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1.
Haematologica ; 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31048357

RESUMO

The functional diversity of cells that compose myeloid malignancies, i.e. the respective role of genetic and epigenetic heterogeneity in this diversity, remains poorly understood. This question is addressed in chronic myelomonocytic leukemia, a myeloid neoplasm in which clinical diversity contrasts with limited genetic heterogeneity. To generate induced pluripotent stem cell clones, we reprogrammed CD34-positive cells collected from a patient with a chronic myelomonocytic leukemia in which whole exome sequencing of peripheral blood monocyte DNA had identified 12 gene mutations, including a mutation in KDM6A and 2 heterozygous mutations in TET2 in the founding clone and a secondary KRASG12D mutation. CD34-positive cells from an age-matched healthy donor were also reprogrammed. We captured a part of the genetic heterogeneity observed in the patient, i.e. we analyzed five clones with two genetic backgrounds, without and with KRASG12D mutation. Hematopoietic differentiation of these clones recapitulated the main features of the patient disease, including overproduction of granulomonocytes and dysmegakaryopoiesis. These analyses also disclosed significant discrepancies in the behavior of hematopoietic cells derived from induced pluripotent stem cell clones with similar genetic background, correlating with limited epigenetic changes. These analyses suggest that, beyond the coding mutations, several levels of intraclonal heterogeneity may participate to the yet unexplained clinical heterogeneity of the disease.

3.
BMJ Open ; 9(3): e025649, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30898821

RESUMO

INTRODUCTION: Recurrent miscarriage (RM), defined by three or more consecutive losses during the first trimester of pregnancy, affects 1%-2% of fertile couples. Standard investigations fail to reveal any apparent cause in ~50% of couples. However, on the basis of animal models and clinical studies, several hypotheses have been put forward concerning underlying mechanisms of RM: altered ovarian reserve, progesterone defect, thrombotic and/or endothelial dysfunction and immunological disturbances. Nonetheless, no study has yet reached conclusive beneficial clinical evidence for a potential treatment in unexplained RM. Hydroxychloroquine (HCQ) is a molecule with extensive safety data during pregnancy. The pharmacological properties of HCQ (eg, antithrombotic, vascular protective, immunomodulatory, improved glucose tolerance, lipidlowering and anti-infectious) could be effective against some mechanisms of unexplained RM. Furthermore, eventhough clinical benefit of HCQ is suggested in prevention of thrombotic and late obstetric events in antiphospholipid (APL) syndrome, there are no data suggesting the benefit of HCQ in RM in the presence of APL antibodies. METHODS AND ANALYSIS: Taken all together and given the low cost of HCQ, the aim of this multicentre, randomised, placebo-controlled, double-blind study is to investigate whether HCQ would improve the live birth rate in women with RM, irrespective of maternal thrombophilic status: (1) no known thrombophilia, (2) inherited thrombophilia or (3) APL antibodies. The primary end point is a live and viable birth. After confirming eligibility and obtaining consent, 300 non-pregnant women will be randomised into two parallel groups for a daily oral treatment (HCQ 400 mg or placebo), initiated before conception and stopped at 10 weeks' gestation. If pregnancy does not occur after 1 year, the treatment will be stopped. ETHICS AND DISSEMINATION: Agreement from the French National Public Health and Drug Security Agency (160765A-22) and ethical approval from the Committee for the Protection of Persons of NORD-OUEST I (2016-001330-97) have been obtained. TRIAL REGISTRATION NUMBERS: NCT0316513; Pre-results.

4.
Leukemia ; 33(10): 2466-2480, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30894665

RESUMO

Islands of CD123high cells have been commonly described in the bone marrow of patients with chronic myelomonocytic leukemia (CMML). Using a multiparameter flow cytometry assay, we detected an excess of CD123+ mononucleated cells that are lineage-negative, CD45+, CD11c-, CD33-, HLA-DR+, BDCA-2+, BDCA-4+ in the bone marrow of 32/159 (20%) patients. Conventional and electron microscopy, flow cytometry detection of cell surface markers, gene expression analyses, and the ability to synthesize interferon alpha in response to Toll-like receptor agonists identified these cells as bona fide plasmacytoid dendritic cells (pDCs). Whole-exome sequencing of sorted monocytes and pDCs identified somatic mutations in genes of the oncogenic RAS pathway in the two cell types of every patient. CD34+ cells could generate high amount of pDCs in the absence of FMS-like tyrosine kinase 3-ligand (FLT3L). Finally, an excess of pDCs correlates with regulatory T cell accumulation and an increased risk of acute leukemia transformation. These results demonstrate the FLT3L-independent accumulation of clonal pDCs in the bone marrow of CMML patients with mutations affecting the RAS pathway, which is associated with a higher risk of disease progression.

5.
Nat Med ; 24(8): 1167-1177, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30013198

RESUMO

Mutations in the gene encoding isocitrate dehydrogenase 2 (IDH2) occur in several types of cancer, including acute myeloid leukemia (AML). In model systems, mutant IDH2 causes hematopoietic differentiation arrest. Enasidenib, a selective small-molecule inhibitor of mutant IDH2, produces a clinical response in 40% of treated patients with relapsed/refractory AML by promoting leukemic cell differentiation. Here, we studied the clonal basis of response and acquired resistance to enasidenib treatment. Using sequential patient samples, we determined the clonal structure of hematopoietic cell populations at different stages of differentiation. Before therapy, IDH2-mutant clones showed variable differentiation arrest. Enasidenib treatment promoted hematopoietic differentiation from either terminal or ancestral mutant clones; less frequently, treatment promoted differentiation of nonmutant cells. Analysis of paired diagnosis/relapse samples did not identify second-site mutations in IDH2 at relapse. Instead, relapse arose by clonal evolution or selection of terminal or ancestral clones, thus highlighting multiple bypass pathways that could potentially be targeted to restore differentiation arrest. These results show how mapping of clonal structure in cell populations at different stages of differentiation can reveal the response and evolution of clones during treatment response and relapse.

6.
Blood ; 132(12): 1318-1331, 2018 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-29914977

RESUMO

Congenital neutropenias (CNs) are rare heterogeneous genetic disorders, with about 25% of patients without known genetic defects. Using whole-exome sequencing, we identified a heterozygous mutation in the SRP54 gene, encoding the signal recognition particle (SRP) 54 GTPase protein, in 3 sporadic cases and 1 autosomal dominant family. We subsequently sequenced the SRP54 gene in 66 probands from the French CN registry. In total, we identified 23 mutated cases (16 sporadic, 7 familial) with 7 distinct germ line SRP54 mutations including a recurrent in-frame deletion (Thr117del) in 14 cases. In nearly all patients, neutropenia was chronic and profound with promyelocytic maturation arrest, occurring within the first months of life, and required long-term granulocyte colony-stimulating factor therapy with a poor response. Neutropenia was sometimes associated with a severe neurodevelopmental delay (n = 5) and/or an exocrine pancreatic insufficiency requiring enzyme supplementation (n = 3). The SRP54 protein is a key component of the ribonucleoprotein complex that mediates the co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). We showed that SRP54 was specifically upregulated during the in vitro granulocytic differentiation, and that SRP54 mutations or knockdown led to a drastically reduced proliferation of granulocytic cells associated with an enhanced P53-dependent apoptosis. Bone marrow examination of SRP54-mutated patients revealed a major dysgranulopoiesis and features of cellular ER stress and autophagy that were confirmed using SRP54-mutated primary cells and SRP54 knockdown cells. In conclusion, we characterized a pathological pathway, which represents the second most common cause of CN with maturation arrest in the French CN registry.

7.
ACS Med Chem Lett ; 9(4): 300-305, 2018 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-29670690

RESUMO

Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alterations and impaired cellular differentiation. IDH1 mutations have been described in an array of hematologic malignancies and solid tumors. Here, we report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1 mutant enzyme that exhibits profound 2-HG lowering in tumor models and the ability to effect differentiation of primary patient AML samples ex vivo. Preliminary data from phase 1 clinical trials enrolling patients with cancers harboring an IDH1 mutation indicate that AG-120 has an acceptable safety profile and clinical activity.

8.
Blood Adv ; 2(6): 703-714, 2018 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-29581109

RESUMO

The TET2 gene encodes an α-ketoglutarate-dependent dioxygenase able to oxidize 5-methylcytosine into 5-hydroxymethylcytosine, which is a step toward active DNA demethylation. TET2 is frequently mutated in myeloid malignancies but also in B- and T-cell malignancies. TET2 somatic mutations are also identified in healthy elderly individuals with clonal hematopoiesis. Tet2-deficient mouse models showed widespread hematological differentiation abnormalities, including myeloid, T-cell, and B-cell malignancies. We show here that, similar to what is observed with constitutive Tet2-deficient mice, B-cell-specific Tet2 knockout leads to abnormalities in the B1-cell subset and a development of B-cell malignancies after long latency. Aging Tet2-deficient mice accumulate clonal CD19+ B220low immunoglobulin M+ B-cell populations with transplantable ability showing similarities to human chronic lymphocytic leukemia, including CD5 expression and sensitivity to ibrutinib-mediated B-cell receptor (BCR) signaling inhibition. Exome sequencing of Tet2-/- malignant B cells reveals C-to-T and G-to-A mutations that lie within single-stranded DNA-specific activation-induced deaminase (AID)/APOBEC (apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide-like) cytidine deaminases targeted motif, as confirmed by the lack of a B-cell tumor in compound Tet2-Aicda-deficient mice. Finally, we show that Tet2 deficiency accelerates and exacerbates T-cell leukemia/lymphoma 1A-induced leukemogenesis. Together, our data establish that Tet2 deficiency predisposes to mature B-cell malignancies, which development might be attributed in part to AID-mediated accumulating mutations and BCR-mediated signaling.

11.
Leuk Lymphoma ; 58(12): 2875-2879, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28593791

RESUMO

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic disorder that associates dysplastic and proliferative features. Tissue inflammatory disorders occur in a fraction of CMML patients during the course of their disease. Here, we describe the occurrence of eosinophil-rich tissue inflammation, including eosinophilic pneumonia, chondritis, and cystitis, in CMML patients. Whole exome sequencing of leukemic cells did not identify a recurrent genetic abnormality among these three patients who were clinically improved by local or oral corticosteroids. Hypomethylating drugs were subsequently added in two of them, allowing decreasing corticosteroid doses and further treating their hematopoietic malignancy.


Assuntos
Eosinófilos/patologia , Leucemia Mielomonocítica Crônica/patologia , Infiltração Leucêmica , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Biomarcadores , Medula Óssea/patologia , Análise Citogenética , Eosinófilos/metabolismo , Evolução Fatal , Feminino , Humanos , Imunofenotipagem , Leucemia Mielomonocítica Crônica/diagnóstico , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Leucemia Mielomonocítica Crônica/genética , Contagem de Leucócitos , Masculino , Mutação , Resultado do Tratamento , Sequenciamento Completo do Exoma
12.
Cancer Discov ; 7(5): 478-493, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28193778

RESUMO

Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation. In vitro studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach. We report the discovery and characterization of AG-221, an orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed 2HG production and induced cellular differentiation in primary human IDH2 mutation-positive acute myeloid leukemia (AML) cells ex vivo and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2R140Q-mutant AML xenograft mouse model. These findings supported initiation of the ongoing clinical trials of AG-221 in patients with IDH2 mutation-positive advanced hematologic malignancies.Significance: Mutations in IDH1/2 are identified in approximately 20% of patients with AML and contribute to leukemia via a block in hematopoietic cell differentiation. We have shown that the targeted inhibitor AG-221 suppresses the mutant IDH2 enzyme in multiple preclinical models and induces differentiation of malignant blasts, supporting its clinical development. Cancer Discov; 7(5); 478-93. ©2017 AACR.See related commentary by Thomas and Majeti, p. 459See related article by Shih et al., p. 494This article is highlighted in the In This Issue feature, p. 443.


Assuntos
Aminopiridinas/farmacologia , Antineoplásicos/farmacologia , Isocitrato Desidrogenase/antagonistas & inibidores , Leucemia Mieloide Aguda/genética , Triazinas/farmacologia , Animais , Linhagem Celular Tumoral , Humanos , Isocitrato Desidrogenase/genética , Camundongos , Mutação , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Eur J Obstet Gynecol Reprod Biol ; 203: 156-61, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27318182

RESUMO

Shoulder dystocia (SD) is defined as a vaginal delivery in cephalic presentation that requires additional obstetric maneuvers to deliver the fetus after the head has delivered and gentle traction has failed. It complicates 0.5-1% of vaginal deliveries. Risks of brachial plexus birth injury (level of evidence [LE]3), clavicle and humeral fracture (LE3), perinatal asphyxia (LE2), hypoxic-ischemic encephalopathy (LE3) and perinatal mortality (LE2) increase with SD. Its main risk factors are previous SD and macrosomia, but both are poorly predictive; 50-70% of SD cases occur in their absence, and most deliveries when they are present do not result in SD. No study has proven that the correction of these risk factors (except gestational diabetes) would reduce the risk of SD. Physical activity is recommended before and during pregnancy to reduce the occurrence of some risk factors for SD (Grade C). In obese women, physical activity should be coupled with dietary measures to reduce fetal macrosomia and weight gain during pregnancy (Grade A). Women with gestational diabetes require diabetes care (diabetic diet, glucose monitoring, insulin if needed) (Grade A) because it reduces the risk of macrosomia and SD (LE1). Only two measures are proposed for avoiding SD and its complications. First, induction of labor is recommended in cases of impending macrosomia if the cervix is favorable at a gestational age of 39 weeks or more (professional consensus). Second, cesarean delivery is recommended before labor in three situations and during labor in one: (i) estimated fetal weight (EFW) >4500g if associated with maternal diabetes (Grade C), (ii) EFW >5000g in women without diabetes (Grade C), (iii) history of SD associated with severe neonatal or maternal complications (professional consensus), and finally during labor, (iv) in case of fetal macrosomia and failure to progress in the second stage, when the fetal head station is above +2 (Grade C). In cases of SD, it is recommended to avoid the following actions: excessive traction on the fetal head (Grade C), fundal pressure (Grade C), and inverse rotation of the fetal head (professional consensus). The McRoberts maneuver, with or without suprapubic pressure, is recommended first (Grade C). If it fails and the posterior shoulder is engaged, Wood's maneuver should be performed preferentially; if the posterior shoulder is not engaged, it is preferable to attempt to deliver the posterior arm next (professional consensus). It appears necessary to know at least two maneuvers to perform should the McRoberts maneuver fail (professional consensus). A pediatrician should be immediately informed of SD. The initial clinical examination should check for complications, such as brachial plexus injury or clavicle fracture (professional consensus). If no complications are observed, neonatal monitoring need not be modified (professional consensus). The implementation of practical training with simulation for all care providers in the delivery room is associated with a significant reduction in neonatal (LE3) but not maternal (LE3) injury. SD remains an unpredictable obstetric emergency. All physicians and midwives should know and perform obstetric maneuvers if needed, quickly but calmly.


Assuntos
Traumatismos do Nascimento/prevenção & controle , Maturidade Cervical , Cesárea , Distocia/prevenção & controle , Medicina Baseada em Evidências , Trabalho de Parto Induzido , Traumatismos do Nascimento/epidemiologia , Traumatismos do Nascimento/etiologia , Maturidade Cervical/efeitos dos fármacos , Distocia/epidemiologia , Distocia/etiologia , Distocia/terapia , Exercício , Feminino , Macrossomia Fetal/fisiopatologia , França/epidemiologia , Humanos , Manipulações Musculoesqueléticas/efeitos adversos , Manipulações Musculoesqueléticas/educação , Manipulações Musculoesqueléticas/métodos , Obstetrícia/educação , Obstetrícia/métodos , Obstetrícia/tendências , Gravidez , Cuidado Pré-Natal , Recidiva , Fatores de Risco , Ombro , Treinamento por Simulação , Sociedades Médicas , Recursos Humanos
14.
Artigo em Inglês | MEDLINE | ID: mdl-27131892

RESUMO

A recent update of the hallmarks of cancer includes metabolism with deregulating cellular energetics. Activating mutations in isocitrate dehydrogenase (IDH) metabolic enzymes leading to the abnormal accumulation of 2-hydroxyglutaric acid (2-HGA) have been described in hematologic malignancies and solid tumours. The diagnostic value of 2-HGA levels in blood to identify IDH mutations and its prognostic significance have been reported. We developed a liquid chromatography tandem mass spectrometry method allowing a rapid, accurate and precise simultaneous quantification of both L and D enantiomers of 2-HGA in blood samples from acute myeloid leukaemia (AML) patients, suitable for clinical applications. The method was also develop for preclinical applications from cellular and tissues samples. Deuterated (R,S)-2-hydroxyglutaric acid, disodium salt was used as internal standard and added to samples before a solid phase extraction on Phenomenex STRATA™-XL-A (200mg-3mL) 33µm cartridges. A derivatization step with (+)- o,o'-diacetyl-l-tartaric anhydride permitted to separate the two resulting diastereoisomers without chiral stationary phase, on a C18 column combined to a Xevo TQ-MS Waters mass spectrometer with an electrospray ionization (ESI) source. This method allows standard curves to be linear over the range 0.34-135.04µM with r(2) values>0.999 and low matrix effects (<11.7%). This method, which was validated according to current EMA guidelines, is accurate between-run (<3.1%) and within-run (<7.9%) and precise between-run (<5.3CV%) and within-run (<6.2CV%), and is suitable for clinical and preclinical applications.


Assuntos
Biomarcadores Tumorais/sangue , Cromatografia Líquida/métodos , Glutaratos/sangue , Isocitrato Desidrogenase/metabolismo , Espectrometria de Massas em Tandem/métodos , Biomarcadores Tumorais/química , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Glutaratos/química , Glutaratos/metabolismo , Humanos , Leucemia Mieloide Aguda/metabolismo , Modelos Lineares , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Estereoisomerismo
15.
Blood ; 125(23): 3618-26, 2015 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-25852055

RESUMO

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome/ myeloproliferative neoplasm whose diagnosis is currently based on the elevation of peripheral blood monocytes to >1 × 10(9)/L, measured for ≥3 months. Diagnosis can be ambiguous; for example, with prefibrotic myelofibrosis or reactive monocytosis. We set up a multiparameter flow cytometry assay to distinguish CD14(+)/CD16(-) classical from CD14(+)/CD16(+) intermediate and CD14(low)/CD16(+) nonclassical monocyte subsets in peripheral blood mononucleated cells and in total blood samples. Compared with healthy donors and patients with reactive monocytosis or another hematologic malignancy, CMML patients demonstrate a characteristic increase in the fraction of CD14(+)/CD16(-) cells (cutoff value, 94.0%). The associated specificity and sensitivity values were 95.1% and 90.6% in the learning cohort (175 samples) and 94.1% and 91.9% in the validation cohort (307 samples), respectively. The accumulation of classical monocytes, which demonstrate a distinct gene expression pattern, is independent of the mutational background. Importantly, this increase disappears in patients who respond to hypomethylating agents. We conclude that an increase in the fraction of classical monocytes to >94.0% of total monocytes is a highly sensitive and specific diagnostic marker that rapidly and accurately distinguishes CMML from confounding diagnoses.


Assuntos
Citometria de Fluxo/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Receptores de Lipopolissacarídeos/sangue , Monócitos , Receptores de IgG/sangue , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Monócitos/patologia , Sensibilidade e Especificidade
17.
Blood ; 125(14): 2200-5, 2015 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-25636341

RESUMO

It is common practice in many centers to offer antithrombotic medications to women with unexplained recurrent miscarriage, in the presence or absence of inherited thrombophilia. Although no benefit of aspirin vs placebo has been clearly demonstrated, a double-blind placebo-controlled trial on the effect of low-molecular-weight heparin is lacking. We enrolled 258 pregnant women with a history of unexplained recurrent miscarriage (≥2 consecutive miscarriages before 15 weeks' gestation) and a negative thrombophilia workup. They were randomly assigned to receive one daily subcutaneous injection of enoxaparin 40 mg or placebo until 35 weeks' gestation. We included 256 women (mean age 32 years, ≥3 miscarriages: 72%; mean gestational age 39 days of amenorrhea) in the intention-to-treat analysis; 66.6% of 138 who received enoxaparin had a live birth vs 72.9% of 118 who received placebo. The absolute difference was -6% (95% CI, -17.1 to 5.1), excluding a 10% increase in the rate of live-birth on enoxaparin (P = .34). In this first randomized, double-blind, placebo-controlled trial, enoxaparin (40 mg once daily) did not improve the chance of a live birth in nonthrombophilic women with unexplained recurrent miscarriage. This trial is registered at www.ClinicalTrials.gov as #NCT00740545 and the French National Health and Drug Safety Agency (EudraCT #2006-003350-18).


Assuntos
Aborto Habitual/prevenção & controle , Enoxaparina/uso terapêutico , Complicações na Gravidez/prevenção & controle , Adulto , Anticoagulantes , Método Duplo-Cego , Feminino , Seguimentos , Idade Gestacional , Heparina de Baixo Peso Molecular , Humanos , Nascimento Vivo , Gravidez , Prognóstico
18.
Br J Haematol ; 165(1): 117-125, 2014 04.
Artigo em Inglês | MEDLINE | ID: mdl-24666094

RESUMO

Haemophagocytic lymphohistiocytosis (HLH) has been rarely described in children treated for an anaplastic large-cell lymphoma (ALCL). We evaluated the incidence, the clinical and histological characteristics and the prognosis of HLH associated-ALCL. The medical, biological, cytological and histological data of patients treated for ALK-positive ALCL in the paediatric department of a single institution between 1975 and 2008 were analysed and assessed for HLH according to diagnosis criteria of the Histiocyte Society. Data concerning a series of 50 consecutive children with ALCL were reviewed. HLH-associated ALCL was observed in 12% of the patients. Lung involvement was significantly more frequent in HLH-associated ALCL patients than in the group without HLH (P = 0·004), as well as central nervous system (CNS) and bone marrow involvement (P = 0·001 and P = 0·007 respectively). The histological subtype in children with HLH-associated ALCL did not differ from that of the group without HLH. There was no significant difference between the two groups in 5-year EFS and OS (P = 0·91 and P > 0·99 respectively). In conclusion, HLH is not rare in paediatric ALCL. Despite a high incidence of visceral, CNS and bone marrow involvement, HLH does not seem to exert a significant impact on outcome in children treated for ALCL.

19.
J Clin Oncol ; 32(4): 297-305, 2014 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-24344214

RESUMO

PURPOSE: Mutated isocitrate dehydrogenases (IDHs) 1 and 2 produce high levels of 2-hydroxyglutarate (2-HG). We investigated whether, in acute myeloid leukemia (AML), serum 2-HG would predict the presence of IDH1/2 mutations at diagnosis and provide a marker of minimal residual disease (MRD). PATIENTS AND METHODS: Serum samples from 82 patients at diagnosis of de novo AML (IDH1/2 mutated, n = 53) and 68 patients without AML were analyzed for total 2-HG and its ratio of D to L stereoisomers by mass spectrometry. We measured 2-HG levels and molecular markers of MRD (WT1 and NPM1) in serial samples of 36 patients with IDH1/2 mutations after induction therapy. RESULTS: In patients with AML with IDH1/2 mutations, 2-HG serum levels were significantly higher than in patients with IDH1/2 wild type (P < .001). Area under the receiver operating characteristic curve was 99%. The optimum diagnostic cutoff between IDH1/2 mutated and normal was 2 µmol/L (sensitivity, 100%; specificity, 79%). Quantification of the D/L stereoisomers increased specificity (100%; 95% CI, 83% to 100%) compared with total 2-HG (P = .031). In patients with IDH2 R172 mutations, 2-HG levels were higher relative to those with other IDH1/2 mutations (P < .05). During follow-up, serum 2-HG levels showed strong positive correlation with WT1 and NPM1 (P < .001). After induction therapy, total 2-HG serum levels < 2 µmol/L were associated with better overall (P = .008) and disease-free survival (P = .005). CONCLUSION: Serum 2-HG is a predictor of the presence of IDH1/2 mutations and outcome in these patients. Discrimination between D/L stereoisomers improved specificity.


Assuntos
Biomarcadores Tumorais/sangue , Glutaratos/sangue , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/diagnóstico , Mutação , Adulto , Idoso , Área Sob a Curva , Feminino , França , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/genética , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Neoplasia Residual/sangue , Proteínas Nucleares/sangue , Valor Preditivo dos Testes , Prognóstico , Curva ROC , Sensibilidade e Especificidade , Estereoisomerismo , Proteínas WT1/sangue
20.
Head Neck Pathol ; 8(2): 234-8, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24101200

RESUMO

BACKGROUND: Myeloid sarcoma (MS) is a rare extra-medullary tumour of the myeloid lineage, which can be a difficult diagnosis to make. CASE PRESENTATION: We report the case of a 73-year-old male with a right-sided nasopharyngeal mass revealed on CT scan and MRI. RESULTS: An initial cytological and histological examination suggested a high-grade lymphoma. Nevertheless, the final diagnosis was a MS with an unusual involvement of the nasopharynx that was treated with a conventional induction leukemia therapy. Eight months later, the patient had persistent thrombocytopenia and a bone marrow aspiration showed the dysplasia of a high grade myelodysplastic syndrome and cytogenetics detected t(3;21). The patient was treated with a 5-Azacitidine (Vidaza) protocol until overt progression and disease evolution. CONCLUSION: In conclusion few cases of MS involving the nasopharynx have been reported. Its diagnosis is often difficult and should be considered especially when a high index of suspicion is present and the immunophenotype of the malignant haematological cells is not clearly in favour of a lymphoma.


Assuntos
Diagnóstico Diferencial , Linfoma/patologia , Neoplasias Nasofaríngeas/patologia , Sarcoma Mieloide/patologia , Idoso , Humanos , Imunofenotipagem , Leucemia Mieloide Aguda/patologia , Masculino , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/patologia , Segunda Neoplasia Primária/patologia
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