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H Gadner

Publications and source records attributed to H Gadner.

At least 91 records · Page 5Linked to original sources
PubMed2000

Expression of tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptors and sensitivity to TRAIL-induced apoptosis in primary B-cell acute lymphoblastic leukaemia cells.

Because tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) (Apo2 ligand) preferentially kills malignant cells while sparing normal cells, it may be therapeutically useful against cancers, including those of haematopoietic origin. Although the activity of TRAIL has been studied in tumour cell lines and in a limited number of different primary tumours, its overall activity in a large number of uniform cases of primary tumours is not known. We therefore studied the activity of TRAIL in 29 primary precursor B-cell acute lymphoblastic leukaemia (ALL) samples. TRAIL was found to have a modest activity as it killed a maximum of 29% of ALL cells within 18 h compared with killing 75% of Jurkat cells. The sensitivity to TRAIL did not correlate with the pattern of TRAIL receptor expression or FLIP expression, as determined by Western blot analysis. The CD40 receptor, which can transduce survival signals in mature malignant B cells, was less frequently expressed on ALL cells, but incubation with an exogenous soluble CD40 ligand trimer did not rescue them from spontaneous apoptosis and did not mediate their resistance to TRAIL. Further, although ALL cells expressed TRAIL protein, they failed to kill target Jurkat cells in a TRAIL-dependent manner. Our data delineate major biological differences between mature and precursor malignant B cells and suggest a limited therapeutic role for TRAIL as a single agent in primary B-cell ALL.

Adolescent↗
PubMed2000

Granulocyte colony-stimulating factor versus granulocyte-macrophage colony-stimulating factor for collection of peripheral blood progenitor cells from healthy donors.

The harvesting of peripheral blood progenitor cells (PBPCs) after granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor stimulation instead of bone marrow in healthy donors has become increasingly popular. Donors, given the choice between bone marrow and PBPC donation, often prefer cytapheresis because of the easier access, no necessity for general anesthesia, and no multiple bone marrow punctures. In addition, accelerated engraftment and immunomodulation by granulocyte colony-stimulating factor-mobilized PBPCs are advantageous for the recipient. However, because of donor inconvenience and poor mobilization, there is a need to develop improved procedures. Aspects such as durability of hematopoietic engraftment, characterization of the earliest stem cell, and composition of PBPCs are not yet well defined, and international donor registration and follow-up must be considered when evaluating long-term safety profiles in healthy donors. This review concentrates on the most significant developments on mobilization of PBPCs published during the past year.

Consumer Product Safety↗
PubMed2000

Prognostic factors in Ewing's tumor of bone: analysis of 975 patients from the European Intergroup Cooperative Ewing's Sarcoma Study Group.

PURPOSE: To further elaborate on prognostic factors for Ewing's sarcoma of bone and to document improvements in relapse-free survival (RFS) and trends in local therapy over the study period (1977 to 1993). PATIENTS AND METHODS: A retrospective analysis was performed on a combined Gesellschaft Für Pädiatrische Onkologie und Hämatologie/Cooperative Ewing Sarcoma Study and United Kingdom Children's Cancer Study Group/Medical Research Council data set of 975 patients registered with the respective trial offices before the current collaborative European Intergroup Cooperative Ewing's Sarcoma Study trial. Both groups independently undertook studies with similar chemotherapy during the period. RESULTS: The key adverse prognostic factor is metastases at diagnosis (5-year RFS, 22% of patients with metastases at diagnosis v 55% of patients without metastases at diagnosis; P: <.0001). For the group with metastases, there was a trend for better survival for those with lung involvement compared with those with bone metastases or a combination of lung and bone metastases (P: <.0001). In the group of patients with no metastases at diagnosis, multivariate analysis demonstrated that site (axial v other), age-group (< 15 v > or = 15 years), and period of diagnosis had significant influence on RFS (all P: <.005). RFS was superior in the period after 1985 compared with the period before 1985 for nonmetastatic patients (45% v 60%, respectively; P: <.0001) and for metastatic patients (16% v 30%, respectively; P: =.016). Patients who relapsed within 2 years of diagnosis had a less favorable prognosis than patients who relapsed later (5-year survival after relapse, 4% v 23%, respectively; P: <. 0001). There were other changes over the period; in particular, radiotherapy or amputation were more common in the period before 1986, whereas endoprosthetic surgery was widely used in the later period. CONCLUSION: Survival and RFS improved over the period. Prognostic factors are metastases at diagnosis, primary site, and age.

Adolescent↗
PubMed2000

Detection of residual disease in pediatric B-cell precursor acute lymphoblastic leukemia by comparative phenotype mapping: method and significance.

The present review summarizes our efforts in developing a novel immunologic approach ("Comparative Phenotype Mapping") targeted at assessing minimal residual disease (MRD) in B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) patients. The method relies on quantitatively aberrant, leukemia-associated antigen expression patterns which allow to discriminate leukemic from normal BCP using a limited panel of antibody combinations and multidimensional flow cytometry. In an analysis of 63 follow up bone marrow samples of patients with BCP-ALL we show that this approach enables to efficiently detect MRD. Further clinical observation revealed that the patients which were MRD-positive by flow cytometry (although in morphological remission) had a very high probability of early disease recurrence compared to the good chances of a relapse-free survival (RFS) in the MRD-negative cohort (RFS 0.0 vs. 0.76 at 3 years). Comparative Phenotype Mapping thus proves to be a reliable method for MRD detection in BCP-ALL. Concluding remarks relate to the optional applications of the method as well as to future perspectives. An ongoing large prospective study which we are now conducting on the basis of Comparative Phenotype Mapping will clarify the clinical significance of MRD detection in ALL patients by this method, and will determine its value compared to related as well as molecular-genetic techniques.

Adolescent↗
PubMed1999

Prednisone response is the strongest predictor of treatment outcome in infant acute lymphoblastic leukemia.

To define prognostic factors in infant acute lymphoblastic leukemia (ALL), the outcome of 106 infants (age </=12 months) during 3 consecutive multicenter trials of the Berlin-Frankfurt-Münster group (ALL-BFM 83, 86, and 90) was retrospectively analyzed according to presenting features and early in vivo response to prednisone. The prednisone response was defined as the cytoreduction (number of blood blasts per microliter at day 8) to a 7-day prednisone prephase and 1 intrathecal dose of methotrexate on day 1. Prednisone good responder (PGR; <1,000 blasts/microL) received conventional therapy and prednisone poor responder (PPR; >/=1,000 blasts/microL) received intensified therapy. Infant ALL was characterized by a high incidence of a white blood cell count greater than 100 x 10(3)/microL (57%), central nervous system leukemia (24%), lack of CD10 expression (59%), 11q23 rearrangement (49%) including the translocation t(4;11) (29%), and a comparatively high proportion of PPR (26%), which were all significantly associated with inferior outcome by univariate analysis. The estimated probability for an event-free survival at 6 years (pEFS) was by far better for PGR compared with PPR, who had a dismal prognosis despite intensified treatment (pEFS, 53% +/- 6% v 15% +/- 7%, P =.0001). Infant PGR, who were less than 6 months of age (n = 40), lacked CD10 expression (n = 43), and/or had an 11q23 rearrangement (n = 17) fared significantly better compared with corresponding PPR, as indicated by a pEFS of 44% +/- 8%, 49% +/- 8%, and 41% +/- 12%, respectively. In multivariate analysis, PPR was the strongest adverse prognostic factor (relative risk, 3.3; 95% confidence interval, 1.9 to 5.8; P <.0001). Infants with PGR, comprising a major subgroup (74%) among infants, might successfully be treated with conventional therapy, whereas PPR require new therapeutic strategies, including early treatment intensification or bone marrow transplantation in first remission.

Antineoplastic Agents, Hormonal↗
PubMed1999

Intensive treatment of children with acute lymphoblastic leukemia according to ALL-BFM-86 without cranial radiotherapy: results of Dutch Childhood Leukemia Study Group Protocol ALL-7 (1988-1991).

In The Netherlands from July 1988 to October 1991, children (0 to 16 years of age) with de novo acute lymphoblastic leukemia (ALL) were treated according to protocol ALL-7 of the Dutch Childhood Leukemia Study Group (DCLSG). In this protocol, chemotherapy and treatment stratification were identical to the ALL-BFM-86 protocol (Reiter et al, Blood 84:3122, 1994), but cranial irradiation was restricted to patients with initial central nervous system (CNS) involvement. Patients were stratified into 3 risk groups, based on leukemia cell mass and response to initial treatment: standard-risk group (SRG), risk group (RG), and experimental group (EG). As in ALL-BFM-86, a randomized study on late intensification (protocol S) was performed in RG patients, and during the study (since October 1990), early reinduction treatment (protocol II) was introduced for SRG patients. Treatment duration for all patients was 18 months. Two hundred eighteen children entered the study: 74 SRG, 127 RG, and 17 EG patients. The overall complete remission (CR) rate was 98%. The 5-year event-free survival (EFS) for all DCLSG ALL-7 patients was 65. 3% (standard error [SE] 3.2%), which was significantly different from the 73% (SE 1%) 5-year EFS achieved in the ALL-BFM-86 study (P =.02, Z-test). However, restricting the analysis to SRG patients receiving protocol II with a total duration of treatment of 18 months, the 5-year EFS rates were 64.6% (SE 4.0%) and 67% (SE 4%), respectively, and no significant difference could be established (P =.67, Z-test). The 5-year EFS rates for SRG, RG, and EG patients were 63.5% (SE 5.6%), 66.6% (SE 4.2%), and 63.3% (SE 12.0%), respectively. SRG patients receiving protocol II fared better than patients not receiving protocol II (5-year EFS 76.7% [SE 7.7] and 54. 5% [SE 7.5], respectively). No difference in 5-year EFS was observed in RG patients randomized to receive or not to receive late intensification with protocol S. The overall CNS relapse rate at 5 years was 5.5%. The incidence rate at 5 years was 11.4% in SRG patients not receiving protocol II, whereas no CNS relapses occurred in SRG patients receiving protocol II. Six children died in first complete remission and 2 children developed a second malignancy (thyroid carcinoma and acute nonlymphoblastic leukemia). Systemic high-dose methotrexate (MTX) and intrathecal chemotherapy is a safe and effective method of CNS prophylaxis in the context of BFM-oriented treatment for all children with ALL, regardless of the risk group (with the possible exception of T-ALL patients with high white blood cell counts). The results of the DCLSG ALL-7 study confirm those of the ALL-BFM-86 study showing that early reinduction with protocol II is essential in the treatment of SRG patients and that late intensification with protocol S does not improve the prognosis for RG patients.

Adolescent↗
PubMed1999

[Congenital syphilis: late diagnosis in spite of screening].

We report the case of an infant in whom congenital syphilis was diagnosed at the age of 5 weeks. The case is remarkable because of (a) the negative venereal disease laboratory test from the cord blood, (b) the incidental diagnosis of the disease in the fifth week of life, (c) pneumonia alba being one of the symptoms, (d) the occurrence of a mild Jarisch-Herxheimer reaction after initiation of penicillin therapy and (e) the successful treatment of infection related anaemia with recombinant human erythropoietin.

False Negative Reactions↗
PubMed1999

Prognostic impact of deletions at 1p36 and numerical aberrations in Ewing tumors.

Ewing's sarcoma, peripheral primitive neuroectodermal tumors, and Askin tumors are referred to as Ewing tumors (ETs), and are characterized by high MIC2 expression and a t(11;22)(q24;q12) or other rearrangements involving 22q12. In addition to these constant aberrations, facultative numerical and structural aberrations have been reported: gains of chromosomes 8 and 12, the unbalanced translocation t(1;16), and deletions at the short arm of chromosome 1. To evaluate the frequency and to study the biological impact of these facultative aberrations, we analyzed tumor specimens from 58 ET patients by classical cytogenetics and/or in situ hybridization techniques and compared these data with clinical parameters. Gains of chromosomes 8 and 12 were detected in 55% (32/58) and 24% (14/58) of the cases, respectively. Loss of chromosome 16 or der (16)t(1;16) chromosomes were found in 20% (10/51); deletions at 1p36 were observed in 18% (9/51) of the cases evaluated. The presence of these aberrations did not correlate with age and sex of the patients, with the location of the primary tumor or with the extent of disease at diagnosis by chi-square analysis and Fisher's exact test. Patients with tumors harboring gains of chromosome 8 showed a slightly better clinical outcome (n = 14/30, P = 0.17), whereas gains of chromosome 12 did not influence the clinical outcome (n = 7/30, P = 0.63). However, Kaplan and Meier analysis revealed that deletions at the short arm of chromosome 1 were associated with an unfavorable outcome in patients with localized disease (n = 6/22; P = 0.004).

Adolescent↗
PubMed1999

G-CSF versus GM-CSF for stimulation of peripheral blood progenitor cells (PBPC) and leukocytes in healthy volunteers: comparison of efficacy and tolerability.

This study compared two recombinant human (rh) hematopoietic growth factors in healthy volunteers for stem cell stimulation. Granulocyte colony-stimulating factor (G-CSF, n=9) or granulocyte-macrophage colony-stimulating factor (GM-CSF, n=8) was given subcutaneously for 5 days (5 microg/kg/day). Controls (n=5) received no growth factor. Laboratory parameters and side effects were monitored for 8 days. Within 24 h, both cytokines led to a rapid increase of leukocytes, the majority of which were granulocytes. Compared with the controls (n=5), the increase on day 5 in the G-CSF/GM-CSF groups was 37-/10-fold (CD34+ cells), 5.2-/2.4-fold (leukocytes), 7.2-/3.0-fold (granulocytes), 7.4-/4.4-fold (monocytes), 1.7-/1.1-fold (lymphocytes), 9.8-/2.7-fold (basophils), 2.3-/9.6-fold (eosinophils), and 1.9-/1.6-fold (reticulocytes). The mobilization of myeloblasts, promyelocytes, myelocytes, and metamyelocytes coincided with the pronounced increase of CD34 + PBPC observed on day 4. Serum levels of uric acid (UA) and lactic dehydrogenase (LDH) increased under G-CSF, and platelets decreased after G-CSF discontinuation. Rash at the injection site occurred in 50% of the GM-CSF-treated volunteers. Seven volunteers in the GM-CSF group and six in the G-CSF cohort complained of flu-like symptoms, including musculoskeletal pain. We conclude that, in terms of tolerance and mobilization of CD34+ cells and leukocytes, G-CSF is superior to GM-CSF, but higher levels of UA and LDH and late decrease in platelets make monitoring of these parameters necessary.

Adult↗
PubMed1999

Skin-associated lymphocytes in the peripheral blood of patients with atopic dermatitis: signs of subset expansion and stimulation.

BACKGROUND: Skin-associated T cells are defined by the cutaneous lymphocyte-associated antigen (CLA). In atopic dermatitis (AD), CLA+ T cells harbor allergen-reactive memory cells, spontaneously secrete TH2 cytokines, and display signs of increased in vivo activation, thus relating the subset to the central disease pathomechanisms. OBJECTIVES: It is not known whether the proportion of circulating CLA+ T cells might be expanded in AD. We were therefore prompted to compare the peripheral blood lymphocyte subpopulations of patients with AD with those of control subjects. METHODS: We used 3-color flow cytometry to investigate age-matched peripheral blood samples of pediatric and young adult patients with mild (n = 21) or severe (n = 15) AD, patients with allergic/atopic diseases not involving the skin (n = 9), and healthy control subjects (n = 14). RESULTS: We found no differences among the study groups with respect to the general proportions of T cells, CD4(+) T cells, CD8(+) T cells, B cells, NK cells, CD103(+) T cells, and CD25(+) T cells among total circulating lymphocytes. However, there were slightly more CD4(+) memory cells and clearly more HLA-DR+ T cells in patients with severe AD. Most remarkably, patients with severe AD had a significantly expanded proportion of CLA+ T cells (P =.024) and CLA+/CD4(+) T cells (P =.006) but similar proportions of CLA+/CD8(+) T cells compared with control subjects. Patients with severe AD also had distinctly more HLA-DR+/CLA+ T cells than control subjects (P =. 005). Similar alterations were seen in patients with mild AD, but these were not statistically significant. After correction for age, all differences were significant only in probands less than 10 years of age. CONCLUSIONS: Circulating skin-associated T cells (CLA+) show signs of subset expansion and enhanced activation in patients with AD. These alterations, compared with control values, affect CD4(+) memory T cells in particular and are prominent only in children less than 10 years of age.

Adolescent↗
PubMed1999

Heterogeneous TCR delta Vdelta2-Ddelta3 rearrangements and their relation to IgH and TCR gamma gene status in childhood B cell precursor leukaemias.

In this study we aimed to test the hypothesis that leukaemias with oligoclonal Vdelta2-Ddelta3 rearrangements are clonal at the IgH and TCRG gene status and that the oligoclonality is a poor prognostic marker. In ten leukaemias the individual Vdelta2-Ddelta3 rearrangements characterised different populations as deduced from single cell analysis and/or from densitometric differences of PCR products. Five of these leukaemias were clonal by the IgH and/or TCRG gene status. We therefore conclude that ALL is a clonal disease despite the presence of heterogeneous TCRD rearrangements. Our clinical data show that oligoclonality at the TCRD level does not represent an adverse prognostic factor.

Aneuploidy↗
PubMed1999

Detection of residual disease in pediatric B-cell precursor acute lymphoblastic leukemia by comparative phenotype mapping: a study of five cases controlled by genetic methods.

We recently investigated samples of pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and normal bone marrow (BM). We found that leukemic blasts, compared to their physiologic counterpart cells, frequently display aberrant phenotypes with respect to levels of expression of certain antigens. Using multiparameter flow cytometry, these differences enabled us to trace leukemic cells admixed to normal BM, which suggested that this approach might be a useful strategy for minimal residual disease detection. In the present study, we used the same multiparameter approach ("comparative phenotype mapping") to prove that such quantitative phenotypic differences really exist between malignant and normal BCP when simultaneously present in the BM. We demonstrate this by five exemplary follow-up BM samples from patients with BCP-ALL, all of which showed phenotypically aberrant cells according to levels of expression of CD10, CD11a, CD19, CD34, CD44, or CD45RA, as well as according to altered orthogonal light scattering properties. We confirmed the leukemic nature of these cells by polymerase chain reaction-based detection of bcr1/abl transcripts, and of leukemia clone-specific immunoglobulin heavy chain rearrangements in only the suspicious cells when sorted by flow cytometry, but not in normal BCP or non-B cells. Comparative phenotype mapping thus allows one to distinguish between normal and leukemic cells, and we show that it may enable rapid, specific, and quantitative detection of residual/resurgent leukemia in BCP-ALL.

Adolescent↗
PubMed1999

Organ toxicity and quality of life after allogeneic bone marrow transplantation in pediatric patients: a single centre retrospective analysis.

One hundred and fifty five pediatric patients underwent allogeneic bone marrow transplantation between 1980 and 1996 in the St Anna Children's Hospital in Vienna with an overall survival of 52.3% (81 patients). Seventy-three patients with a minimum observation time of 1 year (1-13 years, median: 4.6) were analyzed retrospectively for chronic GVHD, organ toxicity (WHO score), growth and pubertal development. Chronic GVHD was diagnosed in 20 patients (27.3%), being extensive in 17 cases. Maximum organ toxicity was WHO III in two patients (3%) and WHO II in 11 patients (15%) 1 year after BMT and WHO III in one patient (2%) and WHO II in five patients (11%) 3 years after BMT. Impaired growth and pubertal development were detected in more than 30% 3 years after BMT. As all patients presented with a Karnofsky or Lansky score of more than 80%, they were asked to complete a questionnaire comprising 12 questions concerning physical state of health and psychosocial state of health. Restricted contacts were classified as imposing a severe handicap by six patients (8%), restriction in mobility and 'normal life activities' by three patients (4%) and two patients classified themselves as severely physically handicapped. Most patients (75%) reported no physical or psychical impairment.

Adolescent↗
PubMed1999

Psychosocial adjustment of pediatric patients after allogeneic stem cell transplantation.

The purpose of this study was to assess the psychosocial adjustment of patients who had been treated with allogeneic stem cell transplantation (SCT) in our clinic. Selection criteria for patients were to be aged 14-30 years at the time of the follow-up, to be at least 2 years post-SCT and to have a very good knowledge of German. Among 31 eligible patients, 26 participated (84% response rate). The patients were between 15 and 27 years old and were on average 7 years (range 2-13) post-SCT. Research instruments consisted of a demographic questionnaire and various subscales of established psychological measures for which data from a sample of bone cancer survivors and population norms were available. About 35% of patients showed high levels of anxiety, 62% appeared to be extremely sensitive and vulnerable, and 35% showed strong, unfulfilled needs in their love lives. In the other domains tested (self-esteem, family and peer relationships, school/vocational performance, etc), no noticeable differences were found between the subjects and comparable populations. There was no significant association between psychosocial outcome and demographic features or clinical data. Our results suggest that patients who underwent SCT in their childhood or adolescence are at risk of developing long-term emotional or social problems. Due to the retrospective design of our study and the small sample size, no predictive factors for psychosocial distress could be identified.

Adolescent↗
PubMed1999

Low incidence of molecular evidence for tumour in PBPC harvests from patients with high risk Ewing tumours.

Reverse transcriptase polymerase chain reaction (RT-PCR) was applied to evaluate the frequency of tumour cells in PBPC products from 15 high risk Ewing tumour (ET) patients who were treated according to EICESS 92 with high-dose chemotherapy (HDC) and stem cell rescue. Initial tumour cell contamination of the bone marrow (BM) detected by light microscopy was found in five and by RT-PCR in eight cases. RT-PCR was performed on each PBPC sample repeatedly at a sensitivity comparable to 20-100 highly EWS-Fli1 expressing tumour cells per 10 ml of fresh blood. Irrespective of the extent of BM involvement at diagnosis, all BM samples obtained before harvest were RT-PCR negative. Among 12 of 35 analysed apheresis products with single positive RT-PCR results only one sample tested reproducibly positive for tumour cell contamination in independent determinations. These preliminary data suggest that tumour cell contamination of PBPC is rarely found in patients with ET.

Adolescent↗