Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents

GermlineGATA2 mutations cause cellular deficiencieswith high propensity for myeloid disease. We investigated 426 children and adolescents with primary myelodysplastic syndrome (MDS) and 82 cases with secondary MDS enrolled in 2 consecutive prospective studies of the European Working Group of MDS in Childhood (EWOGMDS) conducted in Germany over a period of 15 years. Germline GATA2 mutations accounted for 15% of advanced and 7% of all primary MDS cases, but were absent in children with MDS secondary to therapy or acquired aplastic anemia. Mutation carriers were older at diagnosis and more likely to present with monosomy 7 and advanced disease compared with wild-type cases. For stratified analysis according to karyotype, 108 additional primary MDS patients registered with EWOG-MDS were studied. Overall, we identified 57 MDS patients with germline GATA2mutations. GATA2 mutations were highly prevalent among patients with monosomy 7 (37%, all ages) reaching its peak in adolescence (72%of adolescents withmonosomy 7).Unexpectedly, monocytosis was more frequent in GATA2-mutated patients. However, when adjusted for the selection bias from monosomy 7, mutational status had no effect on the hematologic phenotype. Finally, overall survival and outcome of hematopoietic stem cell transplantation (HSCT) were not influenced by mutational status. This study identifies GATA2 mutations as the most common germline defect predisposing to pediatric MDS with a very high prevalence in adolescents with monosomy 7. GATA2 mutations do not confer poor prognosis in childhood MDS. However, the high risk for progression to advanced diseasemust guide decision-making toward timely HSCT

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. Cox regression analysis revealed the presence of a monosomal and structurally complex karyotype to be strongly associated with poor prognosis (hazard ratio = 4.6, P < .01). Notably, a structurally complex karyotype without a monosomy was associated with a very short 2-year overall survival probability of only 14% (hazard ratio = 14.5; P < .01). The presence of a structurally complex karyotype was the strongest independent prognostic marker predicting poor outcome in children with advanced myelodysplastic syndrome

Development of an allele-specific minimal residual disease assay for patients with juvenile myelomonocytic leukemia

Juvenile myelomonocytic leukemia is an aggressive and frequently lethal myeloproliferative disorder of childhood. Somatic mutations in NRAS, KRAS, or PTPN11 occur in 60% of cases. Monitoring disease status is difficult because of the lack of characteristic leukemic blasts at diagnosis. We designed a fluorescently based, allele-specific polymerase chain reaction assay called TaqMAMA to detect the most common RAS or PTPN11 mutations. We analyzed peripheral blood and/or bone marrow of 25 patients for levels of mutant alleles over time. Analysis of pre–hematopoietic stem-cell transplantation, samples revealed a broad distribution of the quantity of the mutant alleles. After hematopoietic stem-cell transplantation, the level of the mutant allele rose rapidly in patients who relapsed and correlated well with falling donor chimerism. Simultaneously analyzed peripheral blood and bone marrow samples demonstrate that blood can be monitored for residual disease. Importantly, these assays provide a sensitive strategy to evaluate molecular responses to new therapeutic strategies

Development of an allele-specific minimal residual disease assay for patients with juvenile myelomonocytic leukemia

Juvenile myelomonocytic leukemia is an aggressive and frequently lethal myeloproliferative disorder of childhood. Somatic mutations in NRAS, KRAS, or PTPN11 occur in 60% of cases. Monitoring disease status is difficult because of the lack of characteristic leukemic blasts at diagnosis. We designed a fluorescently based, allele-specific polymerase chain reaction assay called TaqMAMA to detect the most common RAS or PTPN11 mutations. We analyzed peripheral blood and/or bone marrow of 25 patients for levels of mutant alleles over time. Analysis of pre–hematopoietic stem-cell transplantation, samples revealed a broad distribution of the quantity of the mutant alleles. After hematopoietic stem-cell transplantation, the level of the mutant allele rose rapidly in patients who relapsed and correlated well with falling donor chimerism. Simultaneously analyzed peripheral blood and bone marrow samples demonstrate that blood can be monitored for residual disease. Importantly, these assays provide a sensitive strategy to evaluate molecular responses to new therapeutic strategies

Umwelt-Survey - 1990/92. Bd. 7 Quecksilber-Zusammenhanganalyse

A representative sample of adults (aged 25 to 69) as well as a sample of children (aged 6 to 14) from the general population were studied with respect to mercury levels in their blood and urine. The present report sets out the results of multivariate analyses used to find the main factors (predictors) influencing mercury levels in the blood and urine (criteria) and to quantify their impact. The regression models for mercury levels in urine were nearly the same for subjects from West- and East Germany, which allowed a joint regression model to be formed from the German population. With lower levels of creatinine lower levels of mercury in the urine occur. The number of teeth with amalgam fillings is a significant predictor for adults also the age of the most recent amalgam filling. Mercury levels in urine decrease with increasing age. body mass index, education and gender make up further significant predictors in the case of adults. Mercury levels in the urine of children from East Germany and urban residential areas are higher. No satisfactory model was obtained from the regression analyses for mercury levels in blood. for adults from West and East Germany as well as for children from West Germany, frequency of fish consumption is a significant predictor. Other specific predictors comprise the community size category and family income in the case of adults from West Germany, outdoor physical activity, gender and type of housing in the case of children from West Germany, and the presence of individually operated heating units in the case of children from East Germany. (orig.)Es wurde eine repraesentative Stichprobe von Erwachsenen (25 bis 69 Jahre) sowie eine Stichprobe von Kindern (6 bis 14 Jahre) hinsichtlich ihrer Quecksilbergehalte im Blut und im Urin untersucht. Es werden die Ergebnisse multivariater Zusammenhangsanalysen dargestellt, mit denen die massgeblichen Praediktoren fuer die Quecksilbergehalte in Blut und Urin in ihrer Bedeutung erfasst und in ihrer Wirkung quantifiziert werden. Die Regressionsmodelle fuer die Probanden aus den alten und den neuen Laendern sind annaehernd gleich, so dass ein gemeinsames Regressionsmodell fuer den Quecksilbergehalt im Urin der deutschen Bevoelkerung gebildet werden konnte. Je geringer der Creatiningehalt im Urin ist, desto geringer ist auch der Quecksilbergehalt im Urin. Die Anzahl der Zaehne mit Amalgamfuellungen ist ein starker Praediktor, bei Erwachsenen zusaetzlich das Alter der letzten Amalgamfuellung. Mit zunehmendem Lebensalter liegt ein geringerer Quecksilbergehalt im Urin vor. Der Body Mass Index, der Schulabschluss und das Geschlecht sind weitere Praediktoren. Bei den Kindern treten in den neuen Bundeslaendern und in staedtischen Wohngebieten hoehere Quecksilbergehalte im Urin auf. Die Regressionsanalysen fuer den Quecksilbergehalt im Blut fuehrten zu keinem befriedigenden Modell. Die Haeufigkeit des Fischverzehrs ist bei den Erwachsenen der alten und der neuen Laender sowie bei den Kindern der alten Laender ein bedeutsamer Praediktor. Weitere spezifische Praediktoren sind Gemeindegroessenklasse und Haushaltseinkommen bei Erwachsenen der alten Laender, koerperliche Anstrengung im Freien, Geschlecht und Bebauungsart bei Kindern aus den alten Laendern sowie das Vorhandensein einzeln zu bedienender Oefen bei Kindern aus den neuen Laendern. (orig.)Available from TIB Hannover: RO 2237(1996,7) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEBundesministerium fuer Umwelt, Naturschutz und Reaktorsicherheit, Bonn (Germany)DEGerman

Induction in arbitrarily shaped oceans. IV, sq for a simple case

World curves are presented of electric currents induced in electrically insulated oceans by Sq using a perfectly conducting sphere to simulate the underlying mantle. The curves are valid everywhere away from those coastal regions at which the sea bed rises steeply. In such cases an edge correction may be needed. The numerical computations are for periods of 6, 8, 12 and 24 hr and comparison is made with results obtained by others for a 24-hr period. Circulation conditions around the island are ignored in this note

T-cell receptor Vβ skewing frequently occurs in refractory cytopenia of childhood and is associated with an expansion of effector cytotoxic T cells: A prospective study by EWOG-MDS

Immunosuppressive therapy (IST), consisting of antithymocyte globulin and cyclosporine A, is effective in refractory cytopenia of childhood (RCC), suggesting that, similar to low-grade myelodysplastic syndromes in adult patients, T lymphocytes are involved in suppressing hematopoiesis in a subset of RCC patients. However, the potential role of a T-cell-mediated pathophysiology in RCC remains poorly explored. In a cohort of 92 RCC patients, we prospectively assessed the frequency of T-cell receptor (TCR) b-chain variable (Vβ) domain skewing in bone marrow and peripheral blood by heteroduplex PCR, and analyzed T-cell subsets in peripheral blood by flow cytometry. TCRVβ skewing was present in 40% of RCC patients. TCRVβ skewing did not correlate with bone marrow cellularity, karyotype, transfusion history, HLA-DR15 or the presence of a PNH clone. In 28 patients treated with IST, TCRVβ skewing was not clearly related with treatment response. However, TCRVβ skewing did correlate with a disturbed CD4+/CD8+ T-cell ratio, a reduction in naive CD8+ T cells, an expansion of effector CD8 + T cells and an increase in activated CD8+ T cells (defined as HLA-DR+, CD57+ or CD56+). These data suggest that T lymphocytes contribute to RCC pathogenesis in a proportion of patients, and provide a rationale for treatment with IST in selected patients with RCC. © 2014 Macmillan Publishers Limited. All rights reserved

The clinical relevance of minor paroxysmal nocturnal hemoglobinuria clones in refractory cytopenia of childhood: A prospective study by EWOG-MDS

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