Biomedical subjects
Publications and source records attributed to H Gadner.
Two simple statements can be given which reflect our helplessness with respect to myelodysplasia. MDS are rare in childhood, but features and course of disease resemble those in adults. JCMML should be considered as a pediatric subtype of MDS, but with a worse prognosis than CMML in adult patients.
Conventional chemotherapy results in high mortality rates in patients with solid tumors involving the bones or the bone marrow. High dose melphalan (MEL) with or without total body irradiation followed by bone marrow transplantation (BMT) has prolonged survival, but curative potential has remained disappointing. In order to improve survival 20 children with generalized or relapsed solid tumors (neuroblastoma, peripheral neuroectodermal tumor, Ewing's sarcoma, rhabdomyosarcoma) underwent autologous (n = 16) or allogeneic (n = 4) BMT. The myeloablative regimen consisted of 12 Gy fractionated total body irradiation (FTBI) and high dose MEL. In 12 of these patients this regimen was intensified by giving 60 mg/kg etoposide (1800 mg/m2 VP), and 1.5 g/m2 carboplatin (CBDCA) was added in seven of these 12 patients. The intensification of FTBI and MEL by adding VP and CBDCA was followed by acceptable toxicity. Acute liver toxicity in 15/20 patients (75%) and acute renal toxicity in 17/20 patients (85%) did not exceed WHO grade 1. The use of the conditioning regimen FTBI-MEL-VP-CBDCA during first chemotherapy response is a promising approach in treatment of children suffering from generalized solid tumors.
Low-density cells were prepared from 11 bone marrow samples by centrifugation on Ficoll-sodium diatrizoate. Repeated density gradient centrifugation of the cells collected from the interface of the first gradient removed most nonnucleated erythroid cells. A mean of 47.9% (19.4% to 76.0%) of the mononuclear cells collected after the initial centrifugation were recovered from the interface of the second gradient, whereas 13.3% (3.7% to 34.9%) of the MNCs were counted in the high-density pellet and 38.9% (3.8% to 65.7%) of the MNCs were lost unspecifically. In contrast, a mean of 71.7% (43.0% to 91.3%) of the colony-forming units were recovered from the interface after the second centrifugation (as determined by colony formation assays), whereas only 3.2% (0.5% to 7.0%) were found in the high-density pellet. The unspecific loss of colony-forming units was 25.1% (1.7% to 51.4%). The results demonstrate a relative enrichment of colony-forming units in the culture assay by 1.7 times (average). The method is recommended as an additional preparative step before fluorescence-activated sorting of viable cells, because removal of most erythrocytes and late normoblasts strongly reduces the time required for sorting.
Acute leukemias account for one third of all childhood malignancies. The incidence of acute lymphoblastic leukemias (ALL) is 5 times greater than that of acute non-lymphoblastic leukemias (ANLL). Presenting symptoms of acute leukemias reflect bone marrow failure (anemia, bleeding, infections). Diagnostic procedures are extensive (cytology, cytochemistry, immunophenotyping, cytogenetics, molecular biology). Therapy schedules are adapted in respect to individual risk factors. Two thirds of children with ALL are cured. A general reduction of treatment intensity is not possible. Only the radiotherapy of the CNS could be reduced within the last years. Remission induction failures and relapses are the main problems in the treatment of ANLL. One third of the children with ANLL are cured. Because of their worse prognosis infant leukemias represent a special problem.
We studied amphotericin B (AMB) serum levels (n = 590) in 41 pediatric patients, who underwent allogeneic (21) or autologous (20) bone marrow transplantation (BMT). All patients received AMB orally as part of a total gut decontamination; 30/41 patients (73%) had AMB i.v. either for prophylaxis or therapy of fungal infections. Rapid initial dose escalation of AMB and the infusion over 1 h only were well tolerated by the children. Serum level monitoring allowed AMB long-term treatment safely to be administered in children suffering from transplantation-related complications (veno-occlusive disease of the liver, graft-versus-host disease of the liver). An h.p.l.c. method was used for monitoring AMB serum trough levels to avoid levels exceeding 2 mg/l. One lethal fungal infection was observed in 41 pediatric BMT recipients (2.4%). Rapidly increasing doses of AMB at start of therapy and drug monitoring by h.p.l.c. might help to reduce fungal mortality and renal toxicity by a dose sparing effect in BMT recipients.
We prospectively treated 127 children with ALL with a risk-adapted regimen. All patients received the identical induction-consolidation therapy. The early maintenance included intermediate dose methotrexate in patients with standard risk (n = 79) and medium risk (n = 39). In addition patients with high risk (n = 6) received high dose ARA-C followed by L-asparaginase. Intensification treatment and prophylactic cranial irradiation was also tailored according to the risk group. Treatment duration was 2 years. Complete remission was achieved in 97.6% of all patients. Treatment-related toxicity accounted for one death in complete remission. The probability of event-free survival (pEFS) for the combined group was 72% at a median follow-up of 42 months. The pEFS was higher in patients with standard risk (SR) than in patients with medium risk (MR) (80% versus 65%; p less than 0.05) at 30 months, but attenuated in the follow-up evaluation at 42 months (76% versus 63%; p less than 0.1). The number of high-risk patients was too small for statistical evaluation. Relapse within the first 18 months after diagnosis indicated a poor prognosis and was more common in patients with MR than in patients with SR. The immunophenotype of the leukemic cells was not found to constitute an independent risk factor after treatment has been risk-adapted. Patients with an initial white blood cell count of more than 50 X 10(9)/l had a worse prognosis than patients with a lower white blood cell count (p less than 0.01).
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A 20 years old man with peripheral primitive neuroectodermal tumor involving the bone marrow received 12 Gy fractionated total body irradiation, 140 mg/m2 melphalan, 1800 mg/m2 etoposide, and 1500 mg/m2 carboplatin for consolidation of first remission. Thereafter, 250 micrograms/m2/day recombinant human granulocyte-macrophage colony-stimulating factor (rh GM-CSF) (Behring Werke) were administered as continuous infusion 4 days after infusion of autologous bone marrow and peripheral stem cells to accelerate granulocyte reconstitution for control of a continued febrile state. The clinical picture of capillary leak syndrome developed with weight gain, pleural effusions and peripheral edema. The patient's condition stabilized after discontinuation of rh GM-CSF. Eight days later he died of invasive aspergillosis. The clinical course of our patient suggests a potentially fatal toxic effect of rh GM-CSF, even in low dose, in the setting of septicemia or fungemia.
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The first case of unstable Hb Genova from North Africa is described. It was found in a 13-year-old girl from Libya suffering from chronic Heinz body haemolytic anaemia and growth retardation. The available data strongly suggest that this case represents a new example for a spontaneous mutation.
Autologous blood-derived stem cells were used for stem-cell rescue in a 5-year-old boy with chemotherapy-resistant B-Non-Hodgkin's lymphoma (B-NHL) involving bone marrow. The high dose chemoradiotherapy was carried out 5 months after initial diagnosis during partial remission. The preparative regimen consisted of 12 Gy fractionated, total-body irradiation (FTBI) before 60 mg/kg etoposide. There were 22.96 X 10(4)/kg body weight myeloid precursor cells, granulocyte-macrophage committed stem cells (CFU-GM) collected by intermittent blood flow separation with a Haemonetics 30R in two cytaphereses and stored in liquid nitrogen. Also 11, 82 X 10(4) CFU-GM/kg body weight were recovered and transfused after thawing. Rapid hematopoietic reconstitution ensued: Erythroid precursors were detected on day 9, 1 X 10(9)/L leucocytes were counted on day 11, and 0.5 X 10(9)/L granulocytes on day 13, respectively. The patient required 3 single-donor platelet transfusions, the last one on day 10. On day 17, 100 X 10(9)/L platelets were reached. A bone marrow aspirate on the same day showed good trilineage regeneration. The patient remained in complete remission 7 months after autografting with a normal stem cell content of the bone marrow and in the peripheral blood. On day 226, after stem cell infusion, a bone marrow relapse occurred.
This is a report of a case of acute respiratory failure following the administration of intrathecal methotrexate (MTX) for prophylaxis of central nervous system leukemia (CNS) in a 3-year-old girl with acute lymphoblastic leukemia. This could be attributed to acute metabolic or direct toxic effects of methotrexate to the central nervous system tissue. Although the specific agent responsible for this complication following intrathecal injection of MTX is unclear, it is worthwhile to describe this event.
Ewing's Sarcoma (ES), the second most frequent bone tumor in childhood and adolescence, and the probably closely related peripheral primitive neuroectodermal tumor (pPNET) share a unique cytogenetic translocation between chromosomes 11 and 22. Both of them expose high amounts of a glycoprotein on their cell surface, which can be specifically detected by the mAb HBA-71. The cDNA coding for the HBA-71 antigen was isolated by screening a cDNA expression library constructed from a pPNET-derived cell line. Nucleotide sequencing revealed the HBA-71 antigen to be the product of the pseudoautosomal gene MIC2 previously identified by the mAb 12E7 in haematopoietic cells. This antigen is a glycoprotein with a molecular weight of about 29,000 and is expressed in low amounts in most human cell lines and probably normal tissues and tumors with only a few exceptions. In T-cells the antigen is involved in cell adhesion processes. In ES- and pPNET-derived cell lines MIC2 expression is significantly enhanced. No gross changes in posttranslational modification could be observed. The high expression results in easy and specific detection of the antigen in immunocytochemical analysis of paraffin embedded tissue sections making HBA-71 a useful tool in tumor diagnosis.
22 consecutive patients with a median age of 11 years (range 3-23) underwent 103 leucaphereses after a chemotherapy induced aplasia. They suffered from various solid tumors and hematological malignancies. The stem cell yield of 69 aphereses which were done during the 8 days following the first platelet rise, was median 1.02 x 10(4) myeloid committed stem cells (CFU-GM)/kg/apheresis (range 0.02-13.3), whereas only 0.27 x 10(4) CFU-GM/kg/apheresis (range 0.01-1.11) were obtained in 34 "random" collections (p less than .05). The CFU-GM yield of 69 "well timed" collections depended on the absolute number of circulating leucocytes (p = .002) and mononuclear cells (p less than .001). The median daily increment of leucocytes was a reliable predictor of the stem cell yield (p = .002) and could be used to select the optimal days for leucaphereses during the well timed period. By careful timing alone high stem cell numbers could be collected in various malignancies without using exogenous growth factors.
Sera from 32 bone marrow allograft recipients were screened for the presence of autoantibodies 4-61 months post-graft. Sera from 12 of 19 patients with extensive chronic graft-versus-host disease (c-GVHD) stained the nucleolar region strongly in immunofluorescence, indicating the presence of specific antinucleolar antibodies. In contrast, none of three patients with limited and none of 10 patients without c-GVHD had antinucleolar antibodies. Antibodies reacting with nuclear constituents other than nucleoli were found in five of the 12 antinucleolar positive patients. The appearance of antinucleolar antibodies coincided with early clinical symptoms of c-GVHD. We conclude that the appearance of antinucleolar antibodies after bone marrow transplantation is specific for patients with extensive c-GVHD. Furthermore, the development of extensive c-GVHD is paralleled by the emergence of these antinucleolar antibodies.
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Twenty-two consecutive patients with a median age of 11 years (range 3-23) underwent 103 leukaphereses for collection of peripheral stem cells. They suffered from various solid tumors and hematologic malignancies. Our aim was to collect at least 2.5 x 10(4) myeloid committed stem cells (CFU-GM) per kg body weight. This stem cell number has reliably resulted in rapid and sustained hematopoietic reconstitution after autografting in our institution. Peripheral stem cell mobilization was induced by myelosuppressive therapy alone. If the stem cell collections were started at the first platelet rise and were continued during the following 8 days, the stem cell yield of one procedure was high - median 1.02 x 10(4) CFU-GM/kg body weight (range 0.02-13.3). In 69 such 'well-timed' collections, a median of only 4 leukaphereses (range 2-6) were needed to collect high numbers of CFU-GM. The yield from leukaphereses carried out at any other time was unsatisfactory. In 34 'random' collections, a median of only 0.27 x 10(4) CFU-GM/kg body weight (range 0.01-1.11) was obtained in one procedure. In 69 well-timed collections the CFU-GM yield depended on the absolute number of circulating leukocytes (r = 0.369, p = 0.002) and mononuclear cells (r = 0.476, p less than 0.001). The median daily increment of leukocytes to the day of apheresis proved to be an excellent parameter for the prediction of the yield and could be used to select the best days for leukaphereses (r = 0.403, p = 0.002). These findings may help to make the collection of blood-derived stem cells more efficient in pediatric patients.