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Eva Hellström-Lindberg

Publications and source records attributed to Eva Hellström-Lindberg.

15 recordsLinked to original sources
PubMed2006

A pharmacodynamic study of 5-azacytidine in the P39 cell line.

OBJECTIVE: 5-azacytidine (azacytidine), a DNA hypomethylating agent, was recently approved as the first therapeutic agent for the treatment of myelodysplastic syndromes. The present subcutaneous dosing schedule, 75 mg/m(2) for 7/28 days, is based on early clinical studies and may constitute a practical problem for patients. The present in vitro study aimed at evaluating the pharmacodynamics of azacytidine, thereby providing a rationale for clinical dose-finding studies. METHODS: P39 cells were incubated with 0.1, 0.5, and 1 microM azacytidine daily for 24, 48, and 72 hours, followed by 48 hours in drug-free medium. The effects of azacytidine on cell growth, proliferation, apoptosis, cell cycle status, and promoter methylation of E-cadherin, ER, and HIC genes were studied. RESULTS: Azacytidine decreased cell growth and proliferation, increased apoptosis, and affected cell cycle status in a dose-dependent manner. However, the exposure time, 24 to 72 hours, at doses between 0.5 and 1 microM, did not significantly affect any of these variables. Using first-order exponential pharmacokinetic model, we found that the effect of 1, 2, or 3 microM over 24 hours did not differ from that of 0.5 to 1 microM given over 48 to 72 hours. Induction of promoter hypomethylation was observed already after 24 hours of exposure with >or=0.5 microM azacytidine with no clear dose-effect relationship. CONCLUSION: Our results indicate that optimal cellular effects of azacytidine might be achieved by shorter exposure times. The model provides information about the relation between azacytidine dose intensity and exposure time on malignant myeloid cells, which could serve as a rationale for further clinical development of practical, safe, and cost-effective dosing schedules.

Apoptosis↗
PubMed2005

Lead poisoning from souvenir earthenware.

A case of massive lead poisoning from juice contained in a Greek earthenware jug as well as six satellite cases of high lead exposure of similar origin is reported. The intoxicated patient was successfully treated with dimercaptosuccinic acid. Ceramic producers should adhere to the longstanding European legislation.

Adult↗
PubMed2005

Antiapoptotic role of growth factors in the myelodysplastic syndromes: concordance between in vitro and in vivo observations.

PURPOSE: Erythroid apoptosis in low-risk myelodysplastic syndrome (MDS) maybe mediated via mitochondrial release of cytochrome c and subsequent caspase activation. In the present study, we compared the in vitro and in vivo effects of proerythroid treatment with erythropoietin + granulocyte colony-stimulating factor (G-CSF) on myelodysplastic erythropoiesis regarding apoptosis and preferential growth of clones with cytogenetic abnormalities. EXPERIMENTAL DESIGN: We enrolled 15 refractory anemia (RA) and 11 refractory anemia with ringed sideroblasts (RARS), including 5q- aberration, monosomy 7, and trisomy 8, before initiation of treatment and followed nine patients after successful treatment. The effects of G-CSF and erythropoietin were assessed. The expression of G-CSF receptor (G-CSFR) was explored during erythroid maturation. The relative growth of erythroid progenitors with cytogenetic aberrations in presence of erythropoietin was investigated. RESULTS: Significant redistribution of cytochrome c was seen before treatment at all stages of erythroid differentiation. This release was blocked by G-CSF during the whole culture period and by erythropoietin during the latter phase. Both freshly isolated glycophorin A+ bone marrow cells and intermediate erythroblasts during cultivation retained their expression of G-CSFR. Cytochrome c release and caspase activation were significantly less pronounced in progenitors obtained from successfully treated nonanemic patients and showed no further response to G-CSF in vitro. Moreover, erythropoietin significantly promoted growth of cytogenetically normal cells from 5q- patients, whereas no such effect was observed on erythroblasts from monosomy 7 or trisomy 8 patients. CONCLUSION: We conclude that growth factors such as erythropoietin and G-CSF can act both via inhibition of apoptosis of myelodysplastic erythroid precursors and via selection of cytogenetically normal progenitors.

Adult↗
PubMed2005

Angiogenesis in relation to clinical stage, apoptosis and prognostic score in myelodysplastic syndromes.

The International Prognostic Scoring System (IPSS), based on the number of cytopenias, percentage of bone marrow blasts and cytogenetics, is an important prognostic tool for patients with myelodysplastic syndrome (MDS). In addition, factors such as high bone marrow cellularity and lactate dehydrogenase levels have been associated with an adverse outcome, spontaneously and after chemotherapy. Recently, increased bone marrow angiogenesis, measured as, e.g. microvascular density (MVD), was reported to be more intense in high-risk than in low-risk MDS. To assess the prognostic role of MVD in MDS, a cohort of 56 patients, thoroughly investigated for various clinical and morphological parameters, were followed-up for survival > or =60 months after the diagnostic analysis. As a group MDS patients had higher MVD compared to healthy controls (p<0.02). The highest median MVD value was observed in the RAEB group, but there was no overall significant difference between the FAB groups. No significant correlations were observed between MVD and peripheral blood counts, bone marrow cellularity, percentage of bone marrow blasts and CD34 positive cells, apoptotic index (TUNEL), proliferation index (MIB-1), erythroid index, FAB group and IPSS score. MVD was not correlated to overall survival. In contrast, bone marrow blast count <5%, low or normal cellularity, as well as a high erythroid index, indicated a favorable survival. Thus, our data do not support an important prognostic role of angiogenesis, reflected by microvessel density, in the myelodysplastic syndromes.

Adult↗
PubMed2005

Long-term outcome of treatment of anemia in MDS with erythropoietin and G-CSF.

We report long-term results of treatment of myelodysplastic syndrome (MDS) with erythropoietin and granulocyte colony-stimulating factor (G-CSF). A total of 129 patients were followed up 45 months after last inclusion in the Nordic MDS Group studies. Erythroid response rate was 39% and median response duration 23 months (range, 3-116 months or more). Complete responders showed longer response duration than partial responders (29 versus 12 months, P = .006). The International Prognostic Scoring System (IPSS) groups Low/Intermediate-1 (Low/Int-1) had longer response duration than Int-2/High (25 versus 7 months, P = .002). The time until 25% developed acute myeloid leukemia (AML) was longer in the good and intermediate predictive groups for erythroid response compared with the poor predictive group (52 versus 13 months, P = .008). Only 1 of 20 long-term responders developed AML. We assessed the effect on long-term outcome by comparing treated patients with untreated patients selected from the IPSS database using multivariate Cox regression, adjusting for major prognostic variables. There was no difference in survival (odds ratio [OR], 0.9; 95% confidence interval [CI], 0.7-1.2; P = .55) or risk of AML evolution (OR, 1.3; 95% CI, 0.7-2.2; P = .40) between treated and untreated patients. Patients with high/intermediate probability of response and with IPSS Low/Int-1 show frequent and durable responses without adverse effects on outcome, while other patients should not be considered candidates for this treatment.

Adolescent↗
PubMed2005

Aberrant mitochondrial iron distribution and maturation arrest characterize early erythroid precursors in low-risk myelodysplastic syndromes.

Early erythroblasts from patients with refractory anemia (RA) and RA with ringed sideroblasts (RARS) show constitutive mitochondrial release of cytochrome c. Moreover, mature erythroblasts in RARS, but not in RA, display aberrant accumulation of mitochondrial ferritin (MtF). We analyzed cytochrome c release, MtF expression, and gene expression during erythroid differentiation in bone marrow cells from myelodysplastic syndrome (MDS) patients and healthy controls. Whereas none or few cultured erythroid cells from healthy individuals and RA patients expressed MtF, those from RARS patients showed MtF expression at an early stage, when cells were CD34+ and without morphologic signs of erythroid differentiation. The proportion of RARS erythroblasts that were MtF+ increased further upon in vitro maturation. Moreover, a significant overexpression of mRNA encoding cytochrome c, and proapoptotic Bid and Bax, was seen in freshly isolated cells from MDS patients. Genes involved in erythroid differentiation were also dysregulated in MDS cells. Importantly, GATA-1 expression increased during normal erythroid maturation, but remained low in MDS cultures, indicating a block of erythroid maturation at the transcriptional level. In conclusion, aberrant MtF expression in RARS erythroblasts occurs at a very early stage of erythroid differentiation and is paralleled by an up-regulation of genes involved in this process.

Adenosine Triphosphate↗
PubMed2005

Update on supportive care and new therapies: immunomodulatory drugs, growth factors and epigenetic-acting agents.

Patients with "low-risk" myelodysplastic syndrome (MDS) are mostly treated with approaches aiming to reduce the negative consequences of ineffective hematopoiesis. Transfusion therapy should be tailored to allow adequate oxygenation and optimal quality of life, and may lead to the need for iron chelation therapy. Growth factors (erythropoietin and granulocyte colony-stimulating factor [G-CSF]) may induce long-lasting improvement of hemoglobin levels and does not increase the risk for leukemic transformation. Growth factors should be offered to defined subgroups of patients. Immunosuppression with anti-thymoglobulin or cyclosporine A may be an alternative for younger patients with refractory anemia (RA). The new immunomodulating compound lenalidomide, CC5013, is very active in the 5q- syndrome and is under evaluation for other low-risk MDS subtypes. "High-risk" MDS is associated with poor survival and high risk for leukemic transformation. The DNA hypomethylating compounds azacytidine and decitabine may offer improved long-term outcomes in this group of patients, although there has so far been no effect on survival rates. The efficacy of farnesyl transferase inhibitors has been evaluated in a series of phase II trials. The overall response rate was low, but the majority of responses were CRs. Finally, a number of new drugs directed to various biological and genetic targets are entering clinical trials.

Angiogenesis Inhibitors↗
PubMed2004

Kostmann syndrome: severe congenital neutropenia associated with defective expression of Bcl-2, constitutive mitochondrial release of cytochrome c, and excessive apoptosis of myeloid progenitor cells.

Kostmann syndrome, or severe congenital neutropenia (SCN), is an autosomal recessive disorder of neutrophil production. To investigate the potential role of apoptosis in SCN, bone marrow aspirates and biopsies were obtained from 4 patients belonging to the kindred originally described by Kostmann and 1 patient with SCN of unknown inheritance. An elevated degree of apoptosis was observed in the bone marrow of these patients, and a selective decrease in B-cell lymphoma-2 (Bcl-2) expression was seen in myeloid progenitor cells. Furthermore, in vitro apoptosis of bone marrow-derived Kostmann progenitor cells was increased, and mitochondrial release of cytochrome c was detected in CD34(+) and CD33(+) progenitors from patients, but not in controls. Administration of granulocyte colony-stimulating factor (G-CSF) restored Bcl-2 expression and improved survival of myeloid progenitor cells. In addition, cytochrome c release was partially reversed upon incubation of progenitor cells with G-CSF. In sum, these studies establish a role for mitochondria-dependent apoptosis in the pathogenesis of Kostmann syndrome and yield a tentative explanation for the beneficial effect of growth factor administration in these patients.

Apoptosis↗
PubMed2004

Hypochromic red blood cells in low-risk myelodysplastic syndromes: effects of treatment with hemopoietic growth factors.

BACKGROUND AND OBJECTIVES: The anemia of low-risk myelodysplastic syndromes (MDS), refractory anemia (RA) and RA with ringed sideroblasts (RARS), may respond to treatment with hematopoietic growth factors (GF)); erythropoietin (Epo) +/- granulocyte colony-stimulating factor (G-CSF). The present study was designed to assess whether functional iron deficiency may develop in MDS patients receiving these treatments. DESIGN AND METHODS: Erythrocyte scattergrams from 34 patients with RA and RARS (untreated, transfused, or GF-treated with partial or complete erythroid response) were analyzed with Bayer-Advia equipment. RESULTS: In untreated RARS, the proportion of hypochromic erythrocytes (Hypo-e, median 6.2%, range 1.1-8%) and hypochromic reticulocytes (Hypo-r, median 45%, range 22-48%), as well as mean corpuscular volume (MCV, median 101 fL) were significantly elevated compared to corresponding values in controls. These values increased further after GF-treatment (median 11%, 57%, and 105 fL, respectively), in spite of improved hemoglobin values and adequate body iron stores. The values observed in untreated RA patients largely fell within the normal range, and there was no significant influence of GF treatment. Notably, the hemoglobin content of reticulocytes (MCHr) did not differ between MDS and controls, and was not influenced by GF treatment. INTERPRETATION AND CONCLUSIONS: The red cell population in RARS shows morphological abnormalities in terms of varying but overall increased size, and reduced hemoglobin concentration. The proportion of abnormal cells increases after successful pro-erythroid GF treatment, indicating that GF promote erythroblast survival, and maturation into erythrocytes. Hence, the finding of hypochromic red cells should not routinely be interpreted as a marker for Epo-induced functional iron deficiency in MDS.

Anemia, Refractory↗
PubMed2003

The WHO classification of MDS does make a difference.

The purpose of this study was to determine the facility and reliability of the World Health Organization (WHO) classification of myelodysplastic syndromes (MDSs) with several observers reviewing the same diagnostic specimens. We also wanted to determine if the WHO classification provided additional information about predictability of clinical response outcome. To accomplish these goals we reviewed 103 previously diagnosed cases of low-risk MDS. We found 92% interobserver agreement (P <.001). Sixty-four of these patients had been entered into clinical trials using growth factors by the Nordic MDS Study Group. The WHO classification reliably predicted therapeutic response to the combination of granulocyte colony-stimulating factor (G-CSF) and erythropoietin (Epo). The response rate differed significantly between refractory anemia with ringed sideroblasts (RARS) and refractory anemia with multilineage dysplasia and ringed sideroblasts (RCMD/RS) with regard to therapeutic response (75% versus 9%; P =.003). Also, in the group of patients with less than 5% marrow blasts, there was a difference in median survival between patients with unilineage dysplasia (51% surviving at 67 months) and those with multilineage dysplasia (median survival, 28.5 months; P =.03).

Classification↗
PubMed2003

A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: significant effects on quality of life.

We have published previously a prototype of a decision model for anaemic patients with myelodysplastic syndromes (MDS), in which transfusion need and serum erythropoietin (S-Epo) were used to define three groups with different probabilities of erythroid response to treatment with granulocyte colony-stimulating factor (G-CSF) + Epo. S-Epo </= 500 U/l and a transfusion need of < 2 units/month predicted a high probability of response to treatment, S-Epo > 500 U/l and >/= 2 units/month for a poor response, whereas the presence of only one negative prognostic marker predicted an intermediate response. A total of 53 patients from a prospective study were included in our evaluation sample. Patients with good or intermediate probability of response were treated with G-CSF + Epo. The overall response rate was 42% with 28.3% achieving a complete and 13.2% a partial response to treatment. The response rates were 61% and 14% in the good and intermediate predictive groups respectively. The model retained a significant predictive value in the evaluation sample (P < 0.001). Median duration of response was 23 months. Scores for global health and quality of life (QOL) were significantly lower in MDS patients than in a reference population, and fatigue and dyspnoea was significantly more prominent. Global QOL improved in patients responding to treatment (P = 0.01). The validated decision model defined a subgroup of patients with a response rate of 61% (95% confidence interval 48-74%) to treatment with G-CSF + Epo. The majority of these patients have shown complete and durable responses.

Aged↗
PubMed2003

Approach to anemia associated with myelodysplastic syndromes.

Severe and transfusion-dependent anemia is a major symptom for patients with myelodysplastic syndromes (MDSs). Recent translational research studies have improved treatment approaches for these patients and contributed to our understanding of the pathophysiology of MDSs. For example, the response to antithymoglobulin treatment in certain patients with refractory anemia has elucidated potential immune mechanisms underlying bone marrow failure, whereas the observed effects of erythropoietin with or without granulocyte colony-stimulating factor in other low-risk patients have offered insights into the role of mitochondria-mediated erythroid apoptosis in MDS-related anemia. Current research is aimed at defining the role for other potential pathogenetic mechanisms in the development of MDS. Such studies may lead to individually tailored therapy for MDS patients based on a detailed analysis of the role of different contributing mechanisms to the origins of their disease.

Anemia↗
PubMed2002

Involvement and functional impairment of the CD34(+)CD38(-)Thy-1(+) hematopoietic stem cell pool in myelodysplastic syndromes with trisomy 8.

Clonality studies of mature cells suggest that the primary transformation event in myelodysplastic syndrome (MDS) most frequently occurs in a myeloid-restricted progenitor, a hypothesis supported by recent studies of purified CD34(+)Thy1(+) hematopoietic stem cells (HSCs) in cases with trisomy 8 (+8). In contrast, we recently demonstrated that a lymphomyeloid HSC is the target for transformation in MDS cases with del(5q), potentially reflecting heterogeneity within MDS. However, since +8 is known to frequently be a late event in the MDS transformation process, it remained a possibility that CD34(+)CD38(-)Thy1(+) HSC disomic for chromosome 8 might be part of the MDS clone. In the present studies, although a variable fraction of CD34(+)CD38(-)Thy1(+) cells were disomic for chromosome 8, they did not possess normal HSC activity in long-term cultures and nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice. Mixing experiments with normal CD34(+)CD38(-) cells suggested that this HSC deficiency was intrinsic and not mediated by indirect mechanisms. Furthermore, investigation of 4 MDS cases with combined del(5q) and +8 demonstrated that the +8 aberration was always secondary to del(5q). Whereas del(5q) invariably occurs in CD34(+)CD38(-)Thy-1(+) HSCs, the secondary +8 event might frequently arise in progeny of MDS HSCs. Thus, CD34(+)CD38(-)Thy1(+) HSCs are invariably part of the MDS clone also in +8 patients, and little HSC activity can be recovered from the CD34(+) CD38(-)Thy1(+) HSC. Finally, in advanced cases of MDS, the MDS reconstituting activity is exclusively derived from the minor CD34(+)CD38(-) HSC population, demonstrating that MDS stem cells have a similar phenotype as normal HSCs, potentially complicating the development of autologous transplantation for MDS.

ADP-ribosyl Cyclase↗
PubMed2000

Achievements in Understanding and Treatment of Myelodysplastic Syndromes.

The myelodysplastic syndromes (MDS) constitute a challenge for the biologist as well as for the treating physician. In Section I, Dr. Willman reviews the current classifications and disease mechanisms involved in this heterogeneous clonal hematopoietic stem cell disorder. A stepwise genetic progression model is proposed in which inherited or acquired genetic lesions promote the acquisition of "secondary" genetic events mainly characterized by gains and losses of specific chromosome regions. The genetic risk to develop MDS is likely multifactorial and dependent on various constellations of risk-producing and -protecting alleles. In Section II Dr. Barrett with Dr. Saunthararajah addresses the immunologic factors that may act as important secondary events in the development of severe pancytopenia. T cells from patients with MDS may suppress autologous erythroid and granulocytic growth in vitro, and T cell suppression by antithymocyte globulin or cyclosporine may significantly improve cytopenia, especially in refractory anemia. Recent studies have also demonstrated an increased vessel density in MDS bone marrow, and a phase II trial of thalidomide showed responses in a subgroup of MDS patients especially in those with low blast counts. In Section III Dr. Hellström-Lindberg presents results of allogeneic and autologous stem cell transplantation (SCT), intensive and low-dose chemotherapy. The results of allogeneic SCT in MDS are slowly improving but are still poor for patients with unfavorable cytogenetics and/or a high score according to the International Prognostic Scoring System. A recently published study of patients between 55-65 years old showed a disease-free survival (DFS) at 3 years of 39%. Consolidation treatment with autologous SCT after intensive chemotherapy may result in long-term DFS in a proportion of patients with high-risk MDS. Low-dose treatment with 5-azacytidine has been shown to significantly prolong the time to leukemic transformation or death in patients with high-risk MSA. Erythropoietin and granulocyte colony-stimulating factor may synergistically improve hemoglobin levels, particularly in sideroblastic anemia. Recent therapeutic advances have made it clear that new biological information may lead to new treatment modalities and, in combination with statistically developed predictive models, help select patients for different therapeutic options.

Journal Article↗