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O Bruserud

Publications and source records attributed to O Bruserud.

At least 37 records · Page 2Linked to original sources
PubMed2000

New strategies in the treatment of acute myelogenous leukemia: mobilization and transplantation of autologous peripheral blood stem cells in adult patients.

During the last decade high-dose Ara-C (HIDAC; single doses of 3 g/m(2)) and autologous stem cell transplantation have been increasingly used as postremission therapy in adult acute myelogenous leukemia (AML). Controlled clinical trials have demonstrated a long-term disease-free survival of 40%-50% for patients treated with at least two courses of HIDAC. Other studies have demonstrated that postremission autologous bone marrow transplantation results in a disease-free survival equal to or better than conventional chemotherapy. However, autotransplantation with mobilized peripheral blood stem cells (PBSC) would now be preferred instead of autologous bone marrow, due to the shorter hematopoietic reconstitution period. The results reviewed in the present article suggest that HIDAC and autologous PBSC transplantation can be combined in the postremission treatment of adult AML, and this combination therapy may also reduce minimal residual disease and the risk of posttransplant relapse. From the available studies it cannot be concluded whether graft purging further reduces the relapse risk. However, the possible advantage of combination therapy with repeated courses of HIDAC and autologous PBSC transplantation needs to be demonstrated in prospective clinical trials before it can be recommended as a part of the routine treatment in AML.

Adult↗
PubMed2000

Induction of differentiation and apoptosis- a possible strategy in the treatment of adult acute myelogenous leukemia.

A differentiation block with accumulation of immature myeloid cells characterizes acute myelogenous leukemia (AML). However, native AML cells often show some morphological signs of differentiation that allow a classification into different subsets, and further differentiation may be induced by exposure to various soluble mediators, e.g., all trans-retinoic acid (ATRA) and several cytokines. Combination therapy with ATRA and chemotherapy should now be regarded as the standard treatment for the acute promyelocytic leukemia variant of AML. Several agents can induce leukemic cell differentiation for other AML subtypes, although these effects differ between patients. Differentiation may then be associated with induction of apoptosis, and differentiation-inducing therapy may therefore become useful in combination with intensive chemotherapy to increase the susceptibility of AML blasts to drug-induced apoptosis. However, it should be emphasized that differentiation and apoptosis can occur as separate events with different regulation in AML cells, and future studies in AML should therefore focus on: A) the identification of new agents with more predictable effects on differentiation and apoptosis; B) the use of clinical and laboratory parameters to define new subsets of AML patients in which differentiation/apoptosis induction has a predictable and beneficial effect, and C) further characterization of how AML blast sensitivity to drug-induced apoptosis is modulated by differentiation induction.

Adult↗
PubMed1999

[A management program for primary thrombocytopenia].

Essential thrombocythemia is a chronic myeloproliferative disease characterized by persistent thrombocytosis and an increased risk of thromboembolic complications. Most patients are asymptomatic at the time of diagnosis. In this article guidelines for diagnosis and treatment of this disorder are presented on behalf of the Norwegian Society of Hematology. On the basis of a literature search in international databases (Medline) and international medical journals, articles have been selected according to their clinical relevance. The risk of major thrombosis is higher in patients older than 60 years and highest among those with a previous occlusive event. In individual patients there is no clear relationship between platelet count and risk of thrombosis. Low-dose aspirin (75-100 mg/day) is recommended to all patients with platelet count < 1,000 x 10(9)/l and in the absence of previous bleeding episodes. All patients with disease-related complications and asymptomatic patients with platelet count above 1,000-1,500 x 10(9)/l should receive cytoreductive treatment. Hydroxyurea is recommended for patients over 60 years of age. In younger patients, potential leukemogens should be avoided, and anagrelide or interferon-alpha is recommended.

Adult↗
PubMed1999

Expression and release of adhesion molecules by human acute myelogenous leukemia blasts.

The expression and release of adhesion molecules by acute myelogenous leukemia (AML) blasts was investigated in vitro. For most patients AML blasts expressed relatively low levels of membrane-bound L-selectin and Intercellular adhesion molecule 1 (ICAM-1), but their soluble forms were detected in the supernatants for the majority of patients when AML blasts were cultured in vitro. These in vitro levels of SL-selectin and sICAM-1 were considerably lower than the normal serum levels. Divergent and relatively small alterations in SL-selectin and sICAM-1 levels were usually observed when exogenous growth factors were present during AML blast culture, whereas increased SL-selectin levels were observed after coculture of AML blasts and normal leucocytes. E- and P-selectin were neither expressed nor released by AML blasts. We conclude that AML blasts are a source of soluble adhesion molecules.

Adult↗
PubMed1999

Acute myelogenous leukemia blasts as accessory cells during T lymphocyte activation: possible implications for future therapeutic strategies.

Both clinical and experimental evidence indicate that T lymphocytes can mediate antileukemic effects in acute myelogenous leukemia (AML). These antileukemic effects can be either nonspecific cytotoxicity (killer cell activity) or reactivity against leukemia-specific antigenic peptides presented by self-HLA molecules. The antigen-specific T cell activation requires recognition of specific peptides together with costimulatory signalling. For most patients the AML blasts express both HLA class I and class II molecules for antigenic presentation, but patients are heterogeneous with regard to: (1) expression of costimulatory binding molecules; (2) expression of receptors/counterreceptors involved in induction of apoptosis; (3) constitutive release of immunomodulatory soluble mediators. This heterogeneity suggests that the ability of AML blasts to initiate an antileukemic T cell response will differ between individual patients. Thus, clinical approaches for immunotherapy in AML have to overcome three major problems. First, the therapy should reduce the patient heterogeneity so that therapeutic effects become more predictable; or alternatively one should define patient subsets which are likely to benefit from immunotherapy. Second, immunotherapy should enhance antileukemic T cell reactivity or blast susceptibility to immune attacks. Third, the therapeutic procedures must be safe and suitable for routine use. All three problems probably have to be solved before immunotherapy can become a routine treatment.

Cell Adhesion Molecules↗
PubMed1999

In vitro culture of acute myelogenous leukemia blasts: a comparison of four different culture media.

Proliferative responses and cytokine secretion were compared when AML blasts were cultured in the three serum-free media, X-Vivo 10, X-Vivo 15, and defined serum-free medium (IMDM with mercaptoethanol, low-density lipoprotein, albumin, and transferrin) and in media containing 10% inactivated fetal bovine serum (FBS). The following AML blast functions were investigated: (a) constitutive cytokine secretion, (b) autonomous and cytokine-dependent proliferation, and (c) accessory cell function during T cell activation. Constitutive cytokine secretion and accessory cell function differed markedly when using different culture media. For the constitutive AML blast secretion of IL-1beta, IL-6, and tumor necrosis factor (TNF)-alpha, no qualitative differences were seen, but quantitative differences were observed with decreased cytokine levels for cells cultured in X-Vivo 10 and X-Vivo 15. The accessory cell function of AML blasts was also decreased in the X-Vivo media, whereas differences were less pronounced when comparing AML blast proliferation. Our results clearly demonstrate that a well-characterized culture system is essential for in vitro studies of AML blast functions.

Adult↗
PubMed1999

Effects of gamma-irradiation on acute myelogenous leukemia blasts: in vitro studies of proliferation, constitutive cytokine secretion, and accessory cell function during T cell activation.

Generation of cellular immune responses against acute myelogenous leukemia (AML) blasts is a possible therapeutic approach in leukemia therapy. However, when using native AML blasts as stimulator cells during ex vivo generation of leukemia-reactive T cells, one has to ensure that the T cell population is not contaminated with proliferating AML blasts. Our results demonstrate that gamma-irradiation could be used to stop AML blast proliferation for all patients investigated. However, gamma-irradiation also caused a dose-dependent reduction in the constitutive AML blast secretion of the potentially T cell stimulatory cytokines IL-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha). At the same time, gamma-irradiation resulted in a dose-dependent decrease in anti-CD3-stimulated proliferative responses of T cell clones in the presence of AML blast accessory cells. When using 50 Gy irradiation, however, AML blast expansion was avoided, and anti-CD3 and PHA-stimulated T cell proliferation was detected in the presence of accessory AML blasts for most AML/T cell combinations investigated. When AML blasts were cultured with GM-CSF + IL-4 to develop a dendritic cell phenotype, enhanced T cell proliferation in the presence of in vitro precultured AML blasts was observed for most patients even after 50 Gy irradiation. We conclude that when using native AML blasts as accessory cells during in vitro generation of leukemia-reactive T cells, an irradiation dose of 50 Gy can be used for a majority of AML patients to avoid the risk of leukemia cell expansion during culture and with the maintenance of AML blast accessory cell function. However, when in vitro expanded cells are used in clinical trials, this antiproliferative effect should be documented with appropriate in vitro testing for every patient so that the possibility of decreased sensitivity to gamma-irradiation in exceptional patients is excluded.

Adult↗
PubMed1999

In vitro effects of insulin-like growth factor-1 (IGF-1) on proliferation and constitutive cytokine secretion by acute myelogenous leukemia blasts.

The effects of insulin-like growth factor 1 (IGF-1) on autonomous proliferation, cytokine-dependent proliferation and constitutive cytokine secretion by acute myelogenous leukemia (AML) blasts were investigated using serum-free in vitro conditions. IGF-1 enhanced AML blast proliferation independent of the presence of other exogenous cytokines only for 2 of 21 patients, but for 10 additional patients IGF-1 altered blast proliferation in the presence of certain exogenous cytokines or cytokine combinations. IGF-1 had minor effects on AML blast cytokine secretion only for a subset of the patients (decreased levels for 1 patient, increased levels for 7 patients). Our in vitro observations indicate that IGF-1 can modulate AML blast proliferation and/or cytokine secretion for a subset of patients.

Acute Disease↗
PubMed1999

Functional differentiation of acute myeloid leukaemia blast cells.

Little is known of the functional status of blast cells from patients with acute myeloid leukaemia (AML). We have studied phagocytosis and membrane receptors by flow cytometry (FCM), and secretory activities in blast cells from 24 AML patients prior to treatment. Blast cells from 11/16 patients attached N. meningitidis, and internalization occurred in 7/14. The phagocytosis of zymosan particles and N. meningitidis correlated linearly (r = 0.9, p<0.01, n = 11). Surface membrane expression of CD32 and CD11b was sufficient to account for opsonin-dependent attachment in all except one patient. A significant fraction of the blast cells attached, but did not internalize meningococci. CD32 and CD11b were non-functional in all the blasts from five patients, and in a subpopulation from seven additional patients. Significantly more large than small blasts expressed CD32, CD35 and CD11b (p<0.001). Phagocytosis was unrelated to the secretion of IL-1alpha, IL-1beta, and TNFalpha. In conclusion, AML blast cell function is related to receptor expression, cell size and granularity, and to FAB-type.

Adult↗
PubMed1998

[Future requirements for hematologists].

Today there are not enough specialists in haematology in Norway. During the period 1990-1995 2.5 specialists in haematology qualified per year. In order to meet future requirements for haematologists at Norwegian municipal and university hospitals, it has been estimated by the Norwegian Society for Haematology that the number of specialists qualifying per year should be increased to ten for the next ten years.

Education, Medical, Continuing↗
PubMed1998

[Large granular lymphocytic leukemia].

Large granular lymphocyte leukaemia (LGL leukaemia) is a rare, chronic lymphoproliferative bone marrow disease which can be considered a subtype of chronic T-cell lymphocytic leukaemia (T-CLL). We describe three patients with large granular lymphocyte leukaemia. They all suffered from chronic disease with neutropenia and relative lymphocytosis. An expansion of mature lymphocytes with the CD3+, CD8+, CD57+ immunophenotype was demonstrated in all three patients. Two patients had a history of recurring infections. Serological findings compatible with rheumatic disease were present in all three patients, and two suffered from rheumatoid arthritis. We have made a brief survey of this disease, which is characterized by relative or absolute lymphocytosis, neutropenia, and an increased risk of infection. Rheumatoid arthritis and other associated autoimmune manifestations occur frequently. Large granular lymphocyte leukaemia should be considered a possible diagnosis in patients with chronic neutropenia and relative lymphocytosis, in particular if rheumatic manifestations are also present. Flow cytometric immunophenotyping is a sensitive method in diagnosing this disease.

Aged↗
PubMed1998

Insulin-like growth factor-1 (IGF-1) has a costimulatory effect on proliferation of committed progenitors derived from human umbilical cord CD34+ cells.

The effects of insulin-like growth factor-1 (IGF-1) on highly enriched human umbilical cord CD34+ cells were investigated in vitro. CD34+ cells were cultured in serum-free medium containing stem cell factor (SCF), GM-CSF, and interleukin-3 (IL-3). Culture of CD34+ cells for one week in the presence of these cytokines resulted in a dose-dependent increase in total cell number. Addition of G-CSF together with SCF+IL-3+GM-CSF increased the proliferation of myelopoietic cells as determined by the number of cells expressing the myelomonocytic marker CD64 and the granulocytic marker CD15 without significantly altering the number of CD34+ cells in the cultures. In the presence of G-CSF, IGF-1 induced a dose-dependent increase in the total cell number and a moderate but significant increase in the percentages of CD15+, CD64+ cells with sustained CD34+ cell proliferation. We conclude that IGF-1 can enhance the in vitro proliferation of committed progenitor cells derived from umbilical cord CD34+ cells.

Antigens, CD↗
PubMed1998

Cellular immune responses in acute leukaemia patients with severe chemotherapy-induced leucopenia; characterization of the cytokine repertoire of clonogenic T cells.

T lymphocytes are important both for the host defence against infections and probably also as antileukaemic effector cells in patients with acute leukaemia. To investigate the T lymphocyte cytokine repertoire of clonogenic T lymphocytes, CD4+ and CD8+ T lymphocyte clones were prepared from acute leukaemia patients with chemotherapy-induced cytopenia (leucocytes <0.5x 10(9)/l). A majority of both CD4+ and CD8+ clones secreted detectable interleukin-2 (IL-2), IL-10, IL-13, granulocyte/macrophage-colony-stimulating factor and interferon gamma (IFNgamma) in response to phytohaemagglutinin + accessory cells (Epstein-Barr-virus-transformed B cell line, 80-Gy-irradiated). The CD4+ clones showed significantly higher levels of IL-10 secretion than the CD8+ clones. Decreased levels of IL-2, IL-13 and IFNgamma were observed when acute myelogenous leukaemia (AML) blasts were used instead of cells from the B cell line as accessory cells during phytohaemagglutinin activation, but the differences in IL-13 and IFNgamma levels were reversed by addition of exogenous IL-2. On the basis of these results we conclude: (i) the remaining clonogenic T lymphocytes derived from acute leukaemia patients with therapy-induced leucopenia can respond to activation with a broad cytokine response, and T-cell-derived cytokines may then contribute to cytokine responses during complicating infections in these patients; (ii) although T cells can modulate AML blast functions and mediate antileukaemic effects, the leukaemia blasts will also modulate T cell functions and alter the cytokine profile of activated T lymphocytes.

Acute Disease↗
PubMed1998

Ribosomal proteins sustain morphology, function and phenotype in acute myeloid leukemia blasts.

Translation of mRNA is a prerequisite for cell proliferation, differentiation and viability. We have studied the effect of ribosome protein factors (GPRE) on acute myeloid leukemia (AML) blast cells. Ribosomes were isolated from MPC-11 cells using ultra-centrifugation. GPRE were extracted using a high KCl procedure. Blast cells from six AML patients were grown in suspension cultures for 24 and 96 h. GPRE or granulocyte macrophage-colony stimulating factor (GM-CSF) were added at the start of the incubation. GPRE, but not GM-CSF, prevented chromatin condensation and fragmentation of blast cell nuclei in AML-M2, -M4 and -M5 and the loss of nucleoli in AML-M2 and -M5. The fraction of phagocytosing blast cells in AML-M1, -M2, -M4 and -M5 was increased by GPRE. GPRE stimulated opsonin-dependent and -independent attachment and internalisation of N. meningitidis. GPRE increased the fraction of blasts expressing CD11b and CD32 in AML-M2 and -M5. GPRE diminished the fraction of AML-M5 cells bearing CD35 and CD32. GPRE also decreased the fraction of CD11c-bearing AML-M2 and -M5 cells. GM-CSF potentiated effects of GPRE in AML-M1, -M2, -M4 and -M5. GPRE and GM-CSF in combination affected phagocytosis and surface antigen expression in blast cells that were not influenced by either factor alone. Neither GPRE nor GM-CSF induced terminal differentiation or DNA-synthesis. We conclude that GPRE affects AML blast cell morphology, function and surface molecule expression, possibly by inhibiting apoptosis. The effects of GPRE may be mediated by ribosomal proteins that regulate translation and modulate the subcellular distribution of mRNA species.

Acute Disease↗
PubMed1998

T-lymphocyte functions in acute leukaemia patients with severe chemotherapy-induced cytopenia: characterization of clonogenic T-cell proliferation.

Intensive chemotherapy for acute leukaemia is followed by a period of severe chemotherapy-induced leukopenia. We used a limiting dilution assay to investigate whether remaining CD4+ and CD8+ T lymphocytes derived from such leukopenic patients could be activated and undergo clonogenic proliferation. The activation signal in our model was accessory cells (irradiated normal peripheral blood mononuclear cells) + phytohaemagglutinin (PHA) + interleukin-2 (IL-2). During severe leukopenia a majority of circulating lymphocytes were CD4+ T cells. Clonogenic proliferating T lymphocytes were detected for all patients. Higher frequencies of clonogenic cells were detected in the CD8+ subset as compared to the CD4+ subset. However, for both subsets frequencies of proliferating cells were decreased compared with healthy individuals. The CD4+ and CD8+ lymphocytes were also capable of proliferation in response to alloactivation, and accessory cells mainly containing acute myelogenous leukaemia blast were efficient as accessory cells for activation. For the CD4+ cells, increased proliferation was detected in the presence of acute myelogenous leukaemia (AML) blasts compared with normal accessory cells. Based on our results we conclude that: (1) although acute leukaemia patients with therapy-induced leukopenia have both a quantitative and a qualitative T-cell defect, (2) the remaining T-cell population includes a subset capable of clonogenic proliferation. However, (3) proliferation of the clonogenic CD4+ cells can be modulated by AML blasts.

Adult↗
PubMed1998

IL-4, IL-10 and IL-13 in acute myelogenous leukemia.

Cytokines are important regulators of acute myelogenous leukemia (AML) blast proliferation. For a subset of patients the AML blasts show constitutive cytokine secretion and can undergo autonomous proliferation in vitro, whereas for other patients the blasts are dependent on exogenous cytokines for proliferation. The capability of autocrine proliferation is an adverse prognostic factor in AML. The three cytokines interleukin (IL)-4, IL-10 and IL-13 modulate in vitro blast proliferation, but the final effect of each cytokine (enhancement/inhibition/no effect) depends on differences between individual patients as well as the presence of other exogenous cytokines. In contrast to these divergent effects on blast proliferation, all three cytokines inhibit constitutive in vitro cytokine secretion by AML blasts. Because of the divergent effects on blast proliferation, it seems less likely that clinical therapy with these cytokines can be used to directly modulate AML blast proliferation. However, their effects on normal immunocompetent cells (and possibly the antigen-presenting capacity of AML blasts) are easier to predict. Thus direct (therapy with exogenous IL-4, IL-10 or IL-13) or indirect (enhancement of endogenous release of IL-4, IL-10 or IL-13) modulation of these cytokine effects on immunocompetent cells may become a useful clinical approach for enhancement of antileukemic immune effects. Such a modulation of immune reactivity can be used either as in vivo patient therapy or as manipulation of stem cell grafts prior to transplantation.

Cytotoxicity, Immunologic↗
PubMed1997

Interleukin-13 secretion by normal and posttransplant T lymphocytes; in vitro studies of cellular immune responses in the presence of acute leukaemia blast cells.

T lymphocyte secretion of interleukin-13 (IL-13) in response to different activation signals was characterized in vitro. IL-13 release was investigated when virus transformed B lymphocytes or acute myelogenous leukaemia (AML) blasts were used as accessory cells during T cell activation. First, a majority of both CD4+ and CD8+ TCR alpha beta + T lymphocyte clones, derived from normal individuals and bone marrow transplant recipients, secreted IL-13 in response to a standardized mitogenic activation signal (phytohaemagglutinin + IL-2 + B lymphocyte accessory cells). The CD4+ cells showed significantly higher IL-13 levels than the CD8+ subsets. Second, when leukaemic accessory cells (more than 95% AML blasts) were used during T cell activation, IL-13 was released both during alloactivation of normal T lymphocytes and during mitogen activation of posttransplant T cells. Third, when normal T lymphocytes were stimulated with allogeneic AML blasts, addition of IL-13-neutralizing monoclonal antibodies decreased interferon gamma levels. Although addition of IL-13-neutralizing antibodies did not alter granulocyte-colony-stimulating factor secretion by allostimulating AML blasts, altered blast proliferation was detected for certain patients. Thus, most T cell clones can release IL-13, and IL-13 can modulate cytokine responses during T cell recognition of allogeneic AML cells.

Adult↗