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1.  Plasma protein alterations in the refractory anemia with excess blasts subtype 1 subgroup of myelodysplastic syndrome 
Proteome Science  2012;10:31.
Background
Refractory anemia with excess blasts subtype 1 (RAEB-1) is a subgroup of myelodysplastic syndrome. It represents a heterogeneous group of oncohematological bone marrow diseases, which occur particularly in elderly patients. The aim of this proteomic study was to search for plasma protein alterations in RAEB-1 patients.
Results
A total of 24 plasma samples were depleted of fourteen high-abundant plasma proteins, analyzed with 2D SDS-PAGE, compared, and statistically processed with Progenesis SameSpots software. Proteins were identified by nanoLC-MS/MS. Retinol-binding protein 4 and leucine-rich alpha-2-glycoprotein were relatively quantified using mass spectrometry. 56 significantly differing spots were found; and in 52 spots 50 different proteins were successfully identified. Several plasma proteins that changed either in their level or modification have been described herein. The plasma level of retinol-binding protein 4 was decreased, while leucine-rich alpha-2-glycoprotein was modified in RAEB-1 patients. Changes in the inter-alpha-trypsin inhibitor heavy chain H4, altered protein fragmentation, or fragments modifications were observed.
Conclusions
This study describes proteins, which change quantitatively or qualitatively in the plasma of RAEB-1 patients. It is the first report on qualitative changes in the leucine-rich alpha-2-glycoprotein in the RAEB-1 subgroup of myelodysplastic syndrome. Described changes in the composition or modification of inter-alpha-trypsin inhibitor heavy chain H4 fragments in RAEB-1 are in agreement with those changes observed in previous study of refractory cytopenia with multilineage dysplasia, and thus H4 fragments could be a marker specific for myelodysplastic syndrome.
doi:10.1186/1477-5956-10-31
PMCID: PMC3470985  PMID: 22568928
Myelodysplastic syndrome; RAEB-1; Plasma proteome; Refractory anemia
2.  UNRELATED DONOR BONE MARROW TRANSPLANTATION FOR MYELODYSPLASTIC SYNDROME IN CHILDREN 
We describe long-term disease-free survival after unrelated donor bone marrow transplantation (BMT) for myelodysplastic syndrome (MDS) in 118 patients aged ≤18 years. Forty-six patients had refractory cytopenia (RC), 55, refractory anemia with excess blasts (RAEB) and 17, refractory anemia with excess blasts in transformation (RAEB-t). Transplant-related mortality was higher after mismatched BMT (relative risk [RR] 3.29, p=0.002). Disease recurrence was more likely with advanced stages of MDS at the time of BMT: RAEB (RR 6.50, p=0.01) or RAEB-t (RR 11.00, p=0.004). Treatment failure (recurrent disease or death from any cause; inverse of disease-free survival [DFS]) occurred in 68 patients. Treatment failure was higher after mismatched BMT (RR 2.79, p=0.001) and in those with RAEB-t (RR 2.38, p=0.02). Secondary MDS or chemotherapy prior to BMT was not associated with recurrence or treatment failure. Similarly, cytogenetic abnormalities were not associated with transplant outcomes. Eight-year DFS for patients with RC after matched and mismatched unrelated donor BMT was 65% and 40%, respectively. Corresponding DFS for patients with RAEB and RAEB-t was 48% and 28%, respectively. When a matched adult unrelated donor is available, BMT should be offered as first-line therapy and children with RC can be expected to have the best outcome.
doi:10.1016/j.bbmt.2010.08.016
PMCID: PMC3033968  PMID: 20813197
pediatric myelodysplastic syndrome; unrelated donor; bone marrow transplantation
3.  Alteration in Endoglin-Related Angiogenesis in Refractory Cytopenia with Multilineage Dysplasia 
PLoS ONE  2013;8(1):e53624.
The functional mechanisms involved in angiogenesis and the potential role of endoglin (ENG), recently described as a new marker for this process, have not been explored in Myelodysplastic Syndromes (MDS). In order to gain insight in MDS angiogenesis a combined analysis in bone marrow (BM) of gene expression levels, angiogenesis-related soluble factors and functional angiogenesis-related studies was carried out. Ninety-seven MDS patients and forty-two normal BM samples were studied. The morphology of the capillary-like structures originated by two endothelial cells lines in the BM environment of patients with refractory cytopenia with multilineage dysplasia (RCMD) was different from those of the remaining MDS. In addition, the BM mononuclear cells from RCMD patients displayed over-expression of VEGF, HIF and FN1 while they showed reduced expression of ENG in contrast to the normal ENG expression of the remaining low-risk MDS and the high expression of ENG in high-risk MDS subtype. Moreover, higher soluble ENG and soluble FLT-1 levels in BM microenvironment were observed in RCMD cases, which distinguished them from other individuals. Therefore, the present study suggests that the patterns of angiogenesis are different between the MDS subtypes. The differences in angiogenesis observed in RCMD patients could be related to ENG abnormalities.
doi:10.1371/journal.pone.0053624
PMCID: PMC3547003  PMID: 23341958
4.  Clinical and genetic characteristics of congenital sideroblastic anemia: comparison with myelodysplastic syndrome with ring sideroblast (MDS-RS) 
Annals of Hematology  2012;92(1):1-9.
Sideroblastic anemia is characterized by anemia with the emergence of ring sideroblasts in the bone marrow. There are two forms of sideroblastic anemia, i.e., congenital sideroblastic anemia (CSA) and acquired sideroblastic anemia. In order to clarify the pathophysiology of sideroblastic anemia, a nationwide survey consisting of clinical and molecular genetic analysis was performed in Japan. As of January 31, 2012, data of 137 cases of sideroblastic anemia, including 72 cases of myelodysplastic syndrome (MDS)–refractory cytopenia with multilineage dysplasia (RCMD), 47 cases of MDS–refractory anemia with ring sideroblasts (RARS), and 18 cases of CSA, have been collected. Hemoglobin and MCV level in CSA are significantly lower than those of MDS, whereas serum iron level in CSA is significantly higher than those of MDS. Of 14 CSA for which DNA was available for genetic analysis, 10 cases were diagnosed as X-linked sideroblastic anemia due to ALAS2 gene mutation. The mutation of SF3B1 gene, which was frequently mutated in MDS-RS, was not detected in CSA patients. Together with the difference of clinical data, it is suggested that genetic background, which is responsible for the development of CSA, is different from that of MDS-RS.
Electronic supplementary material
The online version of this article (doi:10.1007/s00277-012-1564-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s00277-012-1564-5
PMCID: PMC3536986  PMID: 22983749
Congenital sideroblastic anemia; Myelodysplastic syndrome; ALAS2
5.  The Role of the Iron Transporter ABCB7 in Refractory Anemia with Ring Sideroblasts 
PLoS ONE  2008;3(4):e1970.
Refractory Anemia with Ring Sideroblasts (RARS) is an acquired myelodysplastic syndrome (MDS) characterized by an excess iron accumulation in the mitochondria of erythroblasts. The pathogenesis of RARS and the cause of this unusual pattern of iron deposition remain unknown. We considered that the inherited X-linked sideroblastic anemia with ataxia (XLSA/A) might be informative for the acquired disorder, RARS. XLSA/A is caused by partial inactivating mutations of the ABCB7 ATP-binding cassette transporter gene, which functions to enable transport of iron from the mitochondria to the cytoplasm. Furthermore, ABCB7 gene silencing in HeLa cells causes an accumulation of iron in the mitochondria. We have studied the role of ABCB7 in RARS by DNA sequencing, methylation studies, and gene expression studies in primary CD34+ cells and in cultured erythroblasts. The DNA sequence of the ABCB7 gene is normal in patients with RARS. We have investigated ABCB7 gene expression levels in the CD34+ cells of 122 MDS cases, comprising 35 patients with refractory anemia (RA), 33 patients with RARS and 54 patients with RA with excess blasts (RAEB), and in the CD34+ cells of 16 healthy controls. We found that the expression levels of ABCB7 are significantly lower in the RARS group. RARS is thus characterized by lower levels of ABCB7 gene expression in comparison to other MDS subtypes. Moreover, we find a strong relationship between increasing percentage of bone marrow ring sideroblasts and decreasing ABCB7 gene expression levels. Erythroblast cell cultures confirm the low levels of ABCB7 gene expression levels in RARS. These data provide an important link between inherited and acquired forms of sideroblastic anemia and indicate that ABCB7 is a strong candidate gene for RARS.
doi:10.1371/journal.pone.0001970
PMCID: PMC2276313  PMID: 18398482
6.  Plasma proteome changes associated with refractory anemia and refractory anemia with ringed sideroblasts in patients with myelodysplastic syndrome 
Proteome Science  2013;11:14.
Background
Refractory anemia and refractory anemia with ringed sideroblasts are two myelodysplastic syndrome (MDS) subgroups linked with anemia. MDS is a group of heterogeneous oncohematological bone marrow disorders characterized by ineffective hematopoiesis, blood cytopenias, and progression of the disease toward acute myeloid leukemia. The aim of this study was to search for plasma proteome changes in MDS patients with refractory anemia and refractory anemia with ringed sideroblasts.
Results
A total of 26 patient and healthy donor plasma samples were depleted of fourteen high-abundant plasma proteins, separated with 2D electrophoresis, and statistically processed with Progenesis SameSpots software. 55 significantly differing spots were observed and corresponded to 39 different proteins identified by nanoLC-MS/MS. Changes in the fragments of the inter-alpha-trypsin inhibitor heavy chain H4 protein were observed. Using mass spectrometry-based relative label-free quantification of tryptic peptides, there were differences in alpha-2-HS-glycoprotein peptides, while no differences were observed between the control and patient sample groups for retinol-binding protein 4 peptides.
Conclusions
This study describes plasma proteome changes associated with MDS patients with refractory anemia and refractory anemia with ringed sideroblasts. Changes observed in the inter-alpha-trypsin inhibitor heavy chain H4 fragments were in agreement with our previous studies of other MDS subgroups: refractory cytopenia with multilineage dysplasia and refractory anemia with excess blasts subtype 1. Mass spectrometry-based relative quantification of retinol-binding protein 4 peptides has shown that there are differences in the modification of this protein between refractory anemia with excess blasts subtype 1 patients and MDS patients with refractory anemia and refractory anemia with ringed sideroblasts. Alpha-2-HS-glycoprotein seems to be a new potential MDS biomarker candidate.
doi:10.1186/1477-5956-11-14
PMCID: PMC3635902  PMID: 23566303
Myelodysplastic syndrome; Refractory anemia; Refractory anemia with ringed sideroblasts; Proteome changes; Alpha-2-HS-glycoprotein
7.  Management and supportive care measures for adverse events in patients with myelodysplastic syndromes treated with azacitidine* 
European journal of haematology  2010;85(2):130-138.
Objective
Myelodysplastic syndrome (MDS) treatment can initially worsen patients’ clinical condition and they may discontinue therapy before achieving benefit. We present previously unpublished data from two large phase III trials describing common adverse events (AEs) associated with azacitidine and methods to manage them.
Methods
In the Cancer and Leukemia Group B (CALGB) 9221 study, patients with any French-American-British (FAB) subtype of MDS were randomized to azacitidine or best supportive care (BSC). After 56 d, patients randomized to BSC with disease progression could cross over to receive azacitidine. In the AZA-001 study, patients with higher-risk MDS (FAB-defined refractory anemia with excess blasts (RAEB), RAEB in transformation, or chronic myelomonocitic leukaemia and IPSS int-2 or high) were randomized to azacitidine or to conventional care regimens (CCR), which included low-dose ara-C, BSC, or intensive chemotherapy. In both studies, azacitidine dose was 75 mg/m2/d SC for 7 d every 28 d. AEs were graded per National Cancer Institute’s Common Toxicity Criteria version 2.0 (AZA-001) or CALGB Expanded CTC (CALGB 9221).
Results
In safety-evaluable patients in AZA-001 (N = 175) or CALGB 9221 (N = 150), the most common AEs with azacitidine included hematologic (eg, cytopenias) and non-hematologic administration-related events (eg, injection-site reactions and gastrointestinal disorders). Most AEs were transient and resolved during ongoing therapy (> 83%). Hematologic AEs, most frequently observed during early treatment cycles, decreased during subsequent cycles and were usually managed with dosing delays (23–29%). Gastrointestinal symptoms were primarily managed with anti-emetics and laxatives.
Conclusion
Hematologic and non-hematologic AEs with azacitidine decreased in frequency as treatment continued. Awareness of the onset, duration and management of AEs can facilitate treatment, permitting patients to continue therapy for maximum benefit.
doi:10.1111/j.1600-0609.2010.01456.x
PMCID: PMC4000014  PMID: 20394651
azacitidine; safety; disease management; myelodysplastic syndromes; adverse drug event
8.  Interphase ribosomal RNA cistron silver staining in refractory anaemias with and without excess blasts. 
Molecular Pathology  1997;50(2):92-95.
AIM: To evaluate the haemopoietic function of bone marrow blood forming cells in human myelodysplastic syndromes (MDS) by silver staining of nucleolar organiser regions (AgNORs). METHODS: Nucleoli were investigated in bone marrow blast cells and in erythroid, granulocytic, and megakaryocytic cells from 12 haematologically healthy subjects, and from 26 patients with MDS, including 14 with refractory anaemia (RA), nine with RA with excess blasts (RAEB), and three with RAEB in transformation (RAEB-t). The investigation was performed before treatment using a one step silver staining method. In each case 50 to 100 blasts, promyelocytes, myelocytes, immature (pronormoblastic and basophilic normoblastic) and mature (polychromatic normoblastic) erythroid elements, and megakaryocytes were evaluated for the mean numbers of nucleoli and AgNORs per nucleus. Student's t test was used to compare the patient and control groups. Other statistical analyses were carried out by the computer assisted "HEMA" system. RESULTS: Compared with controls, the number of AgNORs in blasts, promyelocytes, immature erythroid elements, and megakaryocytes was decreased, whereas in myelocytes and polychromatic normoblasts it was similar. There was also a difference in the AgNOR scores in blood forming cells from patients with RAEB/ RAEB-t v RA. CONCLUSIONS: The loss of AgNOR sites in cellular series in MDS may result from the decrease of their proliferative potential with disease progression, intrinsic defects in maturation, and extensive apoptosis.
PMCID: PMC379590  PMID: 9231157
9.  Haematological features of primary myelodysplastic syndromes (PMDS) at initial presentation: a study of 118 cases. 
Journal of Clinical Pathology  1983;36(10):1129-1135.
The haematological features of 118 cases of primary myelodysplastic syndromes (PMDS) were reviewed to see how these could be related and classified according to the recent FAB proposals. A majority of the cases were elderly who presented with a macrocytic or normocytic anaemia and reticulocytopenia. Cases of acquired idiopathic sideroblastic anaemia (AISA) usually had normal leucocyte and platelet counts, erythroid hyperplasia, marked dyserythropoiesis and more than 20% ringed sideroblasts. Cases of refractory anaemia with excess of blasts (RAEB) had frequent neutropenia and thrombopenia usually with prominent dysgranulopoiesis and dysthrombopoiesis. Refractory anaemia or refractory cytopenia appeared morphologically to be a heterogeneous group. Leukaemic transformation did not occur in any of these 16 cases of AISA whereas six of the 34 cases of RAEB transformed into acute leukaemia. It appears that the cases of PMDS present with well defined haematological features which permit recognition of different groups; these latter groups appear to be morphologically and prognostically distinct.
PMCID: PMC498488  PMID: 6619310
10.  Prolonged survival with improved tolerability in higher-risk myelodysplastic syndromes: azacitidine compared with low dose ara-C 
British journal of haematology  2010;149(2):244-249.
Summary
In the phase III AZA-001 trial, low-dose cytarabine (LDara-C), the most widely used low-dose chemotherapy in patients with higher-risk myelodysplastic syndrome (MDS) who are ineligible for intensive treatment, was found to be associated with poorer survival compared with azacitidine. This analysis further compared the efficacy and the toxicity of these two drug regimens. Before randomization, investigators preselected patients to receive a conventional care regimen, one of which was LDara-C. Of 94 patients preselected to LDara-C, 45 were randomized to azacitidine and 49 to LDara-C. Azacitidine patients had significantly more and longer haematologicalal responses and increased red blood cell transfusion independence. Azacitidine prolonged overall survival versus LDara-C in patients with poor cytogenetic risk, presence of −7/del(7q), and French-American-British subtypes refractory anaemia with excess blasts (RAEB) and RAEB in transformation. When analyzed per patient year of drug exposure, azacitidine treatment was associated with fewer grade 3–4 cytopenias and shorter hospitalisation time than LDara-C in these higher-risk MDS patients.
doi:10.1111/j.1365-2141.2010.08082.x
PMCID: PMC4000023  PMID: 20136825
azacitidine; higher-risk myelodysplastic syndromes; low-dose cytarabine (ara-C); myelodysplastic syndromes; survival
11.  A Meta-Analysis of the Relationship between Cigarette Smoking and Incidence of Myelodysplastic Syndromes 
PLoS ONE  2013;8(6):e67537.
Background
In recent years, epidemiologic studies have reported controversial results relating cigarette smoking to myelodysplastic syndromes (MDS) risk. A meta-analysis was performed to assess such potential relationship between cigarette smoking and incidence of MDS.
Methods
A search of literature published before October 2012 for observational studies evaluating the association between cigarette smoking and MDS, returned 123 articles and of these, 14 were selected for this study. The outcomes from these studies were calculated and reported as odds ratios (OR). Quality assessments were performed with the Newcastle-Ottawa Scale. Heterogeneity was evaluated by the I2 index and source of heterogeneity was detected by sensitivity analyses. Finally, publication bias was assessed through visual inspection of funnel plots and Egger’s test.
Results
The pooled OR of developing MDS in ever-smokers was 1.45 (95% CI, 1.25 to 1.68) versus non-smokers. Current and former smokers had increased risks of MDS, with ORs of 1.81 (95% CI, 1.24 to 2.66) and 1.67 (95% CI, 1.42 to 1.96), respectively. In subset analyses, ever-smokers had increased risks of developing MDS if they were living in the United States, or in Europe, female in gender, had refractory anemia (RA)/RA with ringed sideroblasts (RARS) or RA with excess blasts (RAEB)/RAEB in transformation (RAEBt), respectively. Our results demonstrated that the association was stronger in individuals who smoked ≥20 cigarettes/day (OR, 1.62; 95% CI, 1.03 to 2.55) versus those who smoked <20 cigarettes/day (OR, 1.36; 95% CI, 1.13 to 1.64). Moreover, individuals who smoked more than 20 pack-years had increased MDS risk (OR, 1.94; 95% CI, 1.29 to 2.92).
Conclusion
Our outcomes show that smoking increases the risk of developing MDS in ever-smokers who are current or former smokers. We also demonstrate here that positive association between cigarette smoking and risk of MDS exists, and occurs in a dose-dependent manner.
doi:10.1371/journal.pone.0067537
PMCID: PMC3689714  PMID: 23805315
12.  Refractory myelodysplastic anaemias with hypocellular bone marrow. 
Journal of Clinical Pathology  1988;41(7):763-767.
Thirty three patients with refractory myelodysplastic anaemias (RMDA) with marrow hypocellularity were reviewed to see whether they differed from those with normocellular or hypercellular marrows. The median age was 65 years with a male:female ratio of 26:7. There were 11 cases of refractory anaemia (RA), four of refractory anaemia with ringed sideroblasts (RARS), and 18 of refractory anaemia with excess of blasts (RAEB). All presented with peripheral cytopenias, mostly pancytopenia or bicytopenia dysplasia in one or more cell lineages, and a marrow biopsy specimen with less than normal numbers of nucleated cells for the age. Twenty four patients died, including 14 of the 16 who developed acute non-lymphocytic leukaemia (ANLL). The results suggest that patients with hypocellular RMDA have a similar prognosis to those with normocellular or hypercellular marrows at presentation.
PMCID: PMC1141585  PMID: 3410972
13.  Ras-proximate-1 GTPase-activating protein and Rac2 may play pivotal roles in the initial development of myelodysplastic syndrome 
Oncology Letters  2012;4(2):289-298.
Myelodysplastic syndrome (MDS) is a stem cell disease that has a characteristic morphological dysplasia. Adhesion molecules and the Wnt signaling pathway are mostly involved with the self-renewal, proliferation and differentiation of hematopoietic stem cells (HSCs) while Rho GTPases are closely correlated with the cytoskeleton and therefore cell morphology. To gain insight into the poorly understood pathophysiology of MDS, the present study focused on analyzing the gene expression profiles of these molecules with whole genomic array using CD34+ cells from MDS patients. These profiles showed that N-cadherin, E-cadherin and c-myc binding protein tended to be downregulated, whereas β-catenin, Ras-proximate-1 GTPase-activating protein (Rap1GAP), c-myc promoter binding protein, Rac1, Rac2 and CDC42 tended to be upregulated. However, no change in the expression of genes involved in the canonical Wnt signaling pathway, with the exception of β-catenin, was observed. The array results were confirmed by real-time quantitative polymerase chain reaction (RQ-PCR) using CD34+ cells from a cohort of patients with MDS-refractory anemia (RA) [WHO (2008) RCUD, RCMD and MDS-U] who had normal karyotypes. Only Rap1GAP and Rac2 showed higher expression levels when mononuclear cells were used from another group of patients with MDS-RA [WHO (2008) RCUD, RCMD and MDS-U] who also had normal karyotypes. We believe that the cadherin-β-catenin-c-myc signaling axis is crucial in the hematopoiesis of HSCs in the early stages of MDS. In addition, Ras-proximate-1 (Rap1), which is negatively regulated by Rap1GAP, may serve as an initiator of this axis through interplay with cadherin. This pathway is strengthened by the upregulation of Rac2, which may allow the nuclear translocation of β-catenin. The aberrant expression of Rho GTPases may also be responsible for the dysplasia characteristics observed in MDS. This study provides vital and new insights into the pathophysiology of MDS. The two small G proteins, Rap1GAP and Rac2, may act as new molecular markers for the diagnosis of MDS.
doi:10.3892/ol.2012.736
PMCID: PMC3402722  PMID: 22844372
myelodysplastic syndrome; Ras-proximate-1 GTPase-activating protein; Rac2; cadherin; catenin
14.  The Hematologic Response to Anti-apoptotic Cytokine Therapy: Results of Pentoxifylline, Ciprofloxacin, and Dexamethasone Treatment for Patients with Myelodysplastic Syndrome 
TNF-α mediated apoptosis of the hematopoietic cells has been thought to contribute to the ineffective hematopoiesis observed in myelodysplastic syndrome (MDS). The combination of pentoxifylline (P) and ciprofloxacin (C) has been shown to reduce the serum levels of TNF-α, and an earlier trial of P and C with dexamethasone (D) provided good palliation for patients with MDS. The purpose of this study is to assess the hematologic response to PCD therapy for patients suffering with MDS. 21 of 25 patients who completed at least of 12 weeks of treatment were evaluable for the treatment efficacy. At baseline, the patient's median age was 60 yr (range: 18-75 yr). The diagnoses according to WHO classification included: RA (n=5), RCMD (n=10), RARS (n=1), RCMD/RS (n=1), RAEB (3), and CMML (n=1). 11 patients (52%) had at least single lineage response. 3 patients (11%) showed improvement of triple lineage cytopenia. There were no differences in the response rates between the FAB subtypes. The median time to response was 4 weeks (range: 2-12 weeks), and it is interesting that 9 of 11 patients who had a response remained without relapse for a median of 177 days (range: 78-634 days). These preliminary results indicate that anti-cytokine therapy with PCD is an effective and well tolerated palliative treatment for patients with MDS.
doi:10.3346/jkms.2006.21.1.40
PMCID: PMC2733976  PMID: 16479063
Myelodysplastic Syndromes; Tumor Necrosis Factor-alpha; Apoptosis
15.  Myelodysplastic syndromes/neoplasms: recent classification system based on World Health Organization Classification of Tumors – International Agency for Research on Cancer for Hematopoietic and Lymphoid Tissues 
Journal of blood medicine  2010;1:171-182.
The myelodysplastic Syndromes (MDS) are a group of clonal hematopoietic stem cell diseases characterized by cytopenia(s), dysplasia in one or more of the major myeloid cell lines, ineffective hematopoiesis, and increased risk of development of acute myeloid leukemia. The classification and the diagnostic criteria have been redefined by the recent World Health Organization Classification of Tumors – International Agency for Research on Cancer for Hematopoietic and Lymphoid Tissues. The myelodysplastic syndromes are now classified into the following categories – refractory cytopenia with unilineage dysplasia, refractory anemia with ring sideroblasts, refractory cytopenia with multilineage dysplasia, refractory anemia with excess blasts, myelodysplastic syndrome associated with isolated del (5q), myelodysplastic syndrome – unclassifiable, and childhood myelodysplastic syndrome. The clinicopathologic features, morphology, differential diagnosis, immunophenotyping, cytogenetics, prognosis and predictive factors are presented in the light of recent World Health Organization Classification of Tumors – International Agency for Research on Cancer.
doi:10.2147/JBM.S12257
PMCID: PMC3262332  PMID: 22282696
myelodysplastic syndromes; leukemia
16.  Defective neutrophil function and microbicidal mechanisms in the myelodysplastic disorders. 
Journal of Clinical Pathology  1983;36(10):1120-1128.
Neutrophil function studies have been carried out in a series of 44 patients with primary myelodysplastic syndromes (MDS). In vitro tests of phagocytosis and killing of Candida guilliermondii and Staphylococcus aureus identified 13 patients with abnormal neutrophil function at presentation and a further 10 who developed abnormalities during the course of their disease. The incidence of defective function in the five disease categories in this series was: refractory cytopenia (RC) 8/17; refractory cytopenia with sideroblastic change (RC + SC) 5/8; acquired idiopathic sideroblastic anaemia (AISA) 2/4; refractory anaemia with excess blasts (RAEB) 7/11; chronic myelomonocytic leukaemia (CMML) 1/4. Eleven of 23 patients with defective neutrophil function experienced severe infective complications; in only three of these patients were neutrophil counts less than 1 X 10(9)/l and susceptibility to infection was considered to reflect, at least partially, qualitative neutrophil abnormalities. There was no correlation between absolute neutrophil count and defective function. Abnormal overall neutrophil microbicidal activity was equally associated with impaired and normal phagocytosis. Some patients with intracellular killing defects had reduced myeloperoxidase (MPO) activities and one had reduced hexose monophosphate shunt (HMPS) activity. In two patients, whose neutrophils showed markedly impaired candidacidal activity, levamisole corrected function when added in vitro at 10(-7) M and also when administered in therapeutic dosage. It is suggested that deranged function, probably reflecting abnormalities in maturation of the granulocyte series, occurs across the myelodysplastic spectrum and that several microbicidal mechanisms may be defective.
PMCID: PMC498487  PMID: 6311878
17.  Treatment of Myelodysplastic Syndrome with Two Schedules and Doses of Oral Topotecan: A Randomized Phase II Trial by the Cancer and Leukemia Group B (CALGB 19803) 
Cancer  2009;115(1):84-93.
Background
The CALGB evaluated oral topotecan administered at two schedules and doses for MDS.
Methods
Patients with previously untreated primary or therapy-related MDS were eligible. Patients with refractory anemia (RA), RA with ringed sideroblasts (RARS), or refractory cytopenia with multilineage dysplasia (RCMD) were eligible only if red cell transfusion dependent, platelet count < 50,000/ul, or absolute neutrophil count < 1,000/ul with a recent infection requiring antibiotics.
Treatment
Patients were randomized to receive oral topotecan either at a dose of 1.2 mg/m2 twice daily for 5 days (Arm A) or once daily for 10 days (Arm B), repeated every 21 days for at least 2 cycles. Responding patients continued until progression, or unacceptable toxicity, or two cycles beyond a complete response.
Results
Ninety patients received treatment: 46 on Arm A and 44 on Arm B. Partial responses with improvement in all three cell lines occurred in 6 patients (7%) and hematologic improvement (in 1–2 cell lines) was seen in 21 patients (23%), for an overall response rate of 30%. Response duration was longer on Arm A (23 vs 14 months, p = 0.02). Seven out of fourteen patients with chronic myelomonocytic leukemia responded. There were 8 treatment-related deaths from infection (6) and bleeding (2). Diarrhea was the most frequent non-hematologic toxicity (Grade 3: 11%; Grade 4: 2%).
Conclusions
Oral topotecan in the dose and schedules evaluated in this trial demonstrated only a modest response rate with a troublesome toxicity profile in the treatment of MDS.
doi:10.1002/cncr.23995
PMCID: PMC2887616  PMID: 19025972
18.  Epidemiological characteristics of myelodysplastic syndrome in a well-defined French population. 
British Journal of Cancer  1996;74(2):288-290.
Data on myelodysplastic syndromes (MDS) are seldom collected by cancer registries and unbiased findings from population-based studies remain rare. We report detailed information on MDS in a well-defined French population in the period 1980-1990. The crude incidence rate was 3.2 per 100000 per year and no significant change in incidence was noted in the study period. The sex ratio was 1.9 and the male predominance was present in all age groups. We observed a rise in incidence after 60 years of age but no significant change in incidence of MDS as a whole was observed over the period studied. Refractory anaemia with excess of blasts (RAEB) was the most frequent subtype. Overall 5 year transformation rate of MDS was 31% (+/- 4%) but it was 100% in RAEB in transformation. The observed 5 year survival rate was 23% +/- 3% and the corresponding corrected rate was 33%. The prognosis of RAEB in transformation was worse than the prognosis of other subtypes (P < 0.01). Discrepancies with epidemiological data from other European countries are discussed.
PMCID: PMC2074591  PMID: 8688338
19.  Antiretroviral activity of 5-azacytidine during treatment of a HTLV-1 positive myelodysplastic syndrome with autoimmune manifestations 
Virology Journal  2012;9:1.
Myelodysplastic syndromes (MDS) are often accompanied by autoimmune phenomena. The underlying mechanisms for these associations remain uncertain, although T cell activation seems to be important. Human T-lymphotropic virus (HTLV-1) has been detected in patients with myelodysplastic syndromes, mostly in regions of the world which are endemic for the virus, and where association of HTLV-1 with rheumatological manifestation is not rare. We present here the case of a 58 year old man who presented with cytopenias, leukocytoclastic vasculitis of the skin and glomerulopathy, and was diagnosed as MDS (refractory anemia with excess blasts - RAEB 1). The patient also tested positive for HTLV-1 by PCR. After 8 monthly cycles of 5-azacytidine he achieved a complete hematologic remission. Following treatment, a second PCR for HTLV-1 was carried out and found to be negative. This is the first report in the literature of a HTLV-1-positive MDS with severe autoimmune manifestations, which was treated with the hypomethylating factor 5-azacitidine, achieving cytogenetic remission with concomitant resolution of the autoimmune manifestations, as well as HTLV-1-PCR negativity. HTLV-1-PCR negativity may be due to either immune mediated clearance of the virus, or a potential antiretroviral effect of 5-azacytidine. 5-azacytidine is known for its antiretroviral effects, although there is no proof of its activity against HTLV-1 infection in vivo.
doi:10.1186/1743-422X-9-1
PMCID: PMC3305386  PMID: 22214262
HTLV-1; 5-azacytidine; Myelodysplastic syndrome; RAEB-1; Leukocytoclastic vasculitis; autoimmunity
20.  Diagnostic Challenges Related to Myeloid/Natural Killer Cells, a Variant of Myeloblasts 
The authors report herein two diagnostically challenging cases centered on the myeloid/natural killer (myeloid/NK) cells, a variant of myeloblasts, to illustrate the importance of advanced flow cytometric immunophenotyping and an updated understanding of surface markers in hematopoietic malignancies. Myeloid/NK cell acute leukemia is a very rare subtype of leukemia. Although its NK-cell nature is debatable, it represents a variant of leukemia with distinct morphological and immunophenotypical features. The first case is a de novo myeloid/NK-cell acute leukemia with a striking clinical, morphologic and immunophenotypic resemblance to acute promyelocytic leukemia (APL), but which could be distinguished by its CD11a, CD18, CD117 and CD9 expression. This case illustrates the importance of utilizing the APL surrogate surface phenotype of HLA-DRlow, CD11alow and CD18low by flow cytometric study to rule in/out APL immunophenotypically. In the second case, we show that myeloid/NK-cell blasts can present as a variant of blasts in a preleukemic disease as refractory anemia with excess blasts-1 (RAEB-1), where the blasts were negative for CD34, CD117 and HLA-DR. The recognition of such blast variant is important in appropriately classifying such preleukemic diseases by blast percentage.
PMCID: PMC2480585  PMID: 18787634
Acute leukemia; flow cytometric immunophenotyping; myeloblast; natural killer cell
21.  Bullous Pemphigoid in an Elderly Patient with Myelodysplastic Syndrome and Refractory Anemia Coupled with Excess of Blast 
Annals of Dermatology  2011;23(Suppl 3):S390-S392.
Bullous pemphigoid (BP) has a recognized association with solid organ tumors, but is relatively rare in hematological malignancies. We report a 67-year-old male who developed BP after being diagnosed with myelodysplastic syndrome and refractory anemia with excess of blast (RAEB). Skin biopsy elucidated sub-epidermal bulla using direct immunofluorescence, revealing linear C3 and IgG deposits along the basement membrane. His BP was recalcitrant to the conventional treatment and only responded to a combination of high dose oral prednisolone and azathioprine. The relative refractory nature of his condition and concurrent RAEB supports a paraneoplastic nature.
doi:10.5021/ad.2011.23.S3.S390
PMCID: PMC3276805  PMID: 22346286
Anemia; refractory; with excess blast; Myelodysplastic syndromes; Paraneoplastic syndromes; Pemphigoid; bullous
22.  DNA hypermethylation regulates the expression of members of the Mu-class Glutathione-S-Transferases and Glutathione Peroxidases in Barrett's adenocarcinoma 
Gut  2008;58(1):5-15.
BACKGROUND
The accumulation of reactive oxygen species and subsequent oxidative DNA damage underlie the development of Barrett's esophagus (BE) and its progression to Barrett's dysplasia (BD) and adenocarcinoma (BAC).
METHODS
We systematically analyzed the promoter regions of 23 genes of the Glutathione S-transferase (GST) and Glutathione peroxidase (GPX) families. Quantitative bisulfite pyrosequencing, real-time RT-PCR (qRT-PCR), Western blot, and immunohistochemical (IHC) analysis methods were utilized in this study.
RESULTS
We identified 14 genes that have CpG islands around their transcription start sites; GSTs (M2-M5, A4, P1, Z1, T2, O1-O2) and GPXs (GPX1, GPX3, GPX4, GPX7). Analysis of an initial set of 20 primary samples demonstrated promoter DNA hypermethylation and mRNA down-regulation of GPX3, GPX7, GSTM2, GSTM3, and GSTM5 in more than half of the BACs samples. Further analysis of 159 primary human samples (37 normal, 11 BE, 11 BD, and 100 BACs) indicated frequent hypermethylation (≥10% methylation) of GPX3 (62%), GPX7 (67%), GSTM2 (69.1%), and GSTM3 (15%) in BACs. A significant inverse correlation between DNA methylation and mRNA expression level was shown for GPX3 (P<.0001), GPX7 (P=.002), GSTM2 (P<.0001), and GSTM5 (P=.01). Treatment of esophageal cancer cell lines with 5-Aza-2’-deoxycytidine and Trichostatin-A led to reversal of the methylation pattern and re-expression of these genes at the mRNA and protein levels. The IHC analysis of GPX3, GPX7, and GSTM2 on a tissue microarray that contained 75 BACs with normal squamous esophageal samples demonstrated an absent-to-weak staining in tumors (52% for GPX3, 57% for GPX7, and 45% for GSTM2) and a moderate-to-strong immunostaining in normal samples.
CONCLUSION
Epigenetic inactivation of members of the glutathione pathway can be an important mechanism in Barrett's tumorigenesis.
doi:10.1136/gut.2007.146290
PMCID: PMC2845391  PMID: 18664505
DNA methylation; Glutathione-S-Transferases; Glutathione Peroxidases; Esophagus; Barrett's adenocarcinoma
23.  A Phase I Trial of Vorinostat and Alvocidib in Patients with Relapsed, Refractory or Poor Prognosis Acute Leukemia, or Refractory Anemia with Excess Blasts-2 
Purpose
This phase I study was conducted to identify the MTD of alvocidib when combined vorinostat in patients with relapsed, refractory, or poor prognosis acute leukemia, or refractory anemia with excess blasts-2 (RAEB-2). Secondary objectives included investigating the pharmacokinetic and pharmacodynamic effects of the combination.
Experimental Design
Patients received vorinostat (200 mg orally, 3 times a day [TID], for 14 days), on a 21-day cycle, combined with 2 different alvocidib administration schedules: a 1-h intravenous infusion, daily x 5; or a 30-min loading infusion followed by a 4-h maintenance infusion, weekly x 2. The alvocidib dose was escalated using a standard 3+3 design.
Results
Twenty-eight patients were enrolled and treated. The alvocidib MTD was 20 mg/m2 (30-min loading infusion) followed by 20 mg/m2 (4-h maintenance infusion) on days 1 and 8, in combination with vorinostat. The most frequently encountered toxicities were cytopenias, fatigue, hyperglycemia, hypokalemia, hypophosphatemia, and QT prolongation. Dose limiting toxicities (DLTs) were cardiac arrhythmia-atrial fibrillation and QT prolongation. No objective responses were achieved, although 13 of 26 evaluable patients exhibited stable disease. Alvocidib appeared to alter vorinostat pharmacokinetics, whereas alvocidib pharmacokinetics were unaffected by vorinostat. Ex vivo exposure of leukemia cells to plasma obtained from patients after alvocidib treatment blocked vorinostat-mediated p21CIP1 induction and down-regulated Mcl-1 and p-RNA Pol II for some specimens, although parallel in vivo bone marrow responses were infrequent.
Conclusions
Alvocidib combined with vorinostat is well tolerated. Although disease stabilization occurred in some heavily pretreated patients, objective responses were not obtained with these schedules.
doi:10.1158/1078-0432.CCR-12-2926
PMCID: PMC3618599  PMID: 23515411
Vorinostat; Alvocidib; Acute Leukemia; Clinical Trial; Phase I
24.  Pattern of Hypomethylating Agents Use among Elderly Patients with Myelodysplastic Syndromes 
Leukemia research  2010;35(7):904-908.
Little is known about how hypomethylating agents (HMAs) have been adopted into the treatment of myelodysplastic syndromes (MDS). We conducted a population-based study to assess the use of HMAs among 4,416 MDS patients (age ≥66 years) who were diagnosed during 2001–2005 and followed up through the end of 2007. Multivariate logistic regression models were utilized to evaluate the role of various patient characteristics. 475 (10.8%) patients had received HMAs by 2007, with the proportion increasing over time. Patients who were white (odds ratio (OR)= 0.66, 95% confidence interval (CI): 0.46–0.95), male (OR= 1.47, 95% CI: 1.19–1.82), young (Ptrend <0.01), more recently diagnosed (OR= 1.90, 95% CI: 1.54–2.34), had fewer comorbidities (Ptrend <0.01), or had a history of other cancer (OR=1.28, 95% CI: 1.00–1.63) were more likely to receive HMAs. Compared with patients with refractory anemia, those diagnosed with refractory anemia with excess blasts or refractory cytopenia with multilineage dysplasia had a higher chance to be treated with HMAs (OR = 3.52 and 2.32, respectively). Relatively few MDS patients were treated with HMAs during the introduction period of these agents, and multiple patient characteristics such as sex, comorbidities, and MDS subtype influence the likelihood a patient receives HMAs.
doi:10.1016/j.leukres.2010.10.007
PMCID: PMC3114277  PMID: 21067809
myelodysplastic syndromes; chemotherapy; new agents; hematology - medical
25.  Circulating micromegakaryocytes in myelodysplasia. 
Journal of Clinical Pathology  1987;40(11):1349-1352.
The alkaline phosphatase-antialkaline phosphatase (APAAP) immunocytochemical staining technique was used to look for circulating cells of megakaryocyte lineage in peripheral blood smears from 67 cases of myelodysplasia. Small numbers of micromegakaryocytes positive for platelet glycoprotein IIIa were found in 23 cases. These cells superficially resemble small lymphoid cells and are hence difficult or impossible to recognise in conventional Romanowsky stained smears. Circulating micromegakaryocytes were found most commonly in more aggressive types of myelodysplasia (such as refractory anaemia with excess blasts (RAEB) and refractory anaemia with excess blasts in transformation (RAEB-t], and their presence may therefore indicate a poor prognosis. Because of the simplicity of this immunocytochemical labelling technique, it could be of wide use in the initial assessment of patients with myelodysplasia, and possibly for the early detection of acute leukaemic transformation.
Images
PMCID: PMC1141238  PMID: 3320097

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