Transcript Myelodysplastic Syndromes

Myelodysplastic
Syndromes
Nicole N. Balmer M.D.
June 3rd, 2005
History of MDS
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First described in 1938 - 100 patients with
refractory anemia were described; Subsequently,
the terms "preleukemic anemia“ and
“preleukemia” were used.
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In 1963, a variant of acute leukemia was
described, characterized by a prolonged and
often benign clinical course, with a
comparatively lower but variable percentage of
bone marrow blasts; the authors termed this
condition "smoldering acute leukemia"
History of MDS
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In the 1970s, chronic myelomonocytic leukemia (CMML)
was recognized as a unique preleukemic syndrome.
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In 1976, the French-American-British (FAB) Cooperative
Group initially defined refractory anemia with excess
blasts (RAEB) and CMML as preleukemic states. Six years
later, the FAB group added three more categories to this
classification scheme and adopted the present term
"myelodysplastic syndromes".
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These disorders, and other members of the MDS "family“
were subsequently defined by the WHO.
The Myelodyplastic Syndromes
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Six types of myelodysplastic syndromes
according to WHO.
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Refractory anemia
Refractory anemia with ringed sideroblasts
Refractory cytopenia with multilineage dysplasia
Refractory anemia with excess blasts
Myelodysplastic syndrome, unclassifiable
5q- syndrome (myelodysplastic syndrome associated
with isolated del (5q) chromosome abnormality
Related syndromes:
– Myelodysplastic/Myeloproliferative diseases
Myelodysplastic Syndromes
MDS Definition:
 A group of disorders presenting with some
evidence of bone marrow failure and
dysplasia of one or more of the myeloid
lineages, with <20% blasts in the blood or
marrow.
 Epidemiology:
 Occur primarily in older patients (most
common > 70 years).
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MDS – Clinical Symptoms
Ecchymoses
 Fatigue
 Pallor
 Ecchymoses/petechiae
 Abnormal bleeding
 Infection
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MDS Etiology
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Two etiologic categories of MDS:
1.) De Novo:
Associated with:
-benzene exposure (gasoline)
-cigarettesmoking
-viruses
-Fanconi’s anemia
2.) Therapy related:
Associated with:
-alkylating agent chemotherapy
-radiation
Prognostic Groups
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Two groups based on survival and evolution to acute
leukemia
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1.) “Good” group
– Refractory anemia (RA)
– Refractory anemia with ringed sideroblasts (RARS)
– 5q - syndrome
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2.) “Bad” group
– Refractory anemia with excess blasts (RAEB)
– Refractory cytopenia with multilineage dysplasia (RCMD)
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MDS unclassified can be either
Median Survival – Myelodysplastic
Syndromes
120
# Months
100
80
60
40
20
0
RA
EB-2
RA RCMD
EB-1
RC
MDRS
RA
MDS Category
RARS
5q-
Prognostic Scoring
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The International Myelodysplastic Syndrome Working
Group developed a scoring system based on 3 variables:
% Blasts
0
0.5
<5
5-10
Karyotype Normal, -Y,
del(5q),
del(20q)
Cytopenia
0-1
Abnormalities
NOS
2-3
1.0
-≥3
abnormalities,
chr 7
abnormalities
1.5
2.0
11-20
20-30
International Prognostic Scoring
System Data (IPSS)
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Overall median survival was
5.7, 3.5, 1.2, and 0.4 years for
patients with IPSS scores of
zero (low risk), 0.5 to 1.0
(intermediate-1 risk), 1.5 to
2.0 (intermediate-2 risk), and
2.5 to 3.5 (high risk),
respectively.
The time for 25 percent of
the patients in each of the four
risk groups to evolve into
acute leukemia was 9.4, 3.3,
1.1, and 0.2 years,
respectively.
IPSS
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Other adverse prognostic factors which may improve the
prognostic value of the IPSS include:
-CD34 positivity of bone marrow nucleated cells
-Increased expression of the Wilms' tumor gene
(WT1)
-Increased serum beta-2 microglobulin concentration
-Mutations of the FLT3 gene
-Abnormal localization of immature precursors (ALIP).
Refractory Anemia
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RA Definition:
Dyplasia of the erythroid series only.
Clinically, anemia is refractory to hematinic
therapy
Myeloblasts < 1% blood and < 5% marrow
<15% ringed sideroblasts in marrow
No Auer rods
Other etiologies of erythroid abnormalities must
be excluded. These include:
– drug/toxin exposure
– viral infection
-vitamin deficiency
-congenital disease
Refractory Anemia
Epidemiology:
 5-10% of MDS cases.
 Older patients
 Morphology:
 Anisopoikilocytosis on peripheral smears
 Dyserythropoiesis with nuclear
abnormalities (megaloblastoid change)
 < 15% ringed sideroblasts
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Refractory Anemia
Genetics:
 25% may have genetic abnormalities
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Prognosis:
 Median survival is 66 months
 6% rate of progression to acute leukemia
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Peripheral Smear Anisopoikilocytosis
Dyserythropoeisis on Bone Marrow
Aspirate
Megaloblastoid Change on Bone
Marrow Aspirate
Refractory Anemia with Ringed
Sideroblasts
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RARS definition:
Dyplasia of the erythroid series only.
Clinically, anemia is refractory to hematinic
therapy
Myeloblasts < 5% in marrow, absent in blood
>15% ringed sideroblasts in marrow
No Auer rods
Other etiologies of ringed sideroblasts must be
excluded. These include:
– Anti- tuberculosis drugs
– Alcoholism
Refractory Anemia with Ringed
Sideroblasts
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Epidemiology:
10-12% of MDS cases.
Older patients
Males > females
Morphology:
Dimorphic pattern on peripheral smears
– Majority RBC’s normochromic, 2nd population
hypochromic
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Dyserythropoiesis with nuclear abnormalities
(megaloblastoid change)
Refractory Anemia with Ringed
Sideroblasts
Morphology (con’t.)
 < 15% ringed sideroblasts (RS)
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– RS = Erythroid precursor with ≥ 10 siderotic
granules encircling 1/3 or more of the
nucleus.
– If excess blasts present, this dictates
diagnosis, despite percentage of RS’s.
Refractory Anemia with Ringed
Sideroblasts
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Genetics:
Clonal chromosomal abnormalities in
<10%; in fact, development of such an
abnormality should prompt reassessment of
diagnosis.
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Prognosis:
Median survival 6 years (72 months)
1-2% rate of progression to acute leukemia
Dimorphic Red Cell Population
Ringed Sideroblasts
Ringed Sideroblasts
Megaloblastoid Change
Refractory Cytopenia with
Multilineage Dysplasia
RCMD definition:
 Dyplasia in 10% or more of cells in 2 or
more myeloid lines.
 Myeloblasts < 1% blasts in the blood and
< 5% in marrow.
 No Auer rods
9
 < 1 x 10 /L monocytes in blood
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Refractory Cytopenia with
Multilineage Dysplasia
Epidemiology:
 24% of MDS cases.
 Older patients
Morphology:
 Neutrophil abnormalities may include:
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– Hypogranulation
– Pseudo-Pelger-huet (hyposegmentation/barbells)
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Megkaryocyte abnormalities may include
– Hypolobation
-Micromegakaryocytes
Refractory Cytopenia with
Multilineage Dysplasia
Morphology (con’t.)
 Erythroid abnormalities may include
nuclear abnormalities such as:
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– megaloblastoid change
– multinucleation
– In addition:
-multilobation
 Erythroid presursors may be PAS positive
 If >15% of erythroid precursors are ringed
sideroblasts, call = RCMD-RS
Refractory Cytopenia with
Multilineage Dysplasia
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Genetics:
Clonal chromosomal abnormalities found in up to 50% of
RCMD and RCMD-RS cases. The abnormalities include:
– Trisomy 8
-del(7q)
– Monosomy 7
-Monosomy 5
– Complex karyotypes
-del(5q)
-del(20q)
Prognosis:
 Median survival 33 months
 11% rate of progression to acute leukemia
 RCMD and RCMD-RS = similar survival
 Complex karyotypes = worse survival (10-18 months)
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Pelgeroid (pseudo Pelger-Huet)
Neutrophil
Pelgeroid (pseudo Pelger-Huet)
Neutrophil
Dyserythropoiesis on Bone Marrow
Aspirate
Hypersegmented Neutrophil
Micromegakaryocyte
Refractory Anemia with Excess
Blasts
RAEB definition:
 Refractory anemia with 5-19%
myeloblasts in the bone marrow.
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– RAEB-1:
 5-9% blasts in bone marrow and <5% blasts in
blood.
– RAEB-2:
 10-19% blasts in the bone marrow
 Auer rods present
Refractory Anemia with Excess
Blasts
Epidemiology: 40% of MDS cases.
 Older patients (over 50 years)
Morphology:
 Dysplasia of all three cell lines often present
 Neutrophil abnormalities may include:
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– Hypogranulation
-hypersegmentation
– Pseudo-Pelger-huet (hyposegmentation/barbells)
– Pseudo Chediak-Higashi granules
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Megkaryocyte abnormalities may include
– Hypolobation
-Micromegakaryocytes
Refractory Anemia with Excess
Blasts
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Morphology (con’t.)
Erythroid precursor abnormalities may include:
– Abnormal lobulation -megaloblastoid change
– Multinucleation
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0-19% myeloblasts in the blood
5-19% in the marrow
Bone marrow:
– Usually hypercellular (10-15% hypocellular)
– Abnormal localization of immature precursors (ALIP) may be
present
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Immunophenotype:
– Blasts express CD 13, CD33 or CD117
– The only MDS with a relevant phenotype
Refractory Anemia with Excess
Blasts
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Genetics:
Clonal chromosomal abnormalities found in 30% - 50%
of RAEB cases. The abnormalities include:
– +8
– -7
– -5
– del(7q)
– del(5q)
– Complex karyotypes
Prognosis:
Median survival, RAEB-1 = 18 months
 Median survival, RAEB-2 = 10 months
 RAEB-1 = 25% rate of progression to acute leukemia
 RAEB-2 = 33% rate of progression to acute leukemia
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Hypercellular Bone Marrow
Blasts and Hypogranulation
Myeloblast with Auer Rod
Chediak-Higashi-like Granules
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Photograph courtesy of John Scariano, University of New Mexico, Dept. of Pathology
Myelodysplastic Syndrome,
Unclassifiable
MDS-U definition:
 Dysplasia of the neutrophil and/or
megkaryocytic lines and no increased
blasts
 Not otherwise classifiable as RA, RARS,
RCMD and RAEB
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Myelodysplastic Syndrome,
Unclassifiable
Epidemiology:
 Incidence unknown
 Older or younger persons
 Associated with a history of exposure to
cytotoxic or radiation therapy
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Morphology:
 BmBx usually hypercellular
 Dyplastic megakaryocytes may be prominent
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Myelodysplastic Syndrome,
Unclassifiable
Genetics:
 May be normal, or clonal abnormalities the
same as those found in other MDS syndromes.
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Prognosis:
 Unknown
 Occasionally defining characteristics develop.
Then case should be reclassified.
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Myelodysplastic Syndrome Associated With
Isolated del(5q) Chromosome Abnormality
( 5q- Syndrome)
 5q- syndrome definition:
 MDS with an isolated del(5q)
 <5% blasts in blood and bone marrow
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Epidemiology:
Middle age to older women
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Clinical Presentation:
Refractory anemia, often severe
Thrombocytosis may be present.
Myelodysplastic Syndrome Associated with
Isolated del(5q) Chromosome Abnormality
( 5q- Syndrome)
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Morphology:
– Peripheral Smear:
 Marked macrocytic anemia.
 Slight leukopenia
 Normal to elevated platelets
– BmBx:
 Erythroid dysplasia, varying degrees
 Small, hypolobated megakaryocytes
 Scattered aggregates of small lymphocytes
Myelodysplastic Syndrome Associated with
Isolated del(5q) Chromosome Abnormality
( 5q- Syndrome)
 Genetics:
 Deletion between bands q31 and q 33 on
chromosome 5.
 Size of deletion and breakpoints are variable.
 Any additional cytogenetic abnormality excludes
placement in this category.
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Prognosis:
Good = long survival
Those who develop more than 5% blasts may
have shorter survival
Hypolobated megakaryocytes
Myelodysplastic/myeloproliferative
diseases
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WHO category consists of 4 entities
– Chronic myelomonocytic leukemia (CMML)
 Formerly an MDS
– Atypical chronic myeloid leukemia (aCML)
 CML without BCR/ABL fusion gene
– Juvenile myelomonocytic leukemia (JMML)
– MDS/MPD-unclassified
CMML Diagnostic Criteria
MDS/MPD
High vs. low intensity treatment
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High intensity = treatment requiring
hospitalization, and included intensive
combination chemotherapy and hematopoietic
cell transplantation.
Low intensity = outpatient-type treatments,
such as use of hematopoietic growth factors,
differentiation-inducing agents, biologic
response modifiers, and low intensity
chemotherapy.
MDS Treatment
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Patients < 60 years of age, who have good or excellent performance
status and who are in the IPSS intermediate-2 or high risk categories
(expected survival 0.3 to 1.8 years) = high intensity therapies.
Patients < 60 years of age, who have good or excellent performance
status and who are in the low or intermediate-1 category (expected survival
5 to 12 years) = low intensity therapy or supportive care.
Patients >60 years of age with good performance status and who are in
the IPSS intermediate-2 or high risk categories (expected survival 0.5 to 1.1
years) = low intensity therapy, although selected patients could be
candidates for high intensity therapies.
Patients >60 years of age with good performance status and who are in
the low or intermediate-1 category (expected survival 3 to 5 years) =
supportive care or low intensity therapy
Stem Cell Transplant
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HEMATOPOIETIC CELL
TRANSPLANTATION Allogeneic HCT should be
considered for patients with MDS who are under
the age of 60 and who have an HLA-matched
sibling donor.
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60 and 40% chance of cure after allo-HCT in
low and intermediate risk patients respectively
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Transplant-related mortality and the relapse rate
at five years are as high as 40 percent.
Azacitidine
Azacitadine (Vidaza) the first approved
treatment of MDS
 Azacitidine is a member of a class of drugs in
development known as "hypomethylating" or
"demethylating" agents..
 About 15% of patients in the three trials had
complete or partial responses to Vidaza. (complete or
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partial normalization of blood in the bone marrow and normal levels of
blood cells and need for blood transfusions was eliminated)
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Side effects = nausea, anemia, low platelets in
blood, diarrhea, fatigue, irritation at the injection
site, and constipation.
Revlimid
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Thalidomide derivative (revlimid) — Revlimid is a
thalidomide derivative without the neurologic toxicity of
the parent compound. Used in MM and promising in
MDS.
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Restoration of a normal karyotype was noted in 11 of 17
informative patients.
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Erythroid response was highest in patients with Low/Int1 IPSS scores (71 percent) and in those with the 5qsyndrome (91 percent).
Dose-dependent myelosuppression was the most
common adverse event.
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The results of multicenter phase II trials of this agent
are awaited.
Decitabine
Decitabine — Another pyrimidine nucleoside
similar to 5-aza is 5-aza-2'-deoxycytidine (DAC,
decitabine). Both agents strongly inhibit DNA
methylation and are capable of inducing cell
differentiation [86-88].
 25-61% resopnse rate
 Major cytogenetic responses were noted in 31
percent of those with abnormal pretreatment
cytogenetics and were associated with a reduced
risk of death
 High toxicity = fever, infection, sepsis,
neutropenia, anemia, and thrombocytopenia
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Hypocellular MDS Treatment
Immunosuppressive drugs — Patients
with hypocellular MDS are believed to
have immune-mediated hematopoietic
suppression, perhaps due to the presence
of an abnormal T cell response
 Some of these patients have responded to
immunosuppressive therapies such as
antithymocyte globulin (ATG)
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Future Therapies
Valproic acid (VPA) has been shown to
inhibit histone deacetylase activity and to
synergize with all-trans retinoic acid
(ATRA) in the differentiation induction of
acute myelogenous leukemia (AML) blasts
in vitro.
 Recent studies have found that VPA is of
therapeutic benefit for patients with MDS,
and ATRA may be effective when added
later.
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References
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1.)Brunning, RD, Bennett, JM, Flandrin, G, et al.
Myelodysplastic syndromes: Introduction. In Jaffe, ES,
Harris, NL, Stein, H, Vardiman, JW, editors. World Health
Organization Classification of Tumours. Pathology and
Genetics of Tumours of Haematopoietic and Lymphoid
Tissues. IARC Press: Lyon 2001.
2.)Wells, DA, Benesch, M, Loken, MR, et al. Myeloid and
monocytic dyspoiesis as determined by flow cytometric
scoring in myelodysplastic syndrome correlates with the
IPSS and with outcome after hematopoietic stem cell
transplantation. Blood 2003; 102:394.
References
3.)Seo, IS, Li, CY, Yam, LT. Myelodysplastic syndrome:
Diagnostic implications of cytochemical and
immunocytochemical studies. Mayo Clin Proc 1993;
68:47.
 4.)So, CC, Wong, KF. Valproate-associated
dysmyelopoiesis in elderly patients. Am J Clin Pathol
2002; 118:225.
 5.)Ooi, J, Iseki, T, Takahashi, S, et al. Unrelated cord
blood transplantation for adult patients with advanced
myelodysplastic syndrome. Blood 2003; 101:4711.
 6.) Albitar, M, Manshouri, T, Shen, Y, et al.
Myelodysplastic syndrome is not merely "preleukemia".
Blood 2002; 100:791.
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References
7.)Passmore, SJ, Chessells, JM, Kempski, H, et al.
Paediatric myelodysplastic syndromes and juvenile
myelomonocytic leukaemia in the UK: a populationbased study of incidence and survival. Br J Haematol
2003; 121:758
 8.)Cheson, BD, Zwiebel, JA, Dancey, J, Murgo, A. Novel
therapeutic agents for the treatment of myelodysplastic
syndromes. Semin Oncol 2000; 27:560.
 9.)Estey E, Schrier S. Treatment and prognosis of mds
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www.uptodate.com, 2005.
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10.)Coll DC, Landaw, SA Clnical manifestations and
diagnosis of the myelodysplastic syndromes. Blood.
2004, 1;104(5):1266-9.
Acknowledgments
Dr. John Ryder
 Dr. Bryan Abbott
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