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1.  Population Pharmacokinetics and Dosing Optimization of Vancomycin in Children with Malignant Hematological Disease 
An increase in vancomycin dose has been proposed in adults with malignant hematological disease. As pediatric data are limited, our aim was to evaluate the population pharmacokinetics of vancomycin in order to define the appropriate dosing regimen in children with malignant hematological disease. Vancomycin concentrations were collected prospectively during therapeutic monitoring. Population pharmacokinetic analysis was performed using NONMEM software. Seventy children (age range, 0.3 to 17.7 years) were included. With the current recommended dosing regimen of 40 to 60 mg/kg/day, 53 children (76%) had subtherapeutic steady-state trough concentrations (Css/min of <10 mg/liter). A one-compartment model with first-order elimination was developed. Systematic covariate analysis identified that weight significantly influenced clearance (CL) and volume of distribution (V) with power functions of 0.677 for CL and 0.838 for V. Vancomycin CL also significantly increased with increases in creatinine clearance and seemed to be higher in children with malignant hematological disease than in the general pediatric population. The model was validated internally. Its predictive performance was further confirmed in an external validation by Bayesian estimation. A patient-tailored dosing regimen was developed based on the final pharmacokinetic model and showed that a higher proportion of patients reached the target Css/min than with the traditional mg/kg-basis dose (60% versus 49%) and that the risks associated with underdosing or overdosing were reduced. This is the first population pharmacokinetic study of vancomycin in children with malignant hematological disease. An optimized dosing regimen, taking into account patient weight, creatinine clearance, and susceptibility of the pathogens involved, could routinely be used to individualize vancomycin therapy in this vulnerable population.
PMCID: PMC4068451  PMID: 24663023
2.  Broad-Range PCR-Electrospray Ionization Mass Spectrometry for Detection and Typing of Adenovirus and Other Opportunistic Viruses in Stem Cell Transplant Patients 
Journal of Clinical Microbiology  2013;51(12):4186-4192.
Hematopoietic stem cell transplant patients are highly susceptible to viral infections. Follow-up after transplantation includes weekly screening using single, virus-specific real-time PCR tests, mainly for viruses in the families Herpesviridae and Adenoviridae that contribute to a high morbidity, especially in pediatric populations. The Abbott PLEX-ID platform combines broad-range PCR with electrospray ionization mass spectrometry to enable the simultaneous detection of multiple pathogens in a single assay. The Viral IC Spectrum assay detects human adenoviruses, viruses from the family Herpesviridae (herpes simplex virus 1 [HSV-1], HSV-2, cytomegalovirus [CMV], Epstein-Barr virus [EBV], varicella-zoster virus [VZV], and human herpesvirus 8 [HHV-8]), human enterovirus, polyomaviruses (BK and JC), and parvovirus B19. We evaluated the performance of the Viral IC Spectrum assay with samples from 16 adult and 36 pediatric stem cell transplant patients. The sensitivity of the Viral IC Spectrum assay compared to real-time PCR quantification using the adenovirus Rgene kit for the detection of adenovirus was 96.7% from plasma samples (n = 92) and 78% from stool samples (n = 100). No adenovirus was detected in samples from noninfected patients (n = 30). PLEX-ID species identification was perfectly concordant with species-specific real-time PCR assays. In plasma and stool samples, the level of amplified products measured by PLEX-ID and the quantity in copies/ml (r = 0.82 and 0.78, respectively) were correlated up to 6 log10 copies/ml. In 67.4% of adenovirus-positive plasma samples, at least one other viral infection was detected; these included BK virus (n = 41), CMV (n = 30), EBV (n = 26), JC virus (n = 9), and HSV-1 (n = 6). The results of this study suggest that the Viral IC Spectrum assay performed on the PLEX-ID platform is reliable for adenovirus infection diagnosis in immunocompromised patients.
PMCID: PMC3838038  PMID: 24108617
3.  Interleukin-18 produced by bone marrow-derived stromal cells supports T-cell acute leukaemia progression 
EMBO Molecular Medicine  2014;6(6):821-834.
Development of novel therapies is critical for T-cell acute leukaemia (T-ALL). Here, we investigated the effect of inhibiting the MAPK/MEK/ERK pathway on T-ALL cell growth. Unexpectedly, MEK inhibitors (MEKi) enhanced growth of 70% of human T-ALL cell samples cultured on stromal cells independently of NOTCH activation and maintained their ability to propagate in vivo. Similar results were obtained when T-ALL cells were cultured with ERK1/2-knockdown stromal cells or with conditioned medium from MEKi-treated stromal cells. Microarray analysis identified interleukin 18 (IL-18) as transcriptionally up-regulated in MEKi-treated MS5 cells. Recombinant IL-18 promoted T-ALL growth in vitro, whereas the loss of function of IL-18 receptor in T-ALL blast cells decreased blast proliferation in vitro and in NSG mice. The NFKB pathway that is downstream to IL-18R was activated by IL-18 in blast cells. IL-18 circulating levels were increased in T-ALL-xenografted mice and also in T-ALL patients in comparison with controls. This study uncovers a novel role of the pro-inflammatory cytokine IL-18 and outlines the microenvironment involvement in human T-ALL development.
PMCID: PMC4203358  PMID: 24778454
IL-18; inflammation; stromal cells; T-ALL
4.  French “real life” experience of clofarabine in children with refractory or relapsed acute lymphoblastic leukaemia 
Clofarabine alone or in combination with cyclophosphamide and etoposide has shown a good efficacy and a tolerable toxicity profile in previous studies of children with relapsed or refractory leukaemia. This report describes a retrospective study of 38 French patients who received clofarabine as a monotherapy or in combination for relapsed or refractory acute lymphoblastic leukaemia (ALL) outside of clinical trials after marketing authorization.
We retrospectively analysed data for 38 patients, up to 21 years old, attending 17 French centres. Thirty patients received clofarabine alone or in combination for a bone marrow relapse of acute lymphoblastic leukaemia (ALL) or refractory disease and eight patients for a high level of minimal residual disease (MRD). Survival and response durations were estimated by the Kaplan-Meier method.
For the 30 patients who received clofarabine for a bone marrow relapse of ALL (number of relapse, 1-3; median, 1), the overall remission rate (ORR) was 37%: eight complete remission (CR) and three complete remission without platelet recovery (CRp). Ten of the 11 responding patients subsequently underwent haematopoietic stem cell transplantation (HSCT).
Only four of the eight patients who received clofarabine while in remission for a high level of MRD, showed a moderate improvement of MRD. Seven of these eight patients received HSCT and six of them were alive at the end of the study. One other patient was alive without receiving HSCT.
However, clofarabine treatment was associated with a high risk of infection and hepatotoxicity. Febrile neutropenia grade ≥ 3 was reported in 79% of patients and documented infections grade ≥ 3 occurred in nine patients (24%). Hepatotoxicity grade 3 was reported in nine patients (24%). We observed four deaths related to treatment.
In our experience, the efficacy of clofarabine is poorer than previously reported. Its toxicity is high and can be life threatening. Prospective studies on clofarabine used during earlier phases of the disease may help to define how best this new drug can be exploited for childhood and adolescent ALL.
PMCID: PMC3599405  PMID: 23227903
Acute lymphoblastic leukaemia; Childhood leukaemia; Refractory; Relapsed; Leukaemia; Clofarabine
5.  Outcomes after Induction Failure in Childhood Acute Lymphoblastic Leukemia 
The New England Journal of Medicine  2012;366(15):1371-1381.
Failure of remission-induction therapy is a rare but highly adverse event in children and adolescents with acute lymphoblastic leukemia (ALL).
We identified induction failure, defined by the persistence of leukemic blasts in blood, bone marrow, or any extramedullary site after 4 to 6 weeks of remission-induction therapy, in 1041 of 44,017 patients (2.4%) 0 to 18 years of age with newly diagnosed ALL who were treated by a total of 14 cooperative study groups between 1985 and 2000. We analyzed the relationships among disease characteristics, treatments administered, and outcomes in these patients.
Patients with induction failure frequently presented with high-risk features, including older age, high leukocyte count, leukemia with a T-cell phenotype, the Philadelphia chromosome, and 11q23 rearrangement. With a median follow-up period of 8.3 years (range, 1.5 to 22.1), the 10-year survival rate (±SE) was estimated at only 32±1%. An age of 10 years or older, T-cell leukemia, the presence of an 11q23 rearrangement, and 25% or more blasts in the bone marrow at the end of induction therapy were associated with a particularly poor outcome. High hyperdiploidy (a modal chromosome number >50) and an age of 1 to 5 years were associated with a favorable outcome in patients with precursor B-cell leukemia. Allogeneic stem-cell transplantation from matched, related donors was associated with improved outcomes in T-cell leukemia. Children younger than 6 years of age with precursor B-cell leukemia and no adverse genetic features had a 10-year survival rate of 72±5% when treated with chemotherapy only.
Pediatric ALL with induction failure is highly heterogeneous. Patients who have T-cell leukemia appear to have a better outcome with allogeneic stem-cell transplantation than with chemotherapy, whereas patients who have precursor B-cell leukemia without other adverse features appear to have a better outcome with chemotherapy. (Funded by Deutsche Krebshilfe and others.)
PMCID: PMC3374496  PMID: 22494120
6.  Clinical Outcome of Children With Newly Diagnosed Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia Treated Between 1995 and 2005 
Journal of Clinical Oncology  2010;28(31):4755-4761.
In a previous analysis of 326 children with Philadelphia chromosome (Ph) –positive acute lymphoblastic leukemia (ALL) treated between 1986 and 1996, hematopoietic stem-cell transplantation from HLA-matched related donors, but not from unrelated donors, offered a superior outcome than chemotherapy alone. To evaluate the impact of recent improvements in chemotherapy and transplantation, we performed a similar analysis on patients treated in the following decade.
Patients and Methods
We analyzed 610 patients with Ph-positive ALL treated between 1995 and 2005 without tyrosine kinase inhibitor therapy. The median follow-up duration was 6.3 years.
Complete remission was achieved in 89% of patients. The 7-year event-free survival and overall survival rates were superior in the present cohort compared with the previous cohort (32.0% ± 2.0% v 25.0% ± 3.0, respectively, P = .007; and 44.9% ± 2.2% v 36.0% ± 3.0%, respectively, P = .017). Compared with chemotherapy alone, transplantation with matched related donors or unrelated donors in first remission (325 patients) showed an advantage with increasing follow-up, suggesting greater protection against late relapses (hazard ratio at 5 years, 0.37; P < .001). In the multivariate Cox regression analysis accounting for treatment (transplantation v no transplantation), age, leukocyte count, and early response had independent impact on treatment outcome.
Clinical outcome of children and adolescents with Ph-positive ALL has improved with advances in transplantation and chemotherapy. Transplantations with matched related donors and unrelated donors were equivalent and offered better disease control compared with chemotherapy alone. Age, leukocyte count, and early treatment response were independent prognostic indicators. The results of this study will serve as a historical reference to evaluate the therapeutic impact of tyrosine kinase inhibitors on the outcome of Ph-positive ALL.
PMCID: PMC3020705  PMID: 20876426
7.  Clonal selection in xenografted human T cell acute lymphoblastic leukemia recapitulates gain of malignancy at relapse 
Compared with T-ALL diagnosis samples, samples obtained at relapse or after xenograft into immunodeficient mice exhibit additional genomic lesions in oncogenes and/or tumor suppressor genes; these lesions contribute to leukemia-initiating activity.
Genomic studies in human acute lymphoblastic leukemia (ALL) have revealed clonal heterogeneity at diagnosis and clonal evolution at relapse. In this study, we used genome-wide profiling to compare human T cell ALL samples at the time of diagnosis and after engraftment (xenograft) into immunodeficient recipient mice. Compared with paired diagnosis samples, the xenograft leukemia often contained additional genomic lesions in established human oncogenes and/or tumor suppressor genes. Mimicking such genomic lesions by short hairpin RNA–mediated knockdown in diagnosis samples conferred a selective advantage in competitive engraftment experiments, demonstrating that additional lesions can be drivers of increased leukemia-initiating activity. In addition, the xenograft leukemias appeared to arise from minor subclones existing in the patient at diagnosis. Comparison of paired diagnosis and relapse samples showed that, with regard to genetic lesions, xenograft leukemias more frequently more closely resembled relapse samples than bulk diagnosis samples. Moreover, a cell cycle– and mitosis-associated gene expression signature was present in xenograft and relapse samples, and xenograft leukemia exhibited diminished sensitivity to drugs. Thus, the establishment of human leukemia in immunodeficient mice selects and expands a more aggressive malignancy, recapitulating the process of relapse in patients. These findings may contribute to the design of novel strategies to prevent or treat relapse.
PMCID: PMC3135355  PMID: 21464223
8.  Road Traffic and Childhood Leukemia: The ESCALE Study (SFCE) 
Environmental Health Perspectives  2010;119(4):566-572.
Traffic is a source of environmental exposures, including benzene, which may be related to childhood leukemia.
A national registry–based case–control study [ESCALE (Etude Sur les Cancers et les Leucémies de l’Enfant, Study on Environmental and Genetic Risk Factors of Childhood Cancers and Leukemia)] carried out in France was used to assess the effect of exposure to road traffic exhaust fumes on the risk of childhood leukemia.
Over the study period, 2003–2004, 763 cases and 1,681 controls < 15 years old were included, and the controls were frequency matched with the cases on age and sex. The ESCALE data were collected by a standardized telephone interview of the mothers. Various indicators of exposure to traffic and pollution were determined using the geocoded addresses at the time of diagnosis for the cases and of interview for the controls. Indicators of the distance from, and density of, main roads and traffic nitrogen dioxide (NO2) concentrations derived from traffic emission data were used. Odds ratios (ORs) were estimated using unconditional regression models adjusted for potential confounders.
Acute leukemia (AL) was significantly associated with estimates of traffic NO2 concentration at the place of residence > 27.7 μg/m3 compared with NO2 concentration < 21.9 μg/m3 [OR = 1.2; confidence interval (CI), 1.0–1.5] and with the presence of a heavy-traffic road within 500 m compared with the absence of a heavy-traffic road in the same area (OR = 2.0; 95% CI, 1.0–3.6). There was a significant association between AL and a high density of heavy-traffic roads within 500 m compared with the reference category with no heavy-traffic road within 500 m (OR = 2.2; 95% CI, 1.1–4.2), with a significant positive linear trend of the association of AL with the total length of heavy-traffic road within 500m.
This study supports the hypothesis that living close to heavy-traffic roads may increase the risk of childhood leukemia.
PMCID: PMC3080942  PMID: 21147599
acute leukemia; benzene; children; environment; epidemiology; road traffic
9.  NKX3.1 is a direct TAL1 target gene that mediates proliferation of TAL1-expressing human T cell acute lymphoblastic leukemia 
The Journal of Experimental Medicine  2010;207(10):2141-2156.
TAL1 (also known as SCL) is expressed in >40% of human T cell acute lymphoblastic leukemias (T-ALLs). TAL1 encodes a basic helix-loop-helix transcription factor that can interfere with the transcriptional activity of E2A and HEB during T cell leukemogenesis; however, the oncogenic pathways directly activated by TAL1 are not characterized. In this study, we show that, in human TAL1–expressing T-ALL cell lines, TAL1 directly activates NKX3.1, a tumor suppressor gene required for prostate stem cell maintenance. In human T-ALL cell lines, NKX3.1 gene activation is mediated by a TAL1–LMO–Ldb1 complex that is recruited by GATA-3 bound to an NKX3.1 gene promoter regulatory sequence. TAL1-induced NKX3.1 activation is associated with suppression of HP1-α (heterochromatin protein 1 α) binding and opening of chromatin on the NKX3.1 gene promoter. NKX3.1 is necessary for T-ALL proliferation, can partially restore proliferation in TAL1 knockdown cells, and directly regulates miR-17-92. In primary human TAL1-expressing leukemic cells, the NKX3.1 gene is expressed independently of the Notch pathway, and its inactivation impairs proliferation. Finally, TAL1 or NKX3.1 knockdown abrogates the ability of human T-ALL cells to efficiently induce leukemia development in mice. These results suggest that tumor suppressor or oncogenic activity of NKX3.1 depends on tissue expression.
PMCID: PMC2947082  PMID: 20855495
10.  Inhibin B and anti-Müllerian hormone as markers of gonadal function after hematopoietic cell transplantation during childhood 
BMC Pediatrics  2011;11:20.
It is difficult to predict the reproductive capacity of children given hematopoietic cell transplantation (HCT) before pubertal age because the plasma concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are not informative and no spermogram can be done.
We classified the gonadal function of 38 boys and 34 girls given HCT during childhood who had reached pubertal age according to their pubertal development and FSH and LH and compared this to their plasma inhibin B and anti-Müllerian hormone (AMH).
Ten (26%) boys had normal testicular function, 16 (42%) had isolated tubular failure and 12 (32%) also had Leydig cell failure. All 16 boys given melphalan had tubular failure. AMH were normal in 25 patients and decreased in 6, all of whom had increased FSH and low inhibin B.
Seven (21%) girls had normal ovarian function, 11 (32%) had partial and 16 (47%) complete ovarian failure. 7/8 girls given busulfan had increased FSH and LH and 7/8 had low inhibin B. AMH indicated that ovarian function was impaired in all girls.
FSH and inhibin B were negatively correlated in boys (P < 0.0001) and girls (P = 0.0006). Neither the age at HCT nor the interval between HCT and evaluation influenced gonadal function.
The concordance between FSH and inhibin B suggests that inhibin B may help in counselling at pubertal age. In boys, AMH were difficult to use as they normally decrease when testosterone increases at puberty. In girls, low AMH suggest that there is major loss of primordial follicles.
PMCID: PMC3058047  PMID: 21352536
11.  Vaccination and the risk of childhood acute leukaemia: the ESCALE study (SFCE) 
In 2002, a poster alerted the French health authorities to the possibility that the risk of childhood leukaemia might be increased by hepatitis B vaccination. Elucidating the role of vaccination in the etiology of childhood acute leukaemia was therefore included in the objectives of an ongoing national study.
The ESCALE study was a French national population-based case-control study conducted in France in 2003 and 2004 in order to investigate the role of infectious, environmental and genetic factors in 4 childhood neoplastic diseases (leukaemia, lymphoma, neuroblastoma, and brain tumor). The controls were randomly selected from the French population and age and gender frequency matched with the cases. A total of 776 cases of acute leukaemia (91% of the eligible cases) and 1681 controls (69% of the eligible controls) were included. In a specific standardized telephone interview, which was the same for both the cases and controls, each mother was asked to read out her child’s complete vaccination record.
No association between vaccination and the risk of childhood acute leukaemia (ALL or AML) was observed. No relationship between the risk of leukaemia and the type of vaccine, number of doses of each vaccine, total number of injections, total number of vaccine doses or number of early vaccinations was evidenced. No confounding factor was observed.
The study did not show any evidence of a role of vaccination in the etiology of childhood leukaemia.
PMCID: PMC2292812  PMID: 17227780
Adolescent; Age Distribution; Case-Control Studies; Child; Child, Preschool; Drug Administration Schedule; Female; France; epidemiology; Hepatitis B Vaccines; administration & dosage; adverse effects; immunology; Humans; Infant; Leukemia; epidemiology; immunology; virology; Leukemia, Myeloid, Acute; epidemiology; immunology; virology; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; epidemiology; immunology; virology; Risk Assessment; methods; Sex Distribution; Vaccination; adverse effects
12.  Household exposure to pesticides and risk of childhood acute leukaemia 
Investigating the relationship between childhood acute leukemia (AL) and household exposure to pesticides.
The study included 280 incident cases of acute leukaemia and 288 controls frequency matched on gender, age, hospital and ethnic origin. The data were obtained from standardised face-to-face interviews of the mothers with detailed questions on parental occupational history, home and garden insecticide use, and insecticidal treatment of pediculosis. Odds ratios were estimated using unconditional regression models including the stratification variables, parental socioeconomic status and housing characteristics.
Acute leukaemia was observed to be significantly associated with maternal home insecticide use during pregnancy (OR=1.8 [1.2–2.8]) and during childhood (OR=1.7 [1.1–2.4]), with garden insecticide use (OR=2.4 [1.3–4.3]) and fungicide use (OR=2.5 [1.0–6.2]) during childhood. Insecticidal shampoo treatment of pediculosis was also associated with childhood acute leukaemia (OR=1.9 [1.2–3.3]).
The results reported herein support the hypothesis that various types of insecticide exposure may be a risk factor for childhood acute leukaemia. The observed association with insecticidal shampoo treatment of pediculosis, which has never been investigated before, requires replications.
PMCID: PMC2078075  PMID: 16421392
Acute Disease; Adolescent; Child; Child, Preschool; Environmental Exposure; adverse effects; Epidemiologic Methods; Female; Humans; Infant; Infant, Newborn; Insecticides; toxicity; Leukemia; chemically induced; Lice Infestations; drug therapy; Male; Maternal Exposure; adverse effects; Paternal Exposure; adverse effects; Pesticides; toxicity; Pregnancy; Prenatal Exposure Delayed Effects; Scalp Dermatoses; drug therapy; Epidemiology; case-control study;; childhood leukaemia;; pesticide exposure
13.  Household Exposure to Pesticides and Risk of Childhood Hematopoietic Malignancies: The ESCALE Study (SFCE) 
Environmental Health Perspectives  2007;115(12):1787-1793.
We investigated the role of household exposure to pesticides in the etiology of childhood hematopoietic malignancies.
The national registry-based case–control study ESCALE (Etude sur les cancers de l’enfant) was carried out in France over the period 2003–2004. Population controls were frequency matched with the cases on age and sex. Maternal household use of pesticides during pregnancy and paternal use during pregnancy or childhood were reported by the mothers in a structured telephone questionnaire. Insecticides (used at home, on pets, or for garden crops), herbicides, and fungicides were distinguished. We estimated odds ratios (ORs) using unconditional regression models closely adjusting for age, sex, degree of urbanization, and type of housing (flat or house).
We included a total of 764 cases of acute leukemia (AL), 130 of Hodgkin lymphoma (HL), 166 of non-Hodgkin lymphoma (NHL), and 1,681 controls. Insecticide use during pregnancy was significantly associated with childhood AL [OR = 2.1; 95% confidence interval (CI), 1.7–2.5], both lymphoblastic and myeloblastic, NHL (OR = 1.8; 95% CI, 1.3–2.6), mainly for Burkitt lymphoma (OR = 2.7; 95% CI, 1.6–4.5), and mixed-cell HL (OR = 4.1; 95% CI, 1.4–11.8), but not nodular sclerosis HL (OR = 1.1; 95% CI, 0.6–1.9). Paternal household use of pesticides was also related to AL (OR = 1.5; 95% CI, 1.2–1.8) and NHL (OR = 1.7; 95% CI, 1.2–2.6); but for AL the relationships did not remain after adjustment for maternal pesticide use during pregnancy.
The study findings strengthen the hypothesis that domestic use of pesticides may play a role in the etiology of childhood hematopoietic malignancies. The consistency of the findings with those of previous studies on AL raises the question of the advisability of preventing pesticide use by pregnant women.
PMCID: PMC2137105  PMID: 18087601
acute leukemia; children; Hodgkin lymphoma; non-Hodgkin lymphoma; pesticide; pregnancy
14.  Efficacy and tolerability of gemtuzumab ozogamicin (anti-CD33 monoclonal antibody, CMA-676, Mylotarg®) in children with relapsed/refractory myeloid leukemia 
BMC Cancer  2006;6:172.
Gemtuzumab ozogamicin (GO) is a cytotoxic anti-CD33 monoclonal antibody that has given promising preliminary results in adult myeloid CD33+ AML. We conducted a retrospective multicenter study of 12 children treated with GO on a compassionate basis (median age 5.5 y). Three patients (2 MDS/AML, 1 JMML) were refractory to first-line treatment, 8 patients with de novo AML were in refractory first relapse, and one patient with de novo AML was in 2nd relapse after stem cell transplantation (SCT). CD33 expression exceeded 20% in all cases.
GO was administered alone, at a unit dose of 3–9 mg/m2, once (3 patients), twice (3 patients), three (5 patients) or five times (1 patient). Mean follow-up was 128 days (8–585 d).
There were three complete responses (25%) leading to further curative treatment (SCT). Treatment failed in the other nine patients, and only one patient was alive at the end of follow-up. NCI-CTC grade III/IV adverse events comprised hematological toxicity (n = 12), hypertransaminasemia (n = 2), allergy and hyperbilirubinemia (1 case each). There was only one major adverse event (grade IV allergy). No case of sinusoidal obstruction syndrome occurred.
These results warrant a prospective trial of GO in a larger population of children with AML.
PMCID: PMC1523361  PMID: 16805911

Results 1-14 (14)