Different types of NPM1 mutations in children and adults: evidence for an effect of patient age on the prevalence of the TCTG-tandem duplication in NPM1-exon 12.
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Adolescent↗
Biomedical subjects
D Reinhardt
Publications and source records attributed to D Reinhardt.
Low efficacy of methotrexate in childhood acute myeloid leukemia (AML): single-agent therapeutic window study in relapsed AML.
BACKGROUND: The efficacy in pediatric acute myeloid leukemia (AML) of single-agent methotrexate (MTX) at a higher dose than previously applied, 1,000 mg/m2, given as a theoretically beneficial 36-hr continuous infusion, is unknown, but may be beneficial based on preclinical data. PROCEDURE: We performed a therapeutic window study in children with first relapsed AML treated in four different countries. RESULTS: Based on a comparison between the percentage of leukemic blasts in the bone marrow shortly before and 7-10 days after the MTX infusion, none of the first cohort of nine patients showed a good response, defined as a reduction of blasts of at least 50%. Therefore, the study was closed, concluding that the probability of a good response in this patient-group was most likely to be less than 30%. By that time, another four patients had been enrolled, of which one patient with a late relapsed AML FAB type M7 showed a good response. Toxicity of MTX was limited and tolerable. CONCLUSIONS: This study shows that single-agent MTX in the applied regimen in pediatric relapsed AML has limited efficacy. However, it also demonstrates the feasibility of an international and therapeutic window phase II study in pediatric relapsed AML.
Adolescent↗
Respiratory health and individual estimated exposure to traffic-related air pollutants in a cohort of young children.
OBJECTIVES: To estimate long-term exposure to traffic-related air pollutants on an individual basis and to assess adverse health effects using a combination of air pollution measurement data, data from geographical information systems (GIS) and questionnaire data. METHODS: 40 measurement sites in the city of Munich, Germany were selected at which to collect particulate matter with a 50% cut-off aerodynamic diameter of 2.5 microm (PM2.5) and to measure PM2.5 absorbance and nitrogen dioxide (NO2). A pool of GIS variables (information about street length, household and population density and land use) was collected for the Munich metropolitan area and was used in multiple linear regression models to predict traffic-related air pollutants. These models were also applied to the birth addresses of two birth cohorts (German Infant Nutritional Intervention Study (GINI) and Influence of Life-style factors on the development of the Immune System and Allergies in East and West Germany (LISA)) in the Munich metropolitan area. Associations between air pollution concentrations at birth address and 1-year and 2-year incidences of respiratory symptoms were analysed. RESULTS: The following means for the estimated exposures to PM2.5, PM2.5 absorbance and NO2 were obtained: 12.8 microg/m3, 1.7x10(-5) m(-1) and 35.3 mug/m3, respectively. Adjusted odds ratios (ORs) for wheezing, cough without infection, dry cough at night, bronchial asthma, bronchitis and respiratory infections indicated positive associations with traffic-related air pollutants. After controlling for individual confounders, significant associations were found between the pollutant PM2.5 and sneezing, runny/stuffed nose during the first year of life (OR 1.16, 95% confidence interval 1.01 to 1.34) Similar effects were observed for the second year of life. These findings are similar to those from our previous analysis that were restricted to a subcohort in Munich city. The extended study also showed significant effects for sneezing, running/stuffed nose. Additionally, significant associations were found between NO2 and dry cough at night (or bronchitis) during the first year of life. The variable "living close to major roads" (<50 m), which was not analysed for the previous inner city cohort with birth addresses in the city of Munich, turned out to increase the risk of wheezing and asthmatic/spastic/obstructive bronchitis. CONCLUSIONS: Effects on asthma and hay fever are subject to confirmation at older ages, when these outcomes can be more validly assessed.
Air Pollutants↗
Stability and prognostic influence of FLT3 mutations in paired initial and relapsed AML samples.
In acute myeloid leukemia (AML), activating mutations in the fms-like tyrosine kinase 3 (FLT3) gene predict poor prognosis. We determined FLT3 internal tandem duplications (FLT3/ITD) and D835 point mutations in paired initial and relapse samples from 80 pediatric and adult AML patients. One D835 point mutation was found in an initial pediatric AML sample. Fms-like tyrosine kinase 3/ITDs were present in 21 initial and 22 relapse samples (26.3 and 27.5%, respectively). Interestingly, FLT3/ITD positivity was related to a significantly shorter time to relapse, most pronounced when the ITD-positive status was found at relapse (P<0.001). However, FLT3/ITD status changed between diagnosis and relapse in 14 cases. In four patients, the FLT3/ITD became undetectable at relapse in five patients FLT3/ITDs were only detected at relapse, and in five patients the length or number of FLT3/ITDs changed. Gain of FLT3/ITDs may suggest oligoclonality with selective outgrowth of the FLT3/ITD-positive clone, whereas losses may reflect ITDs in the more mature leukemic cells rather than in the leukemic stem cell, or, alternatively, that other genetic aberrations provided a greater selective advantage. Studying FLT3/ITD kinetics in minimal residual disease setting may provide some answers for the changes we observed. Fms-like tyrosine kinase 3/ITD is a relevant marker for prognosis, and remains an important target for therapeutic inhibition.
Adolescent↗
Diagnostic and prognostic value of serum antibodies against Pseudomonas aeruginosa in cystic fibrosis.
BACKGROUND: Eradication of Pseudomonas aeruginosa in patients with cystic fibrosis (CF) is possible if initiated early in the course of colonisation. To detect P aeruginosa as early as possible is therefore a major goal. This study was undertaken to validate a commercialised test for the detection of serum Pseudomonas antibodies in patients with CF. METHODS: A representative cross sectional analysis of serum antibodies against three Pseudomonas antigens (alkaline protease, elastase, and exotoxin A) was performed in 183 patients with CF of mean age 16.7 years and FEV1 85.9% predicted. The results were correlated with microbiological results from the previous 2 years to calculate sensitivity, specificity, positive and negative predictive values. The following 2 years were assessed to determine prognostic predictive values. RESULTS: A combination of all three tested antibodies yielded the best results with a sensitivity of 86%, specificity of 96%, and a positive predictive value of 97%. These values were higher if only patients in whom sputum cultures were available were considered (n = 76, sensitivity 95%, specificity 100%, positive predictive value 100%). The prognostic positive predictive value was high in intermittently infected patients (83%) but low in patients free of infection (33%), whereas the prognostic negative predictive value was high in patients free of infection (78%) and low in intermittently infected patients (58%). CONCLUSIONS: Regular determination of serum antibodies may be useful in CF patients with negative or intermittent but not with positive P aeruginosa status. A rise in antibody titres indicates probable infection and eradication treatment may be initiated even in the absence of microbiological detection of P aeruginosa.
Adolescent↗
[Implantation of a re-synchronization device in a patient with persistent left superior vena cava-a case report].
We report an implantation of a cardiac re-synchronization system in a patient with persistent left superior vena cava. This anomaly occurs in 0.3 to 0.5% of healthy individuals and remains usually asymptomatic. Variations of the superior vena cava should be considered in venous catheterization and other procedures such as implantation of pacemaker and ICD systems as well as port catheter insertion. In re-synchronization systems, persistent left superior vena cava can be an obstacle for cannulation of the coronary sinus and placement of a transvenous left ventricular lead.
Aged↗
Lack of expression of the chondroitin sulphate proteoglycan neuron-glial antigen 2 on candidate stem cell populations in paediatric acute myeloid leukaemia/abn(11q23) and acute lymphoblastic leukaemia/t(4;11).
It has increasingly been acknowledged that only a few leukaemic cells possess the capability to renew themselves and that only these self-renewing leukaemic stem cells are able to initiate relapses. Therefore, these leukaemic stem cells should be the target cells for therapy and for minimal residual disease (MRD) detection. Because of its presence on blasts of 11q23-rearranged high-risk leukaemic patients, neuron-glial antigen 2 (NG2) is thought to be a valuable marker for detecting leukaemic stem cells. Six acute myeloid leukaemia (AML)/abn(11q23) and three acute lymphoblastic leukaemia (ALL)/t(4;11) samples were analysed by four-colour flow cytometry for NG2 expression on primitive cell populations. Candidate leukaemic cell populations were defined by the antigen profiles CD34+CD38- in AML and CD34+CD19-CD117+ in ALL. Surprisingly, in all patients these candidate stem cell populations were shown to lack expression of NG2. Instead, a correlation between the expression of the myeloid differentiation marker CD33 and increasing levels of NG2 on maturing cells could be demonstrated. Similarly, in ALL patients CD34+CD19+ cells showed a higher expression of NG2 mRNA compared with CD34+CD19-. Thus, NG2 appears to be upregulated with differentiation and not to be expressed on primitive disease-maintaining cells. This hampers the clinical use of NG2 as a therapeutic target and as a sensitive marker for MRD detection.
Acute Disease↗
Posaconazole for treatment of refractory invasive fungal disease.
Invasive fungal infections are usually associated with immunocompromised states About 40-60% of these patients are refractory to standard antifungal therapy We describe the effect of posaconazole in the treatment of a 12 years-old girl with uncontrolled diabetes mellitus with life-threatening cerebral mucor mycosis and a 4 year old girl boy with chronic granulomatous disease presenting with invasive Aspergillus nidulans infection.
Antifungal Agents↗
Chemotactic activity of serum obtained from patients with idiopathic dilated cardiomyopathy.
Elevated circulating levels of alpha- and beta-chemokines in heart failure have been reported. The objective of this study was to investigate the interrelation of chemotactic activity of serum and circulating chemokine levels in patients suffering from idiopathic dilated cardiomyopathy (IDCM). Chemokine serum levels (MCP-1, MIP1-alpha, RANTES, IL-8 and TNF-alpha) were determined in patients with IDCM (n = 10), patients with coronary artery disease with normal (CAD-1; n = 10) or depressed (CAD-2; n = 10) left ventricular function and healthy controls (n = 10). The chemotactic effect of sera obtained from these groups was measured using an in vitro chemotaxis assay. Sera obtained from IDCM (5475 +/- 681 cells) showed the highest chemotactic activity when compared to controls (1850 +/- 215 cells), CAD-1 (3325 +/- 275 cells) and CAD-2 (2800 +/- 275 cells, P < 0.05) associated with significantly higher circulating MCP-1 levels. Sera obtained from IDCM patients show a high chemotactic activity associated with significantly elevated circulating MCP-1.
Adult↗
AML bearing the translocation t(11;17)(q23;q21): involvement of MLL and a region close to RARA, with no differentiation response to retinoic acid.
We describe a case of acute myeloid leukemia (AML) bearing the translocation t(11;17)(q23;q21). The morphological phenotype represented a monoblastic leukemia, AML French-American-British (FAB) M5a. Further analysis of the translocation revealed an involvement of the mixed-lineage leukemia (MLL) gene and a region closely proximal to the retinoic acid (RA) receptor alpha (RARA) gene. AMLs involving both a rearranged MLL and the 17q21 region, in which the RARA gene is located, have only been described in some individual cases. The functional role of this translocation is still unknown. Rearrangements of the MLL (11q23) gene in AML are usually related to the morphological phenotype FAB M5. In general, they are associated with an adverse prognosis. In acute promyelocytic leukemia, the translocation (15;17)(q22;q11-21) involving the RARA leads to a maturation arrest that can be overcome by RA, often inducing remission. In other forms of AML, however, the effects of RA are limited and diverse. To study whether RA might have a therapeutical potential in our case, we performed an in vitro analysis of RA effects on AML cells. We found that RA leads to enhanced cell death and up-regulation of CD38 and CD117. However, no hints of RA-induced in vitro differentiation were visible. Our data indicate that in AML cells bearing the t(11;17)(q23;q21), a differentiation arrest that is overcome by RA is not present. On the contrary, RA induces alterations in cellular regulation that are similar to the RA-induced changes observed in early hematogenic progenitors; thus, a possible therapeutical benefit of RA in such cases remains open.
ADP-ribosyl Cyclase 1↗
AML patients with Down syndrome have a high cure rate with AML-BFM therapy with reduced dose intensity.
Despite improved prognosis in acute myelogenous leukaemia (AML) children with Down syndrome (DS), therapy-related toxicity remained a problem. We compared 67 DS patients from study AML-BFM 98 with 51 DS patients of the previous study AML-BFM 93, and the non-DS groups of both studies. Compared to non-DS patients, DS patients were treated with reduced anthracycline doses, without high-dose cytarabine/mitoxantrone and without cranial irradiation. AML-DS patients were in median 1.8 years old, and 102/118 (86%) showed the typical morphology of acute megakaryoblastic leukaemia. In study 93, seven DS patients did not receive AML-specific chemotherapy, and treatment modifications were more common. Results improved significantly for patients treated in study 98 with a 3-year survival of 91+/-4 vs 70+/-7% in study 93 (P=0.001). There were no differences in outcome concerning the age groups 0-<or=2 and 2-<or=4 years (event-free survival for treated patients 0-<or=2 years 83+/-4%, 2-<or=4 years 81+/-7%). The cumulative incidence of relapses was significantly lower in DS (7+/-3%) than in non-DS patients (28+/-7%). Therapy-related toxicity was generally lower in DS patients treated according to study 98. We conclude that a standardised and dose-reduced treatment schedule including the main components of AML treatment is advisable for AML children with DS.
Adolescent↗
Acute megakaryoblastic leukemia in children and adolescents, excluding Down's syndrome: improved outcome with intensified induction treatment.
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Adolescent↗
Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia.
Activating mutations in RAS and receptor tyrosine kinases such as KIT and FLT3 are hypothesized to cooperate with chimeric transcription factors in the pathogenesis of acute myeloid leukemia (AML). To test this hypothesis, we genotyped 150 pediatric AML samples for mutations in KIT (exons 8, 17), NRAS and KRAS (exons 1, 2) and FLT3/ITD. This is the largest cohort of pediatric AML patients reported thus far screened for all four mutations. Of the children with AML, 40% had a mutation in KIT (11.3%), RAS (18%) or FLT3/ITD (11.1%), and 70% of cases of core-binding factor (CBF) leukemia were associated with a mutation of KIT or RAS. Mutations in RAS or FLT3/ITD were frequently found in association with a normal karyotype. Patients with a FLT3/ITD mutation had a significantly worse clinical outcome. However, the presence of a KIT or RAS mutation did not significantly influence clinical outcome. We demonstrate that KIT exon 8 mutations result in constitutive ligand-independent kinase activation that can be inhibited by clinically relevant concentrations of imatinib. Our results demonstrate that abnormalities of signal transduction pathways are frequent in pediatric AML. Future clinical studies are needed to determine whether selective targeting of these abnormalities will improve treatment results.
Acute Disease↗
Treatment strategies and long-term results in paediatric patients treated in four consecutive AML-BFM trials.
A total of 1111 children with acute myeloblastic leukaemia (AML) were treated in four consecutive Berlin-Frankfurt-Münster (BFM) studies from 1978 to 1998. The first cooperative trial AML-BFM 78 established intensive chemotherapy with seven drugs, CNS irradiation and 2-year maintenance, achieving a long-term survival (overall survival (OS)) of 40%. Induction intensification in AML-BFM 83 resulted in significant improvement of disease-free survival (DFS). The risk of haemorrhage, especially in children with hyperleukocytosis, proved the high relevance of supportive care. In AML-BFM 87, the benefit of CNS irradiation in preventing CNS/systemic relapses was demonstrated. In AML-BFM 93, the introduction of idarubicin during first induction followed by intensification with HAM increased the 5-year EFS, DFS and OS to 50+/-2, 61+/-3 and 57+/-2%, respectively. Stem cell transplantation (SCT), as applied in high-risk patients with a matched related donor, did not significantly improve the outcome compared to chemotherapy alone. In spite of treatment intensification, the therapy-related death rate decreased from trial to trial, mainly during induction. The future aim is to reduce long-term sequelae, especially cardiotoxicity, by administration of less cardiotoxic drugs, and toxicity of SCT by risk-adapted indications. The AML-BFM studies performed in three European countries with >70 cooperating centres have significantly improved the outcome in AML children; nevertheless, increasing experience with these intensive treatment regimens is of fundamental importance to reduce fatal complications.
Adolescent↗
Common genetic variants in the interleukin-6 and chitotriosidase genes are associated with the risk for serious infection in children undergoing therapy for acute myeloid leukemia.
Infectious complications represent a substantial cause of morbidity and mortality in children undergoing therapy for acute myeloid leukemia (AML). Since it has been shown that alterations in innate immune pathways contribute to the risk for serious infections, we analyzed well-characterized variants in innate immune genes (TNF, IL6, IL8, MPO, CHIT, FCGR2A, TLR2, and TLR4) to determine their possible contribution to infectious complications during therapy for pediatric AML. The study population consisted of 168 North European Caucasian children enrolled on the clinical trial AML-BFM 93. We found an association between Gram-negative bacterial infection and common, functional variants in two genes, IL6 and CHIT. The risk for infection was significantly higher in children with the G allele in the IL6 promoter at -174 bp (P=0.026) and in patients with the H allele of CHIT (P=0.033). The promoter variant in IL6 has been shown to increase expression while the H allele disrupts both function and circulating levels. Our data suggest that variant alleles of both IL6 and CHIT could influence susceptibility to infection with Gram-negative bacteria in children undergoing therapy for AML. Follow-up studies, namely replication association studies and in vitro investigation of these common polymorphisms, are warranted to confirm these observations.
Acute Disease↗
Differences in the prevalence of PTPN11 mutations in FAB M5 paediatric acute myeloid leukaemia.
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Acute Disease↗
Mutations in the high-affinity IgE receptor beta-chain are not associated with nonresponder status.
BACKGROUND: Basophils of some individuals do not release histamine upon activation of their high-affinity immunoglobulin E (IgE) receptor (Fc(epsilon)RI), but do so if this receptor is circumvented for cell activation. This so-called nonresponder phenomenon is clinically relevant, because in various studies atopy was less frequent or absent in nonresponder individuals. So far, it is unknown if this phenomenon is acquired during adulthood or exists from birth on. METHODS: Histamine release was determined from isolated leucocytes stimulated with anti-IgE or calciumionophor. Also, random primed cDNA was synthesized and the open reading frame (ORF) of the Fc(epsilon)RI beta-subunit amplified and sequenced. RESULTS: In the first part of our study, we examined the role of atopic status, type of atopy, and age in a random population of 95 children of whom we found 22% to be nonresponder. None of these parameters correlated with the nonresponder status. Except for food allergy, no specific type of atopy correlated with histamine release. The mechanism underlying the nonresponder phenomenon is assumed to occur early in the signalling cascade. We hypothesized that mutations in the Fc(epsilon)RI beta-chain may be associated with the nonresponder status, and in the second part of our study sequenced the beta-subunit in 20 responders and 20 nonresponders. Two conservative and two nonconservative heterozygous one base mutations (Thr179Thr, Asp216Asp, Ile147Leu and Glu237Gly) were found in two nonresponders and one responder. Three of these mutations have not been described so far. CONCLUSION: The nonresponder phenomenon is present from birth on and genetically determined. In our population, it was not associated with age or the presence of atopy, and appeared not to be caused by mutations in the Fc(epsilon)RI beta-chain.
Age Factors↗
Modern diagnostics in chronic myeloproliferative diseases (CMPDs).
According to the new WHO classification a group of chronic myeloproliferative diseases (CMPDs) were defined: chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia and hypereosinophilic syndrome (CEL/HES), polycythemia vera (PV), chronic idiopathic myelofibrosis (with extramedullary hematopoiesis, CIMF), essential thrombocythemia (ET), and so called CMPD/unclassifiable. As clinical features and laboratory findings differ widely between these diseases several diagnostic approaches are mandatory at diagnosis for classification and are needed also for follow up studies, especially for the measurement of minimal residual disease (MRD). We here outline the laboratory set up at diagnosis and during follow up in CMPDs with specific focus on the respective therapeutical consequences. Only by using a comprehensive diagnostic panel including cytomorphology, cytogenetics, and molecular genetic methods establishing the correct diagnosis, optimizing treatment as well as evaluating treatment response is possible in CMPDs today.
Blood Cell Count↗