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example, improving blood viscosity could theoretically help alleviate acute vaso-occlusion, and published industry-sponsored Phase 1/2 results with polaxmer- 188 (Flocor) were encouraging, 58 but no further Phase 3 investigation ensued. Similarly, a novel Gardos channel blocker that improves erythrocyte hydration showed promising cellular effects in a Phase 2 trial, 59 but the industry-sponsored Phase 3 trial was halted when it did not significantly reduce pain when tested as a single treatment modality. An industry-sponsored trial using inhaled nitric oxide was closed prematurely without release of results to date. Without industry backing, however, agents that are off-patent can suffer from lack of sponsorship and interest. Therapeutic interventions directed against the adhesive properties on circulating leukocytes, endothelial cells, and microparticles offer an exciting new opportunity to treat acute vaso-occlusion. General inhibitors of adhesion such as intravenous immunoglobulin show efficacy in an animal model of SCA, 60 suggesting that interruption of cell-endothelial contacts may be therapeutic. Specific inhibitors of individual adhesion molecules also show promise, 61-62 especially a novel “panselectin” compound that should theoretically provide broad yet specific inhibition of leukocytes and other circulating cells. 63 Targeted therapy for the endothelium itself reflects the observation that the chronic inflammatory vasculopathy triggers and participates in acute vaso-occlusion. Treatment to reduce the activation state of endothelial cells 24,64 has shown promise in animal models, and direct delivery of nitric oxide could restore vascular tone to help prevent vaso-occlusion. 65 Indeed, treatment of vaso-occlusion may require treatment for the endothelium as well as the erythrocyte, 66 since both are important in the pathophysiology. The idea of multimodal therapy for SCA has been proposed, 67 much like that often required for optimal therapeutic outcomes of treatment for infections or malignancies. Open clinical trials The large number of currently open therapeutic clinical trials for acute vaso-occlusion suggests that the treatment armamentarium may improve in the near future. A search for “sickle cell crisis” on the ClinicalTrials.gov website in January 2011 identified a total of 15 open therapeutic clinical trials (Table 2). A variety of Phase 1, 2, and 3 trials are currently enrolling subjects. Treatments range widely from specific (e.g., Adenosine 2A agonist, GMI-1070 anti-panselectin compound, eptifibatide, L-glutamine) to non-specific (e.g., IVIG, fish oil capsules) interventions. Some trials are being conducted in the US, while others originate from Europe; some are industry-sponsored, while others have governmental funding. The ClinicalTrials.gov website also lists a large number of completed therapeutic trials for acute vaso-occlusion in SCA. While most results have not been provided on the website to date, interventions with widely diverse agents such as fructose, corticosteroids, ketamine, ketorolac, sodium nitrite, aspirin, magnesium pidolate, nitroglycerin, sildenafil, poloxamer 188, stem cell factor, varespladib, nitric oxide, ICA-17043 channel blocker, and far red infrared radiation have all been completed over the past few years. Prevention London, United Kingdom, June 9-12, 2011 In light of the severe clinical consequences and morbidity associated with vaso-occlusion, as well as the chronic inflammatory state with endothelial dysfunction that develops as a result of repeated vaso-occlusion, it is perhaps obvious that prevention of the process would be preferable to acute intervention. Toward that goal, hydroxyurea is now a well-established oral agent with proven laboratory and clinical efficacy for SCA, ranging from infants to children to teens to adults. 68-71 The primary benefit of hydroxyurea derives from its Table 2. Active registered clinical trials involving therapeutic intervention for patients with SCA and vaso-occlusive events, typically designed to treat acute pain in the emergency or inpatient setting. All trials registered at clinicaltrials.gov with open recruitment as of January 2011 are listed, along with two studies scheduled to open recruitment soon. Clinical Trials # Intervention Phase Current Status NCT01085201 Adenosine 2A agonist 1 Recruiting NCT01256281 Femoral nerve block 1 Recruiting NCT00644865 IV immunoglobulin vs placebo 1,2 Recruiting NCT01033227 Sodium nitrite, open label 1,2 Recruiting NCT00834899 Eptifibratide vs placebo 1,2 Recruiting NCT00142051 Inhaled nitric oxide vs placebo 2 Recruiting NCT01119833 GMI-1070 (anti-panselectin) 2 Recruiting NCT01197417 Magnesium sulfate vs placebo 2,3 Recruiting NCT00748423 Inhaled nitric oxide vs placebo 2,3 Recruiting NCT00999245 High vs Low demand narcotics 3 Recruiting NCT00313963 Magnesium sulfate vs placebo 3 Recruiting NCT01179217 L-glutamine vs placebo 3 Recruiting NCT00874172 Nitrous oxide and nefopam vs usual 3 Recruiting NCT01202812 Omega-3 fatty acids vs placebo 2 Recruiting soon NCT00880373 Ibuprofen vs placebo 3 Recruiting soon Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 327 |
16 th Congress of the European Hematology Association induction of HbF, yet it offers additional benefits through a wide range of mechanisms of action, including reduction in the number of circulating reticulocytes and leukocytes, improved erythrocyte shape and deformability, and even local NO production. 72 Importantly for the pathogenesis of vaso-occlusion, the benefits of hydroxyurea in SCA have been reported for reducing adhesiveness of erythrocytes, 73-76 reticulocytes, 77 leukocytes, 78 and even endothelial cells. 79 Reduction in plasma endothelin-1, a marker of inflammation, has been measured, 80 as well as a number of cytokines, in a small number of patients. 81 While it is tempting to hypothesize that hydroxyurea has a broad salutary influence on adhesion and inflammation, a large prospective study is needed to test this formally. For example, a large panel of plasma inflammatory markers should be measured using newly available multiplex platforms, before any definitive conclusions can be reached about the impact of hydroxyurea therapy on the inflammatory pathophysiology of vaso-occlusion in SCA. A clearer understanding of these non-HbF effects of hydroxyurea will likely increase our enthusiasm for this drug and add to the argument that this potent oncedaily oral agent should be offered to most, if not all, patients with SCA. 82 Conclusions The pathogenesis and pathophysiology of vaso-occlusion in SCA has been investigated for over 40 years, yet important questions still remain. With recent increased understanding of the complexity of vaso-occlusion, we now have opportunities for targeted therapies to interrupt the process; several key clinical trials with novel agents are currently underway. Ultimately, however, prevention of vaso-occlusion should be viewed as the optimal treatment outcome. Until a better agent or treatment regimen is developed, hydroxyurea should be offered more often and better utilized in this patient population. References 1. Hoover R, Rubin R, Wise G, et al. Adhesion of normal and sickle erythrocytes to endothelial monolayer cultures. Blood. 1979;54:872-6. 2. Hebbel RP, Yamada O, Moldow CF, et al. Abnormal adherence of sickle erythrocytes to cultured vascular endothelium: possible mechanism for microvascular occlusion in sickle cell disease. J Clin Invest. 1980;65:154-60. 3. Turhan A, Weiss LA, Mohandas N, Coller BS, Frenette PS. Primary role for adherent leukocytes in sickle cell vascular occlusion: a new paradigm. Proc Natl Acad Sci USA. 2002;99 (5):3047-51. 4. Frenette PS. Sickle cell vaso-occlusion: multistep and multicellular paradigm. Curr Opin Hematol. 2002;9:101-6. 5. Chiang EY, Frenette PS. Sickle cell vaso-occlusion. Hematol Oncol Clin NA. 2005;19(5):771-84. 6. Hebbel RP. Adhesion of sickle red cells to endothelium: Myths and future directions. Trans Clin Biol. 2008;15(1-2):14-8. 7. Gill FM, Sleeper LA, Weiner SJ, et al. Clinical events in the first decade in a cohort of infants with sickle cell disease. Cooperative Study of Sickle Cell Disease. Blood. 1995;86 (2):776-83. 8. Natta CL, Niazi GA, Ford S, Bank A. Balanced globin chain synthesis in hereditary persistence of fetal hemoglobin. J Clin Invest. 1974;54(2):433-8. 9. Mohandas N, Evans E. Adherence of sickle erythrocytes to vascular endothelial cells: requirement for both cell membrane changes and plasma factors. Blood. 1984;64:282-7. 10. Barabino GA, McIntire LB, Eskin SG, et al. Rheological studies of erythrocyte-endothelial cell interactions in sickle cell disease. Prog Clin Biol Res. 1987;240:113-27. 11. Sugihara K, Sugihara T, Mohandas N, et al. Thrombospondin mediates adherence of CD36+ sickle reticulocytes to endothelial cells. Blood. 1992;80:2634-42. 12. Joneckis CC, Shock DD, Cunningham ML, et al. Glycoprotein IV-independent adhesion of sickle red blood cells to immobilized thrombospondin under flow conditions. Blood. 1996;87: 4862-70. 13. Hillery CA, Du MC, Montgomery RR, et al. Increased adhesion of erythrocytes to components of the extracellular matrix: isolation and characterization of a red blood cell lipid that binds thrombospondin and laminin. Blood. 1996;87:4879-86. 14. Adherence of phosphatidylserine-exposing erythrocytes to endothelial matrix thrombospondin. Blood. 2000;95:1293-1300. 15. Brittain JE, Milinar KJ, Anderson CS, et al. Integrin-associated protein is an adhesion receptor on sickle red blood cells for immobilized thrombospondin. Blood. 2001;97:2159-64. 16. Brittain JE, Mlinar KJ, Anderson CS, et al. Activation of sickle red blood cell adhesion via integrin-associated protein/CD47induced signal transduction. J Clin Invest. 2001;107:1555-62. 17. Kaul DK, Hebbel RP. Hypoxia/reoxygenation causes inflammatory response in transgenic sickle mice but not in normal mice. J Clin Invest. 2000;106:411-20. 18. Solovey A, Lin Y, Browne P, Choong S, Wayner E, Hebbel RP. Circulating activated endothelial cells in sickle cell anemia. N Engl J Med. 1997;337(22):1584-90. 19. Strijbos MH, Landburg PP, Nur E, et al. Circulating endothelial cells: a potential parameter of organ damage in sickle cell anemia? Blood Cells Molec Dis. 2009;43(1):63-7. 20. Shet AS, Aras O, Gupta K, et al. Sickle blood contains tissue factor-positive microparticles derived from endothelial cells and monocytes. Blood. 2003;102:2678-83. 21. Swerlick RA, Eckman JR, Kumar A, et al. Alpha 4 beta 1-integrin expression on sickle reticulocytes: vascular cell adhesion molecule-1-dependent binding to endothelium. Blood. 1993;82: 1891-99. 22. Gee BE, Platt OS. Sickle reticulocytes adhere to VCAM-1. Blood. 1995;85:268-74. 23. Matsui NM, Borsig L, Rosen SD, et al. P-selectin mediates the adhesion of sickle erythrocytes to the endothelium. Blood. 2001; 98:1955-62. 24. Solovey A, Kollander R, Shet A, et al. Endothelial cell expression of tissue factor in sickle mice is augmented by hypoxia/ reoxygenation and inhibited by lovastatin. Blood. 2004;104(3): 840-6. 25. West MS, Wethers D, Smith J, Steinberg M. Laboratory profile of sickle cell disease: a cross-sectional analysis. The Cooperative Study of Sickle Cell Disease. J Clin Epidemiol. 1992;45(8):893- 909. 26. Butcher EC. Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity. Cell. 1991;67:1033-6. 27. Turhan A, Weiss LA, Mohandas N, et al. P- and E-selectin deficiency protects against tnf-alpha-induced venular occlusion in sickle mice: evidence for a critical role for adherent leukocytes. Thromb Haemost. 2001;85:1333. 28. Belcher JD, Marker PH, Weber JP, Hebbel RP, Vercellotti GM. Activated monocytes in sickle cell disease: potential role in the activation of vascular endothelium and vaso-occlusion. Blood. 2000;96(7):2451-9. 29. Shet AS, Aras O, Gupta K, et al. Sickle blood contains tissue factor-positive microparticles derived from endothelial cells and monocytes. Blood. 2003;102(7):2678-83. 30. Lee SP, Ataga KI, Orringer EP, Phillips DR, Parise LV. Biologically active CD40 ligand is elevated in sickle cell anemia: potential role for platelet-mediated inflammation. Arter Thromb Vasc Biol. 2006;26(7):1626-31. 31. Vilas-Boas W, Cerqueira BA, Zanette AM, Reis MG, Barral- Netto M, Goncalves MS. Arginase levels and their association with Th17-related cytokines, soluble adhesion molecules (sICAM-1 and sVCAM-1) and hemolysis markers among steady-state sickle cell anemia patients. Ann Hematol. 2010; 89(9):877-82. 32. Ataga KI, Orringer EP. Hypercoagulability in sickle cell disease: a curious paradox. Am J Med. 2003;115(9):721-8. 33. Wun T, Paglieroni T, Field CL, et al. Platelet-erythrocyte adhesion in sickle cell disease. J Invest Med. 1999;47:121-7. 34. Wautier JL, Pintigny D, Wautier MP, et al. Fibrinogen, a modulator of erythrocyte adhesion to vascular endothelium. J Lab Clin Med. 1983;101:911-20. 35. Guchhait P, Dasgupta SK, Le A, Yellapragada S, Lopez JA, Thiagarajan P. Lactadherin mediates sickle cell adhesion to vascular endothelial cells in flowing blood. Haematologica. 2007; | 328 | 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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karyotype represents a distinct gen
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Table 1. Meta-analysis of 23 random
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A recent study by the Center for In
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Patients with HLA-matched related o
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After allogeneic HSCT, an autologou
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A. Bacigalupo Ospedale San Martino,
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Table 2. The effect of HLA mismatch
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References 1. Petersdorf EW, Malkki
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neutrophil and platelet recovery an
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Figure 2. One Year-Overall Survival
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infused on day 21. No serious adver
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W, et al. Effect of graft source on
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TRM was higher for patients who rec
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following a myeloablative preparati
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effect. Surprisingly, none of the p
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nancies. Bone Marrow Transplant. 20
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J.G. Gilles Center for Molecular an
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14C12 was humanized by grafting VH
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Table 1. VWD Classification. VWD Su
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Figure 1. Missense mutations found
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associated with an increased bleedi
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49. Brown SA, Eldridge A, Collins P
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leed. These issues are especially i
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estored function. 43,44 A phase I t
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years’ experience of prophylactic
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J.A. Burger Department of Leukemia,
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chemotaxis, migration across vascul
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Regulatory T cells (T reg), identif
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16. Burger JA, Ghia P, Rosenwald A,
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TE, Nowakowski GS, et al. CD49d exp
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andomized trial demonstrating impro
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Conclusions Chemoimmunotherapy has
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with multiple comorbidities (≥ 2)
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ment was finished in all 100 patien
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Table 2. Treatment recommendation f
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34. Ferrajoli A. The combination of
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to be the source of additional gene
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potential to prevent LSCs from acce
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ABL1 confirms that eradication of d
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65. Fiskus W, Pranpat M, Balasis M,
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alive after 10 years. 11 Hence, CCy
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each arm). A minimal change in myel
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Any discussion about the definition
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H. Kantarjian J. Cortes Leukemia De
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59%; the CCyR rate was 44%. Among p
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ern era of BCR-ABL1 tyrosine kinase
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the hematopoietic system, 10 nor in
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over the period of 6 weeks, demonst
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Data on clonal changes in the blood
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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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Page 296 and 297: Table 1. Conventional chemotherapy
Page 298 and 299: Novel agents given as consolidation
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Page 302 and 303: 31. Barlogie B, Tricot G, Anaissie
Page 304 and 305: Table 1. Major differences between
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Page 312 and 313: Table 1. Clinical signs of possible
Page 314 and 315: Table 4. Distribution of CSF involv
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Page 320 and 321: U. Nowak-Göttl 1 R. Junker 1 A. Kr
Page 322 and 323: Based on the data obtained from the
Page 324 and 325: 59. Male C, Chait P, Ginsberg JS, e
Page 326 and 327: Table 1. Characteristic features of
Page 328 and 329: Table 2. Mutational spectrum of CDA
Page 330 and 331: megarakaryoblastic leukemia (AMKL)
Page 332 and 333: R.E. Ware Professor and Vice-Chairm
Page 334 and 335: protein, cytokines, and soluble adh
Page 338 and 339: 92(9):1266-7. 36. Bensinger TA, Gil
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Page 342 and 343: port have also been used. 5 Combina
Page 344 and 345: Wingard JR, Young J-AH, Boeckh MJ.
Page 346 and 347: K. Rezvani 1 J. Barrett 2 1 Haemato
Page 348 and 349: include the childhood infectious il
Page 350 and 351: Summary Patients undergoing hematop
Page 352 and 353: Table 1. Key issues. In a retrospec
Page 354 and 355: invasive method to assess iron over
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Page 358 and 359: T.M. Hackeng Department of Biochemi
Page 360 and 361: and inhibits FVIIa, and that the se
Page 362 and 363: Figure 4. Regulation of coagulation
Page 364 and 365: T. Baglin Department of Haematology
Page 366 and 367: Figure 1. Illustration of alternati
Page 368 and 369: compared with 3.5% in patients with
Page 370 and 371: 49. Hron G, Kollars M, Binder BR, E
Page 372 and 373: Women receiving vitamin K antagonis
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Page 378 and 379: the HOD construct. Furthermore, the
Page 380 and 381: Goals of future murine studies incl
Page 382 and 383: F. Noizat-Pirenne C. Tournamille Et
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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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