Publications by authors named "Arnaud Petit"

71 Publications

Oncogenetic landscape and clinical impact of IDH1 and IDH2 mutations in T-ALL.

J Hematol Oncol 2021 May 3;14(1):74. Epub 2021 May 3.

Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Université de Paris, 149 rue de Sèvres, 75015, Paris, France.

IDH1 and IDH2 mutations (IDH1/2) are recognized as recurrent genetic alterations in acute myeloid leukemia (AML) and associated with both clinical impact and therapeutic opportunity due to the recent development of specific IDH1/2 inhibitors. In T-cell acute lymphoblastic leukemia (T-ALL), their incidence and prognostic implications remain poorly reported. Our targeted next-generation sequencing approach allowed comprehensive assessment of genotype across the entire IDH1 and IDH2 locus in 1085 consecutive unselected and newly diagnosed patients with T-ALL and identified 4% of, virtually exclusive (47 of 49 patients), IDH1/2. Mutational patterns of IDH1/2 in T-ALL present some specific features compared to AML. Whereas IDH2 mutation was frequent in T-ALL (25 of 51 mutations), the IDH2 AML hotspot was absent. IDH2 mutations were associated with older age, an immature phenotype, more frequent RAS gain-of-function mutations and epigenetic regulator loss-of-function alterations (DNMT3A and TET2). IDH2 mutations, contrary to IDH1 mutations, appeared to be an independent prognostic factor in multivariate analysis with the NOTCH1/FBXW7/RAS/PTEN classifier. IDH2 were significantly associated with a high cumulative incidence of relapse and very dismal outcome, suggesting that IDH2-mutated T-ALL cases should be identified at diagnosis in order to benefit from therapeutic intensification and/or specific IDH2 inhibitors.
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http://dx.doi.org/10.1186/s13045-021-01068-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091755PMC
May 2021

End-of-life care in children and adolescents with cancer: perspectives from a French pediatric oncology care network.

Tumori 2021 May 4:3008916211013384. Epub 2021 May 4.

RIFHOP, Île-de-France Regional Network of Pediatric Hematology-Oncology, Paris, France.

Background: In developed countries, cancer remains the leading cause of pediatric death from illness after the neonatal period.

Objective: To describe the end-of-life care characteristics of children and adolescents with solid tumors (ST) or hematologic malignancies (HM) who died from tumor progression in the Île-de-France area.

Methods: This is a regional, multicentric, retrospective review of medical files of all children and adolescents with cancer who died over a 1-year period. Extensive data from the last 3 months of life were collected.

Results: A total of 99 eligible patients died at a median age of 9.8 years (range, 0.3-24 years). The most frequent terminal symptoms were pain (n = 86), fatigue (n = 84), dyspnea (n = 49), and anorexia (n = 41). Median number of medications per patient was 8 (range, 3-18). Patients required administration of opioids (n = 91), oxygen (n = 36), and/or sedation (n = 61). Decision for palliative care was present in all medical records and do-not-resuscitate orders in 90/99 cases. Symptom prevalence was comparable between children and adolescents with ST and HM. A wish regarding the place of death had been expressed for 64 patients and could be respected in 42 cases. Death occurred in hospital for 75 patients.

Conclusions: This study represents a large and informative cohort illustrating current pediatric palliative care approaches in pediatric oncology. End-of-life remains an active period of care requiring coordination of multiple care teams.
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http://dx.doi.org/10.1177/03008916211013384DOI Listing
May 2021

COVID19 and acute lymphoblastic leukemias of children and adolescents: Updated recommendations (Version 2) of the Leukemia Committee of the French Society for the fight against Cancers and leukemias in children and adolescents (SFCE).

Bull Cancer 2021 May 11;108(5):490-500. Epub 2021 Mar 11.

Université de Paris, service d'hémato-immunologie pédiatrique, hôpital universitaire Robert-Debré (APHP), boulevard Sérurier, 75019 Paris, France. Electronic address:

Since the emergence of the SARS-CoV-2 infection, many recommendations have been made. However, the very specific nature of acute lymphoblastic leukemias and their treatment in children and adolescents led the Leukemia Committee of the French Society for the fight against Cancers and leukemias in children and adolescents (SFCE) to propose more specific recommendations. Here is the second version of these recommendations updated according to the evolution of knowledge on COVID19.
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http://dx.doi.org/10.1016/j.bulcan.2021.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951944PMC
May 2021

Infant Acute Myeloid Leukemia: A Unique Clinical and Biological Entity.

Cancers (Basel) 2021 Feb 13;13(4). Epub 2021 Feb 13.

Pediatric Hematology and Immunology Department, Robert Debré University Hospital (APHP and Université de Paris), 75019 Paris, France.

Infant acute myeloid leukemia (AML) is a rare subgroup of AML of children <2 years of age. It is as frequent as infant acute lymphoblastic leukemia (ALL) but not clearly distinguished by study groups. However, infant AML demonstrates peculiar clinical and biological characteristics, and its prognosis differs from AML in older children. Acute megakaryoblastic leukemia (AMKL) is very frequent in this age group and has raised growing interest. Thus, AMKL is a dominant topic in this review. Recent genomic sequencing has contributed to our understanding of infant AML. These data demonstrated striking features of infant AML: fusion genes are able to induce AML transformation without additional cooperation, and unlike AML in older age groups there is a paucity of associated mutations. Mice modeling of these fusions showed the essential role of ontogeny in the infant leukemia phenotype compared to older children and adults. Understanding leukemogenesis may help in developing new targeted treatments to improve outcomes that are often very poor in this age group. A specific diagnostic and therapeutic approach for this age group should be investigated.
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http://dx.doi.org/10.3390/cancers13040777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918235PMC
February 2021

Effect of Blinatumomab vs Chemotherapy on Event-Free Survival Among Children With High-risk First-Relapse B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial.

JAMA 2021 03;325(9):843-854

Charité-Universitätsmedizin Berlin, Berlin, Germany.

Importance: Blinatumomab is a CD3/CD19-directed bispecific T-cell engager molecule with efficacy in children with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL).

Objective: To evaluate event-free survival in children with high-risk first-relapse B-ALL after a third consolidation course with blinatumomab vs consolidation chemotherapy before allogeneic hematopoietic stem cell transplant.

Design, Setting, And Participants: In this randomized phase 3 clinical trial, patients were enrolled November 2015 to July 2019 (data cutoff, July 17, 2019). Investigators at 47 centers in 13 countries enrolled children older than 28 days and younger than 18 years with high-risk first-relapse B-ALL in morphologic complete remission (M1 marrow, <5% blasts) or with M2 marrow (blasts ≥5% and <25%) at randomization.

Intervention: Patients were randomized to receive 1 cycle of blinatumomab (n = 54; 15 μg/m2/d for 4 weeks, continuous intravenous infusion) or chemotherapy (n = 54) for the third consolidation.

Main Outcomes And Measures: The primary end point was event-free survival (events: relapse, death, second malignancy, or failure to achieve complete remission). The key secondary efficacy end point was overall survival. Other secondary end points included minimal residual disease remission and incidence of adverse events.

Results: A total of 108 patients were randomized (median age, 5.0 years [interquartile range {IQR}, 4.0-10.5]; 51.9% girls; 97.2% M1 marrow) and all patients were included in the analysis. Enrollment was terminated early for benefit of blinatumomab in accordance with a prespecified stopping rule. After a median of 22.4 months of follow-up (IQR, 8.1-34.2), the incidence of events in the blinatumomab vs consolidation chemotherapy groups was 31% vs 57% (log-rank P < .001; hazard ratio [HR], 0.33 [95% CI, 0.18-0.61]). Deaths occurred in 8 patients (14.8%) in the blinatumomab group and 16 (29.6%) in the consolidation chemotherapy group. The overall survival HR was 0.43 (95% CI, 0.18-1.01). Minimal residual disease remission was observed in more patients in the blinatumomab vs consolidation chemotherapy group (90% [44/49] vs 54% [26/48]; difference, 35.6% [95% CI, 15.6%-52.5%]). No fatal adverse events were reported. In the blinatumomab vs consolidation chemotherapy group, the incidence of serious adverse events was 24.1% vs 43.1%, respectively, and the incidence of adverse events greater than or equal to grade 3 was 57.4% vs 82.4%. Adverse events leading to treatment discontinuation were reported in 2 patients in the blinatumomab group.

Conclusions And Relevance: Among children with high-risk first-relapse B-ALL, treatment with 1 cycle of blinatumomab compared with standard intensive multidrug chemotherapy before allogeneic hematopoietic stem cell transplant resulted in an improved event-free survival at a median of 22.4 months of follow-up.

Trial Registration: ClinicalTrials.gov Identifier: NCT02393859.
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http://dx.doi.org/10.1001/jama.2021.0987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926287PMC
March 2021

Hypoxia favors chemoresistance in T-ALL through an HIF1α-mediated mTORC1 inhibition loop.

Blood Adv 2021 01;5(2):513-526

Team Niche and Cancer in Hematopoiesis, Unité 1274, INSERM, Fontenay-aux-Roses, France.

Resistance to chemotherapy, a major therapeutic challenge in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), can be driven by interactions between leukemic cells and the microenvironment that promote survival of leukemic cells. The bone marrow, an important leukemia niche, has low oxygen partial pressures that highly participate in the regulation of normal hematopoiesis. Here we show that hypoxia inhibits T-ALL cell growth by slowing down cell cycle progression, decreasing mitochondria activity, and increasing glycolysis, making them less sensitive to antileukemic drugs and preserving their ability to initiate leukemia after treatment. Activation of the mammalian target of rapamycin (mTOR) was diminished in hypoxic leukemic cells, and treatment of T-ALL with the mTOR inhibitor rapamycin in normoxia mimicked the hypoxia effects, namely decreased cell growth and increased quiescence and drug resistance. Knocking down (KD) hypoxia-induced factor 1α (HIF-1α), a key regulator of the cellular response to hypoxia, antagonized the effects observed in hypoxic T-ALL and restored chemosensitivity. HIF-1α KD also restored mTOR activation in low O2 concentrations, and inhibiting mTOR in HIF1α KD T-ALL protected leukemic cells from chemotherapy. Thus, hypoxic niches play a protective role of T-ALL during treatments. Inhibition of HIF-1α and activation of the mTORC1 pathway may help suppress the drug resistance of T-ALL in hypoxic niches.
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http://dx.doi.org/10.1182/bloodadvances.2020002832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839374PMC
January 2021

Head and neck tumors in children and adolescents: Impact of a multidisciplinary tumor board.

Oral Oncol 2021 03 20;114:105145. Epub 2021 Jan 20.

Pediatric Ear, Nose, and Throat Department, Robert Debré Hospital, Public Assistance-Hospitals of Paris, Paris, France.

Introduction: Cancer treatment in France is based on Multidisciplinary Tumor Board (MTB). In the Ile-de-France region (IDF), which includes 12 million inhabitants from Paris and the surrounding area, pediatric tumors of head and neck are discussed since 2013 in a dedicated Interregional Pediatric Multicentric MTB (IPMTB). The purpose of this study is to analyze the impact of the IDF head and neck IPMTB on the management of these tumors, 5 years after their implementation.

Materials And Methods: Retrospective study of all patient files presented in the IPMTB for a benign or malignant head-and-neck tumor, between 2013 and 2018.

Results: A total of 679 discussions were analyzed representing 428 patients. Median age was 7.5 years (range: 0-31 years). Malignant tumors represented 71% of cases, including 36% of rhabdomyosarcoma. Overall, 12% percent of the cases discussed came from centers outside of IDF. All meetings complied with multidisciplinary criteria required by French law. Proposals made during the IPMTB were followed in 86% of cases. Among the 251 proposals made by the referring teams prior to the IPMTB, 29% were secondarily modified after being discussed in the IPMTB.

Conclusion: Thanks to their multidisciplinarity, high number of cases discussed and usual respect of their proposals, the IPMTB have made it possible to improve the coordination between all specialties involved in the patient's management, to apply the most recent and scientifically validated protocols, and to share the knowledge of different teams concerning the management of particularly rare tumors.
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http://dx.doi.org/10.1016/j.oraloncology.2020.105145DOI Listing
March 2021

Bone Mineral Density Evolution and Its Determinants in Long-term Survivors of Childhood Acute Leukemia: A Leucémies Enfants Adolescents Study.

Hemasphere 2021 Feb 12;5(2):e518. Epub 2021 Jan 12.

Department of Paediatric Haematology and Oncology and EA3279, Timone Children Hospital and Aix-Marseille University, Marseille, France.

This prospective study aimed to analyze determinants that can influence bone mineral density evolution in childhood acute leukemia survivors. Patients included were selected from the long-term follow-up LEA cohort and had dual energy radiograph absorptiometry scan between 10 and 18 years and after the age of 18. All scans were centrally reviewed. Bone mineral density was measured at the lumbar spine, femoral neck, total hip, and whole body, and expressed as z-score. Eighty-nine patients (female 39, lymphoblastic leukemia 68, relapse 25, hematopoietic stem cell transplantation 44, and mean age 15.4 and 20.1 years at the first and second scans, respectively) were studied. The first and second scan z-scores were significantly correlated ( < 10). Mean femoral neck and total hip z-scores improved significantly between the first and second scans, whereas no significant evolution occurred at the lumbar spine and whole-body level. On the second evaluation, 14.6% of patients had z-score <-2 at the lumbar spine and 4.3% at the femoral neck level. Gender, type of leukemia, transplantation, relapse, cumulative corticosteroid doses, or growth hormone deficiency did not have any significant impact on z-score variation. Younger age at diagnosis (≤8.5 years) proved an unfavorable risk factor for z-score evolution at the lumbar spine ( = 0.041); the trend did not reach statistical significance for metabolic syndrome ( = 0.054). At the femoral neck, both were associated with unfavorable z-score evolution ( = 0.003 and 0.025, respectively). Patients treated at a younger age and those with metabolic syndrome seem to be at higher risk of bone mineral density decline and should benefit from specific interventions.
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http://dx.doi.org/10.1097/HS9.0000000000000518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806242PMC
February 2021

Lymphoblastic predominance of blastic phase in children with chronic myeloid leukaemia treated with imatinib: A report from the I-CML-Ped Study.

Eur J Cancer 2020 09 13;137:224-234. Epub 2020 Aug 13.

Inserm CIC 1402, University Hospital, Poitiers, France.

Background: Chronic myeloid leukaemia (CML) is a rare disease in children. The frequency and outcome of children evolving to accelerated phase (AP) or blastic phase (BP) under treatment with imatinib is unknown. The aim of the current study is to assess the incidence of progression from CML in chronic phase with imatinib frontline in a paediatric setting and describe the management and outcome of these patients.

Patients And Methods: In the I-CML-Ped Study database (www.clinicaltrials.gov, #NCT01281735), 19 of 339 paediatric patients in chronic phase treated with imatinib in the frontline evolved to CML-AP or CML-BP.

Results: With a median follow-up of 38 months (range: 2-190 months), the cumulative incidence of progression at 1 and 3 years was 3% (confidence interval [CI] 95%: 1-5%) and 7% (CI 95%: 4-11%), respectively. We observed a large predominance of lymphoid-BP (70%) over myeloid-BP (30%) with imatinib in frontline therapy. Sixteen patients underwent haematopoietic stem cell transplantation, and eight were treated with a tyrosine kinase inhibitor after transplant. Only the transplanted patients are alive. The 5-year overall survival rate of children with CML-AP/BP is 44%, with no statistical difference between the lymphoid-BP and myeloid-BP outcome.

Conclusion: Children evolving to AP or BP under treatment with imatinib have a very poor prognosis with an overall survival under 50%, much worse than children with advanced phase at diagnosis.
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http://dx.doi.org/10.1016/j.ejca.2020.06.024DOI Listing
September 2020

Blueprint of human thymopoiesis reveals molecular mechanisms of stage-specific TCR enhancer activation.

J Exp Med 2020 09;217(9)

Université de Paris (Descartes), Institut Necker-Enfants Malades, Institut National de la Santé et de la Recherche Médicale U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris, France.

Cell differentiation is accompanied by epigenetic changes leading to precise lineage definition and cell identity. Here we present a comprehensive resource of epigenomic data of human T cell precursors along with an integrative analysis of other hematopoietic populations. Although T cell commitment is accompanied by large scale epigenetic changes, we observed that the majority of distal regulatory elements are constitutively unmethylated throughout T cell differentiation, irrespective of their activation status. Among these, the TCRA gene enhancer (Eα) is in an open and unmethylated chromatin structure well before activation. Integrative analyses revealed that the HOXA5-9 transcription factors repress the Eα enhancer at early stages of T cell differentiation, while their decommission is required for TCRA locus activation and enforced αβ T lineage differentiation. Remarkably, the HOXA-mediated repression of Eα is paralleled by the ectopic expression of homeodomain-related oncogenes in T cell acute lymphoblastic leukemia. These results highlight an analogous enhancer repression mechanism at play in normal and cancer conditions, but imposing distinct developmental constraints.
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http://dx.doi.org/10.1084/jem.20192360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478722PMC
September 2020

Exome sequencing for diagnosis of congenital hemolytic anemia.

Orphanet J Rare Dis 2020 07 8;15(1):180. Epub 2020 Jul 8.

Univ Paris Est Creteil, INSERM, IMRB, F-94010, Creteil, France.

Background: Congenital hemolytic anemia constitutes a heterogeneous group of rare genetic disorders of red blood cells. Diagnosis is based on clinical data, family history and phenotypic testing, genetic analyses being usually performed as a late step. In this study, we explored 40 patients with congenital hemolytic anemia by whole exome sequencing: 20 patients with hereditary spherocytosis and 20 patients with unexplained hemolysis.

Results: A probable genetic cause of disease was identified in 82.5% of the patients (33/40): 100% of those with suspected hereditary spherocytosis (20/20) and 65% of those with unexplained hemolysis (13/20). We found that several patients carried genetic variations in more than one gene (3/20 in the hereditary spherocytosis group, 6/13 fully elucidated patients in the unexplained hemolysis group), giving a more accurate picture of the genetic complexity of congenital hemolytic anemia. In addition, whole exome sequencing allowed us to identify genetic variants in non-congenital hemolytic anemia genes that explained part of the phenotype in 3 patients.

Conclusion: The rapid development of next generation sequencing has rendered the genetic study of these diseases much easier and cheaper. Whole exome sequencing in congenital hemolytic anemia could provide a more precise and quicker diagnosis, improve patients' healthcare and probably has to be democratized notably for complex cases.
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http://dx.doi.org/10.1186/s13023-020-01425-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341591PMC
July 2020

Caution encouraged in next-generation sequencing immunogenetic analyses in acute lymphoblastic leukemia.

Blood 2020 08;136(9):1105-1107

Onco-Hematology, Assistance Publique-Hôpitaux de Paris, Université de Paris and Institut Necker Enfants Malades, Paris, France.

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http://dx.doi.org/10.1182/blood.2020005613DOI Listing
August 2020

COVID-19 and acute lymphoblastic leukemias of children and adolescents: First recommendations of the Leukemia committee of the French Society for the fight against Cancers and Leukemias in children and adolescents (SFCE).

Bull Cancer 2020 Jun 30;107(6):629-632. Epub 2020 Apr 30.

Hôpital Universitaire Robert-Debré AP-HP, Université de Paris, service d'hémato-immunologie pédiatrique, Paris, France.

Since the emergence of the SARS-CoV-2 infection, many recommendations have been made. However, the very nature of acute lymphoblastic leukemias and their treatment in children and adolescents led the Leukemia Committee of the French Society for the fight against cancers and leukemias in children and adolescents (SFCE) to propose more specific recommendations, even if data for this population are still scarce. They may have to evolve according to the rapid evolution of knowledge on COVID-19.
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http://dx.doi.org/10.1016/j.bulcan.2020.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190519PMC
June 2020

CDK6 is an essential direct target of NUP98 fusion proteins in acute myeloid leukemia.

Blood 2020 07;136(4):387-400

Institute for Medical Biochemistry, University of Veterinary Medicine Vienna, Vienna, Austria.

Fusion proteins involving Nucleoporin 98 (NUP98) are recurrently found in acute myeloid leukemia (AML) and are associated with poor prognosis. Lack of mechanistic insight into NUP98-fusion-dependent oncogenic transformation has so far precluded the development of rational targeted therapies. We reasoned that different NUP98-fusion proteins deregulate a common set of transcriptional targets that might be exploitable for therapy. To decipher transcriptional programs controlled by diverse NUP98-fusion proteins, we developed mouse models for regulatable expression of NUP98/NSD1, NUP98/JARID1A, and NUP98/DDX10. By integrating chromatin occupancy profiles of NUP98-fusion proteins with transcriptome profiling upon acute fusion protein inactivation in vivo, we defined the core set of direct transcriptional targets of NUP98-fusion proteins. Among those, CDK6 was highly expressed in murine and human AML samples. Loss of CDK6 severely attenuated NUP98-fusion-driven leukemogenesis, and NUP98-fusion AML was sensitive to pharmacologic CDK6 inhibition in vitro and in vivo. These findings identify CDK6 as a conserved, critical direct target of NUP98-fusion proteins, proposing CDK4/CDK6 inhibitors as a new rational treatment option for AML patients with NUP98-fusions.
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http://dx.doi.org/10.1182/blood.2019003267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115844PMC
July 2020

Infant cancers in France: Incidence and survival (2000-2014).

Cancer Epidemiol 2020 04 7;65:101697. Epub 2020 Mar 7.

Centre de Recherche en Epidémiologie et en Statistique Sorbonne-Paris Cité (CRESS), UMR 1153, INSERM, Université Paris, 75014, Paris, France; Registre National des cancers de l'Enfant, Registre National des hémopathies malignes de l'Enfant, AP-HP, Hôpital Paul Brousse, GHU Paris-Sud, Villejuif, F-94000, France.

Background: On average 185 children are diagnosed each year in France with a cancer in their first year of life, representing 11 % of cancers diagnosed in children less than 15 years.

Methods: A retrospective population-based observational study was conducted between 2000 and 2014 of all infants with a diagnosis of cancer using the National Registry of Childhood Cancers Database.

Results: Out of 2760 cases of primary cancers in infancy, there were mainly neuroblastomas 30.1 %), central nervous system (CNS) tumors (16.1 %), leukemias (15.3 %), retinoblastomas (11.6 %), and Wilms tumors (6.9 %). Embryonal malignancies accounted for 55.2 % of cases. Most diagnoses showed a male excess, particularly for malignant gonadal germ-cell tumors (GCT) with a 17.5 sex-ratio. The annual incidence rate, 242.9 per million infants overall, was stable over the study period for all types of cancer. Most deaths occurred within the first month of life (70.8 % of deaths). The 5-year overall survival (5-y OS) was 81.0 % (95 %CI, 79.4-82.4) with large contrasts between diagnoses. The best 5-y OS (>85 %) were observed for retinoblastomas, carcinomas, nephroblastomas, GCT, neuroblastomas, and hepatoblastomas. Conversely, the lowest 5-y OS (<65 %) were observed for acute myeloid leukemias, CNS tumors, and lymphoid leukemias. We observed no substantial change over time (80.5 % [95 %CI, 77.7-82.9] in 2000-2004 and 82.6 % [95 %CI, 80.0-84.9] in 2010-2014) for all cancers combined. The same result has been found whatever the diagnostic group.

Conclusion: Our results contribute to better understand these tumors by quantifying their impact on the French population and assessing the burden of some devastating infant cancers.
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http://dx.doi.org/10.1016/j.canep.2020.101697DOI Listing
April 2020

Safety and Efficacy of Fidaxomicin and Vancomycin in Children and Adolescents with Clostridioides (Clostridium) difficile Infection: A Phase 3, Multicenter, Randomized, Single-blind Clinical Trial (SUNSHINE).

Clin Infect Dis 2020 12;71(10):2581-2588

Astellas Pharma B.V., Leiden, the Netherlands.

Background: Fidaxomicin, a narrow-spectrum antibiotic approved for Clostridioides (Clostridium) difficile infection (CDI) in adults, is associated with lower rates of recurrence than vancomycin; however, pediatric data are limited. This multicenter, investigator-blind, phase 3, parallel-group trial assessed the safety and efficacy of fidaxomicin in children.

Methods: Patients aged <18 years with confirmed CDI were randomized 2:1 to 10 days of treatment with fidaxomicin (suspension or tablets, twice daily) or vancomycin (suspension or tablets, 4 times daily). Safety assessments included treatment-emergent adverse events. The primary efficacy end point was confirmed clinical response (CCR), 2 days after the end of treatment (EOT). Secondary end points included global cure (GC; CCR without CDI recurrence) 30 days after EOT (end of study; EOS). Plasma and stool concentrations of fidaxomicin and its active metabolite OP-1118 were measured.

Results: Of 148 patients randomized, 142 were treated (30 <2 years old). The proportion of participants with treatment-emergent adverse events was similar with fidaxomicin (73.5%) and vancomycin (75.0%). Of 3 deaths in the fidaxomicin arm during the study, none were CDI or treatment related. The rate of CCR at 2 days after EOT was 77.6% (76 of 98 patients) with fidaxomicin and 70.5% (31 of 44) with vancomycin, whereas the rate of GC at EOS was significantly higher in participants receiving fidaxomicin (68.4% vs 50.0%; adjusted treatment difference, 18.8%; 95% confidence interval, 1.5%-35.3%). Systemic absorption of fidaxomicin and OP-1118 was minimal, and stool concentrations were high.

Conclusions: Compared with vancomycin, fidaxomicin was well tolerated and demonstrated significantly higher rates of GC in children and adolescents with CDI.

Clinical Trials Registration: NCT02218372.
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http://dx.doi.org/10.1093/cid/ciz1149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744996PMC
December 2020

Maintenance Therapy With Interleukin-2 for Childhood AML: Results of ELAM02 Phase III Randomized Trial.

Hemasphere 2018 Dec 29;2(6):e159. Epub 2018 Nov 29.

Department of Pediatric Hematology and Oncology, Assistance Publique-Hôpitaux de Paris, GH HUEP, Armand Trousseau Hospital, Paris, France; Sorbonne Université, UMRS_938, Paris, France.

Despite significant progress in the treatment of pediatric acute myeloblastic leukemia (AML), relapse remains the commonest cause of death. Randomized ELAM02 trial questioned if maintenance therapy with interleukin-2 (IL2), for 1 year, improves disease-free survival (DFS). Patients aged 0 to 18 years, with newly diagnosed AML (excluding patients with acute promyelocytic leukemia or down syndrome AML) were enrolled. They received 1 course of induction treatment (cytarabine and mitoxantrone) and 3 courses of consolidation treatment (high-dose cytarabine in courses 1 and 3). According to the cytogenetics risk, patients not undergoing hematopoietic stem cell transplantation, still in complete remission (CR) after the third course of consolidation treatment, were eligible for randomization to 1 year of maintenance therapy with monthly courses of IL2 or no maintenance treatment. There were 438 evaluable patients, 154 of whom were randomized to the IL2/no maintenance groups. Relapse occurred in 28 patients from the IL2+ group and 29 patients in the IL2- group. Survival was similar in the 2 groups, with a 4-year DFS of 62% without IL2 and 66% with IL2 ( = 0.75). In the CBF population, 4-year DFS was 55% without IL2 and 78% with IL2 ( = 0.07). No deaths from toxicity or excess of serious adverse events related to IL2 treatment were recorded. Prolonged IL2 for maintenance therapy after intensive chemotherapy is feasible and safe in pediatric AML patients in their first CR. Such treatment did not improve DFS in this study, but a positive trend was observed in favor of IL2 maintenance therapy among core binding factor acute myeloblastic leukemia.
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http://dx.doi.org/10.1097/HS9.0000000000000159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745961PMC
December 2018

Ontogenic Changes in Hematopoietic Hierarchy Determine Pediatric Specificity and Disease Phenotype in Fusion Oncogene-Driven Myeloid Leukemia.

Cancer Discov 2019 12 29;9(12):1736-1753. Epub 2019 Oct 29.

INSERM U1170, Gustave Roussy, Villejuif, France.

Fusion oncogenes are prevalent in several pediatric cancers, yet little is known about the specific associations between age and phenotype. We observed that fusion oncogenes, such as , are associated with acute megakaryoblastic or other myeloid leukemia subtypes in an age-dependent manner. Analysis of a novel inducible transgenic mouse model showed that expression in fetal hematopoietic stem cells induced rapid megakaryoblastic leukemia whereas expression in adult bone marrow hematopoietic stem cells resulted in a shift toward myeloid transformation with a strikingly delayed leukemogenic potential. Chromatin accessibility and single-cell transcriptome analyses indicate ontogeny-dependent intrinsic and -induced differences in the activities of key transcription factors, including ERG, SPI1, GATA1, and CEBPA. Importantly, switching off the fusion oncogene restored terminal differentiation of the leukemic blasts. Together, these data show that aggressiveness and phenotypes in pediatric acute myeloid leukemia result from an ontogeny-related differential susceptibility to transformation by fusion oncogenes. SIGNIFICANCE: This work demonstrates that the clinical phenotype of pediatric acute myeloid leukemia is determined by ontogeny-dependent susceptibility for transformation by oncogenic fusion genes. The phenotype is maintained by potentially reversible alteration of key transcription factors, indicating that targeting of the fusions may overcome the differentiation blockage and revert the leukemic state...
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http://dx.doi.org/10.1158/2159-8290.CD-18-1463DOI Listing
December 2019

Clinical and biological features of PTPN2-deleted adult and pediatric T-cell acute lymphoblastic leukemia.

Blood Adv 2019 07;3(13):1981-1988

Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades, Institut National de Recherche Médicale U1151, Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris, France.

Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) is a phosphatase known to be a tumor suppressor gene in T-cell acute lymphoblastic leukemia (T-ALL). Because the full clinicobiologic characteristics of PTPN2 loss remain poorly reported, we aimed to provide a comprehensive analysis of PTPN2 deletions within a cohort of 430 patients, including 216 adults and 214 children treated according to the GRAALL03/05 (#NCT00222027 and #NCT00327678) and the FRALLE2000 protocols, respectively. We used multiplex ligation-dependent probe amplification to identify an 8% incidence of PTPN2 deletion, which was comparable in adult (9%) and pediatric (6%) populations. PTPN2 deletions were significantly associated with an αβ lineage and TLX1 deregulation. Analysis of the mutational genotype of adult T-ALL revealed a positive correlation between PTPN2 deletions and gain-of-function alterations in the IL7R/JAK-STAT signaling pathway as well as PHF6 and WT1 mutations. Of note, PTPN2 and PTEN (phosphatase and tensin homolog) deletions were mutually exclusive. Regarding treatment response, PTPN2-deleted T-ALLs were associated with a higher glucocorticoid response and a trend for improved survival in children, but not in adults, with a 5-year cumulative incidence of relapse of 8% for PTPN2-deleted pediatric cases vs 26% ( = .177).
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http://dx.doi.org/10.1182/bloodadvances.2018028993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616254PMC
July 2019

[Pediatric lumbar puncture: indications, execution and complications].

Rev Prat 2018 Apr;68(4):426-430

Service d'hématologieoncologie pédiatrique, hôpital Armand- Trousseau, AP-HP, Paris, France. Université Pierre-et-Marie- Curie, Sorbonne Universités, Paris, France.

Pediatric lumbar puncture : indications, execution and complications. Lumbar puncture (LP) is a commonly performed procedure with specific indications and technical considerations in pediatrics. The principal indication is for the diagnosis of central nervous system infection, but in case of meningitis in infants, nuchal rigidity may be absent and the clinical picture is more likely to be marked by axial hypotonia associated with abnormal behavior and/or a bulging fontanel. Pharmacological agents and non-pharmacological techniques (reassuring approach, distraction, presence of a parent) should be used whenever possible, to create successful environmental conditions for the completion of the LP procedure in childhood. During the procedure, the LP needle should be moved forward slightly and perpendicularly to the patient's back, and the stylet should be removed regularly to check CSF reflux, as resistance related to the spinal ligaments and dura mere are often absent in young children. In children, post-LP headaches may be prevented by the use of atraumatic and/or the smallest LP needle, and the replacement of the stylet prior to needle removal.
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April 2018

Parental smoking, maternal alcohol consumption during pregnancy and the risk of neuroblastoma in children. A pooled analysis of the ESCALE and ESTELLE French studies.

Int J Cancer 2019 12 21;145(11):2907-2916. Epub 2019 Feb 21.

CRESS, UMRS1153, INSERM, Université Paris-Descartes, Paris, France.

Neuroblastoma (NB) is the most common extra-cranial tumour in children. Little is known about the aetiology of NB. The early age at onset and the embryonic nature suggest a role for perinatal exposures. We conducted a pooled analysis of two French national population-based case-control studies to explore whether there was an association between parental smoking and alcohol consumption and the risk of NB. The mothers of 357 NB cases and 1,783 controls from general population, frequency matched by age and sex, were interviewed on demographic, socioeconomic and perinatal characteristics, maternal reproductive story, and life-style and childhood environment. Unconditional logistic regression was used to estimate pooled odds ratios and 95% confidence intervals. A meta-analysis of our findings with those of previous studies was also conducted. Maternal smoking during pregnancy was slightly more often reported for the cases (24.1%) than for the controls (19.7%) (OR 1.3 [95% CI 0.9-1.7]; summary OR from meta-analysis 1.1 [95% CI 1.0-1.3]. Paternal smoking in the year before child's birth were not associated with NB as independent exposure (OR 1.1 [95% CI 0.9-1.4] but the association was stronger when both parents reported having smoked during pregnancy (OR 1.5 [95% CI 1.1-2.1]. No association was observed with maternal alcohol intake during pregnancy (OR 1.0 [95% CI 0.8-1.4], summary OR from meta-analysis 1.0 [95% CI 0.9-1.2]. Our findings provide some evidence of an association between maternal smoking during pregnancy and NB and add another reason to recommend that women refrain from smoking during pregnancy.
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http://dx.doi.org/10.1002/ijc.32161DOI Listing
December 2019

The stem cell-associated gene expression signature allows risk stratification in pediatric acute myeloid leukemia.

Leukemia 2019 02 8;33(2):348-357. Epub 2018 Aug 8.

UMR-S 1172, JPArc - Jean-Pierre AUBERT Research Center Neurosciences et Cancer, Univ. Lille, Inserm, CHU Lille, Lille, France.

Despite constant progress in prognostic risk stratification, children with acute myeloid leukemia (AML) still relapse. Treatment failure and subsequent relapse have been attributed to acute myeloid leukemia-initiating cells (LSC), which harbor stem cell properties and are inherently chemoresistant. Although pediatric and adult AML represent two genetically very distinct diseases, we reasoned that common LSC gene expression programs are shared and consequently, the highly prognostic LSC17 signature score recently developed in adults may also be of clinical interest in childhood AML. Here, we demonstrated prognostic relevance of the LSC17 score in pediatric non-core-binding factor AML using Nanostring technology (ELAM02) and RNA-seq data from the NCI (TARGET-AML). AML were stratified by LSC17 quartile groups (lowest 25%, intermediate 50% and highest 25%) and children with low LSC17 score had significantly better event-free survival (EFS: HR = 3.35 (95%CI = 1.64-6.82), P < 0.001) and overall survival (OS: HR = 3.51 (95%CI = 1.38-8.92), P = 0.008) compared with patients with high LSC17 scores. More importantly, the high LSC17 score was an independent negative EFS and OS prognosticator determined by multivariate Cox model analysis (EFS: HR = 3.42 (95% CI = 1.63-7.16), P = 0.001; OS HR = 3.02 (95%CI = 1.16-7.85), P = 0.026). In conclusion, we have demonstrated the broad applicability of the LSC17 score in the clinical management of AML by extending its prognostic relevance to pediatric AML.
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http://dx.doi.org/10.1038/s41375-018-0227-5DOI Listing
February 2019

The M-Y Axilloplasty After Massive Weight Loss: Analysis of 159 Consecutive Patients.

Aesthetic Plast Surg 2018 Aug 10;42(4):1059-1064. Epub 2018 May 10.

Plastic, Reconstructive and Cosmetic and Burn Surgery Unit, Hôpital Saint Louis, 1 avenue Vellefaux, 75010, Paris, France.

Background: Brachioplasties often culminate in unsightly scars that are a source of disappointment to patients. We aimed to evaluate the results of M-Y axilloplasty following massive weight loss.

Patients: We performed a retrospective assessment of our technique for brachioplasty with an M-Y axilloplasty in 159 female patients after massive weight loss. This retrospective study covered a study period of 10 years.

Method: After substantial lipoaspiration, the incision is placed on the internal side of the arm, with an M-shaped axilloplasty.

Results: The satisfaction rate was 154/159 (97%) and 120/159 (75.5%) being happy with their esthetic results. Nineteen percent (30/159) of the patients had complications and 12/159 (7.5%) underwent a surgical revision.

Conclusion: M-Y axilloplasty for brachioplasty is an effective procedure for treating women who are unhappy with their upper arms after massive weight loss. The satisfaction rate is high, and the result leaves no excess skin on the chest.

Level Of Evidence Iv: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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http://dx.doi.org/10.1007/s00266-018-1133-yDOI Listing
August 2018

Clonal interference of signaling mutations worsens prognosis in core-binding factor acute myeloid leukemia.

Blood 2018 07 24;132(2):187-196. Epub 2018 Apr 24.

INSERM Lille, University of Lille, Lille, France.

Mutations in receptor tyrosine kinase/RAS signaling pathway genes are frequent in core-binding factor (CBF) acute myeloid leukemias (AMLs), but their prognostic relevance is debated. A subset of CBF AML patients harbors several signaling gene mutations. Genotyping of colonies and of relapse samples indicates that these arise in independent clones, thus defining a process of clonal interference (or parallel evolution). Clonal interference is pervasive in cancers, but the mechanisms underlying this process remain unclear, and its prognostic impact remains unknown. We analyzed a cohort of 445 adult and pediatric patients with CBF AML treated with intensive chemotherapy and with deep sequencing of 6 signaling genes (, , , , , ). A total of 152 (34%), 167 (38%), and 126 (28%) patients harbored no, a single, and multiple signaling clones (clonal interference), respectively. Clonal interference of signaling mutations was associated with older age ( = .004) and inv(16) subtype ( = .025) but not with white blood cell count or mutations in chromatin or cohesin genes. The median allele frequency of signaling mutations was 31% in patients with a single clone or clonal interference ( = .14). The repertoire of , , and / variants differed between groups. Clonal interference did not affect complete remission rate or minimal residual disease after 1-2 courses, but it did convey inferior event-free survival ( < 10), whereas the presence of a single signaling clone did not ( = .44). This inferior outcome was independent of clinical parameters and of the presence of specific signaling clones. Our results suggest that specific clonal architectures can herald distinct prognoses in AML.
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http://dx.doi.org/10.1182/blood-2018-03-837781DOI Listing
July 2018
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