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G-EXJ-1030713 May 2012 CYTOGENERIC ASSESSMENT IN MDS NOTE: These slides are for use in educational oral presentations only. If any published figures/tables.

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Presentation on theme: "G-EXJ-1030713 May 2012 CYTOGENERIC ASSESSMENT IN MDS NOTE: These slides are for use in educational oral presentations only. If any published figures/tables."— Presentation transcript:

1 G-EXJ May 2012 CYTOGENERIC ASSESSMENT IN MDS NOTE: These slides are for use in educational oral presentations only. If any published figures/tables from these slides are to be used for another purpose (e.g. in printed materials), it is the individual’s responsibility to apply for the relevant permission. Specific local use requires local approval.

2 2 G-EXJ May 2012 Outline ● MDS Classification and prognosis scoring ● Practical guide to bone marrow aspirate analysis in MDS ● Cytogenetics of MDS in bone marrow aspirates ● Summary LIC = liver iron concentration; MRI = magnetic resonance imaging; SF = serum ferritin; SIR = signal intensity ratio; SQUID = superconducting quantum interface device.

3 3 G-EXJ May 2012 What are the myelodysplastic syndromes (MDS)? ● MDS are a spectrum of heterogeneous myeloid clonal disorders ● Occurrence: –De novo (primary MDS) –Secondary or treatment-related MDS ● MDS are associated with significant morbidity and mortality due to: –Risk of transformation to acute myeloid leukemia (AML) –Cytopenias –Impaired quality of life (frequent transfusions, iron overload, etc)

4 4 G-EXJ May 2012 Common features of MDS ● MDS are marked by ineffective haematopoiesis and defective development of blood cells, e.g.: –dyserythropoiesis (affects red blood cells production) –dysgranulopoiesis (affects granulocytes production) –dysmegakaryopoiesis (affects platelet production) ● Ineffective haematopoiesis and maturation of the blood cells results in one or more cytopenias, e.g.: –anaemia (reduced red blood cell count) –neutropenia (reduced absolute neutrophil count) –thrombocytopenia (reduced number of platelets)

5 5 G-EXJ May 2012 Minimal diagnostic criteria in MDS consensus, Vienna 2006 ● Prerequisite criteria –constant cytopenia in one or more cell lineages complete blood count –exclusion of all other causes of cytopenia / dysplasia ● MDS-related (decisive) criteria –dysplasia in > 10% of all bone marrow cells in one or more of the lineages, or > 15% ringed sideroblasts complete blood count iron staining of bone marrow smears –5–19% blast cells bone marrow smears –typical chromosomal abnormality karyotyping or FISH FISH = fluorescence in situ hybridization. Loken MR, et al. Leuk Res. 2008;32:5-17. Nimer SD. Blood. 2008;111: Valent P, et al. Leuk Res. 2007;31:

6 6 G-EXJ May 2012 Minimal diagnostic criteria in MDS consensus, Vienna 2006 (cont.) ● Additional criteria (for patients not fulfilling the decisive MDS criteria) –abnormal phenotype of bone marrow cells flow cytometry –molecular signs of a monoclonal cell population HUMARA assay, gene chip profiling, point mutation or SNP analysis –markedly and persistently reduced colony formation CFU assay CFU = colony-forming unit; SNP-a = single-nucleotide polymorphism. Loken MR, et al. Leuk Res. 2008;32:5-17. Van de Loosdrecht AA. Leuk Res. 2008;32: Van de Loosdrecht AA, et al. Blood. 2008;111: Van de Loosdrecht AA, et al. Haematologica. 2009;94: Nimer SD. Blood. 2008;111: Valent P, et al. Leuk Res. 2007;31:

7 G-EXJ May 2012 MDS classification and prognostic scoring

8 8 G-EXJ May 2012 Diagnostic and prognostic of MDS Risk-stratification is necessary for clinical decision-making: ● predicts treatment outcomes ● predicts survival ● predicts risk of progression to AML Classification systemBasis of evaluation Derived prognostic score system FAB (1982)Cellular morphologyIPSS (1997) WHO (2002) Cellular morphology, cytogenetics WPSS (2007) FAB, French-American-British; IPSS, International Prognostic Scoring System; WPSS, WHO-based Prognostic Scoring System. Bennett JM, et al. Br J Haematol 1982;51:189–199; Jaffe, et al, eds. Lyon: IARC Press; 2001; Greenberg P, et al. Blood 1997;89:2079–2088; Malcovati L, et al. J Clin Oncol 2007;23:3503–3510.

9 9 G-EXJ May 2012 French-American-British (FAB) classification Blast percentage MDS Subtype Peripheral blasts (%) Bone marrow blasts (%) Additional features AML transformation (%) RARefractory anaemia≤1<510–20 RARS Refractory anaemia with ringed sideroblasts ≤1<5 >15% ringed sideroblasts in bone marrow 10–35 RAEB Refractory anaemia with excess blasts <55–20>50 RAEB-T Refractory anaemia with excess blasts in transformation ≥521–29 optional Auer-rods 60–100 CMML Chronic myelomonocytic leukaemia <5≤20 Peripheral monocytosis (>10 3 /µl) >40 Bennett JM, et al. Br J Haematol 1982;51:189–199.

10 10 G-EXJ May 2012 Survival by cytogenetic presentation in MDS patients Survival (%) Time (years) Patients n(%) −Y17(2) del(5q)48(6) Normal489(69) del(20q)16(2) Misc. single74(9) +838(5) Double29(3) Misc. double14(2) Chrom 7 abn.10(1) Misc. complex15(2) Complex66(8) Greenberg P, et al. Blood. 1998;89:

11 11 G-EXJ May 2012 Risk stratification and prognosis scoring for MDS: IPSS Influence of karyotype according to IPSS ● Good = normal, −Y, del(5q), del(20q) ● Poor = complex (≥ 3 abnormalities) or chromosome 7 anomalies ● Int. = all other abnormalities Variable BM blasts (%)< 55–10–11–2021–30 KaryotypeGoodInt.Poor Cytopenia(s)0/12/3 Greenberg P, et al. Blood. 1998;89: IPSS score

12 12 G-EXJ May 2012 Years Cumulative survival of MDS patients by IPSS Low Int-1 Int-2 High Survival Years Percent Percent AML Evolution Low Int-1 Int-2 High Greenberg P, et al. Blood 1997;89:2079–

13 13 G-EXJ May 2012 MDS: WHO classification 2008 Blast percentage MDS Subtype Dysplasia Peripheral blasts (%) Bone marrow blasts (%) Ringed sideroblasts (%) Cytogenetics 5q− syndromeMostly DysE< 1%< 5%< 15%5q− sole RA, RN, RT, RCUDDysE, N, T< 1%< 5%< 15%Various RARSMostly DysE0< 5%> 15%Various RCMD2–3 lineagesrare< 5%< 15%Various RAEB-11–3 lineages< 5%5–9%< 15%Various RAEB-21–3 lineages5–19% Auer rods +/- 10–19% Auer rods +/- < 15%Various MDS-U1 lineage< 1%< 5%< 15%Various BM = bone marrow; DysE = dyserythropoiesis; MDS-U = myelodysplastic syndrome, unclassified; N = neutropenia; pB = peripheral blood; RCMD = refractory cytopenia with multilineage dysplasia; RCUD = refractory cytopenia with unilineage dysplasia; RN = refractory neutropenia; RT = refractory thrombocytopenia; T = thrombocytopenia. Swerdlow SH, et al., eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2008:

14 14 G-EXJ May 2012 Survival of MDS patients according to transfusion dependency Transfusion-dependent patients Transfusion-independent patients Time (months) Proportion surviving Cazzola M, Malcovati L. N Engl J Med. 2005;352:536-8.

15 15 G-EXJ May 2012 The WHO classification-based prognostic scoring system (WPSS) for MDS Points 0123 WHO subtype RA, RARS, del(5q) RCMD, RCMD-RS RAEB-1RAEB-2 Transfusion requirementNoneRegular–– Cytogenetic categoryGoodInt.Poor– Risk groupsScoreMedian survival (months) Very low0103 Low172 Intermediate240 High3–421 Very high5–612 Malcovati L, et al. J Clin Oncol. 2007;25: Transfusion dependence is an independent indicator of severity of disease and has a significant effect on survival

16 16 G-EXJ May 2012 Overall survival and AML risk assessments in MDS by WPSS Malcovati L et al. J Clin Oncol 2007;25:3503–3510.

17 17 G-EXJ May 2012 WHO prognosis scoring system allows time dependent prognosis scoring IPSSWPSS ProsMore widely used and recognized Allows time-dependent prognosis scoring and risk stratification Takes into account individual patient transfusion need ConsApplies only at the time of diagnosis Underestimates the impact of transfusion requirement and cytogenetics Underestimates the impact of poor cytogenetics Greenberg P, et al. Blood 1997;89:2079–2088. Malcovati L, et al. J Clin Oncol. 2007;25:3503–3510. Schanz J, et al. Blood. 2007;110:[abstract 248]. Kantarjian H, et al. Cancer. 2008;113: Garcia-Manero G, et al. Leukemia. 2008;22:

18 G-EXJ May 2012 Practical guide to bone marrow aspirate analysis in MDS

19 19 G-EXJ May 2012 Bone marrow biopsy ● How is it done: –Marrow aspirate and bone (trephine) biopsy are removed by physician in an outpatient procedure under local anesthesia heparinized sample can be stored at room temperature for 24 hours ● What tests are done? –assessment of cellularity, architecture and focal collection of blasts for hematopoietic dysplasia smear staining examination –cytogenetic analysis karyotype FISH ● What other tests might be done? –flow cytometry cell counts cell sorting immunophenotyping Hellström-Lindberg E. Myelodysplastic Syndromes. London: Remedica; Van de Loosdrecht, et al, Haematologica.2009; 94: Image from: Medline Plus. NIH/NLM. Accessed Jan, 2011.

20 20 G-EXJ May 2012 Analysis of bone marrow smears ● Bone marrow aspirate smears are prepared on a slide by a medical technician using: –Wright’s stain –Perl’s staining (for ringed sideroblasts) –May-Grünwald-Giemsa staining –Immunohistochemical stainings, i.e. CD34 ● A pathologist or hematologist then examines the slides for cell abnormalities under microscope: –at least 400 nucleated cells and 20 megakaryocytes should be examined for morphology Hellström-Lindberg E. Myelodysplastic Syndromes. London: Remedica; 2008.

21 21 G-EXJ May 2012 Abnormal large megakaryocyte (double arrow), abnormal hypo-granular and Pelger neutrophils (single arrows). Refractory anaemia (RA) Analysis of bone marrow smears (cont.) Refractory anaemia with excess blasts (RAEB) Erythroid cells with peri-nuclear iron accumulation Prussian blue staining (left); Perl’s stain showing ringed sideroblasts with peri-nuclear (mitochondrial) deposition of iron (right) ASH Image Bank, used with permission, all rights reserved. Courtesy of J. Goasguen, Université de Rennes, France.

22 22 G-EXJ May 2012 Immunophenotyping by flow cytometry ● Various lineages are labeled with antibodies that recognize specific haematopoeitic identifiers ● Combination of no more than four labels recommended ● Important for identification of blasts - CD34+/abnormal granularity/CD45dim ● Well-correlated with other diagnostic techniques and prognostic systems Van de Loosdrecht, et al. Haematologica.2009; 94: Image from:

23 G-EXJ May 2012 Cytogenetics of MDS in bone marrow aspirates

24 24 G-EXJ May 2012 Importance of cytogenetic analysis in MDS ● Nearly half of the patients with MDS present with cytogenetic abnormalities 1 –changes have a pathogenetic relevance (i.e. loss or gain of gene function) ● Cytogenetic analysis is essential for the diagnosis and classification of MDS according to IPSS and WPSS 2 ● Chromosomal aberrations have prognostic relevance for OS and for the time to leukaemic transformation, independent of other factors ● Cytogenetic analysis forms the basis for therapeutic decisions –cytogenetics is indicative of response to therapy, i.e. lenalidomide in del(5q) 3 and azacitidine in −7/del(7q) 4 IPSS = International Prognostic Scoring System; OS = overall survival; WPSS = WHO classification-based Prognostic Scoring System. 1 Haase D, et al. Blood. 2007;110: Greenberg P, et al. Blood. 1998;89: List AF, et al. N Engl J Med. 2006;355: Fenaux P, et al. Lancet Oncol. 2009;10:

25 25 G-EXJ May 2012 Cytogenetic aberrations are frequent in patients with MDS 9% 14% 29% 48% Normal karyotype One abnormality Two abnormalities Complex karyotype N = 2,072 patients with MDS Haase D, et al. Blood. 2007;110:

26 26 G-EXJ May 2012 WHO 2008: Incidence of the most common cytogenetic aberrations in MDS (over 5%) Unbalanced aberrations De novo MDS (%) Secondary MDS (%) +810 −7/del(7q)1050 −5/del(5q)1040 del(20q)5–85–8 −Y5 iso(17q)/t(17p)/del(17p)3–53–5 Swerdlow SH, et al. In: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon: IARC; 2008:441. Unbalanced aberrations with loss of genetic information (deletions or monosomies) are most common in MDS; balanced aberrations are rare

27 27 G-EXJ May 2012 When should cytogenetic testing be performed in patients with MDS: Diagnosis ● WHO 2008 guidelines recommend a complete cytogenetic analysis of BM at initial diagnosis in all patients with MDS ● Cytogenetic analysis is mandatory for –diagnosis of MDS associated with del(5q) –patients with refractory cytopenia(s) who lack MDS diagnostic features; these patients may be considered as having presumptive evidence of MDS if they have MDS-related cytogenetic abnormalities (slides 4 and 5) rather than indicating abnormality, isolated loss of Y chromosome might be an age-related phenomenon and mosaicism with trisomy 8 might be a constitutional change. Therefore, they might not be sufficient to prove MDS BM = bone marrow. Swerdlow SH, et al. In: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon: IARC; 2008:441. Valent P, Horny HP. Eur J Clin Invest. 2009;39: Vardiman JW, et al. Blood. 2009;114:

28 28 G-EXJ May 2012 Is cytogenetic testing required for all patients? Yes, cytogenetic testing should be performed whenever possible at initial diagnosis and every 6–12 months during follow-up since karyotype and prognosis might change during the course of the disease. There are a few exceptions that will have no therapeutic consequences, e.g. very frail and multi-morbid patients. Are there disease presentations that correlate with specific cytogenetic abnormalities? There is no correlation between specific abnormalities and disease presentation (with exception of the association between isolated del(5q) syndrome and RA, with typical dysplasia of megakaryocytes). FAQs: Cytogenetic testing for diagnosis of patients with MDS Questions and answers were prepared under the review of Dr. Haase, University of Göttingen, Germany.

29 29 G-EXJ May 2012 FAQs: Cytogenetic testing during treatment in patients with MDS Why is it important to perform cytogenetic testing during the treatment course? Cytogenetic remissions represent a better quality of remission and are more reliable than those determined by blood films or cytomorphology from the BM. Furthermore, karyotype might change during the course of the disease affecting the prognosis and the treatment of the patient. First data show that a cytogenetic progression might be detectable several weeks before clinical manifestation. Is cytogenetic testing important for all patients or is it recommended for specific focus groups? All patients with clonal abnormalities identified before start of therapy should be followed up during therapy. Also, patients with initially normal karyotype might develop abnormalities during the course of disease and, therefore, require regular monitoring. Questions and answers were prepared under the review of Dr. Haase, University of Göttingen, Germany.

30 30 G-EXJ May 2012 Cytogenetics from BM is recommended when possible at least once every 6 months during therapy. When FISH is performed using peripheral blood (i.e. CD34-FISH), testing should be conducted every 3rd month. How often should cytogenetic testing be performed? When should treatment be altered as a result of changes in the cytogenetic profile? When a clear cytogenetic progression is seen, or when an abnormal clone is completely eliminated and karyotype turns normal and stays normal over time (at least 3 months); this depends on the type of therapy. What is the definition of cytogenetic progression in MDS? 1) Occurrence of new cytogenetic abnormalities (first in patients with normal karyotype or additional for patients with abnormalities). 2) Significant increase (> 50%) of the size of the clone with certain cytogenetic abnormalities. FAQs: Cytogenetic testing during treatment in patients with MDS (cont.) Questions and answers were prepared under the review of Dr. Haase, University of Göttingen, Germany.

31 31 G-EXJ May 2012 Chromosome analysis in MDS: Karyotyping ● Each cell in the body contains 46 chromosomes representing the normal human karyotype ● MDS patients frequently have a clonal abnormality in the hematopoietic progenitor cells, where a proportion of these have an abnormal karyotype with altered number of chromosomes and/or large alterations in their structure –Changes in the number of the chromosomes is due to monosomies (loss of a chromosome) and/or polysomies (more then 2 copies of a chromosome) –Changes in the structure of the chromosomes are commonly noted as: deletions, when part or entire chromatid is missing insertions, when additional material is included in a chromosome translocations, when genetic material is exchanged between chromosomes

32 32 G-EXJ May 2012 How to perform cytogenetic testing in patients with MDS: Karyotyping Sample ● Collect at least 10–20 mL of heparinized BM aspirates Storage ● Samples should reach the lab within 24 hours after biopsy Number of metaphases needed ● Analyse 25 metaphases if possible, especially if the karyotype is normal, to exclude a small aberrant cell clone Metaphase quality ●To detect structural abnormalities, adequate chromosome banding is required (≥ 150–250 bands per karyogram) See presenter for references.

33 33 G-EXJ May 2012 How to perform cytogenetic testing in patients with MDS: Karyotyping (cont.) ● Medical technician prepares metaphase slides for karyotyping, by: –culturing bone marrow aspirate for hours, and then –exposing the cells to slightly hypotonic solution –synchronizing them in metaphase (e.g. using colchicine) –finally, staining them (e.g. DAPI staining) and fixing them on slides ● A pathologist or hematologist then examines the slides for chromosomal abnormalities under microscope: –Samples are examined under microscope manually or with aid of analysis software (separating, enhancing banding pattern, chromosome pairing) –At least 25 metaphases should be examined, especially if the karyotype is normal, to exclude a small aberrant cell clone Holland and Frei. Cancer Medicine 6. American Cancer Society; Lucia Cytogenetics. Accessed Feb.2011.

34 34 G-EXJ May 2012 Can peripheral blood be used? Peripheral blood is usually not an alternative. No BM available: attempt banding analysis from peripheral blood (CD34-FISH), especially when blasts are present. Metaphase yield from peripheral blood is generally worse than that from BM aspirates. CD34-FISH can be an option. 1 What sample-related factors could influence the accuracy of the test? Ex-vivo time over 24 hours: clotting; bacterial/fungal contamination; and low cellular content (e.g. hypocellular BM, or if several syringes are filled during biopsy and the last syringe is used for banding analysis). Need for dividing cells; cell clones < 10% of abnormal cells can be overlooked; submicroscopic abnormalities cannot be detected. What are the limitations of this method? FISH = fluorescent in situ hybridization. 1 Braulke F, et al. Leuk Res. 2010;34: Questions and answers were prepared under the review of Dr. Haase, University of Göttingen, Germany. FAQs: Karyotyping

35 35 G-EXJ May 2012 Chromosome analysis in MDS: Fluorescence in situ hybridization (FISH) ● Fluorescently labeled DNA probes recognize complementary sequences on the chromosomes –probes that recognize centromeres detect changes in the number of chromosomes –probes that recognize specific genes can detect changes in the chromosome sequence Fluorescently labeled probes for bcr and abl genes show exchange of DNA between Chromosomes in chronic myelogenous leukemia Images from: Accessed Feb.2011.

36 36 G-EXJ May 2012 Preparation of the FISH sample Metaphase slides for karyotyping could also use bone marrow smears and paraffin-embedded bone marrow biopsies) Denature DNA (heat up the sample) Hybridize with denatured (pre-heated) labeled probes Wash to remove excess probe DAPI stain for DNA View with fluorescence microscope and take photographs Image from: Accessed Feb Protocol from: labs.mmg.pitt.edu/gjoerup/FISH%20protocol%20Vysis.doc. Accessed Feb Preparation of the FISH could be done by trained medical technician or clinical geneticist. The analysis of the samples is carried by clinical geneticists and/or hematologists.

37 37 G-EXJ May 2012 FISH: Selection of probes ● MDS FISH panel for initial diagnosis detects the most common aberrations, and typically includes probes for 5q, 7q, #8, 11q, 12p, 13q, 17p, and 20q Probes*ManufacturerWeb site Multiprobe MDS/AML panelCytocellwww.cytocell.com 5/5q, 7/7q, 8cen, 20q Genzyme Genetics 5p/q, 7q, 17p13, 20q13Kreatechwww.kreatech.com 5p/q, 7cen/q, 8cen, 17p13, 20q13, Ycen Abbott Molecular 5/5q, 7/7q, 20qMetasystems international.com Selection of the FISH probes is essential part of the analysis and is typically done by clinical geneticists in cooperation with hematologists *Examples are not representative of the complete spectrum of probes available from each provider. 1 Cherry AM, et al. Blood. 2010;116:[abstract 2922].

38 38 G-EXJ May 2012 How is a probe selected? Use the standard MDS FISH panel for initial diagnosis. When the aberration is known/suspected, use additional probes in the region. If disease morphology is suggestive of a certain genotype, one could directly use the respective probe – e.g. if RA with typical dysplasia of megakaryocytes occurs, then use probes for del(5q). Note, however, that one can miss other genetic changes with this approach. How many probes are typically used in a panel? A standard panel consists of 7–8 probes. 1 An extended panel can include up to 12 probes. FAQs: FISH 1 Cherry AM, et al. Blood. 2010;116:[abstract 2922]. Questions and answers were prepared under the review of Dr. Haase, University of Göttingen, Germany.

39 39 G-EXJ May 2012 The available survival data are based on karyotyping (banding) studies. However, in addition to karyotyping, one should use a standard FISH panel: 5p/q, 7cen/q, #8cen, 17p13, 20q13, and Ycen (in males). What probes should be used for survival prognosis? What are the limitations of FISH? One sees/finds what one is looking for; therefore, one could overlook complex or rare abnormalities (e.g. finding an isolated del(5q) by FISH might give a false good prognosis if it is a part of a complex genotype that has been misidentified). FAQs: FISH (cont.) Questions and answers were prepared under the review of Dr. Haase, University of Göttingen, Germany.

40 G-EXJ May 2012 Summary

41 41 G-EXJ May 2012 Summary ● WHO 2008 guidelines recommend complete cytogenetic analysis of BM at initial diagnosis of MDS ● Chromosomal aberrations, among other factors, have prognostic relevance on overall survival and time to leukaemic transformation –IPSS was first to define cytogenetic risk groups and to show an association with the survival prognosis of the patient –improved understanding of the cytogenetic risk factors provides a better prognosis scoring for the patients with MDS ● Approximately 50% of MDS patients have abnormal cytogenetics –in addition, it is supposed that many patients with “normal cytogenetics” actually have clonal abnormalities that remain undetected by metaphase cytogenetics

42 42 G-EXJ May 2012 Summary (cont.) ● Cytogenetic analysis is essential for making therapeutic decisions with regard to patients with MDS as it has shown associations with the response to hypomethylating and immunomodulating agents ● Sequential cytogenetic analysis is recommended to improve clinical management in MDS

43 G-EXJ May 2012 GLOSSARY OF TERMS

44 44 G-EXJ May 2012 GLOSSARY ● AML = acute myeloid leukemia ● APFR = Atrialp peak filling rate ● BA = basilar artery ● ß-TM = Beta Thalassemia Major ● ß-TI = Beta Thalassemia Intermedia ● BM = bone marrow ● BTM = bone marrow transplantation ● BW = bandwidth ● CFU = colony-forming unit ● CMML = chronic myelomonocytic leukemia ● CT2 = cardiac T2*. ● DAPI = 4',6-diamidino-2-phenylindole

45 45 G-EXJ May 2012 GLOSSARY ● DFS = = disease-free survival. ● DysE = dyserythropoiesis ● ECG = electrocardiography ● EDV = end-diastolic velocity ● EF = ejection fraction ● EPFR = early peak filling rate ● FatSat = fat saturation ● FAQ = frequently asked questions ● FDA = Food and Drug Administration ● FISH = fluorescence in situ hybridization. ● FOV = field of view ● GBP = Currency, pound sterling (£)

46 46 G-EXJ May 2012 GLOSSARY ● Hb = hemoglobin ● HbE = hemoglobin E ● HbF = fetal hemoglobin ● HbS = sickle cell hemoglobin. ● HbSS = sickle cell anemia. ● HIC = hepatic iron concentration ● HU = hydroxyurea ● ICA = internal carotid artery. ● ICT = iron chelation therapy ● IDL = interface description language ● IPSS = International Prognostic Scoring System ● iso = isochromosome

47 47 G-EXJ May 2012 GLOSSARY ● LIC = liver iron concentration ● LVEF = left-ventricular ejection fraction ● MCA = middle cerebral artery ● MDS = Myelodysplastic syndromes ● MDS-U = myelodysplastic syndrome, unclassified ● MRA = magnetic resonance angiography ● MRI = magnetic resonance imaging ● MV = mean velocity. ● N = neutropenia ● NEX = number of excitations ● NIH = National Institute of Health ● OS = overall survival

48 48 G-EXJ May 2012 GLOSSARY ● pB = peripheral blood ● PI = pulsatility index ● PSV = peak systolic Velocity ● RA =refractory anemia ● RAEB = refractory anemia with excess blasts ● RAEB -T = refractory anemia with excess blasts in transformation ● RARS = refractory anemia with ringed sideroblasts ● RBC = red blood cells ● RF = radio-frequency ● RCMD = refractory cytopenia with multilineage dysplasia ● RCMD-RS = refractory cytopenia with multilineage dysplasia with ringed sideroblasts ● RCUD = refractory cytopenia with unilineage dysplasia

49 49 G-EXJ May 2012 GLOSSARY ● RN = refractory neutropenia ● ROI = region of interest ● RT = refractory thrombocytopenia ● SCD = sickle cell disease ● SD = standard deviation ● SI = signal intensity ● SIR = signal intensity ratio ● SF = serum ferritin ● SNP-a = single-nucleotide polymorphism ● SQUID = superconducting quantum interface device. ● STOP = = Stroke Prevention Trial in Sickle Cell Anemia ● STOP II = Optimizing Primary Stroke Prevention in Sickle Cell Anemia

50 50 G-EXJ May 2012 GLOSSARY ● T = thrombocytopenia ● TAMMV = time-averaged mean of the maximum velocity. ● TCCS = transcranial colour-coded sonography ● TCD = transcranial doppler ultrasonography ● TCDI = duplex (imaging TCD) ● TE = echo time ● TR = repetition time ● WHO = World Health Organization ● WPSS = WHO classification-based Prognostic Scoring System


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