Granier C.,University of Paris Descartes |
Dariane C.,University of Paris Descartes |
Combe P.,University of Paris Descartes |
Verkarre V.,Hopital Europeen Georges Pompidou |
And 17 more authors.
Cancer Research | Year: 2017
Inhibitory receptors expressed by T cells mediate tolerance to tumor antigens, with coexpression of these receptors exacerbating this dysfunctional state. Using the VectraR automated multiparametric immunofluorescence technique, we quantified intratumoral CD8+ T cells coexpressing the inhibitory receptors PD-1 and Tim-3 from patients with renal cell carcinoma (RCC). A second validation cohort measured the same parameters by cytometry. The percentage of tumor-infiltrating CD8+ T cells coexpressing PD-1 and Tim-3 correlated with an aggressive phenotype and a larger tumor size at diagnosis. Coexpression of PD-1 and Tim-3 above the median conferred a higher risk of relapse and a poorer 36-month overall survival. Notably, other CD8+Tcell subsets did not exert a similar effect on overall survival. Moreover, only the PD-1+Tim-3+ subset ofCD8+ T cells exhibited impaired function after stimulation. Our findings establish intratumoral Tim-3+PD1+CD8+ T cells as critical mediators of an aggressive phenotype in RCC. Use of the Vectra tool may be useful to identify similarly critical prognostic and predictive biomarkers in other tumor types and their response to immunotherapy. © 2016 American Association for Cancer Research.
Menoni V.,Unite Of Recherche Clinique Paris Center |
Menoni V.,University of Paris Descartes |
Lucas N.,University of Paris Descartes |
Leforestier J.-F.,University of Paris Descartes |
And 10 more authors.
PLoS ONE | Year: 2011
Background: The aim was to evaluate the readability of research information leaflets (RIL) for minors asked to participate in biomedical research studies and to assess the factors influencing this readability. Methods and Findings: All the pediatric protocols from three French pediatric clinical research units were included (N = 104). Three criteria were used to evaluate readability: length of the text, Flesch's readability score and presence of illustrations. We compared the readability of RIL to texts specifically written for children (school textbooks, school exams or extracts from literary works). We assessed the effect of protocol characteristics on readability. The RIL had a median length of 608 words [350 words, 25th percentile; 1005 words, 75th percentile], corresponding to two pages. The readability of the RIL, with a median Flesch score of 40 [30; 47], was much poorer than that of pediatric reference texts, with a Flesch score of 67 [60; 73]. A small proportion of RIL (13/91; 14%) were illustrated. The RIL were longer (p<0.001), more readable (p<0.001) and more likely to be illustrated (p<0.009) for industrial than for institutional sponsors. Conclusion: Researchers should routinely compute the reading ease of study information sheets and make greater efforts to improve the readability of written documents for potential participants. © 2011 Menoni et al.
Foissac F.,University of Paris Descartes |
Foissac F.,Unite Of Recherche Clinique Paris Center |
Treluyer J.-M.,University of Paris Descartes |
Treluyer J.-M.,Unite Of Recherche Clinique Paris Center |
And 7 more authors.
British Journal of Clinical Pharmacology | Year: 2013
Aims: Vitamin D deficiency is prevalent in HIV-infected patients and has been associated with osteopenia and HIV disease progression. Our aims were to investigate the pharmacokinetics of 25-hydroxycholecalciferol [25(OH)D], the effect of antiretroviral treatment (ARV) and others factors that may influence the pharmacokinetics, and to determine a vitamin D3 dosing scheme to reach the 30ngml-1 threshold (defined as 25(OH)D sufficiency). Methods: This monocentric retrospective study included 422 HIV-infected patients aged 16 to 85 years. A total of 723 25(OH)D concentrations were available for pharmacokinetic evaluation and a population pharmacokinetic model was developed with MONOLIX 3.2. Results: Median 25(OH)D at baseline was 16ngml-1 (interquartile range 11-23ngml-1) for the total population, 17% of patient had concentrations below 10ngml-1, 68% between 10 and 30ngml-1 and 15% above 30ngml-1. 25(OH)D pharmacokinetics were best described by a one compartment model with an additional endogenous production. The effects of season and skin phototype were significant on production rate. The endogenous production was 20% lower in non-white skin phototype patients and was decreased by 16% during autumn, winter and spring. No significant differences in 25(OH)D concentrations were related to antiretroviral drugs (ARV). To obtain concentrations between 30 and 80ngml-1, the dosing recommendation was 100000IU every month. Conclusions: Season and skin phototype had an influence on the endogenous production of 25(OH)D. However no effect of ARV was found. A dosing scheme to reach sufficient 25(OH)D concentrations is proposed. © 2012 The British Pharmacological Society.
Meyzer C.,Unite Of Recherche Clinique Paris Center |
Meyzer C.,University of Paris Descartes |
Frange P.,University of Paris Descartes |
Chappuy H.,Unite Of Recherche Clinique Paris Center |
And 14 more authors.
Pediatric Infectious Disease Journal | Year: 2013
BACKGROUND: Vitamin D insufficiency and HIV infection are both risk factors for chronic disorders, so it is important to consider vitamin D status in HIV-infected patients. METHODS: We prospectively investigated serum 25-hydroxyvitamin D (25(OH)D) concentrations, determined by radioimmunoassay, in 113 HIV-infected children (age ≤24 years) and 54 healthy controls matched for age and phototype. We assessed the prevalence of vitamin D deficiency and insufficiency (VDD and VDI) defined as 25(OH)D titers of <10 ng/mL and between 10 and 30 ng/mL, respectively, and their predictive factors. RESULTS: The overall prevalence of VDD and VDI was 38.9% and 58.7%, respectively. Mean serum 25(OH)D concentrations were significantly higher in the HIV group than the control group (14.2 ± 6.9 ng/mL vs. 10.4 ± 5 ng/mL, P < 0.001). Variables significantly associated with low serum 25(OH)D concentrations in HIV-infected children were dark phototype (P < 0.001) and age (r = -0.19, P = 0.03). Patients receiving efavirenz had a trend toward lower serum 25(OH)D concentrations (11.1 ± 4.6 ng/mL vs. 14.6 ± 7 ng/mL, P = 0.1). Dark phototype was the only independent risk factor for VDD in HIV-infected children (odds ratio = 14.6; 95% confidence interval: 2.4-89.9, P = 0.004). CONCLUSIONS: VDD and VDI were common in both HIV-infected and control groups, and serum 25(OH)D concentrations were significantly lower in controls than in HIV-infected children. Copyright © 2013 by Lippincott Williams & Wilkins.
Simon A.,Unite dEndocrinologie Pediatrique |
Simon A.,University of Paris Descartes |
Warszawski J.,French Institute of Health and Medical Research |
Warszawski J.,University Paris - Sud |
And 16 more authors.
JAMA - Journal of the American Medical Association | Year: 2011
Context: Lopinavir-ritonavir is a human immunodeficiency virus 1 (HIV-1) protease inhibitor boosted by ritonavir, a cytochrome p450 inhibitor. A warning about its tolerance in premature newborns was recently released, and transient elevation of 17-hydroxyprogesterone (17OHP) was noted in 2 newborns treated with lopinavir-ritonavir in France. Objective: To evaluate adrenal function in newborns postnatally treated with lopinavir-ritonavir. Design, Setting, and Participants: Retrospective cross-sectional analysis of the database from the national screening for congenital adrenal hyperplasia (CAH) and the French Perinatal Cohort. Comparison of HIV-1-uninfected newborns postnatally treated with lopinavir-ritonavir and controls treated with standard zidovudine. Main Outcome Measures: Plasma 17OHP and dehydroepiandrosterone-sulfate (DHEA-S) concentrations during the first week of treatment. Clinical and biological symptoms compatible with adrenal deficiency. Results: Of 50 HIV-1-uninfected newbornswhoreceived lopinavir-ritonavir at birth for a median of 30 days (interquartile range [IQR], 25-33), 7 (14%) had elevated 17OHP levels greater than 16.5 ng/mL for term infants (>23.1 ng/mL for preterm) on days 1 to 6 vs 0 of 108 controls having elevated levels. The median 17OHP concentration for 42 term newborns treated with lopinavir-ritonavir was 9.9 ng/mL (IQR, 3.9-14.1 ng/mL) vs 3.7 ng/mL (IQR, 2.6-5.3 ng/mL) for 93 term controls (P<.001). The difference observed in median 17OHP values between treated newborns and controls was higher in children also exposed in utero (11.5 ng/mL vs 3.7 ng/mL; P<.001) than not exposed in utero (6.9 ng/mL vs 3.3 ng/mL; P=.03). The median DHEA-S concentration among 18 term newborns treated with lopinavir-ritonavir was 9242 ng/mL (IQR, 1347-25 986 ng/mL) compared with 484 ng/mL (IQR, 218-1308 ng/mL) among 17 term controls (P<.001). The 17OHP and DHEA-Sconcentrations were positively correlated (r=0.53;P=.001). All term newborns treated with lopinavir-ritonavir were asymptomatic, although 3 premature newborns experienced life-threatening symptoms compatible with adrenal insufficiency, including hyponatremia and hyperkalemia with, in 1 case, cardiogenic shock. All symptoms resolved following completion of the lopinavir-ritonavir treatment. Conclusion: Among newborn children of HIV-1-infected mothers exposed in utero to lopinavir-ritonavir, postnatal treatment with a lopinavir-ritonavir-based regimen,compared with a zidovudine-based regimen, was associated with transient adrenal dysfunction. ©2011 American Medical Association. All rights reserved.
Chappuy H.,University of Paris Descartes |
Baruchel A.,University Paris Diderot |
Leverger G.,University Paris - Sud |
Oudot C.,University Paris Diderot |
And 7 more authors.
Archives of Disease in Childhood | Year: 2010
Objective: To evaluate the extent to which parents are satisfied with and understand the information they are given when their consent is sought for their child to participate in a phase III randomised clinical trial and the reasons for their decision. Patients and method: The authors carried out a prospective study. The authors included all parents whose consent was sought for their child to participate in the FRALLE 2000A protocol (acute lymphoblastic leukaemia) at two centres. The parents were questioned twice by a qualified psychologist using a semidirected interview, 1 and 6 months after consent was sought. Results: 43 first interviews were carried out. All the parents declared they were satisfied with the explanations provided by the physician. 35 (81%) parents felt that the information provided with the request for consent was appropriate. Eight (19%) parents did not realise that their child had been included in a research protocol. 16 (39%) parents did not understand the concept of randomisation. Half the parents could explain neither the aim of the clinical trial nor the potential benefit of inclusion to their child. Only one third of the parents were aware that they had an alternative. The principal factor underlying their decision, as stated by 29 parents (67%), was confidence in the medical team. Conclusions: The parents signed consent forms without having fully understood all the elements specific to the experimental protocol. Rather, the parents based their decision on their confidence in the medical team, even when their child's life was at risk.
PubMed | Medical Oncology, Oncology, Urology, Hopital Cochin. and 9 more.
Type: | Journal: Cancer research | Year: 2016
Inhibitory receptors expressed by T cells mediate tolerance to tumor antigens with coexpression of these receptors exacerbating this dysfunctional state. Using the VectraR automated multiparametric immunofluorescence technique, we quantified intratumoral CD8+T cells coexpressing the inhibitory receptors PD-1 and Tim-3 from patients with renal cell carcinoma (RCC). A second validation cohort measured the same parameters by cytometry. The percentage of tumor-infiltrating CD8+T cells coexpressing PD-1 and Tim-3 correlated with an aggressive phenotype and a larger tumor size at diagnosis. Co-expression of PD 1 and Tim-3 above the median conferred a higher risk of relapse and a poorer 36-month overall survival. Notably, other CD8+T cell subsets did not exert a similar effect on overall survival. Moreover, only the PD-1+Tim-3+ subset of CD8+T cells exhibited impaired function after stimulation. Our findings establish intratumoral Tim-3+PD1+CD8+T cells as critical mediators of an aggressive phenotype in RCC. Use of the VectraR tool may be useful to identify similarly critical prognostic and predictive biomarkers in other tumor types and their response to immunotherapy.