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Biomedical subjects

F Zintl

Publications and source records attributed to F Zintl.

At least 73 records · Page 4Linked to original sources
PubMed1996

Expression and prognostic value of the retinoblastoma tumour suppressor gene (RB-1) in childhood acute lymphoblastic leukaemia.

In a retrospective analysis, acute lymphoblastic leukaemia (ALL) blast cells of 102 children were investigated for the expression of the retinoblastoma susceptibility (RB)-1 gene at mRNA level by dot blot hybridization and semiquantitative RT-PCR. 56 patients were analysed by dot blot hybridization and 35 representative patients out of this group by semiquantitative RT-PCR. Two additional groups of patients (23 patients with initial and 23 patients with relapsed ALL) were also investigated by semiquantitative RT-PCR. RB-1 gene expression was detectable in all investigated ALL at different levels. According to the relative mRNA expression the patients were discriminated by the median value in groups with low or high RB-1 expression. The Kaplan-Meier estimates showed that patients with low RB-1 expression had a lower probability of remaining in first remission (P = 0.03) and a significantly higher risk to succumb to their disease (P = 0.03). Furthermore, the comparison of the results between initial and relapsed ALL showed that the relapses had significantly lower RB-1 mRNA expression (P = 0.02). The overall survival of the patients was shorter in both groups when RB-1 gene expression was low. A multivariate analysis, including age, sex, immunological subtype, initial white blood cell count and RB-1 expression, identified RB-1 as an independent prognostic predictor (P = 0.017) in addition to the initial white blood cell count (P = 0.00001). In conclusion, low RB-1 expression is an unfavourable prognostic predictor in initial and relapsed childhood ALL. The RB-1 gene expression in relapsed ALL is significantly lower than in initial ALL.

Adolescent↗
PubMed1996

Humoral immunodeficiency in patients after bone marrow transplantation.

Ex vivo IgG production was determined in 17 children and adolescents and in 14 adult patients between 10 months and 6 years after BMT. Twenty-four patients received allogeneic transplants. Seven patients were transplanted with autografts. Seven patients received immunosuppressive therapy. B cells were purified by positive selection with a CD20 antibody. After IL-2 or IL-10 stimulation, IgG production of SAC-preactivated B cells in patients with immunosuppression (median/range: 11/4-15 ng/ml or 14210-29 ng/ml) was significantly reduced compared with patients receiving allogenic (30/3-860 ng/ml or 33/2-3431 ng/ml; P < 0.01) or autologous transplants (75/7-1431 ng/ml or 269-/7-13600 ng/ml, P < 0.01). In 14/31 patients ex vivo IgG production was defective. Investigations of B cell function in patients with defective IgG production was performed significantly earlier after BMT compared with patients with normal IgG production ex vivo (2 +/- 1 years vs 3.3 +/- 1.5 years; P < 0.05). In addition, only patients with a B cell deficiency received immunosuppression. However, patients ex vivo IgG produced by B cells was decreased, but IgG production/sIgG+ B cells was within range of healthy volunteers. The number of IgG-committed B cells in these patients was significantly reduced compared to patients without deficiency (23/19-45/microliter vs 100/14-336/microliter; P < 0.05), indicating an in vivo switching defect. Although IL-10 is known to induce IgG-isotype switching in vitro, production of IL-10 by anti-CD3 activated MNCs obtained from patients with a switching defect did not differ from patients without B cell defects (1699/400-2662 pg/ml vs 724-112-1826 pg/ml). In nine patients IgG production and IgG production/sIgG+ B cells were impaired. The number of sIgG+ B cells was not decreased compared with patients without B cell deficiency (115/18-288/microliter), indicating a defective terminal differentiation of IgG-committed B cells to plasma cells. Although autocrine IL-6 is essential for plasma cell formation of isotype-determined B cells, it was comparable in patients with a terminal deficiency and without deficiency (3838/583-5967 pg/ml vs 2423/1643-6184 pg/ml). However, IL-10 production by anti-CD3 activated MNCs in patients with a terminal B cell defect (426/54-2262 pg/ml, P < 0.05) was significantly lower than in patients without deficiency, indicating a deviant cytokine production by T cells which might in part account for the B cell defect. Defective isotype switching as well as impaired terminal differentiation of B cells were found. Further analysis of factors regulating isotype-switching in vivo as well as cytokine receptor expression or signalling processes of differentiation factors in activated B cells might help to characterize the nature of these B cell deficiencies after BMT.

Adolescent↗
PubMed1995

Autologous bone-marrow transplants compared with chemotherapy for children with acute lymphoblastic leukaemia in a second remission: a matched-pair analysis. The Berlin-Frankfurt-Münster Study Group.

It is unclear how best to treat children with acute lymphoblastic leukaemia (ALL) who are in a second remission. Treatment with bone-marrow transplants from HLA-identical siblings results in a statistically greater likelihood of leukaemia-free survival than does chemotherapy. Less than 25% of relapsed patients are able to benefit from this therapy due to a lack of matching donors; chemoradiotherapy or autologous BMT are considered for the rest. We compared treatment results for children who underwent autologous BMT with those who had chemotherapy. All patients were registered between 1983-94 in the multicentre trials. We selected groups of patients by matching variables associated with treatment outcome and duration of second remission. 52 matched-pairs were studied. The probability of event-free survival at 9 years was 0.32 (SD 0.07) for patients receiving chemotherapy versus 0.26 (SD 0.07) for patients who underwent autologous BMT. For two groups--children with prognostic factors indicating high risk of relapse and those with factors indicating lower risk--the outcome from transplantation did not differ significantly from that of chemotherapy: no advantage of autologous BMT over chemotherapy as post-induction treatment for children with ALL in a second remission could be detected with regard to event-free survival. Because autologous BMT has been used as the final step of treatment it is possible that its relative ineffectiveness has been due to the lack of continuation therapy after transplant. Attempts should be made to complement autologous BMT by subsequent immunotherapy, molecular biotherapy, chemotherapy, or a combination of these.

Adolescent↗
PubMed1994

Expression of metallothionein in initial and relapsed childhood acute lymphoblastic leukemia.

In a retrospective study we analyzed the expression of metallothionein (MT) in initial acute lymphoblastic leukemia (ALL) of 92 children and in relapsed ALL of 27 children using immunohistochemistry. MT expression was detectable in 33% of the patients with initial ALL and in 33% of the patients with relapsed ALL. No differences were seen concerning the intensity and the proportion of positively stained cells between initial and relapsed patients. The expression of MT was independent of clinical prognostic factors such as age, sex, immunological subtype, and initial blast cell count. Patients with initial ALL and MT expression tended to have a lower probability of disease-free survival compared with the MT-negative group. The relapsed patients with MT expression showed also a trend toward a shorter survival in comparison to the MT-negative group. However, the differences were not statistically significant. Thus, the results show that MT expression is not an important prognostic factor in the clinical drug resistance of childhood All.

Child↗
PubMed1994

P-glycoprotein and glutathione S-transferase pi in childhood acute lymphoblastic leukaemia.

Blast cells obtained from 104 children with untreated acute lymphoblastic leukaemia were analysed for the expression of P-glycoprotein (P-170) and glutathione S-transfer pi (GST-pi) using immunohistochemistry. Expression of P-170 was detected in 36 of 104 patients (35%) and increased GST-pi was seen in 52 patients (50%). Coexpression of both resistance proteins was observed in 22 leukaemias (21%), whereas no evidence of the resistance markers was found in 38 cases (37%). In patients with P-170-positive leukaemic cells, a significantly lower probability of remaining in first continuous complete remission (CCR) was observed when compared with patients with P-170-negative tumours (P < 0.05). However, only a trend for a more frequent expression of P-170 was found in the leukaemic cells of patients who experienced relapses (P = 0.099). Overexpression of GST-pi was correlated with a higher relapse rate (P = 0.001) and a lower probability of remaining in first CCR (P = 0.01). Expression of P-170 and GST-pi was independent of sex, FAB type, immunological subtype and initial blast cell count. The multivariate analysis indicated that only the expression of P-170 is an unfavourable prognostic factor for children with acute lymphoblastic leukaemia in addition to the prognostic clinical factors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Female twins with severe Christmas disease (hemophilia B).

Hemophilia B is an X-linked bleeding disorder. We report on female twins, who were conspicious in prolonged bleeding after venipuncture as well as hematomas after intramuscular injections even in the first months of their life. Their father suffering from a severe hemophilia B deceased in 1992. Their mother, half-brother and grandmother from their father's side had no signs of bleeding disorders. Clotting analysis performed in both twins revealed a markedly prolonged partial thromboplastin time (> 100 s). The factor IX levels were below 2%. In order to detect mutations, a general screen using the polymerase chain reaction (PCR) followed by single strand conformation polymorphism (SSCP) analysis of the PCR products have been performed. PCR products have been cut into smaller fragments using restriction endonucleases (RE) for an in-depth SSCP screen. A general screen for gross abnormalities in the factor IX gene including deletions, insertions and rearrangements was performed by Southern blot analysis of RE-digests of genomic DNA using the factor IX cDNA as a hybridization probe. Furthermore, we screened for mutations in the CG dinucleotides comprising part of RE-recognition sequences (exon 1, 2, 3, 4, 5, and 8). By all methods applied herein, no mutations have been detected in these twins. On the basis of our results the hemophilia B of these twins might be explained by extreme non-random lyonization.

Child, Preschool↗
PubMed1993

Monoclonal antibodies against neuroblastoma. Production and preliminary characterization of their specificity.

Neuroblastoma (NB) is a common childhood tumor that originates from neuroblasts of the neural crest. In this paper we will describe the production of murine monoclonal antibodies (mAbs) to human NB cell lines. The hybridomas were selected by ELISA and immunofluorescence for antibody binding to multiple human neuroblastoma cultured cell lines, but not to hematopoietic cells and leukemic cells. The mAbs were characterized in terms of their ability to bind to human cell lines and tissues. The IgG2a and IgG2b mAbs may prove useful in the diagnosis of therapy of neuroblastoma.

Animals↗
PubMed1992

[Infections after bone marrow transplantation in childhood].

In 66 children having undergone bone marrow transplantation (BMT) the occurrence of infections was studied retrospectively. Bacterial infections were mostly found in the early period after transplantation before marrow engraftment. The analysis of positive blood cultures showed a dominance of gram-positive bacteria, especially of coagulase-negative staphylococci. Cytomegalovirus (CMV) infections were most important, because of its high rate and the risk of CMV associated interstitial pneumonia (IP), two patients suffered from. Infections from herpes simplex virus (HSV), varizella zoster virus (VZV) and Epstein Barr virus (EBV) had no influence on prognosis. In fungal infections the systemic aspergillosis was the most important complication. To increase the effectiveness and safety of therapy the serum levels of antibiotics and antifungal drugs should be determined.

Adolescent↗
PubMed1992

[Kinetics of vaccination antibodies against tetanus toxoid, diphtheria toxoid, measles virus, poliomyelitis virus and pneumococcus after allogenic and autologous bone marrow transplantation and booster vaccination. 2: Kinetics of vaccination antibodies against diphtheria toxoid after allogenic and autologous bone marrow transplantation].

In the second part of the paper we report on the results of the diphtheria antitoxin valuation of 8 children after allogeneic bone marrow transplantation (BMT) with and without graft versus host disease (GvHD) as well as on the kinetics of the diphtheria antitoxin of 5 children after allogeneic BMT with and without GvHD and of 5 children after autologous transplantation. The antibody valuation was done by a cell-culture assay. Whereas the inspection of the isolated data gives the impression of a swift antibody decrease up to the non-protective level from the 7th month after BMT, the kinetic tests are more highly differentiated. Besides rapidly decreasing values below the accepted protection rate of 0.01 IU/ml in the allogeneic transplanted groups, there are patients with positive antibody titres within an observation period of up to 24 months after BMT in the allogeneic as well as in the autologous transplantation group.

Bone Marrow Transplantation↗
PubMed1992

[The kinetics of vaccine antibodies against tetanus toxoid, diphtheria toxoid, measles virus, poliomyelitis virus and pneumococcus after allogeneic and autologous bone marrow transplantation and revaccination. 3: The kinetics of vaccine antibodies against tetanus toxoid and diphtheria toxoid after allogeneic and autologous bone marrow transplantation and combined revaccination against diphtheria and tetanus].

The 3rd part of the paper deals with the results of a combined revaccination against diphtheria and tetanus in a group of 25 children after allogeneic bone marrow transplantation (BMT) with and without graft versus host disease (GvHD) and after autologous transplantation. It can be shown that in the allogeneic transplanted groups with and without GvHD it is possible to build up a tetanus and diphtheria antitoxin titre in a safe protective cause by a 2nd basic immunisation consisting of 3 single vaccinations starting about 9 to 12 months later. For autologous transplanted children only 1 to 2 vaccinations at a later term than for the allogeneic transplanted children may possibly be sufficient.

Bone Marrow Transplantation↗
PubMed1992

[Kinetics of vaccine antibodies to tetanus toxoid, diphtheria toxoid, measles virus, poliomyelitis virus and pneumococci after allogenic and autologous bone marrow transplantation and booster immunization. 1: The kinetics of vaccine antibodies to tetanus toxoid after allogenic and autologous bone marrow transplantation].

Today BMT belongs to the established methods of treatment in haematology and oncology. Because of the constant increase of healthy long-term survivors after BMT the problem of immunological reconstitution and eventual possible late effects gets more and more importance. One problem, which til now has been few attention paid to, is that of the protection by vaccination after BMT. We report on the kinetics of the tetanus-antitoxin in 20 patients after allogeneic or autologous BMT and demonstrate the influence of a graft-versus-host disease and its therapy on the antibody kinetics. In the group of allogeneic transplanted children without a GvHD the tetanus-antitoxin titers felt below their detection range after a time of about 8 months whereas in the group with GvHD this effect already occurred after nearly 4 months. The autologous transplanted patients have a positive antibody level til the time of 20 months after BMT. As a consequence of the lost protection by vaccination after BMT follows the necessity of revaccinations respectively of boostering after immunological reconstitution.

Adolescent↗
PubMed1992

[Results of allogenic and autologous bone marrow transplantation in children with acute myeloid leukemia].

We report on our experience of bone marrow transplantation (BMT) in children with acute myeloblastic leukaemia (AML) and high risk of relapse (initial WBC greater than 20 x 10(9)/l, FAB M 5, M 6, M 7). 32 children were grafted between november 1982 and october 1991 at the Children's Hospital of the University of Jena. Two patients underwent an allogenous BMT in relapse and died from progressive disease. In 13 children an allogeneic BMT was performed in first complete remission. One patient relapsed, two patients died from severe acute graft-versus-host disease, and two patients died from encephalopathy and cardiomyopathy. Eight of the 13 patients are living and well 18 months to eight and a half year after BMT. Seventeen patients received an autologous (unpurged) BMT. Four of them relapsed four to seven months after BMT. The disease free survival (DFS) for the 29 patients grafted in remission was 0.65. There was no statistical significant difference in DFS between patients with allogeneic and autologous BMT. We conclude that in children with AML and high risk for relapse BMT offers a real chance for better survival. Autologous BMT avoids the problems of graft-versus-host disease and of finding suitable donors for allogeneic marrow transplantation.

Adolescent↗
PubMed1991

Model experiments for immunomagnetic elimination of leukemic cells from human bone marrow. Presentation of a novel magnetic separation system.

Optimal conditions for removing leukemic cells from human bone marrow with monoclonal antibodies (mAb) and magnetic immunobeads were investigated. Monodisperse 3 microns polystyrene microspheres containing magnetite were coated with affinity-purified rabbit antimouse IgG at 4 degrees C, pH 9.6 for 18 h. SKW-3 cells (T-CLL cell line) were marked with the supravital DNA stain Hoechst 33342, seeded into normal human bone marrow, and then incubated with the mAb CD1, CD6, and CD8 at 4 degrees C for 30 min. In preliminary experiments REH cells (cALL cells) and mouse anti-REH cell antibodies were used to find the most favorable conditions for the binding of magnetic beads to tumor cells. Optimal formation of cell-bead rosettes was achieved by rotating beads and tumor cells together at room temperature at a concentration of 1 x 10(7) cells/ml, a bead: tumor cell ratio of 100:1 and an incubation time of one hour. The novel magnetic separation apparatus consists of three polystyrene chambers connected by silicone rubber tubing. The chambers contain four steel inserts each equipped with 32 nickel wires, which are magnetized by permanent magnets in such a way that the inhomogeneous high gradient magnetic field could be established within the cell suspension containing the cells to be depleted. The fluid flow was established by a peristaltic pump. At a flow rate of 1.5 ml/min and a field strength of 160 kA/m, no beads could be detected in the purged marrow. A cocktail of the three mAb was more effective than any single antibody in forming bead-cell rosettes. Two sequential purging cycles were superior to one. The marrow recovered was highly viable as assessed by trypan blue dye exclusion and by growth of CFU-GM.

Antibodies, Monoclonal↗
PubMed1991

[Therapy of acute myeloid leukemia in children--results of the AML II/87 multicenter study].

Fifty seven patients entered the cooperative study AML II/87 of the working group "Pediatric Hematology and Oncology" of East Germany. Two patients with initial hyperleukocytosis died prior therapy. 13 patients died within the first 4 weeks of therapy, 3 patients did not respond to therapy, and one patient is not yet in remission. 38 patients (70%) attained a complete remission. 15 patients get a bone marrow transplantation in first CR (10 autologous BMT without purging, 5 allogenous BMT). 12 of them are living and well 3 to 34 months after BMT. 9 of the 23 patients under chemotherapy relapsed, one patient is lost to follow up. 13 patients are living in continuous complete remission. The life table probabilities 48 months after the start of the protocol are 0.43 for disease free survival (DFS) and 0.60 for event free interval (EFI). The respective results of the former protocol AML I/82 were 0.34 for DFS and 0.47 for EFI.

Adolescent↗