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CYTOGENERIC ASSESSMENT IN MDS
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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.
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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) 3
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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)
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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 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:
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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:
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MDS classification and prognostic scoring
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Diagnostic and prognostic of MDS
Classification system Basis of evaluation Derived prognostic score system FAB (1982) Cellular morphology IPSS (1997) WHO (2002) Cellular morphology, cytogenetics WPSS (2007) Risk-stratification is necessary for clinical decision-making: predicts treatment outcomes predicts survival predicts risk of progression to AML 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. 8
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French-American-British (FAB) classification
Blast percentage MDS Subtype Peripheral blasts (%) Bone marrow blasts (%) Additional features AML transformation (%) RA Refractory anaemia ≤1 <5 10–20 RARS Refractory anaemia with ringed sideroblasts >15% ringed sideroblasts in bone marrow 10–35 RAEB Refractory anaemia with excess blasts 5–20 >50 RAEB-T Refractory anaemia with excess blasts in transformation ≥5 21–29 optional Auer-rods 60–100 CMML Chronic myelomonocytic leukaemia ≤20 Peripheral monocytosis (>103/µl) >40 Bennett JM, et al. Br J Haematol 1982;51:189–199. 9
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Survival by cytogenetic presentation in MDS patients
100 90 80 70 60 50 40 30 20 10 Patients n (%) −Y 17 (2) del(5q) 48 (6) Normal 489 (69) del(20q) 16 Misc. single 74 (9) +8 38 (5) Double 29 (3) Misc. double 14 Chrom 7 abn. 10 (1) Misc. complex 15 Complex 66 (8) Time (years) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Greenberg P, et al. Blood. 1998;89:
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Risk stratification and prognosis scoring for MDS: IPSS
IPSS score Variable 0.5 1.0 1.5 2.0 BM blasts (%) < 5 5–10 – 11–20 21–30 Karyotype Good Int. Poor Cytopenia(s) 0/1 2/3 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 Greenberg P, et al. Blood. 1998;89: 11
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Cumulative survival of MDS patients by IPSS
AML Evolution 10 20 30 40 50 60 70 80 90 100 10 20 30 40 50 60 70 80 90 100 Low Int-1 Int-2 High Low Int-1 Int-2 High Percent Percent 2 4 6 8 10 12 14 16 18 2 4 6 8 10 12 14 16 18 Years Years Greenberg P, et al. Blood 1997;89:2079–2088.
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MDS: WHO classification 2008
Blast percentage MDS Subtype Dysplasia Peripheral blasts (%) Bone marrow blasts (%) Ringed sideroblasts (%) Cytogenetics 5q− syndrome Mostly DysE < 1% < 5% < 15% 5q− sole RA, RN, RT, RCUD DysE, N, T Various RARS > 15% RCMD 2–3 lineages rare RAEB-1 1–3 lineages 5–9% RAEB-2 5–19% Auer rods +/- 10–19% MDS-U 1 lineage 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:
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Survival of MDS patients according to transfusion dependency
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Transfusion-independent patients Proportion surviving Transfusion-dependent patients 20 40 60 80 100 120 140 Time (months) Cazzola M, Malcovati L. N Engl J Med. 2005;352:536-8. 14
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The WHO classification-based prognostic scoring system (WPSS) for MDS
Points 1 2 3 WHO subtype RA, RARS, del(5q) RCMD, RCMD-RS RAEB-1 RAEB-2 Transfusion requirement None Regular – Cytogenetic category Good Int. Poor Risk groups Score Median survival (months) Very low 103 Low 1 72 Intermediate 2 40 High 3–4 21 Very high 5–6 12 Transfusion dependence is an independent indicator of severity of disease and has a significant effect on survival Malcovati L, et al. J Clin Oncol. 2007;25: 15
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Overall survival and AML risk assessments in MDS by WPSS
A. Overall survival at diagnosis (n=426) B. Risk of AML at diagnosis (n=426) C. Time-dependent overall survival (n=271) D. Time-dependent risk of AML (n=271) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Cumulative probability of survival Cumulative risk Time (months) Risk group Very Low Low Intermediate High Very High Malcovati L et al. J Clin Oncol 2007;25:3503–3510. 16
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WHO prognosis scoring system allows time dependent prognosis scoring
IPSS WPSS Pros More widely used and recognized Allows time-dependent prognosis scoring and risk stratification Takes into account individual patient transfusion need Cons Applies 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:
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Practical guide to bone marrow aspirate analysis in MDS
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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.
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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.
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Analysis of bone marrow smears (cont.)
Refractory anaemia with excess blasts (RAEB) Refractory anaemia (RA) Abnormal large megakaryocyte (double arrow), abnormal hypo-granular and Pelger neutrophils (single arrows). 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.
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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:
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Cytogenetics of MDS in bone marrow aspirates
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Importance of cytogenetic analysis in MDS
Nearly half of the patients with MDS present with cytogenetic abnormalities1 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 WPSS2 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. 1Haase 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: 24 24
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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:
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WHO 2008: Incidence of the most common cytogenetic aberrations in MDS (over 5%)
Unbalanced aberrations De novo MDS (%) Secondary MDS (%) +8 10 −7/del(7q) 50 −5/del(5q) 40 del(20q) 5–8 −Y 5 iso(17q)/t(17p)/del(17p) 3–5 Unbalanced aberrations with loss of genetic information (deletions or monosomies) are most common in MDS; balanced aberrations are rare Swerdlow SH, et al. In: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon: IARC; 2008:441.
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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:
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FAQs: Cytogenetic testing for diagnosis of patients with MDS
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). Questions and answers were prepared under the review of Dr. Haase, University of Göttingen, Germany.
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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.
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FAQs: Cytogenetic testing during treatment in patients with MDS (cont
How often should cytogenetic testing be performed? 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. 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. 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. Questions and answers were prepared under the review of Dr. Haase, University of Göttingen, Germany.
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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
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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 Metaphase quality To detect structural abnormalities, adequate chromosome banding is required (≥ 150–250 bands per karyogram) Number of metaphases needed Analyse 25 metaphases if possible, especially if the karyotype is normal, to exclude a small aberrant cell clone Source of the BM aspirate photo: Source of cytogenetics lab photo: Source of metaphase quality photo: Dr D. Haase slides Source of metaphase photo: 6 7 8 9 10 See presenter for references.
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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; 2003. Lucia Cytogenetics. Accessed Feb.2011.
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FAQs: Karyotyping 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). What are the limitations of this method? Need for dividing cells; cell clones < 10% of abnormal cells can be overlooked; submicroscopic abnormalities cannot be detected. FISH = fluorescent in situ hybridization. 1Braulke F, et al. Leuk Res. 2010;34: Questions and answers were prepared under the review of Dr. Haase, University of Göttingen, Germany.
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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.
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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 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. Image from: Accessed Feb. 2011 Protocol from: labs.mmg.pitt.edu/gjoerup/FISH%20protocol%20Vysis.doc. Accessed Feb
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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* Manufacturer Web site Multiprobe MDS/AML panel Cytocell 5/5q, 7/7q, 8cen, 20q Genzyme Genetics 5p/q, 7q, 17p13, 20q13 Kreatech 5p/q, 7cen/q, 8cen, 17p13, 20q13, Ycen Abbott Molecular 5/5q, 7/7q, 20q Metasystems 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. 1Cherry AM, et al. Blood. 2010;116:[abstract 2922].
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FAQs: FISH 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. 1Cherry AM, et al. Blood. 2010;116:[abstract 2922]. Questions and answers were prepared under the review of Dr. Haase, University of Göttingen, Germany.
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FAQs: FISH (cont.) What probes should be used for survival prognosis?
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 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). Questions and answers were prepared under the review of Dr. Haase, University of Göttingen, Germany.
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Summary
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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
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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
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GLOSSARY OF TERMS
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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 References Kassab MY et al. J Am Board Fam Med 2007;20:65–71. Krejza J et al. AJR Am J Roentgenol 2000;174:1297–1303.
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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 (£)
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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
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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
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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
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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
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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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