18 research outputs found

    Patients characteristics.

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    <p>WIN = window phase; CONS = consolidation phase LR = low risk; SHR = standard/high risk.</p

    Homocysteine concentration-time courses with and without co-administration of folinate.

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    <p>Excerpt of 1000 per-protocol simulations each of the low-risk (A) and standard/high-risk (B) study population. The solid grey line represents the median of the simulations without folinate with the 90% prediction interval (PI) as solid grey area, the solid black line represents the median of the simulations under influence of folinate with the 90% PI as shaded area.</p

    Visual predictive check of the pharmacodynamic model for low-risk (A) and standard/high-risk (B) patients from the evaluation dataset.

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    <p>The black circles represent the measured homocysteine concentrations relative to baseline. The solid line represents the median predicted concentration, the dashed lines represent the 90% prediction interval of 1000 simulations.</p

    Pharmacokinetic and pharmacodynamic model parameters.

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    <p>CI<sub>90%</sub> = 90% confidence interval.</p><p>(CI<sub>90%</sub> by bootstrapping).</p

    Visual predictive check of the pharmacokinetic model for all patients of the evaluation dataset receiving a 24 h MTX infusion with a dose of 2500±20 mg/m<sup>2</sup> (A) and 5000±20 mg/m<sup>2</sup> (B), respectively.

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    <p>The black circles represent the measured methotrexate concentrations. The solid line represents the median predicted concentration, the dashed lines represent the 90% prediction interval of 10000 simulations.</p

    Antileukemic Efficacy of Continuous vs Discontinuous Dexamethasone in Murine Models of Acute Lymphoblastic Leukemia

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    <div><p>Osteonecrosis is one of the most common, serious, toxicities resulting from the treatment of acute lymphoblastic leukemia. In recent years, pediatric acute lymphoblastic leukemia clinical trials have used discontinuous rather than continuous dosing of dexamethasone in an effort to reduce the incidence of osteonecrosis. However, it is not known whether discontinuous dosing would compromise antileukemic efficacy of glucocorticoids. Therefore, we tested the efficacy of discontinuous dexamethasone against continuous dexamethasone in murine models bearing human acute lymphoblastic leukemia xenografts (n = 8 patient samples) or murine BCR-ABL+ acute lymphoblastic leukemia. Plasma dexamethasone concentrations (7.9 to 212 nM) were similar to those achieved in children with acute lymphoblastic leukemia using conventional dosages. The median leukemia-free survival ranged from 16 to 59 days; dexamethasone prolonged survival from a median of 4 to 129 days in all seven dexamethasone-sensitive acute lymphoblastic leukemias. In the majority of cases (7 of 8 xenografts and the murine BCR-ABL model) we demonstrated equal efficacy of the two dexamethasone dosing regimens; whereas for one acute lymphoblastic leukemia sample, the discontinuous regimen yielded inferior antileukemic efficacy (log-rank p = 0.002). Our results support the clinical practice of using discontinuous rather than continuous dexamethasone dosing in patients with acute lymphoblastic leukemia.</p></div

    Leukemia cells generally became less sensitive to dexamethasone after <i>in vivo</i> treatment.

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    <p>Dexamethasone sensitivity of leukemic bone marrow cells at diagnosis (orange), the passage prior to <i>in vivo</i> treatment (purple), or at the time of sacrifice after <i>in vivo</i> treatment (continuous dexamethasone, red; discontinuous dexamethasone, green; no dexamethasone, blue). Symbols indicate individual mice, the horizontal line indicates the mean, and error bars indicate standard error of the mean (SEM). Incubation time for all diagnosis samples in the MTT assay was 4 days. Incubation time for cells from the mice receiving continuous dexamethasone, discontinuous dexamethasone, and no dexamethasone was 4 days for SJTALL021916, SJTALL033, SJBALL215, 3 days for SJTALL030, and 2 days for SJMLL005 and SJMLL009. <i>Ex vivo</i> sensitivity was not tested in SJE2A007 due to poor viability after two days <i>ex vivo</i> (<50%), and SJHYPO123 due to resistance of the sample at the time of diagnosis (LC50 > highest concentration tested, 15 uM, which was recapitulated in the xenograft sample prior to <i>in vivo</i> treatment).</p

    Anti-leukemic survival was equivalent between dexamethasone treatment regimens in the murine ALL model.

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    <p>Mice of the 129X1SvJ strain (A) and C57Bl/6 strain (B) were injected with <i>Arf</i>-/- BCR-ABL+ luciferase+ leukemia and treated with continuous (Cont dex, red), discontinuous dexamethasone (Disc dex, green), or no dexamethasone (blue) regimens. Boxes indicate leukemic events, while + indicates censored events. P-values indicated are log-rank p-values comparing the continuous and discontinuous dexamethasone regimens, see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135134#pone.0135134.t001" target="_blank">Table 1</a> for comparisons of dexamethasone vs no dexamethasone.</p

    Antileukemic efficacy of continuous, discontinuous, and no dexamethasone for xenografted patient ALL samples.

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    <p>Red indicates continuous dexamethasone (Cont dex), green indicates discontinuous dexamethasone (disc dex), and blue indicates no dexamethasone. Squares on the curve indicate leukemic events, and + indicates censoring due to toxicity, accidental death, or the end of the experiment. Red and green boxes indicate treatment period—red indicates continuous dexamethasone (4 mg/L) and green indicates discontinuous dexamethasone (8 mg/L for 3.5 days, 0 for 3.5 days). P-values shown were calculated with the log-rank test, comparing the continuous and discontinuous dexamethasone treatment arms, see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135134#pone.0135134.t001" target="_blank">Table 1</a> for comparisons of dexamethasone vs no dexamethasone.</p
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