Imatinib and Nilotinib Inhibit Hematopoietic Progenitor Cell Growth, but Do Not Prevent Adhesion, Migration and Engraftment of Human Cord Blood CD34+ Cells

in PLoS ONE (2012), 7(12), 52564

Background: The availability of tyrosine kinase inhibitors (TKIs) has considerably changed the management of Philadelphia chromosome positive leukemia. The BCR-ABL inhibitor imatinib is also known to ... [more ▼]

Background: The availability of tyrosine kinase inhibitors (TKIs) has considerably changed the management of Philadelphia chromosome positive leukemia. The BCR-ABL inhibitor imatinib is also known to inhibit the tyrosine kinase of the stem cell factor receptor, c-Kit. Nilotinib is 30 times more potent than imatinib towards BCR-ABL in vitro. Studies in healthy volunteers and patients with chronic myelogenous leukemia or gastrointestinal stromal tumors have shown that therapeutic doses of nilotinib deliver drug levels similar to those of imatinib. The aim of this study was to compare the inhibitory effects of imatinib and nilotinib on proliferation, differentiation, adhesion, migration and engraftment capacities of human cord blood CD34+ cells. Design and Methods: After a 48-hour cell culture with or without TKIs, CFC, LTC-IC, migration, adhesion and cell cycle analysis were performed. In a second time, the impact of these TKIs on engraftment was assessed in a xenotransplantation model using NOD/SCID/IL-2Rc (null) mice. <br />Results: TKIs did not affect LTC-IC frequencies despite in vitro inhibition of CFC formation due to inhibition of CD34+ cell cycle entry. Adhesion of CD34+ cells to retronectin was reduced in the presence of either imatinib or nilotinib but only at high concentrations. Migration through a SDF-1a gradient was not changed by cell culture in the presence of TKIs. Finally, bone marrow cellularity and human chimerism were not affected by daily doses of imatinib and nilotinib in a xenogenic transplantation model. No significant difference was seen between TKIs given the equivalent affinity of imatinib and nilotinib for KIT. <br />Conclusions: These data suggest that combining non-myeloablative conditioning regimen with TKIs starting the day of the transplantation could be safe. [less ▲]

What is the Contribution of Host-Derived CMV Immunity after Allogeneic Transplantation following Non-Myeloablative Conditioning?

in Haematologica (2012), 97(Supplement 1), 720

Adaptation of a Murine Chronic GVH Model to Study Graft versus Myeloma Effect after Allogeneic Transplantation

in Belgian Journal of Hematology (2012), Abstracts book(Supplement of 27th General Meeting of the Belgian Hematological Society), 16

High prevalence of anaemia and limited use of therapy in cancer patients : a Belgian survey (Anaemia Day 2008)

in Supportive Care in Cancer (2012), 20

Objectives: The aim of this study is to provide relevant and accurate information on prevalence and treatment patterns of anaemia in Belgian cancer patients. Methods The Anaemia Day 2008 survey was a ... [more ▼]

Objectives: The aim of this study is to provide relevant and accurate information on prevalence and treatment patterns of anaemia in Belgian cancer patients. Methods The Anaemia Day 2008 survey was a single visit, multi-centre, non-interventional study in adult cancer patients under systemic therapy (chemotherapy, hormonal, immunological and/or targeted therapy) and/or radiotherapy. Efforts were made to enrol the maximum number of patients seen in each centre that day. Patients signed an informed consent and relevant data were collected from their files, i.e. disease and disease stage, cancer therapy and anti-anaemic treatment, including transfusions and the use of erythropoietin stimulating agents (ESA). A blood count of each included patient was performed. Haemoglobin (Hb) values (grams per decilitre) were classified into four categories to assess the severity of anaemia, as defined byWHO: no anaemia: Hb≥12 g/dL; mild 10≤Hb≤11.9 g/dL; moderate 8≤Hb≤9.9 g/dL; severe Hb< 8 g/dL. Univariate and multivariate analyses were carried out with anaemia as the dependent variable. Results A total of 1,403 eligible patients aged 63±13 years (mean age±SD) were enrolled in 106 oncology or haematology centres. The mean Hb level (±SD) was 11.6 g/dL (±1.8 g/dL) and the prevalence of anaemia (Hb<12 g/dL) was 55.7% (95% CI, 53.1–58.3%), respectively, 35.9% mild, 17.8% moderate and 2.1% severe anaemia. Anaemia was more frequent in females than in males, and in patients with haematological malignancies (73.4%) than in those with solid tumours (51.4%; p<0.001). Anaemia prevalence was higher in hospitalised patients (75.5%) compared to those seen in one-day-clinic (54.3%) or in consultation (33.9%; p<0.001), and in patients treated with chemotherapy (61.3%) compared to those receiving radiotherapy (34.4%) or hormonal therapy (19.5%; p<0.001). There was a clear correlation between severity of anaemia and WHO performance status (p< 0.001). Among anaemic patients, 53.1% received no treatment (mean Hb 10.8±0.9 g/dL). Among the anaemic patients who received therapy for their anaemia (mean Hb 9.7±1.1 g/dL), the most frequent treatments were RBC transfusions (42%), ESA (34.6%), transfusions+ESA (12%), ESA+iron (7.9%) and iron alone (3.5%). Comparison to the ECAS survey shows that there has been no major change in attitude towards anaemia management in the last decade. Conclusion This survey shows that cancer-related anaemia is still frequently observed in cancer patients. Even if in our study ESA were used more frequently than about 10 years ago, still a large amount of anaemic patients who could be treated for anaemia according to EORTC guidelines, were not. [less ▲]

Less vasoocclusive disease after intravenous ersus oral busulfan for autologous hematopoietic cell transplantation : the Belgian pediatric experience

in Belgian Journal of Hematology (2012), 3(2), 34-40

Busulfan is commonly used in preparative conditioning regimens prior to hematopoietic stem cell transplantation in children and young adults for malignant and non-malignant disorders. For many years ... [more ▼]

Busulfan is commonly used in preparative conditioning regimens prior to hematopoietic stem cell transplantation in children and young adults for malignant and non-malignant disorders. For many years Busulfan was only available in an oral form, resulting in large inter- and intra-patients variability in plasma exposure, associated with higher graft failure rate as well as higher toxicity such as venoocclusive disease. With the development of an intravenous formulation of Busulfan, a more accurate control of both the inter- and intra-patient variability has been provided. The goal of this study was to evaluate the use and efficacy of intravenous Busulfan in comparison with the oral formulation in children undergoing an autologous transplantation after conditioning with Busulfan. Despite the small number of patients, this study confirmed the apparent benefit of intravenous Busulfan in children undergoing an autologous HSCT. The use of a 5-level dose schedule defined by body weight resulted in an efficient engraftment with marked reduction in the incidence of veno-occlusive disease compared with oral Bu. In terms of diseasefree outcome, survival and event-free survival, similar results have been obtained in both groups. The choice of this formulation of Busulfan should therefore be considered. [less ▲]

Differential signalling through ALK-1 and ALK-5 regulates leptin expression in Mesenchymal Stem Cells

in Stem Cells & Development (2012), 21(11), 1948-54

Leptin plays a central role in maintaining energy balance, with multiple other systemic effects. Despite leptin importance in peripheral regulation of mesenchymal stem cells (MSC) differentiation, little ... [more ▼]

Leptin plays a central role in maintaining energy balance, with multiple other systemic effects. Despite leptin importance in peripheral regulation of mesenchymal stem cells (MSC) differentiation, little is known on its expression mechanism. Leptin is often described as adipokine, while it is expressed by other cell types. We have recently shown an in vitro leptin expression, enhanced by glucocorticoids in synovial fibroblasts. Here, we investigated leptin expression in MSC from bone marrow (BM-MSC), cord matrix (UMSC), and primary and dedifferentiated chondrocytes (DCH). Results showed that BM-MSC, but not UMSC, expressed leptin that was strongly enhanced by glucocorticoids. Interestingly, chondrocytes gained leptin expression progressively with dedifferentiation. This dedifferentiation was correlated with downregulation of ALK-5 expression, Smad2 phosphorylation (p-Smad2), and gain of ALK-1 expression and Smad1/5 phosphorylation (p-Smad1/5). TGF-β1 was shown to signal via ALK-5-Smad2/3 and/or ALK-1-Smad1/5 pathways. In BM-MSC, TGF-β1 increased p-Smad2 expression and markedly inhibited endogenous- and glucocorticoidinduced leptin expression, while ALK-5 inhibitor (SB431542) induced and restored this expression. In addition, both prednisolone and SB431542 increased p-Smad1/5 expression. These results suggested ALK-5-Smad2 pathway as inhibitor of leptin expression, while ALK-1-Smad1/5 as activator. Indeed, Smad1 expression silencing induced leptin expression inhibition. Furthermore, prednisolone enhanced the expression of TGF-βRII while decreasing p-Smad2 in BM-MSC and SVF but not in UMSC. In vitro differentiation revealed differential osteogenic potential in SVF, BM-MSC and UMSC that correlates to their leptin expression potential. Our results suggest that ALK-1/ALK-5 balance regulates leptin expression in MSC. It also underlines UMSC as leptin non-producer MSC for cell therapy protocols where leptin expression is not suitable. [less ▲]

Prise en charge du lymphome B diffus à grandes cellules en 2012

in Revue Médicale Suisse (2012), 8

Diffuse Large B Cells Lymphoma (DLBCLI is the mast comman non-Hodgkin Iymphoma and comprises a large numberof different entities with different clinico-pathological characteristics. The role of positron ... [more ▼]

Diffuse Large B Cells Lymphoma (DLBCLI is the mast comman non-Hodgkin Iymphoma and comprises a large numberof different entities with different clinico-pathological characteristics. The role of positron emission tomography is essential dudog the Ini tial staging and post treatment assessment, and potentially at early or mid-treatmentevaluation of response. First-line therapy comprises immuno-chemotherapy with rituximab and different cytotox ic agents that differforcomponents, dosages and frequency of administration taking worldwlderecognized pre-treatment prognostic variables into account. After relapse, peripheral blood stem cells transplantation remains the only chance of cu re. This review attempts to summarize the current state of our knowledge by highlighting the leads pursued to further improve current therapeutic results. [less ▲]

Expression of growth hormone (GH)/insulin-like growth factor (IGF) axis during Balb/c ontogeny and effects of GH upon ex-vivo T-cell differentiation

in Neuroimmunomodulation (2012), 19

Aims: We here address the question of expression and role of GH/IGF axis in the thymus. Methods: Using RT-qPCR, the expression profile of various components of the somatotrope GH/IGF axis was measured in ... [more ▼]

Aims: We here address the question of expression and role of GH/IGF axis in the thymus. Methods: Using RT-qPCR, the expression profile of various components of the somatotrope GH/IGF axis was measured in different thymic cell types and during thymus embryogenesis in Balb/c mice. Effect of GH on T-cell differentiation was explored through thymic organotypic culture. Results: Transcription of Gh, Igf1, Igf2 and their related receptors predominantly occurred in thymic epithelial cells (TEC), while a low level of Gh and Igf1r transcription was also evidenced in thymic T cells (thymocytes). Gh, Ghr, Ins2, Igf1, Igf2, and Igfr1, displayed distinct expression profiles depending on the developmental stage. The protein concentration of IGF-1 and IGF-2 were in accordance with the profile of their gene expression. In fetal thymus organ cultures (FTOC) derived from Balb/c mice, treatment with exogenous GH resulted in a significant increase of double negative CD4-CD8- T cells and CD4+ T cells, together with a decrease in double positive CD4+CD8+ T cells. These changes were inhibited by concomitant treatment with GH and GHR antagonist pegvisomant. However, GH treatment also induced a significant decrease in FTOC Gh, Ghr and Igf1 expression. Conclusion: These data show that the thymotropic properties of the somatotrope GH/IGF-1 axis involve an interaction between exogenous GH and GHR expressed by TEC. Since thymic IGF-1 is not increased by GH treatment, the effects of GH upon T-cell differentiation could implicate a different local growth factor or cytokine. [less ▲]

Liver transplantation for acute hepatic failure due to chemotherapy-induced HBV reactivation in lymphoma patients.

in World journal of gastroenterology : WJG (2011), 17(25), 3069-72

Hepatitis B (HBV) reactivation induced by chemotherapy is problem encountered recently in the management of malignant diseases. Chemotherapy-induced HBV reactivation may ultimately lead to terminal acute ... [more ▼]

Hepatitis B (HBV) reactivation induced by chemotherapy is problem encountered recently in the management of malignant diseases. Chemotherapy-induced HBV reactivation may ultimately lead to terminal acute liver failure. Liver transplantation (LT) currently remains the only definitive treatment option for such cases, but is generally denied to patients suffering from malignancy. Here, the authors describe 2 cases of cancer-free and HBV graft re-infection-free survival after LT performed for terminal liver failure arising from HBV reactivation induced by chemotherapy for advanced stage lymphoma. These 2 cases, and some other reports in the literature, may suggest that patients suffering from hematologic malignancies and terminal liver disease can be considered for LT if the prognosis of their hematologic malignancy is good. [less ▲]

LIVER TRANSPLANTATION FOR ACUTE HEPATIC FAILURE DUE TO CHEMOTHERAPY-INDUCED HEPATITIS B VIRUS REACTIVATION IN LYMPHOMA PATIENTS

in Transplant International (2011, February), 24(1), 10-10