Identification of residual leukemic cells by flow cytometry in childhood B-cell precursor acute lymphoblastic leukemia: verification of leukemic state by flow-sorting and molecular/cytogenetic methods.

Reduction in minimal residual disease, measured by real-time quantitative PCR or flow cytometry, predicts prognosis in childhood B-cell precursor acute lymphoblastic leukemia. We explored whether cells reported as minimal residual disease by flow cytometry represent the malignant clone harboring clone-specific genomic markers (53 follow-up bone marrow samples from 28 children with B-cell precursor acute lymphoblastic leukemia). Cell populations (presumed leukemic and non-leukemic) were flow-sorted during standard flow cytometry-based minimal residual disease monitoring and explored by PCR and/or fluorescence in situ hybridization.

Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D.

Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive, often-fatal hyperinflammatory disorder. Mutations in PRF1, UNC13D, STX11, and STXBP2 are causative of FHL2, 3, 4, and 5, respectively. In a majority of suspected FHL patients from Northern Europe, sequencing of exons and splice sites of such genes required for lymphocyte cytotoxicity revealed no or only monoallelic UNC13D mutations.

Analysis of GATA1 mutations in Down syndrome transient myeloproliferative disorder and myeloid leukemia.

Children with Down syndrome (DS) up to the age of 4 years are at a 150-fold excess risk of developing myeloid leukemia (ML-DS). Approximately 4%-5% of newborns with DS develop transient myeloproliferative disorder (TMD). Blast cell structure and immunophenotype are similar in TMD and ML-DS.

Acute respiratory failure in 3 children with juvenile myelomonocytic leukemia.

Background: Juvenile myelomonocytic leukemia is a rare hematopoietic stem cell disease in children with features of both myelodysplasia and myeloproliferation. Extramedullary involvement has been reported and pulmonary involvement secondary to leukemic infiltration is an initial manifestation, which may result in acute respiratory failure.

Observation: We present 3 children with juvenile myelomonocytic leukemia and suspected pulmonary leukemic cell infiltration who all also suffered from respiratory insufficiency.

Prognostic significance of additional cytogenetic aberrations in 733 de novo pediatric 11q23/MLL-rearranged AML patients: results of an international study.

We previously demonstrated that outcome of pediatric 11q23/MLL-rearranged AML depends on the translocation partner (TP). In this multicenter international study on 733 children with 11q23/MLL-rearranged AML, we further analyzed which additional cytogenetic aberrations (ACA) had prognostic significance. ACAs occurred in 344 (47%) of 733 and were associated with unfavorable outcome (5-year overall survival [OS] 47% vs 62%, P < .

Cancer in Noonan, Costello, cardiofaciocutaneous and LEOPARD syndromes.

Noonan syndrome (NS), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFCS), and LEOPARD syndrome (now also referred to as Noonan syndrome with multiple lentigines or NSML) are clinically overlapping dominant disorders that are caused by mutations in RAS signaling pathway genes. The spectrum of cancer susceptibility in this group of disorders has not been studied in detail. We identified more than 1900 cases of NS, CS, CFCS, or NSML reported in the literature between 1937 and 2010; 88 cancers were reported.

Aberrant DNA methylation characterizes juvenile myelomonocytic leukemia with poor outcome.

Aberrant DNA methylation contributes to the malignant phenotype in virtually all types of cancer, including myeloid leukemia. We hypothesized that CpG island hypermethylation also occurs in juvenile myelomonocytic leukemia (JMML) and investigated whether it is associated with clinical, hematologic, or prognostic features. Based on quantitative measurements of DNA methylation in 127 JMML cases using mass spectrometry (MassARRAY), we identified 4 gene CpG islands with frequent hypermethylation: BMP4 (36% of patients), CALCA (54%), CDKN2B (22%), and RARB (13%).

Risk factors for treatment related mortality in childhood acute lymphoblastic leukaemia.

Background: In spite of major improvements in the cure rate of childhood acute lymphoblastic leukaemia (ALL), 2-4% of patients still die from treatment related complications.

Procedure: We investigated the pattern of treatment related deaths (TRDs) and possible risk factors in the NOPHO ALL-92 and ALL-2000 protocols. Fifty-five TRDs were identified among the 1,645 ALL-92 patients and 33 among the 1,090 ALL-2000 patients.

Treatment-related deaths in second complete remission in childhood acute myeloid leukaemia.

The frequency and causes of treatment-related deaths (TRD) in second complete remission (CR2) in acute myeloid leukaemia (AML) were investigated in a historical, prospective cohort study of 429 children included in the Nordic Society of Paediatric Haematology and Oncology (NOPHO)-AML-88 and -93 trials. Relapse occurred in 158 children (39%). Seventeen (18%) of the 96 patients entering CR2 suffered TRD.

Response-guided induction therapy in pediatric acute myeloid leukemia with excellent remission rate.

Purpose: To evaluate the early treatment response in children with acute myeloid leukemia (AML) using a response-guided induction strategy that includes idarubicin in the first course.

Patients And Methods: All Nordic children with AML younger than 15 years (n = 151) were treated on the Nordic Society for Pediatric Hematology and Oncology (NOPHO) AML 2004 protocol. After the first course of idarubicin, cytarabine, etoposide, and 6-thioguanin, patients with good response were allowed hematologic recovery before the second course, whereas patients with a poor (≥ 15% blasts) or intermediate (5% to 14.

Early and treatment-related deaths in childhood acute myeloid leukaemia in the Nordic countries: 1984-2003.

Despite major improvements in the cure rate of childhood acute myeloid leukaemia (AML), 5-15% of patients still die from treatment-related complications. In a historical prospective cohort study, we analysed the frequency, clinical features and risk factors for early deaths (ED) and treatment-related deaths (TRD) in 525 children included in the Nordic Society of Paediatric Haematology and Oncology (NOPHO)-AML-84, -88 and -93 trials. Seventy patients (13%) died before starting treatment or from treatment-related complications.

Complex karyotype newly defined: the strongest prognostic factor in advanced childhood myelodysplastic syndrome.

To identify cytogenetic risk factors predicting outcome in children with advanced myelodysplastic syndrome, overall survival of 192 children prospectively enrolled in European Working Group of Myelodysplastic Syndrome in Childhood studies was evaluated with regard to karyotypic complexity. Structurally complex constitutes a new definition of complex karyotype characterized by more than or equal to 3 chromosomal aberrations, including at least one structural aberration. Five-year overall survival in patients with more than or equal to 3 clonal aberrations, which were not structurally complex, did not differ from that observed in patients with normal karyotype.

Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia.

CBL encodes a member of the Cbl family of proteins, which functions as an E3 ubiquitin ligase. We describe a dominant developmental disorder resulting from germline missense CBL mutations, which is characterized by impaired growth, developmental delay, cryptorchidism and a predisposition to juvenile myelomonocytic leukemia (JMML). Some individuals experienced spontaneous regression of their JMML but developed vasculitis later in life.

Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2.

Hemophagocytic lymphohistiocytosis (HLH) is an often-fatal hyperinflammatory syndrome characterized by fever, hepatosplenomegaly, cytopenia, and in some cases hemophagocytosis. Here, we describe the mutation analysis, clinical presentation, and functional analysis of natural killer (NK) cells in patients with mutations in STXBP2 encoding Munc18-2, recently associated with familial HLH type 5. The disease severity among 11 persons studied here was highly variable and, accordingly, age at diagnosis ranged from 2 months to 17 years.

Gene expression-based classification as an independent predictor of clinical outcome in juvenile myelomonocytic leukemia.

PURPOSE Juvenile myelomonocytic leukemia (JMML) is a rare early childhood myelodysplastic/myeloproliferative disorder characterized by an aggressive clinical course. Age and hemoglobin F percentage at diagnosis have been reported to predict both survival and outcome after hematopoietic stem cell transplantation (HSCT). However, no genetic markers with prognostic relevance have been identified so far.

Malignant diseases in Noonan syndrome and related disorders.

The overall risk of cancer in children with Noonan (NS), cardio-facial-cutaneous, Costello or LEOPARD syndrome is high, although no precise estimates are available. There are few data on cancer in adults with NS, but the reported numbers of malignancies in adults do not seem excessive. Juvenile myelomonocytic leukemia (JMML) is a rare aggressive leukemia in young children.

Mitotic recombination and compound-heterozygous mutations are predominant NF1-inactivating mechanisms in children with juvenile myelomonocytic leukemia and neurofibromatosis type 1.

Children with neurofibromatosis type 1 (NF-1), being constitutionally deficient for one allele of the NF1 gene, are at greatly increased risk of juvenile myelomonocytic leukemia (JMML). NF1 is a negative regulator of RAS pathway activity, which has a central role in JMML. To further clarify the role of biallelic NF1 gene inactivation in the pathogenesis of JMML, we investigated the somatic NF1 lesion in 10 samples from children with JMML/NF-1.

Salvage treatment for children with refractory first or second relapse of acute myeloid leukaemia with gemtuzumab ozogamicin: results of a phase II study.

The prognosis of children with relapsed/refractory acute myeloid leukaemia (AML) is poor, and new therapies are needed. Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody linked to the antitumor antibiotic calicheamicin. We conducted an investigator-initiated phase II study with GO to assess its efficacy and safety, administering two dosages of 7.

Clinical presentation of Griscelli syndrome type 2 and spectrum of RAB27A mutations.

Background: Griscelli syndrome type 2 (GS2) is an autosomal-recessive immunodeficiency caused by mutations in RAB27A, clinically characterized by partial albinism and haemophagocytic lymphohistocytosis (HLH). We evaluated the frequency of RAB27A mutations in 21 unrelated patients with haemophagocytic syndromes without mutations in familial HLH (FHL) causing genes or an established diagnosis of GS2. In addition, we report three patients with known GS2.