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H Gadner

Publications and source records attributed to H Gadner.

At least 127 records · Page 7Linked to original sources
PubMed1998

Comparative phenotype mapping of normal vs. malignant pediatric B-lymphopoiesis unveils leukemia-associated aberrations.

Leukemic cells of B-lineage acute lymphoblastic leukemia (ALL) are regarded as the malignant counterparts of immature, physiologic B cell precursors (BCPs). To determine whether phenotypic differences exist between these corresponding cell types, we investigated samples of normal pediatric bone marrow (n=30) as well as of B-precursor ALL at diagnosis (n=53; common and pre-B subtype). Using three-color multiparameter flow cytometric analysis, we compared the leukemic populations with the physiologic BCPs of corresponding maturity with respect to the intensity with which they expressed a series of antigens. In some of these antigens, leukemia-associated aberrations were frequently observed. In particular, overexpression of CD10 was displayed by 65% of ALL samples, whereas 58% of leukemic cases aberrantly exhibited very low or no CD45RA expression. Regarding CD11a and CD44, 47% and 35% of ALL populations were aberrant as defined by either the absence or significant overexpression of the antigen. In contrast, antigen densities of CD49d, CD49e, and CD99 on leukemic cells were in the normal range of values for BCPs. Combining the patterns of frequently aberrant markers in a comprehensive analysis, we were able to identify individual phenotypic leukemic cell aberrations in up to 98% of investigated cases. CD10 and/or CD45RA were aberrant in 86% of cases overall, emphasizing the high discriminative potential of these two markers. Using comparative phenotype mapping based on quantitatively aberrant, leukemia-associated antigenic patterns, we were able to detect leukemic blasts among normal bone marrow cells at frequencies as low as 10(-5). We speculate that our approach may have a profound impact on the development of new strategies for minimal residual disease investigations in patients with BCP-ALL.

Adolescent↗
PubMed1998

CMV-viraemia during allogenic bone marrow transplantation in paediatric patients: association with survival and graft-versus-host disease.

Sixty-one consecutive paediatric patients undergoing allogenic bone marrow transplantation (BMT) were screened prospectively for cytomegalovirus (CMV)-viraemia by PCR. Sixteen patients (26%) presented with single or recurrent CMV-viraemia between day -7 and + 100. Although only four of them had evidence of CMV-disease, there was a significant difference in the incidence of acute Graft versus Host Disease (GVHD) grade III-IV (75% vs 15.5%), liver-involvement (68% vs 13%) and the incidence of chronic GVHD (83% vs 13.8%) between CMV-PCR-positive and CMV-PCR-negative patients. Transplant-related mortality (TRM) was 43.7% in the CMV-PCR-positive group versus 13% in patients which had no evidence for CMV-viraemia. In all but one cases mortality in CMV-PCR positive patients was GVHD-associated. Pre-emptive therapy with gancyclovir in case of CMV-viraemia seemed to have no impact on incidence and severity of GVHD.

Adolescent↗
PubMed1998

Proposal for standard recommendations for prophylaxis of graft-versus-host disease in children. European Group for Blood and Marrow Transplantation (EBMT) Working Party Paediatric Diseases and the International Study Committee of the BFM family-subcommittee Bone Marrow Transplantation (IBFM-STG).

Great variations exist in the practices of graft-versus-host disease prophylaxis for children undergoing allogeneic stem cell transplantation. It was the aim of the EBMT Working Party on Paediatric Diseases and the International Study Group of the BFM-Family, subcommittee bone marrow transplantation (IBFM-SG) to define standard recommendation for prevention of GVHD. Thus a survey was carried out among the local representatives of the EBMT WP and IBFM-SG members to define standards for GVHD prophylaxis basing on available literature data, discussion with colleagues and their own experience. Presently the majority of regimen for GVHD prophylaxis are centred on CsA and a short course of MTX with addition of some other immunosuppression (eg ATG or ALG) in patients with high risk for severe GVHD. The proposal defined different category of patients: patients with malignant disease who are either transplanted from HLA matched sibling donors or HLA mismatched family donors (or volunteer unrelated donors) and patients with non malignant disease who might not benefit from graft-versus-leukaemia effect having either an HLA matched sibling donor or an HLA mismatched family donor (or volunteer unrelated donor). Homogeneous GVHD prophylaxis for defined patient groups should provide better information to optimise strategies in reducing treatment related toxicity and incidence of relapse by increasing GVL effect.

Adolescent↗
PubMed1997

The present role of bone marrow and stem cell transplantation in the therapy of children with acute leukemia.

Hematopoetic stem cell transplantation (SCT) often represents a unique opportunity for curing children with leukemia. Nevertheless, selecting the patient who could really benefit from this procedure remains a controversial issue. The current consensus is as follows: About 20% of children with ALL can be defined as high-risk patients by criteria such as t(9;22), t(4;11), no complete remission at day 42, poor prednisone response, and T-immunophenotype or pre-pre B-ALL, myeloid markers or more than 100,000 white blood cells/microliter. This high-risk group is eligible for alloBMT in first remission, provided a family-matched donor is available. At relapse the majority of patients will benefit from alloBMT, and alternative donor sources can be considered in high-risk patients. Only early alloBMT relapses (up to 6 months after end of initial therapy) are sure candidates, whereas late relapses, especially extramedullary sites, may equally benefit from an intensive conventional relapse treatment. However, any alloBMT relapse beyond second remission should be transplanted with allogeneic stem cells (bone marrow or peripheral stem cells). In particular, family mismatched donors or matched unrelated donors may be acceptable in high-risk cases beyond first remission. In contrast, ASCR in ALL seems not to be superior to conventional therapy. In AML the standard-risk patient, defined by criteria such as FAB M1/M2-Auer rods positive, all FAB M3, and FAB M4, is not a candidate for SCT in first remission. Patients presenting other criteria or more than 5% of blasts in the bone marrow at day 15 are at high risk in first remission and should be considered for allo BMT if a family matched donor is available. ASCR in first remission AML remains a controversial issue. In contrast, in second remission alloBMT as well as ASCR are superior to conventional chemotherapy.

Acute Disease↗
PubMed1997

Risk of secondary leukemia after treatment with etoposide (VP-16) for Langerhans' cell histiocytosis in Italian and Austrian-German populations.

To estimate the risk of secondary leukemias after treatment with etoposide (VP-16), we evaluated subjects treated for Langerhans' cell histiocytosis (LCH) according to cooperative protocols in Italy or in Austria, Germany, Holland and Switzerland (AGDS). For each subject, information was collected on the cumulative dosages of chemotherapy and radiotherapy received, vital status and occurrence of secondary leukemia. The expected number of leukemias was estimated using age-specific incidence rates from the cancer registries in Italy and Germany. Standardized incidence ratios (SIR) were used to measure the risk of secondary leukemia among LCH patients. Five leukemias occurred among the 241 Italian study patients (SIR 520), whereas no cases were reported among the 363 AGDS patients. Interestingly, and in contrast to previous descriptions of epipodophyllotoxin-related leukemias which are mostly FAB M4 or M5, these leukemias showed typical FAB M3 features, and received a dose of VP-16 > 4,000 mg/m2. Among the AGDS cohort, very few subjects were exposed to high doses of VP-16. The risk of secondary acute non-lymphoblastic leukemia (s-ANLL) among the Italian subjects exposed to VP-16 was more than 1,000 times greater than expected. The study suggests that high doses of VP-16 appear to increase the risk of s-ANLL in LCH patients. The fact that all the leukemias described in the Italian LCH cohort were promyelocytic, and evidence of a higher incidence of promyelocytic leukemias among Italians and Latinos, suggest that high doses of etoposide in subjects of Latino origin may lead to aberrations on chromosomes 15 and 17.

Adolescent↗
PubMed1997

Molecular and functional characterization of the urokinase receptor on human mast cells.

The urokinase receptor system is involved in several biological processes including extracellular proteolysis, cell invasion, and chemotaxis. Mast cells are multifunctional perivascular cells that play an important role in the regulation of microenvironmental events. We report that primary human mast cells and the human mast cell line HMC-1 express the receptor for urokinase. As assessed by Northern blotting and reverse transcription polymerase chain reaction technique, purified human lung mast cells and HMC-1 cells expressed urokinase receptor mRNA in a constitutive manner. Using a toluidine blue/immunofluorescence double staining technique and monoclonal antibodies, surface expression of urokinase receptor was demonstrable in lung, skin, uterus, heart, and tonsil mast cells, whereas the low density lipoprotein receptor-related protein was not detectable. Binding of monoclonal antibody VIM5 (recognizing the urokinase binding domain of urokinase receptor) to HMC-1 could be blocked by high molecular weight but not low molecular weight urokinase. Binding analyses performed with 123I-urokinase revealed expression of 271,000 +/- 55,000 high affinity urokinase binding sites per HMC-1 cell, with a calculated dissociation constant of 1. 29 +/- 0.3 nM. Purified urokinase induced dose-dependent migration of primary mast cells and HMC-1 in a chemotaxis assay without inducing release of histamine. The mast cell agonist stem cell factor also induced migration of HMC-1 and caused up-regulation of expression of urokinase receptor mRNA. Together, our data show that human mast cells express functional receptors for urokinase. Expression of urokinase receptors on mast cells may have implications for mast cell-dependent microvascular processes associated with fibrinolysis, migration, or local tissue repair.

Binding Sites↗
PubMed1997

Neuroblastoma screening in infants postponed after the sixth month of age: a trial to reduce "overdiagnosis" and to detect cases with "unfavorable" biologic features.

BACKGROUND: Encouraged by Japanese reports of the benefits of screening 6 month-old infants for neuroblastoma, a neuroblastoma screening program was introduced in Austria in 1991. However, because of concerns related to "overdiagnosis" by screening at this age, the screening test was performed at a later age. METHODS: From March 1991 to February 1995 neuroblastoma screening was performed on filter paper urine specimens in 100,043 Austrian infants (median age 8.5 months). Primary analysis of urine catecholamines (vanillylmandelic acid and homovanillic acid was performed by use of an E1A method. Questionable or positive results were confirmed by high performance liquid chromatography (HPLC). A double retest was requested following a positive HPLC result. RESULTS: Twenty-one infants were admitted to a hospital following repeatedly elevated values of vanillymandelic acid (VMA) and/or homovanillic acid (HVA). Eleven infants were found to have neuroblastoma (three stage 1, four stage 2B, four stage 3). Treatment consisted of surgery alone with total or subtotal resection in eight cases, surgery and chemotherapy in two cases, and chemotherapy alone in one case. Biologic features were assessed in all tumors excluding ploidy in one case. The majority of the tumors analyzed were near-triploid (9/10), however, two tumors revealed N-myc amplification. CONCLUSIONS: Our results demonstrate that stage distribution and biologic features of neuroblastomas diagnosed by screening at 8.5 months are different from the results of screening at 6 months. Furthermore, the detection of one neuroblastoma among 9,100 screened infants is significantly lower than the incidence of the Japanese screening program. Our results suggest that screening at an age of 7 to 10 months reduces overdiagnosis and may be of more benefit than earlier screening.

Age Factors↗
PubMed1997

Contemporary classification of histiocytic disorders. The WHO Committee On Histiocytic/Reticulum Cell Proliferations. Reclassification Working Group of the Histiocyte Society.

Pathologists and pediatric hematologist/ oncologists of the World Health Organization's Committee on Histiocytic/Reticulum Cell Proliferations and the Reclassification Working Group of the Histiocyte Society present a classification of the histiocytic disorders that primarily affect children. Nosology, based on the lineage of lesional cells and biological behavior, is related to the ontogeny of histiocytes (macrophages and dendritic cells of the immune system). Dendritic cell-related disorders of varied biological behavior are dominated by Langerhans cell histiocytosis, but separate secondary proliferations of dendritic cells must be differentiated. Juvenile xanthogranuloma represents a disorder of dermal dendrocytes, another dendritic cell of skin. The hemophagocytic syndromes are the most common of the macrophage-related disorders of varied biological behavior. Guidelines for distinguishing the exceedingly rare malignant diseases of histiocytes from large cell lymphomas through the use of a battery of special studies are provided.

Cell Lineage↗
PubMed1997

Acute leukemias express a functional receptor for the human growth hormone.

The potential influence of the human growth hormone (hGH) on the behavior of acute leukemias is a matter of controversy. We investigated primary childhood and adult leukemias (n = 44) and leukemic cell lines (n = 13) for the expression of the hGH receptor (hGHR) by immunohistochemistry and flow cytometry. All leukemias expressed the hGHR in the cytoplasm; expression on the surface was undetectable in some of the leukemias. In leukemic cell lines, hGHR expression on the surface was demonstrated in a dose-dependent manner after incubation with rhGH. Physiologic concentrations of hGH were more efficient than higher doses in increasing hGHR surface expression. A proliferative response to hGH was accomplished in cell lines REH, Molt4, and K562. However, only one of 19 primary leukemias (ALL, n = 12; AML, n = 7) showed increased cell counts after the addition of 50-800 ng/ml recombinant hGH (rhGH). These cells were of an immature T-cell phenotype. We thus conclude that acute leukemias can be stimulated by hGH to up-regulate its receptor, but that most primary leukemias may require additional signals for the induction of proliferation.

Adult↗
PubMed1997

Neuroblastoma cells can actively eliminate supernumerary MYCN gene copies by micronucleus formation--sign of tumour cell revertance?

Human neuroblastoma cell lines frequently exhibit MYCN amplification and many are characterised by the presence of morphologically distinct cell types. The neuronal cells (N-cells) and the so-called flat cells (F-cells) are thought to represent manifestations of different neural crest cell lineages and are considered to be the consequence of neuroblastoma cell pluripotency. In this study, various neuroblastoma cell lines were examined for micronuclei. In F-cells of neuroblastoma cell lines with extrachromosomally amplified MYCN, we observed the frequent occurrence of micronuclei. Using fluorescence in situ hybridisation (FISH) with a MYCN specific probe, we demonstrated that these micronuclei were packed with MYCN hybridisation signals. In addition, in a minor percentage of cells, MYCN signals occurred in clusters, adhered to the nuclear membrane and aggregated in nuclear protrusions. In F-cells, a substantial reduction or lack of amplified MYCN copies was observed. These observations let us conclude that extrachromosomally amplified genes can be actively eliminated from the nucleus resulting in a dramatic loss of amplified sequences in the F-cells. Moreover, reduction or loss of amplified sequences in F-cells was shown to be accompanied by downregulation of MYCN expression, by a decrease in proliferative activity and by upregulation of molecules of the major histocompatibility complex class I (MHC I). Interestingly, F-cells are not restricted to neuroblastoma cell cultures, but also occur in cell lines of other tissue origin. All F-cells share important biological features, interpreted as cell revertance, i.e. loss of the malignant phenotype and properties. This fact, together with the demonstration that neuroblastoma cells do not differentiate into Schwann cells in vivo [1] Ambros et al. NEJM 1996, 334, 1505-1511, do not support the hypothesis that F-cells represent Schwannian/glial differentiation in vitro. We therefore postulate that the elimination of amplified MYCN gene copies in cultivated neuroblastoma cells is in line with the phenomenon of tumour cell revertance.

Cell Division↗
PubMed1997

Allogeneic bone marrow transplantation for a subset of children with acute lymphoblastic leukemia in third remission: a conceivable alternative?

In the BFM Relapse Study registry we retrospectively identified 136 patients with a first marrow relapse who had undergone BMT in second complete remission (CR2) (group A) and 33 patients who received transplants only after a 2nd bone marrow (BM) relapse had occurred (group B). Event-free survival (EFS) rates at 6 years after BMT were 0.49 +/- 0.05 and 0.48 +/- 0.09 for patients transplanted in CR2 and CR3, respectively. In context with the BFM chemotherapy trials for relapsed childhood ALL there is a clear benefit from BMT in 2nd CR for children with unfavorable prognostic features (isolated early BM relapse, very early BM relapse or BM relapse of T cell ALL). Similar control of leukemia can be achieved with either chemotherapy or BMT in late BM relapse of ALL. Assuming a 60% failure rate with chemotherapy for patients in second relapse, a third remission can be achieved in about 60% of patients who have received chemotherapy, rendering them eligible for BMT in 3rd CR. With this strategy 58% of these patients would survive and late sequelae of BMT be restricted to a minority. To withhold BMT in CR2 and not perform BMT before a 2nd BM relapse has occurred, may be a conceivable alternative for children with late ALL BM relapse, at least if no related donor is available.

Adolescent↗
PubMed1997

Multiparameter phenotype mapping of normal and post-chemotherapy B lymphopoiesis in pediatric bone marrow.

We studied the differentiation profiles of B cell precursors (BCP) in normal and post-chemotherapy pediatric bone marrow (BM) using multiparameter flow cytometry. The goal of our study was to draw a comprehensive phenotypic map of the three major maturational BCP stages in BM. By correlating lineage-associated markers, CD45RA, and several adhesion molecules, the stage-specific patterns were found to differ in certain details from previously published concepts. Among the earliest BCP, a subset of CD34+ CD10(lo) precursors was repeatedly observed in addition to the well characterized CD34+ CD10(hi) CD19+ majority of cells. Only two-thirds of these CD34+ CD10(lo) cells expressed CD19. However, uniformity of phenotypic features, absence of T lineage markers, and the regeneration kinetics after chemotherapy suggest the B lineage affiliation of the CD34+ CD10(lo) precursors in general. In the more mature BCP, expression of CD10, CD20, cytoplasmic and surface mu chains (c mu and s mu) was observed to overlap more than previously recognized. We found that CD20 and c mu appear early during B cell ontogeny (already on CD34+ BCP), and that CD10 is lost late, following the onset of s mu expression. Differences between normal and post-chemotherapy BM specimens regarding the phenotypic appearance of BCP were exclusively due to differences in the subset composition, as post-chemotherapy samples showed a preponderance of immature stages. Our observations may build a framework for comparing leukemic cells with their normal counterparts to define possible leukemia-associated aberrations useful for residual disease studies.

Adolescent↗
PubMed1997

Among genes involved in the RB dependent cell cycle regulatory cascade, the p16 tumor suppressor gene is frequently lost in the Ewing family of tumors.

The pRB cell cycle regulatory cascade is frequently perturbed in neoplasia by overexpression of a component of the pRB-phosphorylating cyclin D1/CDK4 complex or by inactivation of pRB or the CDK4 inhibitors p16 and p15. We investigated the status and expression of p16, p15, CCND1, CDK4 and RB genes in the Ewing family of tumors. P16 loss was observed in 8 of 27 tumors (30%) and in 12 of 23 (52%) tumor cell lines from unrelated patients. There were no discrepancies in the p16 status between primary tumors and the corresponding cell lines and between cell lines established from consecutive tumor samples. p15 was codeleted in most cases but p15 mRNA was absent also in cell lines retaining the gene. In addition, posttranscriptional p16 inactivation was observed in two cases. Although no evidence for CDK4 or CCND1 amplification was obtained, expression of these genes varied considerably in the cell lines in a case specific manner. In wild-type p16 cell lines, pRB expression was lost in one case. Our data indicate that, despite the absence of cytogenetically detectable 9p21 chromosomal aberrations, p16 deletions constitute the most frequent secondary molecular aberration in Ewing tumors so far. These results are discussed in the context of the stage of disease and the clinical outcome of the patients. The potential prognostic impact of these findings remains to be further evaluated.

Cell Cycle↗
PubMed1997

Crosslineage TCR delta rearrangements occur shortly after the DJ joinings of the IgH genes in childhood precursor B ALL and display age-specific characteristics.

In order to test the hypothesis that the most immature T-cell receptor (TCR) rearrangements occur after the DJ joining of the immunoglobulin heavy chain genes (IgH), we analysed the TCR Vdelta2-Ddelta3 rearrangements in precursor B-cell leukaemias (PBC ALL) from 25 children younger than 3 years at disease onset and found that most of the junctional regions had N nucleotides inserted. We then selected 14 of these PCB ALLs for DJH (DJ joining of the IgH) characterization. These joining regions showed homology-directed recombination and lack of N regions, indicating absence of terminal deoxynucleotidyl transferase (TdT) activity during their rearrangement. Most leukaemias with a DJH rearrangement without N region have no, or only one, nucleotide in the joining regions of their Vdelta2-Ddelta3 rearrangements. The N regions of the TCR delta rearrangements displayed 'age-specific' differences: in children younger than 3 years of age the N regions were shorter than in those older than 3 years, and the rearrangements frequently contained complete segments. We conclude that the Vdelta2-Ddelta3 rearrangement in childhood PCB ALLs is an early event following DJH rearrangement and that it occurs shortly before or after the first hit, leading to malignant transformation.

Adolescent↗
PubMed1997

Low risk of secondary leukemias after chemotherapy without mechlorethamine in childhood Hodgkin's disease. German-Austrian Pediatric Hodgkin's Disease Group.

BACKGROUND: In the last two decades, it has become evident that secondary leukemias after Hodgkin's disease (HD) are mainly caused by the treatment with alkylating agents, especially mechlorethamine. Since 1978, the German-Austrian trials for childhood HD have used combined chemoradiotherapy without mechlorethamine. PATIENTS AND METHODS: The risk of secondary hematologic malignancies (SHM) was assessed in the total cohort of 667 children treated in four consecutive German-Austrian trials between 1978 and 1990. Primary chemotherapy for stages IA/B and IIA consisted of two cycles of vincristine, procarbazine, prednisone, and doxorubicin (OPPA) or OPA (without procarbazine) and, for more advanced stages, of two cycles of OPPA or OPA plus two, four, or six cycles of COPP or COMP (C, cyclophosphamide; M, methotrexate). Radiotherapy was given in the first study to extended fields, and in later trials to involved fields only. In 591 patients, only primary therapy was given; 76 patients (11%) needed additional salvage therapy. The actuarial survival rate at 15 years is 94%. RESULTS: SHM developed in 5 of 667 patients: four acute myeloid leukemias (AMLs) and one myelodysplastic syndrome (MDS). The estimated cumulative risk for SHM at 15 years is 1.1% (95% CI, 0.0% to 2.2%). Salvage therapy was a significant risk factor for SHM (relative risk, 7.25; P = .03), whereas age, sex, stage of HD, splenectomy, and amount of alkylating agents were not. CONCLUSION: The observed risk of SHM is smaller than in other studies (adults and children) in which chemotherapy with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) was given. This difference can be attributed to the lower cumulative doses of alkylating agents, the absence of mechlorethamine in the chemotherapy, and the small number of patients who needed salvage therapy in the presented cohort. In general, differences in the incidence of SHM after HD reflect complex differences between treatment strategies.

Adolescent↗
PubMed1996

Isochromosome 12p and maternal loss of 1p36 in a pediatric testicular germ cell tumor.

Analysis of a pediatric germ cell tumor by conventional cytogenetic investigation and fluorescence in situ hybridization showed consistently the presence of two isochromosomes 12p, loss of the maternal band 1p36, and other numerical and structural chromosome changes. The rearrangements observed resulted mainly from breaks occurring at paracentromeric regions. This report represents the first description of i(12)(p10) in a pediatric testicular embryonal carcinoma.

Adolescent↗