SBRT.

  19. A Genetically Determined Dose-Volume Histogram Predicts for Rectal Bleeding among Patients Treated With Prostate Brachytherapy

    SciTech Connect

    Cesaretti, Jamie A. . E-mail: jamie.cesaretti@msnyuhealth.org; Stock, Richard G.; Atencio, David P.; Peters, Sheila A.; Peters, Christopher A.; Burri, Ryan J.; Stone, Nelson N.; Rosenstein, Barry S.

    2007-08-01

    Purpose: To examine whether possession of genetic alterations in the ATM (ataxia telangiectasia) gene is associated with rectal bleeding in a dose-dependent and volume-dependent manner. Methods and Materials: One hundred eight prostate cancer patients who underwent brachytherapy using either an {sup 125}I implant, a {sup 103}Pd implant, or the combination of external beam radiotherapy with a {sup 103}Pd implant and had a minimum of 1 year follow-up were screened for DNA sequence variations in the 62 coding exons of the ATM gene using denaturing high-performance liquid chromatography. Rectal dose was reported as the volume (in cubic centimeters) of rectum receiving the brachytherapy prescription dose. The two-sided Fisher exact test was used to compare differences in proportions. Results: A significant correlation between the presence of any ATM sequence alteration and Grade 1 to 2 proctitis was obtained when the radiation dose to rectal tissue was quantified. Rectal bleeding occurred in 4 of 13 patients (31%) with a variant versus 1 of 23 (4%) without a genetic alteration for patients who had <0.7 cm{sup 3} of rectal tissue receiving the implant prescription dose (p = 0.05). Of patients in whom 0.7-1.4 cm{sup 3} of the rectum received the implant prescription, 4 of 11 (36%) with an ATM alteration exhibited Grade 1 to 2 proctitis, whereas 1 of 21 (5%) without a variant (p = 0.04) developed this radiation-induced late effect. Conclusions: The possession of genetic variants in the ATM gene is associated with the development of radiation-induced proctitis after prostate cancer radiotherapy for patients who receive the full prescription dose to either a low or a moderate volume of rectal tissue.

  20. PREDICTING THE ACUTE BEHAVIORAL EFFECTS OF TOLUENE INHALED FOR 24 HRS IN RATS: DOSE METRICS, METABOLISM AND BEHAVIORAL TOLERANCE

    EPA Science Inventory

    Purpose: Recent research on the acute effects of volatile organic compounds (VOCs) suggests that extrapolation from short (~ 1 h) to long durations (up to 4 h) is improved by using estimates of brain toluene concentration ( Br[ToI)] instead of cumulative inhaled dose (C x t) as a...

  1. Predicting the probability of successful efficacy of a dissociated agonist of the glucocorticoid receptor from dose-response analysis.

    PubMed

    Conrado, Daniela J; Krishnaswami, Sriram; Shoji, Satoshi; Kolluri, Sheela; Hey-Hadavi, Judith; McCabe, Dorothy; Rojo, Ricardo; Tammara, Brinda K

    2016-06-01

    PF-04171327 is a dissociated agonist of the glucocorticoid receptor (DAGR) being developed to retain anti-inflammatory efficacy while reducing unwanted effects. Our aim was to conduct a longitudinal dose-response analysis to identify the DAGR doses with efficacy similar to or greater than prednisone 10 mg once daily (QD). The data included were from a Phase 2, randomized, double-blind, parallel-group study in 323 subjects with active rheumatoid arthritis on a background of methotrexate. Subjects received DAGR 1, 5, 10 or 15 mg, prednisone 5 or 10 mg, or placebo QD for 8 weeks. The Disease Activity Score 28-4 calculated using C-Reactive Protein (DAS28-4 CRP) was the efficacy endpoint utilized in this dose-response model. For DAGR, the maximum effect (Emax) on DAS28-4 CRP was estimated to be -1.2 points (95 % CI -1.7, -0.84), and the evaluated dose range provided 31-87 % of the Emax; for prednisone 5 and 10 mg, the estimated effects were -0.27 (95 % CI -0.55, 0.006) and -0.94 point (95 % CI -1.3, -0.59), respectively. Stochastic simulations indicated that the DAGR 1, 5, 10 and 15 mg have probabilities of 0.9, 29, 54 and 62 %, respectively, to achieve efficacy greater than prednisone 10 mg at week 8. DAGR 9 mg estimated probability was 50 % suggesting that DAGR ≥9 mg QD has an effect on DAS28-4 CRP comparable to or greater than prednisone 10 mg QD. This work informs dose selection for late-stage confirmatory trials. PMID:27178257

  2. Prediction of error rates in dose-imprinted memories on board CRRES by two different methods. [Combined Release and Radiation Effects Satellite

    NASA Technical Reports Server (NTRS)

    Brucker, G. J.; Stassinopoulos, E. G.

    1991-01-01

    An analysis of the expected space radiation effects on the single event upset (SEU) properties of CMOS/bulk memories onboard the Combined Release and Radiation Effects Satellite (CRRES) is presented. Dose-imprint data from ground test irradiations of identical devices are applied to the predictions of cosmic-ray-induced space upset rates in the memories onboard the spacecraft. The calculations take into account the effect of total dose on the SEU sensitivity of the devices as the dose accumulates in orbit. Estimates of error rates, which involved an arbitrary selection of a single pair of threshold linear energy transfer (LET) and asymptotic cross-section values, were compared to the results of an integration over the cross-section curves versus LET. The integration gave lower upset rates than the use of the selected values of the SEU parameters. Since the integration approach is more accurate and eliminates the need for an arbitrary definition of threshold LET and asymptotic cross section, it is recommended for all error rate predictions where experimental sigma-versus-LET curves are available.

  3. Use of a statistical model to predict the potential for repeated dose and developmental toxicity of dermally administered crude oil and relation to reproductive toxicity.

    PubMed

    McKee, Richard H; Nicolich, Mark; Roy, Timothy; White, Russell; Daughtrey, Wayne C

    2014-01-01

    Petroleum (commonly called crude oil) is a complex substance primarily composed of hydrocarbon constituents. Based on the results of previous toxicological studies as well as occupational experience, the principal acute toxicological hazards are those associated with exposure by inhalation to volatile hydrocarbon constituents and hydrogen sulfide, and chronic hazards are associated with inhalation exposure to benzene and dermal exposure to polycyclic aromatic compounds. The current assessment was an attempt to characterize the potential for repeated dose and/or developmental effects of crude oils following dermal exposures and to generalize the conclusions across a broad range of crude oils from different sources. Statistical models were used to predict the potential for repeated dose and developmental toxicity from compositional information. The model predictions indicated that the empirical data from previously tested crude oils approximated a "worst case" situation, and that the data from previously tested crude oils could be used as a reasonable basis for characterizing the repeated dose and developmental toxicological hazards of crude oils in general. PMID:24179028

  4. Combinatorial DNA Damage Pairing Model Based on X-Ray-Induced Foci Predicts the Dose and LET Dependence of Cell Death in Human Breast Cells

    SciTech Connect

    Vadhavkar, Nikhil; Pham, Christopher; Georgescu, Walter; Deschamps, Thomas; Heuskin, Anne-Catherine; Tang, Jonathan; Costes, Sylvain V.

    2014-09-01

    In contrast to the classic view of static DNA double-strand breaks (DSBs) being repaired at the site of damage, we hypothesize that DSBs move and merge with each other over large distances (m). As X-ray dose increases, the probability of having DSB clusters increases as does the probability of misrepair and cell death. Experimental work characterizing the X-ray dose dependence of radiation-induced foci (RIF) in nonmalignant human mammary epithelial cells (MCF10A) is used here to validate a DSB clustering model. We then use the principles of the local effect model (LEM) to predict the yield of DSBs at the submicron level. Two mechanisms for DSB clustering, namely random coalescence of DSBs versus active movement of DSBs into repair domains are compared and tested. Simulations that best predicted both RIF dose dependence and cell survival after X-ray irradiation favored the repair domain hypothesis, suggesting the nucleus is divided into an array of regularly spaced repair domains of ~;;1.55 m sides. Applying the same approach to high-linear energy transfer (LET) ion tracks, we are able to predict experimental RIF/m along tracks with an overall relative error of 12percent, for LET ranging between 30 350 keV/m and for three different ions. Finally, cell death was predicted by assuming an exponential dependence on the total number of DSBs and of all possible combinations of paired DSBs within each simulated RIF. Relative biological effectiveness (RBE) predictions for cell survival of MCF10A exposed to high-LET showed an LET dependence that matches previous experimental results for similar cell types. Overall, this work suggests that microdosimetric properties of ion tracks at the submicron level are sufficient to explain both RIF data and survival curves for any LET, similarly to the LEM assumption. Conversely, high-LET death mechanism does not have to infer linear-quadratic dose formalism as done in the LEM. In addition, the size of repair domains derived in our model

  5. Baseline tumour necrosis factor alpha levels predict the necessity for dose escalation of infliximab therapy in patients with rheumatoid arthritis

    PubMed Central

    Takeuchi, Tsutomu; Miyasaka, Nobuyuki; Tatsuki, Yoshihiko; Yano, Toshiro; Yoshinari, Toru; Abe, Tohru; Koike, Takao

    2011-01-01

    Objectives To investigate the possible role of baseline plasma tumour necrosis factor alpha levels (baseline-TNF) on the clinical response to infliximab in patients with rheumatoid arthritis (RA). Methods Patients with RA refractory to methotrexate received 3, 6, or 10 mg/kg of infliximab every 8 weeks, in a randomised, double-blind manner: the RISING study. Clinical response (disease activity score in 28 joints based on C-reactive protein or American College of Rheumatology core set) at week 54 and serum infliximab levels were compared in three patient groups with low, intermediate, or high baseline-TNF (TNF-low, TNF-int, or TNF-high). Results In TNF-low patients, the clinical response to different doses of infliximab was comparable, whereas TNF-int patients exhibited a dose-dependent trend. In contrast, TNF-high patients (approximately 13% of the total patients) had a clinical response to 10 mg/kg significantly better than the response to 3 and 6 mg/kg of infliximab. In TNF-high patients, the median trough serum levels of infliximab were below the detection limit (<0.1 μg/ml) at 3 and 6 mg/kg but were greater than 2 μg/ml at 10 mg/kg, whereas the levels were approximately 1 μg/ml for each dosage group in TNF-low patients. Conclusion In patients with RA, baseline-TNF is significantly associated with the clinical response to infliximab in patients with a high baseline-TNF. A higher dose of infliximab may be necessary in these patients, whereas lower doses of infliximab are sufficient for those with a low baseline-TNF. Baseline-TNF may be a useful measure for personalising the treatment of RA using infliximab. PMID:21478189

  6. Weekly Dose-Volume Parameters of Mucosa and Constrictor Muscles Predict the Use of Percutaneous Endoscopic Gastrostomy During Exclusive Intensity-Modulated Radiotherapy for Oropharyngeal Cancer

    SciTech Connect

    Sanguineti, Giuseppe; Gunn, G. Brandon; Parker, Brent C.; Endres, Eugene J.; Zeng Jing; Fiorino, Claudio

    2011-01-01

    Purpose: To define predictors of percutaneous endoscopic gastrostomy (PEG) use during intensity-modulated radiotherapy (IMRT) for oropharyngeal cancer. Methods and Materials: Data for 59 consecutive patients treated with exclusive IMRT at a single institution were recovered. Of 59 patients, 25 were treated with hyperfractionation (78 Gy, 1.3 Gy per fraction, twice daily; 'HYPER'); and 34 of 59 were treated with a once-daily fractionation schedule (66 Gy, 2.2 Gy per fraction, or 70 Gy, 2 Gy per fraction; 'no-HYPER'). On the basis of symptoms during treatment, a PEG tube could have been placed as appropriate. A number of clinical/dosimetric factors, including the weekly dose-volume histogram of oral mucosa (OM DVHw) and weekly mean dose to constrictors and larynx, were considered. The OM DVHw of patients with and without PEG were compared to assess the most predictive dose-volume combinations. Results: Of 59 patients, 22 needed a PEG tube during treatment (for 15 of 22, {>=}3 months). The best cutoff values for OM DVHw were V9.5 Gy/week <64 cm{sup 3} and V10 Gy/week <54 cm{sup 3}. At univariate analysis, fractionation, mean weekly dose to OM and superior and middle constrictors, and OM DVHw were strongly correlated with the risk of PEG use. In a stepwise multivariate logistic analysis, OM V9.5 Gy/week ({>=}64 vs. <64 cm{sup 3}) was the most predictive parameter (odds ratio 30.8, 95% confidence interval 3.7-254.2, p = 0.0015), confirmed even in the no-HYPER subgroup (odds ratio 21, 95% CI 2.1 confidence interval 210.1, p = 0.01). Conclusions: The risk of PEG use is drastically reduced when OM V9.5-V10 Gy/week is <50-60 cm{sup 3}. These data warrant prospective validation.

  7. Cervical Gross Tumor Volume Dose Predicts Local Control Using Magnetic Resonance Imaging/Diffusion-Weighted Imaging—Guided High-Dose-Rate and Positron Emission Tomography/Computed Tomography—Guided Intensity Modulated Radiation Therapy

    SciTech Connect

    Dyk, Pawel; Jiang, Naomi; Sun, Baozhou; DeWees, Todd A.; Fowler, Kathryn J.; Narra, Vamsi; Garcia-Ramirez, Jose L.; Schwarz, Julie K.; Grigsby, Perry W.

    2014-11-15

    Purpose: Magnetic resonance imaging/diffusion weighted-imaging (MRI/DWI)-guided high-dose-rate (HDR) brachytherapy and {sup 18}F-fluorodeoxyglucose (FDG) — positron emission tomography/computed tomography (PET/CT)-guided intensity modulated radiation therapy (IMRT) for the definitive treatment of cervical cancer is a novel treatment technique. The purpose of this study was to report our analysis of dose-volume parameters predicting gross tumor volume (GTV) control. Methods and Materials: We analyzed the records of 134 patients with International Federation of Gynecology and Obstetrics stages IB1-IVB cervical cancer treated with combined MRI-guided HDR and IMRT from July 2009 to July 2011. IMRT was targeted to the metabolic tumor volume and lymph nodes by use of FDG-PET/CT simulation. The GTV for each HDR fraction was delineated by use of T2-weighted or apparent diffusion coefficient maps from diffusion-weighted sequences. The D100, D90, and Dmean delivered to the GTV from HDR and IMRT were summed to EQD2. Results: One hundred twenty-five patients received all irradiation treatment as planned, and 9 did not complete treatment. All 134 patients are included in this analysis. Treatment failure in the cervix occurred in 24 patients (18.0%). Patients with cervix failures had a lower D100, D90, and Dmean than those who did not experience failure in the cervix. The respective doses to the GTV were 41, 58, and 136 Gy for failures compared with 67, 99, and 236 Gy for those who did not experience failure (P<.001). Probit analysis estimated the minimum D100, D90, and Dmean doses required for ≥90% local control to be 69, 98, and 260 Gy (P<.001). Conclusions: Total dose delivered to the GTV from combined MRI-guided HDR and PET/CT-guided IMRT is highly correlated with local tumor control. The findings can be directly applied in the clinic for dose adaptation to maximize local control.

  8. Maximum Age Predictions for Optical Dating on Mars Based on Dose/Depth Models and Martian Meteorite Compositions

    NASA Astrophysics Data System (ADS)

    Franklund, R. T.; Lepper, K.

    2004-12-01

    A fundamental need in the Mars exploration portfolio is in-situ absolute dating. Optical dating has been proposed for determining the age of Mars surface features and landforms as well as the rates of martian surface processes. On Earth, the method is employed for Quaternary studies because the technique currently has a terrestrial maximum age limit of approximately 350 ka. This maximum age limit is a function of the saturation dose of the dosimeter material (silicate sediments) and the local ionizing radiation dose rate. The sources of ionizing radiation germane to optical dating are K, Rb, U, Th in the sediment/soil environment and cosmic rays. On Mars the near surface dose rate will be dominated by cosmic rays, however, at depth the decay of radioisotopes will be the principle contributor of ionizing radiation. In this work we present an evaluation of the maximum age limits for OSL dating on Mars as a function of depth. At this time we have considered only static burial. Our calculations are based on published models of and data for: (i) Mars surface cosmic dose rate and its attenuation by martian regolith, (ii) elemental analyses of Mars meteorites, (iii) an experimental evaluation of the saturation dose for the martian soil simulant JSC Mars-1. Our analysis confirms earlier inferences that optical dating should have a greater effective age range on Mars than on Earth. At depths easily accessible by penetrators or moles (1-3 m), maximum optical ages greater than 600 ka are possible. Geochronology on this scale would include at least two stadial/interstadial cycles within Mars' last "Glacial Epoch" (synchronized insolation variations between the poles). A wide range of landforms and surface processes associated with climate variability -- e.g. outwash and lacustrine deposition, large-scale eolian activation -- could potentially be optically dated. At greater depths, that could be reached by mobile drilling rigs or cryobots (10-30m), optical age maximums of 4

  9. Assessing the safety of cosmetic chemicals: Consideration of a flux decision tree to predict dermally delivered systemic dose for comparison with oral TTC (Threshold of Toxicological Concern).

    PubMed

    Williams, Faith M; Rothe, Helga; Barrett, Gordon; Chiodini, Alessandro; Whyte, Jacqueline; Cronin, Mark T D; Monteiro-Riviere, Nancy A; Plautz, James; Roper, Clive; Westerhout, Joost; Yang, Chihae; Guy, Richard H

    2016-04-01

    Threshold of Toxicological Concern (TTC) aids assessment of human health risks from exposure to low levels of chemicals when toxicity data are limited. The objective here was to explore the potential refinement of exposure for applying the oral TTC to chemicals found in cosmetic products, for which there are limited dermal absorption data. A decision tree was constructed to estimate the dermally absorbed amount of chemical, based on typical skin exposure scenarios. Dermal absorption was calculated using an established predictive algorithm to derive the maximum skin flux adjusted to the actual 'dose' applied. The predicted systemic availability (assuming no local metabolism), can then be ranked against the oral TTC for the relevant structural class. The predictive approach has been evaluated by deriving the experimental/prediction ratio for systemic availability for 22 cosmetic chemical exposure scenarios. These emphasise that estimation of skin penetration may be challenging for penetration enhancing formulations, short application times with incomplete rinse-off, or significant metabolism. While there were a few exceptions, the experiment-to-prediction ratios mostly fell within a factor of 10 of the ideal value of 1. It can be concluded therefore, that the approach is fit-for-purpose when used as a screening and prioritisation tool. PMID:26825378

  10. Prediction of human observer performance in a 2-alternative forced choice low-contrast detection task using channelized Hotelling observer: Impact of radiation dose and reconstruction algorithms

    SciTech Connect

    Yu Lifeng; Leng Shuai; Chen Lingyun; Kofler, James M.; McCollough, Cynthia H.; Carter, Rickey E.

    2013-04-15

    Purpose: Efficient optimization of CT protocols demands a quantitative approach to predicting human observer performance on specific tasks at various scan and reconstruction settings. The goal of this work was to investigate how well a channelized Hotelling observer (CHO) can predict human observer performance on 2-alternative forced choice (2AFC) lesion-detection tasks at various dose levels and two different reconstruction algorithms: a filtered-backprojection (FBP) and an iterative reconstruction (IR) method. Methods: A 35 Multiplication-Sign 26 cm{sup 2} torso-shaped phantom filled with water was used to simulate an average-sized patient. Three rods with different diameters (small: 3 mm; medium: 5 mm; large: 9 mm) were placed in the center region of the phantom to simulate small, medium, and large lesions. The contrast relative to background was -15 HU at 120 kV. The phantom was scanned 100 times using automatic exposure control each at 60, 120, 240, 360, and 480 quality reference mAs on a 128-slice scanner. After removing the three rods, the water phantom was again scanned 100 times to provide signal-absent background images at the exact same locations. By extracting regions of interest around the three rods and on the signal-absent images, the authors generated 21 2AFC studies. Each 2AFC study had 100 trials, with each trial consisting of a signal-present image and a signal-absent image side-by-side in randomized order. In total, 2100 trials were presented to both the model and human observers. Four medical physicists acted as human observers. For the model observer, the authors used a CHO with Gabor channels, which involves six channel passbands, five orientations, and two phases, leading to a total of 60 channels. The performance predicted by the CHO was compared with that obtained by four medical physicists at each 2AFC study. Results: The human and model observers were highly correlated at each dose level for each lesion size for both FBP and IR. The

  11. Using a decline in serum hCG between days 0–4 to predict ectopic pregnancy treatment success after single-dose methotrexate: a retrospective cohort study

    PubMed Central

    2013-01-01

    Background The current measure of treatment efficacy of single-dose methotrexate for ectopic pregnancy, is a fall in serum hCG of ≥15% between days 4–7 of treatment, which has a positive predictive value of 93% for treatment success. Two small studies have proposed a fall in serum hCG between days 0–4 after treatment confers similar, earlier prognostic information, with positive predictive values of 100% and 88% for treatment success. We sought to validate this in a large, independent cohort because of the potentially significant clinical implications. Methods We conducted a retrospective study of women (n=206) treated with single-dose methotrexate for ectopic pregnancy (pre-treatment serum hCG levels ≤3000 IU/L) at Scottish hospitals between 2006–2011. Women were divided into two cohorts based on whether their serum hCG levels rose or fell between days 0–4 after methotrexate. Treatment outcomes of women in each cohort were compared, and the test performance characteristics calculated. This methodology was repeated for the current measure (≥15% fall in serum hCG between days 4–7 of treatment) and an alternate early measure (<20% fall in serum hCG between days 0–4 of treatment), and all three measures were compared for their ability to predict medical treatment success. Results In our cohort, the positive predictive value of the current clinical measure was 89% (95% CI 84-94%) (121/136). A falling serum hCG between days 0–4 predicted treatment success in 85% (95% CI 79-92%) of cases (94/110) and a <20% fall in serum hCG between days 0–4 predicted treatment success in 94% (95% CI 88-100%) of cases (59/63). There was no significant difference in the ability of these tests to predict medical treatment success. Conclusions We have verified that a decline in serum hCG between days 0–4 after methotrexate treatment for ectopic pregnancies, with pre-treatment serum hCG levels ≤3000 IU/L, provides an early indication of likelihood of treatment

  12. Measurement and model prediction of proton-recoil track length distributions in NTA film dosimeters for neutron energy spectroscopy and retrospective dose assessment

    NASA Astrophysics Data System (ADS)

    Taulbee, Timothy D.

    The goal of this research was to determine whether neutron dose reconstruction could be improved through re-analysis of historic NTA films worn by workers in the 1950 through the 1970s. To improve neutron dose reconstruction, the underlying neutron energy spectra is critical in determining the organ dose due to energy dependence of the dose conversion factor as well as the application of radiation weighting factors used in epidemiology and probability of causation calculations. Monte Carlo models of proton-recoil track length distributions were developed and benchmarked against measurement data for both NTA and Ilford films. These models, when applied to several NTA film dosimeter configurations, demonstrated that proton-recoil track length distributions change based upon incident neutron energy. The neutron energy spectra changes that result from the general work environment such as source term and shielding can subsequently be modeled to predict the response of the NTA film dosimeter. An Automatic NTA Film Analyzer has been designed and developed to determine if the difference in proton-recoil track length distributions predicted by the Monte Carlo models could be measured and whether these differences could be correlated to the incident neutron energy spectra. The design required the development of a 2D-3D hybrid track recognition algorithm for a three dimensional analysis of the NTA film in order to accurately determine the proton-recoil track length for subsequent neutron energy determination. NTA films exposed to a plutonium fluoride (PuF4) and polonium boron (PoB) calibration sources were measured and compared. The proton-recoil track lengths were used to reconstruct the incident neutron energy spectra demonstrating the functionality of the analyzer and that reconstruction of the neutron energy spectra from NTA films is feasible. These measurements were compared to the Monte Carlo models and confirmed the applicability of using models to determine the NTA

  13. Intravenous myocardial contrast echocardiography predicts regional and global left ventricular remodelling after acute myocardial infarction: comparison with low dose dobutamine stress echocardiography

    PubMed Central

    Abe, Y; Muro, T; Sakanoue, Y; Komatsu, R; Otsuka, M; Naruko, T; Itoh, A; Yoshiyama, M; Haze, K; Yoshikawa, J

    2005-01-01

    Objective: To assess the role of intravenous myocardial contrast echocardiography (MCE) in predicting functional recovery and regional or global left ventricular (LV) remodelling after acute myocardial infarction (AMI) compared with low dose dobutamine stress echocardiography (LDSE). Methods: 21 patients with anterior AMI and successful primary angioplasty underwent MCE and LDSE during the subacute stage (2–4 weeks after AMI). Myocardial perfusion and contractile reserve were assessed in each segment (12 segment model) with MCE and LDSE. The 118 dyssynergic segments in the subacute stage were classified as recovered, unchanged, or remodelled according to wall motion at six months’ follow up. Percentage increase in LV end diastolic volume (%ΔEDV) was also calculated. Results: The presence of perfusion was less accurate than the presence of contractile reserve in predicting regional recovery (55% v 81%, p < 0.0001). However, the absence of perfusion was more accurate than the absence of contractile reserve in predicting regional remodelling (83% v 48%, p < 0.0001). The number of segments without perfusion was an independent predictor of %ΔEDV, whereas the number of segments without contractile reserve was not. The area under the receiver operating characteristic curve showed that the number of segments without perfusion predicted substantial LV dilatation (%ΔEDV > 20%) more accurately than did the number of segments without contractile reserve (0.88 v 0.72). Conclusion: In successfully revascularised patients with AMI, myocardial perfusion assessed by MCE is predictive of regional and global LV remodelling rather than of functional recovery, whereas contractile reserve assessed by LDSE is predictive of functional recovery rather than of LV remodelling. PMID:15797931

  14. The high-dose aldesleukin (IL-2) "select" trial: a trial designed to prospectively validate predictive models of response to high-dose IL-2 treatment in patients with metastatic renal cell carcinoma.

    PubMed

    Clement, Jessica M; McDermott, David F

    2009-08-01

    For patients with metastatic renal cell carcinoma (RCC), the prognosis is poor. Despite the recent approval of drugs such as sorafenib, sunitinib, and temsirolimus, durable remissions of metastatic disease are rare. This is largely due to the fact that these drugs, while effective, do not result in the eradication of disease. In 1992, the FDA approved the use of high-dose interleukin-2 (IL-2) for the treatment of patients with metastatic RCC because of a small number of patients that achieved durable responses. However, IL-2 has not become a mainstay of treatment because of the expense and toxicity associated with this therapy. This review article discusses a phase II trial that investigates predictive biomarkers that might help clinicians identify the patient population with metastatic RCC that would benefit from IL-2 therapy and therefore limit patients who receive this toxic therapy to those most likely to benefit. PMID:19692326

  15. Geometrical Sparing Factors for the Rectum and Bladder in the Prediction of Grade 2 and Higher Complications After High-Dose-Rate Brachytherapy for Cervical Cancer

    SciTech Connect

    Chen, S.-W.; Liang, J.-A.; Hung, Y.-C.; Yeh, L.-S.; Chang, W.-C.; Yang, S.-N.; Lin, F.-J.

    2009-12-01

    Purpose: This study aimed to assess the predictive values of geometrical sparing factors for the rectum and bladder in high-dose-rate intracavitary brachytherapy (HDRICB) for Grade 2 and higher late sequelae in patients with cervical cancer. Methods: A total of 392 patients were enrolled in this study. They were treated with external beam radiotherapy to the pelvis, after which HDRICB was performed using Ir-192 remote after-loading at 1-week intervals for three or four sessions. The geometrical sparing factor (GSF) was defined as the average of the ratios between the reference doses and the Point A dose. Results: A total of 46 patients (11.7%) had Grade 2 or higher late rectal complications (36 Grade 2, 9 Grade 3, and 1 Grade 4). In all, 32 patients (8.2%) had Grade 2 or higher late bladder complications (14 Grade 2, 16 Grade 3, and 2 Grade 4). Multivariate analysis demonstrated a high risk of rectal sequelae in patients who developed bladder complications (p = 0.0004, hazard ratio 3.54) and had a rectal GSF greater than 0.7 (p = 0.01, hazard ratio 1.99). The high risk factors for bladder complications were development of rectal complications (p = 0.0004, hazard ratio 3.74), concurrent chemotherapy (p = 0.0001, relative risk 3.94), and a bladder GSF greater than 0.9 (p = 0.01, hazard ratio, 2.53). Conclusion: This study demonstrates the predictive value of GSFs in HDRICB for cervical cancer. Patients with rectal GSFs greater than 0.7 or bladder GSFs greater than 0.9 are at risk for Grade 2 and higher late sequelae.

  16. An Improved Model for Predicting Radiation Pneumonitis Incorporating Clinical and Dosimetric Variables;Lung cancer; Radiation pneumonitis; Dose-volume histogram; Angiotensin converting enzyme inhibitor

    SciTech Connect

    Jenkins, Peter; Watts, Joanne

    2011-07-15

    Purpose: Single dose-volume metrics are of limited value for the prediction of radiation pneumonitis (RP) in day-to-day clinical practice. We investigated whether multiparametric models that incorporate clinical and physiologic factors might have improved accuracy. Methods and Materials: The records of 160 patients who received radiation therapy for non-small-cell lung cancer were reviewed. All patients were treated to the same dose and with an identical technique. Dosimetric, pulmonary function, and clinical parameters were analyzed to determine their ability to predict for the subsequent development of RP. Results: Twenty-seven patients (17%) developed RP. On univariate analysis, the following factors were significantly correlated with the risk of pneumonitis: fractional volume of lung receiving >5-20 Gy, absolute volume of lung spared from receiving >5-15 Gy, mean lung dose, craniocaudal position of the isocenter, transfer coefficient for carbon monoxide (KCOc), total lung capacity, coadministration of angiotensin converting enzyme inhibitors, and coadministration of angiotensin receptor antagonists. By combining the absolute volume of lung spared from receiving >5 Gy with the KCOc, we defined a new parameter termed Transfer Factor Spared from receiving >5 Gy (TFS{sub 5}). The area under the receiver operator characteristic curve for TFS{sub 5} was 0.778, increasing to 0.846 if patients receiving modulators of the renin-angiotensin system were excluded from the analysis. Patients with a TFS{sub 5} <2.17 mmol/min/kPa had a risk of RP of 30% compared with 5% for the group with a TFS{sub 5} {>=}2.17. Conclusions: TFS{sub 5} represents a simple parameter that can be used in routine clinical practice to more accurately segregate patients into high- and low-risk groups for developing RP.

  17. Radiation transport modeling and assessment to better predict radiation exposure, dose, and toxicological effects to human organs on long duration space flights.

    PubMed

    Denkins, P; Badhwar, G; Obot, V; Wilson, B; Jejelewo, O

    2001-01-01

    NASA is very interested in improving its ability to monitor and forecast the radiation levels that pose a health risk to space-walking astronauts as they construct the International Space Station and astronauts that will participate in long-term and deep-space missions. Human exploratory missions to the moon and Mars within the next quarter century, will expose crews to transient radiation from solar particle events which include high-energy galactic cosmic rays and high-energy protons. Because the radiation levels in space are high and solar activity is presently unpredictable, adequate shielding is needed to minimize the deleterious health effects of exposure to radiation. Today, numerous models have been developed and used to predict radiation exposure. Such a model is the Space Environment Information Systems (SPENVIS) modeling program, developed by the Belgian Institute for Space Aeronautics. SPENVIS, which has been assessed to be an excellent tool in characterizing the radiation environment for microelectronics and investigating orbital debris, is being evaluated for its usefulness with determining the dose and dose-equivalent for human exposure. Thus far. the calculations for dose-depth relations under varying shielding conditions have been in agreement with calculations done using HZETRN and PDOSE, which are well-known and widely used models for characterizing the environments for human exploratory missions. There is disagreement when assessing the impact of secondary radiation particles since SPENVIS does a crude estimation of the secondary radiation particles when calculating LET versus Flux. SPENVIS was used to model dose-depth relations for the blood-forming organs. Radiation sickness and cancer are life-threatening consequences resulting from radiation exposure. In space. exposure to radiation generally includes all of the critical organs. Biological and toxicological impacts have been included for discussion along with alternative risk mitigation

  18. Radiation transport modeling and assessment to better predict radiation exposure, dose, and toxicological effects to human organs on long duration space flights

    NASA Astrophysics Data System (ADS)

    Denkins, Pamela; Badhwar, Gautam; Obot, Victor; Wilson, Bobby; Jejelewo, Olufisayo

    2001-08-01

    NASA is very interested in improving its ability to monitor and forecast the radiation levels that pose a health risk to space-walking astronauts as they construct the International Space Station and astronauts that will participate in long-term and deep-space missions. Human exploratory missions to the moon and Mars within the next quarter century, will expose crews to transient radiation from solar particle events which include high-energy galactic cosmic rays and high-energy protons. Because the radiation levels in space are high and solar activity is presently unpredictable, adequate shielding is needed to minimize the deleterious health effects of exposure to radiation. Today, numerous models have been developed and used to predict radiation exposure. Such a model is the Space Environment Information Systems (SPENVIS) modeling program, developed by the Belgian Institute for Space Aeronautics. SPENVIS, which has been assessed to be an excellent tool in characterizing the radiation environment for microelectronics and investigating orbital debris, is being evaluated for its usefulness with determining the dose and dose-equivalent for human exposure. Thus far, the calculations for dose-depth relations under varying shielding conditions have been in agreement with calculations done using HZETRN and PDOSE, which are well-known and widely used models for characterizing the environments for human exploratory missions. There is disagreement when assessing the impact of secondary radiation particles since SPENVIS does a crude estimation of the secondary radiation particles when calculating LET versus Flux. SPENVIS was used to model dose-depth relations for the blood-forming organs. Radiation sickness and cancer are life-threatening consequences resulting from radiation exposure. In space, exposure to radiation generally includes all of the critical organs. Biological and toxicological impacts have been included for discussion along with alternative risk mitigation

  19. Radiation transport modeling and assessment to better predict radiation exposure, dose, and toxicological effects to human organs on long duration space flights

    NASA Technical Reports Server (NTRS)

    Denkins, P.; Badhwar, G.; Obot, V.; Wilson, B.; Jejelewo, O.

    2001-01-01

    NASA is very interested in improving its ability to monitor and forecast the radiation levels that pose a health risk to space-walking astronauts as they construct the International Space Station and astronauts that will participate in long-term and deep-space missions. Human exploratory missions to the moon and Mars within the next quarter century, will expose crews to transient radiation from solar particle events which include high-energy galactic cosmic rays and high-energy protons. Because the radiation levels in space are high and solar activity is presently unpredictable, adequate shielding is needed to minimize the deleterious health effects of exposure to radiation. Today, numerous models have been developed and used to predict radiation exposure. Such a model is the Space Environment Information Systems (SPENVIS) modeling program, developed by the Belgian Institute for Space Aeronautics. SPENVIS, which has been assessed to be an excellent tool in characterizing the radiation environment for microelectronics and investigating orbital debris, is being evaluated for its usefulness with determining the dose and dose-equivalent for human exposure. Thus far. the calculations for dose-depth relations under varying shielding conditions have been in agreement with calculations done using HZETRN and PDOSE, which are well-known and widely used models for characterizing the environments for human exploratory missions. There is disagreement when assessing the impact of secondary radiation particles since SPENVIS does a crude estimation of the secondary radiation particles when calculating LET versus Flux. SPENVIS was used to model dose-depth relations for the blood-forming organs. Radiation sickness and cancer are life-threatening consequences resulting from radiation exposure. In space. exposure to radiation generally includes all of the critical organs. Biological and toxicological impacts have been included for discussion along with alternative risk mitigation

  20. Preliminary experience of a predictive model to define rectal volume and rectal dose during the treatment of prostate cancer

    PubMed Central

    Falco, M D; D'Andrea, M; Fedele, D; Barbarino, R; Benassi, M; Giudice, E; Hamoud, E; Ingrosso, G; Ladogana, P; Santarelli, F; Tortorelli, G; Santoni, R

    2011-01-01

    Objectives The aim of this study was to define a method to evaluate the total dose delivered to the rectum during the whole treatment course in six patients undergoing irradiation for prostate cancer using an offline definition of organ motion with images from a cone beam CT (CBCT) scanner available on a commercial linear accelerator. Methods Patient set-up was verified using a volumetric three-dimensional CBCT scanner; 9–14 CBCT scans were obtained for each patient. Images were transferred to a commercial treatment planning system for offline organ motion analysis. The shape of the rectums were used to obtain a mean dose–volume histogram (), which was the average of the DVHs of the rectums as they appeared in each verification CBCT. A geometric model of an average rectum (AR) was produced using the rectal contours delineated on the CBCT scans (DVHAR). To check whether the first week of treatment was representative of the whole treatment course, we evaluated the DVHs related to only the first five CBCT scans ( and DVHAR5). Finally, the influence of a dietary protocol on the goodness of our results was considered. Results In all six patients the original rectal DVH for the planning CT scan showed higher values than all DVHs. Conclusion Although the application of the model to a larger set of patients is necessary to confirm this trend, reconstruction of a representative volume of the rectum throughout the entire treatment course seems feasible. PMID:21849366

  1. Superoxide radical-generating compounds activate a predicted promoter site for paraquat-inducible genes of the Chromobacterium violaceum bacterium in a dose-dependent manner.

    PubMed

    Gabriel, J E; Guerra-Slompo, E P; de Souza, E M; de Carvalho, F A L; Madeira, H M F; de Vasconcelos, A T R

    2015-01-01

    The purpose of the present study was to functionally evaluate the influence of superoxide radical-generating compounds on the heterologous induction of a predicted promoter region of open reading frames for paraquat-inducible genes (pqi genes) revealed during genome annotation analyses of the Chromobacterium violaceum bacterium. A 388-bp fragment corresponding to a pqi gene promoter of C. violaceum was amplified using specific primers and cloned into a conjugative vector containing the Escherichia coli lacZ gene without a promoter. Assessments of the expression of the β-galactosidase enzyme were performed in the presence of menadione (MEN) and phenazine methosulfate (PMS) compounds at different final concentrations to evaluate the heterologous activation of the predicted promoter region of interest in C. violaceum induced by these substrates. Under these experimental conditions, the MEN reagent promoted highly significant increases in the expression of the β-galactosidase enzyme modulated by activating the promoter region of the pqi genes at all concentrations tested. On the other hand, significantly higher levels in the expression of the β-galactosidase enzyme were detected exclusively in the presence of the PMS reagent at a final concentration of 50 μg/mL. The findings described in the present study demonstrate that superoxide radical-generating compounds can activate a predicted promoter DNA motif for pqi genes of the C. violaceum bacterium in a dose-dependent manner. PMID:26345950

  2. The minimum knowledge base for predicting organ-at-risk dose-volume levels and plan-related complications in IMRT planning

    NASA Astrophysics Data System (ADS)

    Zhang, Hao H.; Meyer, Robert R.; Shi, Leyuan; D'Souza, Warren D.

    2010-04-01

    IMRT treatment planning requires consideration of two competing objectives: achieving the required amount of radiation for the planning target volume and minimizing the amount of radiation delivered to all other tissues. It is important for planners to understand the tradeoff between competing factors so that the time-consuming human interaction loop (plan-evaluate-modify) can be eliminated. Treatment-plan-surface models have been proposed as a decision support tool to aid treatment planners and clinicians in choosing between rival treatment plans in a multi-plan environment. In this paper, an empirical approach is introduced to determine the minimum number of treatment plans (minimum knowledge base) required to build accurate representations of the IMRT plan surface in order to predict organ-at-risk (OAR) dose-volume (DV) levels and complications as a function of input DV constraint settings corresponding to all involved OARs in the plan. We have tested our approach on five head and neck patients and five whole pelvis/prostate patients. Our results suggest that approximately 30 plans were sufficient to predict DV levels with less than 3% relative error in both head and neck and whole pelvis/prostate cases. In addition, approximately 30-60 plans were sufficient to predict saliva flow rate with less than 2% relative error and to classify rectal bleeding with an accuracy of 90%.

  3. Predicting of Effective Dose as Biomarker for Cytotoxicity Using Partial Least Square-Fourier Transform Infrared Spectroscopy (PLS_FTIR)

    PubMed Central

    Zendehdel, Rezvan; Khodakarim, Soheila; H. Shirazi, Farshad

    2015-01-01

    Toxicity bioassays are important tools to determine biological effects of chemical agents on species. The questions remained on, what effects have been imposed on each of the different molecular site of cells by chemical exposure and how to find a pattern for chemical toxicity. To address the questions, HepG2 cell lines were exposed to the different concentrations of cisplatin for 24 hours to result cell mortality in the range of one to one hundred percent. Fourier Transform Infrared spectroscopy (FTIR) has been used in this study to analyze the chemical alterations on HepG2 cell line by cisplatin. Partial least square regression (PLS) analysis was then applied to the FTIR spectrum results to search for a biomarker peak and present the desire cellular effects of cisplatin. The comparison of cellular FTIR spectra after exposure to different concentrations of cisplatin confirmed the binding of cisplatin to DNA through direct interaction of platinum to guanine and thymine bases of DNA. Biochemical Index Spectra (BIS) were defined based on the differences between of normal and cisplatin exposed cells. Information from the BIS was subjected to PLS analysis to trigger any particular relationship between the toxicity spectral response and cisplatin concentration. This approach was capable of predicting the concentration of cisplatin for any particular effects observed in the cellular FTIR spectrum (R2 = 0.968 ± 0.037). Our work supports the promises that, FTIR can demonstrate the trace of toxicity before the cells dies. Finally, PLS of FTIR data directly predicts the effective concentration of chemicals in particular cellular components. PMID:26664386

  4. High XRCC1 Protein Expression Is Associated with Poorer Survival in Patients with Head and Neck Squamous Cell Carcinoma

    PubMed Central

    Ang, Mei-Kim; Patel, Mihir R.; Yin, Xiao-Ying; Sundaram, Sneha; Fritchie, Karen; Zhao, Ni; Liu, Yufeng; Freemerman, Alex J.; Wilkerson, Matthew D.; Walter, Vonn; Weissler, Mark C.; Shockley, William W.; Couch, Marion E.; Zanation, Adam M.; Hackman, Trevor; Chera, Bhishamjit S.; Harris, Stephen L.; Miller, C. Ryan; Thorne, Leigh B.; Hayward, Michele C.; Funkhouser, William K.; Olshan, Andrew F.; Shores, Carol G.; Makowski, Liza; Hayes, D. Neil

    2012-01-01

    Purpose We evaluated X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1) protein in head and neck squamous cell carcinoma (HNSCC) patients in association with outcome. Experimental Design XRCC1 protein expression was assessed by immunohistochemical (IHC) staining of pretreatment tissue samples in 138 consecutive HNSCC patients treated with surgery (n = 31), radiation (15), surgery and radiation (23), surgery and adjuvant chemoradiation (17), primary chemoradiation (51), and palliative measures (1). Results Patients with high XRCC1 expression by IHC (n = 77) compared with patients with low XRCC1 expression (n = 60) had poorer median overall survival (OS; 41.0 months vs. OS not reached, P = 0.009) and poorer progression-free survival (28.0 months vs. 73.0 months, P = 0.031). This association was primarily due to patients who received chemoradiation (median OS of high- and low-XRCC1 expression patients, 35.5 months and not reached respectively, HR 3.48; 95% CI: 1.44–8.38; P = 0.006). In patients treated with nonchemoradiation modalities, there was no survival difference by XRCC1 expression. In multivariable analysis, high XRCC1 expression and p16INK4a-positive status were independently associated with survival in the overall study population (HR = 2.62; 95% CI: 1.52–4.52; P < 0.001 and HR = 0.21; 95% CI: 0.06–0.71; P = 0.012, respectively) and among chemoradiation patients (HR = 6.02; 95% CI: 2.36–15.37; P < 0.001 and HR = 0.26; 95% CI: 0.08–0.92, respectively; P = 0.037). Conclusions In HNSCC, high XRCC1 protein expression is associated with poorer survival, particularly in patients receiving chemoradiation. Future validation of these findings may enable identification of HNSCC expressing patients who benefit from chemoradiation treatment. PMID:21908577

  5. Predictive value of pyramidal lobe, percentage thyroid uptake and age for ablation outcome after 15 mCi fixed dose of radioiodine-131 in Graves’ disease

    PubMed Central

    Zaman, Maseeh uz; Fatima, Nosheen; Zaman, Unaiza; Sajjad, Zafar; Zaman, Areeba; Tahseen, Rabia

    2015-01-01

    Purpose: The purpose was to find out the efficacy of fixed 15 mCi radioactive iodine-131 (RAI) dose and predictive values of various factors for inducing hypothyroidism in Graves’ disease (GD). Materials and Methods: Retrospective study conducted from January 2012 till August 2014. Patients with GD who had a technetium-99m thyroid scan, thyroid antibodies, received fixed 15 mCi RAI and did follow endocrine clinics for at least 6 months were selected. RAI was considered successful if within 6 months of RAI therapy patients developed hypothyroidism. Results: Of the 370 patients with GD who had RAI during study period, 210 (57%) qualified study criteria. Mean age of patients was 48 ± 15 years with female: male ratio of 69:31, positive thyroid antibodies in 61%, means thyroid uptake of 15.09 ± 11.23%, and presence of pyramidal lobe in 40% of total population. Hypothyroidism was achieved in 161 (77%) patients while 49 (23%) patients failed to achieve it (remained either hyperthyroid or euthyroid on antithyroid medication). Patients who became hypothyroid were significantly younger with higher proportion of presence of thyroid antibodies and pyramidal lobe and lower percentage thyroid uptake than those who failed. Multiple logistic regression analysis revealed that age (odds ratio; OR = 2.074), pyramidal lobe (OR = 3.317), thyroid antibodies (OR = 8.198), and percentage thyroid uptake (OR = 3.043) were found to be significant prognostic risk factors for post-RAI hypothyroidism. Gender was found to have nonsignificant association with the development of hypothyroidism. Receiver operating characteristic analysis revealed age <42 years and thyroid uptake <15% as threshold values for the development of post-RAI hypothyroidism. Conclusion: We conclude that fixed (15 mCi) RAI dose is highly effective in rendering hypothyroidism in patients with GD. Age (≤42 years), thyroid uptake (≤15%) and presence of pyramidal lobe are strong predictors of hypothyroidism and must be

  6. A Novel Method for Predicting Late Genitourinary Toxicity After Prostate Radiation Therapy and the Need for Age-Based Risk-Adapted Dose Constraints

    SciTech Connect

    Ahmed, Awad A.; Egleston, Brian; Alcantara, Pino; Li, Linna; Pollack, Alan; Horwitz, Eric M.; Buyyounouski, Mark K.

    2013-07-15

    Background: There are no well-established normal tissue sparing dose–volume histogram (DVH) criteria that limit the risk of urinary toxicity from prostate radiation therapy (RT). The aim of this study was to determine which criteria predict late toxicity among various DVH parameters when contouring the entire solid bladder and its contents versus the bladder wall. The area under the histogram curve (AUHC) was also analyzed. Methods and Materials: From 1993 to 2000, 503 men with prostate cancer received 3-dimensional conformal RT (median follow-up time, 71 months). The whole bladder and the bladder wall were contoured in all patients. The primary endpoint was grade ≥2 genitourinary (GU) toxicity occurring ≥3 months after completion of RT. Cox regressions of time to grade ≥2 toxicity were estimated separately for the entire bladder and bladder wall. Concordance probability estimates (CPE) assessed model discriminative ability. Before training the models, an external random test group of 100 men was set aside for testing. Separate analyses were performed based on the mean age (≤ 68 vs >68 years). Results: Age, pretreatment urinary symptoms, mean dose (entire bladder and bladder wall), and AUHC (entire bladder and bladder wall) were significant (P<.05) in multivariable analysis. Overall, bladder wall CPE values were higher than solid bladder values. The AUHC for bladder wall provided the greatest discrimination for late bladder toxicity when compared with alternative DVH points, with CPE values of 0.68 for age ≤68 years and 0.81 for age >68 years. Conclusion: The AUHC method based on bladder wall volumes was superior for predicting late GU toxicity. Age >68 years was associated with late grade ≥2 GU toxicity, which suggests that risk-adapted dose constraints based on age should be explored.

  7. Schizotypal Traits are Associated with Poorer Executive Functioning in Healthy Adults.

    PubMed

    Louise, Stephanie; Gurvich, Caroline; Neill, Erica; Tan, Eric J; Van Rheenen, Tamsyn E; Rossell, Susan

    2015-01-01

    Previous research has shown mild forms of the neurocognitive impairments seen in schizophrenia among healthy individuals exhibiting high schizotypal traits. This study aimed to explore associations between schizotypy and cognitive performance in an adult community sample. Ninety-five females and 79 males completed the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE), which measures four separable aspects of schizotypy: cognitive disorganization, unusual experiences, introvertive anhedonia, and impulsive non-conformity. Subsequently, participants were administered a neurocognitive battery incorporating measures of executive skills including inhibition, cognitive flexibility, reasoning, and problem solving along with measures of attention and processing speed and both verbal and spatial working memory. In line with predictions, the current study found that higher scores on the subscales of unusual experiences, cognitive disorganization, and impulsive non-conformity related to worse performance on a measure of inhibition. Additionally, as introvertive anhedonia increased, both attention and processing speed and reasoning and problem-solving performance became more impaired. In conclusion, this study extends schizotypy literature by examining the subscales of the O-LIFE, and enables inferences to be drawn in relation to cognitive impairment in schizophrenia. PMID:26082726

  8. Schizotypal Traits are Associated with Poorer Executive Functioning in Healthy Adults

    PubMed Central

    Louise, Stephanie; Gurvich, Caroline; Neill, Erica; Tan, Eric J.; Van Rheenen, Tamsyn E.; Rossell, Susan

    2015-01-01

    Previous research has shown mild forms of the neurocognitive impairments seen in schizophrenia among healthy individuals exhibiting high schizotypal traits. This study aimed to explore associations between schizotypy and cognitive performance in an adult community sample. Ninety-five females and 79 males completed the Oxford–Liverpool Inventory of Feelings and Experiences (O-LIFE), which measures four separable aspects of schizotypy: cognitive disorganization, unusual experiences, introvertive anhedonia, and impulsive non-conformity. Subsequently, participants were administered a neurocognitive battery incorporating measures of executive skills including inhibition, cognitive flexibility, reasoning, and problem solving along with measures of attention and processing speed and both verbal and spatial working memory. In line with predictions, the current study found that higher scores on the subscales of unusual experiences, cognitive disorganization, and impulsive non-conformity related to worse performance on a measure of inhibition. Additionally, as introvertive anhedonia increased, both attention and processing speed and reasoning and problem-solving performance became more impaired. In conclusion, this study extends schizotypy literature by examining the subscales of the O-LIFE, and enables inferences to be drawn in relation to cognitive impairment in schizophrenia. PMID:26082726

  9. Pharmacokinetic-directed high-dose busulfan combined with cyclophosphamide and etoposide results in predictable drug levels and durable long-term survival in lymphoma patients undergoing autologous stem cell transplantation.

    PubMed

    Zhang, Hongzheng; Graiser, Michael; Hutcherson, Donald A; Dada, M Olufemi; McMillan, Stephanie; Ali, Zahir; Flowers, Christopher R; Waller, Edmund K

    2012-08-01

    The clinical advantage of pharmacokinetic (PK)-directed-based dosing on intravenous (i.v.) versus oral busulfan-related toxicity and survival remains unclear. We performed a retrospective cohort study of sequential cohorts of patients comparing PK-directed oral and i.v. busulfan-based conditioning regimens in lymphoma patients undergoing autologous hematopoietic cell transplantation (ASCT). Patients received oral (n = 95), every 6 hours i.v. (IV16, n = 113), or once-daily i.v. (IV4, n = 86) busulfan, cyclophosphamide, and etoposide. PK-directed dosing was performed to achieve a predefined target area under the curve (AUC) of 20,000 μM-min (range: 18,400-21,600 μM-min). PK-directed dose adjustments markedly reduced the number of patients in the oral group with total AUC higher than the targeted AUC range, and reduced the variations of total AUC values in all patient groups. One hundred-day mortality was 2.1%, 3.6%, and 3.5% for oral, IV16, and IV4 cohorts, respectively. Five-year overall survival (OS) was 57% (95% confidence interval [CI] 45%-66%) and 64% (95% CI 53%-73%) for patients who received oral and i.v. busulfan, respectively. Both multivariable and instrumental variable analyses indicated the route of delivery had no significant impact on OS, whereas refractory disease and age ≥55 were significantly associated with poorer OS. In lymphoma patients undergoing ASCT, PK-directed i.v. or oral busulfan-based conditioning regimens have comparable toxicity and OS. PMID:22370160

  10. Long-term low-level arsenic exposure is associated with poorer neuropsychological functioning: a Project FRONTIER study.

    PubMed

    O'Bryant, Sid E; Edwards, Melissa; Menon, Chloe V; Gong, Gordon; Barber, Robert

    2011-03-01

    Exposure to elements in groundwater (toxic or beneficial) is commonplace yet, outside of lead and mercury, little research has examined the impact of many commonly occurring environmental exposures on mental abilities during the aging process. Inorganic arsenic is a known neurotoxin that has both neurodevelopmental and neurocognitive consequences. The aim of this study was to examine the potential association between current and long-term arsenic exposure and detailed neuropsychological functioning in a sample of rural-dwelling adults and elders. Data were analyzed from 434 participants (133 men and 301 women) of Project FRONTIER, a community-based participatory research study of the epidemiology of health issues of rural-dwelling adults and elders. The results of the study showed that GIS-based groundwater arsenic exposure (current and long-term) was significantly related to poorer scores in language, visuospatial skills, and executive functioning. Additionally, long-term low-level exposure to arsenic was significantly correlated to poorer scores in global cognition, processing speed and immediate memory. The finding of a correlation between arsenic and the domains of executive functioning and memory is of critical importance as these are cognitive domains that reflect the earliest manifestations of Alzheimer's disease. Additional work is warranted given the population health implications associated with long-term low-level arsenic exposure. PMID:21556183

  11. Is quality of life poorer for older adults with HIV/AIDS? International evidence using the WHOQOL-HIV.

    PubMed

    Skevington, S M

    2012-01-01

    Increasingly older adults are being diagnosed with HIV/AIDS. In 2002, UNAIDS indicated that 13 aspects of quality of life (QoL) were poorer for older adults, but only sparse, inconsistent cross-cultural evidence is available. This statement was investigated using a reliable, valid measure (the WHOQOL-HIV) distributed in nine cultures (eight countries). HIV positive and well adults (n = 2089) were assessed across 30 QoL facets; 403 were 40+ years. It was confirmed that sleep, fatigue and sex-life were poorer areas of QoL for older HIV adults than younger. Furthermore, they could be misinterpreted as normal ageing signs. Moreover, older people reported greater dependency on medication. However, older HIV adults had better QoL than expected on 11 dimensions; negative feelings, social inclusion, and several environmental and spiritual facets. This highlights the extent of poor QoL in younger adults. After accounting for culture and gender, overall QoL and health in older HIV adults was explained by eight facets comprising 61.3% of the variance. Social relationships were paramount, especially personal relationships (41%), but support and sex-life also. Energy, negative feelings, cognitions, financial resources and HIV symptoms also contributed. Social interventions for ageing communities would improve well-being. This evidence could support global ageing and HIV policy. PMID:22428745

  12. The High-Dose Aldesleukin “Select” Trial: A Trial to Prospectively Validate Predictive Models of Response Treatment in Patients with Metastatic Renal Cell Carcinoma

    PubMed Central

    McDermott, David F.; Cheng, Su-Chun; Signoretti, Sabina; Margolin, Kim A.; Clark, Joseph I.; Sosman, Jeffrey A.; Dutcher, Janice P.; Logan, Theodore F.; Curti, Brendan D.; Ernstoff, Marc S.; Appleman, Leonard; Wong, Michael K.K.; Khushalani, Nikhil I.; Oleksowicz, Leslie; Vaishampayan, Ulka N.; Mier, James W.; Panka, David J.; Bhatt, Rupal S.; Bailey, Alexandra S.; Leibovich, Bradley C.; Kwon, Eugene D.; Kabbinavar, Fairooz F.; Belldegrun, Arie S.; Figlin, Robert A.; Pantuck, Allan J.; Regan, Meredith M.; Atkins, Michael B.

    2014-01-01

    Purpose High-dose aldesleukin (HD IL-2) received FDA approval for the treatment of mRCC in 1992, producing a 14% objective response rate (ORR) and durable remissions. Retrospective studies suggested that clinical and pathologic features could predict for benefit. The Cytokine Working Group conducted this prospective trial to validate proposed predictive markers of response to HD IL-2. Experimental Design Standard HD IL-2 was administered to prospectively evaluate whether the ORR of mRCC patients with “good” predictive pathologic features based on an “integrated selection” model (ISM) (e.g. clear-cell histology sub-classification and carbonic anhydrase-9 (CA-9) IHC staining) was significantly higher than the ORR of a historical, unselected population. Archived tumor was collected for pathologic analysis including tumor programmed death-ligand 1 (PD-L1) expression. Results 120 eligible patients enrolled between 11/06 and 7/09; 70% were MSKCC intermediate risk, 96% had clear cell RCC and 99% had prior nephrectomy. The independently assessed ORR was 25% (30/120, 95% CI = 17.5%–33.7%, p=0.0014) (3 CR, 27 PR) and was higher than a historical ORR. Thirteen patients (11%) remained progression-free at 3 years and the median OS was 42.8 months. ORR was not statistically different by ISM classification (“good-risk” 23% vs. “poor-risk” 30%, (p=0.39)). ORR was positively associated with tumor PD-L1 expression (p=0.01) by IHC. Conclusions In this prospective, biomarker validation study, HD IL-2 produced durable remissions and prolonged survival in both “good” and “poor-risk” patients. The proposed ISM was unable to improve the selection criteria. Novel markers (e.g. tumor PD-L1expression) appeared useful, but require independent validation. PMID:25424850

  13. Prediction of a potentially effective dose in humans for BAY 60–5521, a potent inhibitor of cholesteryl ester transfer protein (CETP) by allometric species scaling and combined pharmacodynamic and physiologically-based pharmacokinetic modelling

    PubMed Central

    Weber, Olaf; Willmann, Stefan; Bischoff, Hilmar; Li, Volkhart; Vakalopoulos, Alexandros; Lustig, Klemens; Hafner, Frank-Thorsten; Heinig, Roland; Schmeck, Carsten; Buehner, Klaus

    2012-01-01

    AIMS The purpose of this work was to support the prediction of a potentially effective dose for the CETP-inhibitor, BAY 60–5521, in humans. METHODS A combination of allometric scaling of the pharmacokinetics of the CETP-inhibitor BAY 60–5521 with pharmacodynamic studies in CETP-transgenic mice and in human plasma with physiologically-based pharmacokinetic (PBPK) modelling was used to support the selection of the first-in-man dose. RESULTS The PBPK approach predicts a greater extent of distribution for BAY 60–5521 in humans compared with the allometric scaling method as reflected by a larger predicted volume of distribution and longer elimination half-life. The combined approach led to an estimate of a potentially effective dose for BAY 60–5521 of 51 mg in humans. CONCLUSION The approach described in this paper supported the prediction of a potentially effective dose for the CETP-inhibitor BAY 60–5521 in humans. Confirmation of the dose estimate was obtained in a first-in-man study. PMID:21762205

  14. BRCA1-like profile predicts benefit of tandem high dose epirubicin-cyclophospamide-thiotepa in high risk breast cancer patients randomized in the WSG-AM01 trial.

    PubMed

    Schouten, Philip C; Gluz, Oleg; Harbeck, Nadia; Mohrmann, Svjetlana; Diallo-Danebrock, Raihana; Pelz, Enrico; Kruizinga, Janneke; Velds, Arno; Nieuwland, Marja; Kerkhoven, Ron M; Liedtke, Cornelia; Frick, Markus; Kates, Ronald; Linn, Sabine C; Nitz, Ulrike; Marme, Frederik

    2016-08-15

    BRCA1 is an important protein in the repair of DNA double strand breaks (DSBs), which are induced by alkylating chemotherapy. A BRCA1-like DNA copy number signature derived from tumors with a BRCA1 mutation is indicative for impaired BRCA1 function and associated with good outcome after high dose (HD) and tandem HD DSB inducing chemotherapy. We investigated whether BRCA1-like status was a predictive biomarker in the WSG AM 01 trial. WSG AM 01 randomized high-risk breast cancer patients to induction (2× epirubicin-cyclophosphamide) followed by tandem HD chemotherapy with epirubicin, cyclophosphamide and thiotepa versus dose dense chemotherapy (4× epirubicin-cyclophospamide followed by 3× cyclophosphamide-methotrexate-5-fluorouracil). We generated copy number profiles for 143 tumors and classified them as being BRCA1-like or non-BRCA1-like. Twenty-six out of 143 patients were BRCA1-like. BRCA1-like status was associated with high grade and triple negative tumors. With regard to event-free-survival, the primary endpoint of the trial, patients with a BRCA1-like tumor had a hazard rate of 0.2, 95% confidence interval (CI): 0.07-0.63, p = 0.006. In the interaction analysis, the combination of BRCA1-like status and HD chemotherapy had a hazard rate of 0.19, 95% CI: 0.067-0.54, p = 0.003. Similar results were observed for overall survival. These findings suggest that BRCA1-like status is a predictor for benefit of tandem HD chemotherapy with epirubicin-thiotepa-cyclophosphamide. PMID:26946057

  15. Prostate-specific antigen nadir after high-dose-rate brachytherapy predicts long-term survival outcomes in high-risk prostate cancer

    PubMed Central

    Satoh, Takefumi; Ishiyama, Hiromichi; Tabata, Ken-ichi; Komori, Shouko; Sekiguchi, Akane; Ikeda, Masaomi; Kurosaka, Shinji; Fujita, Tetsuo; Kitano, Masashi; Hayakawa, Kazushige; Iwamura, Masatsugu

    2016-01-01

    Purpose To evaluate the prognostic value of prostate-specific antigen nadir (nPSA) after high-dose-rate (HDR) brachytherapy in clinically non-metastatic high-risk prostate cancer patients. Material and methods Data from 216 patients with high-risk or locally advanced prostate cancer who underwent HDR brachytherapy and external beam radiation therapy with long-term androgen deprivation therapy (ADT) between 2003 and 2008 were analyzed. The median prostate-specific antigen (PSA) level at diagnosis was 24 ng/ml (range: 3-338 ng/ml). The clinical stage was T1c-2a in 55 cases (26%), T2b-2c in 48 (22%), T3a in 75 (35%), and T3b-4 in 38 (17%). The mean dose to 90% of the planning target volume was 6.3 Gy/fraction of HDR brachytherapy. After 5 fractions, external beam radiation therapy with 10 fractions of 3 Gy was administered. All patients initially underwent neoadjuvant ADT for at least 6 months, and adjuvant ADT was continued for 36 months. The median follow-up was 7 years from the start of radiotherapy. Results The 7-year PSA relapse-free rate among patients with a post-radiotherapy nPSA level of ≤ 0.02 ng/ml was 94%, compared with 23% for patients with higher nPSA values (HR = 28.57; 95% CI: 12.04-66.66; p < 0.001). Multivariate analysis revealed that the nPSA value after radiotherapy was a significant independent predictor of biochemical failure, whereas pretreatment predictive values for worse biochemical control including higher level of initial PSA, Gleason score ≥ 8, positive biopsy core rate ≥ 67%, and T3b-T4, failed to reach independent predictor status. The 7-year cancer-specific survival rate among patients with a post-radiotherapy nPSA level of ≤ 0.02 ng/ml was 99%, compared with 82% for patients with higher nPSA values (HR = 32.25; 95% CI: 3.401-333.3; p = 0.002). Conclusions A post-radiotherapy nPSA value of ≤ 0.02 ng/ml was associated with better long-term biochemical tumor control even if patients had pretreatment predictive values for worse

  16. Integration of the predictions of two models with dose measurements in a case study of children exposed to the emissions of a lead smelter

    SciTech Connect

    Bonnard, R.; McKone, T.E.

    2009-03-01

    The predictions of two source-to-dose models are systematically evaluated with observed data collected in a village polluted by a currently operating secondary lead smelter. Both models were built up from several sub-models linked together and run using Monte-Carlo simulation, to calculate the distribution children's blood lead levels attributable to the emissions from the facility. The first model system is composed of the CalTOX model linked to a recoded version of the IEUBK model. This system provides the distribution of the media-specific lead concentrations (air, soil, fruit, vegetables and blood) in the whole area investigated. The second model consists of a statistical model to estimate the lead deposition on the ground, a modified version of the model HHRAP and the same recoded version of the IEUBK model. This system provides an estimate of the concentration of exposure of specific individuals living in the study area. The predictions of the first model system were improved in terms of accuracy and precision by performing a sensitivity analysis and using field data to correct the default value provided for the leaf wet density. However, in this case study, the first model system tends to overestimate the exposure due to exposed vegetables. The second model was tested for nine children with contrasting exposure conditions. It managed to capture the blood levels for eight of them. In the last case, the exposure of the child by pathways not considered in the model may explain the failure of the model. The interest of this integrated model is to provide outputs with lower variance than the first model system, but at the moment further tests are necessary to conclude about its accuracy.

  17. Poorer Neurodevelopmental Outcomes Associated with Cystoid Macular Edema Identified in Preterm Infants in the Intensive Care Nursery

    PubMed Central

    Rothman, Adam L.; Tran-Viet, Du; Gustafson, Kathryn E.; Goldstein, Ricki F.; Maguire, Maureen G.; Tai, Vincent; Sarin, Neeru; Tong, Amy Y.; Huang, Jiayan; Kupper, Laura; Cotten, C. Michael; Freedman, Sharon F.; Toth, Cynthia A.

    2014-01-01

    Purpose To evaluate the association between cystoid macular edema (CME) observed in very preterm infants and developmental outcomes at 18 to 24 months corrected age. Design Cohort study. Participants Infants born at or less than 1500 g or at or less than 30 weeks postmenstrual age who underwent screening for retinopathy of prematurity (ROP) in an intensive care nursery. Methods Bedside handheld spectral-domain optical coherence tomography (SD OCT; Envisu, Bioptigen, Inc, Research Triangle Park, NC) imaging was obtained from preterm infants who were being screened for ROP and graded for presence of CME, central foveal thickness (CFT), inner nuclear layer thickness, and foveal-to-parafoveal thickness ratio. At 18 to 24 months corrected age, the children were assessed with the Bayley Scales of Infant and Toddler Development, Third Edition. Main Outcome Measures Scores on the Bayley cognitive, language, and motor subscales. Results Among 77 children with SD OCT imaging, 53 were evaluated with the Bayley Scales. Compared with children who did not have CME as infants (n = 22), the mean score for children who had CME (n = 31) was 7.3 points (95% confidence interval [CI], −15.5 to 0.9; P = 0.08) lower on the cognitive subscale, 14.1 points (95% CI, −22.7 to −5.5; P = 0.002) lower for the language subscale, and 11.5 points (95% CI, −21.6 to −1.3; P = 0.03) lower for the motor subscale. Differences were maintained after adjusting for gestational age and birth weight. Severity of CME, as assessed by foveal-to-parafoveal thickness ratio, within the CME group correlated with poorer cognitive (R2 = 0.16, P = 0.03) and motor (R2 = 0.15, P = 0.03) development. Conclusions Cystoid macular edema observed on SD OCT in very preterm infants screened for ROP is associated with poorer language and motor skills at 18 to 24 months corrected age. Evaluation of the retina with SD-OCT may serve as an indicator of neurodevelopmental health for very preterm infants in the intensive

  18. Poorer frontolimbic white matter integrity is associated with chronic cannabis use, FAAH genotype, and increased depressive and apathy symptoms in adolescents and young adults

    PubMed Central

    Shollenbarger, Skyler G.; Price, Jenessa; Wieser, Jon; Lisdahl, Krista

    2015-01-01

    Background The heaviest period of cannabis use coincides with ongoing white matter (WM) maturation. Further, cannabis-related changes may be moderated by FAAH genotype (rs324420). We examined the association between cannabis use and FAAH genotype on frontolimbic WM integrity in adolescents and emerging adults. We then tested whether observed WM abnormalities were linked with depressive or apathy symptoms. Methods Participants included 37 cannabis users and 37 healthy controls (33 female; ages 18–25). Multiple regressions examined the independent and interactive effects of variables on WM integrity. Results Regular cannabis users demonstrated reduced WM integrity in the bilateral uncinate fasciculus (UNC) (MD, right: p = .009 and left: p = .009; FA, right: p = .04 and left: p = .03) and forceps minor (fMinor) (MD, p = .03) compared to healthy controls. Marginally reduced WM integrity in the cannabis users was found in the left anterior thalamic radiation (ATR) (FA, p = .08). Cannabis group ∗ FAAH genotype interaction predicted WM integrity in bilateral ATR (FA, right: p = .05 and left: p = .001) and fMinor (FA, p = .02). In cannabis users, poorer WM integrity was correlated with increased symptoms of depression and apathy in bilateral ATR and UNC. Conclusions Consistent with prior findings, cannabis use was associated with reduced frontolimbic WM integrity. WM integrity was also moderated by FAAH genotype, in that cannabis-using FAAH C/C carriers and A carrying controls had reduced WM integrity compared to control C/C carriers. Observed frontolimbic white matter abnormalities were linked with increased depressive and apathy symptoms in the cannabis users. PMID:26106535

  19. First month prednisone dose predicts prednisone burden during the following 11 months: an observational study from the RELES cohort

    PubMed Central

    Ruiz-Irastorza, G; Garcia, M; Espinosa, G; Caminal, L; Mitjavila, F; González-León, R; Sopeña, B; Canora, J; Villalba, M V; Rodríguez-Carballeira, M; López-Dupla, J M; Callejas, J L; Castro, A; Tolosa, C; Sánchez-García, M E; Pérez-Conesa, M; Navarrete-Navarrete, N; Rodríguez, A P; Herranz, M T; Pallarés, L

    2016-01-01

    Aim To study the influence of prednisone dose during the first month after systemic lupus erythematosus (SLE) diagnosis (prednisone-1) on glucocorticoid burden during the subsequent 11 months (prednisone-2–12). Methods 223 patients from the Registro Español de Lupus Eritematoso Sistémico inception cohort were studied. The cumulative dose of prednisone-1 and prednisone-2–12 were calculated and recoded into a four-level categorical variable: no prednisone, low dose (up to 7.5 mg/day), medium dose (up to 30 mg/day) and high dose (over 30 mg/day). The association between the cumulative prednisone-1 and prednisone-2–12 doses was tested. We analysed whether the four-level prednisone-1 categorical variable was an independent predictor of an average dose >7.5 mg/day of prednisone-2–12. Adjusting variables included age, immunosuppressives, antimalarials, methyl-prednisolone pulses, lupus nephritis and baseline SLE Disease Activity Index (SLEDAI). Results Within the first month, 113 patients (51%) did not receive any prednisone, 24 patients (11%) received average low doses, 46 patients (21%) received medium doses and 40 patients (18%) received high doses. There was a strong association between prednisone-1 and prednisone-2–12 dose categories (p<0.001). The cumulative prednisone-1 dose was directly associated with the cumulative prednisone-2–12 dose (p<0.001). Compared with patients on no prednisone, patients taking medium (adjusted OR 5.27, 95% CI 2.18 to 12.73) or high-dose prednisone-1 (adjusted OR 10.5, 95% CI 3.8 to 29.17) were more likely to receive prednisone-2–12 doses of >7.5 mg/day, while patients receiving low-dose prednisone-1 were not (adjusted OR 1.4, 95% CI 0. 0.38 to 5.2). If the analysis was restricted to the 158 patients with a baseline SLEDAI of ≥6, the model did not change. Conclusion The dose of prednisone during the first month after the diagnosis of SLE is an independent predictor of prednisone burden during the following

  20. Prediction of formulation effects on dermal absorption of topically applied ectoparasiticides dosed in vitro on canine and porcine skin using a mixture-adjusted quantitative structure permeability relationship.

    PubMed

    Riviere, J E; Brooks, J D; Collard, W T; Deng, J; de Rose, G; Mahabir, S P; Merritt, D A; Marchiondo, A A

    2014-10-01

    Topical application of ectoparasiticides for flea and tick control is a major focus for product development in animal health. The objective of this work was to develop a quantitative structure permeability relationship (QSPeR) model sensitive to formulation effects for predicting absorption and skin deposition of five topically applied drugs administered in six vehicle combinations to porcine and canine skin in vitro. Saturated solutions (20 μL) of (14) C-labeled demiditraz, fipronil, permethrin, imidacloprid, or sisapronil were administered in single or binary (50:50 v/v) combinations of water, ethanol, and transcutol (6 formulations, n = 4-5 replicates per treatment) nonoccluded to 0.64 cm(2) disks of dermatomed pig or dog skin mounted in flow-through diffusion cells. Perfusate flux over 24 h and skin deposition at termination were determined. Permeability (logKp), absorption, and penetration endpoints were modeled using a four-term Abrahams and Martin (hydrogen-bond donor acidity and basicity, dipolarity/polarizability, and excess molar refractivity) linear free energy QSPeR equation with a mixture factor added to compensate for formulation ingredient interactions. Goodness of fit was judged by r(2) , cross-validation coefficient, coefficients (q(2) s), and Williams Plot to visualize the applicability domain. Formulation composition was the primary determinant of permeation. Compounds generally penetrated dog skin better than porcine skin. The vast majority of permeated penetrant was deposited within the dosed skin relative to transdermal flux, an attribute for ectoparasiticides. The best QSPeR logKp model for pig skin permeation (r(2) = 0.86, q(2) s = 0.85) included log octanol/water partition coefficient as the mixture factor, while for dogs (r(2) = 0.91, q(2) s = 0.90), it was log water solubility. These studies clearly showed that the permeation of topical ectoparasiticides could be well predicted using QSPeR models that account for both the physical

  1. Circulating immune cell phenotype can predict the outcome of lenalidomide plus low-dose dexamethasone treatment in patients with refractory/relapsed multiple myeloma.

    PubMed

    Lee, Sung-Eun; Lim, Ji-Young; Ryu, Da-Bin; Kim, Tae Woo; Yoon, Jae-Ho; Cho, Byung-Sik; Eom, Ki-Seong; Kim, Yoo-Jin; Kim, Hee-Je; Lee, Seok; Cho, Seok-Goo; Kim, Dong-Wook; Lee, Jong-Wook; Min, Woo-Sung; Kim, Myungshin; Min, Chang-Ki

    2016-08-01

    Although the antimyeloma effect of lenalidomide is associated with activation of the immune system, the exact in vivo immunomodulatory mechanisms of lenalidomide combined with low-dose dexamethasone (Len-dex) in refractory/relapsed multiple myeloma (RRMM) patients remain unclear. In this study, we analyzed the association between immune cell populations and clinical outcomes in patients receiving Len-dex for the treatment of RRMM. Peripheral blood samples from 90 RRMM patients were taken on day 1 of cycles 1 (baseline), 2, 3, and 4 of Len-dex therapy. Peripheral blood CD3(+), CD4(+), and CD8(+) cell frequencies were significantly decreased by 3 cycles of therapy, whereas NK cell frequency was significantly increased after the 3rd cycle. For the myeloid-derived suppressor cell (MDSC) subset, the frequency of granulocytic MDSCs transiently increased after the 1st cycle, whereas there was an increase in monocytic MDSC (M-MDSC) frequency after the 1st and 3rd cycles. Among 81 evaluable patients, failure to achieve a response of VGPR or greater was associated with a decrease in CD8(+) cell frequency and increase in M-MDSC frequency after 3 cycles of Len-dex treatment. A high proportion of natural killer T (NKT)-like cells (CD3(+)/CD56(+)) prior to Len-dex treatment might predict a longer time to progression. In addition, patients with a smaller decrease in the frequency of both CD3(+) cells and CD8(+) cells by 3 cycles exhibited a longer time to the next treatment. These results demonstrated that early changes in immune cell subsets are useful immunologic indicators of the efficacy of Len-dex treatment in RRMM. PMID:27342591

  2. SHEDS-PM: A POPULATION EXPOSURE MODEL FOR PREDICTING DISTRIBUTIONS OF PM EXPOSURE AND DOSE FROM BOTH OUTDOOR AND INDOOR SOURCES

    EPA Science Inventory

    The US EPA National Exposure Research Laboratory (NERL) has developed a population exposure and dose model for particulate matter (PM), called the Stochastic Human Exposure and Dose Simulation (SHEDS) model. SHEDS-PM uses a probabilistic approach that incorporates both variabi...

  3. Poorer prognosis in Taiwanese female ever smokers with stage IV lung adenocarcinoma who were readministered a tyrosine kinase inhibitor

    PubMed Central

    Yang, Chih-Jen; Tsai, Ming-Ju; Hung, Jen-Yu; Tsai, Ying-Ming; Lee, Jui-Ying; Chou, Shah-Hwa; Liu, Ta-Chih; Shen, Mei-Chiou; Huang, Ming-Shyan; Chong, Inn-Wen

    2016-01-01

    Background Readministering a second epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in patients with lung adenocarcinoma with acquired resistance to an initial EGFR TKI is a common treatment strategy. However, the prognostic factors for the second EGFR TKI are still uncertain. Patients and methods In this retrospective study, we enrolled patients with stage IV lung adenocarcinoma diagnosed between June 2009 and October 2013 at two university-affiliated hospitals in Taiwan. Basic characteristics including age, sex, smoking status, performance status, EGFR mutation status, tumor response, and progression-free survival (PFS) of the second EGFR TKI (PFS2) were recorded. Results A total of 72 patients with stage IV adenocarcinoma with susceptible EGFR gene mutations who had been treated with a second EGFR TKI were enrolled. Survival analysis using the Kaplan–Meier method and log-rank test showed a significant difference in PFS2 when classifying the patients according to smoking history and sex (P=0.0179). When stratifying the patients by sex, a significant difference was found in PFS2 between ever smokers and never smokers in the female (1.87 vs 4.87 months, P=0.0081) but not in the male (2.83 vs 2.9 months, P=0.9605) patients. A reduced multivariate model developed using the backward variable selection method showed that only ever smoking remained an independent poor prognostic factor for PFS2, and that sex and ever smoking remained independent poor prognostic factors for PFS2 in the female patients (hazard ratio [HR] =3.386, 95% confidence interval [CI]: 1.015–11.298, P=0.0473). Conclusion This study is the first to demonstrate that female ever smokers have a poorer PFS if they have acquired resistance to an initial EGFR TKI and receive a second EGFR TKI. Further large-scale studies are urgently needed to elucidate the mechanism. PMID:27042119

  4. Cholecystectomy is associated with higher risk of early recurrence and poorer survival after curative resection for early stage hepatocellular carcinoma

    PubMed Central

    Li, Tao; Wang, Shu-Kang; Zhi, Xu-Ting; Zhou, Jian; Dong, Zhao-Ru; Zhang, Zong-Li; Sun, Hui-Chuan; Ye, Qing-Hai; Fan, Jia

    2016-01-01

    Although cholecystectomy has been reported to be associated with increased risk of developing hepatocellular carcinoma (HCC), the association between cholecystectomy and prognosis of HCC patients underwent curative resection has never been examined. Through retrospective analysis of the data of 3933 patients underwent curative resection for HCC, we found that cholecystectomy was an independent prognostic factor for recurrence-free survival (RFS) of patients at early stage (BCLC stage 0/A) (p = 0.020, HR: 1.29, 95% CI: 1.04–1.59), and the 1-, 3-, 5-year RFS rates for patients at early stage were significantly worse in cholecystectomy group than in non-cholecystectomy group (80.5%, 61.8%, 52.0% vs 88.2%, 68.8%, 56.8%, p = 0.033). The early recurrence rate of cholecystectomy group was significantly higher than that of non-cholecystectomy group for patients at early stage (59/47 vs 236/333, p = 0.007), but not for patients at advanced stage (BCLC stage C) (p = 0.194). Multivariate analyses showed that cholecystectomy was an independent risk factor for early recurrence (p = 0.005, HR: 1.52, 95% CI: 1.13–2.03) of early stage HCC, but not for late recurrence (p = 0.959). In conclusion, cholecystectomy is an independent predictor for early recurrence and is associated with poorer RFS of early stage HCC. Removal of normal gallbladder during HCC resection may be avoided for early stage patients. PMID:27320390

  5. Executive dysfunction is associated with poorer health-related quality of life in pediatric brain tumor survivors.

    PubMed

    Netson, Kelli L; Ashford, Jason M; Skinner, Traci; Carty, Lynne; Wu, Shengjie; Merchant, Thomas E; Conklin, Heather M

    2016-06-01

    Children with a brain tumor (BT) are at risk for a number of physical and cognitive problems that may lower their health-related quality of life (HRQoL). Executive functioning (EF) and intellectual ability are hypothesized to associate with HRQoL and deficits in these areas may be amenable to interventions. This study aimed to investigate intellectual function, EF, and HRQoL following conformal radiation therapy (CRT) for pediatric BT. Forty-five BT survivors (age 12.68 ± 2.56) treated with CRT participated. Thirty-six siblings of BT patients (age 12.36 ± 2.13) and 33 survivors of non-CNS solid tumors (ST; age 12.18 ± 2.88) were comparison groups. IQ estimate (Wechsler Abbreviated Scale of Intelligence; WASI), EF ratings (Behavior Rating Inventory of Executive Function; BRIEF), and HRQoL ratings (KINDL-R) were obtained. BT survivors reported lower overall HRQoL than ST survivors (p = .012). Parents reported lower overall HRQoL for BT survivors than siblings (p = .014). Parent-report on individual areas of HRQoL was higher than self-report for most subscales. IQ and HRQoL ratings were not related (Parent r = .17, p = .27; Child r = .11, p = .49). EF ratings correlated with Parent (r = -.15 to -.73) but not Child HRQoL ratings. Children with BT experienced poorer HRQoL than controls. Children's HRQoL was consistently rated higher by parent- than self-report across all domains. HRQoL was associated with EF, but not with IQ. These findings identify interventions targeting EF (e.g., cognitive rehabilitation, medication) as a possible avenue for improving HRQoL in childhood BT survivors. PMID:27033060

  6. Having pancreatic cancer with tumoral loss of ATM and normal TP53 protein expression is associated with a poorer prognosis

    PubMed Central

    Kim, Haeryoung; Saka, Burcu; Knight, Spencer; Borges, Michael; Childs, Erica; Klein, Alison; Wolfgang, Christopher; Herman, Joseph; Adsay, Volkan N.; Hruban, Ralph H.; Goggins, Michael

    2014-01-01

    Purpose To determine how often loss of ATM protein expression occurs in primary pancreatic ductal adenocarcinomas and to determine its prognostic significance. Experimental Design The expression of ATM and TP53 was determined by immunohistochemistry in 397 surgically-resected pancreatic ductal adenocarcinomas (Hopkins), a second set of 159 cases (Emory) and 21 cancers after neoadjuvant chemoradiotherapy. Expression was correlated with the clinicopathologic parameters, including survival. Results Tumoral ATM loss was observed in one cancer known to have bi-allelic inactivation of ATM and 50 of the first 396 (12.8%) cases, significantly more often in patients with a family history of pancreatic cancer (12/49; 24.5%) than in those without (38/347; 11.0%) (p=0.019). In the Hopkins series, ATM loss was associated with a significantly decreased overall survival in patients whose cancers had normal TP53 expression (p=0.019) and was a significant independent predictor of decreased overall survival (p=0.014). Seventeen (10.7%) of 159 Emory cases had tumoral ATM loss and tumoral ATM loss/normal TP53 was associated with poorer overall survival (p=0.1). Multivariate analysis of the combined Hopkins/Emory cases found tumoral ATM loss/normal TP53 was an independent predictor of decreased overall survival (HR 2.61, CI1.27–5.37, p=0.009). Of 21 cancers examined after neoadjuvant chemoradiotherapy one had tumoral loss of ATM; it had no histological evidence of tumor response. Conclusions Tumoral loss of ATM protein was detected more often in patients with a family history of pancreatic cancer than in those without. Patients whose pancreatic cancers had loss of ATM but normal TP53 had worse overall survival after pancreatic resection. PMID:24486587

  7. Predictive value of early 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) during salvage chemotherapy in relapsing/refractory Hodgkin lymphoma (HL) treated with high-dose chemotherapy.

    PubMed

    Castagna, Luca; Bramanti, Stefania; Balzarotti, Monica; Sarina, Barbara; Todisco, Elisabetta; Anastasia, Antonella; Magagnoli, Massimo; Mazza, Rita; Nozza, Andrea; Giordano, Laura; Rodari, Marcello; Rinifilo, Eva; Chiti, Arturo; Santoro, Armando

    2009-05-01

    This retrospective study evaluated whether early 2-[fluorine-18]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) after two cycles of salvage chemotherapy (PET2) could predict survival after high-dose chemotherapy (HDC). Twenty-four Hodgkin lymphoma (HL) patients were included. PET2 was negative in 58% and positive in 42% of patients. Ninety per cent of patients (9/10) with positive PET2 relapsed after HDC while all but one patient with negative PET2 maintained a complete remission. The 2-year progression-free survival was 93% vs. 10% for patients with negative and positive PET2, respectively (P < 0.001). This study shows that interim PET can predict the outcome after high-dose chemotherapy in HL patients. PMID:19344403

  8. Predicting Grade 3 Acute Diarrhea During Radiation Therapy for Rectal Cancer Using a Cutoff-Dose Logistic Regression Normal Tissue Complication Probability Model

    SciTech Connect

    Robertson, John M.; Soehn, Matthias; Yan Di

    2010-05-01

    Purpose: Understanding the dose-volume relationship of small bowel irradiation and severe acute diarrhea may help reduce the incidence of this side effect during adjuvant treatment for rectal cancer. Methods and Materials: Consecutive patients treated curatively for rectal cancer were reviewed, and the maximum grade of acute diarrhea was determined. The small bowel was outlined on the treatment planning CT scan, and a dose-volume histogram was calculated for the initial pelvic treatment (45 Gy). Logistic regression models were fitted for varying cutoff-dose levels from 5 to 45 Gy in 5-Gy increments. The model with the highest LogLikelihood was used to develop a cutoff-dose normal tissue complication probability (NTCP) model. Results: There were a total of 152 patients (48% preoperative, 47% postoperative, 5% other), predominantly treated prone (95%) with a three-field technique (94%) and a protracted venous infusion of 5-fluorouracil (78%). Acute Grade 3 diarrhea occurred in 21%. The largest LogLikelihood was found for the cutoff-dose logistic regression model with 15 Gy as the cutoff-dose, although the models for 20 Gy and 25 Gy had similar significance. According to this model, highly significant correlations (p <0.001) between small bowel volumes receiving at least 15 Gy and toxicity exist in the considered patient population. Similar findings applied to both the preoperatively (p = 0.001) and postoperatively irradiated groups (p = 0.001). Conclusion: The incidence of Grade 3 diarrhea was significantly correlated with the volume of small bowel receiving at least 15 Gy using a cutoff-dose NTCP model.

  9. Incidence of malignant thyroid tumors in humans after exposure to diagnostic doses of /sup 131/I. II. Estimation of thyroid gland size, thyroid radiation dose, and predicted versus observed number of malignant thyroid tumors

    SciTech Connect

    Holm, L.E.; Eklund, G.; Lundell, G.

    1980-12-01

    The size of the thyroid glands was analyzed for 10% of the patients in a selected group that had been exposed to diagnostic doses of /sup 131/I. The mean thyroid gland weight +- SD was 50 +- 33 g for patients 20 or more years of age and 10 +- 5 g for patients less than 20 years of age. With the present follow-up, diagnostic doses of /sup 131/I appeared not to be associated with an increased risk for later development of malignant thyroid tumors. Possible reasons for the difference between the observed number of such tumors and the number expected (47 to 124) on the basis of risk estimates of the United Nations Scientific Committee on the Effects of Atomic Radiation are discussed.

  10. Comparison of MCNPX and GEANT4 to Predict the Contribution of Non-elastic Nuclear Interactions to Absorbed Dose in Water, PMMA and A150

    NASA Astrophysics Data System (ADS)

    Shtejer, K.; Arruda-Neto, J. D. T.; Schulte, R.; Wroe, A.; Rodrigues, T. E.; de Menezes, M. O.; Moralles, M.; Guzmán, F.; Manso, M. V.

    2008-08-01

    Proton induced non-elastic nuclear reactions play an important role in the dose distribution of clinically used proton beams as they deposit dose of high biological effectiveness both within the primary beam path as well as outside the beam to untargeted tissues. Non-elastic nuclear reactions can be evaluated using transport codes based on the Monte Carlo method. In this work, we have utilized the Los Alamos code MCNPX and the CERN GEANT4 toolkit, which are currently the most widely used Monte Carlo programs for proton radiation transport simulations in medical physics, to study the contribution of non-elastic nuclear interactions to the absorbed dose of proton beams in the therapeutic energy range. The impact of different available theoretical models to address the nuclear reaction process was investigated. The contribution of secondary particles from non-elastic nuclear reactions was calculated in three materials relevant in radiotherapy applications: water, PMMA and A150. The results evidence that there are differences in the calculated contribution of the secondary particles heavier than protons to the absorbed dose, with different approaches to model the nuclear reactions. The MCNPX calculation give rise to a larger contribution of d, t, α3He to the total dose compared to the GEANT4 physical models chosen in this work.

  11. Comparison of MCNPX and GEANT4 to Predict the Contribution of Non-elastic Nuclear Interactions to Absorbed Dose in Water, PMMA and A150

    SciTech Connect

    Shtejer, K.; Arruda-Neto, J. D. T.; Rodrigues, T. E.; Schulte, R.; Wroe, A.; Menezes, M. O. de; Moralles, M.

    2008-08-11

    Proton induced non-elastic nuclear reactions play an important role in the dose distribution of clinically used proton beams as they deposit dose of high biological effectiveness both within the primary beam path as well as outside the beam to untargeted tissues. Non-elastic nuclear reactions can be evaluated using transport codes based on the Monte Carlo method. In this work, we have utilized the Los Alamos code MCNPX and the CERN GEANT4 toolkit, which are currently the most widely used Monte Carlo programs for proton radiation transport simulations in medical physics, to study the contribution of non-elastic nuclear interactions to the absorbed dose of proton beams in the therapeutic energy range. The impact of different available theoretical models to address the nuclear reaction process was investigated. The contribution of secondary particles from non-elastic nuclear reactions was calculated in three materials relevant in radiotherapy applications: water, PMMA and A150. The results evidence that there are differences in the calculated contribution of the secondary particles heavier than protons to the absorbed dose, with different approaches to model the nuclear reactions. The MCNPX calculation give rise to a larger contribution of d, t, {alpha}{sup 3}He to the total dose compared to the GEANT4 physical models chosen in this work.

  12. A STUDY OF PREDICTED BONE MARROW DISTRIBUTION ON CALCULATED MARROW DOSE FROM EXTERNAL RADIATION EXPOSURES USING TWO SETS OF IMAGE DATA FOR THE SAME INDIVIDUAL

    PubMed Central

    Caracappa, Peter F.; Chao, T. C. Ephraim; Xu, X. George

    2010-01-01

    Red bone marrow is among the tissues of the human body that are most sensitive to ionizing radiation, but red bone marrow cannot be distinguished from yellow bone marrow by normal radiographic means. When using a computational model of the body constructed from computed tomography (CT) images for radiation dose, assumptions must be applied to calculate the dose to the red bone marrow. This paper presents an analysis of two methods of calculating red bone marrow distribution: 1) a homogeneous mixture of red and yellow bone marrow throughout the skeleton, and 2) International Commission on Radiological Protection cellularity factors applied to each bone segment. A computational dose model was constructed from the CT image set of the Visible Human Project and compared to the VIP-Man model, which was derived from color photographs of the same individual. These two data sets for the same individual provide the unique opportunity to compare the methods applied to the CT-based model against the observed distribution of red bone marrow for that individual. The mass of red bone marrow in each bone segment was calculated using both methods. The effect of the different red bone marrow distributions was analyzed by calculating the red bone marrow dose using the EGS4 Monte Carlo code for parallel beams of monoenergetic photons over an energy range of 30 keV to 6 MeV, cylindrical (simplified CT) sources centered about the head and abdomen over an energy range of 30 keV to 1 MeV, and a whole-body electron irradiation treatment protocol for 3.9 MeV electrons. Applying the method with cellularity factors improves the average difference in the estimation of mass in each bone segment as compared to the mass in VIP-Man by 45% over the homogenous mixture method. Red bone marrow doses calculated by the two methods are similar for parallel photon beams at high energy (above about 200 keV), but differ by as much as 40% at lower energies. The calculated red bone marrow doses differ

  13. Effectiveness of low-dose pasireotide in a patient with Cushing’s disease: antiproliferative effect and predictivity of a short pasireotide suppression test

    PubMed Central

    Grossrubatscher, Erika; Zampetti, Benedetta; Dalino Ciaramella, Paolo; Doneda, Paola; Loli, Paola

    2015-01-01

    Key Clinical Message This case shows efficacy of low-dose pasireotide in biochemical and clinical control of severe hypercortisolism and in tumor volume reduction in a patient with an ACTH-secreting macroadenoma. The drug may be an option for long-term treatment in some patients where control of tumor mass is an important clinical endpoint. PMID:26331021

  14. Effectiveness of low-dose pasireotide in a patient with Cushing's disease: antiproliferative effect and predictivity of a short pasireotide suppression test.

    PubMed

    Grossrubatscher, Erika; Zampetti, Benedetta; Dalino Ciaramella, Paolo; Doneda, Paola; Loli, Paola

    2015-08-01

    This case shows efficacy of low-dose pasireotide in biochemical and clinical control of severe hypercortisolism and in tumor volume reduction in a patient with an ACTH-secreting macroadenoma. The drug may be an option for long-term treatment in some patients where control of tumor mass is an important clinical endpoint. PMID:26331021

  15. Assessment of the accuracy of an MCNPX-based Monte Carlo simulation model for predicting three-dimensional absorbed dose distributions

    PubMed Central

    Titt, U; Sahoo, N; Ding, X; Zheng, Y; Newhauser, W D; Zhu, X R; Polf, J C; Gillin, M T; Mohan, R

    2014-01-01

    In recent years, the Monte Carlo method has been used in a large number of research studies in radiation therapy. For applications such as treatment planning, it is essential to validate the dosimetric accuracy of the Monte Carlo simulations in heterogeneous media. The AAPM Report no 105 addresses issues concerning clinical implementation of Monte Carlo based treatment planning for photon and electron beams, however for proton-therapy planning, such guidance is not yet available. Here we present the results of our validation of the Monte Carlo model of the double scattering system used at our Proton Therapy Center in Houston. In this study, we compared Monte Carlo simulated depth doses and lateral profiles to measured data for a magnitude of beam parameters. We varied simulated proton energies and widths of the spread-out Bragg peaks, and compared them to measurements obtained during the commissioning phase of the Proton Therapy Center in Houston. Of 191 simulated data sets, 189 agreed with measured data sets to within 3% of the maximum dose difference and within 3 mm of the maximum range or penumbra size difference. The two simulated data sets that did not agree with the measured data sets were in the distal falloff of the measured dose distribution, where large dose gradients potentially produce large differences on the basis of minute changes in the beam steering. Hence, the Monte Carlo models of medium- and large-size double scattering proton-therapy nozzles were valid for proton beams in the 100 MeV–250 MeV interval. PMID:18670050

  16. Threshold doses and prediction of visually apparent liver dysfunction after stereotactic body radiation therapy in cirrhotic and normal livers using magnetic resonance imaging

    PubMed Central

    Doi, Hiroshi; Shiomi, Hiroya; Masai, Norihisa; Tatsumi, Daisaku; Igura, Takumi; Imai, Yasuharu; Oh, Ryoong-Jin

    2016-01-01

    The purpose of the present study was to investigate the threshold dose for focal liver damage after stereotactic body radiation therapy (SBRT) in cirrhotic and normal livers using magnetic resonance imaging (MRI). A total of 64 patients who underwent SBRT for liver tumors, including 54 cirrhotic patients with hepatocellular carcinoma (HCC) and 10 non-cirrhotic patients with liver metastases, were analyzed. MRI was performed 3−6 months after SBRT, using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced T1-weighted sequences. All MRI datasets were merged with 3D dosimetry data. All dose distributions were corrected to the biologically effective dose using the linear–quadratic model with an assumed α/β ratio of 2 Gy. The development of liver dysfunction was validly correlated with isodose distribution. The median biologically effective dose (BED2) that provoked liver dysfunction was 57.3 (30.0−227.9) and 114.0 (70.4−244.9) Gy in cirrhotic and normal livers, respectively (P = 0.0002). The BED2 associated with a >5% risk of liver dysfunction was 38.5 in cirrhotic livers and 70.4 Gy in normal livers. The threshold BED2 for liver dysfunction was not significantly different between Child−Pugh A and B patients (P = 0.0719). Moreover, the fractionation schedule was not significantly correlated with threshold BED2 for liver dysfunction in the cirrhotic liver (P = 0.1019). In the cirrhotic liver, fractionation regimen and Child−Pugh classification did not significantly influence the threshold BED2 for focal liver damage after SBRT. We suggest that the threshold BED2 for liver dysfunction after SBRT is 40 and 70 Gy in the cirrhotic and normal liver, respectively. PMID:26983986

  17. Predicting the "First dose in children" of CYP3A-metabolized drugs: Evaluation of scaling approaches and insights into the CYP3A7-CYP3A4 switch at young ages.

    PubMed

    Strougo, Ashley; Yassen, Ashraf; Monnereau, Claire; Danhof, Meindert; Freijer, Jan

    2014-09-01

    First-dose-in-children relies on the prediction of clearance from adults for which little information is available on the accuracy of the scaling-approaches applied. For CYP3A-metabolized compounds, scaling of clearance is further challenged by different isoforms and by the CYP3A7 to CYP3A4 switch at young ages. This investigation aimed to evaluate the accuracy of two frequently used scaling approaches and to gain insights into the ontogeny of CYP3A. Hence, a literature database was compiled containing 203 clearance values from term-neonates to adults for 18 CYP3A-metabolized compounds. The clearances in adults were scaled to children using (i) allometric scaling plus maturation function and (ii) a mechanistic approach based on the well-stirred model. Three maturation functions were separately evaluated. In children >3 months, all approaches were interchangeable heeding the maturation function applied and biases were mostly observed in children <3 months. The results from a sensitivity analysis indicate that these biases are possibly caused by disregarding the CYP3A7 activity which could account for up to 86% of the metabolism in term-neonates. Only the mechanistic approach using an overall-CYP3A maturation function led to unbiased predictions of clearances across all ages. The current investigation adds to the predictions of the first-dose-in-children of compounds (partially) metabolized by CYP3A. PMID:24676942

  18. Preclinical pharmacokinetics of MHAA4549A, a human monoclonal antibody to influenza A virus, and the prediction of its efficacious clinical dose for the treatment of patients hospitalized with influenza A.

    PubMed

    Gupta, Priyanka; Kamath, Amrita V; Park, Summer; Chiu, Henry; Lutman, Jeff; Maia, Mauricio; Tan, Man-Wah; Xu, Min; Swem, Lee; Deng, Rong

    2016-07-01

    MHAA4549A is a human immunoglobulin G1 (IgG1) monoclonal antibody that binds to a highly conserved epitope on the stalk of influenza A hemagglutinin and blocks the hemagglutinin-mediated membrane fusion in the endosome, neutralizing all known human influenza A strains. Pharmacokinetics (PK) of MHAA4549A and its related antibodies were determined in DBA/2J and Balb-c mice at 5 mg/kg and in cynomolgus monkeys at 5 and 100 mg/kg as a single intravenous dose. Serum samples were analyzed for antibody concentrations using an ELISA and the PK was evaluated using WinNonlin software. Human PK profiles were projected based on the PK in monkeys using species-invariant time method. The human efficacious dose projection was based on in vivo nonclinical pharmacological active doses, exposure in mouse infection models and expected human PK. The PK profiles of MHAA4549A and its related antibody showed a linear bi-exponential disposition in mice and cynomolgus monkeys. In mice, clearance and half-life ranged from 5.77 to 9.98 mL/day/kg and 10.2 to 5.76 days, respectively. In cynomolgus monkeys, clearance and half-life ranged from 4.33 to 4.34 mL/day/kg and 11.3 to 11.9 days, respectively. The predicted clearance in humans was ∼2.60 mL/day/kg. A single intravenous dose ranging from 15 to 45 mg/kg was predicted to achieve efficacious exposure in humans. In conclusion, the PK of MHAA4549A was as expected for a human IgG1 monoclonal antibody that lacks known endogenous host targets. The predicted clearance and projected efficacious doses in humans for MHAA4549A have been verified in a Phase 1 study and Phase 2a study, respectively. PMID:27031797

  19. The significance of antral follicle size prior to stimulation in predicting ovarian response in a multiple dose GnRH antagonist protocol.

    PubMed

    Lai, Qiaohong; Chen, Cai; Zhang, Zhijun; Zhang, Shu; Yu, Qilin; Yang, Ping; Hu, Jun; Wang, Cong-Yi

    2013-01-01

    Prediction of ovarian responses prior to stimulation is not only useful for patient counseling, but also important in tailoring the optimal dosage of gonadotrophin for individual patients. By prospectively study of 214 women undergoing in vitro fertilization and embryo transfer (IVF-ET) treatment, we obtained data supporting that antral follicle size could be an additional valuable predictive marker other than the antral follicle count (AFC) in predicting ovarian response. Our studies revealed that AFC achieved the best predictive value in relation to the number of oocyte obtained, followed by antral follicle size, basal follicle stimulating hormone (FSH) and body mass index (BMI). Unlike AFC, antral follicle size was noted to be negatively correlated with the dosage (R = -0.493) and duration (R = -0.465) of rFSH stimulation. Antral follicle size was also found with higher negative regression coefficient (B = -0.661) as compared with that of basal FSH concentration (B = -0.326) and BMI (b = -0.281). More importantly, women with antral follicle size 6-7 mm showed significantly higher AFC, oocytes retrieved, fertilized oocytes and grade I/II embryos along with much lower transfer cycle cancellation rate (7.5% vs. 16-17%). Together, our data suggest that basal antral follicle size could be a valued predictive marker in women with IVF-ET treatment, in which women with antral follicle size 6-7 mm are likely predisposed to better IVF-ET outcomes. PMID:23330011

  20. Nutritional status is superior to the ECOG performance status in predicting the dose-intensity of the GEMOX chemotherapy regimen in patients with advanced cancer.

    PubMed

    Cessot, Anatole; Coriat, Romain; Mir, Oliver; Boudou-Rouquette, Pascaline; Giroux, Julie; Durand, Jean-Philippe; Alexandre, Jérôme; Goldwasser, Francois

    2013-01-01

    The increasing number of unfit patients calls for better risk assessment prior to initiating anti-tumor treatment. This is a major concern in the prevention and reduction of treatment-related complications. The aim of our study was to evaluate the nutritional status for the risk assessment of patients qualifying to receive the gemcitabine and oxaliplatin (GEMOX) regimen. This single-center, retrospective study examined baseline clinical and biological characteristics in a cohort of 165 unselected, consecutive cancer patients receiving GEMOX. Malnutrition was defined as either body mass index (BMI) <18.5 kg/m(2), body weight loss >10% over 3 mo, or albuminemia <35 g/L. A total of 165 patients (median age 61 yr, PS 0-1: 71%) were studied. Malnutrition was seen in 43% of PS 0-1 patients, vs. 60% of PS 2 and 66% of PS 3 patients (P > 0.05). Median relative dose-intensity was 0.90 (0.17-1.04). GEMOX dose-intensity correlated negatively with loss of baseline weight (r = -0.24, P < 0.02). In patients who did not complete more than 2 cycles of chemotherapy, median PS (P < 0.01), mean C-reactive protein (CRP; P < 0.01), and mean albuminemia (P < 0.05) were, respectively, significantly higher, higher, and lower. Malnutrition is associated with a high risk of early discontinuance of treatment. Systematic basal evaluation of the nutritional status, including albuminemia and BMI, is recommended. PMID:24099412

  1. Validation of mathematical models for the prediction of organs-at-risk dosimetric metrics in high-dose-rate gynecologic interstitial brachytherapy

    SciTech Connect

    Damato, Antonio L.; Viswanathan, Akila N.; Cormack, Robert A.

    2013-10-15

    Purpose: Given the complicated nature of an interstitial gynecologic brachytherapy treatment plan, the use of a quantitative tool to evaluate the quality of the achieved metrics compared to clinical practice would be advantageous. For this purpose, predictive mathematical models to predict the D{sub 2cc} of rectum and bladder in interstitial gynecologic brachytherapy are discussed and validated.Methods: Previous plans were used to establish the relationship between D2cc and the overlapping volume of the organ at risk with the targeted area (C0) or a 1-cm expansion of the target area (C1). Three mathematical models were evaluated: D{sub 2cc}=α*C{sub 1}+β (LIN); D{sub 2cc}=α– exp(–β*C{sub 0}) (EXP); and a mixed approach (MIX), where both C{sub 0} and C{sub 1} were inputs of the model. The parameters of the models were optimized on a training set of patient data, and the predictive error of each model (predicted D{sub 2cc}− real D{sub 2cc}) was calculated on a validation set of patient data. The data of 20 patients were used to perform a K-fold cross validation analysis, with K = 2, 4, 6, 8, 10, and 20.Results: MIX was associated with the smallest mean prediction error <6.4% for an 18-patient training set; LIN had an error <8.5%; EXP had an error <8.3%. Best case scenario analysis shows that an error ≤5% can be achieved for a ten-patient training set with MIX, an error ≤7.4% for LIN, and an error ≤6.9% for EXP. The error decreases with the increase in training set size, with the most marked decrease observed for MIX.Conclusions: The MIX model can predict the D{sub 2cc} of the organs at risk with an error lower than 5% with a training set of ten patients or greater. The model can be used in the development of quality assurance tools to identify treatment plans with suboptimal sparing of the organs at risk. It can also be used to improve preplanning and in the development of real-time intraoperative planning tools.

  2. Urinary Metabolites of the Dietary Carcinogen PhIP are Predictive of Colon DNA Adducts After a Low Dose Exposure in Humans

    SciTech Connect

    Malfatti, M; Dingley, K; Nowell, S; Ubick, E; Mulakken, N; Nelson, D; Lang, N; Felton, J; Turteltaub, K

    2006-04-28

    Epidemiologic evidence indicates that exposure to heterocyclic amines (HAs) in the diet is an important risk factor for the development of colon cancer. Well-done cooked meats contain significant levels of HAs which have been shown to cause cancer in laboratory animals. To better understand the mechanisms of HA bioactivation in humans, the most mass abundant HA, 2-amino-l-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), was used to assess the relationship between PhIP metabolism and DNA adduct formation. Ten human volunteers were administered a dietary relevant dose of [{sup 14}C]PhIP 48-72 h prior to surgery to remove colon tumors. Urine was collected for 24 h after dosing for metabolite analysis, and DNA was extracted from colon tissue and analyzed by accelerator mass spectrometry for DNA adducts. All ten subjects were phenotyped for CYP1A2, NAT2, and SULT1A1 enzyme activity. Twelve PhIP metabolites were detected in the urine samples. The most abundant metabolite in all volunteers was N-hydroxy-PhIP-N{sup 2}-glucuronide. Metabolite levels varied significantly between the volunteers. Interindividual differences in colon DNA adducts levels were observed between each individual. The data showed that individuals with a rapid CYP1A2 phenotype and high levels of urinary N-hydroxy-PhIP-N{sup 2}-glucuronide, had the lowest level of colon PhIP-DNA adducts. This suggests that glucuronidation plays a significant role in detoxifying N-hydroxy-PhIP. The levels of urinary N-hydroxy-PhIP-N{sup 2}-glucuronide were negatively correlated to colon DNA adduct levels. Although it is difficult to make definite conclusions from a small data set, the results from this pilot study have encouraged further investigations using a much larger study group.

  3. The importance of depression and alcohol use in coronary artery bypass graft surgery patients: risk factors for delirium and poorer quality of life

    PubMed Central

    Humphreys, Joanne M; Denson, Linley A; Baker, Robert A; Tully, Phillip J

    2016-01-01

    Objective To investigate whether depression, anxiety and stress increase the risk for delirium and poor quality of life (QOL) after coronary artery bypass (CABG) surgery. Methods A total of 180 CABG patients (mean age of 63.5 ± 10.1 years, 82.2% males) completed baseline and postoperative self-report questionnaires to assess distress and QOL. Incident delirium was diagnosed postoperatively with a structured clinical interview and patients were monitored every day post-operatively for confusion and disturbance in consciousness. Results Delirium developed in 63 persons (35% of sample). After adjustment for covariates, delirium was significantly associated with depression [odds ratio (OR): 1.08; 95% confidence interval (CI): 1.03–1.13, P = 0.003], anxiety (OR: 1.07; 95% CI: 1.02–1.13, P = 0.01) and stress (OR: 1.05; 95% CI: 1.00–1.09, P = 0.03). Preoperative depression scores were associated with poorer QOL including bodily pain (β = −0.39, P = 0.013), vitality (β = −0.32, P = 0.020), social functioning (β = −0.51, P ≤ 0.001), emotional role function (β = −0.44, P = 0.003) and general health (β = −0.33, P = 0.038). Among the covariates, harmful levels of alcohol use was consistently associated with poorer QOL. Conclusions Depression and harmful levels of alcohol use were consistently associated with poorer QOL whereas depression, anxiety and stress were associated with delirium risk. These findings point to further research examining depression and harmful levels of alcohol use in coronary heart disease populations undergoing coronary revascularization. PMID:26918013

  4. Both F-18 FDG-avidity and Malignant Shape of Cervical Lymph Nodes on PET/CT after Total Thyroidectomy Predict Resistance to High-dose I-131 Therapy in Patients with Papillary Thyroid Cancer

    PubMed Central

    Byun, Byung Hyun; Kwon, Seong Young; Chong, Ari; Kim, Jahae; Yoo, Su Woong; Min, Jung-Joon; Song, Ho-Chun; Bom, Henry Hee-Seung

    2013-01-01

    Objective: Resistance of metastatic lymph nodes (LNs) to high dose I-131 therapy is associated with high morbidity in patients with differentiated thyroid cancer. We evaluated the role of F-18 FDG PET/CT in the prediction of resistance to high dose I-131 therapy in patients with papillary thyroid cancer. Methods: The subjects were 307 patients who underwent total or near total thyroidectomy followed by high dose (5.55-6.66 GBq) I-131 therapy. We divided the patients into three subgroups by visual assessment of regional LNs: FDG-avid LNs with a malignant shape on CT (PET/CT-positive group), FDG-avid LNs with a benign shape on CT (PET/CT-intermediate group) and no FDG-avid lesion (PET/CT-negative group). We measured the maximum SUV (SUVmax) of FDG-avid LNs in each patient. The presence or absence of focal increased uptake of I-131 was evaluated by whole body scan (WBS), and was denoted as WBS-positive group or WBS-negative group, respectively. Resistance to therapy was defined as presence of thyroglobulin (Tg) in serum (Tg ≥1.0 ng/ml) 3-6 months after I-131 therapy. Univariate and multivariate analyses were performed to determine the relationship between resistance to I-131 therapy and various clinico-pathologic variables. Results: PET/CT-positive, intermediate, and negative groups included 20 (6.5%), 44 (14.3%) and 243 (79.2%) patients, respectively. The mean SUVmax was significantly higher in the PET/CT-positive group than that of the PET/CT-intermediate group (4.6 vs. 2.7, P <0.001). Univariate analysis revealed that the PET/CT-positive group (P <0.001), T2-4 stage (P <0.001), N1b stage (P = 0.001), lower dose (5.55 GBq) of I-131 (P <0.001), and the WBS-positive group (P = 0.029) were associated with resistance to therapy. In multivariate analysis, the PET/CT-positive group, lower dose of I-131, N1b stage, and T2-4 stage remained significant with odds ratios of 10.07 (P <0.001), 3.82 (P <0.001), 3.58 (P = 0.001), and 2.53 (P = 0.009), respectively. Conclusion

  5. The Percent of Positive Biopsy Cores Improves Prediction of Prostate Cancer-Specific Death in Patients Treated With Dose-Escalated Radiotherapy

    SciTech Connect

    Qian Yushen; Feng, Felix Y.; Halverson, Schuyler; Blas, Kevin; Sandler, Howard M.; Hamstra, Daniel A.

    2011-11-01

    Purpose: To examine the prognostic utility of the percentage of positive cores (PPC) at the time of prostate biopsy for patients treated with dose-escalated external beam radiation therapy. Methods and Materials: We performed a retrospective analysis of patients treated at University of Michigan Medical Center to at least 75 Gy. Patients were stratified according to PPC by quartile, and freedom from biochemical failure (nadir + 2 ng/mL), freedom from metastasis (FFM), cause-specific survival (CSS), and overall survival (OS) were assessed by log-rank test. Receiver operator characteristic (ROC) curve analysis was used to determine the optimal cut point for PPC stratification. Finally, Cox proportional hazards multivariate regression was used to assess the impact of PPC on clinical outcome when adjusting for National Comprehensive Cancer Network (NCCN) risk group and androgen deprivation therapy. Results: PPC information was available for 651 patients. Increasing-risk features including T stage, prostate-specific antigen, Gleason score, and NCCN risk group were all directly correlated with increasing PPC. On log-rank evaluation, all clinical endpoints, except for OS, were associated with PPC by quartile, with worse clinical outcomes as PPC increased, with the greatest impact seen in the highest quartile (>66.7% of cores positive). ROC curve analysis confirmed that a cut point using two-thirds positive cores was most closely associated with CSS (p = 0.002; area under ROC curve, 0.71). On univariate analysis, stratifying patients according to PPC less than or equal to 66.7% vs. PPC greater than 66.7% was prognostic for freedom from biochemical failure (p = 0.0001), FFM (p = 0.0002), and CSS (p = 0.0003) and marginally prognostic for OS (p = 0.055). On multivariate analysis, after adjustment for NCCN risk group and androgen deprivation therapy use, PPC greater than 66.7% increased the risk for biochemical failure (p = 0.0001; hazard ratio [HR], 2.1 [95% confidence

  6. Small Bowel Dose Parameters Predicting Grade ≥3 Acute Toxicity in Rectal Cancer Patients Treated With Neoadjuvant Chemoradiation: An Independent Validation Study Comparing Peritoneal Space Versus Small Bowel Loop Contouring Techniques

    SciTech Connect

    Banerjee, Robyn; Chakraborty, Santam; Nygren, Ian; Sinha, Richie

    2013-04-01

    Purpose: To determine whether volumes based on contours of the peritoneal space can be used instead of individual small bowel loops to predict for grade ≥3 acute small bowel toxicity in patients with rectal cancer treated with neoadjuvant chemoradiation therapy. Methods and Materials: A standardized contouring method was developed for the peritoneal space and retrospectively applied to the radiation treatment plans of 67 patients treated with neoadjuvant chemoradiation therapy for rectal cancer. Dose-volume histogram (DVH) data were extracted and analyzed against patient toxicity. Receiver operating characteristic analysis and logistic regression were carried out for both contouring methods. Results: Grade ≥3 small bowel toxicity occurred in 16% (11/67) of patients in the study. A highly significant dose-volume relationship between small bowel irradiation and acute small bowel toxicity was supported by the use of both small bowel loop and peritoneal space contouring techniques. Receiver operating characteristic analysis demonstrated that, for both contouring methods, the greatest sensitivity for predicting toxicity was associated with the volume receiving between 15 and 25 Gy. Conclusion: DVH analysis of peritoneal space volumes accurately predicts grade ≥3 small bowel toxicity in patients with rectal cancer receiving neoadjuvant chemoradiation therapy, suggesting that the contours of the peritoneal space provide a reasonable surrogate for the contours of individual small bowel loops. The study finds that a small bowel V15 less than 275 cc and a peritoneal space V15 less than 830 cc are associated with a less than 10% risk of grade ≥3 acute toxicity.

  7. Attachment forces of ants measured with a centrifuge: better 'wax-runners' have a poorer attachment to a smooth surface.

    PubMed

    Federle, W; Rohrseitz, K; Hölldobler, B

    2000-02-01

    The symbiotic ant partners of glaucous Macaranga ant-plants show an exceptional capacity to run on the slippery epicuticular wax crystals covering the plant stem without any difficulty. We test the hypothesis that these specialised 'wax-runners' have a general, superior attachment capacity. We compared attachment on a smooth surface for 11 ant species with different wax-running capacities. The maximum force that could be withstood before an ant became detached was quantified using a centrifuge recorded by a high-speed video camera. This technique has the advantage of causing minimum disruption and allows measurements in very small animals. When strong centrifugal forces were applied, the ants showed a conspicuous 'freezing reflex' advantageous to attachment. Attachment forces differed strongly among the ant species investigated. This variation could not be explained by different surface area/weight ratios of smaller and larger ants. Within species, however, detachment force per body weight (F/W) scaled with the predicted value of W(-)(0.33), where W is body weight in newtons. Surprisingly, our results not only disprove the hypothesis that 'wax-runners' generally attach better but also provide evidence for the reverse effect. Superior 'wax-runners' (genera Technomyrmex and Crematogaster) did not cling better to smooth Perspex, but performed significantly worse than closely related congeners that are unable to climb up waxy stems. This suggests an inverse relationship between adaptations to run on wax and to attach to a smooth surface. PMID:10637179

  8. Autocrine TGF-β/ZEB/microRNA-200 signal transduction drives epithelial-mesenchymal transition: Kinetic models predict minimal drug dose to inhibit metastasis.

    PubMed

    Rateitschak, Katja; Kaderali, Lars; Wolkenhauer, Olaf; Jaster, Robert

    2016-08-01

    The epithelial-mesenchymal transition (EMT) is the crucial step that cancer cells must pass before they can undergo metastasis. The transition requires the activity of complex functional networks that downregulate properties of the epithelial phenotype and upregulate characteristics of the mesenchymal phenotype. The networks frequently include reciprocal repressions between transcription factors (TFs) driving the EMT and microRNAs (miRs) inducing the reverse process, termed mesenchymal-epithelial transition (MET). In this work we develop four kinetic models that are based on experimental data and hypotheses describing how autocrine transforming growth factor-β (TGF-β) signal transduction induces and maintains an EMT by upregulating the TFs ZEB1 and ZEB2 which repress the expression of the miR-200b/c family members. After successful model calibration we validate our models by predicting requirements for the maintenance of the mesenchymal steady state which agree with experimental data. Finally, we apply our validated kinetic models for the design of experiments in cancer therapy. We demonstrate how steady state properties of the kinetic models, combined with data from tumor-derived cell lines of individual patients, can predict the minimal amount of an inhibitor to induce a MET. PMID:27000495

  9. ITPA and SLC29A1 Genotyping for the Prediction of Ribavirin Dose Reduction in Anti-HCV Triple Therapy with Protease Inhibitors.

    PubMed

    Lombardi, Andrea; Landonio, Simona; Magni, Carlo; Cheli, Stefania; Mazzali, Cristina; Mondelli, Mario U; Rizzardini, Giuliano; Clementi, Emilio; Falvella, Felicia Stefania

    2015-01-01

    Chronic hepatitis C is one of the most important causes of liver disease, leading to cirrhosis, hepatic decompensation and hepatocellular carcinoma. Recently some important advances in therapy have been achieved with the introduction of first wave, first generation direct acting antiviral agents (DAAs) such as boceprevir (BOC), in combination with pegylated interferon (Peg-IFN) and ribavirin (RBV). The superior rate of sustained virological response with this treatment is accompanied by an elevated frequency of anaemia. Several studies have evidenced the importance of single nucleotide polymorphisms (SNPs) in inosine triphosphatase (ITPA) and solute carrier family 29, member 1 (SLC29A1) genes in the development of this adverse event. Here, we investigated haemoglobin levels and the best-known functional SNPs in ITPA and SLC29A1 genes in 22 patients treated with triple therapy with BOC/Peg-IFN/RBV. The identification of ITPA protective and SLC29A1 risk genotypes still appears to be a current methodology in RBV dosing during hepatitis C virus therapy with DAAs. PMID:26279293

  10. Integrating in vitro sensitivity and dose-response slope is predictive of clinical response to ABL kinase inhibitors in chronic myeloid leukemia.

    PubMed

    Vainstein, Vladimir; Eide, Christopher A; O'Hare, Thomas; Shukron, Ofir; Druker, Brian J

    2013-11-01

    BCR-ABL mutations result in clinical resistance to ABL tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). Although in vitro 50% inhibitory concentration (IC(50)) values for specific mutations have been suggested to guide TKI choice in the clinic, the quantitative relationship between IC(50) and clinical response has never been demonstrated. We used Hill's equation for in vitro response of Ba/F3 cells transduced with various BCR-ABL mutants to determine IC(50) and the slope of the dose-response curve. We found that slope variability between mutants tracked with in vitro TKI resistance, provides particular additional interpretive value in cases where in vitro IC(50) and clinical response are disparate. Moreover, unlike IC(50) alone, higher inhibitory potential at peak concentration (IPP), which integrates IC(50), slope, and peak concentration (Cmax), correlated with improved complete cytogenetic response (CCyR) rates in CML patients treated with dasatinib. Our findings suggest a metric integrating in vitro and clinical data may provide an improved tool for BCR-ABL mutation-guided TKI selection. PMID:24062017