A novel mutation in the CUB sequence of matriptase-2 (TMPRSS6) is implicated in iron-resistant iron deficiency anaemia (IRIDA).

in British Journal of Haematology (2013), 160(4), 564-565

Kinetics of IL-7 and IL-15 Levels after Allogeneic Peripheral Blood Stem Cell Transplantation following Nonmyeloablative Conditioning

in PLoS ONE (2013), 8(2), 55876

Background: We analysed kinetics of IL-7 and IL-15 levels in 70 patients given peripheral blood stem cells after nonmyeloablative conditioning. Methods: EDTA-anticoagulated plasma and serum samples were ... [more ▼]

Background: We analysed kinetics of IL-7 and IL-15 levels in 70 patients given peripheral blood stem cells after nonmyeloablative conditioning. Methods: EDTA-anticoagulated plasma and serum samples were obtained before conditioning and about once per week after transplantation until day 100. Samples were aliquoted and stored at 280uC within 3 hours after collection until measurement of cytokines. IL-7 and IL-15 levels were measured by ELISAs. Results: Median IL-7 plasma levels remained below 6 pg/L throughout the first 100 days, although IL-7 plasma levels were significantly higher on days 7 (5.1 pg/mL, P = 0.002), 14 (5.2 pg/mL, P,0.001), and 28 (5.1 pg/mL, P = 0.03) (but not thereafter) than before transplantation (median value of 3.8 pg/mL). Median IL-15 serum levels were significantly higher on days 7 (12.5 pg/mL, P,0.001), 14 (10.5 pg/mL, P,0.001), and 28 (6.2 pg/mL, P,0.001) than before transplantation (median value of 2.4 pg/mL). Importantly, IL-7 and IL-15 levels on days 7 or 14 after transplantation did not predict grade II–IV acute GVHD. Conclusions: These data suggest that IL-7 and IL-15 levels remain relatively low after nonmyeloablative transplantation, and that IL-7 and IL-15 levels early after nonmyeloablative transplantation do not predict for acute GVHD. [less ▲]

Allogreffe de cellules souches hématopoïétiques chez le patient âgé : jusqu'à quel âge ?

in Revue Médicale de Liège (2013), 68(1), 38-43

In the last decades, the upper age limit for allogeneic hematopoietic cell transplantation has increased from 50-60 years to 70-75 years of age, in part due to the development of allogeneic ... [more ▼]

In the last decades, the upper age limit for allogeneic hematopoietic cell transplantation has increased from 50-60 years to 70-75 years of age, in part due to the development of allogeneic transplantation following reducedintensity or truly nonmyeloablative conditioning. This review describes challenges and opportunities of allogeneic hematopoietic cell transplantation in the elderly. [less ▲]

Rapamycin prevents experimental sclerodermatous chronic graft-versus-host disease in mice

Conference (2012)

Background: The most widely used mice model of chronic graft-versus-host disease (cGvHD) is an MHC-matched bone marrow transplantation model of sclerodermatous cGvHD. A limitation of that model is that ... [more ▼]

Background: The most widely used mice model of chronic graft-versus-host disease (cGvHD) is an MHC-matched bone marrow transplantation model of sclerodermatous cGvHD. A limitation of that model is that mortality is relatively low, making difficult to study the impact of potentially therapeutic compounds. Aims: To develop a more severe model of cGVHD and to assess the impact of Rapamycin administration in that model. Results: Lethally irradiated Balb/C mice were injected with 10x106 bone marrow cells and 70x106 splenocytes from B10.D2 donor mice. Twenty-one days later, all mice developed cGvHD. For the severe model, donor B10.D2 mice were injected with 0.5x106 splenocytes from Balb/C twenty-one days before transplantation. All mice from the severe model (n=8) died a median of 32 days while 3 of 7 mice in the classical model survived beyond day 52. Mean survival was decreased in the severe model compared to the classical model (32 days versus 37 days; p=0.0185). Recipient mice in the severe group experienced higher weight loss, hair loss and skin fi brosis. Numbers of T lymphocytes (231.9 ± 151.4 versus 951 ± 532.8; p=0.0032) and CD4+ T cells (63.25 ± 41.93 versus 135.0 ± 14.39; p=0.0018) per microliter of blood at day 21 were lower in the severe group than in the classical model. Moreover, number of regulatory T cells (Tregs) was decreased in the severe model (1.250 ± 0.8864 versus 8.000 ± 6.753; p=0.0151). We then investigated whether rapamycin administration could prevent GVHD in the severe model. All (n=8) mice treated with PBS (placebo) died a median of 32 days after transplantation, while 6 of 8 mice given 1 mg/kg/day i.p. rapamycin survived beyond day 52 (p=0.0012). Number of Tregs/μl was higher at day 21 in rapamycin-treated mice than in mice given PBS (2.000±1.195 versus 1.250±0.8864; p=0.0796). Moreover, number of naïve CD4+T (10.00±4.192 versus 30.25±5.185; p= 0.0089) and effector memory T cells (EMT) (30.67±3.180 versus 67.33±7.881; p= 0.0125) were higher in rapamycin mice. Finally, proliferation of EMT (assessed by fl ow cytometry using Ki-67) was higher in PBS than in rapamycin mice (45.28%±4.084 versus 31.90%± 2.003; p=0.0474). Conclusion: We have developed a mice model of severe cGVHD. Interestingly, rapamycin prevented death from cGVHD in that model, perhaps through in vivo expansion of Treg. [less ▲]

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 ▲]