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

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egression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol. 2004;165:35-52. 70. Kane RC, Farrell AT, Saber H, Tang S, Williams G, Jee JM, et al. Sorafenib for the treatment of advanced renal cell carcinoma. Clin Cancer Res. 2006;12:7271-8. 71. Cabebe E, Wakelee H. Sunitinib: a newly approved small-molecule inhibitor of angiogenesis. Drugs Today (Barc). 2006;42: 387-98. 72. Lin B, Podar K, Gupta D, Tai YT, Li S, Weller E, et al. The vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584 inhibits growth and migration of multiple myeloma cells in the bone marrow microenvironment. Cancer Res. 2002;62:5019-26. 73. Pandiella A, Carvajal-Vergara X, Tabera S, Mateo G, Gutiérrez N, San Miguel JF. Imatinib mesylate (STI571) inhibits multiple myeloma cell proliferation and potentiates the effect of common antimyeloma agents. Br J Haematol. 2003;123:858-68. 74. Dispenzieri A, Gertz MA, Lacy MQ, Geyer SM, Greipp PR, Rajkumar SV, et al. A phase II trial of imatinib in patients with refractory/relapsed myeloma. Leuk Lymphoma. 2006;47:39-42. 75. Zangari M, Anaissie E, Stopeck A, Morimoto A, Tan N, Lancet J, et al. Phase II study of SU5416, a small molecule vascular endothelial growth factor tyrosine kinase receptor inhibitor, in patients with refractory multiple myeloma. Clin Cancer Res. 2004;10:88-95. 76. Kovacs MJ, Reece DE, Marcellus D, Meyer RM, Mathews S, Dong RP, et al. A phase II study of ZD6474 (Zactima, a selective inhibitor of VEGFR and EGFR tyrosine kinase in patients with relapsed multiple myeloma--NCIC CTG IND.145. Invest New Drugs. 2006;24:529-35. 77. Podar K, Catley LP, Tai YT, Shringarpure R, Carvalho P, Hayashi T, et al. GW654652, the pan-inhibitor of VEGF receptors, blocks the growth and migration of multiple myeloma cells in the bone marrow microenvironment. Blood. 2004; 103:3474-9. 78. Prince HM, Honemann D, Spencer A, Rizzieri DA, Stadtmauer EA, Roberts AW, et al. Vascular endothelial growth factor inhibition is not an effective therapeutic strategy for relapsed or refractory multiple myeloma: a phase 2 study of pazopanib (GW786034). Blood. 2009;113:4819-20. London, United Kingdom, June 9-12, 2011 79. Ramakrishnan V, Timm M, Haug JL, Kimlinger TK, Wellik LE, Witzig TE, et al. Sorafenib, a dual Raf kinase/vascular endothelial growth factor receptor inhibitor has significant anti-myeloma activity and synergizes with common antimyeloma drugs. Oncogene. 2010;29:1190-202. 80. Avet-Loiseau H, Li JY, Facon T, Brigaudeau C, Morineau N, Maloisel F, et al. High incidence of translocations t(11;14)(q13;q32) and t(4;14)(p16;q32) in patients with plasma cell malignancies. Cancer Res. 1998;58:5640-5. 81. Keats JJ, Reiman T, Maxwell CA, Taylor BJ, Larratt LM, Mant MJ, et al. In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression. Blood. 2003;101:1520-9. 82. Qing J, Du X, Chen Y, Chan P, Li H, Wu P, et al. Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice. J Clin Invest. 2009;119:1216-29. 83. Grand EK, Chase AJ, Heath C, Rahemtulla A, Cross NC. Targeting FGFR3 in multiple myeloma: inhibition of t(4;14)positive cells by SU5402 and PD173074. Leukemia 2004; 18:962-6. 84. Paterson JL, Li Z, Wen XY, Masih-Khan E, Chang H, Pollett JB, et al. Preclinical studies of fibroblast growth factor receptor 3 as a therapeutic target in multiple myeloma. Br J Haematol. 2004;124:595-603. 85. Trudel S, Ely S, Farooqi Y, Affer M, Robbiani DF, Chesi M, et al. Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma. Blood. 2004;103:3521-8. 86. Clezardin P. The antitumor potential of bisphosphonates. Semin Oncol. 2002;29:33-42. 87. Wood J, Bonjean K, Ruetz S, Bellahcène A, Devy L, Foidart JM, et al. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther. 2002;302:1055-61. 88. Scavelli C, Di Pietro G, Cirulli T, Coluccia M, Boccarelli A, Giannini T, et al. Zoledronic acid affects over-angiogenic phenotype of endothelial cells in patients with multiple myeloma. Mol Cancer Ther. 2007;6:3256-62. 89. Cocco C, Giuliani N, Di Carlo E, Ognio E, Storti P, Abeltino M, et al. Interleukin-27 acts as multifunctional antitumor agent in multiple myeloma. Clin Cancer Res. 2010;16:4188-97. Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 279 |
R. Fonseca Mayo Clinic Cancer Center, Collaborative Research Building, Scottsdale, AZ, USA Acknowledgements: Rafael Fonseca is a Clinical Investigator of the Damon Runyon Cancer Research Fund. This work is supported by grants SPORE CA90297052, P01 CA62242, R01 CA83724, ECOG CA 21115T, Predolin Foundation, Mayo Clinic Cancer Center and the Mayo Foundation. Hematology Education: the education program for the annual congress of the European Hematology Association 2011;5:280-285 Multiple myeloma Role of genetics in myeloma risk stratification Introduction It is now widely accepted that multiple myeloma (MM) is a heterogeneous disease with the major subtypes being defined by the underlying genetic aberrations of the clonal plasma cells (PC). 1,2 These genetic aberrations have been used as the foundation to classify the disease, establish prognostic categories, and to a limited degree, serve as predictive indicators. 1–3 Many aspects of the disease are directly influenced by the presence of specific genetic changes. These include clinical features, “natural history of the disease,” aggressiveness markers and other. Obtaining this genetic information is now considered routine clinical care for MM, and should be required for all ongoing and future clinical trials. 4,5 In general, five to eight subgroups of MM have been identified using the various methodologies, although many of these categories largely overlap. 6–8 Subdivision into many small subgroups carries the risk of creating fragmented analyses that lack statistical power to be reliable9 In response to this challenge, a dichotomy classification has been proposed that segregates patients into high and standard risk categories (+/- and intermediate risk category) (www.msmart.org). 9,10 While no specific therapy exists that is primarily directed at high-risk MM, three important corollaries have emerged: i) clinical trials aimed at highrisk MM are being developed; ii) identification of risk categories has allowed standardrisk patients to be treated with more chronic disease controlling strategies; iii) and identification of high risk features is critical for proper counseling of patients with these variants of the disease (avoidance of “MM is a chronic disease” hue to the patient counseling discussion). Background and techniques The field of MM cytogenetics has invigorated since the first observations were made in A B S T R A C T Risk stratification, mostly done via genetic testing is of paramount importance in the prognostication of myeloma for counseling treatment planning and prognostication. This paper discusses the implications of these novel genetic factors and current therapy for the disease. the mid 1980s and 1990s regarding a potential role for cytogenetic changes to discriminate patients with more aggressive disease. 11–13 The field quickly evolved to the application of molecular cytogenetics (i.e., FISH) 3,14,15 and more recently high throughput genomic platforms (i.e., gene expression profiling (GEP) 16–18 and array based comparative genomic hybridization (aCGH). 19,20 Deployment of more modern genomic tools has been hampered by practical limitations regarding reimbursement and regulatory considerations. However, a recent commercialization of GEP provides a test case in which modern genomics is introduced into routine clinical care for the disease. 21 Until such advances are widespread, FISH remains the standard for disease prognostication. 2,3,14,15 It is imperative, however, that FISH be done in such a manner that the scoring is restricted to PC only. 22 Many commercial laboratories continue to perform FISH in unsorted, or otherwise unselected, nuclei making results interpretation unreliable. Samples submitted to cytogenetic laboratories often represent the last pull of those collected for clinical purposes. It is, therefore, not uncommon to observe a much lower fraction of PC in those aspirates, mostly as a consequence of hemodilution. Clinicians must be wary and look for the specific nomenclature provided in the cytogenetic response. A standard “nuc ish” (for nuclear interphase FISH) should be considered evidence of unreliable testing. PC must be either sorted (for instance using anti-CD138 magnetic beads) 3 or the FISH analysis must be coupled with immunofluorescence detection of the clonal PC. 22 PC identification can readily be done using cytoplasmic light chain staining (e.g., cIg-FISH). 22 Diagnosis and disease classification All cancers can be classified from various perspectives that describe features and attributes of the clonal cells (and sometimes the host as well). 23,24 . In MM, the disease | 280 | 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
Page 238 and 239: trial evaluating different doses an
Page 240 and 241: acid. 62 The second was a large mul
Page 242 and 243: Borthakur G, et al. Cause of death
Page 244 and 245: P. Krishnamurthy 1 G.J. Mufti 1,2 1
Page 246 and 247: etween 1995 and 2005. 11 Five hundr
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Page 250 and 251: attainment of FDC post DLI. Interes
Page 252 and 253: myelodysplastic syndromes is associ
Page 254 and 255: ubiquitous chaperone that promotes
Page 256 and 257: was thought that they are linked to
Page 258 and 259: pathologic induction of miR-28 in M
Page 260 and 261: STATs. Second, levels of HP1 alpha
Page 262 and 263: 72. Irandoust MI, Aarts LH, Roovers
Page 264 and 265: A.M. Vannucchi Section of Hematolog
Page 266 and 267: 2,559 patients with a diagnosis of
Page 268 and 269: tant use of aspirin should be caref
Page 270 and 271: sions at this regard. Based on thes
Page 272 and 273: in bcr-abl-negative myeloproliferat
Page 274 and 275: Table 1. Prognostic scoring systems
Page 276 and 277: Figure 1. Current inhibitors of JAK
Page 278 and 279: Table 4. A risk-based approach to d
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Page 282 and 283: A. Vacca 1 D. Ribatti 2 1 Departmen
Page 284 and 285: neovessel building together with MM
Page 286 and 287: Mevastatin, a specific inhibitor of
Page 290 and 291: diagnosis does not require genetic
Page 292 and 293: Genetics prognostic tools should be
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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
Page 306 and 307: first line therapy have shown survi
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Page 310 and 311: methylation characterizes juvenile
Page 312 and 313: Table 1. Clinical signs of possible
Page 314 and 315: Table 4. Distribution of CSF involv
Page 316 and 317: ently results in a less than 5% cum
Page 318 and 319: 90. German-Austrian-Swiss ALL-BFM S
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
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Page 332 and 333: R.E. Ware Professor and Vice-Chairm
Page 334 and 335: protein, cytokines, and soluble adh
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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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