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Biomedical subjects

K Welte

Publications and source records attributed to K Welte.

At least 19 recordsLinked to original sources
PubMed2007

Substitution of cyclophosphamide and busulfan by fludarabine, treosulfan and melphalan in a preparative regimen for children and adolescents with Shwachman-Diamond syndrome.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only definitive treatment for severe bone marrow dysfunction and clonal disorders in patients diagnosed with Shwachman-Diamond syndrome (SDS). In an attempt to minimize regimen-related toxicity (RRT), we have initiated a fludarabine/treosulfan/melphalan-based pilot protocol avoiding the combination of busulfan and cyclophosphamide. Median age at transplantation was 9.6 years (range 1.5-17 years). All three patients received conditioning with fludarabine (30 mg/m2/day x 6), treosulfan (12 g/m2/day x 3) and melphalan (140 mg/m2/day x 1). CAMPATH-1H (0.1 mg/kg x 2) was added in two cases, while rabbit ATG (Genzyme; 3 x 2.5 mg/kg) was given to the cord blood recipient. One patient was transplanted with a non-manipulated marrow graft from an HLA-identical sibling, one with a marrow graft from a 10/10 matched unrelated donor, and one with a 9/10 matched unrelated umbilical cord blood (UCB) unit. Mean cell doses given were 3.6 x 10(8) nucleated cells/kg BW for the bone marrow recipients and 4.2 x 10(7) nucleated cells/kg BW for UCB recipient. Overall, two of three patients are alive and display 100% donor chimerism. Acute graft-versus-host disease grade II was seen in one patient, while no GVHD exceeding grade I occurred in the remaining two.

Abnormalities, Multiple↗
PubMed2006

Dendritic cell deficiencies in pediatric acute lymphoblastic leukemia patients.

Acute lymphoblastic leukemia (ALL) cells are particularly poor at generating anti-leukemia immunity, despite residing in lymphoid organs. To assess a potential role of dendritic cells (DC) in poor anti-leukemia immunity, we analyzed peripheral blood DC in 55 pediatric ALL patients at the time of initial diagnosis and 19 age-matched healthy controls. Dendritic cells were identified by their expression of HLA-DR, lack of B, T, NK, and monocyte markers, and expression of CD11c (myeloid DC(mDC)) or BDCA-2 (plasmacytoid DC(pDC)) using flow cytometry. We found that in children with B-lineage ALL, numbers of both mDC and pDC were significantly reduced (P = 0.0001). In contrast, T-lineage ALL patients showed normal pDC and significantly elevated mDC (P = 0.003) levels, with normal expression of HLA-DR and co-stimulatory molecules. A decrease in DC could not be explained by general impairment of myelopoiesis, as we could not demonstrate a correlation of DC numbers with granulocyte/monocyte numbers in patients with B-lineage ALL. However, aberrant expression of myeloid surface markers on leukemic blasts was frequent in patients lacking myeloid DC indicating a potential block of DC differentiation. Thus, depletion of DC in B-lineage ALL patients may contribute to poor anti-leukemia immune responses.

Adolescent↗
PubMed2006

Generation and characterization of a novel hematopoietic progenitor cell line with DC differentiation potential.

Studies of hematopoietic stem cell (HSC)-derived dendritic cells (DCs) are often limited by the rarity of HSC. To facilitate the study of DCs, we have generated a novel cell line (CR1) by retroviral Notch(IC) gene transfer into Sca1(+)ckit(+)lin- HSC. CR1 cells proliferated in vitro in the presence of recombinant interleukin-3. They maintained an immature progenitor cell phenotype and an intact karyotype. In the presence of granulocyte-macrophage colony-stimulating factor or Flt3L, CR1 cells differentiated into myeloid and plasmacytoid DCs, respectively. Functionally, CR1 cells were comparable to primary bone-marrow-derived DCs with respect to Toll-like-receptor-mediated maturation, cytokine release and capacity to induce effective antitumor immunity. CR1 cells thus provide an elegant new cellular tool to study DC development, function and preclinical DC-based immunotherapies.

Cell Differentiation↗
PubMed2006

Unsupervised proteome analysis of human leukaemia cells identifies the Valosin-containing protein as a putative marker for glucocorticoid resistance.

The response to initial glucocorticoid therapy in childhood acute lymphoblastic leukaemia (ALL) reliably predicts the response to multiagent chemotherapy. Patients resistant to glucocorticoids (prednisone poor responders (PPR)) have a poorer event-free survival compared to glucocorticoid-sensitive patients (prednisone good responders (PGR)). A case-control study was performed to investigate differential protein expression in leukaemic blasts from PGR and PPR childhood ALL patients. Two-dimensional gel electrophoresis (2-DE) was used for an unsupervised screening and surface enhanced laser desorption/ionisation-time of flight mass spectrometry (SELDI-TOF MS) for the characterisation of protein spots. In difference maps of average gels for the proteomes of each responder group, differentially expressed proteins were identified after tryptic digestion and spotting onto H4-SELDI-TOF-MS chips. Proteins overexpressed in PPR were Catalase, RING finger protein 22 alpha, Valosin-containing protein (VCP) and a G-protein-coupled receptor. Proteins overexpressed in PGR were protein kinase C and malate dehydrogenase. Valosin-containing protein was chosen for validation and quantification by Western blot analysis in a second case-control group of ALL patients. In this second independent cohort, median VCP expression (P25-P75) was 0.15 (0.11-0.28) in PGR and 0.34 (0.14-0.99) in PPR patients (P = 0.04). We conclude that high VCP expression is associated with poor prednisone response in childhood ALL patients.

Adenosine Triphosphatases↗
PubMed2006

Jacobsen syndrome and Beckwith-Wiedemann syndrome caused by a parental pericentric inversion inv(11)(p15q24).

Here we report on a male infant presenting the typical pattern of Jacobsen syndrome including trigonocephaly, thrombocytopenia, congenital heart defect, urethral stenosis, and partial agenesis of the corpus callosum. Conventional karyotyping, FISH, SKY and CGH analyses showed that the region distal to the MLL locus on 11q23 was lost and replaced by the distal region of 11p, leading to a partial trisomy of 11p and a partial monosomy of 11q. According to ISCN (1995) the karyotype can be described as 46,XY,add(11)(q2?3). ish 11ptel(D11S2071x3),11qtel(VIJyRM2072x1). Array-CGH analysis allowed us to narrow down the breakpoints to 11p15.1 and 11q24.1. Methylation analyses of genes located on 11p showed an increased level of the non-methylated paternal allele of the KCNQ1OT1 gene, confirming the concomitant presence of Beckwith-Wiedemann syndrome (BWS). The phenotype resulting from the 11q deletion seems to dominate the phenotype due to the distal 11p trisomy. Investigation of the parents revealed that this chromosomal rearrangement was caused by a paternal pericentric inversion inv(11)(p15q24). Since chromosomal aberrations like the one described here can easily be overlooked during routine chromosome analysis, combined FISH analysis using subtelomeric and possibly additional probes should be applied if there is any doubt about the integrity of telomeric regions.

Abnormalities, Multiple↗
PubMed2005

Transplantation of allogeneic CD34-selected stem cells after fludarabine-based conditioning regimen for children with mucopolysaccharidosis 1H (M. Hurler).

Hurler syndrome (MPS1H) is a progressive inborn error of mucopolysaccharide metabolism leading to premature death. Allogeneic hematopoietic cell transplantation (HCT) can achieve stabilization and improve long-term survival. However, large studies have shown that preparative regimen-related toxicity (RRT) and graft failure rates have been relatively high. We transplanted five Hurler children with a fludarabine-based conditioning regimen, consisting of fludarabine/busulphan/ATG for matched family donor (MFD), with the addition of melphalan for mismatched family donor and matched unrelated donor (MUD) transplantations. Median age at HCT was 27 months (range 10-36). The source of stem cells was bone marrow in one MFD and CD34-selected PBSC in four patients. Median CD34+ cell dose was 25 x 10(6)/kg (range 11.5-54). No RRT > grade II was observed. All patients are surviving at a median of 32 months (range 14-41) and show sustained donor engraftment with 3/5 having full donor chimerism, and 2/5 mixed chimerism (> 85%). We conclude that this regimen is feasible and has low toxicity in Hurler children. In combination with high doses of CD34+ selected cells (> 10 x 10(6)/kg) and donor lymphocyte infusions, stable engraftment could be achieved in unrelated and mismatched related transplantations.

Antigens, CD34↗
PubMed2005

The impact of cyclosporin A on acute graft-versus-host disease after allogeneic bone marrow transplantation in children and adolescents with acute lymphoblastic leukemia.

Experimental and clinical data demonstrate an antileukemia effect of acute graft-versus-host disease (aGVHD). In all, 58 pediatric patients with acute lymphoblastic leukemia (ALL) who had received an allogeneic bone marrow transplant (BMT) at our institution were retrospectively analyzed for a correlation between the development of aGVHD and leukemic relapse. Probability of relapse after 5 (3) years was 13% (7%) in patients developing grade II-IV aGVHD vs 30% in patients with grade 0 or I aGVHD. There was a trend for a difference of the point estimates at 3 years, but no overall significance because of an unusual late relapse. Moreover, we analyzed the impact of cyclosporin A (CsA) on aGVHD in a subgroup of 22 children who had received a matched sibling donor (MSD) BMT. An increased dose of CsA within the first 2 weeks after BMT led to decreased occurrence and severity of aGVHD (P=0.035). The cumulative CsA dose appeared to have more impact than the average CsA whole-blood levels within the first 2 weeks and than the CsA dose given from day 15 to 40. In this subgroup, no life-threatening aGVHD or death from aGVHD occurred. In all cases (6/22), leukemic relapse was the cause of death. We therefore suggest that there is a relation between dose of CsA and relapse rate in childhood ALL transplanted from a MSD.

Adolescent↗
PubMed2005

Complete substitution of cyclophosphamide by fludarabine and ATG in a busulfan-based preparative regimen for children and adolescents with beta-thalassemia.

Children and adolescents with homozygous beta-thalassemia can be cured by transplantation of normal stem cells after eradication of the thalassemic hematopoietic system. In an attempt to achieve durable engraftment and to minimize regimen-related toxicity (RRT), we have initiated a fludarabine-based pilot protocol not containing cyclophosphamide. Between 1999 and 2004, five children with beta-thalassemia major were enrolled. Median age at transplantation was 11.5 years (range 4-14 years). Three patients received conditioning with fludarabine (30 mg/m2/day x 6), oral busulfan (3.5 mg/kg/day x 4), and ATG rabbit Fresenius (10 mg/kg/day x 4). Two children received intravenous busulfan instead of oral busulfan at a dose of 2 x 1.4 mg/kg/day x 4 days. All children were transplanted with a fresh bone marrow graft from an HLA-identical sibling. Mean cell doses given were 3.7 x 10(8) nucleated cells/kg BW (range 2.4-6.2 x 10(8)/kg). Overall, 5/5 patients achieved donor engraftment and are alive and well. No GVHD exceeding grade I was observed, and 2/5 children maintained donor chimerism at 100%. One patient maintains mixed hematopoietic donor chimerism being between 94 and 97% nearly 5 years after transplant.

Adolescent↗
PubMed2005

Immunosurveillance of childhood ALL: polymorphic interferon-gamma alleles are associated with age at diagnosis and clinical risk groups.

Interferon-gamma (IFN-gamma) has been implicated as an important mediator of antitumor immunity in murine model systems. To determine whether a CA-repeat associated with differential NFkappaB-binding and IFN-gamma-expression levels may influence the incidence, manifestation and early clinical treatment response of childhood acute lymphoblastic leukemia, we performed PCR-based genotyping of 393 patients with ALL and 207 healthy controls. We could not find any differences in the allele distribution comparing patients and controls. However, when we further analyzed the allele frequencies with respect to age of clinical manifestation, we found that patients with B-lineage ALL showing the IFN-gamma high-expressing genotype presented at a more advanced age compared to those patients with intermediate and low-expressing genotypes (median 6 vs 4.4 years, P=0.01). Furthermore, we found a significantly higher number of low expressors in the group of high-risk patients (HR n=32 and MR/SR n=266, P=0.025, defined by prednisone response, cytological remission and minimal residual disease (MRD)) with B-lineage ALL. Thus, we provide evidence that polymorphic IFN-gamma alleles are associated with age at clinical presentation and risk groups such as prednisone response in B-lineage ALL, suggesting distinct effects of IFN-gamma in immunosurveillance and early response to steroid therapy.

Cell Lineage↗
PubMed2005

An acquired G-CSF receptor mutation results in increased proliferation of CMML cells from a patient with severe congenital neutropenia.

Severe congenital neutropenia (CN) is characterized by a maturation arrest of myelopoiesis at the promyelocyte stage. Treatment with pharmacological doses of recombinant human granulocyte colony-stimulating factor (rh-G-CSF) stimulates neutrophil production and decreases the risk of major infectious complications. However, approximately 15% of CN patients develop myeloid malignancies that have been associated with somatic mutations in the G-CSF receptor (G-CSFR) and RAS genes as well as with acquired monosomy 7. We report a CN patient with chronic myelomonocytic leukemia (CMML) who never received rh-G-CSF. Molecular analysis demonstrated a somatic G-CSFR mutation (C2390T), which led to expression of a truncated G-CSFR protein in the CMML. Normal G-CSFR expression was unexpectedly absent in primary and cultured CMML. In addition, CMML cells showed monosomy 7 and an oncogenic NRAS mutation. In vitro culture revealed a G-CSF-dependent proliferation of CMML cells, which subsequently differentiated along the monocytic/macrophage lineage. Our results provide direct evidence for the in vivo expression of a truncated G-CSFR in leukemic cells, which emerged in the absence of rh-G-CSF treatment and transduces proliferative signals.

Adolescent↗
PubMed2003

Expression of heat-shock protein 90 in glucocorticoid-sensitive and -resistant childhood acute lymphoblastic leukaemia.

Early reduction of leukaemic cells by chemotherapy is a strong predictor for treatment outcome in childhood acute lymphoblastic leukaemia (ALL). In ALL-(Berlin-Frankfurt-Münster) trials, early treatment response is assessed by the in vivo response to glucocorticoids (prednisone response, PR), the molecular background of which is unknown. The intracellular effects of glucocorticoids (GCs) are mediated by the glucocorticoid receptor (GR). In the absence of GC, the inactive GR resides within a multiprotein complex, consisting predominantly of the chaperone protein hsp90 (heat-shock protein 90). Until now, studies targeting GC resistance mainly focused on GR disorders and alterations of genes known to be associated with drug resistance. In addition, the GR multiprotein complex was associated with GC resistance in in vitro studies. We performed a case-control study for PR to investigate the association of in vivo GC resistance and hsp90 expression in childhood ALL. Hsp90 expression was assessed using a real-time PCR approach (Taqman technology) and Western blot technology. In this setting, we found no association of in vivo GC resistance and hsp90 expression. Therefore, we conclude that the expression of hsp90, the major component of the GR activating complex, is of minor importance for the in vivo GC resistance in childhood ALL.

Adolescent↗
PubMed2003

Invasive fungal infections are responsible for one-fifth of the infectious deaths in children with ALL.

The following report will discuss in detail all lethal invasive fungal infections (IFI) that occurred in a group of 2021 children with acute lymphoblasic leukaemia (ALL). The German ALL-Berlin-Frankfurt-Muenster (BFM) study group is one of the largest cooperation for the treatment of childhood ALL. Between 1995 and 2000, 2021 children with ALL received chemotherapy according to the German BFM 95 protocols (ALL-BFM 95). This population was retrospectively screened, whether a lethal fungal infection occurred: totally, in this group, 43 of 2021 (2.1%) children died because of infections. Nine of 43 (21%) patients died in the context of an IFI: six fatal Aspergillus infections and three fatal yeast infections were reported. The following report will focus on the nine children with ALL who died from IFI. The underlying risk factors (RF) included neutropenia (seven of nine patients) and steroid medication (nine of nine patients). Seven of nine children had additional medical complications (e.g. liver failure, haemolytic uraemic syndrome and acute renal failure). In six of nine children the fungal infection was progressive despite intravenous antimycotic therapy, three patients received no antifungal therapy, as IFI was not considered. The progression of IFI despite antimycotic therapy illustrates the inherent problems of diagnosis and the need for innovative therapeutic modalities. The high percentage (21%) of death from IFI among lethal infections in paediatric ALL patients illustrates the relevance of fungi in this group of patients. On the contrary, the total number of IFI in paediatric ALL patients remains to be determined, as only lethal infections were included in this report.

Acute Kidney Injury↗
PubMed2003

Thrombopoietin is essential for the maintenance of normal hematopoiesis in humans: development of aplastic anemia in patients with congenital amegakaryocytic thrombocytopenia.

Recently, we and others could define the molecular cause of the rare disease congenital amegakaryocytic thrombocytopenia (CAMT) as mutations in the c-mpl gene (Blood 97: 139, 2001). We proposed that c-mpl mutations are the cause not only for the hypomegakaryocytic thrombocytopenia, but also for the development of an aplastic anemia (AA) in patients with CAMT. The effects of thrombopoietin (TPO) on early multipotent hematopoietic progenitors were elucidated by a recent series of in vitro and in vivo studies. Like CAMT patients, mice lacking the TPO receptor c-Mpl demonstrate a major reduction of early hematopoietic progenitor cells of all lineages. However, these mice achieve a normal marrow cellularity and composition, despite the lack of megakaryocytes. On the other hand, the incidence of development of aplastic anemia in CAMT is not clear owing to difficult and not consistent diagnosis of this disease.

Anemia, Aplastic↗
PubMed2002

Efficacy and safety of G-CSF mobilized granulocyte transfusions in four neutropenic children with sepsis and invasive fungal infection.

BACKGROUND: Bacterial and fungal infections are serious complications of cancer therapy. Especially during longstanding neutropenia, patients are at risk for life-threatening infections. The aim of this study was to assess the effect and safety of G-CSF mobilized granulocyte transfusions (GTX) in four neutropenic pediatric patients with sepsis. PATIENTS AND METHODS: The patients were between 4.6-17.5 years old and their diagnoses included very severe aplastic anemia, non-Hodgkin's lymphoma (NHL) and acute myeloid leukemia. Before GTX, all patients had fever despite antibiotic and antimycotic therapy, neutropenia (absolute neutrophil count ANC < 500/microl), increasing C-reactive protein (CRP) values, hypotension requiring dopamine infusion and three patients needed supplemental oxygen. The granulocyte donors received G-CSF (Neupogen, 5 microg/kg body weight) 12 h prior to granulocyte apheresis. RESULTS: In total, 40 GTX were performed (range 2-28 per patient). The mean increase of the granulocyte count 1 h after GTX was 1,310/microl (range 200-2,950/microl). Within the period of GTX the CRP values decreased in all patients. During or 24 h after the last GTX, the hypotension resolved and supplemental oxygen was stopped. One GTX was discontinued because of oxygen desaturation. CONCLUSION: GTX were a safe therapeutic measure with beneficial effects on serious infections in neutropenic children.

Adolescent↗
PubMed2002

Association of initial response to prednisone treatment in childhood acute lymphoblastic leukaemia and polymorphisms within the tumour necrosis factor and the interleukin-10 genes.

Plasma levels of TNF and IL-10 have been associated with therapy outcome in haematological malignancies and are influenced by genetic variation due to germline polymorphisms within the TNF and IL-10 genes. Different TNF and IL-10 genetic polymorphisms might therefore also correlate with clinical outcome in childhood acute lymphoblastic leukaemia (ALL). We analysed the association of TNF and IL-10 polymorphisms with response to initial treatment and risk of relapse in 135 children with ALL, treated according to Berlin-Frankfurt-Münster (BFM) protocols. Our data showed a protective effect from prednisone poor response in patients with the IL-10 G/G genotype, whereas no association of the risk of relapse and IL-10 genotype was found. In the total study group, subjects expressing the TNF2 allele neither showed a statistically significant general association with prednisone response nor with risk of relapse compared to subjects homozygous for the TNF1 allele. Nevertheless, we did find a higher risk of relapse in poor prednisone responders expressing the TNF2 allele compared to poor prednisone responders not expressing the TNF2 allele. We conclude that IL-10 genotype might influence prednisone response in patients with childhood ALL, whereas TNF genotype seems to influence the risk of relapse in high risk ALL patients.

Adolescent↗
PubMed2001

Time course of increasing numbers of mutations in the granulocyte colony-stimulating factor receptor gene in a patient with congenital neutropenia who developed leukemia.

Point mutations in the granulocyte colony-stimulating factor receptor (G-CSFR) gene have been linked to the development of secondary leukemia in patients with congenital neutropenia (CN). This report presents data on a now 18-year-old patient with CN who has received G-CSF treatment since 1989 and who developed acute myeloid leukemia (AML) in 1998. To evaluate whether there is an association between the occurrence of point mutations of the G-CSFR gene and development of secondary AML, DNA/messenger RNA of neutrophils and mononuclear cells from this patient were analyzed at different time points by polymerase chain reaction and subsequent cloning by DNA sequencing of representative numbers of individual clones. Findings suggest an increasing instability of the G-CSFR gene in time as judged by increasing numbers of mutations proposed to be one important step in the development of AML in this patient.

Acute Disease↗
PubMed2001

Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86.

PURPOSE: Cooperative Ewing's Sarcoma Study (CESS) 86 aimed at improving event-free survival (EFS) in patients with high-risk localized Ewing tumor of bone. PATIENTS AND METHODS: We analyzed 301 patients recruited from January 1986 to July 1991 (60% male; median age 15 years). Tumors of volume >100 mL and/or at central-axis sites qualified patients for "high risk" (HR, n = 241), and small extremity lesions for "standard risk" (SR, n = 52). Standard-risk patients received 12 courses of vincristine, cyclophosphamide, and doxorubicin alternating with actinomycin D (VACA); HR patients received ifosfamide instead of cyclophosphamide (VAIA). Tumor sites were pelvis (27%), other central axis (28%), femur (19%), or other extremity (26%). The initial tumor volume was <100 mL in 33% of cases and > or =100 mL in 67%. Local therapy was surgery (23%), surgery plus radiotherapy (49%), or radiotherapy alone (28%). Event-free survival rates were estimated by Kaplan-Meier analyses, comparisons were done by log-rank test, and risk factors were analyzed by Cox models. RESULTS: On May 1, 1999 (median time under study, 133 months), the 10-year EFS was 0.52. Event-free survival did not differ between SR-VACA (0.52) and HR-VAIA (0.51, P =.92). Tumor volume of >200 mL (EFS, 0.36 v 0.63 for smaller tumors; P =.0001) and poor histologic response (EFS, 0.38 v 0.64 for good responders; P =.0007) had negative impacts on EFS. In multivariate analyses, small tumor volumes of <200 mL, good histologic response, and VAIA chemotherapy augured for fair outcome. Six of 301 patients (2%) died under treatment, and four patients (1.3%) developed second malignancies. CONCLUSION: Fifty-two percent of CESS 86 patients survived after risk-adapted therapy. High-risk patients seem to have benefited from intensified treatment that incorporated ifosfamide.

Adolescent↗