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U Dirksen

Publications and source records attributed to U Dirksen.

17 recordsLinked to original sources
PubMed2005

Structure and function of ETAA16: a novel cell surface antigen in Ewing's tumours.

Immunoscreening of an Ewing's family of tumour (EFT)-derived cDNA library using formerly described EFT-specific antibodies led to the isolation of a 3.5 kb cDNA, named Ewing's tumour-associated antigen 16 (ETAA16). The ETAA16 cDNA shows no homology to any functionally characterised human gene. Only a bovine cDNA expressed in bovine testis and hepatocytes is functionally characterised as it encodes for a junction plaque associated protein and showed a homology of 69.9% at amino acid level to ETAA16. The human cDNA encodes for a 926 amino acid tumour antigen with a calculated molecular weight of 103 kDa. The epitope of the ETAA16-specific antibody, Ak16, covers the central region of the protein which is part of an extra cellular domain. The human ETAA16 gene locus has been assigned to chromosome 2p13-15 by FISH analyses and is confirmed by the human genome sequencing project. As demonstrated by flow cytometry, the cell surface expression of ETAA16 antigen is restricted to ET cell lines and not expressed on other small blue round cell tumours or other kind of tumour. RT-PCR analysis revealed a high expression of ETAA16 in brain, liver and kidney while lung and heart were negative. Immunohistochemistry showed an intracellular expression of ETAA16 in different kind of non-Ewing tumour tissues. These results suggest that ETAA16 may function as a tumour-specific cell surface antigen in EFTs.

Amino Acid Sequence↗
PubMed2000

Allogeneic and autologous stem-cell transplantation in advanced Ewing tumors. An update after long-term follow-up from two centers of the European Intergroup study EICESS. Stem-Cell Transplant Programs at Düsseldorf University Medical Center, Germany and St. Anna Kinderspital, Vienna, Austria.

BACKGROUND: An update of results from the High Risk Protocol of the Meta-EICESS Study, conducted at the Pediatric Stem-Cell Transplant Centers of Düsseldorf and Vienna. In order to evaluate a possible therapeutic benefit after allogeneic SCT in patients with advanced Ewing tumors (AET), we compared outcome after autologous and allogeneic stem-cell transplantation (SCT). PATIENTS AND METHODS: We analyzed 36 patients treated with the myeloablative Hyper-ME protocol (hyperfractionated total body irradiation, melphalan, etoposide +/- carboplatin) between November 1986 and December 1994. Minimal follow-up for all patients was five years. All patients underwent remission induction chemotherapy and local treatment before myeloablative therapy. Seventeen of thirty-six patients had multifocal primary Ewing's tumor, eighteen of thirty-six had early, multiple or multifocal relapse, one of thirty-six patients had unifocal late relapse. Twenty-six of thirty-six were treated with autologous and ten of thirty-six with allogeneic hematopoietic stem cells. We analyzed the following risk factors, that could possibly influence the event-free survival (EFS): number of involved bones, degree of remission at time of SCT, type of graft, indication for SCT, bone marrow infiltration, bone with concomitant lung disease, age at time of diagnosis, pelvic involvement, involved compartment radiation, histopathological diagnosis. RESULTS: EFS for the 36 patients was 0.24 (0.21) +/- 0.07. Eighteen of thirty-six patients suffered relapse or died of disease, nine of thirty-six died of treatment related toxicity (DOC). Nine of thirty-six patients are alive in CR. Age > or = 17 years at initial diagnosis (P < 0.005) significantly deteriorated outcome. According to the type of graft, EFS was 0.25 +/- 0.08 after autologous and 0.20 +/- 0.13 after allogeneic SCT. Incidence of DOC was more than twice as high after allogeneic (40%) compared to autologous (19%) SCT, even though the difference did not reach significance (P = 0.08, Fisher's exact test). CONCLUSIONS: Because of the rather short observation period. secondary malignant neoplasms (SMN) may complicate the future clinical course of some of our patients who are currently viewed as event-free survivors. EFS in AET is not improved by allogeneic SCT due to a higher complication rate. The patient group was to small to analyze for a possible graft-versus-tumor effect.

Adolescent↗
PubMed1999

Multimodality diagnostics and megatherapy in poor prognosis Ewing's tumor patients. A single-center report.

BACKGROUND: The prognosis of Ewing's tumor patients has been improved gradually through cooperative therapy studies, so that meanwhile 55 to 65% of the patients survive relapse-free in the long term. Patients with multifocal primary, early or multiply-relapsed Ewing's tumors have a dismal prognosis. Megatherapy with subsequent stem cell transplantation seems to improve outcome in this patient cohort. Feasibility of this intense megatherapy regimen is crucially dependent on collaboration and multidisciplinary coordination of radiologists, radiotherapists, surgeons and oncologists. PATIENTS AND METHODS: Since 1988, 25 patients were treated with megatherapy consisting of melphalan, etoposide and total-body irradiation followed by stem cell transplantation. All patients received 6 courses of an induction therapy. Before the fourth therapy block, tumors that were bulky at initial diagnosis (> 200 ml) were excised, as well as lung metastases which could still be detected after the third chemotherapy block. During the fifth and sixth chemotherapy block, patients received local irradiation on all infiltrated sites. Persisting immunosuppression after high-dose treatment may facilitate the incidence of relapse. To improve proliferation and cytotoxic activity of early regenerating NK-cells, adoptive immunotherapy with systemic IL-2 therapy after megatherapy is part of the treatment protocol. RESULTS: Of 25 patients treated with megatherapy, 10 patients are still alive with a follow-up time of 6 months to 9 years after megatherapy. The time up to engraftment was decreased from 15 +/- 6 days down to 9 +/- 2 days through the use of G-CSF and CD34+ selected stem cells. At the same time, erythrocyte and platelet replacement was shortened. Frequently occurring complications were mucositis and infections. One patient died after developing septicemia and multi-organ failure, another patient developed a myelodysplastic syndrome 4.5 years after megatherapy. However, relapse is still the major cause of death. The influence of IL-2 on event-free survival cannot valued because 21 of 25 patients were treated with adoptive immunotherapy. CONCLUSION: The complex diagnostic and therapeutic strategy renders and EFS of 34% for a patient group with otherwise dismal prognosis. To clarify the efficiency of megatherapy in patients with advanced Ewing's tumors, a standardized treatment strategy is necessary to accumulate a sufficient number of patients for large cooperative studies in this subject.

Adolescent↗
PubMed1998

Attenuated hematopoietic response to granulocyte-macrophage colony-stimulating factor in patients with acquired pulmonary alveolar proteinosis.

The pathogenesis of acquired pulmonary alveolar proteinosis (PAP), a rare lung disease characterized by excessive surfactant accumulation within the alveolar space, remains obscure. Gene-targeted mice lacking the hematopoietic growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF) or the signal-transducing beta-common chain of the GM-CSF receptor have impaired surfactant clearance and pulmonary pathology resembling human PAP. We therefore investigated the hematopoietic effects of GM-CSF in patients with PAP. The hematologic response of 5 infants with congenital PAP to 5 microgram/kg/d was of normal magnitude. By contrast, despite normal expression of GM-CSF receptor alpha- and beta-common chains on peripheral blood myelomonocytic cells (n = 6) and normal binding affinity of bone marrow mononuclear cells for GM-CSF (n = 3), each of the 12 patients with acquired PAP treated displayed impaired responses to GM-CSF; 5 microgram/kg/d produced only minor eosinophilia, and doses of 7.5 to 20 microgram/kg were required to induce >/=1.5-fold neutrophil increments in the 3 patients who underwent dose-escalation. However, neutrophilic responses to 5 microgram/kg granulocyte colony-stimulating factor (G-CSF) were normal (n = 4). In vitro, the proportion of hematopoietic progenitors responsive to GM-CSF (16.1% +/- 8.9%; P = .042) or interleukin-3 (IL-3; 19.3% +/- 7.7%; P = .063), both of which utilize the beta-common chain of the GM-CSF receptor complex, were reduced among patients with acquired PAP (n = 4) compared with normal bone marrow donor controls (47.2% +/- 25.9% and 40.9% +/- 18.6%, respectively). In the one individual who had complete resolution of lung disease during the period of study, this was temporally associated with correction of this defective in vitro response to GM-CSF and IL-3 on serial assessment. These data establish that patients with acquired PAP have an associated impaired responsiveness to GM-CSF that is potentially pathogenic in the development of their lung disease. Based on these observations, we propose a model of the pathogenesis of acquired PAP that suggests the disease arises as a consequence of an acquired clonal disorder within the hematopoietic progenitor cell compartment.

Adolescent↗
PubMed1998

Defective expression of granulocyte-macrophage colony-stimulating factor/interleukin-3/interleukin-5 receptor common beta chain in children with acute myeloid leukemia associated with respiratory failure.

Deficiency of the granulocyte-macrophage colony-stimulating factor (GM-CSF)/interleukin-3 (IL-3)/IL-5 receptors common beta chain (betac) is a cause of fatal respiratory failure. betac deficiency manifests as pulmonary alveolar proteinosis (PAP). PAP has heterogenous etiologies that may be genetic or aquired. Some cases of PAP have been reported to be associated with hematologic malignancies such as acute myeloid leukemia (AML). In mice, the PAP phenotype was generated by targeted deletion of the gene for betac and can be treated by transplantation of wild-type bone marrow into betac -/- mice. Thus, our findings in betac -/- mice provide evidence for a causal relationship between the lung disease and the hematopoietic system. We describe here expression defects of betac or betac plus GM-CSF receptor alpha chain (GM-CSFR alpha) in 3 pediatric patients with AML and PAP symptoms. All of the patients' leukemic cells failed to express normal levels of betac. The leukemic cells of patients no. 2 and 3 additionally lacked the expression of GM-CSFR alpha, as shown by flow cytometry. Strikingly reduced or absent function of betac was demonstrated in clonogenic progenitor assays with absent colony-forming unit (CFU) growth after GM-CSF or IL-3 stimulation. The response to growth factors acting via a growth factor receptor distinct from the GM-CSF/IL-3/IL-5 system (recombinant human granulocyte colony-stimulating factor [rhG-CSF]) was normal. After antileukemic treatment, the pulmonary symptoms resolved and betac or betac plus GM-CSFR alpha expression was normal. Our findings provide evidence that a defect in the expression of betac or betac plus GM-CSFR alpha on AML blasts can be associated with respiratory failure in patients with AML.

Acute Disease↗
PubMed1998

The physiologic role of interleukin-3, interleukin-5, granulocyte-macrophage colony-stimulating factor, and the beta c receptor system.

Gene knockout techniques in the mouse have provided a unique opportunity to examine physiologic gene function. The phenotypes of mutant mice have resulted in a number of predicted as well as totally unexpected results, the latter perhaps providing the most valuable insight into otherwise unexplored biology. An excellent example to illustrate these points are gene knockout studies of interleukin (IL)-3, IL-5, granulocyte-macrophage colony-stimulating factor (GM-CSF), and the receptor system that cells use to bind these ligands. The role of IL-5 appears to be largely restricted to eosinophil biology, fulfilling expectations. However, the vivo function of GM-CSF, IL-3, and their receptor interaction has been more surprising. Neither cytokine nor their combination play an essential or even detectable role in primary bone marrow hematopoiesis, Instead, both IL-3 and GM-CSF play more specialized roles on certain cell subsets, basophil and mast cells, and alveolar macrophages, respectively. This review discusses recent findings with these mice, and based on these results, suggests a more appropriate view of the role of these cytokines and receptors in the hierarchy of molecular events leading to hematopoiesis.

Animals↗
PubMed1997

Human pulmonary alveolar proteinosis associated with a defect in GM-CSF/IL-3/IL-5 receptor common beta chain expression.

Pulmonary alveolar proteinosis (PAP) is a heterogeneous disorder of genetic or acquired etiologies. In some cases congenital PAP is associated with hereditary surfactant protein (SP)-B deficiency. To date, the molecular defect in the majority of patients with PAP has not been identified. In mice, PAP has been generated by targeted deletion of the genes for either the GM-CSF/IL-3/IL-5 receptor common beta chain (beta c) or GM-CSF. Here, we describe an expression defect of beta c in three of seven pediatric patients with PAP and in one patient with severe lung disease suspected to be PAP. The patients failed to express normal levels of beta c as shown by flow cytometry. Strikingly reduced or absent function of beta c was demonstrated by ligand binding studies and progenitor clonogenic assays. Analysis of beta c DNA revealed a point mutation from proline to threonine at codon 602 in one patient. Our findings provide evidence that a defect in the expression of a hematopoietic cytokine receptor is associated with human PAP.

Adult↗
PubMed1996

The pulmonary alveolar proteinosis in granulocyte macrophage colony-stimulating factor/interleukins 3/5 beta c receptor-deficient mice is reversed by bone marrow transplantation.

Mice mutant for granulocyte macrophage colony-stimulating factor (GM-CSF) or the common receptor component (beta c) for GM-CSF, interleukin (IL)-3, and IL-5 exhibit a lung disorder similar to human pulmonary alveolar proteinosis, a rare disease with congenital, infantile, and adult forms. Bone marrow transplantation and hematopoietic reconstitution of beta c mutant mice with wild-type bone marrow reversed the established disease state in the lungs, defining this disease as hematopoietic in nature. It is likely that the disease involves alveolar macrophages, as donor myeloid cell engraftment into the lungs of mutant recipient mice correlated with reverting both the disease and an abnormal macrophage morphology seen in the lungs of affected animals. Recombination Activating Gene-2 mutant donor bone marrow, which lacks the potential to develop lymphocytes, reversed the pathology in the lungs to the same extent as whole bone marrow. These data establish that certain lung disorders, if of cell-autonomous hematopoietic origin, can be manipulated by bone marrow transplantation.

Animals↗
PubMed1996

Differential production of interleukin-3 in human T lymphocytes following either CD3 or CD2 receptor activation.

Interleukin-3 (IL-3) is expressed in T lymphocytes and stimulates the growth of multipotent hematopoietic progenitors. Little is known, however, about the stimuli that lead to IL-3 protein release. We examined IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA expression and protein secretion in human T lymphocytes following activation via the TCR/CD3 complex, the CD2 receptor, and the IL-2 receptor. GM-CSF mRNA expression and protein release were found in CD3 and CD2 activated T cells with maximum GM-CSF release following stimulation with IL-2. IL-3 protein release is regulated via the CD2 receptor with virtually no IL-3 release after T cell stimulation via CD3. In contrast, IL-3 mRNA accumulation is more pronounced after CD3 activation than after CD2 activation. This suggests that upregulation of IL-3 protein release following T cell stimulation via CD-2 occurs largely at the translational or posttranslational level. These data also indicate that differential control of cytokine production can occur in response to activation of the alternative T cell receptor. Interaction of the T cell CD2-receptor with its natural ligand LFA-3 expressed on stromal cells might represent a regulatory mechanism for rapid release of IL-3, facilitating proliferation of multipotent hematopoietic cells.

CD2 Antigens↗
PubMed1995

Treatment of refractory juvenile chronic arthritis by monoclonal CD4 antibodies: a pilot study in two children.

OBJECTIVE--To study the effect of anti-CD4 treatment in patients suffering from refractory systemic onset juvenile chronic arthritis (JCA). METHODS--Two children were treated with the mouse CD4 antibody MAX.16H5. The effects on numbers of circulating CD4 T cells, clinical symptoms and C reactive protein (CRP) level were studied and the appearance of human antimouse immunoglobulin antibodies investigated. RESULTS--In patient one, disappearance of fever and malaise and a reduction of arthritic activity were observed together with a reduction in CRP. When disease activity returned eight weeks later, a second successful course of treatment was administered. It was possible to reduce the corticosteroid dosage permanently. In the other child, a first treatment cycle did not alter disease activity. A marked reduction in clinical and laboratory disease activity markers was observed after the second course. Only transient and mild side effects were observed. One patient exhibited a short lasting febrile reaction with chills, the other an urticarial rash. In both patients, human antibodies to mouse immunoglobulin became detectable. The decrease in the number of CD4 T cells in the peripheral blood was only short lasting and numbers returned to normal values within one to eight weeks, even after the second course of antibody treatment and under concomitant immunosuppressive treatment. No sustained clinical remissions could be achieved. CONCLUSIONS--These preliminary observations support the evidence of positive effects of CD4 antibody treatment in refractory systemic onset JCA. Long term efficacy, however, remains to be established.

Adolescent↗
PubMed1994

Interferon-gamma for treatment of severe atopic eczema in two children.

Two 4- and 5-year-old children suffering from refractory atopic dermatitis were treated with recombinant interferon-gamma (rIFN-gamma). rIFN-gamma was injected at 50 micrograms subcutaneously three times a week in the first child for 3 weeks, followed by three times 25 micrograms in week 4. In the other child two treatment courses of 4 weeks were given after a break of 2 weeks. Therapy was well tolerated. In child one reductions in eczematous body surface and severity of lesions were observed, while no beneficial effect was seen in the other. Clinical chemistry data remained unchanged. Immunological studies performed in parallel showed a decrease in total serum IgE of 50% in child 1, a decrease in spontaneous in vitro IgE production, an increase in in vitro production of interleukin-6, and a normalization of previously decreased in vitro lymphocyte responses to several mitogens. While marked immunological changes were noted during IFN-gamma treatment, clinical benefits were not encouraging. Diminished IFN-gamma production has been claimed to be a major pathogenic factor in atopic eczema. Our results indicate that the pathogenesis is more complex. Clinically, we were unable to confirm previous observations in adults. Further studies are needed before IFN-gamma can be recommended for therapy of pediatric atopic eczema.

Child, Preschool↗
PubMedDate not supplied

Identification of candidate target antigens for antibody-based immunotherapy in childhood B-cell precursor ALL.

BACKGROUND: Contemporary risk adapted treatment protocols for childhood acute lymphoblastic leukemia (ALL) rely on accurate risk assessment strategies for disease re-occurrence by incorporating clinical parameters as well as immunological, molecular and cytogenetic features of the blasts at initial manifestation. Additional risk stratification is provided by analysis of the IN VITRO and IN VIVO response of the blasts towards standard chemotherapy. Despite adapted therapies, a number of children with good and bad prognostic factors still fail therapy. One approach to this problem might be to incorporate monoclonal antibodies (MoAbs) as additional modalities into the first or second line treatment. PATIENTS AND METHODS: In order to identify target antigen structures, we analyzed the immunological expression profiles of blasts from 181 patients with B-cell precursor ALL treated at our institution in 11 years according to the CoALL-92/97/03 protocols. Blasts were classified according to the EGIL guidelines as 9 proB-, 110 common (c-) and 62 preB-ALL. RESULTS: > 99 and 96 % of patients expressed CD19 and CD22 on > 90 % of their blasts, respectively. HLA-DR on > 95 % blasts was present in all patients. CD10 was expressed on all c-/preB-ALL and absent on proB-ALL cells. CD20 was expressed on 11-37 % of B-cell precursor ALL samples. CD34 positive blasts were found in 89, 83 and 68 % of patients with proB-, c- and preB-ALL, respectively. CD37 expression was detected in 0-18 % of patients. < 20 % CD45(+) blasts were found in 11, 19 and 18 % of patients with proB-, c- and preB-ALL. CD33(+) was expressed on 33, 29 and 21 % of patients samples with proB-, c- and preB-ALL. Other myeloid antigens (CD13, CD14, CD15, CD65) were positive on blasts in < 25 % of patients. Analyses of the immunological profile of blasts in 9 consecutive children with relapse revealed that the antigen expression profile varied little compared to the initial diagnosis for CD10, CD19, CD22 and HLA-DR. CONCLUSIONS: These analyses clearly identified the three antigens CD19, CD22 and HLA-DR present on blasts in more than 90 % of patients as potential target structures for targeted therapies with native or toxin-bound monoclonal antibodies in childhood ALL.

Adolescent↗
PubMedDate not supplied

Fanconi anemia and beta c deficiency-associated pulmonary alveolar proteinosis as two hereditary diseases of childhood which are potentially curable by stem cell gene therapy but require different therapeutic approaches.

Fanconi anemia (FANC) and pulmonary alveolar proteinosis associated with deficiency of the beta-chain common to the GM-CSF/IL3/IL5 receptors (beta c-PAP) are rare inherited disorders of childhood or adolescence. Hematopoietic stem cell gene therapy aiming at reintroducing the wildtype cDNA as a new concept for the treatment of hereditary diseases may be applicable to FANC and PAP, as both disorders can be successfully treated by allogeneic stem cell transplantation. However, there are important distinctions to be made between the two diseases: FANC seems to be a disorder with functional stem cell deficiency. Thus, introduction of the wildtype cDNA should provide an in vivo growth advantage to genetically corrected stem cells so that corrected cells and their progeny may expand in vivo and slowly repopulate the entire hematopoietic system. In beta c-PAP, the defect has no major impact on proliferation or differentiation of stem cells. Therefore, introduction of the wildtype gene will probably not provide any selective growth advantage and the percentage of corrected cells in the hematopoietic compartment depend on the percentage of stem cells initially transduced as the current technology only allows for transduction of stem cells with low efficiency. The introduction of a second selectable cDNA into the vector might be used to provide selective growth for modified cells and thus overcome a low gene transfer efficiency of stem cells. The correction of rare monogenetic diseases may serve as a model for gene therapy prior to attempts to treat more common and complex polygenetic diseases. The studies outlined here will be helpful envisioning new treatment strategies for other inherited monogenetic diseases such as mucopolysaccharidosis, Gauchers disease or adrenoleukodystrophy.

Animals↗
PubMedDate not supplied

Defunct hematopoietic progenitor growth and heterogeneous immunological phenotypes in acquired aplastic anemia of childhood: identification of subsets with decreased hematopoietic progenitors and increased IL15 or IL10 production.

Acquired aplastic anemia (AAA) is a disorder with multiple causes. The pathogenetic mechanisms leading to marrow failure are diverse. The clinical finding, that most patients respond to immunosuppressive therapy implicates an immune pathophysiology of AAA. On the other hand successful and long lasting reconstitution after allogeneic stem cell transplantation implicates, that a stem cell defect is a major pathogenetic factor. We analyzed immunological and hematological parameters on 91 pediatric patients with AAA at time of diagnosis. We defined three distinct pathogenetic subgroups by analyzing the frequency of hematopoietic progenitors and the frequency of activated T-cells in patients bone marrow: type I: decreased percentage of hematopoietic progenitors; type II: increased percentage of activated T-cells; type III: increased percentage of pluripotent progenitors. In 51% of the AAA patients we found a relative decreased frequency of hematopoietic progenitors and 29% of the patients demonstrated an increased percentage of activated T-cells, 25% patients showed an increased percentage of pluripotent hematopoietic progenitors. In order to characterize these distinct immunological subgroups, we investigated the plasma levels of IFN-gamma and IL15 as inhibitors and IL10 as stimulator of hematopoiesis. IL15 plasma levels were significantly elevated in AAA patients when compared to controls. In contrast we could not demonstrate a difference between IFN-gamma or IL10 plasma levels in AAA patients when compared to controls. However for IL10 and IL15 we were able to define subgroups of patients with highly elevated plasma levels of the cytokines. These data indicate that the immunopathogenesis of AAA can be heterogeneous. This heterogeneity might reflect exposure to different exogenous agents or heterogeneity in intrinsic susceptibility. The clinical impact of our findings needs to be assessed in long-term follow up of the patients.

Anemia, Aplastic↗
PubMedDate not supplied

Circulating CD34+ cell counts as predictive parameter for the efficacy of peripheral stem cell apheresis in Ewing tumor patients.

The parameters used by different centers for starting peripheral stem cell apheresis following mobilization with chemotherapy and G-CSF are diverse. We retrospectively analysed 62 leukaphereses performed on eleven patients with Ewing Tumors and one patient with Synovial Sarcoma, all after treatment with standardized chemotherapy (according to the EICESS protocol) and subsequent administration of G-CSF. Blood samples, drawn before the apheresis and samples of the apheresis products were analysed by flow cytometry for their content of CD34+ cells, furthermore, the peripheral leukocyte count was determined. Our aim was to define a parameter that reliably predicts the efficacy of leukapheresis in these patients. We found a significant correlation (r = 0.85; p < 0.0001) between the absolute CD34 positive cell count prior to leukapheresis and the yield of CD34+ cells/kg body weight (bw) in the apheresis product. No correlation was observed between the leukocyte count prior to apheresis and CD34+ cells/kg bw in the apheresis product (r = 0.14; p < 0.28). In addition, we found no correlation between the number of CFU-GM in the apheresis product and the CD34+ cells/kg bw (r = 0.22; p < 0.35). Our data indicate that the peripheral CD34 positive cell count prior to leukapheresis is the best parameter for predicting the efficacy of peripheral stem cell apheresis in Ewing Tumor patients after treatment with standardized chemotherapy.

Adolescent↗