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Biomedical subjects

D Niethammer

Publications and source records attributed to D Niethammer.

At least 109 records · Page 6Linked to original sources
PubMed1996

MDR1, MRP, topoisomerase IIalpha/beta, and cyclin A gene expression in acute and chronic leukemias.

Gene expression was analyzed by cDNA-PCR at the mRNA level in bone marrow samples (>80% blasts) from ALL (28 primary, 22 first relapses, 10 recurrent relapses), from AML (14 primary, 23 relapses), In peripheral blood lymphocytes from CLL (five untreated, 10 treated), in one CML in blast crisis in the course of the disease (four samples), and in bone marrow samples from healthy donors (12 specimens). We found low mean MDR1 expression in primary ALL, first relapses of ALL, and primary AML. Significantly higher mean relative MDR1 expression levels were seen in recurrent relapses of ALL, and in the group of relapsed state AML. MDR1 expression measured intermediate in bone marrow samples from healthy donors. The CLL lymphocytes showed generally relatively high MDR1 expression levels. MRP gene expression measured very similar in primary ALL, first relapses of ALL, primary AML, and normal bone marrow. Significantly increased MRP mRNA levels were observed in the groups of recurrent ALL and relapsed state AML. CLL lymphocytes also showed high MRP expression levels. A combined increase of MDRI (about 20-fold) and MRP (about four-fold) was monitored in samples obtained from the CML in blast crisis after chemotherapy. While no significant differences of the mean topoisomerase IIbeta mRNA levels were found throughout, a significantly decreased topoisomerase IIalpha gene expression was measured in first and recurrent relapses of ALL. In CLL lymphocytes either the expression of the topoisomerase IIalpha gene was not detectable by cDNA-PCR, or it measured very low. Topoisomerase IIalpha gene expression was correlated to cyclin A gene expression in the samples of acute leukemias, Indicating the link of topoisomerase IIalpha expression to the proliferative activity of these leukemic blast cells. Our results point to a potentially multifactorial emergence of multidrug resistance in particular states and types of leukemias.

ATP-Binding Cassette Transporters↗
PubMed1996

The superantigen Staphylococcus enterotoxin B induces a strong and accelerated secondary T-cell response rather than anergy.

The primary and secondary immune response of V beta 8+ T cells to the bacterial superantigen Staphylococcus enterotoxin B was compared in BALB/c mice. Secondary responder T cells were found to up-regulate the expression of the adhesion molecule LFA-1 faster, and to enter the cell cycle earlier than primary responder T cells. Both, primary and secondary responder T cells upregulate the expression of CD2 and CD25 and turn into blast cells with superimposable time kinetics. Secondary responder T cells terminate DNA synthesis, blast formation and the upregulation of CD25 and CD2 expression earlier than primary responder T cells and become more rapidly deleted. Two days after superantigen challenge, when primary responder T cells reach peak activity in terms of DNA synthesis and blast formation, secondary responder T cells have returned to the size of microblasts and ceased to replicate their DNA. Whereas our results are consistent with the observations leading to the concept of superantigen-induced T-cell anergy, they demonstrate, by revealing the accelerated vigorous secondary T-cell response to the superantigen, that this concept requires reconsideration.

Animals↗
PubMed1996

[Differential diagnosis of childhood osteomyelitis--classification according to scintigraphic, radiologic and magnetic resonance tomographic characteristics].

We present a retrospective study on children with the final diagnosis osteomyelitis, who have been examined in Tübingen from 1985 to 1991. The different types of infantile osteomyelitis were classified due to the causative organism and findings in 3-phase scintigraphy and X-ray films. For the chronic type of osteomyelitis the study was extended to the years from 1979 to 1991 and the results of an earlier report were included. We worked up 17 cases of acute/peracute osteomyelitis, including 5 cases of early infancy, 2 cases of tuberculosis, 2 Brodie's abscesses, 5 plasmacellular types, 2 cases of primary chronic multifocal osteomyelitis (PCMO), and 5 cases of unspecific chronic osteomyelitis. All cases were examined with scintigraphy, X-ray films and in part with magnetic resonance tomographic imaging. In 23 cases scintigrams and X-ray films were performed in the follow-up. We show the importance of scintigraphy for the early detection and localisation of osteomyelitis, the importance of findings on X-ray films for the specific diagnosis of osteomyelitis, and the importance of magnetic resonance tomography for high-resolution detection of the expansion of osteomyelitis.

Acute Disease↗
PubMed1996

Bone marrow transplant indications for childhood leukemias: achieving a consensus. The EBMT Pediatric Diseases Working Party.

During the "2nd International Course on Bone Marrow Transplantation in Children" a multiple choice questionnaire on bone marrow transplant indications for children with acute leukemias was distributed with the aim of achieving a consensus. The answers obtained from the twenty representatives of fourteen European countries during the meeting were analyzed and assigned to one of the following groups: I. definitive indication: when more than 75% participants were in favour; II. acceptable indication: when 50% to 74% participants were in favour; III. requires further investigation: when 25% to 49% participants were in favour; IV. no indication: when less than 24% participants were in favour. In acute lymphoblastic leukemia the following circumstances were considered a definitive indication for allogeneic bone marrow transplant (BMT) from a matched sibling donor (MSD): infancy, "high risk" (HR) patients in 1st complete remission (CR1); CR2 patients after an early bone marrow relapse (defined as a relapse occurring up to six months after stopping therapy). Patients experiencing an early meningeal relapse and CR2 patients after a late relapse (defined as a relapse occurring later than six months after stopping therapy) were considered an acceptable indication. Further investigation was required in order to better define the role of BMT for patients experiencing an early isolated testicular relapse. If a MSD is not available, HR patients in CR1 and CR2 patients, after an early bone marrow relapse, were considered a definite indication for a matched unrelated donor (MUD). This latter group was considered an acceptable indication for a haploidentical BMT if a MUD was not available. Further investigation was required to better define the role of autologous bone marrow transplant (ABMT) for patients experiencing an early extramedullary relapse and for HR patients in CR1 all of whom lacked MSD's. In acute myeloblastic leukemia (AML), CR2 patients were considered a definitive indication and CR1 patients were considered an acceptable indication for BMT from a MSD. CR2 patients were considered a definitive indication for ABMT and CR1 patients an acceptable indication in cases lacking a MSD. AML was not considered an indication for MUD BMT.

Bone Marrow Transplantation↗
PubMed1996

Which children do benefit from bone marrow transplant? The EBMT Paediatric Diseases Working Party.

The development of chemotherapy in childhood ALL has been the leader of the success story of paediatric oncology. At least 2/3 of the children can be cured nowadays at the first attempt of treatment. From the remaining again 1/3 can be treated successfully for the relapse of their disease with conventional therapeutic strategies. This means, however, that there is no chance for cure with chemotherapy alone for 20 to 25% of the children. BMT has been shown for a long time to be an alternative therapy especially in those cases in which conventional chemotherapy fails. In spite of the fact that many children with ALL have been transplanted during recent years there is still no general agreement on the question which children need BMT. However a few statements can be made: The value of ABMT in ALL is probably not better than that of chemotherapy alone. In 1st CR a group of children can be defined, which might benefit from BMT. In 2nd CR the value of chemotherapy depends very much from the duration of 1st remission. Allogeneic BMT is the only chance for cure in very early relapses, superior to chemotherapy in early and late relapses and possibly equal to chemotherapy in very late relapses. The paper tries to summarise our current knowledge about the situation.

Bone Marrow Transplantation↗
PubMed1995

Presence of iron catalytic for free radical reactions in patients undergoing chemotherapy: implications for therapeutic management.

We investigated the kinetics of generation of iron 'catalytic' for free radical reactions in children with diagnosed acute lymphoblastic leukaemia (ALL) who received high-dose methotrexate infusions. In 76% of the chemotherapy courses studied, 'catalytic' iron appeared in plasma in the concentration range from 0.1 to 3 mumol/l. Positive correlations between maximum levels of 'catalytic' iron and plasma hepatic enzymes could be established in the majority of cases and in one subset of patients (low and medium risk ALL) mean 'catalytic' iron levels correlated well to clinically observable toxicities. The damaging potential of 'catalytic' iron was also demonstrated experimentally: oxidative damage to proteins was significantly (P < 0.05) higher in plasma samples showing the presence of 'catalytic' iron and in addition a strong correlation (r = 0.95, P < 0.02) was seen between plasma concentration of 'catalytic' iron and the ability of the plasma to stimulate lipid peroxidation. Our data show that chemotherapy releases 'catalytic' iron which may relate to toxic side effects. Hence binding this 'catalytic' iron by judicious co-administration of iron chelating agents could be beneficial in minimizing the iatrogenic adverse effects of chemotherapy of acute leukaemia.

Adolescent↗
PubMed1995

Antibody-targeted superantigens induce lysis of major histocompatibility complex class II-negative T-cell leukemia lines.

CTLs bearing certain T-cell receptor V beta-regions are directed by the bacterial superantigen Staphylococcus enterotoxin A (SEA) to lyse MHC class II-positive cells. In order to extend superantigen-dependent cytotoxicity to MHC class II-negative carcinoma cells, covalent conjugates of superantigen and mAbs against surface markers of these cells have been used. We now describe a novel strategy which allows rapid selection of mAb suitable for superantigen targeting against MHC class II-negative tumor cells. A recombinant fusion protein of protein A and SEA binding to the mAbs CD7 or CD38 was able to mediate T cell-dependent lysis of MHC class II-negative Molt-4 and CCRF-CEM acute lymphatic leukemia cell lines. Lysis was dose dependent and correlated with E:T cell ratio. In contrast, SEA alone did not induce any significant lysis. In order to decrease the MHC class II affinity of the protein A-SEA complex, a point mutation was introduced into SEA (protein A-SEA mu9). The mutated fusion protein had similar potency as protein A-SEA against Molt-4 cells but was 100-fold less active against MHC class II-positive cells. Considering the efficiency and specificity of the mutated SEA protein interacting with mAb in targeting T lymphocytes against MHC class II-negative leukemia cells while only marginally affecting normal MHC class II-positive cells, we suggest the development of SEA-mAb fusion proteins as a potential adjuvant therapy of leukemias.

ADP-ribosyl Cyclase↗
PubMed1995

Superantigen-staphylococcal-enterotoxin-A-dependent and antibody-targeted lysis of GD2-positive neuroblastoma cells.

Superantigens such as the staphylococcal enterotoxin A (SEA) are among the most potent T cell activators known. They bind to major histocompatibility complex (MHC) class II molecules and interact with T cells depending on their T cell receptor (TCR) V beta expression. Superantigens also induce a variety of cytokines and trigger a direct cytotoxic effect against MHC-class-II-positive target cells. In order to extend superantigen-dependent cell-mediated cytotoxicity (SDCC) to MHC-class-II-negative neuroblastoma cells, SEA was linked to the anti-ganglioside GD2 human/mouse chimeric monoclonal antibody (mAb) ch14.18. Ganglioside GD2 is expressed on most tumours of neuroectodermal origin but is expressed to a lesser extent on normal tissues. The linkage of ch14.18 to SEA was achieved either with a protein-A-SEA fusion protein or by chemical coupling. Both constructs induced T-cell-mediated cytotoxicity towards GD2-positive neuroblastoma cells in an effector-to-target(E:T)-ratio- and dose-dependent manner in vitro. To reduce the MHC class II affinity of SEA, a point mutation was introduced in the SEA gene (SEAm9) that resulted in 1000-fold less T cell killing of MHC-class-II-expressing cells as compared to native SEA. However, a protein-A-SEAm9 fusion protein mediated cytotoxicity similar to that of protein-A-SEA on ch14.18-coated, MHC-class-II-negative neuroblastoma cells. Taken together, these findings suggest that superantigen-dependent and monoclonal-antibody-targeted lysis may be a potent novel approach for neuroblastoma therapy.

Antibodies, Monoclonal↗
PubMed1995

Clinical strategies for the treatment of neuroblastoma.

Neuroblastoma is the most common solid extracranial tumour in childhood. In spite of intensive efforts of clinicians and scientists the prognosis for advanced disease is still poor. This paper presents a short review of the state-of-the-art in conventional treatment including surgery, chemotherapy, and radiation. This is followed by a review of the treatment attempts with high dose chemotherapy followed by autologous bone marrow or stem cell transplantation. One of the main problems with this approach is the contaminating tumour cells. Finally the various immunotherapeutic strategies are summarised which are used to remove minimal residual disease. Later, our new approach, combining various treatment modalities, is described.

Child↗
PubMed1995

Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of monoamine transporters in neuroblastoma cell lines: correlations to meta-iodobenzylguanidine (MIBG) uptake and tyrosine hydroxylase gene expression.

Radiolabelled meta-iodobenzylguanidine (MIBG) has been widely used in scintigraphy and targeted radiotherapy in patients with neuroblastoma. Recently, it has been demonstrated that MIBG is incorporated into neuroblastoma cells by the noradrenaline transporter. In vitro experiments on SK-N-SH human neuroblastoma cells performed in the present study showed that uptake of MIBG is inhibited by noradrenaline, more so by dopamine and to a lesser extent, by serotonin, indicating that the respective transporters may also contribute to MIBG uptake. However, neither dopamine nor serotonin transporter gene expression was detected. Noradrenaline transporter gene expression was found in 4 of 6 investigated cell lines, which correlated with specific MIBG uptake. Furthermore, an inverse correlation of noradrenaline transporter and tyrosine hydroxylase gene expression, the key regulatory enzyme of catecholamine synthesis, was observed. These data show that MIBG is specifically incorporated only in neuroblastoma cells in which there is noradrenaline transporter gene expression. Furthermore, the catecholamine status in neuroblastoma cells is regulated by a coordinate expression of the key elements of catecholamine synthesis and reuptake systems.

3-Iodobenzylguanidine↗
PubMed1995

Autologous transplantation with peripheral blood stem cells in children and young adults after myeloablative treatment: nonrandomized comparison between GM-CSF and G-CSF for mobilization.

Recombinant human granulocyte-monocyte colony-stimulating factor (rhGM-CSF) was compared with recombinant granulocyte colony-stimulating factor (rhG-CSF) in 34 patients for mobilization of peripheral blood stem cells (PBSC) and for posttransplantation use. Peripheral blood stem cell mobilization was initiated by a single 1 h infusion of cyclophosphamide (4 g/m2) in all patients, followed by either a continuous infusion of rhGM-CSF (250 micrograms/m2/day) in 17 patients (group A) or a daily subcutaneous injection of rhG-CSF (10 micrograms/kg/day) in 17 patients (group B). PBSC were collected using a Fenwal CS 3000 continuous flow blood cell separator in one to three sessions. All patients suffered from various childhood malignancies. No difference in the number of collected cells among both groups was found. A mean of 2.7 x 10(8)/kg mononuclear cells (MNC) and of 7.9 x 10(4)/kg CFU-GM (colony-forming unit-granulocyte-macrophage) were collected in group A. In group B, 2.3 x 10(8)/kg MNC and 11.8 x 10(4)/kg CFU-GM were collected. In 33 patients, PBSC were reinfused after myeloablative therapy. Patients of group A (n = 17) were treated with rhGM-CSF (250 micrograms/m2/day) starting day +1, and patients in group B (n = 16) were treated with rhG-CSF (10 micrograms/kg/day) i.v. All patients showed a rapid and complete hematopoietic recovery without significant differences in both groups. Time to achieve 0.5 x 10(9)/L granulocytes was 10.9 days in group A and 11 days in group B.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Expression of mdr1, mrp, topoisomerase II alpha/beta, and cyclin A in primary or relapsed states of acute lymphoblastic leukaemias.

In a series of 60 ALL samples drawn during different stages of the disease we used a cDNA-PCR approach to analyse the relative mRNA levels of the MDR-associated genes encoding mdr1/P-glycoprotein, mrp, and the topoisomerase II isozymes alpha and beta. Expression analysis of the cyclin A gene was included to examine cellular proliferation activity. The expression of gapdh served as an internal standard. Calculating the mean values we found: (i) a distinctly lower mdr1 gene expression in primary ALL and first relapses compared to bone marrow from healthy donors, (ii) no change in mdr1 and mrp, but a decreased topoisomerase II alpha gene expression in first relapses of ALL compared to the primary leukaemia, and (iii) increased mdr1 and mrp levels combined to decreased topoisomerase II alpha levels in recurrent relapses of ALL showing significant correlations (mdr1/mrp: rs = +0.6833, P < 0.05; mdr1/topoII alpha: rs = -0.6727, P < 0.05). The expression of the topoisomerase II alpha gene was correlated to that of cyclin A, indicating a link of its expression to cellular proliferation. Our findings suggest that a multifactorial MDR including mrp appears particularly in recurrent relapses of ALL, which often do not respond to chemotherapy. Nonetheless, some individual samples showed gene expression levels very different from the mean values calculated for a particular state of the leukaemia, indicating the need of an individual expression analysis of MDR-associated genes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Remission of a lymphoproliferative disorder occurring after second BMT from an unrelated donor in a 5-year-old boy with severe aplastic anemia.

A 5-year-old boy with severe aplastic anemia failed to respond to cyclosporine (CYA), prednisolone and antilymphocyte globulin (ALG). No suitable sibling marrow donor was available, but an HLA-matched unrelated donor was identified. The patient was conditioned with cyclophosphamide (CY), 50 mg/kg/day for 4 days, total nodal irradiation (8 Gy), and ALG 30 mg/kg/day for 3 days. GVHD prophylaxis consisted of daily CYA, methotrexate (MTX) and ALG. The patient failed to achieve sustained engraftment. He was reconditioned with high-dose prednisolone and anti-T lymphocyte monoclonal antibody OKT3. The boy was reinfused with the same donor marrow on day 0 (+49/first BMT). No GVHD prophylaxis was given the second time. He received G-CSF on days 0 to +20 after the second transplant. Full engraftment was achieved on day +16 (+65). However, on day +31 (80) he developed a biopsy-proven B cell lymphoproliferative disorder (BLPD). After the OKT3 administration was stopped and treatment with ganciclovir and high-dose immunoglobulin was initiated, the BLPD resolved and the patient was discharged on day +50 (99). He is currently well with a functioning graft 266 (305) days posttransplant, with no sign of GVHD.

Anemia, Aplastic↗
PubMed1994

Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients. Results and conclusions of the multicenter trial ALL-BFM 86.

In trial ALL-BFM 86, the largest multicenter trial of the Berlin-Frankfurt-Münster (BFM) study group for childhood acute lymphoblastic leukemia (ALL), treatment response was used as an overriding stratification factor for the first time. In the previous trial ALL-BFM 83, the in vivo response to initial prednisone treatment was evaluated prospectively. A blast cell count of > or = 1,000/microL peripheral blood after a 7-day exposure to prednisone and one intrathecal dose of methotrexate (MTX) identified 10% of the patients as having a significantly worse prognosis. In trial ALL-BFM 86 patients with > or = 1,000/microL blood blasts on day 8 were included in an experimental branch EG. Patients with < 1,000/microL blood blasts on day 8 were stratified by their leukemic cell burden into two branches, Standard Risk Group (SRG) and Risk Group (RG). SRG patients received an eight-drug induction followed by consolidation protocol M (6-mercaptopurine, high-dose [HD] MTX 4 x 5 g/m2) and maintenance. RG patients were treated with an additional eight-drug reinduction element. For EG patients protocol M was replaced by protocol E (prednisone, HD-MTX, HD-cytarabine, ifosfamide, mitoxantrone). All patients received intrathecal MTX therapy; only those of branches RG and EG received cranial irradiation. In branch RG, patients were randomized to receive or not to receive late intensification (prednisone, vindesine, teniposide, ifosfamide, HD-cytarabine) in the 13th month. During the trial reinduction therapy was introduced in branch SRG, because in the follow-up of trial ALL-BFM 83 the randomized low-risk patients receiving reinduction did significantly better. Nine hundred ninety-eight evaluable patients were enrolled, 28.6% in SRG, 61.1% in RG, 10.3% in EG. At a median follow-up of 5.0 (range 3.4 to 6.9) years, the estimated 6-year event-free survival was 72% +/- 2% for the study population, 58% +/- 5% in branch SRG for the first 110 patients without reinduction therapy, 87% +/- 3% for the next 175 patients with reinduction therapy, 75% +/- 2% in branch RG, and 48% +/- 5% in branch EG. Late intensification did not significantly affect treatment outcome of RG patients; however, only 23% of the eligible patients were randomized. Prednisone poor response remained a negative prognostic parameter despite intensified therapy. The results confirmed the benefit of intensive reinduction therapy even for low-risk patients. The strategy of induction, consolidation, and intensive reinduction may offer roughly 75% of unselected childhood ALL patients the chance for an event-free survival.

Adolescent↗