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A J Veerman

Publications and source records attributed to A J Veerman.

151 records · Page 9Linked to original sources
PubMedDate not supplied

[In vitro drug resistance as independent prognostic factor in the study COALL-O5-92 Treatment of childhood acute lymphoblastic leukemia; two-tiered classification of treatments based on accepted risk criteria and drug sensitivity profiles in study COALL-06-97].

BACKGROUND: Risk-adapted therapy in acute lymphoblastic leukemia (ALL) of childhood relies on traditional risk factors such as age, white blood count, immunological subtype, chromosomal aberrations and response to treatment. In spite of risk-adapted therapy, however, 20-30% of the patients suffer a relapse and may have profited from more intensive therapy. On the other hand a third of the patients is probably overtreated considering cure rates of 30% with less intensive therapies in the seventies. Additional prognostic criteria are therefore urgently needed. In a retrospective Dutch study in childhood ALL drug sensitivity testing with the MTT assay was identified as a new highly significant prognostic factor. PATIENTS AND METHODS: In study COALL-92 in 140 patients in vitro drug sensitivity was performed on initial bone marrow or blood samples and as in the Dutch study a score was derived from the sensitivity of the 3 drugs prednisolone, vincristine and asparaginase (PVA score). For each drug a score of 1 (highest) to 3 (lowest sensitivity) is given. A score of 3 therefore indicates the best, a score of 9 the worst sensitivity. RESULTS: Probability of event-free survival (pEFS) according to the PVA score was 0.94 for score 3 + 4, 0.80 for score 5-7, 0.35 for Score 8 + 9 (0.47 for score 7-9). For analysis within the low risk (LR) group (age 1-10 years, WBC < 25/nl, common or pre-B-ALL, remission day 28, no translocation 9;22 or 4;11) and high risk (HR) group 252 patients of the Dutch study and the COALL study were combined. In the LR group pEFS was 1.00 for score 3 + 4, 0.76 for score 5-7, 0.38 for score 8 + 9 (0.54 for score 7-9); in the HR group pEFS was 0.91 for score 3 + 4, 0.69 for score 5-7, 0.45 for score 8 + 9 (0.56 for score 7-9). Multivariate analysis identified the PVA score as independent prognostic factor. NEW STUDY COALL-97: In the new study COALL-97 patients are first stratified according to HR and LR criteria and then are stratified again according to the PVA score. LR and HR patients with a score of 3 + 4 receive less intensive treatment in reinduction therapy to reduce the cumulative dose of anthracyclines and to mitigate the high rate of infectious complications during this part of the protocol. LR patients with a score of 7-9 are treated according to the HR protocol; HR patients with a score of 8 + 9 receive BMT if an HLA identical family donor is available. In study COALL-97 the results of the minimal residual disease study and day 15 bone marrow will be compared with the PVA score. CONCLUSIONS: In vitro drug sensitivity testing is an independent prognostic factor which allows adjustment of therapy to the individual risk of relapse in addition to the traditional risk factors. It can be assumed that in patients with a favourable resistance profile therapy can be reduced without loss of efficacy and that patients with an unfavourable resistance profile might profit from more intensive therapy.

Antineoplastic Agents, Hormonal↗
PubMedDate not supplied

Cellular drug resistance in acute myeloid leukemia: literature review and preliminary analysis of an ongoing collaborative study.

Cellular drug resistance is one of the main causes of the frequent ultimate failure of chemotherapy in childhood acute myeloid leukemia (AML). We here summarize the results of a literature review on in vitro drug resistance in childhood AML, focusing on studies using so-called cell culture assays. We also briefly describe some results of an ongoing collaborative study between the Research Laboratory of Pediatric Oncology in Amsterdam (University Hospital Vrije Universiteit) and the German BFM-AML Group. In general, the literature and our preliminary data on in vitro cellular drug resistance in AML are promising in terms of clinical relevance. Cell biological features and clinical response to chemotherapy are related to in vitro drug resistance. However, a large study including multivariate analysis is required to more firmly establish the clinical value of cellular drug resistance testing in childhood AML, and the collaborative study will therefore be continued. Possible applications of cell culture assays include risk-group stratification, rational improvements of current treatment protocols for subgroups of patients based on specific drug resistance profiles, individualised tailored therapy, the study of cross-resistance patterns between drugs, the study of possibilities to modulate or circumvent drug resistance, the study of drug interactions, selection of patients for clinical phase II studies and drug screening.

Acute Disease↗
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Primary ciliary dyskinesia: quantitative investigation of the ciliary ultrastructure with statistical analysis.

In this study the ultrastructure of cilia in patients with primary ciliary dyskinesia was compared to that in patients with other respiratory infections and with that in healthy individuals. After statistical analysis of the findings, the prevalence and the specificity of morphological changes in primary ciliary dyskinesia were established. Guidelines were developed by which the existence of primary ciliary dyskinesia can be ascertained in biopsies of nasal mucosa via transmission electron microscopy.

Biopsy↗
PubMedDate not supplied

Primary ciliary dyskinesia: ciliary activity.

In primary ciliary dyskinesia (PCD) the cilia of the respiratory tract are immotile or they show an incoordinate, abnormal beating pattern. Consequently, mucociliary clearance is lacking. Most patients with PCD have ultrastructural abnormalities in their cilia. In some patients, however, the ciliary ultrastructure is completely normal. In this study a semi-quantitative scoring method is described for studying ciliary motility in biopsies of nasal mucosa. For every cell the frequency, coordination and amplitude of the ciliary beat are scored. Thereafter, a total score of ciliary activity per cell can be calculated. This method is simple and has proved to be reproducible. By using this scoring method the presence of a PCD can be established with certainty, whether the ciliary ultrastructure is abnormal or not. In patients with a normal ciliary ultrastructure the cilia have a rather high beating frequency (vibration). By scoring the ciliary motility in mucosal biopsies, the time-consuming electronmicroscopic investigation of the cilia is no longer necessary in most patients.

Adolescent↗
PubMedDate not supplied

Value of routine bone marrow examination for detection of bone marrow relapse in children with standard risk acute lymphoblastic leukemia.

The value of routine bone marrow examination (RBME) in children during and after treatment for standard risk acute lymphoblastic leukemia (SR-ALL) was investigated. The clinical symptoms and peripheral blood findings at the time of bone marrow relapse of 28 children were reviewed and compared with those of 28 matched controls in continuous complete remission. Five (45%) children with bone marrow relapse during maintenance therapy and six (35%) after cessation of cytostatic treatment were asymptomatic at the time of relapse. Signs indicative of relapse during treatment were lymphoblast cells in the peripheral blood, thrombocytopenia, hepatomegaly, anemia, or leukopenia in decreasing order of frequency. After cessation of treatment these signs were lymphoblasts in the peripheral blood, hepatomegaly, splenomegaly, thrombocytopenia, or leukocytosis. Except for one case with thrombocytopenia, no signs suspicious for relapse were found in the control groups. When each sign was evaluated separately only the presence of lymphoblasts in peripheral blood and hepatomegaly were significant symptoms for relapse after cessation of treatment. The mean percentage of lymphoblasts in the bone marrow at the time of relapse was significantly lower for patients with an unpredicted relapse (46.8%) than patients with clinical and/or laboratory evidence of relapse (79.5%). When lymphoblasts were present in the peripheral blood the percentage of lymphoblasts in the bone marrow was always more than 40%, both during and after cessation of treatment. These data suggest a relation between clinical and laboratory symptoms and progression of the disease. It is concluded that 46% of relapses are detected by RBME in the absence of clinical or laboratory symptoms. This early detection may have a positive prognostic influence with more effective treatment for relapsed ALL.

Adolescent↗
PubMedDate not supplied

Somatic mosaicism in Fanconi anemia: molecular basis and clinical significance.

Approximately 25% of patients with Fanconi anemia (FA) have evidence of spontaneously occurring mosaicism as manifest by the presence of two subpopulations of lymphocytes, one of which is hypersensitive to cross-linking agents (e.g. mitomycin C) while the other behaves normally in response to these agents. The molecular basis of this phenotypic reversion has not yet been determined. We have investigated 8 FA patients with evidence of mosaicism. Epstein-Barr virus-immortalized lymphoblastoid cell lines established from these patients exhibited an IC50 for mitomycin C of 25 to > 100 nM compared to a mean of 2 +/- 2 nM for 20 nonmosaic FA patients and 49 +/- 11 nM for 8 healthy controls. In 3 patients who were compound heterozygotes for pathogenic FAC gene mutations the molecular mechanism of the mosaicism was investigated by haplotype analysis. The results indicated that an intragenic mitotic recombination must have occurred leading to a segregation of a wild-type allele in the reverted cells and suggested two patterns of recombination. In 1 patient a single intragenic crossover between the maternally and paternally inherited mutations occurred associated with markers located distally to the FAC gene; in the other 2 patients (sibs) the mechanism appears to have been gene conversion resulting in segregants which have lost one pathogenic mutation. In 6 of the 8 patients the hematological symptoms were relatively mild despite an age range of 9-30 years.

Adolescent↗