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Biomedical subjects

G J Ossenkoppele

Publications and source records attributed to G J Ossenkoppele.

At least 37 records · Page 2Linked to original sources
PubMed2003

CD40-targeted adenoviral GM-CSF gene transfer enhances and prolongs the maturation of human CML-derived dendritic cells upon cytokine deprivation.

Vaccination with autologous leukaemia-derived dendritic cells (DC) presents an adjuvant treatment option for chronic myeloid leukaemia (CML). Here, we show that high-efficiency CD40-targeted adenoviral gene transfer of GM-CSF to CML-derived DC induces long-lived maturation in the absence of exogenous cytokines and may thus ensure protracted stimulation of CML-specific T cells upon vaccination.

Adenoviridae↗
PubMed2003

CHOP compared with CHOP plus granulocyte colony-stimulating factor in elderly patients with aggressive non-Hodgkin's lymphoma.

PURPOSE: To investigate whether the relative dose-intensity of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy could be improved by prophylactic administration of granulocyte colony-stimulating factor (G-CSF) in elderly patients with aggressive non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Patients aged 65 to 90 years (median, 72 years) with stage II to IV aggressive NHL were randomly assigned to receive standard CHOP every 3 weeks or CHOP plus G-CSF every 3 weeks on days 2 to 11 of each cycle. RESULTS: In 389 eligible patients, the relative dose intensities (RDIs) of cyclophosphamide (median, 96.3% v 93.9%; P =.01) and doxorubicin (median, 95.4% v 93.3%; P =.04) were higher in patients treated with CHOP plus G-CSF. The complete response rates were 55% and 52% for CHOP and CHOP plus G-CSF, respectively (P =.63). The actuarial overall survival at 5 years was 22% with CHOP alone, compared with 24% with CHOP plus G-CSF (P =.76), with a median follow-up of 33 months. Patients treated with CHOP plus G-CSF had an identical incidence of infections, with World Health Organization grade 3 to 4 (34 of 1,191 cycles v 36 of 1,195 cycles). Only the cumulative days with antibiotics were fewer with CHOP plus G-CSF (median, 0 v 6 days; P =.006) than with CHOP alone. The number of hospital admissions and the number of days in hospital were not different. CONCLUSION: In elderly patients, G-CSF improved the RDI of CHOP, but this did not lead to a higher complete response rate or better overall survival. G-CSF did not prevent serious infections.

Aged↗
PubMed2003

[Ulcers on the legs and feet: a seldom recognised side effect of hydroxyurea].

Three male patients aged 52, 49 and 74 years who were treated with hydroxyurea for chronic myeloid leukaemia (CML) or essential thrombocytosis developed severely painful ulcers on the lower legs and feet after an interval varying from 4 months to 2.5 years. These ulcers only healed after discontinuation of the drug. This is an adverse effect of hydroxyurea that is not infrequently seen but is difficult to recognise. The precise pathogenesis is still unclear but micro-circulatory disorders and a direct cytostatic effect on the epidermal cells probably play a role. Often, the drug has already been used for several years before the ulcers develop. They are resistant to treatment unless the hydroxyurea is stopped. Alternatives to hydroxyurea are imatinib for the treatment of CML and interferon alpha-2a or anagrelide for essential thrombocytosis.

Aged↗
PubMed2003

[Drug treatment of chronic myeloid leukemia: a cost effectiveness analysis of first- and second-line treatment ].

OBJECTIVE: To determine the average cost-effectiveness ratio of treatment of patients with chronic myeloid leukaemia (CML): with first-line interferon alpha-2a (IFN) or with second-line imatinib following IFN failure. DESIGN: Cost-effectiveness analysis. METHOD: A general cost-effectiveness analysis was performed using a model. This model consists of two phases: an induction phase of eight months, in which newly-diagnosed patients are treated with either IFN or imatinib, and a chronic treatment phase wherein patients are treated according the result of the induction phase. The model calculated the costs and effects of the treatment. Input for this model was derived from literature and expert opinion. Costs were based on real cost prices and tariffs. RESULTS: Treatment with imatinib resulted in 6.67 quality-adjusted life years (QALYs) and treatment with IFN resulted in 4.98 QALYs. Average costs of treatment with 5 million IU/day of IFN were [symbol: see text] 76,969 and [symbol: see text] 53,257 with 3 million IU/day. For imatinib at 400 mg/day the costs were [symbol: see text] 140,765 per patient. Costs per QALY were [symbol: see text] 15,445, [symbol: see text] 10,687 and [symbol: see text] 21,082, respectively. CONCLUSION: The addition of imatinib to the treatment options in CML resulted in increased quality-adjusted survival, but also higher costs of treatment.

Antineoplastic Agents↗
PubMed2003

High percentage of CD34-positive cells in autologous AML peripheral blood stem cell products reflects inadequate in vivo purging and low chemotherapeutic toxicity in a subgroup of patients with poor clinical outcome.

In this study, a high CD34% in autologous peripheral blood stem cell (PBSC) products from 71 AML patients was associated directly with a high relapse rate (P = 0.006) and inversely with disease-free survival (P = 0.003), irrespective whether patients were transplanted or not. The relapse rate at 12 months was 67% in a group with >0.8% CD34+ cells and 34% in a group with < or = 0.8% CD34+ cells. Although the percentage of malignant CD34+ cells in the CD34+ compartment in the relapses of the first group was not high (median 8%), the total number of malignant cells as a percentage of WBC was about 13 times higher than for the patients remaining >12 months in remission. When all patients evaluable were taken together, this frequency of malignant cells correlated strongly with disease-free survival (P < 0.001). Both this massive mobilization of normal CD34+ cells and high frequency of malignant cells in the subgroup of patients with CD34 >0.8% and relapse within 12 months indicate an insufficient in vivo purging, as well as low chemotherapeutic bone marrow toxicity. This was confirmed by an inverse correlation between hypoplasia period after the induction therapy and CD34% in PBSC products (P < 0.002). It is concluded that a subgroup of patients has been identified that might benefit from a more intensive chemotherapeutic treatment.

Acute Disease↗
PubMed2003

A flow cytometric method to detect apoptosis-related protein expression in minimal residual disease in acute myeloid leukemia.

Minimal residual disease (MRD) cells are thought to be responsible for the persistence and relapse of acute myeloid leukemia (AML). Flow cytometric MRD detection by the establishment of a leukemia-associated phenotype (LAP) at diagnosis can be used in 80% of AML patients, allowing detection and functional characterization of MRD in follow-up bone marrow. One of the mechanisms contributing to inefficient chemotherapy is apoptosis resistance. Measuring apoptosis parameters in MRD cells will help to unravel the importance of apoptosis resistance in AML. We therefore developed a four-color flow cytometry method that enables establishment of apoptosis-related protein expression such as Bcl-2, Bcl-x(L), Mcl-1 and Bax at diagnosis and in MRD. Firstly, validation of this assay using Western blot analysis in five leukemia cell lines showed a significant correlation (R=0.70: P<0.0001). Secondly, the influence of the permeabilization procedure on LAP expression was investigated in 38 AML samples at diagnosis and in 42 MRD samples. Quantification of the frequency of LAP+ cells with and without permeabilization showed no significant differences (diagnosis: P= 0.57, follow-up: P= 0.43). The flow cytometric protocol thus enables analysis of apoptosis-related proteins at different stages of the disease, which will lead to a better understanding of the role of apoptosis resistance in the emergence of MRD in AML.

Acute Disease↗
PubMed2003

ALK-negative anaplastic large-cell lymphoma demonstrates similar poor prognosis to peripheral T-cell lymphoma, unspecified.

AIMS: Anaplastic large cell lymphoma (ALCL) is classically considered a clinicopathological entity separate from other nodal mature T-cell lymphomas (TCL). Recently, the anaplastic lymphoma kinase (ALK) protein was shown to identify a subgroup of nodal ALCL with an excellent prognosis, whereas ALK-negative ALCLs are more heterogeneous. The aim of this study was to investigate the clinicopathological parameters in relation to clinical behaviour of ALK-negative ALCL compared with other nodal mature TCL, i.e. peripheral TCL, unspecified (PTCL-NOS) and angioimmunoblastic lymphoma (AILT). METHODS AND RESULTS: Clinicopathological data of ALK-positive (n = 28) and ALK-negative (n = 46) ALCL; PTCL-NOS (n = 47); and AILT (n = 12) were analysed for their prognostic significance. While ALK-positive ALCL shows favourable clinical features and a good prognosis, ALK-negative ALCL, PTCL-NOS and AILT are all associated with high age groups, advanced disease stage, and poor prognosis (<45% 5-year survival). In multivariate analysis of overall survival time, performed in the combined group of ALK-negative nodal mature T-cell lymphomas, only age and the International Prognostic Index (IPI) remained independent prognostic parameters, while lymphoma subtype (ALCL versus PTCL-NOS versus AILT) gave no additional information. CONCLUSIONS: The distinction between ALK-negative ALCL and PTCL-NOS or AILT is of limited clinical relevance as they show comparable poor prognosis. In these lymphoma subtypes, only age and the IPI are of significant prognostic value.

Adolescent↗
PubMed2002

Effect of radiotherapy and other treatment-related factors on mid-term to long-term cognitive sequelae in low-grade gliomas: a comparative study.

BACKGROUND: Because survival benefits of treatment with radiotherapy are questionable and such treatment can cause substantial damage to the brain over time, the optimum management strategy for low-grade gliomas remains controversial. We aimed to identify the specific effects of radiotherapy on objective and self-reported cognitive function, and on cognitive deterioration over time, in patients with low-grade gliomas treated with early radiotherapy. METHODS: 195 patients with low-grade glioma (of whom 104 had received radiotherapy 1-22 years previously) were compared with 100 low-grade haematological patients and 195 healthy controls. Our analyses aimed to differentiate between the effects of the tumour (eg, disease duration, lateralisation) and treatment effects (neurosurgery, radiotherapy, antiepileptic drugs) on cognitive function and on relative risk of cognitive disability. FINDINGS: Low-grade glioma patients had lower ability in all cognitive domains than did low-grade haematological patients, and did even less well by comparison with healthy controls. Use of radiotherapy was associated with poorer cognitive function; however, cognitive disability in the memory domain was found only in radiotherapy patients who received fraction doses exceeding 2 Gy. Antiepileptic drug use was strongly associated with disability in attentional and executive function. INTERPRETATION: Our findings suggest that the tumour itself has the most deleterious effect on cognitive function and that radiotherapy mainly results in additional long-term cognitive disability when high fraction doses are used. Additionally, the effects of other medical factors, especially antiepileptic drug use, on cognitive function in glioma patients deserve attention.

Adult↗
PubMed2002

Acute myeloid leukemia in a 23-year-old patient with Beckwith-Wiedemann syndrome.

Children with Beckwith-Wiedemann syndrome (BWS) are at an increased risk of developing malignancies early in life. Several malignancies have been described in this fetal overgrowth syndrome; however, to date, only one hematological malignancy developing during early childhood has been reported. We present a patient with BWS developing acute myeloid leukemia at the age of 23. Loss of genomic imprinting of growth regulatory genes is thought to be the cause of BWS. For one of those genes, IGF2, an important role in childhood overgrowth syndromes as well as in the development of adult acute leukemia has been suggested, providing a possible explanation for our presented case.

Adult↗
PubMed2002

[STI571: a new dimension in the treatment of chronic myeloid leukemia].

Three patients suffering from chronic myelogenous leukaemia (CML), a 36-year-old woman in blast crisis, and a 64-year-old woman and a 60-year-old man in the chronic phase, participated in a clinical trial with STI571, a recently developed tyrosine kinase inhibitor with relative specificity for the BCR-ABL kinase. In all three patients, complete haematologic remission occurred within 2 months of the treatment being initiated. Subsequently the patient in blast crisis underwent allogeneic stem-cell transplantation. For the second patient, who had experienced many side effects with the standard treatment, STI571 led to a better quality of life. The third patient reached complete cytogenetic remission after 3 months of treatment. The development of STI571 is a major breakthrough in the treatment of CML. There are few side effects and the short-term results are excellent in specific patient categories. Further research is needed to establish the eventual role of STI571 in the treatment of CML.

Adult↗
PubMed2002

In vitro drug resistance profile of Philadelphia positive acute lymphoblastic leukemia is heterogeneous and related to age: a report of the Dutch and German Leukemia Study Groups.

BACKGROUND: The t(9;22)(q34;q11) translocation leading to the Philadelphia (Ph) chromosome resulting in BCR-ABL gene fusion is associated with a poor prognosis in acute lymphoblastic leukemia (ALL). PROCEDURE: We studied the relation between t(9;22), determined by karyotype, fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR), and in vitro drug resistance, measured by the MTT assay, in precursor B-cell ALL at diagnosis. The findings in twenty-one Ph-positive (Ph+) childhood common/precursorB (c/preB) cases were compared with 254 Ph-negative (Ph-) ALL cases. RESULTS: A large range of LC(50) values was found within the Ph+ patients. Moreover, LC(50) values did not differ significantly between Ph+ and Ph- samples for prednisolone, dexamethasone, L-asparaginase, vincristine, anthracyclines, thiopurines, epipodophyllotoxins, and 4H00-ifosfamide, even after matching for important prognostic features (age, white blood cell count (WBC), and immunophenotype). Adult Ph+ (n = 12) ALL was more resistant to prednisolone (> 270-fold, P = 0.030), and displayed an overall tendency to resistance when compared to matched cases of Ph- (n = 15) adult precursor B-cell ALL. Within Ph+ ALL, in vitro prednisolone resistance increased significantly with age (P = 0.006). The expression of lung resistance protein (LRP), but not P-glycoprotein (P-gp) or multidrug resistance protein (MRP), was significantly higher in all Ph+ patients. CONCLUSIONS: Both childhood and adult Ph+ precursor B-cell ALL samples display a heterogeneous in vitro resistance profile, with relatively sensitive and resistant cases. The adult Ph+ samples, however, are generally more resistant compared to matched Ph- controls, reaching significance for prednisolone. The correlation of prednisolone resistance with age within the Ph+ cases might help explain the poorer prognosis of adult Ph+ ALL.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Extensive early apoptosis in frozen-thawed CD34-positive stem cells decreases threshold doses for haematological recovery after autologous peripheral blood progenitor cell transplantation.

Stem cell doses necessary for engraftment after myelo-ablative therapy as defined for fresh transplants vary largely. Loss of CD34+ cell quality after cryopreservation might contribute to this variation. With a new early apoptosis assay including the vital stain Syto16, together with the permeability marker 7-AAD, CD34+ cell viability in leucapheresis samples of 49 lymphoma patients receiving a BEAM regimen was analysed. After freeze-thawing large numbers of non-viable, early apoptotic cells appeared, leading to only 42% viability compared to 72% using 7-AAD only. Based on this Syto16 staining in the frozen-thawed grafts, threshold numbers for adequate haematological recovery of 2.8-3.0 x 10(6) CD34+ cells/kg body weight determined for fresh grafts, now decreased to 1.2-1.3 x 10(6) CD34+ cells/kg. In whole blood transplantation of lymphoma patients (n = 45) receiving a BEAM-like regimen, low doses of CD34+ cells were sufficient for recovery (0.3-0.4 x 10(6)CD34+ cells/kg). In contrast to freeze-thawing of leucapheresis material, a high viability of CD34+ cells was preserved during storage for 3 days at 4 degrees C, leaving threshold doses for recovery unchanged. In conclusion, the Syto16 assay reveals the presence of many more non-functional stem cells in frozen-thawed transplants than presumed thus far. This led to a factor 2.3-fold adjustment downward of viable CD34+ threshold doses for haematological recovery.

Antigens, CD34↗
PubMed2001

Monocyte-chemoattractant-protein-1-mediated migration of human monocytes towards blasts from patients with acute myeloid leukemia.

PURPOSE: In the present study the possible clinical relevance of monocyte chemoattractant protein (MCP)-1 in patients with acute myeloid leukemia (AML) was established. METHODS: The pattern of migration of human monocytes towards the supernatants of blasts from 15 patients with AML was studied and the role of MCP-1, produced by these blasts, was assessed. RESULTS: In 4 patients (group 1) the amount of monocyte migration was low and not inhibited by the addition of anti-hMCP-1. In 11 patients, the amount of monocyte migration was high; after addition of anti-hMCP-1, monocyte migration was either completely (8 patients, group 2), or partly or not (3 patients, group 3) inhibited to the level of chemokinesis. In groups 1 and 2, there was a good correlation (r = 0.67) between the concentration of MCP-1 in the supernatants and the amount of monocyte migration. In group 3, such a correlation was not evident, suggesting that another chemokine might be involved or MCP-1 function was impaired by an unknown substance. Finally, measurements of MCP-1 during culture of AML blasts showed that the time at which maximal amounts of MCP-1 are produced differs between the AML samples. CONCLUSIONS: AML blasts produce different amounts of MCP-1, which plays an important role in monocyte migration towards most AML blasts. Therefore, in the context of adoptive immunotherapy, MCP-1 might be involved in future tumor vaccination programmes using autologous MCP-1-transfected irradiated AML blasts.

Cancer Vaccines↗
PubMed2001

Large populations of non-clonogenic early apoptotic CD34-positive cells are present in frozen-thawed peripheral blood stem cell transplants.

Apoptosis is the common cell death pathway which is initiated by a variety of different stimuli. The recognition of early apoptotic events would markedly improve reliability and convenience of apoptosis assays. In the present study the vital stain SytoR 16 in combination with the permeability marker 7-amino actinomycin D, (7-AAD) has been used to identify an early stage of apoptosis, not detected with trypan blue or 7-AAD alone or with conventional apoptosis tests and not consistently and only partly detected by the early apoptosis marker annexin V. The method was established using solid tumour cell lines treated with TNF. Subsequently we applied it to determine apoptotic populations in CD34(+) peripheral blood progenitor cells obtained from growth factor and/or chemotherapy mobilised patients and frozen/thawed according to standard stem cell transplantation protocols. In a cell line model as well as CD34(+) progenitor cells, different subpopulations with decreased SytoR 16 fluorescence (SytoR 16int or SytoR 16low, compared with the normal SytoR 16high) appeared which are not, or only partly, apoptotic using conventional techniques including morphology or 7-AAD staining: eg percentages of SytoR 16(int)/7-AAD(-) and SytoR 16(low)/7-AAD(-) may amount to the majority of cells present in a particular CD34(+) sample. Second, upon further incubation these subpopulations become late apoptotic/secondary necrotic much faster than the unmodified SytoR 16high population, as determined with 7-AAD staining and morphology. Third, these cells have strongly or completely reduced clonogenic capacity for committed (CFU-GM) and early (LTC-IC, determined only for CD34(+) cells) progenitors. This technique needs the inclusion of a blocker of P-glycoprotein, which is highly active in CD34(+) progenitor cells. This prevents the interference of the detection of SytoR16(low) apoptotic cells by SytoR 16low cells resulting from P-glycoprotein activity. By comparison with other apoptosis markers we found that early apoptotic subpopulations were detected in the order SytoR 16 > annexin V > 7-AAD. In conclusion, the combination of SytoR 16 and 7-AAD detects apoptotic events earlier than conventional apoptosis techniques or annexin V. Compared to the presently available viability tests, it allows a much better estimation of the number of viable clonogenic CD34(+) cells after freeze/thawing.

Annexin A5↗