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Biomedical subjects

K Welte

Publications and source records attributed to K Welte.

216 records · Page 12Linked to original sources
PubMed1982

[Varicella-zoster-immunoglobulin as a safe prophylaxis of varicella (author's transl)].

The occurrence of varicella in the course of immunosuppressive therapy is always a hazard to life. Up till now, passive immunization is the only method which provides reliable protection. We have had an immunoglobulin compound at our disposal during the last 5 years. This compound was obtained by screening a plasmapool for high-titre varicella antibodies, which were then fractionated. Varicella immunoglobulin was injected on 298 occasions to children incubated with varicella. There were no serious side effects after i.v. administration. These children were on polychemotherapy because of malignant diseases. Only 4 children developed varicella, 3 of them very mildly and none of them was later disabled due to varicella in any form. The protective value of this varicella-immunoglobulin compound is much greater than any other known so far [16].

Adolescent↗
PubMed1981

[Implications of terminal deoxynucleotidyl transferase activity in various forms of childhood leukemia (author's transl)].

Terminal deoxynucleotidyl transferase (TdT) was examined in mononuclear peripheral blood cells (pB) and bone marrow (BM) specimens of 63 children with acute leukemia (AL). The enzyme activity in normal specimens (pB, BM) was below 0.2 U/10(8) cells; whereas, 49 of the 52 children with acute lymphoblastic leukemia (ALL) at diagnosis showed an activity in the range 1.2--60 U/10(8) cells. 2 of the remaining 3, devoid of TdT activity, were found to be B-cell leukemia. Patients with acute non-lymphoblastic leukemia (ANLL) were generally TdT-negative. Elevated level of TdT activity was detected in only one of 11 children with ANLL. In one patient with acute leukemia two distinct populations of cells with lymphoblastic (87%) and myeloblastic characteristics were evident. The clinical course and cell marker studies were consistent with the interpretation of a defect at the level of the common stem cell giving rise to a TdT-positive lymphoblastic cell population at diagnosis and, following the initial ALL-therapy (4 weeks), a predominant TdT-negative myeloblastic population. TdT as a marker for the modulation of chemotherapy was examined in the remission phase of the disease. Of the nine patients in the first 3 months of remission, one was found to have elevated level of TdT activity (2.5 U/10(8) cells). These data define the usefulness of TdT in the classification of acute leukemia.

Acute Disease↗
PubMed1979

Purification and biochemical characterization of a virus-specific reverse transcriptase from human osteosarcoma tissue.

A RNA-dependent DNA polymerase (RTase) was purified from human osteosarcoma tissue by successive column chromatography of the microsomal fraction on DEAE-cellulose (DE-23 and DE-52) and phosphocellulose. The purified enzyme has a molecular weight of about 68,000, a pH optimum of 8.1, a Mg2+ optimum of 0.8 mM, Mn2+ optimum of 1.0 mM and a KCl optimum of 60 mM. The enzyme transcribes (rA)n . (dT)12, (rC)n . (dG)12-18 and (2-O-methyl C)n . (dG)18, but is unable to transcribe (dA)n . (dT)10. The enzyme has no catalytic activity in the presence of oligodeoxynucleotide initiators alone, indicating the absence of terminal deoxynucleotidyl transferase. The purified enzyme is able to transcribe the heteropolymeric regions of a 70S RNA from R(Mu)LV. The presented data support the presence of a RNA-dependent DNA polymerase in human osteosarcoma tissue with biochemical properties, resembling those of C-type RNA tumor viruses.

Adolescent↗
PubMed1977

[The west-berlin therapy study of acute lymphoblastic leukemia in childhood--report after 6 years (author's transl)].

During the last 6 years 73 previously untreated children and adolescents with acute lymphoblastic leukemia were enrolled on a non-randomized therapy protocol. In this longitudinal sutdy the specific accent was put on the intensified induction treatment of 8 weeks' duration which was thought to achieve a higher remission quality. In this phase 8 effective drugs were applied up to the patient's tolerance limits; in addition prophylactic irradiation to the central nervous system was given in two modifications. After 4 weeks all patients were in complete remission. During the first 4 months 6 children died due to complications for which therapy must be at least partially responsible. 17 out of 67 patients relapsed between 4 and 59 months after diagnosis, which corresponds to a remission rate according to the life table analysis of 62% (50 out of 67 patients in first remission). The majority of patients with relapse is characterized at diagnosis by a specific pattern of clinical findings. 2 therapy groups, differently treated in respect to central nervous system irradaiation and duration of continuation therapy, do not at present statistically differ from each other. According to statistics 8 more children may be expected to suffer from relapse. The improved results are due to a lower incidence of bone marrow relapses; it seems that there is a direct relation between intensity of treatment during the induction phase and the occurrence of bone marrow relapses. The specific problems of the presented study take place during the induction phase, which, due to toxicity, regularly results in a number of side effects and severe complications. In order to realize the induction therapy, the use of prophylactic and supportive procedures is of utmost importance. Profound knowledge of possible side effects and complications is most essential as well as the knowledge of how to cope with these problems. It is the authors' opinion that the induction phase can only be performed in specialized institutions, because only at these places enough information may be obtained from an adequate number of patients and only there pediatric oncologists may share in the decisions and responsibilities. Only by using every kind of medical service this method of therapy may be justified at present, according to the results of this study, for the benefit of children with leukemia.

Adolescent↗
PubMedDate not supplied

[Severe congenital neutropenia: trends in diagnosis and therapy].

Severe congenital neutropenia (CN; Kostmann syndrome) is a hematologic disorder characterized by a maturation arrest of myelopoiesis at the promyelocyte/myelocyte stage of development. This arrest results in severe neutropenia with absolute neutrophil counts (ANC) less than 0.2 x 10(9)/l associated with severe systemic bacterial infections from early infancy. Data on over 300 patients with CN collected by the Severe Chronic Neutropenia International Registry (SCNIR) since 1994 indicate that > 90% of these patients respond to recombinant human granulocyte-colony stimulating factor (rHuG-CSF) treatment with an ANC > 1.0 x 10(9)/l. In these patients rHuG-CSF is required daily as subcutaneous injection with individual doses ranging between 0.27 and 120 mcg/kg/day to maintain ANC above 1.0 x 10(9)/l. Adverse events documented in this group of patients include splenomegaly, thrombocytopenia, osteoporosis and malignant transformation into MDS/leukemia. If and how rHuG-CSF treatment impacts on these adverse events remains unclear since there are no historical controls for comparison. For those patients who are refractory to rHuG-CSF treatment and continue to have severe and often life-threatening bacterial infections, hematopoietic stem cell transplantation (HSCT) is still the only currently available treatment.

Adjuvants, Immunologic↗
PubMedDate not supplied

[Congenital amegakaryocytic thrombocytopenia (CAMT) - a defect of the thrombopoietin receptor c-Mpl].

Congenital amegakaryocytic thrombocytopenia (CAMT) is a very rare bone marrow failure syndrome presenting with isolated hypomegakaryocytic thrombocytopenia at birth developing into a pancytopenia during the first years of life. Bone marrow transplantation is the only curative therapy for this disease so far. Thrombopoietin (TPO) is the most important hematopoietic growth factor for the regulation of megakaryopoiesis and thrombopoiesis. We investigated TPO production and reactivity in CAMT patients. TPO plasma levels were high like in other forms of thrombocytopenia due to ineffective megakaryopoiesis. However, we found a defective reactivity to TPO: Neither hematopoietic progenitor cells in the bone marrow nor platelets from the peripheral blood did respond to TPO. Flow cytometric investigations demonstrated a lack of expression of the TPO receptor c-Mpl on the surface of platelets. Accordingly, we found mutations in the c-mpl gene, which are predicted to lead to a complete or at least partial loss of function of the TPO receptor. TPO is not only involved in the regulation of megakaryocytopoiesis but also in early hematopoiesis. This seems to be the reason for the general defect in hematopoiesis in CAMT leading to the development of pancytopenia.

Animals↗
PubMedDate not supplied

Clinical outcome of patients with childhood acute lymphoblastic leukaemia and an initial leukaemic blood blast count of less than 1000 per microliter.

BACKGROUND: One of the strongest predictive factors for therapy outcome in childhood acute lymphoblastic leukaemia (ALL), treated according to ALL-BFM protocols, is the response to initial prednisone treatment. Prednisone response is characterized by the peripheral leukaemic blast count. The threshold value for the characterisation as good or poor prednisone response is 1000 blasts/microliter on day eight of initial prednisone treatment. It is frequently being discussed, whether patients with ALL that initially present with < 1000 blasts/microliter and still show < 1000 blasts/microliter by day eight of treatment, have the same therapy outcome as prednisone good-responders with initially >/= 1000 blasts/microliter. PATIENTS AND METHODS: We evaluated all patients included in the ALL-BFM 90 study showing good prednisone response. This group included 660 patients presenting with < 1000 blasts/microliter at diagnosis. We compared these patients with the prednisone good-responders that initially presented with >/= 1000 blasts/microliter. In addition we analysed all patients who showed an increasing blast count within the threshold of 1000 blasts/microliter by day eight of treatment. RESULTS: Children presenting with ALL and < 1000 blasts/microliter at diagnosis showed a small but significantly better outcome than prednisone good-responders with initially >/= 1000 blasts/microliter (5 year pEFS 0.86 vs. 0.81, P value 0.0064). If analyzed by treatment group, no significant differences were found. Patients with < 1000 blasts/microliter on day eight of treatment but increasing blast count from diagnosis until day eight did not perform worse. CONCLUSION: The prognostic value of the prednisone response is not restricted to childhood ALL patients presenting with >/= 1000 blasts/microliter at diagnosis, but retains its strength as a strong predictor of treatment outcome also in patients with < 1000 blasts/microliter at diagnosis.

Antineoplastic Agents, Hormonal↗
PubMedDate not supplied

[Long-term treatment with recombinant human granulocyte colony stimulating factor in patients with severe congenital neutropenia].

Severe congenital neutropenia is a disorder of myelopoiesis characterized by severe neutropenia secondary to either a maturational arrest of myelopoiesis at the level of promyelocytes (Kostmann-Syndrome; SCN) or regular cyclic fluctuations in the number of blood neutrophils with a median ANC below 500/microliter (cyclic neutropenia). We have treated 32 patients with SCN and 4 patients with cyclic neutropenia. Thirty of 32 patients with SCN and all 4 patients with SCN responded to r-met HuG-CSF treatment with an increase of the median ANC to above 1000/microliter. The doses needed to achieve and maintain the response varied between 0.8 and 120 micrograms/kg/d. Long-term treatment did not exhaust the myelopoiesis: The mean ANC remained stable up to 5 years of treatment. The increase in ANC was associated with dramatic clinical responses: significant reduction of severe bacterial infections, reduction of intravenous antibiotic treatment episodes, and reduction of hospitalizations. No severe bacterial infections occurred in any of the r-met HuG-CSF responders during long-term treatment. Severe adverse event, most likely associated with the underlying disease, included the development of MDS/Leukemia in two patients, and osteopenia/osteoporosis in 12 patients. These results demonstrate the beneficial effects of r-met HuG-CSF treatment in severe congenital neutropenia patients.

Adolescent↗
PubMedDate not supplied

Medulloblastoma cells constitutively produce granulocyte colony-stimulating factor.

Granulocyte colony-stimulating factor (G-CSF) was previously shown to be produced constitutively by malignant epithelial cells and by monocytes/macrophages, fibroblasts and endothelial cells following stimulation. In this study we investigated the ability of medulloblastoma cells, representing malignant embryonal neuroectodermal cells, to produce G-CSF. Conditioned medium was freshly prepared from unstimulated explanted tumor tissue from two patients with medulloblastoma as well as from the medulloblastoma cell lines TE-671 and DAOY, and as controls normal glial cells. Following 72 hours of culture at a density of 5 x 10(5) cells/ml in RPMI 1640 with 10% FCS, the supernatants were harvested and tested for the presence of G-CSF in (1) the CFU-GM asay, (2) proliferation assay using the G-CSF dependent cell line NFS-60, and (3) Western blot analysis using an anti-G-CSF monoclonal antibody. Biological active and immunological detectable G-CSF was secreted by the medulloblastoma cell line DAOY and by one of the explanted tumor biopsies. The cell line TE-671 as well as normal glial cells did not produce G-CSF under identical culture conditions. We conclude that in addition to previously described sources of G-CSF, neuroectodermally derived medulloblastoma cells are also able to produce G-CSF constitutively. The G-CSF production was increased after stimulation with IL-1 alpha or TNF alpha. The role of G-CSF in neuroectodermal tissues remains to be further investigated.

Bone Marrow↗
PubMedDate not supplied

[Granulocyte colony-stimulating factor (G-CSF): biochemistry, biology and pathophysiology].

G-CSF belongs to a family of hematopoietic growth factors, also known as colony stimulating factors. It supports the growth and differentiation of predominantly committed neutrophil precursors and activates the function of peripheral blood neutrophils in vitro. In vivo studies in primates (Cynomolgus monkeys) demonstrated that G-CSF is a potent myeloid growth and differentiation factor causing a dose-dependent increase predominantly in the peripheral blood neutrophils. To assess the effects of G-CSF in chemotherapy induced cytopenias, we administered G-CSF to monkeys that had been treated with cyclophosphamide (60 mg/kg/dx2), or repeated cycles of busulfan (4, 6 or 10 mg/kg/dx3). In both, cyclophosphamide and busulfan induced myelosuppression, G-CSF in doses between 10 and 30 micrograms/kg/d was able to significantly shorten the time of neutropenia. In addition, monkeys were treated with G-CSF (50 or 100 micrograms/kg/d) for one month post autologous bone marrow transplantation following total body irradiation. The time of neutropenia (less than 1000 neutrophils/mm3) was shorter in the G-CSF treated monkeys (10 days in the 100 micrograms/kg/d treated monkey) compared to two controls (21 days). The post transplant absolute neutrophil count of approximately 30,000/mm3 could be maintained for the entire period of G-CSF exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

[Detection of translocation t(8;14)(q24;132) in pediatric Burkitt's lymphomas using "long distance" polymerase chain reaction: a new method for diagnosis of Burkitt's lymphomas].

The pediatric Non-Hodgkin's lymphomas are a heterogeneous group of malignancies of B- or T-cell origin. Approximately half of them are characterized as Burkitt's lymphomas. Typically, one of the reciprocal translocations t(8;14)(q24;q32), t(2;8)(p11;q24) or t(8;22)(q24;q11) is seen in the tumor cell, each involving the protooncogene c-myc on chromosome 8. Characteristically, in most patients the translocation occurs between the distal end of the long arm on chromosome 8 (c-myc) and chromosome 14 (immunoglobulin heavy chain locus, IgH). The breakpoint regions are distributed over a wide range of more than 10 Kb on chr. 8 and over several hundred Kb on chr. 14. With standard-PCR, fragments can only be amplified to a size of about 2 Kb. The development of PCR-applications to generate long products up to 20 Kb now allows a detection of these breakpoints. Several primer pairs from different regions of the IgH-gene and the c-myc-gene were tested in each patient. Until now, 20 patients with Burkitt's Lymphoma or B-ALL characterized by L3 morphology were examined. All patients were treated according the protocols of the NHL-BFM '90 or '95 study. In 11/20 patients, recombinations between chromosomes 8 and 14 could be detected with our primer pairs. In serial dilutions of DNA from malignant cells in DNA from healthy controls, sensitivities of one malignant cell in 2 x 10(4) normal cells could be obtained. This method will now allow us to characterize the involved breakpoints more exactly and to analyze patient samples (blood, bone marrow, aphereses products and residual tumors) during or after therapy for the existence of minimal residual tumor cells.

Adolescent↗
PubMedDate not supplied

[Significance of thrombopoietin and its receptor c-Mpl in regulation of thrombocytopoiesis in thrombocytopenia].

Thrombopoietin (TPO) belongs to the family of hematopoietic growth factors. It supports the growth and differentiation of megakaryocytic progenitors and precursors in vitro and in vivo. The predominant site of production of TPO is the liver. However, regulation of TPO serum levels seems to be not due to transcriptional regulation in the liver but due to degradation of circulating TPO by platelets. Thrombopoietin serum levels in children with thrombocytopenia associated with aplastic anemias, Fanconi anemia and TAR syndrome are elevated whereas in children with idiopathic thrombocytopenia the TPO levels are normal. The defective activation of platelets by TPO in a children with TAR syndrome suggests a defective response of megakaryocytopoiesis to TPO.

Anemia, Aplastic↗
PubMedDate not supplied

Granulocyte-macrophage colony-stimulating factor (GM-CSF) reduces the density of stem cell factor receptors (c-kit oncogene product) on a GM-CSF-dependent human myeloid cell line.

By employing a monoclonal antibody against the stem cell factor receptor (SCF-R), c-kit oncogene product, we analysed in flow cytometric technique the density of SCF-R on GM/SO cells which were incubated under various culture conditions. These experiments revealed that there is an inverse correlation between the SCF-R density on the cells and the doses of granulocyte-macrophage colony-stimulating factor (GM-CSF) in culture medium; the lower the dose, the higher the density of SCF-R on the cells. More detailed analyses showed that, in contrast to SCF which rapidly downregulates its own receptor, GM-CSF does not alter the measurable level of SCF-R in an exposition period of 60 minutes, which suggests that the internalization or shedding of the receptor is not the mechanism of action. Since the most striking difference regarding density of SCF-R between GM-CSF-treated and untreated cells was observed on day 2, the modulation of c-kit oncogene protein by GM-CSF likely occur prior to expression of protein onto the cell surface. In order to exclude the possibility that altered cell viability due to insufficient GM-CSF content in culture medium might be responsible for the increased SCF-R densities on GM-CSF-dependent cells, we subsequently generated a GM-CSF-independent subclone which still responded to GM-CSF as well as the dependent did. The experiments carried out with this subclone confirmed the results presented above. Thus our data suggest that GM-CSF is directly involved in the regulation of SCF receptor density on GM/SO cells.

Antibodies, Monoclonal↗