H e m a t o lo g y E d u c a t io n - European Hematology Association

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J.A. Burger Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Acknowledgement: This work was supported by a CLL Global Research Foundation grant and an ASCO Career Development Award (to J.A.B.). Hematology Education: the education program for the annual congress of the European Hematology Association 2011;5:91-99 Chronic lymphocytic leukemia Mechanisms of leukemia cell trafficking, homing, and tissue retention in chronic lymphocytic leukemia Tissue microenvironments: fatal attraction between CLL and stromal cells Chronic Lymphocytic Leukemia (CLL) cells relentlessly accumulate in vivo, but rapidly undergo spontaneous apoptosis in vitro, implying that their survival and expansion depend upon external signals from the tissue microenvironments. 1–3 This is similar to normal B-cells, which also are selected and expanded within the bone marrow (BM) and secondary lymphatic tissues in response to external signals, 4,5 transmitted by accessory cells, such as T cells, antigen (Ag)-presenting cells (APC), and mesenchymal cells collectively referred to as “stromal cells”. Initial studies in CLL demonstrated the protective effect of unselected BM stromal cells, 6,7 and subsequent studies defined that mesenchymal marrow stromal cells (MSC), 7–9 monocyte-derived nurselike cells (NLC), 8 and follicular dendritic cells (FDC) 10 can protect CLL cells from spontaneous and drug-induced apoptosis. 9 In vitro 8,11 and in vivo 12 leukemia cells are attracted to stromal cells, and the protective effects of stromal cells requires the close proximity between CLL and the stromal counterparts. 7–9,11 The high affinity of CLL cells for stromal cells is exemplified by a striking in vitro phenomenon termed pseudoemperipolesis. 11 Pseudoemperipolesis describes the spontaneous migration of a fraction of CLL cells beneath MSC, which occurs within a few hours of co-culture. In phase contrast microscopy, pseudoemperipolesis is characterized by the dark appearance of lympho- A B S T R A C T Leukemia cell trafficking and homing is a complex, highly regulated process with emerging clinical and therapeutic relevance. Chemokine receptors and adhesion molecules expressed on Chronic Lymphocytic Leukemia (CLL) cells navigate leukemia cell traffic between secondary lymphoid organs, blood, and the bone marrow, and position and retain leukemia cells within marrow and lymphoid tissue sub compartments. In response to signals from the leukemia microenvironment, such as B cell receptor engagement, CLL cells also secrete chemokines, presumably to attract T cells and other immune cells for cognate interactions. CXCR4 is the most prominent chemokine receptor in CLL and targeted in a first clinical trial. Specific inhibitors of the spleen tyrosine kinase (Syk), Bruton’s tyrosine kinase (Btk), and the PI3 kinase isoform delta are in early clinical development in CLL, and characteristically cause a “compartment shift” of CLL cells from the tissues into the peripheral blood. Clinically, this is associated with a transient surge in lymphocyte counts and lymph node shrinkage during the first weeks of treatment. These remarkable effects are thought to be due to inactivation of chemokine receptors and adhesion molecules, thereby antagonizing tissue retention and causing CLL cell mobilization. These findings emphasize that CLL cell trafficking and homing has become a highly dynamic, therapeutically relevant research field. cytes that migrated into the same focal plane as the stromal cells. Generally, the term pseudoemperipolesis is used to describe symbiotic complexes of leukemia cells with their stromal cell component. 13,14 During this cell interaction, leukemia cells migrate beneath the adherent cells or are trapped by membrane projections, but do not become internalized by the stromal cells. Pseudofollicular structures, called proliferation centers or pseudofollicles, are a hallmark feature in CLL histopathology, and thought to be the main areas of leukemia cell proliferation. Proliferation centers are clusters of larger, oftentimes dividing CLL cells intermingled with accessory cells. 2,15,16 The cellular composition of proliferation centers remains incompletely defined but likely includes APC, mesenchymal stromal cells, 17 and numerous, mostly CD4 + T-cells, 18–20 suggesting that some of the cellular interactions required for the expansion of Ag-specific normal B-cells within germinal centers (GC) may also be functional in CLL. At this point, we can conclude that in the tissue compartments (BM, secondary lymphoid tissues) CLL cells engage in complex cellular and molecular interactions with accessory cells that collectively are referred to as the leukemia microenvironment. These interactions, which still remain incompletely understood, shape the unique microanatomy in CLL and are responsible for survival, expansion, and protection of the CLL cells from cytotoxic drugs. These findings also imply that mobilization of CLL cells from Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 91 |
16 th Congress of the European Hematology Association the tissues into the blood would remove CLL cells from supportive stromal cells and make them more vulnerable to conventional drugs. This approach is particularly attractive in CLL, given that conventional, chemotherapy- and antibody-based therapies are not curative, presumably because residual CLL cells survive in protective tissue niches and ultimately pave the way to relapses. Basic mechanism of normal B cell and CLL cell migration and adhesion Normal B cell trafficking and function largely depends upon interactions between B cells and accessory stromal cells. 21,22 For example, stromal cells in secondary lymphatic tissues constitutively express chemokines, such as CXCL12 and CXCL13 that provide guidance for B cell positioning within distinct lymph node compartments. 21,23–25 According to the multistep paradigm, initially proposed by T. Springer, 26 lymphocyte trafficking and homing require the cooperation between chemokine receptors and adhesion molecules, such as integrins, CD44, and L-selectins, which are expressed on normal and malignant lymphocytes. Lymphocytes actively enter and home within tissue microenvironments, such as the secondary lymphatic tissues, where stromal cell networks provide guidance cues by secreting chemokines, establishing chemokine gradients, and expressing ligands for lymphocyte adhesion molecules (Figure 1). Coordinated lymphocyte entry, migration, and territoriality are essential during immune surveillance and induction of specific immune responses. 23,27–29 In B cell lymphomas/leukemias, the neoplastic B cells largely retain the capacity of their normal counterparts for trafficking and homing, as demonstrated in CLL and B cell acute lymphoblastic leukemia (ALL), both in vitro 11,30 and in vivo. 12 Overview: chemokines and their receptors The term chemokines initially was coined in 1992 as a short form of “chemotactic cytokines”. Currently, the human chemokine system includes more than 40 chemokines and 18 chemokine receptors. 31 Chemokines are small secreted proteins that are released either constitutively or in response to stimulation, and cause migration of cells towards a gradient of the chemokine (chemotaxis). The two main subfamilies of chemokines, CXC and CC chemokines, are distinguished based upon two conserved cysteine residues, which either are separated by an intervening amino acid or adjacent, accounting for CXC or CC chemokines, respectively. 31 Chemokines bind to chemokine receptors, which belong to the large family of seven transmembrane domain G-protein-coupled cell surface receptors (GPCRs). Following activation, the intracellular domains cause dissociation of G-proteins, which are composed of three distinct subunits (a, b, g heterotrimers). This leads to formation of the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG), resulting in cytoplasmatic calcium mobilization, and activation of multiple downstream signaling cascades, such as the phosphatidylinositol 3-kinase (PI3K)/Akt and the Ras/mitogen-activated protein-kinase (MAPK, also called ERK 1/2) signaling pathways. Figure 1. CLL cell trafficking between tissues and the peripheral blood. This diagram represents a model of CLL cell trafficking between the different tissue compartments and the blood. Gradients of lymphatic tissue chemokines (CXCL12, CXCL13, CCL19, CCL21), which are constitutively expressed by stromal cells, direct CLL cell migration, and localization within the secondary lymphatic tissues, acting through cognate chemokine receptors expressed on the CLL cells (CXCR4, CXCR5, CCR7). These interactions are likely involved in organization of the specific micro-architecture in CLL, which is characterized by proliferation centers, also called pseudofollicles. Gradients of CXCL12, which is the dominant chemokine in the bone marrow, direct CLL cell migration from the blood into the marrow. During this process, CLL cells attach to adhesion molecules and chemokines presented on the luminal side of the endothelium, causing adhesion, rolling, and trans - endothelial migration. Bone marrow stromal cells express CXCL12, which is in part, dependent on the oxygen partial pressure (pO 2), and direct CLL cell homing and retention in the marrow (adapted after 107 ). T and B lymphocytes express receptors for various chemokines, and their expression and function is modulated during lymphocyte differentiation and activation. 32 Circulating lymphocytes interact transiently and reversibly with vascular endothelium through adhesion molecules (selectins, integrins) in a process called rolling. Chemokines displayed on the luminal endothelial surface activate chemokine receptors on the rolling cells, which triggers integrin activation. 26 This results in the arrest, firm adhesion, and transendothelial migration into tissues, where chemokine gradients guide localization and retention of the cells. 33 These steps are collectively referred to as “homing”, and are essential for normal development of the organism, organization, and function of the immune system and for tissue replacement. Chemokine receptors on CLL cells CXCR4 (CD184) CXCR4 is expressed at high levels on the surface of peripheral blood CLL cells, 11,34–36 and mediates CLL cell | 92 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1)
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H e m a t o l o g y E d u c a t i o
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Copyright Information ©2011 by Eur
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Editorial Board Education Book Edit
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Acute lymphoblastic leukemia 1-8 Th
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S. Schnell P. Van Vlierberghe A. Fe
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lineage cells, and in differentiati
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FLT3 mutations The FMS-like tyrosin
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44. Bar-Eli M, Ahuja H, Foti A, Cli
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J.M. Rowe 1,2 C. Ganzel 1 1 Shaare
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treated on the MRC UKALL XII/ECOG29
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asparaginase (PEG), where the Esche
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or higher. It is, however, importan
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25. Bruggemann M, Schrauder A, Raff
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lymphoblastic leukemia: prospective
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such as high white blood cell count
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doxorubicine, there was a trend tow
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of the aging process with respect t
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K.L. Rice 1 M. Buzzai 2 J. Altman 1
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ing FLT3-ITD, wild-type NPM1, or bo
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ciated with gene activation, via th
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leukemia with inv(16) and t(8;21):
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99. Parsons DW, Jones S, Zhang X, e
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abnormalities, some of which are al
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file. 27,31 Thus, the double gene-m
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Page 52 and 53: Table 1. Meta-analysis of 23 random
Page 54 and 55: A recent study by the Center for In
Page 56 and 57: Patients with HLA-matched related o
Page 58 and 59: After allogeneic HSCT, an autologou
Page 60 and 61: A. Bacigalupo Ospedale San Martino,
Page 62 and 63: Table 2. The effect of HLA mismatch
Page 64 and 65: References 1. Petersdorf EW, Malkki
Page 66 and 67: neutrophil and platelet recovery an
Page 68 and 69: Figure 2. One Year-Overall Survival
Page 70 and 71: infused on day 21. No serious adver
Page 72 and 73: W, et al. Effect of graft source on
Page 74 and 75: TRM was higher for patients who rec
Page 76 and 77: following a myeloablative preparati
Page 78 and 79: effect. Surprisingly, none of the p
Page 80 and 81: nancies. Bone Marrow Transplant. 20
Page 82 and 83: J.G. Gilles Center for Molecular an
Page 84 and 85: 14C12 was humanized by grafting VH
Page 86 and 87: Table 1. VWD Classification. VWD Su
Page 88 and 89: Figure 1. Missense mutations found
Page 90 and 91: associated with an increased bleedi
Page 92 and 93: 49. Brown SA, Eldridge A, Collins P
Page 94 and 95: leed. These issues are especially i
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Page 98 and 99: years’ experience of prophylactic
Page 102 and 103: chemotaxis, migration across vascul
Page 104 and 105: Regulatory T cells (T reg), identif
Page 106 and 107: 16. Burger JA, Ghia P, Rosenwald A,
Page 108 and 109: TE, Nowakowski GS, et al. CD49d exp
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Page 112 and 113: Conclusions Chemoimmunotherapy has
Page 114 and 115: with multiple comorbidities (≥ 2)
Page 116 and 117: ment was finished in all 100 patien
Page 118 and 119: Table 2. Treatment recommendation f
Page 120 and 121: 34. Ferrajoli A. The combination of
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Page 124 and 125: potential to prevent LSCs from acce
Page 126 and 127: ABL1 confirms that eradication of d
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Page 130 and 131: alive after 10 years. 11 Hence, CCy
Page 132 and 133: each arm). A minimal change in myel
Page 134 and 135: Any discussion about the definition
Page 136 and 137: H. Kantarjian J. Cortes Leukemia De
Page 138 and 139: 59%; the CCyR rate was 44%. Among p
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Page 144 and 145: over the period of 6 weeks, demonst
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Page 148 and 149: 2006 Feb 1;107(3):924-30. 41. Liang
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demonstrated that changes in osteob
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“Mafia” transgenic mice in whic
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68. Coetzee T, Fujita N, Dupree J,
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ization. In WASP deficiency, lympho
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Currently the epistatic relationshi
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R. Küppers Institute of Cell Biolo
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Figure 1. TNFAIP3 mutation in HL ce
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Figure 2. HRS cells and their precu
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Hansmann ML, et al. Detection of cl
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fying patients for whom different a
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prognosis HL, whilst those with res
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12. Noordijk EM, Carde P, Dupouy N,
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A. Sureda Consultant in Haematology
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Figure 1. Long-term outcome of pati
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from a MRD and 18 from MUDs. All pa
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Parker PM, Stein AS, et al. High-do
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R. Stasi Department of Haematology,
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common variants in the regulatory r
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against the TPO receptor (cMpl). 61
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W.B. Mitchell A.A. Miller J.B. Buss
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platelet counts and/or bleeding. Th
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Mpl. Cell. 1994;77(7):1117-24. 6. d
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ity and mortality associated with t
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to azathioprine, and is particularl
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stemming from antibodies against PE
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L. Pasqualucci Institute for Cancer
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cation of molecularly distinct subg
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of cases) 46 and amplifications of
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gene alterations in B cell lymphoma
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W. Wilson National Cancer Institute
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clear distinction among the lymphom
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Treatment strategies in germinal ce
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in ABC DLBCL (Hernandez et al., 201
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DLBCL that mostly occurs in young p
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phoma. J Clin Oncol. 2005;23:5347-5
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Table 1. Diffuse Large B cell Lymph
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sion/relapse are similar to those i
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intensive therapy with curative int
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A. Karsan Genome Sciences Centre an
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Balanced translocations In contrast
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some arm 5q have also been implicat
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(H3K27) methyltransferase, and is a
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38. Starczynowski DT, Morin R, McPh
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G. Garcia-Manero Department of Leuk
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trial evaluating different doses an
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acid. 62 The second was a large mul
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Borthakur G, et al. Cause of death
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P. Krishnamurthy 1 G.J. Mufti 1,2 1
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etween 1995 and 2005. 11 Five hundr
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London, United Kingdom, June 9-12,
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attainment of FDC post DLI. Interes
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myelodysplastic syndromes is associ
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ubiquitous chaperone that promotes
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was thought that they are linked to
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pathologic induction of miR-28 in M
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STATs. Second, levels of HP1 alpha
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72. Irandoust MI, Aarts LH, Roovers
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A.M. Vannucchi Section of Hematolog
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2,559 patients with a diagnosis of
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tant use of aspirin should be caref
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sions at this regard. Based on thes
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in bcr-abl-negative myeloproliferat
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Table 1. Prognostic scoring systems
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Figure 1. Current inhibitors of JAK
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Table 4. A risk-based approach to d
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the flexibility to be adjusted as t
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A. Vacca 1 D. Ribatti 2 1 Departmen
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neovessel building together with MM
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Mevastatin, a specific inhibitor of
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egression of tumor vessels, and app
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diagnosis does not require genetic
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Genetics prognostic tools should be
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sone induction improves outcome of
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Table 1. Conventional chemotherapy
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Novel agents given as consolidation
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dence of peripheral neuropathy, gas
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31. Barlogie B, Tricot G, Anaissie
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Table 1. Major differences between
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first line therapy have shown survi
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transplantation, 7,91 and generally
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methylation characterizes juvenile
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Table 1. Clinical signs of possible
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Table 4. Distribution of CSF involv
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ently results in a less than 5% cum
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90. German-Austrian-Swiss ALL-BFM S
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U. Nowak-Göttl 1 R. Junker 1 A. Kr
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Based on the data obtained from the
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59. Male C, Chait P, Ginsberg JS, e
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Table 1. Characteristic features of
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Table 2. Mutational spectrum of CDA
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megarakaryoblastic leukemia (AMKL)
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R.E. Ware Professor and Vice-Chairm
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protein, cytokines, and soluble adh
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example, improving blood viscosity
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92(9):1266-7. 36. Bensinger TA, Gil
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London, United Kingdom, June 9-12,
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port have also been used. 5 Combina
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Wingard JR, Young J-AH, Boeckh MJ.
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K. Rezvani 1 J. Barrett 2 1 Haemato
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include the childhood infectious il
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Summary Patients undergoing hematop
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Table 1. Key issues. In a retrospec
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invasive method to assess iron over
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stitution but even with optimal sub
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T.M. Hackeng Department of Biochemi
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and inhibits FVIIa, and that the se
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Figure 4. Regulation of coagulation
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T. Baglin Department of Haematology
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Figure 1. Illustration of alternati
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compared with 3.5% in patients with
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49. Hron G, Kollars M, Binder BR, E
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Women receiving vitamin K antagonis
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molecular weight heparin as prophyl
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eral morbidity and mortality. 17-21
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the HOD construct. Furthermore, the
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Goals of future murine studies incl
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F. Noizat-Pirenne C. Tournamille Et
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phenotype. 26 In 2010, we investiga
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ody has been involved in DHTR. 37 T
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antigen. Cases can be encountered d
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S.R. Sloan Harvard Medical School &
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We also analyzed patient databases
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Index of authors Altman J. 27 Bacig
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Cornelissen J. Affiliations to disc
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GlaxoSmithKline (Research Support;
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