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University of Technology of Compiègne, France

Pujade-Lauraine E.,Center Des Cancers Of La Femme | Selle F.,Hopitaux Universitaires Of Lest Parisien Site Tenon | Weber B.,Center Alexis Vautrin | Ray-Coquard I.-L.,University of Lyon | And 17 more authors.
Journal of Clinical Oncology | Year: 2016

Purpose: Volasertib is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase. This phase II trial evaluated volasertib or single-agent chemotherapy in patients with platinum-resistant or-refractory ovarian cancer who experienced failure after treatment with two or three therapy lines. Patients and Methods: Patients were randomly assigned to receive either volasertib 300 mg by intravenous infusion every 3 weeks or an investigator's choice of single-agent, nonplatinum, cytotoxic chemotherapy. The primary end point was 24-week disease control rate. Secondary end points included best overall response, progression-free survival (PFS), safety, quality of life, and exploratory biomarker analyses. Results: Of the 109 patients receiving treatment, 54 received volasertib and 55 received chemotherapy; demographics were well balanced. The 24-week disease control rates for volasertib and chemotherapy were 30.6% (95% CI, 18.0% to 43.2%) and 43.1% (95% CI, 29.6% to 56.7%), respectively, with partial responses in seven (13.0%) and eight (14.5%) patients, respectively. Median PFS was 13.1 weeks and 20.6 weeks for volasertib and chemotherapy (hazard ratio, 1.01; 95% CI, 0.66 to 1.53). Six patients (11%) receiving volasertib achieved PFS fore more than 1 year, whereas no patient receiving chemotherapy achieved PFS greater than 1 year. No relationship between the expression of the biomarkers tested and their response was determined. Patients treated with volasertib experienced more grade 3 and 4 drug-related hematologic adverse events (AEs) and fewer nonhematologic AEs than did patients receiving chemotherapy. Discontinuation resulting from AEs occurred in seven (13.0%) and 15 (27.3%) patients in the volasertib and chemotherapy arms, respectively. Both arms showed similar effects on quality of life. Conclusion: Single-agent volasertib showed antitumor activity in patients with ovarian cancer. AEs in patients receiving volasertib were mainly hematologic and manageable. © 2016 American Society of Clinical Oncology. All rights reserved.

Chevrier C.,French Institute of Health and Medical Research | Chevrier C.,University of Rennes 1 | Limon G.,IDHESA | Monfort C.,French Institute of Health and Medical Research | And 12 more authors.
Environmental Health Perspectives | Year: 2011

Background: Despite evidence of atrazine toxicity in developing organisms from experimental studies, few studies-and fewer epidemiologic investigations-have examined the potential effects of prenatal exposure. Objectives: We assessed the association between adverse birth outcomes and urinary biomarkers of prenatal atrazine exposure, while taking into account exposures to other herbicides used on corn crops (simazine, alachlor, metolachlor, and acetochlor). Methods: This study used a case-cohort design nested in a prospective birth cohort conducted in the Brittany region of France from 2002 through 2006. We collected maternal urine samples to examine pesticide exposure biomarkers before the 19th week of gestation. Results: We found quantifiable levels of atrazine or atrazine mercapturate in urine samples from 5.5% of 579 pregnant women, and dealkylated and identified hydroxylated triazine metabolites in 20% and 40% of samples, respectively. The presence versus absence of quantifiable levels of atrazine or a specific atrazine metabolite was associated with fetal growth restriction [odds ratio (OR) = 1.5; 95% confidence interval (CI), 1.0-2.2] and small head circumference for sex and gestational age (OR = 1.7; 95% CI, 1.0-2.7). Associations with major congenital anomalies were not evident with atrazine or its specific metabolites. Head circumference was inversely associated with the presence of quantifiable urinary metolachlor. Conclusions: This study is the first to assess associations of birth outcomes with multiple urinary biomarkers of exposure to triazine and chloroacetanilide herbicides. Evidence of associations with adverse birth outcomes raises particular concerns for countries where atrazine is still in use.

Agnamey P.,University of Picardie Jules Verne | Sarfati C.,University Paris Diderot | Pinel C.,Institut Universitaire de France | Rabodoniriina M.,University Claude Bernard Lyon 1 | And 8 more authors.
Journal of Clinical Microbiology | Year: 2011

In a multicenter study, potassium dichromate-preserved stools from patients infected with Cryptosporidium parvum (n = 20), C. hominis (n = 20), and other Cryptosporidium species (n = 10) and 60 controls were examined using four immunochromatographic assays. Assay sensitivity ranged between 50.1% and 86.7% for C. parvum and C. hominis but was <35% for other species. Copyright © 2011, American Society for Microbiology.

Creemers J.W.M.,Catholic University of Leuven | Choquet H.,Institut Universitaire de France | Stijnen P.,Catholic University of Leuven | Vatin V.,Institut Universitaire de France | And 19 more authors.
Diabetes | Year: 2012

Null mutations in the PCSK1 gene, encoding the proprotein convertase 1/3 (PC1/3), cause recessive monogenic early onset obesity. Frequent coding variants that modestly impair PC1/3 function mildly increase the risk for common obesity. The aim of this study was to determine the contribution of rare functional PCSK1 mutations to obesity. PCSK1 exons were sequenced in 845 nonconsanguineous extremely obese Europeans. Eight novel nonsynonymous PCSK1 mutations were identified, all heterozygous. Seven mutations had a deleterious effect on either the maturation or the enzymatic activity of PC1/3 in cell lines. Of interest, five of these novel mutations, one of the previously described frequent variants (N221D), and the mutation found in an obese mouse model (N222D), affect residues at or near the structural calcium binding site Ca-1. The prevalence of the newly identified mutations was assessed in 6,233 obese and 6,274 lean European adults and children, which showed that carriers of any of these mutations causing partial PCSK1 deficiency had an 8.7-fold higher risk to be obese than wild-type carriers. These results provide the first evidence of an increased risk of obesity in heterozygous carriers of mutations in the PCSK1 gene. Furthermore, mutations causing partial PCSK1 deficiency are present in 0.83% of extreme obesity phenotypes. © 2012 by the American Diabetes Association.

Ades L.,University of Paris 13 | Chevret S.,University of Paris Descartes | Raffoux E.,University of Paris Descartes | Guerci-Bresler A.,University of Lorraine | And 17 more authors.
American Journal of Hematology | Year: 2013

All-trans retinoic acid (ATRA) combined to anthracycline-based chemotherapy is the reference treatment of acute promyelocytic leukemia (APL). Whereas, in high-risk patients, cytarabine (AraC) is often considered useful in combination with anthracycline to prevent relapse, its usefulness in standard-risk APL is uncertain. In APL 2000 trial, patients with standard-risk APL [i.e., with baseline white blood cell (WBC) count <10,000/mm3] were randomized between treatment with ATRA with Daunorubicin (DNR) and AraC (AraC group) and ATRA with DNR but without AraC (no AraC group). All patients subsequently received combined maintenance treatment. The trial had been prematurely terminated due to significantly more relapses in the no AraC group (J Clin Oncol, (24) 2006, 5703-10), but follow-up was still relatively short. With long-term follow-up (median 103 months), the 7-year cumulative incidence of relapses was 28.6% in the no AraC group, compared to 12.9% in the AraC group (P = 0.0065). In standard-risk APL, at least when the anthracycline used is DNR, avoiding AraC may lead to an increased risk of relapse suggesting that the need for AraC is regimen-dependent. © 2013 Wiley Periodicals, Inc.

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