Institute Dhematologie Et Doncologie Pediatrique

Sainte-Foy-lès-Lyon, France

Institute Dhematologie Et Doncologie Pediatrique

Sainte-Foy-lès-Lyon, France
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Goutelle S.,Groupement Hospitalier Of Geriatrie | Goutelle S.,University of Lyon | Goutelle S.,CNRS Biometry and Evolutionary Biology Laboratory | Bourguignon L.,Groupement Hospitalier Of Geriatrie | And 6 more authors.
AAPS Journal | Year: 2013

We present a unified quantitative approach to predict the in vivo alteration in drug exposure caused by either cytochrome P450 (CYP) gene polymorphisms or CYP-mediated drug-drug interactions (DDI). An application to drugs metabolized by CYP2C19 is presented. The metrics used is the ratio of altered drug area under the curve (AUC) to the AUC in extensive metabolizers with no mutation or no interaction. Data from 42 pharmacokinetic studies performed in CYP2C19 genetic subgroups and 18 DDI studies were used to estimate model parameters and predicted AUC ratios by using Bayesian approach. Pharmacogenetic information was used to estimate a parameter of the model which was then used to predict DDI. The method adequately predicted the AUC ratios published in the literature, with mean errors of -0.15 and -0.62 and mean absolute errors of 0.62 and 1.05 for genotype and DDI data, respectively. The approach provides quantitative prediction of the effect of five genotype variants and 10 inhibitors on the exposure to 25 CYP2C19 substrates, including a number of unobserved cases. A quantitative approach for predicting the effect of gene polymorphisms and drug interactions on drug exposure has been successfully applied for CYP2C19 substrates. This study shows that pharmacogenetic information can be used to predict DDI. This may have important implications for the development of personalized medicine and drug development. © 2013 American Association of Pharmaceutical Scientists.


Philippe M.,Institute Dhematologie Et Doncologie Pediatrique | Philippe M.,CNRS Biometry and Evolutionary Biology Laboratory | Henin E.,CNRS Biometry and Evolutionary Biology Laboratory | Bertrand Y.,Institute Dhematologie Et Doncologie Pediatrique | And 6 more authors.
AAPS Journal | Year: 2015

Optimal immunosuppressive therapy in acquired severe aplastic anemia (SAA) remains to be refined, especially cyclosporine (CsA) use. Current recommendations state that CsA trough blood concentrations (TBC) should be maintained between 200 and 400 ng/mL despite the lack of supporting data. This study aimed at quantifying relationships between CsA exposure and neutrophil response and determining an effective range for CsA TBC. Twenty-three SAA patients treated with CsA were retrospectively analyzed. Nonlinear mixed effect modeling approaches were used to develop a pharmacokinetic-pharmacodynamic model. The pharmacokinetic model described the relationships between CsA doses and TBC. The pharmacodynamic model allowed to estimate boundaries for optimal CsA effects, neutrophils being used as biomarker of response. A time-to-event model linked effective concentration to time-to-therapeutic success. CsA TBC were adequately described by a two-compartment model with first-order absorption, a lag time, and a linear elimination. The efficient range of CsA TBC was estimated between 87 and 120 ng/mL. Model-based simulations and external validation in three additional patients confirmed these results. This original modeling approach was successful in describing the relationship between CsA TBC and neutrophil response in SAA patients. Although further evaluation of the model is necessary, this work suggests that an optimal CsA TBC target of 100 ng/mL would be associated with a better neutrophil response in children with SAA. © 2015, American Association of Pharmaceutical Scientists.


Garbay D.,Institute Bergonie | Le Cesne A.,Institute Gustave Roussy | Penel N.,Center Oscar Lambret | Chevreau C.,Institute Claudius Regaud | And 10 more authors.
Annals of Oncology | Year: 2012

Background: Data regarding the role of chemotherapy (CT) in patients with recurrent and/or unresectable desmoid tumors (DTs) are scarce. Patients and methods: Records of patients with DT who were treated with CT in centers from the French Sarcoma Group were reviewed. Results: Sixty-two patients entered the study. The two most common locations were extremities (35.5%) and internal trunk (32.5%). Twelve patients (19.5%) were diagnosed with Gardner syndrome. Thirty-seven patients (54.7%) received previously one or more lines of systemic therapies (nonsteroidal anti-inflammatory drugs: 43.5%, antiestrogens: 43.5% and imatinib: 30.5%). Combination CT was delivered in 44 cases (71%) and single agent in 18 patients (29%), respectively. Thirteen patients (21%) received an anthracycline-containing regimen. The most frequent nonanthracycline regimen was the methotrexate-vinblastine combination (n = 27). Complete response, partial response, stable disease and progressive disease were observed in 1 (1.6%), 12 (19.4%), 37 (59.6%) and 12 (19.4%) patients, respectively. The response rate was higher with anthracycline-containing regimens: 54% versus 12%, P = 0.0011. Median progression-free survival (PFS) was 40.8 months. The sole factor associated with improved PFS was the nonlimb location: 12.1 months (95% confidence interval 5.6-18.7) versus not reached, P = 0.03. Conclusions: CT has significant activity in DT. Anthracycline-containing regimens appear to be associated with a higher response rate. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Merks J.H.M.,University of Amsterdam | de Salvo G.L.,Clinical trials and Biostatistics Unit Instituto Oncologico Veneto | Bergeron C.,Institute dHematologie et dOncologie pediatrique | de Paoli A.,Clinical trials and Biostatistics Unit Instituto Oncologico Veneto | And 8 more authors.
Annals of Oncology | Year: 2014

Background: Parameningeal (PM) site is a well-known adverse prognostic factor in children with localized rhabdomyosarcoma (RMS). To identify risk factors associated with outcome at this site, we pooled data from 1105 patients treated in 10 studies conducted by European and North American cooperative groups between 1984 and 2004. Patients and methods: Clinical factors including age, histology, size, invasiveness, nodal involvement, Intergroup Rhabdomyosarcoma Study (IRS) clinical group, site, risk factors for meningeal involvement (MI), study group, and application of radiotherapy (RT) were studied for their impact on event-free and overall survival (EFS and OS). Results: Ten-year EFS and OS were 62.6 and 66.1% for the whole group. Patients without initial RT showed worse survival (10-year OS 40.8% versus 68.5% for RT treated patients). Multivariate analysis focusing on 862 patients who received RT as part of their initial treatment revealed four unfavorable prognostic factors: age <3 or >10 years, signs of MI, unfavorable site, and tumor size. Utilizing these prognostic factors, patients could be classified into different risk groups with 10-year OS ranging between 51.1 and 80.9%. Conclusions: While, in general, PM localization is regarded as an adverse prognostic factor, the current analysis differentiates those with good prognosis (36% patients with 0-1 risk factor: 10-year OS 80.9%) from high-risk PM patients (28% with 3-4 factors: 10-year OS 51.1%). Furthermore, this analysis reinforces the necessity for RT in PM RMS. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


PubMed | Pediatric Oncology Unit, Paris-Sorbonne University, Institute dhematologie et doncologie pediatrique, Angers University Hospital Center and 6 more.
Type: | Journal: International journal of cancer | Year: 2017

Little is known of the causes of childhood brain tumors (CBT). The aims of this study were to investigate whether extremes of birth weight were associated with increased risk of CBT and whether maternal pre-conceptional folic acid supplementation or breastfeeding reduced the risk. In addition, other maternal characteristics and birth related factors were also investigated. We pooled data from two French national population-based case-control studies with similar designs conducted in 2003-2004 and 2010-2011. The mothers of 510 CBT cases (directly recruited from the national childhood cancer register) and 3102 controls aged under 15 years, frequency matched by age and gender did a telephone interview, which focussed on demographic and perinatal characteristics, and maternal life style habits and reproductive history. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression, adjusted for age, sex, study of origin and relevant confounders. No association was found between CBT and birth weight or fetal growth. The use of pre-conceptional folic acid supplementation was rare (5.3% in cases and 7.8% in controls) and the OR was 0.8 (95% CI 0.5, 1.4). There was no association with breastfeeding, even prolonged (six months or more) (OR 1.0, 95% CI 0.8, 1.4). Neither was there any association between CBT and other investigated factors (maternal body mass index, gestational weight gain, congenital abnormality, maternal reproductive history or use of fertility treatments. Although large, this study was underpowered for subtype analyses. Pooling data with other population-based studies may provide further insight into findings by CBT subtypes. This article is protected by copyright. All rights reserved.


Bleyzac N.,Institute dHematologie et dOncologie Pediatrique | Bleyzac N.,University Claude Bernard Lyon 1 | Kebaili K.,Institute dHematologie et dOncologie Pediatrique | Mialou V.,Etablissement Francais du Sang Rhone Alpes | And 3 more authors.
Therapeutic Drug Monitoring | Year: 2014

BACKGROUND:: Previous reports have suggested that imatinib may increase cyclosporine exposure by CYP3A4 inhibition. However, the magnitude of this drug interaction remains unclear. At present, quantitative information about the interaction profile of imatinib is scarce. METHODS:: The authors report the effect of imatinib on cyclosporine exposure in 6 pediatric patients with Philadelphia chromosome-positive acute lymphoblastic leukemia who received cyclosporine after hematopoietic stem-cell transplantation. Dose-normalized cyclosporine trough blood concentrations (TBC) were obtained before and after imatinib introduction. In addition, a validated model-based approach was used to derive quantitative predictions of CYP3A4-mediated drug interactions with imatinib as a victim or precipitant drug. RESULTS:: The mean dose-normalized cyclosporine TBC significantly increased after 3 to 7 days of imatinib therapy. The modeling approach predicted weak-to-moderate effect of major CYP3A4 inhibitors on imatinib exposure. However, the inhibitory potency of imatinib was found to be similar to that of verapamil, suggesting significant influence of imatinib on the pharmacokinetics of drugs highly metabolized by CYP3A4. Observed increases in cyclosporine dose-normalized TBC of the 6 patients were compatible with model predictions. The observations and predictions suggest that imatinib may substantially increase cyclosporine exposure. CONCLUSIONS:: Cyclosporine dose reduction may be necessary to avoid excessive immunosuppressive effect in case of coadministration of imatinib. © 2014 by Lippincott Williams & Wilkins.


Caye A.,UF de Genetique Moleculaire | Beldjord K.,University Paris Diderot | Mass-Malo K.,UF de Genetique Moleculaire | Drunat S.,UF de Genetique Moleculaire | And 6 more authors.
Haematologica | Year: 2013

Deletion of the Ikaros (IKZF1) gene is an oncogenic lesion frequently associated with BCR-ABL1-positive acute lymphoblastic leukemias. It is also found in a fraction of BCR-ABL1-negative B-cell precursor acute lymphoblastic leukemias, and early studies showed it was associated with a higher risk of relapse. Therefore, screening tools are needed for evaluation in treatment protocols and possible inclusion in risk stratification. Besides monosomy 7 and large 7p abnormalities encompassing IKZF1, most IKZF1 alterations are short, intragenic deletions. Based on cohorts of patients, we mapped the microdeletion breakpoints and developed a breakpoint-specific fluorescent multiplex polymerase chain reaction that allows detection of recurrent intragenic deletions. This sensitive test could also detect IKZF1 sub-clonal deletions, whose prognostic significance should be evaluated. Moreover, we show that consensus breakpoint sequences can be used as clonal markers to monitor minimal residual disease. This paper could be useful for translational studies and in clinical management of BCP-ALL. (ClinicalTrials.gov Identifier: NCT00003728) © 2013 Ferrata Storti Foundation.


Bernard E.,Institute Dhematologie Et Doncologie Pediatrique | Goutelle S.,University Claude Bernard Lyon 1 | Bertrand Y.,Institute Dhematologie Et Doncologie Pediatrique | Bleyzac N.,Institute Dhematologie Et Doncologie Pediatrique
Annals of Pharmacotherapy | Year: 2014

Background: Cyclosporine (CsA) is frequently responsible for hypertension in bone marrow transplant children. Calcium channel blockers (CCBs) are considered to be the best treatment for CsA-induced hypertension, but they may alter the exposure and the effect of CsA by inhibiting the CYP3A4 pathway of CsA metabolism or P-gp. However, the inhibitory effect on CYP3A4 may vary among CCBs. Methods: This study aimed to quantify the pharmacokinetic drug-drug interaction between CsA and nicardipine, amlodipine, and lacidipine. In all, 51 children who received CsA and CCB concomitantly were included. Results: Dose-normalized CsA trough blood concentrations significantly increased in patients treated with nicardipine and amlodipine, whereas they remained stable in patients treated with lacidipine. Conclusions: Because lacidipine appears to have no effect on CsA exposure, it may be the best option among CCBs for treating high blood pressure caused by CsA in children. © The Author(s) 2014.


Ducimetiere F.,University of Lyon | Lurkin A.,University of Lyon | Ranchere-Vince D.,University of Lyon | Decouvelaere A.-V.,University of Lyon | And 12 more authors.
PLoS ONE | Year: 2011

Background: The exact overall incidence of sarcoma and sarcoma subtypes is not known. The objective of the present population-based study was to determine this incidence in a European region (Rhone-Alpes) of six million inhabitants, based on a central pathological review of the cases. Methodology/Principal Findings: From March 2005 to February 2007, pathology reports and tumor blocks were prospectively collected from the 158 pathologists of the Rhone-Alpes region. All diagnosed or suspected cases of sarcoma were collected, reviewed centrally, examined for molecular alterations and classified according to the 2002 World Health Organization classification. Of the 1287 patients screened during the study period, 748 met the criteria for inclusion in the study. The overall crude and world age-standardized incidence rates were respectively 6.2 and 4.8 per 100,000/year. Incidence rates for soft tissue, visceral and bone sarcomas were respectively 3.6, 2.0 and 0.6 per 100,000. The most frequent histological subtypes were gastrointestinal stromal tumor (18%; 1.1/100,000), unclassified sarcoma (16%; 1/100,000), liposarcoma (15%; 0.9/100,000) and leiomyosarcoma (11%; 0.7/100,000). Conclusions/Significance: The observed incidence of sarcomas was higher than expected. This study is the first detailed investigation of the crude incidence of histological and molecular subtypes of sarcomas. © 2011 Ducimetiere et al.


Since ten years, we have been facilitating a support group for parents who have lost a child from cancer. These groups were created in response to a need of parents themselves, and were based on the observation by caregivers that an insufficient support is generally provided to families after the death of a child. From the Institute of Pediatric Hematology and Oncology of Lyon, we invite all the parents whose child passed away during the previous year.We offer them to meet once a month during ten meetings, gathering the same participants for a free exchange without any pre-identified theme. A review of major questions raised by the parents demonstrates their need to express their intense grief at their child’s death, to find an appropriate context to express their loss and to be listened. The parents also feel isolated and lost, notably because of the changes induced by this death, the radical upheaval of their cultural values, and self-identity. Their relationships with others become fragile and unsatisfactory. Fellow human beings appear as mere strangers because the one who did not live this painful experience is often seen as insensitive or awkward, and anyway, never in sync with the parents in mourning, deprived of a part of themselves. They hopelessly seek to put forward their new self-identity, which remains unnamable in our current language. There is no word for the one who is mourning of a child. This event is so inconceivable that it cannot be expressed by language. This new identity is nameless and the parents want it to remain unnamable. The parent in mourning is divided between the claim of this new identity and the wish to remain among the living, to soothe his or her suffering. Within the support group, parents can express their sufferings, find understanding and acceptance, and compare their experience with others. The group can help them to restore personal power and overcome the feeling of isolation. It is a place where they can regain their bearings at a time when they feel most vulnerable. Through paying attention to others and to their reactions, which may be different from their own, violently bereaved parents can sometimes find peace. They can gradually move from a state of survival to a state of “live with”. Even if they remain vulnerable, the group helps them readjust to normal living and normal relationships. © 2015, Springer-Verlag France.

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