Saint-André-lez-Lille, France
Saint-André-lez-Lille, France

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Renneville A.,Biology and Pathology Center | Renneville A.,University of Lille Nord de France | Renneville A.,Cancer Research Institute of Lille | Boissel N.,University Paris Diderot | And 23 more authors.
Leukemia | Year: 2012

Recently, DNA methyltransferase 3A (DNMT3A) mutations have been identified in acute myeloid leukemia (AML), the highest frequency being found within cytogenetically normal (CN) AML. In this study, diagnostic samples from 123 adults younger than 60 years with primary CN-AML homogeneously treated in the Acute Leukemia French Association-9801 and-9802 trials were screened for mutations in DNMT3A-conserved domains by direct sequencing. Patients were also assessed for the presence of FLT3 (fms-like tyrosine kinase receptor-3), NPM1 (nucleophosmin), CEBPA, WT1 (Wilms tumor 1), IDH1 (isocitrate dehydrogenase 1) and IDH2 mutations. Thirty-eight mutations were detected in 36 patients (29%): 36 nucleotide substitutions, mostly affecting amino-acid residue R882 and two frameshift deletions. DNMT3A mutations were significantly associated with the French-American-British subtypes M4/M5 and the presence of NPM1 mutations. In the whole cohort, DNMT3A mutated patients had a shorter event-free survival (5-year EFS: 13% vs 32%, P0.02) and overall survival (5-year OS: 23% vs 45%, P0.02) compared with DNMT3A wild-type patients. In multivariate analysis including age, white blood cell count, NPM1/FLT3-internal tandem duplication/CEBPA risk group and DNMT3A mutational status, the presence of a DNMT3A mutation remained an independent adverse prognostic factor for EFS and OS, suggesting that testing for DNMT3A mutations could help further improve risk stratification in CN-AML. © 2012 Macmillan Publishers Limited.


PubMed | Jean Pierre Research Center, Biology and Pathology Center and Lille University Hospital Center
Type: Journal Article | Journal: Oncotarget | Year: 2016

CD81 is a cell surface protein which belongs to the tetraspanin family. While in multiple myeloma its expression on plasma cells is associated with worse prognosis, this has not yet been explored in acute myeloid leukemia (AML). We measured membrane expression of CD81 on AML cells at diagnosis, evaluated its association with AML characteristics and its influence on patient outcome after intensive chemotherapy in a cohort of 134 patients. CD81 was detected in 92/134 (69%) patients. Patients with AML expressing CD81 had elevated leukocyte count (P=0.02) and were more likely classified as intermediate or adverse-risk by cytogenetics (P<0.001). CD81 expression had a negative impact on survival (event-free survival, overall survival and relapse-free survival) in univariate (P<0.001) and in multivariate analyses (P=0.003, 0.002 and <0.001, respectively). CD81 has a negative impact on OS in patients with NPM1 mutation (P=0.01) and in patients ELN-favorable (P=0.002). In conclusion, this cell surface marker may be a new prognostic marker for diagnostic risk classification and a potential therapeutic target for drug development in AML.


Nahida E.-R.,Makassed General Hospital | Guy L.,Biology and Pathology Center
Acta Paediatrica, International Journal of Paediatrics | Year: 2011

Pseudo-Bartter's (PB) syndrome characterized by hypokalemic metabolic alkalosis and persistent failure to thrive constitutes a rare typical presentation of cystic fibrosis (CF) with prevalence of 16.8%. We present a case of CF presenting with failure to thrive, dehydration, PB syndrome associated with chest infection and primo-colonization with Pseudomonas aeruginosa. Sweat chloride test was 102 mmol/L. DNA analysis identified 2 mutations 3849 + 1G>A (intron 19) and 4382delA (exon 24) present in heterozygous status. To the best of our knowledge, our case is the first reported case in the literature of CF manifested by PB syndrome associated with chest infection and primo-colonization with Pseudomonas aeruginosa. Conclusion: The genotype 3849 + 1G>A/4382delA found in our patient is described for the first time in the literature. It explains the lung involvement with the dehydration and electrolyte disturbances. The role of the mutation in exon 24 in cases of CF with PB syndrome remains to be determined. © 2011 The Author(s)/Acta Pædiatrica © 2011 Foundation Acta Pædiatrica.


Hysi I.,Albert Calmette Hospital | Rousse N.,Albert Calmette Hospital | Claret A.,Albert Calmette Hospital | Bellier J.,Albert Calmette Hospital | And 4 more authors.
Annals of Thoracic Surgery | Year: 2011

Background: Postpneumonectomy empyema (PPE) is a serious complication. The treatment options are similar to the management of any abscess, with drainage, ideally open, often of critical importance. After infection control, many techniques for space obliteration have been described. This study summarizes a 10-year experience in the management of PPE in our center. Methods: From 2000 to 2010, 90 patients (83 men) with PPE were treated. Median follow-up was 5.3 years. Once the diagnosis of empyema was confirmed, chest drainage was performed through open window thoracostomy (OWT), with ensuing extramusculoperiosteal thoracoplasties if healthy tissue was present. Results: Pneumonectomy was performed in 72 patients with lung cancer. Mortality after PPE was 2.2%. OWT achieved infection control in 89 patients. Seven OWT spontaneously healed, and 24 were never closed. The remaining 59 patients with OWT underwent thoracoplasty. Mortality after thoracoplasty was 5%. Empyema recurred in 3 patients. Overall success rate of PPE control after pleural obliteration was 91.5%. Conclusions: Thoracoplasty is a reliable filling procedure. It has a significantly higher success rate and a lower mortality rate than the other techniques. We believe that this procedure has a part to play in the future management of PPE. © 2011 The Society of Thoracic Surgeons.


Giraud M.,French Institute for Research in Computer Science and Automation | Salson M.,French Institute for Research in Computer Science and Automation | Duez M.,French Institute for Research in Computer Science and Automation | Villenet C.,Lille 2 University of Health and Law | And 9 more authors.
BMC Genomics | Year: 2014

Background: V(D)J recombinations in lymphocytes are essential for immunological diversity. They are also useful markers of pathologies. In leukemia, they are used to quantify the minimal residual disease during patient follow-up. However, the full breadth of lymphocyte diversity is not fully understood.Results: We propose new algorithms that process high-throughput sequencing (HTS) data to extract unnamed V(D)J junctions and gather them into clones for quantification. This analysis is based on a seed heuristic and is fast and scalable because in the first phase, no alignment is performed with germline database sequences. The algorithms were applied to TR γ HTS data from a patient with acute lymphoblastic leukemia, and also on data simulating hypermutations. Our methods identified the main clone, as well as additional clones that were not identified with standard protocols.Conclusions: The proposed algorithms provide new insight into the analysis of high-throughput sequencing data for leukemia, and also to the quantitative assessment of any immunological profile. The methods described here are implemented in a C++ open-source program called Vidjil. © 2014 Giraud et al.; licensee BioMed Central Ltd.


Duployez N.,Biology and Pathology Center | Nibourel O.,Biology and Pathology Center | Nibourel O.,French Institute of Health and Medical Research | Marceau-Renaut A.,Biology and Pathology Center | And 14 more authors.
American Journal of Hematology | Year: 2014

Although acute myeloid leukemia (AML) with t(8;21) belongs to the favorable risk AML subset, relapse incidence may reach 30% in those patients. RUNX1-RUNX1T1 fusion transcript is a well-established marker for minimal residual disease (MRD) monitoring. In this study, we investigated the feasibility and performances of RUNX1-RUNX1T1 DNA as MRD marker in AML with t(8;21). In 17/22 patients with t(8;21)-positive AML treated in the French CBF-2006 trial, breakpoints in RUNX1 and RUNX1T1 were identified using long-range PCR followed by next-generation sequencing. RUNX1-RUNX1T1 DNA quantification was performed by real-time quantitative PCR using patient-specific primers and probe. MRD levels were evaluated in 71 follow-up samples from 16 patients, with a median of four samples [range 2-7] per patient. RUNX1 breakpoints were located in intron 5 in all cases. RUNX1T1 breakpoints were located in intron 1b in 15 cases and in intron 1a in two cases. RUNX1-RUNX1T1 MRD levels measured on DNA and RNA were strongly correlated (r=0.8, P<0.0001). Discordant MRD results were observed in 10/71 (14%) of the samples: in three samples from two patients who relapsed, RUNX1-RUNX1T1 was detectable only on DNA, while RUNX1-RUNX1T1 was detectable only on RNA in seven samples. MRD monitoring on genomic DNA is feasible, but with sensitivity variations depending on the patient breakpoint sequence and the qPCR assay efficiency. Although interpretation of the results is easier because it is closely related to the number of leukemic cells, this method greatly increases time, cost and complexity, which limits its interest in routine practice. © 2014 Wiley Periodicals, Inc.


Renneville A.,Biology and Pathology Center | Abdelali R.B.,Biology and Pathology Center | Chevret S.,Biology and Pathology Center | Nibourel O.,Biology and Pathology Center | And 13 more authors.
Oncotarget | Year: 2014

We recently showed that the addition of fractionated doses of gemtuzumab ozogamicin (GO) to standard chemotherapy improves clinical outcome of acute myeloid leukemia (AML) patients. In the present study, we performed mutational analysis of 11 genes (FLT3, NPM1, CEBPA, MLL, WT1, IDH1/2, RUNX1, ASXL1, TET2, DNMT3A), EVI1 overexpression screening, and 6.0 single-nucleotide polymorphism array (SNP-A) analysis in diagnostic samples of the 278 AML patients enrolled in the ALFA-0701 trial. In cytogenetically normal (CN) AML (n=146), 38% of the patients had at least 1 SNP-A lesion and 89% of the patients had at least 1 molecular alteration. In multivariate analysis, the independent predictors of higher cumulative incidence of relapse were unfavorable karyotype (P = 0.013) and randomization in the control arm (P = 0.007) in the whole cohort, and MLL partial tandem duplications (P = 0.014) and DNMT3A mutations (P = 0.010) in CN-AML. The independent predictors of shorter overall survival (OS) were unfavorable karyotype (P <0.001) and SNP-A lesion(s) (P = 0.001) in the whole cohort, and SNP-A lesion(s) (P = 0.006), DNMT3A mutations (P = 0.042) and randomization in the control arm (P = 0.043) in CN-AML. Interestingly, CN-AML patients benefited preferentially more from GO treatment as compared to AML patients with abnormal cytogenetics (hazard ratio for death, 0.52 versus 1.14; test for interaction, P = 0.04). Although the interaction test was not statistically significant, the OS benefit associated with GO treatment appeared also more pronounced in FLT3 internal tandem duplication positive than in negative patients.


Guilhot J.,University of Poitiers | Preudhomme C.,Biology and Pathology Center | Mahon F.X.,University of Bordeaux Segalen | Guilhot F.,University of Poitiers
Cancer | Year: 2015

Clinical trials of chronic myeloid leukemia frequently rely on molecular markers as surrogates for clinical endpoints. Studies suggest that early molecular response (EMR) is a good indicator of a favorable prognosis and yet, to the authors' knowledge, the use of EMR as a robust surrogate marker for clinical response has yet to be fully explored. EMR to therapy appears to be affected by a variety of factors, including disease characteristics, risk score, adherence to treatment, and off-target effects of the treatment. Therefore, although molecular markers improve important research, they also bring with them important questions regarding their reliability. To be useful, markers must be must be easily measureable, capable of generating meaningful data, and clinically relevant. BCR-ABL1 is the hallmark marker in chronic myeloid leukemia. Nevertheless, investigators still struggle with how best to measure and interpret both high and very low BCR-ABL1 levels. Statistical models of BCR-ABL1 kinetics must address these concerns and account for the BCR-ABL1 variability between and within patients. Response models should also incorporate disease characteristics and other important parameters. © 2014 American Cancer Society.


Recently, DNA methyltransferase 3A (DNMT3A) mutations have been identified in acute myeloid leukemia (AML), the highest frequency being found within cytogenetically normal (CN) AML. In this study, diagnostic samples from 123 adults younger than 60 years with primary CN-AML homogeneously treated in the Acute Leukemia French Association-9801 and -9802 trials were screened for mutations in DNMT3A-conserved domains by direct sequencing. Patients were also assessed for the presence of FLT3 (fms-like tyrosine kinase receptor-3), NPM1 (nucleophosmin), CEBPA, WT1 (Wilms tumor 1), IDH1 (isocitrate dehydrogenase 1) and IDH2 mutations. Thirty-eight mutations were detected in 36 patients (29%): 36 nucleotide substitutions, mostly affecting amino-acid residue R882 and two frameshift deletions. DNMT3A mutations were significantly associated with the French-American-British subtypes M4/M5 and the presence of NPM1 mutations. In the whole cohort, DNMT3A mutated patients had a shorter event-free survival (5-year EFS: 13% vs 32%, P = 0.02) and overall survival (5-year OS: 23% vs 45%, P = 0.02) compared with DNMT3A wild-type patients. In multivariate analysis including age, white blood cell count, NPM1/FLT3-internal tandem duplication/CEBPA risk group and DNMT3A mutational status, the presence of a DNMT3A mutation remained an independent adverse prognostic factor for EFS and OS, suggesting that testing for DNMT3A mutations could help further improve risk stratification in CN-AML.


We recently showed that the addition of fractionated doses of gemtuzumab ozogamicin (GO) to standard chemotherapy improves clinical outcome of acute myeloid leukemia (AML) patients. In the present study, we performed mutational analysis of 11 genes (FLT3, NPM1, CEBPA, MLL, WT1, IDH1/2, RUNX1, ASXL1, TET2, DNMT3A), EVI1 overexpression screening, and 6.0 single-nucleotide polymorphism array (SNP-A) analysis in diagnostic samples of the 278 AML patients enrolled in the ALFA-0701 trial. In cytogenetically normal (CN) AML (n=146), 38% of the patients had at least 1 SNP-A lesion and 89% of the patients had at least 1 molecular alteration. In multivariate analysis, the independent predictors of higher cumulative incidence of relapse were unfavorable karyotype (P = 0.013) and randomization in the control arm (P = 0.007) in the whole cohort, and MLL partial tandem duplications (P = 0.014) and DNMT3A mutations (P = 0.010) in CN-AML. The independent predictors of shorter overall survival (OS) were unfavorable karyotype (P <0.001) and SNP-A lesion(s) (P = 0.001) in the whole cohort, and SNP-A lesion(s) (P = 0.006), DNMT3A mutations (P = 0.042) and randomization in the control arm (P = 0.043) in CN-AML. Interestingly, CN-AML patients benefited preferentially more from GO treatment as compared to AML patients with abnormal cytogenetics (hazard ratio for death, 0.52 versus 1.14; test for interaction, P = 0.04). Although the interaction test was not statistically significant, the OS benefit associated with GO treatment appeared also more pronounced in FLT3 internal tandem duplication positive than in negative patients.

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