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Sample records for pediatric myelodysplastic syndromes

  1. Treatment Option Overview (Myelodysplastic Syndromes)

    MedlinePlus

    ... Patient Myelo-proliferative Neoplasms Patient Myelodysplastic Syndromes Treatment Myeloproliferative Neoplasms Treatment Myelodysplastic/ Myeloproliferative Neoplasms Treatment Health Professional Myelodysplastic ...

  2. Treatment Options for Myelodysplastic Syndromes

    MedlinePlus

    ... Patient Myelo-proliferative Neoplasms Patient Myelodysplastic Syndromes Treatment Myeloproliferative Neoplasms Treatment Myelodysplastic/ Myeloproliferative Neoplasms Treatment Health Professional Myelodysplastic ...

  3. General Information about Myelodysplastic Syndromes

    MedlinePlus

    ... Patient Myelo-proliferative Neoplasms Patient Myelodysplastic Syndromes Treatment Myeloproliferative Neoplasms Treatment Myelodysplastic/ Myeloproliferative Neoplasms Treatment Health Professional Myelodysplastic ...

  4. Defective proliferative potential of MSCs from pediatric myelodysplastic syndrome patients is associated with cell senescence

    PubMed Central

    Liu, Qinghua; Zhu, Hongbo; Dong, Jing; Li, Helou; Zhang, Hong

    2015-01-01

    Objectives: Aberrant MSC function was shown to contribute to the pathophysiology of myelodysplastic syndromSe (MDS). In comparison to adult MDS, pediatric MDS displayed different features both in biologically and clinically. The mechanisms for adult MDS may not be applicable in pediatric MDS. However, understanding of the MSCs in pediatric MDS is lacking. In this study, we investigated the proliferation capacity of MSCs from pediatric MDS patients at clone cell level. Material and methods: Clone bone marrow MSCs were isolated from pediatric MDS patients and identified according to the criteria of the International Society for Cellular Therapy for MSCs. The proliferation capacity of pediatric MDS-derived MSCs was compared to healthy controls. Cell cycle was detected by flow cytometry following PI staining, as well as cell senescence was evaluated by β-galactosidase staining and telomere length. Results: Pediatric MDS-derived MSCs displayed similar basic biology characters as MSCs from healthy controls, including differentiation potential and surface markers. However, defective proliferative was displayed by pediatric MDS-derived MSCs. Pediatric MDS-derived MSCs were more prone to cellular senescence than healthy controls, and showed a decrease in the S phase. Conclusion: Pediatric MDS-derived MSCs possess the basic characteristics of normal MSCs, but display defective proliferation, which may be associated with cell senescence. PMID:26722501

  5. Cytogenetic studies of Brazilian pediatric myelodysplastic syndrome cases: challenges and difficulties in a large and emerging country

    PubMed Central

    Velloso, E.D.R.P.; Chauffaille, M.L.; Peliçario, L.M.; Tanizawa, R.S.S.; Toledo, S.R.C.; Gaiolla, R.D.; Lopes, L.F.

    2013-01-01

    Myelodysplastic syndromes (MDS) and juvenile myelomonocytic leukemia (JMML) are rare hematopoietic stem cell diseases affecting children. Cytogenetics plays an important role in the diagnosis of these diseases. We report here the experience of the Cytogenetic Subcommittee of the Brazilian Cooperative Group on Pediatric Myelodysplastic Syndromes (BCG-MDS-PED). We analyzed 168 cytogenetic studies performed in 23 different cytogenetic centers; 84 of these studies were performed in patients with confirmed MDS (primary MDS, secondary MDS, JMML, and acute myeloid leukemia/MDS+Down syndrome). Clonal abnormalities were found in 36.9% of the MDS cases and cytogenetic studies were important for the detection of constitutional diseases and for differential diagnosis with other myeloid neoplasms. These data show the importance of the Cooperative Group for continuing education in order to avoid a late or wrong diagnosis. PMID:23314345

  6. Thalidomide in Treating Patients With Myelodysplastic Syndrome

    ClinicalTrials.gov

    2013-01-23

    Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Refractory Anemia With Ringed Sideroblasts; Secondary Myelodysplastic Syndromes

  7. Ibrutinib and Azacitidine for Treatment of Higher Risk Myelodysplastic Syndrome

    ClinicalTrials.gov

    2016-04-26

    Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndrome; Previously Treated Myelodysplastic Syndrome; Refractory Anemia With Excess Blasts in Transformation; Secondary Myelodysplastic Syndrome

  8. Hereditary Predispositions to Myelodysplastic Syndrome.

    PubMed

    Bannon, Sarah A; DiNardo, Courtney D

    2016-01-01

    Myelodysplastic syndromes (MDS) are heterogeneous clonal hematopoietic disorders characterized by ineffective hematopoiesis, bone marrow dysplasia, and peripheral cytopenias. Familial forms of MDS have traditionally been considered rare, especially in adults; however, the increasing availability of somatic and germline genetic analyses has identified multiple susceptibility loci. Bone marrow failure syndromes have been well-described in the pediatric setting, e.g., Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SBS), hallmarked by clinically-recognizable phenotypes (e.g., radial ray anomalies in FA) and significantly increased risks for MDS and/or acute myeloid leukemia (AML) in the setting of bone marrow failure. However, additional families with multiple cases of MDS or AML have long been reported in the medical literature with little known regarding potential hereditary etiologies. Over the last decade, genomic investigation of such families has revealed multiple genes conferring inherited risks for MDS and/or AML as the primary malignancy, including RUNX1, ANKRD26, DDX41, ETV6, GATA2, and SRP72. As these syndromes are increasingly appreciated in even apparently de novo presentations of MDS, it is important for hematologists/oncologists to become familiar with these newly-described syndromes. Herein, we provide a review of familial MDS syndromes and practical aspects of management in patients with predisposition syndromes. PMID:27248996

  9. Hereditary Predispositions to Myelodysplastic Syndrome

    PubMed Central

    Bannon, Sarah A.; DiNardo, Courtney D.

    2016-01-01

    Myelodysplastic syndromes (MDS) are heterogeneous clonal hematopoietic disorders characterized by ineffective hematopoiesis, bone marrow dysplasia, and peripheral cytopenias. Familial forms of MDS have traditionally been considered rare, especially in adults; however, the increasing availability of somatic and germline genetic analyses has identified multiple susceptibility loci. Bone marrow failure syndromes have been well-described in the pediatric setting, e.g., Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond–Blackfan anemia (DBA), and Shwachman–Diamond syndrome (SBS), hallmarked by clinically-recognizable phenotypes (e.g., radial ray anomalies in FA) and significantly increased risks for MDS and/or acute myeloid leukemia (AML) in the setting of bone marrow failure. However, additional families with multiple cases of MDS or AML have long been reported in the medical literature with little known regarding potential hereditary etiologies. Over the last decade, genomic investigation of such families has revealed multiple genes conferring inherited risks for MDS and/or AML as the primary malignancy, including RUNX1, ANKRD26, DDX41, ETV6, GATA2, and SRP72. As these syndromes are increasingly appreciated in even apparently de novo presentations of MDS, it is important for hematologists/oncologists to become familiar with these newly-described syndromes. Herein, we provide a review of familial MDS syndromes and practical aspects of management in patients with predisposition syndromes. PMID:27248996

  10. [How to improve the results of treatment of myelodysplastic syndromes in the studies of Polish pediatric leukemia/lymphoma group].

    PubMed

    Chybicka, A; Kołecki, P; Pietras, W; Wójcik, D; Turkiewicz, D; Armata, J; Eliasińska, A; Kowalczyk, J; Jackowska, T; Klus, K; Matysiak, M; Krauze, A; Stefańska, K; Rokicka-Milewska, R; Wiśniewska-Slusarz, H

    1998-01-01

    Fourty two children with myelodysplastic syndrome (MDS) treated in seven centres of The Polish Paediatric Leukaemia/Lymphoma Study Group in period 1975-1998 were included in the study. In 16 children RAEB-T, in 3 CMML, in 10 RA and in 13 RAEB were diagnosed. BMT is the best therapy for children with MDS. For children, who have not a donor for BMT, Roacutan therapy seems to be the most effective. PMID:10731943

  11. Allogeneic hematopoetic stem cell transplantation in pediatric myelodysplastic syndromes: improved outcomes for de novo disease.

    PubMed

    Andolina, Jeffrey R; Kletzel, Morris; Tse, William T; Jacobsohn, David A; Duerst, Reggie E; Schneiderman, Jennifer; Helenowski, Irene; Rademaker, Alfred; Chaudhury, Sonali

    2011-05-01

    We report 23 consecutive pediatric patients with MDS who received allogeneic HSCT on IRB approved protocols between 1992 and 2009 at Children's Memorial Hospital (Chicago, IL). Nine patients had de novo MDS, whereas 14 patients had treatment-related MDS. All patients had a documented cytogenetic abnormality, and monosomy 7/7q- was seen in 12 patients (52%). Fourteen of 23 patients received a myeloablative conditioning regimen; RIC regimens were used for the remaining nine. Five patients relapsed post-transplant, including four patients who received RIC transplant and four patients with treatment-related MDS. For the entire group, estimated five-yr RFS and OS were 47% and 50%, respectively. Treatment-related MDS was associated with decreased RFS in comparison with de novo MDS (33% vs. 70%, p = 0.05). Five-year OS rates reached 80% for those with de novo MDS. RIC regimens were associated with decreased three-yr RFS in comparison with myeloablative regimens (22% vs. 68%, p = 0.02). There was no correlation of survival with blast count at diagnosis, IPSS score, cytogenetic abnormality, donor type, or HLA match. Larger series are needed to confirm prognostic factors so that higher-risk patients can be targeted with novel approaches. PMID:21492354

  12. Differentiation Therapy With Decitabine in Treating Patients With Myelodysplastic Syndrome

    ClinicalTrials.gov

    2013-02-25

    Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Myelodysplastic Syndromes; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Ringed Sideroblasts; Refractory Cytopenia With Multilineage Dysplasia; Thrombocytopenia

  13. What Are the Key Statistics about Myelodysplastic Syndromes?

    MedlinePlus

    ... factors for myelodysplastic syndromes? What are the key statistics about myelodysplastic syndromes? In the United States, myelodysplastic ... Symptoms of Cancer Treatments & Side Effects Cancer Facts & Statistics News About Cancer Expert Voices Blog Programs & Services ...

  14. Lenalidomide in Treating Young Patients With Relapsed or Refractory Solid Tumors or Myelodysplastic Syndromes

    ClinicalTrials.gov

    2014-06-10

    Childhood Myelodysplastic Syndromes; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Ringed Sideroblasts; Refractory Cytopenia With Multilineage Dysplasia; Secondary Myelodysplastic Syndromes; Unspecified Childhood Solid Tumor, Protocol Specific

  15. Immunomodulatory drugs in myelodysplastic syndromes.

    PubMed

    Galili, Naomi; Raza, Azra

    2006-07-01

    This review summarises the mechanism of action of immunomodulatory analogues of thalidomide and their use in myelodysplastic syndromes. Thalidomide was found to have a response rate of approximately 20% in these patients. Lenalidomide--which is more potent and less toxic than thalidomide--has been used in three clinical trials and produced the best responses (60 - > 90%) in low- and intermediate-1-risk transfusion-dependent patients with del(5q). The responses are purely erythroid in nature, and are associated with major cytogenetic responses in > 50% of the del(5q) patients. Non-del(5q) low- and intermediate-1-risk transfusion-dependent patients also had a approximately 25% incidence of transfusion independence following therapy with lenalidomide. Median time to response is approximately 4 weeks and 90% of patients respond within 12 weeks. The precise mechanism of action remains unknown but anticytokine, antiangiogenic and immunomodulatory properties are thought to play a role. PMID:16787143

  16. Immune Mechanisms in Myelodysplastic Syndrome

    PubMed Central

    Glenthøj, Andreas; Ørskov, Andreas Due; Hansen, Jakob Werner; Hadrup, Sine Reker; O’Connell, Casey; Grønbæk, Kirsten

    2016-01-01

    Myelodysplastic syndrome (MDS) is a spectrum of diseases, characterized by debilitating cytopenias and a propensity of developing acute myeloid leukemia. Comprehensive sequencing efforts have revealed a range of mutations characteristic, but not specific, of MDS. Epidemiologically, autoimmune diseases are common in patients with MDS, fueling hypotheses of common etiological mechanisms. Both innate and adaptive immune pathways are overly active in the hematopoietic niche of MDS. Although supportive care, growth factors, and hypomethylating agents are the mainstay of MDS treatment, some patients—especially younger low-risk patients with HLA-DR15 tissue type—demonstrate impressive response rates after immunosuppressive therapy. This is in contrast to higher-risk MDS patients, where several immune activating treatments, such as immune checkpoint inhibitors, are in the pipeline. Thus, the dual role of immune mechanisms in MDS is challenging, and rigorous translational studies are needed to establish the value of immune manipulation as a treatment of MDS. PMID:27314337

  17. Immune Mechanisms in Myelodysplastic Syndrome.

    PubMed

    Glenthøj, Andreas; Ørskov, Andreas Due; Hansen, Jakob Werner; Hadrup, Sine Reker; O'Connell, Casey; Grønbæk, Kirsten

    2016-01-01

    Myelodysplastic syndrome (MDS) is a spectrum of diseases, characterized by debilitating cytopenias and a propensity of developing acute myeloid leukemia. Comprehensive sequencing efforts have revealed a range of mutations characteristic, but not specific, of MDS. Epidemiologically, autoimmune diseases are common in patients with MDS, fueling hypotheses of common etiological mechanisms. Both innate and adaptive immune pathways are overly active in the hematopoietic niche of MDS. Although supportive care, growth factors, and hypomethylating agents are the mainstay of MDS treatment, some patients-especially younger low-risk patients with HLA-DR15 tissue type-demonstrate impressive response rates after immunosuppressive therapy. This is in contrast to higher-risk MDS patients, where several immune activating treatments, such as immune checkpoint inhibitors, are in the pipeline. Thus, the dual role of immune mechanisms in MDS is challenging, and rigorous translational studies are needed to establish the value of immune manipulation as a treatment of MDS. PMID:27314337

  18. What's New in Myelodysplastic Syndrome Research and Treatment?

    MedlinePlus

    ... Next Topic Additional resources for myelodysplastic syndromes What`s new in myelodysplastic syndrome research and treatment? Genetics and ... research unfolds, it may be used to design new drugs or eventually in developing gene therapy. This ...

  19. What Are the Risk Factors for Myelodysplastic Syndromes?

    MedlinePlus

    ... surviving an atomic bomb blast or nuclear reactor accident) increases the risk of developing MDS. Long-term ... Myelodysplastic Syndrome? Causes, Risk Factors, and Prevention Early Detection, Diagnosis, and Staging Treating Myelodysplastic Syndrome Talking With ...

  20. Ipilimumab in Treating Patients With Relapsed or Refractory High-Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-06-27

    Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Chronic Myelomonocytic Leukemia; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Secondary Myelodysplastic Syndrome

  1. Autoimmune diseases and myelodysplastic syndromes.

    PubMed

    Komrokji, Rami S; Kulasekararaj, Austin; Al Ali, Najla H; Kordasti, Shahram; Bart-Smith, Emily; Craig, Benjamin M; Padron, Eric; Zhang, Ling; Lancet, Jeffrey E; Pinilla-Ibarz, Javier; List, Alan F; Mufti, Ghulam J; Epling-Burnette, Pearlie K

    2016-05-01

    Immune dysregulation and altered T-cell hemostasis play important roles in the pathogenesis of myelodysplastic syndromes (MDS). Recent studies suggest an increased risk of MDS among patients with autoimmune diseases. Here, we investigated the prevalence of autoimmune diseases among MDS patients, comparing characteristics and outcomes in those with and without autoimmune diseases. From our study group of 1408 MDS patients, 391 (28%) had autoimmune disease, with hypothyroidism being the most common type, accounting for 44% (n = 171) of patients (12% among all MDS patients analyzed). Other autoimmune diseases with ≥5% prevalence included idiopathic thrombocytopenic purpura in 12% (n = 46), rheumatoid arthritis in 10% (n = 41), and psoriasis in 7% (n = 28) of patients. Autoimmune diseases were more common in female MDS patients, those with RA or RCMD WHO subtype, and those who were less dependent on red blood cell transfusion. Median overall survival (OS) was 60 months (95% CI, 50-70) for patients with autoimmune diseases versus 45 months (95% CI, 40-49) for those without (log-rank test, P = 0.006). By multivariate analysis adjusting for revised IPSS and age >60 years, autoimmune diseases were a statistically significant independent factor for OS (HR 0.78; 95% CI, 0.66-0.92; P = 0.004). The rate of acute myeloid leukemia (AML) transformation was 23% (n = 89) in MDS patients with autoimmune disease versus 30% (n = 301) in those without (P = 0.011). Patient groups did not differ in response to azacitidine or lenalidomide treatment. Autoimmune diseases are prevalent among MDS patients. MDS patients with autoimmune diseases have better OS and less AML transformation. PMID:26875020

  2. WEE1 Inhibitor AZD1775 With or Without Cytarabine in Treating Patients With Advanced Acute Myeloid Leukemia or Myelodysplastic Syndrome

    ClinicalTrials.gov

    2016-01-25

    Chronic Myelomonocytic Leukemia; Myelodysplastic Syndrome With Isolated Del(5q); Myelodysplastic/Myeloproliferative Neoplasm; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  3. Filgrastim, Cladribine, Cytarabine, and Mitoxantrone Hydrochloride in Treating Patients With Newly Diagnosed or Relapsed/Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndromes

    ClinicalTrials.gov

    2016-03-30

    Acute Biphenotypic Leukemia; de Novo Myelodysplastic Syndrome; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndrome; Untreated Adult Acute Myeloid Leukemia

  4. Myelodysplastic Syndromes, Version 2.2015

    PubMed Central

    Greenberg, Peter L.; Stone, Richard M.; Bejar, Rafael; Bennett, John M.; Bloomfield, Clara D.; Borate, Uma; De Castro, Carlos M.; Deeg, H. Joachim; DeZern, Amy E.; Fathi, Amir T.; Frankfurt, Olga; Gaensler, Karin; Garcia-Manero, Guillermo; Griffiths, Elizabeth A.; Head, David; Klimek, Virginia; Komrokji, Rami; Kujawski, Lisa A.; Maness, Lori J.; O’Donnell, Margaret R.; Pollyea, Daniel A.; Scott, Bart; Shami, Paul J.; Stein, Brady L.; Westervelt, Peter; Wheeler, Benton; Shead, Dorothy A.; Smith, Courtney

    2015-01-01

    The NCCN Guidelines for Myelodysplastic Syndromes (MDS) comprise a heterogeneous group of myeloid disorders with a highly variable disease course that depends largely on risk factors. Risk evaluation is therefore a critical component of decision-making in the treatment of MDS. The development of newer treatments and the refinement of current treatment modalities are designed to improve patient outcomes and reduce side effects. These NCCN Guidelines Insights focus on the recent updates to the guidelines, which include the incorporation of a revised prognostic scoring system, addition of molecular abnormalities associated with MDS, and refinement of treatment options involving a discussion of cost of care. PMID:25736003

  5. MS-275 and Azacitidine in Treating Patients With Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-07-20

    Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndrome; Leukemia; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndrome; Untreated Adult Acute Myeloid Leukemia

  6. Nuclear inositide signaling in myelodysplastic syndromes.

    PubMed

    Follo, Matilde Y; Mongiorgi, Sara; Finelli, Carlo; Clissa, Cristina; Ramazzotti, Giulia; Fiume, Roberta; Faenza, Irene; Manzoli, Lucia; Martelli, Alberto M; Cocco, Lucio

    2010-04-15

    Myelodysplastic syndromes (MDS) are defined as clonal hematopoietic stem-cell disorders characterized by ineffective hematopoiesis in one or more of the lineages of the bone marrow. Although distinct morphologic subgroups exist, the natural history of MDS is progression to acute myeloid leukemia (AML). However, the molecular the mechanisms the underlying MDS evolution to AML are not completely understood. Inositides are key cellular second messengers with well-established roles in signal transduction pathways, and nuclear metabolism elicited by phosphoinositide-specific phospholipase C (PI-PLC) beta1 and Akt plays an important role in the control of the balance between cell cycle progression and apoptosis in both normal and pathologic conditions. Recent findings evidenced the role played by nuclear lipid signaling pathways, which could become promising therapeutic targets in MDS. This review will provide a concise and updated revision of the state of art on this topic. PMID:20058233

  7. [Research Advances on Pathogenesis of Myelodysplastic Syndrome].

    PubMed

    Xu, Ming; Lu, Jia-Hui

    2015-12-01

    Myelodysplastic syndrome (MDS) is a clonal marrow stem cell disorder, characterized by ineffective haemopoiesis leading to blood cytopenias. As a disease of grey zone, along with the development of research, the exploration on its pathogenesis have been shifted from molecular genetics and the feature of immunophenotype to the epigenetic and micro environment. But at present, the pathogenesis of MDS is still not clear, the research of the molecular genetics and immunophenotype can not meet the needs of experimental and clinical application any longer. The hematopoietic stem cells, cytokines, epigenetic studies, however, have made a lot of achievements. Targeted medicine such as azacitidine and decitabine had promising response in treating MDS patients. In this article the abnormality of stromal cells, cytokines and epigenetic changes in hematopoietic microenvironment of MDS are reviewed in order to optimize the monitoring MDS progress and guide its clinical medication strategy. PMID:26708914

  8. Myelodysplastic syndrome in two young brothers.

    PubMed

    Hirose, M; Kawahito, M; Kuroda, Y

    1995-01-01

    We report the youngest cases of myelodysplastic syndrome (MDS) in two brothers aged 7 and 2 years. The maternal grandfather and maternal grandmother had been exposed to radioactive fallout after the atomic bomb attack on Hiroshima in 1945. The elder brother demonstrated pancytopenia with < 1% blast cells in his peripheral blood and < 5% in his bone marrow at diagnosis. The younger brother was thrombocytopenic without increased blasts. The karyotype of bone marrow cells from the elder brother was 46,XY, -7, +der (7), t(1:7) (lqter-lq11::7q11-7pter), but the younger brother's karyotype was normal. Immature myeloid cells in the bone marrow from both brothers were morphologically abnormal. A diagnosis of refractory anaemia (RA) was made in both brothers. Atavism due to radioactive poisoning was suspected in the development of MDS in these two cases. PMID:7833267

  9. Myelodysplastic Syndrome Occurring in a Patient with Gorlin Syndrome.

    PubMed

    Mull, Jamie L; Madden, Lisa M; Bayliss, Susan J

    2016-07-01

    We report a case of myelodysplastic syndrome (MDS) occurring in an African American boy with Gorlin syndrome with a novel PTCH1 mutation. Before developing MDS, the patient had been treated with chemotherapy and radiation for a medulloblastoma. He received a bone marrow transplant for the MDS and eventually died of treatment complications. Secondary hematologic malignancies are a known complication of certain chemotherapeutics, although whether a patient with Gorlin syndrome has a greater propensity for the development of such malignancies is unclear. PMID:27241746

  10. Azacitidine With or Without Lenalidomide or Vorinostat in Treating Patients With Higher-Risk Myelodysplastic Syndromes or Chronic Myelomonocytic Leukemia

    ClinicalTrials.gov

    2016-07-26

    Adult Myelodysplastic Syndrome; Chronic Myelomonocytic Leukemia; Chronic Myelomonocytic Leukemia-1; Chronic Myelomonocytic Leukemia-2; Previously Treated Myelodysplastic Syndrome; Refractory Anemia With Excess Blasts

  11. Myelodysplastic Syndrome and Autoimmunity: A Case Report of an Unusual Presentation of Myelodysplastic Syndrome

    PubMed Central

    Merrill, Andrea L.; Smith, Hedy

    2011-01-01

    Myelodysplastic syndrome (MDS) commonly presents asymptomatically or with symptomatic cytopenias. However, autoimmune phenomena in association with MDS have been well described in several case reports and case series. Typically, these autoimmune phenomena take the form of vasculitides, arthritis, connective tissue diseases, pulmonary infiltrates, or polymyalgia rheumatica. We present the case of a woman with MDS (karyotype 46,XX,+1,der(1;7)(q10;p10)[20], that evolved with an additional trisomy 8 clone) and a novel spectrum of autoimmune diseases including acute fibrinous and organizing pneumonia (AFOP) and lacrimal gland pseudotumor. PMID:22937307

  12. A Primary Care Approach to Myelodysplastic Syndromes

    PubMed Central

    Samiev, Djamshed; Bhatt, Vijaya R.; Armitage, Joel D.; Maness, Lori J

    2014-01-01

    Myelodysplastic syndromes (MDS) are probably the most common hematologic malignancies in adults over the age of 60 and are a major source of morbidity and mortality among older age groups. Diagnosis and management of this chronic blood cancer has evolved significantly in recent years and there are Food and Drug Administration-approved therapies that can extend patients' life expectancy and improve quality of life. Primary care physicians (PCPs) are often involved in the process of diagnosis and follow-up of MDS patients, especially those in low-risk groups. They can therefore play an important role in improving patient care and quality of life by ensuring early referral and participating in supportive management. There is also a shortage of oncologists which increases the importance of the role of PCPs in management of MDS patients. In the face of limited resources, PCPs can improve access and quality of care in MDS patients. This article provides an overview of the common manifestations, diagnostic approaches, and therapeutic modalities of MDS for PCPs, with a focus on when to suspect MDS, when a referral is appropriate, and how to provide appropriate supportive care for patients diagnosed with MDS. PMID:24921029

  13. Treosulfan, Fludarabine Phosphate, and Total Body Irradiation Before Donor Stem Cell Transplant in Treating Patients With Myelodysplastic Syndrome or Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-06-20

    Acute Myeloid Leukemia in Remission; Chronic Myelomonocytic Leukemia; Minimal Residual Disease; Myelodysplastic Syndrome; Myelodysplastic/Myeloproliferative Neoplasm; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable

  14. Loss of B cells and their precursors is the most constant feature of GATA-2 deficiency in childhood myelodysplastic syndrome

    PubMed Central

    Nováková, Michaela; Žaliová, Markéta; Suková, Martina; Wlodarski, Marcin; Janda, Aleš; Froňková, Eva; Campr, Vít; Lejhancová, Kateřina; Zapletal, Ondřej; Pospíšilová, Dagmar; Černá, Zdeňka; Kuhn, Tomáš; Švec, Peter; Pelková, Vendula; Zemanová, Zuzana; Kerndrup, Gitte; van den Heuvel-Eibrink, Marry; van der Velden, Vincent; Niemeyer, Charlotte; Kalina, Tomáš; Trka, Jan; Starý, Jan; Hrušák, Ondřej; Mejstříková, Ester

    2016-01-01

    GATA-2 deficiency was recently described as common cause of overlapping syndromes of immunodeficiency, lymphedema, familiar myelodysplastic syndrome or acute myeloid leukemia. The aim of our study was to analyze bone marrow and peripheral blood samples of children with myelodysplastic syndrome or aplastic anemia to define prevalence of the GATA2 mutation and to assess whether mutations in GATA-2 transcription factor exhibit specific immunophenotypic features. The prevalence of a GATA2 mutation in a consecutively diagnosed cohort of children was 14% in advanced forms of myelodysplastic syndrome (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and myelodysplasia-related acute myeloid leukemia), 17% in refractory cytopenia of childhood, and 0% in aplastic anemia. In GATA-2-deficient cases, we found the most profound B-cell lymphopenia, including its progenitors in blood and bone marrow, which correlated with significantly diminished intronRSS-Kde recombination excision circles in comparison to other myelodysplastic syndrome/aplastic anemia cases. The other typical features of GATA-2 deficiency (monocytopenia and natural killer cell lymphopenia) were less discriminative. In conclusion, we suggest screening for GATA2 mutations in pediatric myelodysplastic syndrome, preferentially in patients with impaired B-cell homeostasis in bone marrow and peripheral blood (low number of progenitors, intronRSS-Kde recombination excision circles and naïve cells). PMID:27013649

  15. Loss of B cells and their precursors is the most constant feature of GATA-2 deficiency in childhood myelodysplastic syndrome.

    PubMed

    Nováková, Michaela; Žaliová, Markéta; Suková, Martina; Wlodarski, Marcin; Janda, Aleš; Froňková, Eva; Campr, Vít; Lejhancová, Kateřina; Zapletal, Ondřej; Pospíšilová, Dagmar; Černá, Zdeňka; Kuhn, Tomáš; Švec, Peter; Pelková, Vendula; Zemanová, Zuzana; Kerndrup, Gitte; van den Heuvel-Eibrink, Marry; van der Velden, Vincent; Niemeyer, Charlotte; Kalina, Tomáš; Trka, Jan; Starý, Jan; Hrušák, Ondřej; Mejstříková, Ester

    2016-06-01

    GATA-2 deficiency was recently described as common cause of overlapping syndromes of immunodeficiency, lymphedema, familiar myelodysplastic syndrome or acute myeloid leukemia. The aim of our study was to analyze bone marrow and peripheral blood samples of children with myelodysplastic syndrome or aplastic anemia to define prevalence of the GATA2 mutation and to assess whether mutations in GATA-2 transcription factor exhibit specific immunophenotypic features. The prevalence of a GATA2 mutation in a consecutively diagnosed cohort of children was 14% in advanced forms of myelodysplastic syndrome (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and myelodysplasia-related acute myeloid leukemia), 17% in refractory cytopenia of childhood, and 0% in aplastic anemia. In GATA-2-deficient cases, we found the most profound B-cell lymphopenia, including its progenitors in blood and bone marrow, which correlated with significantly diminished intronRSS-Kde recombination excision circles in comparison to other myelodysplastic syndrome/aplastic anemia cases. The other typical features of GATA-2 deficiency (monocytopenia and natural killer cell lymphopenia) were less discriminative. In conclusion, we suggest screening for GATA2 mutations in pediatric myelodysplastic syndrome, preferentially in patients with impaired B-cell homeostasis in bone marrow and peripheral blood (low number of progenitors, intronRSS-Kde recombination excision circles and naïve cells). PMID:27013649

  16. Hematopoietic Cell Transplantation for Myelodysplastic Syndromes.

    PubMed

    Bhatt, Vijaya Raj; Steensma, David P

    2016-09-01

    Allogeneic hematopoietic cell transplantation (HCT) offers the only potential cure for patients with myelodysplastic syndromes (MDS). However, with current approaches to HCT, many older patients with comorbidities are poor HCT candidates, and treatment-related morbidity and mortality may offset benefit for patients with lower-risk disease. Consequently, selection of patients with MDS for HCT should take into consideration disease risk category including mutational status, HCT comorbidity index, functional status, donor options, and available institutional resources. Formal geriatric assessment may further guide use of HCT and, if HCT is chosen, selection of conditioning intensity. Patients with higher-risk MDS should be considered for HCT at the time of diagnosis, whereas expectant nontransplant management is more appropriate for those with lower-risk disease. A high blast burden at the time of HCT increases the risk of subsequent relapse; however, the role of pretransplant cytoreductive therapy and the regimen of choice remain controversial. Patients with MDS younger than 65 years and with an HCT comorbidity index ≤ 4 may benefit from more intense conditioning regimens. The presence of complex or monosomal karyotype or mutations in TP53, DNMT3A, or other genes identify patients with poorer outcomes following HCT. Patients with TP53 mutations have particularly poor survival, and should be enrolled in clinical trials whenever possible. Several important HCT studies are ongoing and will better define the role of HCT in MDS as well as the value of pretransplant cytoreductive therapy or post-transplant relapse-prevention strategies. Given the apparent underuse of HCT in eligible patients and low enrollment in MDS HCT clinical trials to date, timely referral of patients with MDS to such trials and HCT programs is critical. PMID:27621329

  17. Incidence and Burden of the Myelodysplastic Syndromes.

    PubMed

    Cogle, Christopher R

    2015-09-01

    Since 2001, cases of myelodysplastic syndromes (MDSs) have been tracked by cancer registries. Examining registry data in the USA, the reported age-adjusted incidence of MDS per 100,000 was 3.3 per year for 2001-2003 and 4.9 per year for 2007-2011, with increases likely a result of growing awareness of reporting requirements. However, active case-finding methods repeatedly demonstrate that population-based registries have underestimated the incidence of MDS due to underreporting and underdiagnosis. Using keyword search strategies of electronic pathology reports or other novel case capture methods, the true incidence of MDS has been estimated between 5.3 and 13.1 per 100,000. Using Medicare billing claims data, the incidence of MDS per 100,000 in patients aged ≥65 years has been estimated between 75 and 162. MDS prevalence is estimated to be 60,000 and -170,000 in the USA and projected to grow. Epidemiologic data can help estimate the burden of MDS and expose unmet clinical needs. For example, patients with MDS receiving transfusions had significantly higher reported health care costs versus those that did not (3-year mean of $88,824 vs $29,519). Epidemiologic data also revealed that most MDS patients receiving transfusions do not receive active therapies, despite strong evidence that hypomethylating agents and lenalidomide significantly reduce transfusion burden. Other unmet needs identified by epidemiologic studies include high need for treatment options after failing first-line therapy and shared decision making by older MDS patients. PMID:26134527

  18. Lactobacillus in Preventing Infection in Patients Undergoing a Donor Stem Cell Transplant for Hematologic Cancer or Myelodysplastic Syndrome

    ClinicalTrials.gov

    2015-03-18

    Breast Cancer; Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Neuroblastoma; Ovarian Cancer; Testicular Germ Cell Tumor

  19. Mutations of myelodysplastic syndromes (MDS): An update.

    PubMed

    Ganguly, Bani Bandana; Kadam, N N

    2016-01-01

    The plethora of knowledge gained on myelodysplastic syndromes (MDS), a heterogeneous pre-malignant disorder of hematopoietic stem cells, through sequencing of several pathway genes has unveiled molecular pathogenesis and its progression to AML. Evolution of phenotypic classification and risk-stratification based on peripheral cytopenias and blast count has moved to five-tier risk-groups solely concerning chromosomal aberrations. Increased frequency of complex abnormalities, which is associated with genetic instability, defines the subgroup of worst prognosis in MDS. However, the independent effect of monosomal karyotype remains controversial. Recent discoveries on mutations in RNA-splicing machinery (SF3B1, SRSF2, ZRSR2, U2AF1, U2AF2); DNA methylation (TET2, DNMT3A, IDH1/2); chromatin modification (ASXL1, EZH2); transcription factor (TP53, RUNX1); signal transduction/kinases (FLT3, JAK2); RAS pathway (KRAS, NRAS, CBL, NF1, PTPN11); cohesin complex (STAG2, CTCF, SMC1A, RAD21); DNA repair (ATM, BRCC3, DLRE1C, FANCL); and other pathway genes have given insights into the independent effects and interaction of co-occurrence of mutations on disease-phenotype. RNA-splicing and DNA methylation mutations appeared to occur early and are reported as 'founder' mutations in over 50% MDS patients. TET2 mutation, through altered DNA methylation, has been found to have independent prognostic response to hypomethylating agents. Moreover, presence of DNMT3A, TET2 and ASXL1 mutations in normal elderly individuals forms the basis of understanding that accumulation of somatic mutations may not cause direct disease-development; however, cooperation with other mutations in the genes that are frequently mutated in myeloid and other hematopoietic cancers might result in clonal expansion through self-renewal and/or proliferation of hematopoietic stem cells. Identification of small molecules as inhibitors of epigenetic mutations has opened avenues for tailoring targeted drug development. The

  20. Myelodysplastic syndrome evolving from aplastic anemia treated with immunosuppressive therapy: efficacy of hematopoietic stem cell transplantation

    PubMed Central

    Kim, Sung-Yong; Le Rademacher, Jennifer; Antin, Joseph H.; Anderlini, Paolo; Ayas, Mouhab; Battiwalla, Minoo; Carreras, Jeanette; Kurtzberg, Joanne; Nakamura, Ryotaro; Eapen, Mary; Deeg, H. Joachim

    2014-01-01

    A proportion of patients with aplastic anemia who are treated with immunosuppressive therapy develop clonal hematologic disorders, including post-aplastic anemia myelodysplastic syndrome. Many will proceed to allogeneic hematopoietic stem cell transplantation. We identified 123 patients with post-aplastic anemia myelodysplastic syndrome who from 1991 through 2011 underwent allogeneic hematopoietic stem cell transplantation, and in a matched-pair analysis compared outcome to that in 393 patients with de novo myelodysplastic syndrome. There was no difference in overall survival. There were no significant differences with regard to 5-year probabilities of relapse, non-relapse mortality, relapse-free survival and overall survival; these were 14%, 40%, 46% and 49% for post-aplastic anemia myelodysplastic syndrome, and 20%, 33%, 47% and 49% for de novo myelodysplastic syndrome, respectively. In multivariate analysis, relapse (hazard ratio 0.71; P=0.18), non-relapse mortality (hazard ratio 1.28; P=0.18), relapse-free survival (hazard ratio 0.97; P=0.80) and overall survival (hazard ratio 1.02; P=0.88) of post-aplastic anemia myelodysplastic syndrome were similar to those of patients with de novo myelodysplastic syndrome. Cytogenetic risk was independently associated with overall survival in both groups. Thus, transplant success in patients with post-aplastic anemia myelodysplastic syndrome was similar to that in patients with de novo myelodysplastic syndrome, and cytogenetics was the only significant prognostic factor for post-aplastic anemia myelodysplastic syndrome patients. PMID:25107891

  1. Combination Chemotherapy in Treating Young Patients With Down Syndrome and Acute Myeloid Leukemia or Myelodysplastic Syndromes

    ClinicalTrials.gov

    2016-03-16

    Childhood Acute Basophilic Leukemia; Childhood Acute Eosinophilic Leukemia; Childhood Acute Erythroleukemia (M6); Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Minimally Differentiated Myeloid Leukemia (M0); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myelomonocytic Leukemia (M4); Childhood Myelodysplastic Syndromes; de Novo Myelodysplastic Syndromes; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

  2. Mitochondrial tRNA mutations in patients with myelodysplastic syndromes.

    PubMed

    Wang, Hui-Rui; Li, Ya-Wei; Wu, Jun-Long; Guo, Shu-Li

    2016-07-01

    Increasing evidence showed that mitochondria play an important role in the development of myelodysplastic syndromes (MDS). Mitochondrial dysfunctions caused by mitochondrial DNA mutations, especially mitochondrial tRNA mutations, were found to be associated with MDS in many studies. However, the link between a candidate mitochondrial tRNA mutation and MDS was not clear. In this study, we investigated the role of some mitochondrial tRNA mutations, and their deleterious roles were further discussed. PMID:25812051

  3. Pediatric epilepsy syndromes.

    PubMed

    Wirrell, Elaine; Nickels, Katherine C

    2010-06-01

    Epilepsy syndromes denote specific constellations of clinical seizure type(s), EEG findings, and other characteristic clinical features. Most syndromes recognized in epilepsy are genetic and developmental disorders that begin in the pediatric years. Epilepsy syndromes are divided into idiopathic (primary) types, in which the presumed etiology is genetic, versus symptomatic (secondary) types, in which there is either an underlying etiology that is known or presumed based on other evidence of brain dysfunction. Epilepsies are also classified by those with generalized seizures and those with localization-related seizures. Identification of a specific syndrome is important to define the best treatment and accurately prognosticate long-term outcome for children with epilepsy. In this chapter, clinical and electrographic features as well as inheritance patterns of common pediatric epilepsy syndromes are discussed. PMID:22810315

  4. Decitabine in Treating Patients With Myelodysplastic Syndromes or Acute Myeloid Leukemia

    ClinicalTrials.gov

    2013-09-27

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; de Novo Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Myeloid Leukemia

  5. Vorinostat and Idarubicin in Treating Patients With Relapsed or Refractory Leukemia or Myelodysplastic Syndromes

    ClinicalTrials.gov

    2013-09-27

    Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Promyelocytic Leukemia (M3); Blastic Phase Chronic Myelogenous Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

  6. BMS-214662 in Treating Patients With Acute Leukemia, Myelodysplastic Syndrome, or Chronic Myeloid Leukemia

    ClinicalTrials.gov

    2013-01-22

    Adult Acute Promyelocytic Leukemia (M3); Blastic Phase Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia

  7. Vorinostat and Azacitidine in Treating Patients With Myelodysplastic Syndromes or Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-06-27

    Acute Erythroid Leukemia; Acute Megakaryoblastic Leukemia; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Chronic Myelomonocytic Leukemia; Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Refractory Anemia With Ring Sideroblasts

  8. Molecular dissection of the 5q deletion in myelodysplastic syndrome

    PubMed Central

    Ebert, Benjamin L.

    2011-01-01

    The 5q- syndrome is a subtype of myelodysplastic syndrome (MDS) with a defined clinical phenotype associated with heterozygous deletions of Chromosome 5q. While no genes have been identified that undergo recurrent homozygous inactivation, functional studies have revealed individual genes that contribute to the clinical phenotype of MDS through haploinsufficient gene expression. Heterozygous loss of the RPS14 gene on 5q leads to activation of p53 in the erythroid lineage and the macrocytic anemia characteristic of the 5q- syndrome. The megakaryocytic and platelet phenotype of the 5q- syndrome has been attributed to heterozygous deletion of miR145 and miR146a. Murine models have implicated heterozygous loss of APC, EGR1, DIAPH1, and NPM1 in the pathophysiology of del(5q) MDS. These findings indicate that the phenotype of MDS patients with deletions of Chromosome 5q is due to haploinsufficiency of multiple genes. PMID:21943668

  9. Acquired Myelodysplasia or Myelodysplastic Syndrome: Clearing the Fog

    PubMed Central

    Natelson, Ethan A.; Pyatt, David

    2013-01-01

    Myelodysplastic syndromes (MDS) are clonal myeloid disorders characterized by progressive peripheral blood cytopenias associated with ineffective myelopoiesis. They are typically considered neoplasms because of frequent genetic aberrations and patient-limited survival with progression to acute myeloid leukemia (AML) or death related to the consequences of bone marrow failure including infection, hemorrhage, and iron overload. A progression to AML has always been recognized among the myeloproliferative disorders (MPD) but occurs only rarely among those with essential thrombocythemia (ET). Yet, the World Health Organization (WHO) has chosen to apply the designation myeloproliferative neoplasms (MPN), for all MPD but has not similarly recommended that all MDS become the myelodysplastic neoplasms (MDN). This apparent dichotomy may reflect the extremely diverse nature of MDS. Moreover, the term MDS is occasionally inappropriately applied to hematologic disorders associated with acquired morphologic myelodysplastic features which may rather represent potentially reversible hematological responses to immune-mediated factors, nutritional deficiency states, and disordered myelopoietic responses to various pharmaceutical, herbal, or other potentially myelotoxic compounds. We emphasize the clinical settings, and the histopathologic features, of such AMD that should trigger a search for a reversible underlying condition that may be nonneoplastic and not MDS. PMID:24194760

  10. Brevundimonas diminuta bacteremia in a man with myelodysplastic syndromes.

    PubMed

    Cao, Huiling; Li, Min; Yang, Xuewen; Zhang, Chunbing

    2015-01-01

    Brevundimonas diminuta are ubiquitous in the environment, but are infrequently isolated from clinical samples. Here we report a case of B. diminuta bacteremia in a man with myelodysplastic syndromes (MDS) at a teaching hospital in China and review the previously reported cases. The organism was confirmed by culture and 16s rRNA sequence analysis with highly sensitivity to broad-spectrum antibiotics. Our report and other cases demonstrated that the optimal therapeutic duration for B. diminuta infections in various situations remains to be established. PMID:26275273

  11. Myelodysplastic Syndrome Presenting as Amegakaryocytic Thrombocytopenia in a Collodion Baby

    PubMed Central

    Al Pakra, Mohammed; Al Jabri, Abdullah; Hanafy, Ehab

    2015-01-01

    We report a rare case of myelodysplastic syndrome that presented early as amegakaryocytic thrombocytopenia in a collodion baby, which is a rare congenital disorder characterized by thick, taut membrane resembling oiled parchment or collodion, which is subsequently shed. To our knowledge, this is the first reported case of a collodion baby who presented with amegakaryocytic thrombocytopenia and who has a significant family history of the same condition. We document the rarity of this possible association and also the need for further study to establish whether a causal relationship exists. PMID:26904703

  12. Myeloid sarcoma of the Gingiva with myelodysplastic syndrome

    PubMed Central

    Jin, Seong-Ho; Park, Gyeongsin; Ko, Youngkyung; Park, Jun-Beom

    2016-01-01

    Abstract The purpose of this report is to present a case of myeloid sarcoma of the gingiva with myelodysplastic syndrome. A 52-year-old male diagnosed with myelodysplastic syndrome with skin lesions presented with gingival swelling and gingival redness involving the maxillary left second premolar and the maxillary left first molar. The patient was referred from the Department of Hematology for a biopsy of the lesion. Full-thickness flaps were elevated and inflamed, and neoplastic soft tissue was removed from a lesion and the samples sent for histopathologic analysis. Histopathologic results showed leukemic cell infiltration beneath the oral epithelium, and the specimen was positive for the leukocyte marker. The diagnosis was myeloid sarcoma. Uneventful healing was observed at 2-week follow-up, but relapse of the lesions with the hyperplastic and neoplastic tissue was noted at 4-week follow-up. Further follow-up or treatment could not be performed because the patient did not visit at the next follow-up. In conclusion, myeloid sarcoma should be a diagnosis option for gingival growth because it can involve intraoral lesion. In this report, a biopsy was performed due to referral considering the patient's medical history. Although myeloid sarcoma in the oral cavity is extremely rare, a small biopsy and consultation with a hematologist may be beneficial for patients and may provide a differential diagnosis. PMID:27310987

  13. Beyond the Niche: Myelodysplastic Syndrome Topobiology in the Laboratory and in the Clinic

    PubMed Central

    Flores-Figueroa, Eugenia; Gratzinger, Dita

    2016-01-01

    We review the murine and human microenvironment and hematopoietic stem cell niche in the context of intact bone marrow architecture in man and mouse, both in normal and in myelodysplastic syndrome marrow. We propose that the complexity of the hematopoietic stem cell niche can usefully be approached in the context of its topobiology, and we provide a model that incorporates in vitro and in vivo models as well as in situ findings from intact human marrow to explain the changes seen in myelodysplastic syndrome patients. We highlight the clinical application of the study of the bone marrow microenvironment and its topobiology in myelodysplastic syndromes. PMID:27089321

  14. Pediatric Short Bowel Syndrome

    PubMed Central

    Spencer, Ariel U.; Neaga, Andreea; West, Brady; Safran, Jared; Brown, Pamela; Btaiche, Imad; Kuzma-O'Reilly, Barbara; Teitelbaum, Daniel H.

    2005-01-01

    Objective: To determine predictors of survival and of weaning off parenteral nutrition (PN) in pediatric short bowel syndrome (SBS) patients. Summary Background Data: Pediatric SBS carries extensive morbidity and high mortality, but factors believed to predict survival or weaning from PN have been based on limited studies. This study reviews outcomes of a large number of SBS infants and identifies predictors of success. Methods: Multivariate Cox proportional hazards analysis was conducted on 80 pediatric SBS patients. Primary outcome was survival; secondary outcome was ability to wean off PN. Nonsignificant covariates were eliminated. P < 0.05 was considered significant. Results: Over a mean of 5.1 years of follow-up, survival was 58 of 80 (72.5%) and 51 weaned off PN (63.8%). Cholestasis (conjugated bilirubin ≥2.5 mg/dL) was the strongest predictor of mortality (relative risk [RR] 22.7, P = 0.005). Although absolute small bowel length was only slightly predictive, percentage of normal bowel length (for a given infant's gestational age) was strongly predictive of mortality (if <10% of normal length, RR of death was 5.7, P = 0.003) and of weaning PN (if ≥10% of normal, RR of weaning PN was 11.8, P = 0.001). Presence of the ileocecal valve (ICV) also strongly predicted weaning PN (RR 3.9, P < 0.0005); however, ICV was not predictive of survival. Conclusions: Cholestasis and age-adjusted small bowel length are the major predictors of mortality in pediatric SBS. Age-adjusted small bowel length and ICV are the major predictors of weaning from PN. These data permit better prediction of outcomes of pediatric SBS, which may help to direct future management of these challenging patients. PMID:16135926

  15. Differential expression of ribosomal proteins in myelodysplastic syndromes.

    PubMed

    Rinker, Elizabeth B; Dueber, Julie C; Qualtieri, Julianne; Tedesco, Jason; Erdogan, Begum; Bosompem, Amma; Kim, Annette S

    2016-02-01

    Aberrations of ribosomal biogenesis have been implicated in several congenital bone marrow failure syndromes, such as Diamond-Blackfan anaemia, Shwachman-Diamond syndrome and Dyskeratosis Congenita. Recent studies have identified haploinsufficiency of RPS14 in the acquired bone marrow disease isolated 5q minus syndrome, a subtype of myelodysplastic syndromes (MDS). However, the expression of various proteins comprising the ribosomal subunits and other proteins enzymatically involved in the synthesis of the ribosome has not been explored in non-5q minus MDS. Furthermore, differences in the effects of these expression alterations among myeloid, erythroid and megakaryocyte lineages have not been well elucidated. We examined the expression of several proteins related to ribosomal biogenesis in bone marrow biopsy specimens from patients with MDS (5q minus patients excluded) and controls with no known myeloid disease. Specifically, we found that there is overexpression of RPS24, DKC1 and SBDS in MDS. This overexpression is in contrast to the haploinsufficiency identified in the congenital bone marrow failure syndromes and in acquired 5q minus MDS. Potential mechanisms for these differences and aetiology for these findings in MDS are discussed. PMID:26408650

  16. Clonal leukemic evolution in myelodysplastic syndromes with TET2 and IDH1/2 mutations

    PubMed Central

    Lin, Tung-Liang; Nagata, Yasunobu; Kao, Hsiao-Wen; Sanada, Masashi; Okuno, Yusuke; Huang, Chein-Fuang; Liang, Der-Cherng; Kuo, Ming-Chung; Lai, Chang-Liang; Lee, En-Hui; Shih, Yu-Shu; Tanaka, Hiroko; Shiraishi, Yuichi; Chiba, Kenichi; Lin, Tung-Huei; Wu, Jin-Hou; Miyano, Satoru; Ogawa, Seishi; Shih, Lee-Yung

    2014-01-01

    Somatic mutations of TET2, IDH1, and IDH2 have been described in myelodysplastic syndrome. The impact of these mutations on outcome of myelodysplastic syndrome and their progression to secondary acute myeloid leukemia remains unclear. Mutation status of TET2, IDH1 and IDH2 was investigated in a cohort of 46 paired myelodysplastic syndrome/acute myeloid leukemia samples and 122 non-paired cases with de novo myelodysplastic syndrome, to clarify their roles in the evolution of myelodysplastic syndrome to acute myeloid leukemia. Among the 168 de novo myelodysplastic syndrome patients, the frequency of TET2, IDH1, and IDH2 mutations was 18.5%, 4.2% and 6.0%, respectively. TET2/IDH mutations had no impact on survivals, while TET2 mutations were significantly associated with rapid progression to acute myeloid leukemia. Seventeen of the 46 paired myelodysplastic syndrome/secondary acute myeloid leukemia samples harbored TET2/IDH mutations; none acquired these mutations in acute myeloid leukemia phase. Progression to acute myeloid leukemia was accompanied by evolution of a novel clone or expansion of a minor pre-existing subclone of one or more distinct mutations in 12 of the 17 cases with TET2/IDH mutations. A minor subclone in 3 cases with biallelic TET2 inactivation subsequently expanded, indicating biallelic TET2 mutations play a role in acute myeloid leukemia progression. Twelve patients acquired other genetic lesions, and/or showed increased relative mutant allelic burden of FLT3-ITD, N/K-RAS, CEBPA or RUNX1 during acute myeloid leukemia progression. Our findings provide a novel insight into the role of TET2/IDH mutation in the pathogenesis of myelodysplastic syndrome and subsequent progression to acute myeloid leukemia. PMID:23996483

  17. Importance of Classical Morphology in the Diagnosis of Myelodysplastic Syndrome

    PubMed Central

    Invernizzi, Rosangela; Quaglia, Federica; Porta, Matteo Giovanni Della

    2015-01-01

    Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders characterized by dysplastic, ineffective, clonal and neoplastic hematopoiesis. MDS represent a complex hematological problem: differences in disease presentation, progression and outcome have necessitated the use of classification systems to improve diagnosis, prognostication, and treatment selection. However, since a single biological or genetic reliable diagnostic marker has not yet been discovered for MDS, quantitative and qualitative dysplastic morphological alterations of bone marrow precursors and peripheral blood cells are still fundamental for diagnostic classification. In this paper, World Health Organization (WHO) classification refinements and current minimal diagnostic criteria proposed by expert panels are highlighted, and related problematic issues are discussed. The recommendations should facilitate diagnostic and prognostic evaluations in MDS and selection of patients for new effective targeted therapies. Although, in the future, morphology should be supplemented with new molecular techniques, the morphological approach, at least for the moment, is still the cornerstone for the diagnosis and classification of these disorders. PMID:25960863

  18. Mesenchymal stem cells in pathogenesis of myelodysplastic syndromes

    PubMed Central

    Wang, Jingya

    2014-01-01

    Myelodysplastic syndromes (MDS) are clonal malignant stem cell disorders characterized by inefficient hematopoiesis. The role of the marrow microenvironment in the pathogenesis of the disease has been controversial. Emerging evidence indicated that mesenchymal stem cells (MSC) derived from MDS patients were cytogenetically abnormal, and they showed a deficient hematopoietic-supportive capacity and increased production of cytokine such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), interferon γ (IFN-γ). From the point of some evidence, the abnormal microenvironment seems to participate in the progression of the disease by contributing to the selective expansion of the malignant clone. In this review, we will discuss the most recent progress related to identification of normal MSC and the importance of the stem cell niche in development and maintenance of MDS.

  19. Graphical representation of clinical outcomes for patients with myelodysplastic syndromes.

    PubMed

    Steensma, David P

    2016-01-01

    The causes of death in patients with myelodysplastic syndromes (MDS) are diverse: infections, hemorrhage, complications of chronic anemia and repeated blood transfusions, and complications of progression to acute myeloid leukemia. Since most patients with MDS are diagnosed late in life, some individuals with MDS will succumb to an unrelated condition, such as one of the disorders that are common in geriatric populations. Currently, only a small proportion of patients with MDS - less than 5% - undergo allogeneic stem cell transplantation, a procedure that offers the only possibility of cure. This brief review summarizes outcomes for patients diagnosed with MDS using a pictographical format that illustrates both the challenges patients face and the pressing need for development of novel therapies, as well as highlighting the potential for increased use of allogeneic stem cell transplant. This informational graphic may be useful for teaching or in counseling certain patients. PMID:26098015

  20. More is better: combination therapies for myelodysplastic syndromes.

    PubMed

    Ornstein, Moshe C; Mukherjee, Sudipto; Sekeres, Mikkael A

    2015-03-01

    The myelodysplastic syndromes (MDS) are a heterogenous collection of clonal hematopoietic malignancies that exist as a subgroup of the myeloid neoplasms as classified by the World Health Organization (WHO). They are characterized by ineffective hematopoiesis, subsequent cytopenias, transformation to acute myeloid leukemia (AML), and poor overall survival. There are currently three FDA-approved medications for MDS; lenalidomide, azacitidine, and decitabine. The role of these agents is to diminish the clinical impact of MDS and delay its progression to AML. However, despite known results with these monotherapies, recent clinical trials with a variety of combinations for MDS have demonstrated promising results. These trials include combinations of hypomethylating agents, histone deacetylase inhibitors, growth factors, and chemotherapy among others. In this paper we review the current literature on combination therapies in MDS, analyze on-going and concluded trials, and suggest future possibilities for combination strategies in MDS. PMID:25659727

  1. [Fungemia caused by Scedosporium prolificans in myelodysplastic syndrome].

    PubMed

    Nishio, Hisaaki; Utsumi, Takahiko; Nakamura, Yukiko; Suzuki, Takayo; Kamei, Katsuhiko; Saitoh, Takashi

    2012-01-01

    We report a case of fungemia caused by Scedosporium prolificans, an emerging pathogen. An 83-year-old man with myelodysplastic syndrome (MDS) and agranulocytosis was admitted for pneumonia in January 2009. He was treated with meropenem, minocycline, and gamma-globulin for pneumonia and G-CSF and platelet transfusion for MDS. Although he recovered from pneumonia as neutrophil count increased, intermittent fever continued. On hospital day 17, blood culture yielded fungal colonies indicating S. prolificans. Voriconazole was started immediately, but the man's general condition deteriorated with cerebral infarction and he died of cerebral hemorrhage on hospital day 65. Attention must therefore be paid to the increasing scedosporiosis incidence in Japan. PMID:22416481

  2. Telomere dysfunction drives aberrant hematopoietic differentiation and Myelodysplastic Syndrome

    PubMed Central

    Colla, Simona; Ong, Derrick Sek Tong; Ogoti, Yamini; Marchesini, Matteo; Mistry, Nipun A.; Clise-Dwyer, Karen; Ang, Sonny A.; Storti, Paola; Viale, Andrea; Giuliani, Nicola; Ruisaard, Kathryn; Gomez, Irene Ganan; Bristow, Christopher A.; Estecio, Marcos; Weksberg, David C.; Ho, Yan Wing; Hu, Baoli; Genovese, Giannicola; Pettazzoni, Piergiorgio; Multani, Asha S.; Jiang, Shan; Hua, Sujun; Ryan, Michael C.; Carugo, Alessandro; Nezi, Luigi; Wei, Yue; Yang, Hui; D’Anca, Marianna; Zhang, Li; Gaddis, Sarah; Gong, Ting; Horner, James W.; Heffernan, Timothy P.; Jones, Philip; Cooper, Laurence J.N.; Liang, Han; Kantarjian, Hagop; Wang, Y. Alan; Chin, Lynda; Bueso-Ramos, Carlos; Garcia-Manero, Guillermo; DePinho, Ronald A.

    2015-01-01

    SUMMARY Myelodysplastic syndrome (MDS) risk correlates with advancing age, therapy-induced DNA damage, and/or shorter telomeres but whether telomere erosion directly induces MDS is unknown. Here, we provide the genetic evidence that telomere dysfunction-induced DNA damage drives classical MDS phenotypes and alters common myeloid progenitor (CMP) differentiation by repressing the expression of mRNA splicing/processing genes, including srsf2. RNA-Seq analyses of telomere dysfunctional CMP identified aberrantly spliced transcripts linked to pathways relevant to MDS pathogenesis such as genome stability, DNA repair, chromatin remodeling and histone modification, which are also enriched in mouse CMP haploinsufficient for srsf2 and in CD34+ CMML patient cells harboring srsf2 mutation. Together, our studies establish an intimate link across telomere biology, aberrant RNA splicing and myeloid progenitor differentiation. PMID:25965571

  3. Molecular dissection of the 5q deletion in myelodysplastic syndrome.

    PubMed

    Ebert, Benjamin L

    2011-10-01

    The 5q-syndrome is a subtype of myelodysplastic syndrome (MDS) with a defined clinical phenotype associated with heterozygous deletions of chromosome 5q. While no genes have been identified that undergo recurrent homozygous inactivation, functional studies have revealed individual genes that contribute to the clinical phenotype of MDS through haplo-insufficient gene expression. Heterozygous loss of the RPS14 gene on 5q leads to activation of p53 in the erythroid lineage and the macrocytic anemia characteristic of the 5q-syndrome. The megakaryocytic and platelet phenotype of the 5q-syndrome has been attributed to heterozygous deletion of miR145 and miR146a. Murine models have implicated heterozygous loss of APC, EGR1, DIAPH1, and NPM1 in the pathophysiology of del(5q) MDS. These findings indicate that the phenotype of MDS patients with deletions of chromosome 5q is due to haplo-insufficiency of multiple genes. PMID:21943668

  4. Myelodysplastic syndromes in Chernobyl clean-up workers.

    PubMed

    Gluzman, Daniil F; Sklyarenko, Lilia M; Koval, Stella V; Rodionova, Nataliia K; Zavelevich, Michael P; Ivanivskaya, Tetiana S; Poludnenko, Liudmyla Yu; Ukrainskaya, Nataliia I

    2015-10-01

    The studies of the recent decades posed the question of the association between radiation exposure and myelodysplastic syndromes (MDS). This association has been proved in secondary MDS originating upon exposure to chemotherapeutics and/or radiation therapy. The long-term study in Japanese atomic (A)-bomb survivors demonstrated the significant linear dose-response for MDS confirming the link between radiation exposure and this form of hematopoietic malignancies. All these findings provide the strong basis for studying MDS in the persons exposed to radiation following the Chernobyl disaster, especially those in the cohort of Chernobyl clean-up workers of 1986-1987. The data on MDS among Chernobyl clean-up workers (1986-1987) diagnosed in 1996-2012 at the reference laboratory of RE Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology are summarized. MDS cases were diagnosed in 23 persons (21 males and 2 females) having been exposed to radiation as clean-up workers of 1986-1987. Refractory anemia (RA) has been detected in 13, refractory anemia with ring sideroblasts (RARS)-in 2, and refractory anemia with excess blasts (RAEB)-in 8 patients. The median age of those MDS patients was 62.0 years. In addition, 5 cases of chronic myelomonocytic leukemia (CMML) were recorded in the group of Chernobyl clean-up workers with the median time of 14.8 years from 1986-1987 to diagnosis. The association between radiation exposure and MDS is discussed. The suggested life-long risk for myelodysplastic syndromes among A-bomb survivors in Japan highlights the importance of the continuing follow-up studies in the affected populations in the post-Chernobyl period. PMID:26208666

  5. Causes of death in 2877 patients with myelodysplastic syndromes.

    PubMed

    Nachtkamp, Kathrin; Stark, Romina; Strupp, Corinna; Kündgen, Andrea; Giagounidis, Aristoteles; Aul, Carlo; Hildebrandt, Barbara; Haas, Rainer; Gattermann, Norbert; Germing, Ulrich

    2016-05-01

    Patients with myelodysplastic syndromes face a poor prognosis. The exact causes of death have not been described properly in the past. We performed a retrospective analysis of causes of death using data of 3792 patients in the Düsseldorf registry who have been followed up for a median time of 21 months. Medical files as well as death certificates were screened and primary care physicians were contacted. Death after AML evolution, infection, and bleeding was considered to be clearly disease-related. Further categories of causes of death were heart failure, other possibly disease-related reasons, such as hemochromatosis, disease-independent reasons as well as cases with unclear causes of death. Median age at the time of diagnosis was 71 years. At the time of analysis, 2877 patients (75.9 %) had deceased. In 1212 cases (42.1 %), the exact cause of death could not be ascertained. From 1665 patients with a clearly documented cause of death, 1388 patients (83.4 %) succumbed directly disease-related (AML (46.6 %), infection (27.0 %), bleeding (9.8 %)), whereas 277 patients (16.6 %) died for reasons not directly related with myelodysplastic syndromes (MDS), including 132 patients with cardiac failure, 77 non-disease-related reasons, 23 patients with solid tumors, and 45 patients with possibly disease-related causes like hemochromatosis. Correlation with IPSS, IPSS-R, and WPSS categories showed a proportional increase of disease-related causes of death with increasing IPSS/IPSS-R/WPSS risk category. Likewise, therapy-related MDS were associated with a higher percentage of disease-related causes of death than primary MDS. This reflects the increasing influence of the underlying disease on the cause of death with increasing aggressiveness of the disease. PMID:27025507

  6. Therapeutic approaches in myelofibrosis and myelodysplastic/myeloproliferative overlap syndromes.

    PubMed

    Sochacki, Andrew L; Fischer, Melissa A; Savona, Michael R

    2016-01-01

    The discovery of JAK2 (V617F) a decade ago led to optimism for a rapidly developing treatment revolution in Ph(-) myeloproliferative neoplasms. Unlike BCR-ABL, however, JAK2 was found to have a more heterogeneous role in carcinogenesis. Therefore, for years, development of new therapies was slow, despite standard treatment options that did not address the overwhelming symptom burden in patients with primary myelofibrosis (MF), post-essential thrombocythemia MF, post-polycythemia vera MF, and myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) syndromes. JAK-STAT inhibitors have changed this, drastically ameliorating symptoms and ultimately beginning to show evidence of impact on survival. Now, the genetic foundations of myelofibrosis and MDS/MPN are rapidly being elucidated and contributing to targeted therapy development. This has been empowered through updated response criteria for MDS/MPN and refined prognostic scoring systems in these diseases. The aim of this article is to summarize concisely the current and rationally designed investigational therapeutics directed at JAK-STAT, hedgehog, PI3K-Akt, bone marrow fibrosis, telomerase, and rogue epigenetic signaling. The revolution in immunotherapy and novel treatments aimed at previously untargeted signaling pathways provides hope for considerable advancement in therapy options for those with chronic myeloid disease. PMID:27143923

  7. Myelodysplastic syndromes: pathogenesis, functional abnormalities, and clinical implications.

    PubMed Central

    Jacobs, A

    1985-01-01

    The myelodysplastic syndromes represent a preleukaemic state in which a clonal abnormality of haemopoietic stem cell is characterised by a variety of phenotypic manifestations with varying degrees of ineffective haemopoiesis. This state probably develops as a sequence of events in which the earliest stages may be difficult to detect by conventional pathological techniques. The process is characterised by genetic changes leading to abnormal control of cell proliferation and differentiation. Expansion of an abnormal clone may be related to independence from normal growth factors, insensitivity to normal inhibitory factors, suppression of normal clonal growth, or changes in the immunological or nutritional condition of the host. The haematological picture is of peripheral blood cytopenias: a cellular bone marrow, and functional abnormalities of erythroid, myeloid, and megakaryocytic cells. In most cases marrow cells have an abnormal DNA content, often with disturbances of the cell cycle: an abnormal karyotype is common in premalignant clones. Growth abnormalities of erythroid or granulocyte-macrophage progenitors are common in marrow cultures, and lineage specific surface membrane markers indicate aberrations of differentiation. Progression of the disorder may occur through clonal expansion or through clonal evolution with a greater degree of malignancy. Current attempts to influence abnormal growth and differentiation have had only limited success. Clinical recognition of the syndrome depends on an acute awareness of the signs combined with the identification of clonal and functional abnormalities. PMID:2999194

  8. Therapeutic approaches in myelofibrosis and myelodysplastic/myeloproliferative overlap syndromes

    PubMed Central

    Sochacki, Andrew L; Fischer, Melissa A; Savona, Michael R

    2016-01-01

    The discovery of JAK2V617F a decade ago led to optimism for a rapidly developing treatment revolution in Ph− myeloproliferative neoplasms. Unlike BCR–ABL, however, JAK2 was found to have a more heterogeneous role in carcinogenesis. Therefore, for years, development of new therapies was slow, despite standard treatment options that did not address the overwhelming symptom burden in patients with primary myelofibrosis (MF), post-essential thrombocythemia MF, post-polycythemia vera MF, and myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) syndromes. JAK–STAT inhibitors have changed this, drastically ameliorating symptoms and ultimately beginning to show evidence of impact on survival. Now, the genetic foundations of myelofibrosis and MDS/MPN are rapidly being elucidated and contributing to targeted therapy development. This has been empowered through updated response criteria for MDS/MPN and refined prognostic scoring systems in these diseases. The aim of this article is to summarize concisely the current and rationally designed investigational therapeutics directed at JAK–STAT, hedgehog, PI3K–Akt, bone marrow fibrosis, telomerase, and rogue epigenetic signaling. The revolution in immunotherapy and novel treatments aimed at previously untargeted signaling pathways provides hope for considerable advancement in therapy options for those with chronic myeloid disease. PMID:27143923

  9. Common pediatric epilepsy syndromes.

    PubMed

    Park, Jun T; Shahid, Asim M; Jammoul, Adham

    2015-02-01

    Benign rolandic epilepsy (BRE), childhood idiopathic occipital epilepsy (CIOE), childhood absence epilepsy (CAE), and juvenile myoclonic epilepsy (JME) are some of the common epilepsy syndromes in the pediatric age group. Among the four, BRE is the most commonly encountered. BRE remits by age 16 years with many children requiring no treatment. Seizures in CAE also remit at the rate of approximately 80%; whereas, JME is considered a lifelong condition even with the use of antiepileptic drugs (AEDs). Neonates and infants may also present with seizures that are self-limited with no associated psychomotor disturbances. Benign familial neonatal convulsions caused by a channelopathy, and inherited in an autosomal dominant manner, have a favorable outcome with spontaneous resolution. Benign idiopathic neonatal seizures, also referred to as "fifth-day fits," are an example of another epilepsy syndrome in infants that carries a good prognosis. BRE, CIOE, benign familial neonatal convulsions, benign idiopathic neonatal seizures, and benign myoclonic epilepsy in infancy are characterized as "benign" idiopathic age-related epilepsies as they have favorable implications, no structural brain abnormality, are sensitive to AEDs, have a high remission rate, and have no associated psychomotor disturbances. However, sometimes selected patients may have associated comorbidities such as cognitive and language delay for which the term "benign" may not be appropriate. PMID:25658216

  10. Platelet Proteome Analysis Reveals Integrin-dependent Aggregation Defects in Patients with Myelodysplastic Syndromes*

    PubMed Central

    Fröbel, Julia; Cadeddu, Ron-Patrick; Hartwig, Sonja; Bruns, Ingmar; Wilk, Christian M.; Kündgen, Andrea; Fischer, Johannes C.; Schroeder, Thomas; Steidl, Ulrich G.; Germing, Ulrich; Lehr, Stefan; Haas, Rainer; Czibere, Akos

    2013-01-01

    Bleeding complications are a significant clinical problem in patients with myelodysplastic syndromes even at sufficient platelet counts (>50,000/μl). However, the underlying pathology of this hemorrhagic diathesis is still unknown. Here, we analyzed the platelet proteome of patients with myelodysplastic syndromes by quantitative two-dimensional difference gel electrophoresis followed by mass spectrometric protein identification. Proteins identified with lower concentrations, such as Talin-1, Vinculin, Myosin-9, Filmain-A, and Actin play critical roles in integrin αIIbβ3 signaling and thus platelet aggregation. Despite normal agonist receptor expression, calcium flux, and granule release upon activation, the activation capacity of integrin αIIbβ3 was diminished in myelodysplastic syndrome platelets. Förster resonance energy transfer analysis showed a reduced co-localization of Talin-1 to the integrin's β3-subunit, which is required for receptor activation and fibrinogen binding. In addition, platelet spreading on immobilized fibrinogen was incomplete, and platelet aggregation assays confirmed a general defect in integrin-dependent platelet aggregation in patients with myelodysplastic syndromes. Our data provide novel aspects on the molecular pathology of impaired platelet function in myelodysplastic syndromes and suggest a mechanism of defective integrin αIIbβ3 signaling that may contribute to the hemorrhagic diathesis observed in these patients. PMID:23382103

  11. The Brazilian Pediatric Myelodysplastic Cooperative Group strategies: are they relevant to improve educational approach and correct diagnosis?

    PubMed

    Lopes, Luiz Fernando; Lorand-Metze, Irene; Niero-Melo, Ligia; Tone, Luiz Gonzaga; Velloso, Elvira; Campanaro, Célia Martins; Latorre, Maria do Rosário

    2002-07-01

    Brazil is a wide country with huge contrasts. Its peculiarities can highlight environmental factors that could influence the frequencies of different cancers. The standard treatment and results achieved from several different areas of the country may not be found in others. The establishment of a national cooperative group has the potential to improve outcomes. The The Brazilian Cooperative Group on Pediatric Patients with Myelodysplastic Syndrome (BCG-MDS-PED) was first organized in January 1997 as a working group of hematologists, pediatric oncologists, pediatric-hematologists, molecular biologists and other professionals in order to study pediatric (age <18 years) MDS. Six distinct subcommittees constituted with members from several universities: cytology, histopathology, clinical, cytogenetics, molecular biology and epidemiology. The goals of the BCG-MDS-PED were: (i) to offer support for diagnosis and orientation for treatment; (ii) educational support for the colleagues all over the country and (iii) research on pathogenesis and new approaches for pediatric MDS patients. There are socio-economical differences among the five regions of the country. The BCG-MDS-PED believes that it is absolutely necessary to study the clinical, cellular, molecular and epidemiological aspects of MDS, taking in account these peculiar differences among populations and regions. Since 1997, 114 pediatric cases were referred to the BCG-MDS-PED from 21 centres. Seven Brazilian states have sent cases to the group, 31 patients were referred from universities, 73 patients from pediatric oncology units (foundations ) and 10 patients came from private clinics. Some of these patients have been followed up and/or treated by the physician who referred them to the BCG-MDS-PED for confirmation of the initial diagnosis. The majority of these physicians have required orientation on diagnostic and treatment issues, as well as to complete cytogenetic and molecular studies. From these 114 patients

  12. Tea consumption reduces the risk of de novo myelodysplastic syndromes.

    PubMed

    Liu, Ping; Zhang, Min; Jin, Jie; Holman, C D'Arcy J

    2015-02-01

    Epidemiologic data suggest that green tea consumption may protect against certain cancers, but no previous study has examined myelodysplastic syndromes (MDS). A hospital-based case-control study was conducted in China in 2012-2013 to investigate the association between tea intake and the risk of de novo MDS in adults. The study included 208 cases aged 19-85 years with MDS and 208 controls individually matched to the cases by gender, 5-year age group and residential locality. Odds ratios (ORs) were estimated using conditional logistic regression. Compared with non-tea drinkers, the adjusted ORs (95% confidence intervals) for all MDS combined were 0.39 (0.20-0.74), 0.45 (0.25-0.79), and 0.40 (0.21-0.77) for those who consumed tea >20 years, ≥2 cups daily, and dried tealeaves ≥750g per annum, respectively. Significant dose-response trends were observed across all the measures. The inverse association existed in both genders, in the refractory anemia with excessive blasts subtype, in cytogenetic 'good' and 'intermediated/poor' prognosis groups, and in the International Prognostic Scoring System lower and higher risk groups, but not in the refractory cytopenia with multilineage dysplasia subtype. The study suggests that regular tea consumption reduces the risk of de novo MDS in the Chinese population. PMID:25529769

  13. UNRELATED DONOR BONE MARROW TRANSPLANTATION FOR MYELODYSPLASTIC SYNDROME IN CHILDREN

    PubMed Central

    Woodard, Paul; Carpenter, Paul A.; Davies, Stella M.; Gross, Thomas G.; He, Wensheng; Zhang, Mei-Jie; Horn, Biljana N.; Margolis, David A.; Perentesis, John P.; Sanders, Jean E.; Schultz, Kirk R.; Seber, Adriana; Woods, William G.; Eapen, Mary

    2010-01-01

    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. PMID:20813197

  14. Acute Myeloid Leukemia and Myelodysplastic Syndromes in Older Adults

    PubMed Central

    Klepin, Heidi D.; Rao, Arati V.; Pardee, Timothy S.

    2014-01-01

    Treatment of older adults with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) is challenging because of disease morbidity and associated treatments. Both diseases represent a genetically heterogeneous group of disorders primarily affecting older adults, with treatment strategies ranging from supportive care to hematopoietic stem-cell transplantation. Although selected older adults can benefit from intensive therapies, as a group they experience increased treatment-related morbidity, are more likely to relapse, and have decreased survival. Age-related outcome disparities are attributed to both tumor and patient characteristics, requiring an individualized approach to treatment decision making beyond consideration of chronologic age alone. Selection of therapy for any individual requires consideration of both disease-specific risk factors and estimates of treatment tolerance and life expectancy derived from evaluation of functional status and comorbidity. Although treatment options for older adults are expanding, clinical trials accounting for the heterogeneity of tumor biology and aging are needed to define standard-of-care treatments for both disease groups. In addition, trials should include outcomes addressing quality of life, maintenance of independence, and use of health care services to assist in patient-centered decision making. This review will highlight available evidence in treatment of older adults with AML or MDS and unanswered clinical questions for older adults with these diseases. PMID:25071138

  15. Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes

    PubMed Central

    Gañán-Gómez, I; Wei, Y; Starczynowski, DT; Colla, S; Yang, H; Cabrero-Calvo, M; Bohannan, ZS; Verma, A; Steidl, U; Garcia-Manero, G

    2016-01-01

    Myelodysplastic syndromes (MDSs) are a group of heterogeneous clonal hematologic malignancies that are characterized by defective bone marrow (BM) hematopoiesis and by the occurrence of intramedullary apoptosis. During the past decade, the identification of key genetic and epigenetic alterations in patients has improved our understanding of the pathophysiology of this disease. However, the specific molecular mechanisms leading to the pathogenesis of MDS have largely remained obscure. Recently, essential evidence supporting the direct role of innate immune abnormalities in MDS has been obtained, including the identification of multiple key regulators that are overexpressed or constitutively activated in BM hematopoietic stem and progenitor cells. Mounting experimental results indicate that the dysregulation of these molecules leads to abnormal hematopoiesis, unbalanced cell death and proliferation in patients' BM, and has an important role in the pathogenesis of MDS. Furthermore, there is compelling evidence that the deregulation of innate immune and inflammatory signaling also affects other cells from the immune system and the BM microenvironment, which establish aberrant associations with hematopoietic precursors and contribute to the MDS phenotype. Therefore, the deregulation of innate immune and inflammatory signaling should be considered as one of the driving forces in the pathogenesis of MDS. In this article, we review and update the advances in this field, summarizing the results from the most recent studies and discussing their clinical implications. PMID:25761935

  16. Azacitidine: A Review in Myelodysplastic Syndromes and Acute Myeloid Leukaemia.

    PubMed

    Scott, Lesley J

    2016-05-01

    Azacitidine (Vidaza(®)) is a pyrimidine nucleoside analogue of cytidine and is approved in the EU for use in patients with higher-risk myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), including older patients (aged ≥65 years) with AML with >30 % bone marrow blasts (BMB) who are ineligible for haematopoietic stem cell transplant. This article reviews the clinical efficacy and tolerability of azacitidine in the treatment of these patient populations, as well as summarizing its pharmacological properties. In pivotal, international, phase 3 trials, subcutaneous azacitidine was an effective and well tolerated treatment in patients with higher-risk MDS or AML, including older patients with AML with >30 % BMB, with extensive evidence from the real-world setting confirming its efficacy and safety in these patient populations. Azacitidine is the only approved hypomethylating agent that has been shown to prolong overall survival compared with conventional care regimens and thus, it is recommended as the first-line hypomethylating agent for most patients with higher-risk MDS. Hence, azacitidine remains and important agent for use in the treatment of higher-risk MDS and AML, including in older patients with AML with >30 % BMB. PMID:27193945

  17. Revised international prognostic scoring system for myelodysplastic syndromes.

    PubMed

    Greenberg, Peter L; Tuechler, Heinz; Schanz, Julie; Sanz, Guillermo; Garcia-Manero, Guillermo; Solé, Francesc; Bennett, John M; Bowen, David; Fenaux, Pierre; Dreyfus, Francois; Kantarjian, Hagop; Kuendgen, Andrea; Levis, Alessandro; Malcovati, Luca; Cazzola, Mario; Cermak, Jaroslav; Fonatsch, Christa; Le Beau, Michelle M; Slovak, Marilyn L; Krieger, Otto; Luebbert, Michael; Maciejewski, Jaroslaw; Magalhaes, Silvia M M; Miyazaki, Yasushi; Pfeilstöcker, Michael; Sekeres, Mikkael; Sperr, Wolfgang R; Stauder, Reinhard; Tauro, Sudhir; Valent, Peter; Vallespi, Teresa; van de Loosdrecht, Arjan A; Germing, Ulrich; Haase, Detlef

    2012-09-20

    The International Prognostic Scoring System (IPSS) is an important standard for assessing prognosis of primary untreated adult patients with myelodysplastic syndromes (MDS). To refine the IPSS, MDS patient databases from international institutions were coalesced to assemble a much larger combined database (Revised-IPSS [IPSS-R], n = 7012, IPSS, n = 816) for analysis. Multiple statistically weighted clinical features were used to generate a prognostic categorization model. Bone marrow cytogenetics, marrow blast percentage, and cytopenias remained the basis of the new system. Novel components of the current analysis included: 5 rather than 3 cytogenetic prognostic subgroups with specific and new classifications of a number of less common cytogenetic subsets, splitting the low marrow blast percentage value, and depth of cytopenias. This model defined 5 rather than the 4 major prognostic categories that are present in the IPSS. Patient age, performance status, serum ferritin, and lactate dehydrogenase were significant additive features for survival but not for acute myeloid leukemia transformation. This system comprehensively integrated the numerous known clinical features into a method analyzing MDS patient prognosis more precisely than the initial IPSS. As such, this IPSS-R should prove beneficial for predicting the clinical outcomes of untreated MDS patients and aiding design and analysis of clinical trials in this disease. PMID:22740453

  18. A Rare Case of Myelodysplastic Syndrome with Refractory Thrombocytopenia

    PubMed Central

    Jehangir, Waqas; Webb, John; Singh, Shilpi; Arshed, Sabrina; Sen, Shuvendu; Yousif, Abdalla

    2015-01-01

    Myelodysplastic syndromes (MDS) represent a variety of clonal abnormalities, possibly preleukemic and display numerous phenotypic manifestations. Specific mutations carry high morbidity and mortality rates due to cell line dysplasia. MDS commonly presents with symptoms related to anemia, and approximately two-thirds will develop thrombocytopenia, a rare, but potentially lethal complication that increases complexity in treatment and morbidity, and may be due to unique genetic mutations leading to refractory thrombocytopenia, ultimately leading to an overall reduction in survival. Careful identification and monitoring of this patient subdivision can significantly reduce morbidity and mortality, and potential identification of specific gene mutations and advances in treatment options will hopefully provide guidance on detecting at-risk patients in the future. We present a case of a man with MDS-U (karyotype 46, XY, del (20) (q11.2q13.3) (20) with no detected JAK2 V617F mutation), who in despite of appropriate evidenced based treatment, continued to exhibit refractory thrombocytopenia. PMID:26487931

  19. A Rare Case of Myelodysplastic Syndrome with Refractory Thrombocytopenia.

    PubMed

    Jehangir, Waqas; Webb, John; Singh, Shilpi; Arshed, Sabrina; Sen, Shuvendu; Yousif, Abdalla

    2015-09-23

    Myelodysplastic syndromes (MDS) represent a variety of clonal abnormalities, possibly preleukemic and display numerous phenotypic manifestations. Specific mutations carry high morbidity and mortality rates due to cell line dysplasia. MDS commonly presents with symptoms related to anemia, and approximately two-thirds will develop thrombocytopenia, a rare, but potentially lethal complication that increases complexity in treatment and morbidity, and may be due to unique genetic mutations leading to refractory thrombocytopenia, ultimately leading to an overall reduction in survival. Careful identification and monitoring of this patient subdivision can significantly reduce morbidity and mortality, and potential identification of specific gene mutations and advances in treatment options will hopefully provide guidance on detecting at-risk patients in the future. We present a case of a man with MDS-U (karyotype 46, XY, del (20) (q11.2q13.3) (20) with no detected JAK2 V617F mutation), who in despite of appropriate evidenced based treatment, continued to exhibit refractory thrombocytopenia. PMID:26487931

  20. Costs and quality of life in patients with myelodysplastic syndromes

    PubMed Central

    Lucioni, Carlo; Finelli, Carlo; Mazzi, Silvio; Oliva, Esther N

    2013-01-01

    Myelodysplastic syndromes (MDS) encompass a range of myeloid neoplasms characterised by a defect in haematopoietic stem cell maturation, resulting in peripheral cytopenias. As a major consequence, most MDS patients become anaemic, so as to require red blood cell transfusions. To investigate the costs and the impact on quality of life (QOL) of MDS-separately in transfusion-independent (TI) and -dependent (TD) patients-a literature search was conducted. From Medline and Embase, 742 studies were identified, of which 17 were considered eligible. Total medical costs per patient/year range from $ 9,840 to $ 19,811 for the TI condition and from $ 29,608 to $ 51,066 in the TD condition, more than doubling when moving from the former condition to the latter. With regard to QOL, in the transition from TI to TD, QOL could be reduced by half depending on the studies. The TD condition negatively impacts on costs and the QOL of patients with MDS. Therapeutic strategies that reduce transfusion dependence may lead to broad benefits for patients and the community. PMID:23997987

  1. Epidemiology and risk factors for infections in myelodysplastic syndromes.

    PubMed

    Sullivan, L R; Sekeres, M A; Shrestha, N K; Maciejewski, J P; Tiu, R V; Butler, R; Mossad, S B

    2013-12-01

    We conducted a case-control study to describe the epidemiology and risk factors for infections requiring hospitalization in patients with myelodysplastic syndromes (MDS). Of 497 patients identified, 103 patients developed 201 episodes of infection. The probability of acquiring an infection 1 year from date of MDS diagnosis was 15% (95% confidence interval [CI] 12-18%). Patients developing infections had decreased survival compared to those who did not (P = 0.007). Significant risk factors for infection were higher risk MDS (hazard ratio [HR] = 2.7, 95% CI = 1.7-4.1, P < 0.0001), nadir absolute neutrophil count <500/mL (HR = 1.8, 95% CI = 1.2-2.7, P < 0.007), chronic obstructive pulmonary disease (HR = 2.6, 95% CI = 1.4-4.9, P < 0.003), history of other malignancy (HR 2.0, 95% CI = 1.3-3.1, P < 0.003), and autoimmune disease (HR 2.9, 95% CI = 1.4-6.0, P < 0.005). Age, nadir platelet count <20,000/mL, diabetes mellitus, and MDS treatment were not significant risk factors. Pneumonia was the most common infection, and bacteria the predominant pathogens. PMID:24010918

  2. Clonal diversity of recurrently mutated genes in myelodysplastic syndromes

    PubMed Central

    Walter, MJ; Shen, D; Shao, J; Ding, L; White, BS; Kandoth, C; Miller, CA; Niu, B; McLellan, MD; Dees, ND; Fulton, R; Elliot, K; Heath, S; Grillot, M; Westervelt, P; Link, DC; DiPersio, JF; Mardis, E; Ley, TJ; Wilson, RK; Graubert, TA

    2013-01-01

    Recent studies suggest that most cases of myelodysplastic syndrome (MDS) are clonally heterogeneous, with a founding clone and multiple subclones. It is not known whether specific gene mutations typically occur in founding clones or subclones. We screened a panel of 94 candidate genes in a cohort of 157 patients with MDS or secondary acute myeloid leukemia (sAML). This included 150 cases with samples obtained at MDS diagnosis and 15 cases with samples obtained at sAML transformation (8 were also analyzed at the MDS stage). We performed whole-genome sequencing (WGS) to define the clonal architecture in eight sAML genomes and identified the range of variant allele frequencies (VAFs) for founding clone mutations. At least one mutation or cytogenetic abnormality was detected in 83% of the 150 MDS patients and 17 genes were significantly mutated (false discovery rate ≤0.05). Individual genes and patient samples displayed a wide range of VAFs for recurrently mutated genes, indicating that no single gene is exclusively mutated in the founding clone. The VAFs of recurrently mutated genes did not fully recapitulate the clonal architecture defined by WGS, suggesting that comprehensive sequencing may be required to accurately assess the clonal status of recurrently mutated genes in MDS. PMID:23443460

  3. Discovering Transcription and Splicing Networks in Myelodysplastic Syndromes

    PubMed Central

    Wang, Hongyan; Wen, Jianguo; Chang, Chung-che; Zhou, Xiaobo

    2013-01-01

    More and more transcription factors and their motifs have been reported and linked to specific gene expression levels. However, focusing only on transcription is not sufficient for mechanism research. Most genes, especially in eukaryotes, are alternatively spliced to different isoforms. Some of these isoforms increase the biodiversity of proteins. From this viewpoint, transcription and splicing are two of important mechanisms to modulate expression levels of isoforms. To integrate these two kinds of regulation, we built a linear regression model to select a subset of transcription factors and splicing factors for each co-expressed isoforms using least-angle regression approach. Then, we applied this method to investigate the mechanism of myelodysplastic syndromes (MDS), a precursor lesion of acute myeloid leukemia. Results suggested that expression levels of most isoforms were regulated by a set of selected regulatory factors. Some of the detected factors, such as EGR1 and STAT family, are highly correlated with progression of MDS. We discovered that the splicing factor SRSF11 experienced alternative splicing switch, and in turn induced different amino acid sequences between MDS and controls. This splicing switch causes two different splicing mechanisms. Polymerase Chain Reaction experiments also confirmed that one of its isoforms was over-expressed in MDS. We analyzed the regulatory networks constructed from the co-expressed isoforms and their regulatory factors in MDS. Many of these networks were enriched in the herpes simplex infection pathway which involves many splicing factors, and pathways in cancers and acute or chronic myeloid leukemia. PMID:24244432

  4. Myelodysplastic Syndromes in the Elderly: Treatment Options and Personalized Management.

    PubMed

    Burgstaller, Sonja; Wiesinger, Petra; Stauder, Reinhard

    2015-11-01

    Myelodysplastic syndromes (MDS) are typical diseases of the elderly, with a median age of 68-75 years at initial diagnosis. Demographic changes producing an increased proportion of elderly in our societies mean the incidence of MDS will rise dramatically. Considering the increasing number of treatment options, ranging from best supportive care to hematopoietic stem cell transplantation (HSCT), decision making is rather complex in this cohort of patients. Moreover, aspects of the aging process also have to be considered in therapy planning. Treatment of elderly MDS patients is dependent on the patient's individual risk and prognosis. Comorbidities play an essential role as predictors of survival and therapy tolerance. Age-adjusted models and the use of geriatric assessment scores are described as a basis for individualized treatment algorithms. Specific treatment recommendations for the different groups of patients are given. Currently available therapeutic agents, including supportive care, erythropoiesis-stimulating agents (ESAs), immune-modulating agents, hypomethylating agents, and HSCT are described in detail and discussed with a special focus on elderly MDS patients. The inclusion of elderly patients in clinical trials is of utmost importance to obtain data on efficacy and safety in this particular group of patients. Endpoints relevant for the elderly should be integrated, including maintenance of quality of life and functional activities as well as evaluation of use of healthcare resources. PMID:26476843

  5. [Amifostine used in the treatment of patients with myelodysplastic syndrome].

    PubMed

    Li, Shu-Xia; Zhu, Hong-Li; Lu, Xue-Chun; Fan, Hui; Yao, Shan-Qian; Ma, Jian; Yang, Qing-Ming; Cai, Li-Li; Zhuang, Xiao-Meng; Yang, Yang

    2007-02-01

    The study was aimed to investigate the curative effects and adverse effects of amifostine in the treatment of patients with myelodysplastic syndrome (MDS). Amifostine (AMF) was used alone (4/12) or combined with recombinant human erythropoietin (rh-EPO) (8/12) in 12 MDS patients. The therapeutic regimen was adopted with AMF 0.4 g/day for 5 days, then took a break of 2 days and then went on for 3 weeks consecutively, that was reputed as one treatment cycle. rh-EPO 6 000 U was used for 3 days per week. The results showed that 12 patients all attained hematological improvement in peripheral blood. 11 cases showed major effective response rate (91.7%), while 1 case showed minor response rate (8.3%). The effective response rate of hemoglobin, leukocytes and platelets was 100%, 75% and 58.3% respectively. The intervals of red cell transfusions (RCT) in 2 cases living on red cell transfusion before AMF treatment were prolonged after AMF treatments, and the amount of each RCT was decreased obviously. The side effect was usually discomfort of digestive system, but all patients can endure. In conclusion, Amifostine is a potential drug in the treatment of MDS patients with safety especially to those elder patients who often suffered from other multiple organ disfunctions, and the curative effect will be improved by more treatment cycles. PMID:17490528

  6. Diagnostic Utility of Flow Cytometry in Myelodysplastic Syndromes

    PubMed Central

    Aanei, Carmen Mariana; Picot, Tiphanie; Tavernier, Emmanuelle; Guyotat, Denis; Campos Catafal, Lydia

    2016-01-01

    Myelodysplastic syndromes (MDSs) are clonal disorders of hematopoiesis that exhibit heterogeneous clinical presentation and morphological findings, which complicates diagnosis, especially in early stages. Recently, refined definitions and standards in the diagnosis and treatment of MDS were proposed, but numerous questions remain. Multiparameter flow cytometry (MFC) is a helpful tool for the diagnostic workup of patients with suspected MDS, and various scores using MFC data have been developed. However, none of these methods have achieved the sensitivity that is required for a reassuring diagnosis in the absence of morphological abnormalities. One reason may be that each score evaluates one or two lineages without offering a broad view of the dysplastic process. The combination of two scores (e.g., Ogata and Red Score) improved the sensitivity from 50–60 to 88%, but the positive (PPV) and negative predictive values (NPV) must be improved. There are prominent differences between study groups when these scores are tested. Further research is needed to maximize the sensitivity of flow cytometric analysis in MDS. This review focuses on the application of flow cytometry for MDS diagnosis and discusses the advantages and limitations of different approaches. PMID:27446807

  7. Cytogenetic profile of Indian patients with de novo myelodysplastic syndromes

    PubMed Central

    Chaubey, Rekha; Sazawal, Sudha; Dada, Rima; Mahapatra, Manoranjan; Saxena, Renu

    2011-01-01

    Background & objectives: Myelodysplastic syndrome (MDS) is a clonal haematopoietic stem cell disorder characterized by ineffective haematopoiesis and leukaemia progression. Cytogenetic analysis has proven to be a mandatory part of the diagnosis of MDS as well as a major indicator for predicting clinical course and outcome. Studies on cytogenetics of MDS are reported mostly from the West and only a few are available from Asian countries. We report herein cytogenetic studies on 40 Indian patients with primary MDS to find out the occurrence and type of chromosome abnormalities and recurring defects. Methods: Cytogenetic analysis was done using GTG banding and karyotyped according to the International System for Human Cytogenetic Nomenclature (ISCN). Results: Of the 40 patients, 19 patients (47.5%) showed clonal karyotypic abnormalities with distribution as follows: 3 of 15 (20%) of refractory anaemia (RA), 4 of 7 (57%) of refractory anaemia with excess blasts-1 (RAEB-1), 4 of 6 (67%) of refractory anaemia with excess blasts 2 (RAEB-2), 2 of 3 (67%) of refractory anaemia with ring sideroblasts (RARS), 2 of 4 (50%) of refractory cytopenia with multilineage dysplasia (RCMD), none (0%) RCMD-ringed sideroblasts (RCMD-RS) and 4 patients with 5q syndrome. The frequent abnormalities observed in our study were -7, 5q-and trisomy 8. Interpretation & conclusions: Two rare chromosomal abnormalities (6q-, 3q-) were found with unknown prognostic significance. Hence, cytogenetic analysis may be incorporated in the routine diagnosis of MDS since there are racial differences in clinical pictures and the molecular events. PMID:22089606

  8. Cyclophosphamide and Busulfan Followed by Donor Stem Cell Transplant in Treating Patients With Myelofibrosis, Acute Myeloid Leukemia, or Myelodysplastic Syndrome

    ClinicalTrials.gov

    2014-04-03

    Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Childhood Acute Myeloid Leukemia in Remission; Childhood Myelodysplastic Syndromes; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Myelodysplastic Syndrome With Isolated Del(5q); Polycythemia Vera; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Secondary Myelofibrosis; Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

  9. CPX-351 in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

    ClinicalTrials.gov

    2016-04-25

    Adult Acute Erythroid Leukemia (M6); Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia and Acute Monocytic Leukemia (M5); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

  10. Laboratory-Treated T Cells in Treating Patients With High-Risk Relapsed Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Chronic Myelogenous Leukemia Previously Treated With Donor Stem Cell Transplant

    ClinicalTrials.gov

    2016-08-08

    Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Adult Myelodysplastic Syndrome; Childhood Myelodysplastic Syndrome; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Secondary Acute Myeloid Leukemia; Therapy-Related Acute Myeloid Leukemia

  11. Association between mitochondrial DNA haplogroup and myelodysplastic syndromes.

    PubMed

    Poynter, Jenny N; Richardson, Michaela; Langer, Erica; Hooten, Anthony J; Roesler, Michelle; Hirsch, Betsy; Nguyen, Phuong L; Cioc, Adina; Warlick, Erica; Ross, Julie A

    2016-09-01

    Polymorphisms in mitochondrial DNA (mtDNA) are used to group individuals into haplogroups reflecting human global migration and are associated with multiple diseases, including cancer. Here, we evaluate the association between mtDNA haplogroup and risk of myelodysplastic syndromes (MDS). Cases were identified by the Minnesota Cancer Surveillance System. Controls were identified through the Minnesota State driver's license/identification card list. Because haplogroup frequencies vary by race and ethnicity, we restricted analyses to non-Hispanic whites. We genotyped 15 mtSNPs that capture common European mitochondrial haplogroup variation. We used SAS v.9.3 (SAS Institute, Cary, NC) to calculate odds ratios (OR) and 95% confidence intervals (CI) overall and stratified by MDS subtype and IPSS-R risk category. We were able to classify 215 cases with confirmed MDS and 522 controls into one of the 11 common European haplogroups. Due to small sample sizes in some subgroups, we combined mt haplogroups into larger bins based on the haplogroup evolutionary tree, including HV (H + V), JT (J + T), IWX (I + W + X), UK (U + K), and Z for comparisons of cases and controls. Using haplogroup HV as the reference group, we found a statistically significant association between haplogroup JT and MDS (OR = 0.58, 95% CI 0.36, 0.92, P = 0.02). No statistically significant heterogeneity was observed in subgroup analyses. In this population-based study of MDS, we observed an association between mtDNA haplogroup JT and risk of MDS. While previously published studies provide biological plausibility for the observed association, further studies of the relationship between mtDNA variation and MDS are warranted in larger sample sizes. © 2016 Wiley Periodicals, Inc. PMID:27121678

  12. Anemia as the Main Manifestation of Myelodysplastic Syndromes.

    PubMed

    Santini, Valeria

    2015-10-01

    Myelodysplastic syndromes (MDS) are a constellation of different diseases sharing anemia in the great majority of cases, and this cytopenia defines these pathologies and their most dramatic clinical manifestations. Anemia in MDS is due to ineffective erythropoiesis, with a high degree of apoptosis of marrow erythroid progenitors. These progenitors show distinctive dysplastic features that consent diagnosis, and are recognizable and differentiated, although not easily, from other morphologic alterations present in other types of anemia. Reaching the diagnosis of MDS in a macrocytic anemia and alleviating the symptoms of anemia are therefore an essential objective of the treating physician. In this work, the signs and symptoms of anemia in MDS, as well as its peculiar pathophysiology, are discussed. Erythopoietic stimulating agents (ESAs) are providing the best treatment for anemic MDS patients, but their use is still not approved by health agencies. While still waiting for this waiver, their clinical use is widespread and their effectivness is well known, as well as the dismal prognosis of patients who do not respond to ESAs and require transfusions. MDS with del5q constitute a unique model of anemia whose complex pathophysiology has been clarified at least partially, defining its link to ribosomal alterations likewise what observed in hereditary anemias like Blackfan Diamond anemia. Lenalidomide is the agent that has shown striking and specific erythropoietic activity in del5q MDS, and the basis of this response is starting to be understood. Several new agents are under evaluation for ESA refractory/relapsed MDS patients, targeting different putative mechanisms of ineffective erythropoiesis, and are here reviewed. PMID:26404446

  13. Down-regulation of EZH2 expression in myelodysplastic syndromes.

    PubMed

    Cabrero, Monica; Wei, Yue; Yang, Hui; Ganan-Gomez, Irene; Bohannan, Zach; Colla, Simona; Marchesini, Matteo; Bravo, Guillermo Montalban; Takahashi, Koichi; Bueso-Ramos, Carlos; Garcia-Manero, Guillermo

    2016-05-01

    EZH2 genetic mutations are common in myelodysplastic syndrome (MDS), which implies that this gene has a pathophysiological role in the disease. To further characterize molecular alterations of EZH2, and their potential prognostic impact in MDS, we assessed EZH2 RNA expression in primary bone marrow CD34+ cells from 78 patients. We found that 47% of patients have reduced EZH2 expression compared to normal controls. Further analyses revealed that EZH2 is significantly underexpressed in patients bearing chromosome 7 or 7q deletions (7-alt) when compared to controls, diploid patients, and patients with other cytogenetic alterations (p<0.05). In survival analysis, we found a non-significant trend toward overall survival (OS) being better among patients with EZH2 underexpression (median OS 55 vs. 36 months; p=0.71). Importantly, this trend became significant when the analysis was restricted to the subset of cases without alterations in chromosome 7 (62 vs. 36 months; p=0.033). Furthermore, our previous work has identified a spectrum of innate immune genes in MDS CD34+ cells that are deregulated via abnormal promoter histone methylation. Because EZH2 is a key regulator of histone methylation, we assessed the relationship between deregulation of these genes and EZH2 underexpression. We observed that the mRNA levels of 11 immune genes were higher in the EZH2 underexpression group and that immune gene expression was significantly higher in patients with concomitant EZH2 underexpression and KDM6B (also known as JMJD3, an H3K27 demethylase) overexpression. Taken together, these data indicate that EZH2 underexpression may have unique impact on the molecular pathogenesis and prognosis in MDS and be an important marker for patients without chromosome 7 alteration. PMID:26970171

  14. Low-Dose or High-Dose Conditioning Followed by Peripheral Blood Stem Cell Transplant in Treating Patients With Myelodysplastic Syndrome or Acute Myelogenous Leukemia

    ClinicalTrials.gov

    2014-10-23

    Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Acute Myeloid Leukemia/Transient Myeloproliferative Disorder; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Childhood Acute Myeloid Leukemia in Remission; Childhood Myelodysplastic Syndromes; de Novo Myelodysplastic Syndromes; Myelodysplastic Syndrome With Isolated Del(5q); Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

  15. First Report of Sepsis Caused by Rhodococcus corynebacterioides in a Patient with Myelodysplastic Syndrome

    PubMed Central

    Kitamura, Yuka; Sawabe, Etsuko; Ohkusu, Kiyofumi; Tojo, Naoko

    2012-01-01

    We report a case of sepsis caused by Rhodococcus corynebacterioides, identified using 16S rRNA gene sequencing, in a myelodysplastic syndrome patient who had undergone hematopoietic stem cell transplantation. This is the first report of R. corynebacterioides infection in a human. PMID:22205796

  16. Fatal bacteremia by neisseria cinerea in a woman with myelodysplastic syndrome: a case report

    PubMed Central

    Zhu, Xiaofei; Li, Min; Cao, Huiling; Yang, Xuewen

    2015-01-01

    Neisseria cinerea has been rarely found in blood cultures. In this study, we are reporting a case of a Myelodysplastic Syndrome (MDS) patient in whose blood Neisseria cinerea was found and led a fatal consequence. This case will call our attentions to the uncommon pathogens in the pathogenicity of end-stage patients. PMID:26131259

  17. Excessive naked megakaryocyte nuclei in myelodysplastic syndrome mimicking idiopathic thrombocytopenic purpura: a complicated pre- and post-transplantation course.

    PubMed

    Olcay, Lale; Tuncer, A Murat; Okur, Hamza; Erdemli, Esra; Uysal, Zumrut; Cetin, Mualla; Duru, Feride; Cetinkaya, Duygu Uckan

    2009-09-01

    A boy 3 years 7 months old with thrombocytopenia and history of intracranial hemorrhage who underwent bone marrow transplantation is presented. He was refractory to steroids, immunoglobulin G, vincristine, azathioprine, cyclosporine A, interleukin-11, chemotherapy, and splenectomy. Idiopathic thrombocytopenic purpura was excluded by light /electron microscopic and flow cytometric findings; the diagnosis of refractory cytopenia, a subgroup of pediatric myelodysplastic syndrome, was made. Naked megakaryocyte nuclei were 55.38 +/- 28.2% vs. 31.67 +/- 23.22% of all megakaryocytes in the patient and the control group of 9 patients with idiopathic thrombocytopenic purpura, respectively (p = .016). The posttransplatation course was complicated by delayed platelet engraftment, bronchiolitis obliterans associated with pneumocystis carinii pneumonia, which resolved completely. PMID:19657988

  18. Cediranib Maleate in Treating Patients With Relapsed, Refractory, or Untreated Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

    ClinicalTrials.gov

    2014-09-18

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Myeloid Leukemia

  19. Combination Chemotherapy With or Without Bone Marrow Transplantation in Treating Children With Acute Myelogenous Leukemia or Myelodysplastic Syndrome

    ClinicalTrials.gov

    2013-01-15

    Childhood Acute Erythroleukemia (M6); Childhood Acute Megakaryocytic Leukemia (M7); Childhood Acute Monoblastic Leukemia (M5a); Childhood Acute Monocytic Leukemia (M5b); Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Myeloblastic Leukemia Without Maturation (M1); Childhood Acute Myelomonocytic Leukemia (M4); Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Refractory Anemia With Ringed Sideroblasts; Secondary Myelodysplastic Syndromes; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

  20. Signal transduction inhibitors in treatment of myelodysplastic syndromes.

    PubMed

    Bachegowda, Lohith; Gligich, Oleg; Mantzaris, Ionnis; Schinke, Carolina; Wyville, Dale; Carrillo, Tatiana; Braunschweig, Ira; Steidl, Ulrich; Verma, Amit

    2013-01-01

    Myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by ineffective hematopoiesis that results in reduced blood counts. Although MDS can transform into leukemia, most of the morbidity experienced by these patients is due to chronically low blood counts. Conventional cytotoxic agents used to treat MDS have yielded some encouraging results but are characterized by many adverse effects in the predominantly elderly patient population. Targeted interventions aimed at reversing the bone marrow failure and increasing the peripheral blood counts would be advantageous in this cohort of patients. Studies have demonstrated over-activated signaling of myelo-suppressive cytokines such as TGF-β, TNF-α and Interferons in MDS hematopoietic stem cells. Targeting these signaling cascades could be potentially therapeutic in MDS. The p38 MAP kinase pathway, which is constitutively activated in MDS, is an example of cytokine stimulated kinase that promotes aberrant apoptosis of stem and progenitor cells in MDS. ARRY-614 and SCIO-469 are p38 MAPK inhibitors that have been used in clinical trials and have shown activity in a subset of MDS patients. TGF-β signaling has been therapeutically targeted by small molecule inhibitor of the TGF-β receptor kinase, LY-2157299, with encouraging preclinical results. Apart from TGF-β receptor kinase inhibition, members of TGF-β super family and BMP ligands have also been targeted by ligand trap compounds like Sotatercept (ACE-011) and ACE-536. The multikinase inhibitor, ON-01910.Na (Rigosertib) has demonstrated early signs of efficacy in reducing the percentage of leukemic blasts and is in advanced stages of clinical testing. Temsirolimus, Deforolimus and other mTOR inhibitors are being tested in clinical trials and have shown preclinical efficacy in CMML. EGF receptor inhibitors, Erlotinib and Gefitinib have shown efficacy in small trials that may be related to off target effects. Cell cycle regulator inhibitors

  1. Signal transduction inhibitors in treatment of myelodysplastic syndromes

    PubMed Central

    2013-01-01

    Myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by ineffective hematopoiesis that results in reduced blood counts. Although MDS can transform into leukemia, most of the morbidity experienced by these patients is due to chronically low blood counts. Conventional cytotoxic agents used to treat MDS have yielded some encouraging results but are characterized by many adverse effects in the predominantly elderly patient population. Targeted interventions aimed at reversing the bone marrow failure and increasing the peripheral blood counts would be advantageous in this cohort of patients. Studies have demonstrated over-activated signaling of myelo-suppressive cytokines such as TGF-β, TNF-α and Interferons in MDS hematopoietic stem cells. Targeting these signaling cascades could be potentially therapeutic in MDS. The p38 MAP kinase pathway, which is constitutively activated in MDS, is an example of cytokine stimulated kinase that promotes aberrant apoptosis of stem and progenitor cells in MDS. ARRY-614 and SCIO-469 are p38 MAPK inhibitors that have been used in clinical trials and have shown activity in a subset of MDS patients. TGF-β signaling has been therapeutically targeted by small molecule inhibitor of the TGF-β receptor kinase, LY-2157299, with encouraging preclinical results. Apart from TGF-β receptor kinase inhibition, members of TGF-β super family and BMP ligands have also been targeted by ligand trap compounds like Sotatercept (ACE-011) and ACE-536. The multikinase inhibitor, ON-01910.Na (Rigosertib) has demonstrated early signs of efficacy in reducing the percentage of leukemic blasts and is in advanced stages of clinical testing. Temsirolimus, Deforolimus and other mTOR inhibitors are being tested in clinical trials and have shown preclinical efficacy in CMML. EGF receptor inhibitors, Erlotinib and Gefitinib have shown efficacy in small trials that may be related to off target effects. Cell cycle regulator inhibitors

  2. Myelodysplastic syndromes: Contemporary review and how we treat.

    PubMed

    Gangat, Naseema; Patnaik, Mrinal M; Tefferi, Ayalew

    2016-01-01

    Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders with an inherent tendency for leukemic transformation. Diagnosis is currently based on the presence of peripheral blood cytopenias, peripheral blood and bone marrow dysplasia/blasts, and clonal cytogenetic abnormalities. With the advent of next generation sequencing, recurrent somatic mutations in genes involved in epigenetic regulation (TET2, ASXL1, EZH2, DNMT3A, IDH1/2), RNA splicing (SF3B1, SRSF2, U2AF1, ZRSR2), DNA damage response (TP53), transcriptional regulation (RUNX1, BCOR, ETV6) and signal transduction (CBL, NRAS, JAK2) have been identified in MDS. Conventional prognostication is by the revised International prognostic scoring system (IPSS-R) with additional adverse prognosis conferred by presence of ASXL1, EZH2, or TP53 mutations. Currently Food and Drug administration (FDA)-approved drugs for the treatment of MDS are not curative and their effect on survival is limited; they include the hypomethylating agents (HMA) azacitidine and decitabine and lenalidomide for MDS with isolated del(5q). To date, allogeneic stem cell transplant (ASCT) remains the only treatment option for possible cure. Given the current lack of drugs with convincing evidence of favorable effect on survival, we consider ASCT as the treatment of choice for most patients with symptomatic disease, and especially for those with high-risk disease. For nontransplant candidates, participation in clinical trials is preferred over conventional therapy. There is not one right way of treatment for patients who are not candidates for either ASCT or clinical trials and palliative drugs of choice depend on the clinical problem, such as symptomatic anemia (ESAs, danazol, HMA), thrombocytopenia (HMA), or neutropenia (myeloid growth factors). Conversely, there is no controlled evidence to support the use of iron chelating agents in MDS. Going forward, we believe it is time to incorporate mutation information in

  3. Effect of plasma exchange on refractory hemophagocytic syndrome complicated with myelodysplastic syndrome.

    PubMed

    Satomi, A; Nagai, S; Nagai, T; Niikura, K; Ideura, T; Ogata, H; Akizawa, T

    1999-11-01

    A case of hemophagocytic syndrome (HPS) refractory to corticosteroid therapy was successfully treated by plasma exchange. The patient was a 56-year-old woman who had undergone regular hemodialysis for 10 years for complicated myelodysplastic syndrome (MDS) and then had had lung tuberculosis. After the onset of tuberculosis, she suffered from HPS and was treated by antituberculosis agents and high dose corticosteroid administration without any effect on the HPS. After adding a series of plasma exchanges, the HPS improved gradually, and her MDS began to respond to corticosteroid therapy. Plasma hypercytokinemia due to HPS was corrected by plasma exchange, and the correction of a high level of plasma inflammatory cytokine was considered to be one of the contributing factors for the improvement of HPS. These results suggest that therapeutic plasma exchange should be considered as a therapeutic tool for HPS refractory to conventional therapy. PMID:10608726

  4. Azacitidine With or Without Entinostat in Treating Patients With Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-03-16

    Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Alkylating Agent-Related Acute Myeloid Leukemia; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndrome; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndrome; Untreated Adult Acute Myeloid Leukemia

  5. Vaccine Therapy Plus Immune Adjuvant in Treating Patients With Chronic Myeloid Leukemia, Acute Myeloid Leukemia, or Myelodysplastic Syndrome

    ClinicalTrials.gov

    2013-01-04

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Myeloid Leukemia in Remission; Chronic Phase Chronic Myelogenous Leukemia; Previously Treated Myelodysplastic Syndromes; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia

  6. Diagnosis and classification of myelodysplastic syndrome: International Working Group on Morphology of myelodysplastic syndrome (IWGM-MDS) consensus proposals for the definition and enumeration of myeloblasts and ring sideroblasts.

    PubMed

    Mufti, Ghulam J; Bennett, John M; Goasguen, Jean; Bain, Barbara J; Baumann, Irith; Brunning, Richard; Cazzola, Mario; Fenaux, Pierre; Germing, Ulrich; Hellström-Lindberg, Eva; Jinnai, Itsuro; Manabe, Atsushi; Matsuda, Akira; Niemeyer, Charlotte M; Sanz, Guillermo; Tomonaga, Masao; Vallespi, Teresa; Yoshimi, Ayami

    2008-11-01

    The classification of myelodysplastic syndromes is based on the morphological criteria proposed by the French-American-British (FAB) and World Health Organization (WHO) groups. Accurate enumeration of blast cells, although essential for diagnosis of myelodysplastic syndrome and for assignment to prognostic groups, is often difficult, due to imprecise criteria for the morphological definition of blasts and promyelocytes. An International Working Group on Morphology of Myelodysplastic Syndrome (IWGM-MDS) of hematopathologists and hematologists expert in the field of myelodysplastic syndrome reviewed the morphological features of bone marrows from all subtypes of myelodysplastic syndrome and agreed on a set of recommendations, including recommendations for the definition and enumeration of blast cells and ring sideroblasts. It is recommended that (1) agranular or granular blast cells be defined (replacing the previous type I, II and III blasts), (2) dysplastic promyelocytes be distinguished from cytologically normal promyelocytes and from granular blast cells, (3) sufficient cells be counted to give a precise blast percentage, particularly at thresholds that are important for diagnosis or prognosis and (4) ring sideroblasts be defined as erythroblasts in which there are a minimum of 5 siderotic granules covering at least a third of the nuclear circumference. Clear definitions and a differential count of a sufficient number of cells is likely to improve precision in the diagnosis and classification of myelodysplastic syndrome. Recommendations should be applied in the context of the WHO classification. PMID:18838480

  7. Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents.

    PubMed

    Wlodarski, Marcin W; Hirabayashi, Shinsuke; Pastor, Victor; Starý, Jan; Hasle, Henrik; Masetti, Riccardo; Dworzak, Michael; Schmugge, Markus; van den Heuvel-Eibrink, Marry; Ussowicz, Marek; De Moerloose, Barbara; Catala, Albert; Smith, Owen P; Sedlacek, Petr; Lankester, Arjan C; Zecca, Marco; Bordon, Victoria; Matthes-Martin, Susanne; Abrahamsson, Jonas; Kühl, Jörn Sven; Sykora, Karl-Walter; Albert, Michael H; Przychodzien, Bartlomiej; Maciejewski, Jaroslaw P; Schwarz, Stephan; Göhring, Gudrun; Schlegelberger, Brigitte; Cseh, Annámaria; Noellke, Peter; Yoshimi, Ayami; Locatelli, Franco; Baumann, Irith; Strahm, Brigitte; Niemeyer, Charlotte M

    2016-03-17

    Germline GATA2 mutations cause cellular deficiencies with high propensity for myeloid disease. We investigated 426 children and adolescents with primary myelodysplastic syndrome (MDS) and 82 cases with secondary MDS enrolled in 2 consecutive prospective studies of the European Working Group of MDS in Childhood (EWOG-MDS) conducted in Germany over a period of 15 years. Germline GATA2 mutations accounted for 15% of advanced and 7% of all primary MDS cases, but were absent in children with MDS secondary to therapy or acquired aplastic anemia. Mutation carriers were older at diagnosis and more likely to present with monosomy 7 and advanced disease compared with wild-type cases. For stratified analysis according to karyotype, 108 additional primary MDS patients registered with EWOG-MDS were studied. Overall, we identified 57 MDS patients with germline GATA2 mutations. GATA2 mutations were highly prevalent among patients with monosomy 7 (37%, all ages) reaching its peak in adolescence (72% of adolescents with monosomy 7). Unexpectedly, monocytosis was more frequent in GATA2-mutated patients. However, when adjusted for the selection bias from monosomy 7, mutational status had no effect on the hematologic phenotype. Finally, overall survival and outcome of hematopoietic stem cell transplantation (HSCT) were not influenced by mutational status. This study identifies GATA2 mutations as the most common germline defect predisposing to pediatric MDS with a very high prevalence in adolescents with monosomy 7. GATA2 mutations do not confer poor prognosis in childhood MDS. However, the high risk for progression to advanced disease must guide decision-making toward timely HSCT. PMID:26702063

  8. Reproducibility of the World Health Organization 2008 criteria for myelodysplastic syndromes

    PubMed Central

    Senent, Leonor; Arenillas, Leonor; Luño, Elisa; Ruiz, Juan C.; Sanz, Guillermo; Florensa, Lourdes

    2013-01-01

    The reproducibility of the World Health Organization 2008 classification for myelodysplastic syndromes is uncertain and its assessment was the major aim of this study. The different peripheral blood and bone marrow variables required for an adequate morphological classification were blindly evaluated by four cytomorphologists in samples from 50 patients with myelodysplastic syndromes. The degree of agreement among observers was calculated using intraclass correlation coefficient and the generalized kappa statistic for multiple raters. The degree of agreement for the percentages of blasts in bone marrow and peripheral blood, ring sideroblasts in bone marrow, and erythroid, granulocytic and megakaryocytic dysplastic cells was strong (P<0.001 in all instances). After stratifying the percentages according to the categories required for the assignment of World Health Organization subtypes, the degree of agreement was not statistically significant for cases with 5-9% blasts in bone marrow (P=0.07), 0.1-1% blasts in peripheral blood (P=0.47), or percentage of erythroid dysplastic cells (P=0.49). Finally, the interobserver concordance for World Health Organization-defined subtypes showed a moderate overall agreement (P<0.001), the reproducibility being lower for cases with refractory anemia with excess of blasts type 1 (P=0.05) and refractory anemia with ring sideroblasts (P=0.09). In conclusion, the reproducibility of the World Health Organization 2008 classification for myelodysplastic syndromes is acceptable but the defining criteria for blast cells and features of erythroid dysplasia need to be refined. PMID:23065505

  9. SB-715992 in Treating Patients With Acute Leukemia, Chronic Myelogenous Leukemia, or Advanced Myelodysplastic Syndromes

    ClinicalTrials.gov

    2013-01-10

    Acute Undifferentiated Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Acute Promyelocytic Leukemia (M3); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Blastic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Myeloid Leukemia

  10. Yttrium Y 90 Anti-CD45 Monoclonal Antibody BC8 Followed by Donor Stem Cell Transplant in Treating Patients With High-Risk Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Myelodysplastic Syndrome

    ClinicalTrials.gov

    2016-08-08

    Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Chronic Myelomonocytic Leukemia; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Secondary Acute Myeloid Leukemia

  11. Chronic relapsing remitting Sweet syndrome--a harbinger of myelodysplastic syndrome.

    PubMed

    Kulasekararaj, Austin G; Kordasti, Shahram; Basu, Tanya; Salisbury, Jonathan R; Mufti, Ghulam J; du Vivier, Anthony W P

    2015-09-01

    Sweet syndrome (SS) is an acute febrile neutrophilic dermatosis. It has been associated with malignant disease, especially acute myeloid leukaemia (AML), infections, autoimmune disorders and drugs, particularly granulocyte colony-stimulating factor (GCSF). No cause is found in the rest, which are labelled idiopathic. We describe 15 patients with SS, which we believe represent 'immune dysregulation' secondary to myelodysplastic syndrome (MDS). We initially identified 31 patients with SS in a cohort of 744 patients with MDS and 215 with AML seen over a 6-year period (2004-10). The cause in 16 patients could be attributed either to administration of GCSF or chemotherapy. The eruption was brief and resolved spontaneously or following withdrawal of GCSF. Fifteen patients however, had a chronic debilitating illness dominated by the skin eruptions. Diagnosis of chronic relapsing SS was delayed because the pathology was not always typical of classical neutrophil-rich SS and included lymphocytic and histiocytoid infiltrates and bone marrow was not always performed because the relevance of the eruption to MDS was often not immediately appreciated. All these patients had 'low risk' MDS, diagnosed at a median of 17 months (range 0-157) following the diagnosis of SS. We describe a chronic debilitating episodic clinically distinctive skin eruption with features of SS but not always definitive histopathology often associated with immunological abnormalities affecting other systems related to underlying low risk MDS. PMID:25962438

  12. Multicentric study underlining the interest of adding CD5, CD7 and CD56 expression assessment to the flow cytometric Ogata score in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms

    PubMed Central

    Bardet, Valérie; Wagner-Ballon, Orianne; Guy, Julien; Morvan, Céline; Debord, Camille; Trimoreau, Franck; Benayoun, Emmanuel; Chapuis, Nicolas; Freynet, Nicolas; Rossi, Cédric; Mathis, Stéphanie; Gourin, Marie-Pierre; Toma, Andréa; Béné, Marie C.; Feuillard, Jean; Guérin, Estelle

    2015-01-01

    Although numerous recent publications have demonstrated interest in multiparameter flow cytometry in the investigation of myelodysplastic disorders, it is perceived by many laboratory hematologists as difficult and expensive, requiring a high level of expertise. We report a multicentric open real-life study aimed at evaluating the added value of the technically simple flow cytometry score described by the Ogata group for the diagnosis of myelodysplastic syndromes. A total of 652 patients were recruited prospectively in four different centers: 346 myelodysplastic syndromes, 53 myelodysplastic/myeloproliferative neoplasms, and 253 controls. The Ogata score was assessed using CD45 and CD34 staining, with the addition of CD10 and CD19. Moreover, labeling of CD5, CD7 and CD56 for the evaluation of myeloid progenitors and monocytes was tested on a subset of 294 patients. On the whole series, the specificity of Ogata score reached 89%. Respective sensitivities were 54% for low-risk myelodysplastic syndromes, 68% and 84% for type 1 and type 2 refractory anemia with excess of blasts, and 72% for myelodysplastic/myeloproliferative neoplasms. CD5 expression was poorly informative. When adding CD56 or CD7 labeling to the Ogata score, sensitivity rose to 66% for low-risk myelodysplastic syndromes, to 89% for myelodysplastic/myeloproliferative neoplasms and to 97% for refractory anemia with excess of blasts. This large multicenter study confirms the feasibility of Ogata scoring in routine flow cytometry diagnosis but highlights its poor sensitivity in low-risk myelodysplastic syndromes. The addition of CD7 and CD56 in flow cytometry panels improves the sensitivity but more sophisticated panels would be more informative. PMID:25637056

  13. Autoimmune Syndromes Presenting as a Paraneoplastic Manifestation of Myelodysplastic Syndromes: Clinical Features, Course, Treatment and Outcome.

    PubMed

    Williamson, Bradley T; Foltz, Lynda; Leitch, Heather A

    2016-05-10

    Autoimmune manifestations (AIM) are reported in up to 10-30% of myelodysplastic syndromes (MDS) patients; this association is not well defined. We present herein a retrospective chart review of single center MDS patients for AIM, a case discussion and a literature review. Of 252 MDS patients examined, 11 (4.4%) had AIM around MDS diagnosis. International Prognostic Scoring System scores were: low or intermediate (int)-1 (n=7); int-2 or high (n=4). AIM were: culture negative sepsis (n=7); inflammatory arthritis (n=3); vasculitis (n=4); sweats; pericarditis; polymyalgia rheumatica (n=2 each); mouth ulcers; pulmonary infiltrates; suspicion for Behcet's; polychondritis and undifferentiated (n=1 each). AIM treatment and outcome were: prednisone +/- steroid sparing agents, n=8, ongoing symptoms in 5; azacitidine (n=3), 2 resolved; and observation, n=1, ongoing symptoms. At a median follow up of 13 months, seven patients are alive. In summary, 4.4% of MDS patients presented with concomitant AIM. MDS should remain on the differential diagnosis of patients with inflammatory symptoms. PMID:27499837

  14. Autoimmune Syndromes Presenting as a Paraneoplastic Manifestation of Myelodysplastic Syndromes: Clinical Features, Course, Treatment and Outcome

    PubMed Central

    Williamson, Bradley T.; Foltz, Lynda; Leitch, Heather A.

    2016-01-01

    Autoimmune manifestations (AIM) are reported in up to 10-30% of myelodysplastic syndromes (MDS) patients; this association is not well defined. We present herein a retrospective chart review of single center MDS patients for AIM, a case discussion and a literature review. Of 252 MDS patients examined, 11 (4.4%) had AIM around MDS diagnosis. International Prognostic Scoring System scores were: low or intermediate (int)-1 (n=7); int-2 or high (n=4). AIM were: culture negative sepsis (n=7); inflammatory arthritis (n=3); vasculitis (n=4); sweats; pericarditis; polymyalgia rheumatica (n=2 each); mouth ulcers; pulmonary infiltrates; suspicion for Behcet’s; polychondritis and undifferentiated (n=1 each). AIM treatment and outcome were: prednisone +/- steroid sparing agents, n=8, ongoing symptoms in 5; azacitidine (n=3), 2 resolved; and observation, n=1, ongoing symptoms. At a median follow up of 13 months, seven patients are alive. In summary, 4.4% of MDS patients presented with concomitant AIM. MDS should remain on the differential diagnosis of patients with inflammatory symptoms.

  15. Plasma protein alterations in the refractory anemia with excess blasts subtype 1 subgroup of myelodysplastic syndrome

    PubMed Central

    2012-01-01

    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. PMID:22568928

  16. Selection of Patients With Myelodysplastic Syndrome for Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Mishra, Asmita; Anasetti, Claudio

    2016-08-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for patients with myelodysplastic syndrome (MDS). Because MDS predominantly affects an older population, age-associated comorbidities can preclude patients from cure. HSCT is associated with the risk of morbidity and mortality; however, with safer conditioning regimens and improved supportive care, eligible patients with an appropriately matched donor can receive this therapy without exclusion by older age alone. We discuss the role of improved MDS prognostic scoring systems and molecular testing for selection for HSCT, and review the pre-HSCT tolerability assessment required for this advanced aged population. PMID:27521324

  17. Histiocytoid Sweet Syndrome Is More Frequently Associated With Myelodysplastic Syndromes Than the Classical Neutrophilic Variant

    PubMed Central

    Ghoufi, Lisa; Ortonne, Nicolas; Ingen-Housz-Oro, Saskia; Barhoumi, Walid; Begon, Edouard; Haioun, Corinne; Pautas, Cécile; Beckerich, Florence; Robin, Christine; Wolkenstein, Pierre; Cordonnier, Catherine; Chosidow, Olivier; Toma, Andréa

    2016-01-01

    Abstract Histiocytoid Sweet syndrome (H-SS) is a histological variant of Sweet syndrome (SS) differing from classical neutrophilic SS (N-SS) by a dermal infiltrate mainly composed of lymphocytes and histiocytoid myeloperoxidase-positive cells. We aimed to report a large series of H-SS and compare the frequency and type of hematological malignancies associated to H-SS and N-SS. We included 62 patients with a coding histopathologic diagnosis of SS prospectively registered between 2005 and 2014 in the database of our Department of Pathology. Overall, 22 (35.5%) and 40 (64.5%) patients had a histological diagnosis of H-SS and N-SS, respectively. Median age, sex ratio, and cutaneous lesions were similar in the 2 groups. The frequency of extra-cutaneous manifestations was similar (50% vs 37.5%, P = 0.42). Recurrent forms were significantly more frequent in H-SS than in N-SS patients (21% vs 2.5%, P = 0.01). A hematological malignancy was diagnosed in 22 patients, 12 (55.5%) with H-SS and 10 (25%) with N-SS (P = 0.019). Hematological malignancy was of myeloid origin in 8/22 (36.3%) H-SS and 5/40 (12.5%) N-SS patients (P = 0.02), and of lymphoid origin without myeloid component in 4/22 (18.1%) H-SS and 4/40 (10%) N-SS patients (P = 0.35), respectively. One N-SS patient had a hematological malignancy of mixed (myeloid and lymphoid) phenotype. A myelodysplastic syndrome (MDS) was diagnosed in 7/22 (31.8%) H-SS and 1/40 (2.5%) N-SS patients (P < 0.001). Hematological disease was diagnosed before (in 8 H-SS and 3 N-SS patients) or at the time of the occurrence of the cutaneous lesions (in 1 H-SS and 7 N-SS patients). However, in 3 H-SS patients, all with MDS, cutaneous lesions preceded the hematological disease by ≤6 months. In conclusion, H-SS was associated with MDS in one third of patients but also with lymphoid malignancies, and cutaneous lesions could precede the hematological diagnosis in patients with MDS. A complete hematological assessment is

  18. Myeloid sarcoma of the Gingiva with myelodysplastic syndrome: A Case Report.

    PubMed

    Jin, Seong-Ho; Park, Gyeongsin; Ko, Youngkyung; Park, Jun-Beom

    2016-06-01

    The purpose of this report is to present a case of myeloid sarcoma of the gingiva with myelodysplastic syndrome.A 52-year-old male diagnosed with myelodysplastic syndrome with skin lesions presented with gingival swelling and gingival redness involving the maxillary left second premolar and the maxillary left first molar. The patient was referred from the Department of Hematology for a biopsy of the lesion. Full-thickness flaps were elevated and inflamed, and neoplastic soft tissue was removed from a lesion and the samples sent for histopathologic analysis.Histopathologic results showed leukemic cell infiltration beneath the oral epithelium, and the specimen was positive for the leukocyte marker. The diagnosis was myeloid sarcoma. Uneventful healing was observed at 2-week follow-up, but relapse of the lesions with the hyperplastic and neoplastic tissue was noted at 4-week follow-up. Further follow-up or treatment could not be performed because the patient did not visit at the next follow-up.In conclusion, myeloid sarcoma should be a diagnosis option for gingival growth because it can involve intraoral lesion. In this report, a biopsy was performed due to referral considering the patient's medical history. Although myeloid sarcoma in the oral cavity is extremely rare, a small biopsy and consultation with a hematologist may be beneficial for patients and may provide a differential diagnosis. PMID:27310987

  19. Impaired cytotoxicity associated with defective natural killer cell differentiation in myelodysplastic syndromes

    PubMed Central

    Hejazi, Maryam; Manser, Angela R.; Fröbel, Julia; Kündgen, Andrea; Zhao, Xiaoyi; Schönberg, Kathrin; Germing, Ulrich; Haas, Rainer; Gattermann, Norbert; Uhrberg, Markus

    2015-01-01

    Natural killer cells are well known to mediate anti-leukemic responses in myeloid leukemia but their role in myelodysplastic syndromes is not well understood. Here, in a cohort of newly diagnosed patients (n=75), widespread structural and functional natural killer cell defects were identified. One subgroup of patients (13%) had a selective deficiency of peripheral natural killer cells (count <10/mm3 blood) with normal frequencies of T and natural killer-like T cells. Natural killer cell-deficient patients were predominantly found in high-risk subgroups and deficiency of these cells was significantly associated with poor prognosis. In the second subgroup, comprising the majority of patients (76%), natural killer cells were present but exhibited poor cytotoxicity. The defect was strongly associated with reduced levels of perforin and granzyme B. Notably, natural killer cell function and arming of cytotoxic granules could be fully reconstituted by in vitro stimulation. Further phenotypic analysis of these patients revealed an immature natural killer cell compartment that was biased towards CD56bright cells. The residual CD56dim cells exhibited a significant increase of the unlicensed NKG2A−KIR− subset and a striking reduction in complexity of the repertoire of killer cell immunoglobulin-like receptors. Taken together, these results suggest that the widespread defects in natural killer cell function occurring in patients with myelodysplastic syndromes are mostly due to either unsuccessful or inefficient generation of mature, functionally competent natural killer cells, which might contribute to disease progression through impaired immune surveillance. PMID:25682594

  20. Impaired cytotoxicity associated with defective natural killer cell differentiation in myelodysplastic syndromes.

    PubMed

    Hejazi, Maryam; Manser, Angela R; Fröbel, Julia; Kündgen, Andrea; Zhao, Xiaoyi; Schönberg, Kathrin; Germing, Ulrich; Haas, Rainer; Gattermann, Norbert; Uhrberg, Markus

    2015-05-01

    Natural killer cells are well known to mediate anti-leukemic responses in myeloid leukemia but their role in myelodysplastic syndromes is not well understood. Here, in a cohort of newly diagnosed patients (n=75), widespread structural and functional natural killer cell defects were identified. One subgroup of patients (13%) had a selective deficiency of peripheral natural killer cells (count <10/mm(3) blood) with normal frequencies of T and natural killer-like T cells. Natural killer cell-deficient patients were predominantly found in high-risk subgroups and deficiency of these cells was significantly associated with poor prognosis. In the second subgroup, comprising the majority of patients (76%), natural killer cells were present but exhibited poor cytotoxicity. The defect was strongly associated with reduced levels of perforin and granzyme B. Notably, natural killer cell function and arming of cytotoxic granules could be fully reconstituted by in vitro stimulation. Further phenotypic analysis of these patients revealed an immature natural killer cell compartment that was biased towards CD56(bright) cells. The residual CD56(dim) cells exhibited a significant increase of the unlicensed NKG2A(-)KIR(-) subset and a striking reduction in complexity of the repertoire of killer cell immunoglobulin-like receptors. Taken together, these results suggest that the widespread defects in natural killer cell function occurring in patients with myelodysplastic syndromes are mostly due to either unsuccessful or inefficient generation of mature, functionally competent natural killer cells, which might contribute to disease progression through impaired immune surveillance. PMID:25682594

  1. Donor Peripheral Blood Stem Cell Transplant and Pretargeted Radioimmunotherapy in Treating Patients With High-Risk Advanced Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Myelodysplastic Syndrome

    ClinicalTrials.gov

    2016-03-01

    Chronic Myelomonocytic Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Cytopenia With Multilineage Dysplasia; Refractory Cytopenia With Multilineage Dysplasia and Ringed Sideroblasts; Secondary Acute Myeloid Leukemia

  2. Total Marrow and Lymphoid Irradiation and Chemotherapy Before Donor Transplant in Treating Patients With Myelodysplastic Syndrome or Acute Leukemia

    ClinicalTrials.gov

    2016-08-10

    Adult Acute Lymphoblastic Leukemia in Complete Remission; Acute Myeloid Leukemia in Remission; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Childhood Acute Lymphoblastic Leukemia in Complete Remission

  3. SRSF2 Is Essential for Hematopoiesis, and Its Myelodysplastic Syndrome-Related Mutations Dysregulate Alternative Pre-mRNA Splicing

    PubMed Central

    Komeno, Yukiko; Huang, Yi-Jou; Qiu, Jinsong; Lin, Leo; Xu, YiJun; Zhou, Yu; Chen, Liang; Monterroza, Dora D.; Li, Hairi; DeKelver, Russell C.; Yan, Ming

    2015-01-01

    Myelodysplastic syndromes (MDS) are a group of neoplasms characterized by ineffective myeloid hematopoiesis and various risks for leukemia. SRSF2, a member of the serine/arginine-rich (SR) family of splicing factors, is one of the mutation targets associated with poor survival in patients suffering from myelodysplastic syndromes. Here we report the biological function of SRSF2 in hematopoiesis by using conditional knockout mouse models. Ablation of SRSF2 in the hematopoietic lineage caused embryonic lethality, and Srsf2-deficient fetal liver cells showed significantly enhanced apoptosis and decreased levels of hematopoietic stem/progenitor cells. Induced ablation of SRSF2 in adult Mx1-Cre Srsf2flox/flox mice upon poly(I):poly(C) injection demonstrated a significant decrease in lineage− Sca+ c-Kit+ cells in bone marrow. To reveal the functional impact of myelodysplastic syndromes-associated mutations in SRSF2, we analyzed splicing responses on the MSD-L cell line and found that the missense mutation of proline 95 to histidine (P95H) and a P95-to-R102 in-frame 8-amino-acid deletion caused significant changes in alternative splicing. The affected genes were enriched in cancer development and apoptosis. These findings suggest that intact SRSF2 is essential for the functional integrity of the hematopoietic system and that its mutations likely contribute to development of myelodysplastic syndromes. PMID:26124281

  4. Rebeccamycin Analog in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia, Myelodysplastic Syndrome, Acute Lymphoblastic Leukemia, or Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2013-01-22

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Blastic Phase Chronic Myelogenous Leukemia; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

  5. Sirolimus and Azacitidine in Treating Patients With High Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia That is Recurrent or Not Eligible for Intensive Chemotherapy

    ClinicalTrials.gov

    2016-06-03

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); de Novo Myelodysplastic Syndromes; Myelodysplastic Syndrome With Isolated Del(5q); Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia

  6. CCI-779 in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Myelodysplastic Syndromes, or Chronic Myelogenous Leukemia in Blastic Phase

    ClinicalTrials.gov

    2013-01-22

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Blastic Phase Chronic Myelogenous Leukemia; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Myelodysplastic Syndromes

  7. GTI-2040 in Treating Patients With Relapsed, Refractory, or High-Risk Acute Leukemia, High-Grade Myelodysplastic Syndromes, or Refractory or Blastic Phase Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2015-12-03

    Acute Undifferentiated Leukemia; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Blastic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

  8. [Acquired immunodeficiency syndrome in pediatric patients].

    PubMed

    Molina Moguel, J L; Ruiz Illezcas, R; Forsbach Sánchez, S; Carreño Alvarez, S; Picco Díaz, I

    1990-12-01

    The object of this study was to determine how many of the patients treated at the Pediatric Odontology Clinic, a branch of the Maxillo-Facial Surgery Service at the Veinte de Noviembre Regional Hospital, ISSSTE, are VIH-positive of show serious manifestations of Acquired Immuno-Deficiency Syndrome (AIDS). For such purpose, 100 pediatric patients suffering from different systemic or local diseases were evaluated, the most common being hematological alterations. Results evidenced the presence of VIH in the blood of five of the pediatric subjects, all suffering from Hemophilia. PMID:2132469

  9. Treosulfan, Fludarabine Phosphate, and Total-Body Irradiation Before Donor Stem Cell Transplant in Treating Patients With High-Risk Acute Myeloid Leukemia, Myelodysplastic Syndrome, Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2013-10-29

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

  10. Clofarabine and Cytarabine in Treating Older Patients With Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndromes That Have Relapsed or Not Responded to Treatment

    ClinicalTrials.gov

    2013-08-06

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Myelodysplastic Syndrome With Isolated Del(5q); Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia

  11. In-Silico Identification Of Micro-Loops In Myelodysplastic Syndromes

    NASA Astrophysics Data System (ADS)

    Beck, Dominik; Brandl, Miriam; Pham, Tuan D.; Chang, Chung-Che; Zhou, Xiaobo

    2011-06-01

    Micro-loops are regulatory network motifs that leverage transcriptional and posttranscriptional control to effectively regulate the transcriptome. In this paper a regulatory network for Myelodysplastic Syndromes (MDSs) was constructed from the literature and publicly available data sources. The network was filtered using data from deep-sequencing of small RNAs, exon and microarrays. Motif discovery showed that micro-loops might exist in MDS. We further used the identified micro-loops and performed basic network analysis to identify the known disease gene RUNX1/AML, as well as miRNA family hsa-mir-181. This suggested that the concept of micro-loops can be applied to enhance disease gene identification and biomarker discovery.

  12. MSI2 is required for maintaining activated myelodysplastic syndrome stem cells

    PubMed Central

    Taggart, James; Ho, Tzu-Chieh; Amin, Elianna; Xu, Haiming; Barlowe, Trevor S.; Perez, Alexendar R.; Durham, Benjamin H.; Tivnan, Patrick; Okabe, Rachel; Chow, Arthur; Vu, Ly; Park, Sun Mi; Prieto, Camila; Famulare, Christopher; Patel, Minal; Lengner, Christopher J.; Verma, Amit; Roboz, Gail; Guzman, Monica; Klimek, Virginia M.; Abdel-Wahab, Omar; Leslie, Christina; Nimer, Stephen D.; Kharas, Michael G.

    2016-01-01

    Myelodysplastic syndromes (MDS) are driven by complex genetic and epigenetic alterations. The MSI2 RNA-binding protein has been demonstrated to have a role in acute myeloid leukaemia and stem cell function, but its role in MDS is unknown. Here, we demonstrate that elevated MSI2 expression correlates with poor survival in MDS. Conditional deletion of Msi2 in a mouse model of MDS results in a rapid loss of MDS haematopoietic stem and progenitor cells (HSPCs) and reverses the clinical features of MDS. Inversely, inducible overexpression of MSI2 drives myeloid disease progression. The MDS HSPCs remain dependent on MSI2 expression after disease initiation. Furthermore, MSI2 expression expands and maintains a more activated (G1) MDS HSPC. Gene expression profiling of HSPCs from the MSI2 MDS mice identifies a signature that correlates with poor survival in MDS patients. Overall, we identify a role for MSI2 in MDS representing a therapeutic target in this disease. PMID:26898884

  13. Myelodysplastic syndrome without ring sideroblasts and with Janus kinase 2 gene mutation: An unusual case report

    PubMed Central

    Ornellas, Maria Helena; De França Silva, Monique; Solza, Cristiana; De Lucena Gonçalves, Stella Beatriz Sampaio; Silva De Almeida, Liliane; De Paula Ayres-Silva, Jackline; Seixas, Taís Leite; Bastos, Elenice Ferreira; Liehr, Thomas; Alves, Gilda

    2016-01-01

    Myelodysplastic syndrome (MDS) cases comprise a heterogeneous group of hematological disorders that are characterized by impaired hematopoiesis, with cytopenias of different grades and risk of developing acute myeloid leukemia. MDS may rarely be associated with thrombocytosis. In such cases, myelodysplasia and myeloproliferative disorders may overlap, making correct diagnosis difficult. We herein describe a case of MDS with thrombocytosis, Janus kinase 2 gene mutation-positive and Perls' staining-negative, which was initially classified as essential thrombocythemia (ET). This case highlights that MDS may be misdiagnosed as ET and inappropriate treatment may be initiated. Therefore, it is crucial to carefully combine all available data on morphology and immunophenotyping, and to perform the necessary molecular, cytogenetic and molecular cytogenetic analyses, in order to correctly diagnose this disease.

  14. Potential Relationship between Inadequate Response to DNA Damage and Development of Myelodysplastic Syndrome

    PubMed Central

    Zhou, Ting; Chen, Peishuai; Gu, Jian; Bishop, Alexander J. R.; Scott, Linda M.; Hasty, Paul; Rebel, Vivienne I.

    2015-01-01

    Hematopoietic stem cells (HSCs) are responsible for the continuous regeneration of all types of blood cells, including themselves. To ensure the functional and genomic integrity of blood tissue, a network of regulatory pathways tightly controls the proliferative status of HSCs. Nevertheless, normal HSC aging is associated with a noticeable decline in regenerative potential and possible changes in other functions. Myelodysplastic syndrome (MDS) is an age-associated hematopoietic malignancy, characterized by abnormal blood cell maturation and a high propensity for leukemic transformation. It is furthermore thought to originate in a HSC and to be associated with the accrual of multiple genetic and epigenetic aberrations. This raises the question whether MDS is, in part, related to an inability to adequately cope with DNA damage. Here we discuss the various components of the cellular response to DNA damage. For each component, we evaluate related studies that may shed light on a potential relationship between MDS development and aberrant DNA damage response/repair. PMID:25569081

  15. Late effect of atomic bomb radiation on myeloid disorders: leukemia and myelodysplastic syndromes.

    PubMed

    Tsushima, Hideki; Iwanaga, Masako; Miyazaki, Yasushi

    2012-03-01

    Leukemia was the first malignancy linked to radiation exposure in atomic bomb survivors. Clear evidence of the dose-dependent excess risk of three major types of leukemia (acute lymphocytic leukemia, acute myeloid leukemia [AML], and chronic myeloid leukemia) was found, especially in people exposed at young ages. Such leukemia risks were at their highest in the late 1950s, and declined gradually thereafter over the past 50 years. Findings from recent risk analyses, however, suggest the persistence of AML risk even after 1990, and evidence of increased risk of myelodysplastic syndromes (MDS) due to atomic bomb radiation has recently been shown. High-risk MDS and forms involving complex chromosomal aberrations were found to be much more frequent in people exposed to higher radiation doses. These lines of epidemiological evidence suggest that the risk of radiation-induced hematological malignancies has persisted for six decades since the initial exposure. PMID:22370711

  16. Neural cell adhesion molecule (CD56)-positive acute myelogenous leukemia and myelodysplastic and myeloproliferative syndromes.

    PubMed

    Mann, K P; DeCastro, C M; Liu, J; Moore, J O; Bigner, S H; Traweek, S T

    1997-06-01

    The CD56 antigen is normally expressed on natural-killer cells but has additionally been shown to be present on a variety of hematologic malignancies, including a subset of acute myelogenous leukemia (AML). There is disagreement, however, about its prognostic significance and its association with specific cytogenetic abnormalities. All clinical samples from June 1994, through September 1995, with increased myeloblasts were analyzed by multiparameter flow cytometry for anomalous expression of CD56. Patients with CD56+ blast cells were selected, and morphologic review was performed. Clinical information was obtained, and cytogenetic data were reviewed. Southern blot analysis to detect rearrangement of the mixed lineage leukemia (MLL) gene was performed when possible. The samples from 23 of 114 patients studied demonstrated anomalous expression of CD56 on myeloblasts, including patients with AML, myelodysplastic syndromes (MDS), and chronic myelogenous leukemia in blast crisis. The samples from 10 of 15 patients with CD56+ AML demonstrated at least partial monocytic differentiation. Dysplastic features were displayed in the samples of 12 patients. Correlation with specific cytogenetic abnormalities was not found. The MLL gene was rearranged in five of 18 patients. Seventeen patients have died, with a median survival of 4.6 months for patients with AML. Three have sustained a complete remission. One has findings of high-grade myelodysplastic syndrome. Two were unavailable for follow-up. Expression of CD56 was found in 20% of patients with increased myeloblasts, including patients with high-grade MDS, chronic myelogenous leukemia in blast crisis, and AML. This phenotype was associated with dysplasia, monocytic differentiation, and rearrangement of the MLL gene. PMID:9169661

  17. Myelodysplastic syndromes.

    PubMed

    Koeffler, H P

    1996-04-01

    These two issues of the Seminars in Hematology will provide the physician the necessary knowledge to help make sense of this somewhat confusing array of diseases. The subdivisions of MDS reflect the precision of our techniques of dissection, with morphological and histochemical analyses forming the foundation to identify and subdivide MDS. Although steady refinement has occurred over the last half-century, the basic morphologic technique is unchanged. Cytogenetic analysis, which has been possible since the 1960s and 1970s, should be done at least at initial presentation in all patients to provide refinement of diagnosis and prognosis. FISH is not, at this time, useful as a screening technique. Although the 1990s is an era of rapidly growing knowledge and technical abilities in molecular biology, the use of these techniques in MDS is in its infancy. Very few genes have been identified which are altered in MDS, although many must exist. The molecular assays continue to be cumbersome and impractical to use in the clinical laboratory and remain the domain of the research scientist. Nevertheless, in the future, molecular biology will enable the internist to give each individual a clearer diagnosis and prognosis and may even provide targetted therapies of patients with MDS. At this time the center of management is good supportive care. Some patients, however, will benefit from special interventions, which include the use of growth factors, BMT, and in selected patients, aggressive chemotherapy. Induction of differentiation of the abnormal hematopoietic clone remains only a dream, although some of the differentiation agents may have applicability for their ability to induce apoptosis and prevent growth of the MDS clone of cells. Many of the major advances in our knowledge of cancer developed through the study of hematopoietic malignancy. A lot of these advances are due to the ease of obtaining the abnormal cells. MDS provides an excellent model for studying the progression of cells from their normal to preneoplastic and fully transformed states. A lucid understanding of this progression can form the paradigm for basic science to study neoplastic progression, and the molecular biology techniques used for these studies will be the basic tools used by hematologists and oncologists in the future. PMID:8722680

  18. Increased plasma thrombopoietin levels in patients with myelodysplastic syndrome: a reliable marker for a benign subset of bone marrow failure

    PubMed Central

    Seiki, Yu; Sasaki, Yumi; Hosokawa, Kohei; Saito, Chizuru; Sugimori, Naomi; Yamazaki, Hirohito; Takami, Akiyoshi; Nakao, Shinji

    2013-01-01

    Although myelodysplastic syndromes are heterogeneous disorders comprising a benign subset of bone marrow failure similar to aplastic anemia, no laboratory test has been established to distinguish it from bone marrow failures that can evolve into acute myeloid leukemia. Plasma thrombopoietin levels were measured in 120 patients who had myelodysplastic syndrome with thrombocytopenia (< 100 × 109/L) to determine any correlation to markers associated with immune pathophysiology and outcome. Thrombopoietin levels were consistently low for patients with refractory anemia with excess of blasts, while patients with other myelodysplatic syndrome subsets had more variable results. Patients with thrombopoietin levels of 320 pg/mL and over had increased glycosylphosphatidylinositol-anchored protein-deficient blood cells (49.1% vs. 0%), were more likely to have a low International Prognostic Scoring System (IPSS) score (≤1.0, 100% vs. 65.5%), a higher response rate to immunosuppressive therapy (84.2% vs. 14.3%), and a better 5-year progression-free survival rate (94.1% vs. 63.6% for refractory cytopenia with unilineage dysplasia; 100.0% vs. 44.4% for refractory cytopenia with multilineage dysplasia). In conclusion, increased plasma thrombopoietin levels were associated with a favorable prognosis of bone marrow failure and could, therefore, represent a reliable marker for a benign subset of myelodysplastic syndrome. PMID:23403320

  19. Minimal Identifiable Disease and the Role of Conditioning Intensity in Hematopoietic Cell Transplantation for Myelodysplastic Syndrome and Acute Myelogenous Leukemia Evolving from Myelodysplastic Syndrome.

    PubMed

    Festuccia, Moreno; Deeg, H Joachim; Gooley, Theodore A; Baker, Kelsey; Wood, Brent L; Fang, Min; Sandmaier, Brenda M; Scott, Bart L

    2016-07-01

    Allogeneic hematopoietic cell transplantation (HCT) is the only known treatment with curative potential for myelodysplastic syndrome, but relapse is a major cause of failure. We studied results in 289 patients transplanted between June 2004 and December 2013. Minimal identifiable disease (MID) markers pre-HCT were determined by multiparameter flow cytometry (MFC) and cytogenetics on marrow aspirates. The impact of MID on outcome after low- and high-intensity conditioning HCT was determined. Among 287 assessable patients, 68 (23.7%) had more than 5% marrow blasts at HCT; 219 patients were in morphologic remission but 154 (53.7%) were MID positive, whereas 65 (22.6%) were MID negative. The impact of MID on outcome was significantly different between patients who received low-intensity conditioning and patients who received a high-intensity regimen. The impact of conditioning intensity differed across the various MID categories. In particular, the risk of overall mortality was higher with low-intensity than with high-intensity regimens for patients who were positive for MID by cytogenetics regardless of positivity by MFC (HR, 1.67 if MFC positive/cytogenetics positive, HR, 7.23 if MFC negative/cytogenetics positive). On the other hand, patients who were MID negative by both MFC and cytogenetics had similar risks of mortality with low- and high-intensity regimens (HR, .99). The main factor responsible for mortality after low-intensity conditioning in MID-positive patients was relapse. The presence of MID should be considered when deciding on conditioning intensity because it identifies subgroups of patients who may benefit from high- or low-intensity conditioning. PMID:27064057

  20. Prognostic impact of chromosomal translocations in myelodysplastic syndromes and chronic myelomonocytic leukemia patients. A study by the spanish group of myelodysplastic syndromes.

    PubMed

    Nomdedeu, Meritxell; Calvo, Xavier; Pereira, Arturo; Carrió, Anna; Solé, Francesc; Luño, Elisa; Cervera, José; Vallespí, Teresa; Muñoz, Concha; Gómez, Cándida; Arias, Amparo; Such, Esperanza; Sanz, Guillermo; Grau, Javier; Insunza, Andrés; Calasanz, María-José; Ardanaz, María-Teresa; Hernández-Rivas, Jesús-María; Azaceta, Gemma; Álvarez, Sara; Sánchez, Joaquín; Martín, María-Luisa; Bargay, Joan; Gómez, Valle; Cervero, Carlos-Javier; Allegue, María-José; Collado, Rosa; Campo, Elías; Esteve, Jordi; Nomdedeu, Benet; Costa, Dolors

    2016-04-01

    Chromosomal translocations are rare in the myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). With the exception of t(3q), translocations are not explicitly considered in the cytogenetic classification of the IPSS-R and their impact on disease progression and patient survival is unknown. The present study was aimed at determining the prognostic impact of translocations in the context of the cytogenetic classification of the IPSS-R. We evaluated 1,653 patients from the Spanish Registry of MDS diagnosed with MDS or CMML and an abnormal karyotype by conventional cytogenetic analysis. Translocations were identified in 168 patients (T group). Compared with the 1,485 patients with abnormal karyotype without translocations (non-T group), the T group had a larger proportion of patients with refractory anemia with excess of blasts and higher scores in both the cytogenetic and global IPSS-R. Translocations were associated with a significantly shorter survival and higher incidence of transformation into AML at univariate analysis but both features disappeared after multivariate adjustment for the IPSS-R cytogenetic category. Patients with single or double translocations other than t(3q) had an outcome similar to those in the non-T group in the intermediate cytogenetic risk category of the IPSS-R. In conclusion, the presence of translocations identifies a subgroup of MDS/CMML patients with a more aggressive clinical presentation that can be explained by a higher incidence of complex karyotypes. Single or double translocations other than t(3q) should be explicitly considered into the intermediate risk category of cytogenetic IPSS-R classification. PMID:26690722

  1. Coalesced Multicentric Analysis of 2,351 Patients With Myelodysplastic Syndromes Indicates an Underestimation of Poor-Risk Cytogenetics of Myelodysplastic Syndromes in the International Prognostic Scoring System

    PubMed Central

    Schanz, Julie; Steidl, Christian; Fonatsch, Christa; Pfeilstöcker, Michael; Nösslinger, Thomas; Tuechler, Heinz; Valent, Peter; Hildebrandt, Barbara; Giagounidis, Aristoteles; Aul, Carlo; Lübbert, Michael; Stauder, Reinhard; Krieger, Otto; Garcia-Manero, Guillermo; Kantarjian, Hagop; Germing, Ulrich; Haase, Detlef; Estey, Elihu

    2011-01-01

    Purpose The International Prognostic Scoring System (IPSS) remains the most commonly used system for risk classification in myelodysplastic syndromes (MDSs). The IPSS gives more weight to blast count than to cytogenetics. However, previous publications suggested that cytogenetics are underweighted in the IPSS. Here we investigate the prognostic impact of cytogenetic subgroups compared with that of bone marrow blast count in a large, multicentric, international patient cohort. Patients and Methods In total, 2,351 patients with MDS who have records in the German-Austrian and the MD Anderson Cancer Center databases were included and analyzed in univariate and multivariate models regarding overall survival and risk of transformation to acute myeloid leukemia (AML). The data were analyzed separately for patients treated with supportive care without specific therapy, with AML-like chemotherapy, or with other therapy regimens (low-dose chemotherapy, demethylating agents, immune modulating agents, valproic acid, and cyclosporine). Results The prognostic impact of poor-risk cytogenetic findings (as defined by the IPSS classification) on overall survival was as unfavorable as an increased (> 20%) blast count. The hazard ratio (compared with an abnormal karyotype or a bone marrow blast count < 5%) was 3.3 for poor-risk cytogenetics, 4.8 for complex abnormalities harboring chromosomes 5 and/or 7, and 3.1 for a blast count of 21% to 30% (P < .01 for all categories). The predictive power of the IPSS cytogenetic subgroups was unaffected by type of therapy given. Conclusion The independent prognostic impact of poor-risk cytogenetics on overall survival is equivalent to the impact of high blast counts. This finding should be considered in the upcoming revision of the IPSS. PMID:21519021

  2. Repair of a recurrent pseudoaneurysm of the ascending aorta in an atomic bomb survivor with myelodysplastic syndrome.

    PubMed

    Hattori, Reiji; Nakao, Yoshihisa; Okada, Takayuki; Johno, Hiroyuki; Enoki, Chiharu; Sumida, Tomohiko; Imamura, Hiroji

    2009-01-01

    The occurrence of infective aortic pseudoaneurysms tends to be intractable and difficult to treat. We experienced a very rare case of a recurrent infective pseudoaneurysm in the ascending aorta that occurred after cardiac surgery in an atomic bomb survivor with myelodysplastic syndrome. The pseudoaneurysm was successfully repaired using a femoral artery autograft with an omentopexy and the patient recovered well without any recurrence. PMID:19583613

  3. Sorafenib in Treating Patients With Refractory or Relapsed Acute Leukemia, Myelodysplastic Syndromes, or Blastic Phase Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2015-04-27

    Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Blastic Phase; de Novo Myelodysplastic Syndrome; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndrome

  4. Age-related incidence and other epidemiological aspects of myelodysplastic syndromes.

    PubMed

    Aul, C; Gattermann, N; Schneider, W

    1992-10-01

    Although most haematologists perceive a rising prevalence and incidence of myelodysplastic syndromes (MDS), reliable epidemiological data on these disorders are largely lacking. The bone marrow register of the University of Düsseldorf allowed us to assess among other epidemiological features the incidence of MDS, which was compared to that of acute myeloid leukaemia (AML). Among a total of 18,416 different patients registered between 1975 and 1990, 584 cases of MDS (3.2%) and 506 cases of AML (2.8%) were identified. Over the study period, the percentage of newly diagnosed MDS rose from 1.3% to 4.5%, while there was no upward trend for AML. Among all patients undergoing bone marrow biopsy, the proportion of those over 60 years of age increased from 41.9% in 1975 to 54.1% in 1990. We found a strong correlation between the proportion of elderly patients and the relative frequency of MDS diagnoses. Thirty-one patients (5.3%) were classified as a secondary MDS because of previous treatment with cytotoxic chemotherapy and/or irradiation for a variety of malignancies. Twelve patients were identified in whom occupational exposure to organic solvents could not be ruled out. For calculating age-specific incidence rates, the analysis was confined to the town district of Düsseldorf (575,000 inhabitants), because exact demographical data were available for this population. In the last quinquennium of the study period (1986-90), myelodysplastic syndromes were more frequent than AML in the age group 50-70 years (4.9 v 1.8/100,000/year). In patients over 70, the incidence of MDS was more than 3 times that of AML (22.8 v 6.7/100,000). In this group, men had a higher incidence of MDS (33.9/100,000) than women (18/100,000). Crude annual incidence (all age groups) was also higher for MDS (4.1/100,000) than for AML (2.1/100,000) in recent years. We conclude that MDS are relatively common haematological neoplasias. The rising incidence in recent years is probably not due to changes in

  5. Restless Legs Syndrome in Pediatric Patients With Nephrotic Syndrome.

    PubMed

    Cheung, Victoria; Wertenteil, Sara; Sasson, Susan; Vento, Suzanne; Kothare, Sanjeev; Trachtman, Howard

    2015-01-01

    Background. Restless legs syndrome (RLS) is a sleep disorder characterized by an urge to move or the presence of unpleasant sensations in the extremities. The prevalence of RLS is higher in children and adults with chronic kidney disease and in adults with glomerular disease. Objective. To determine the prevalence of RLS in children with nephrotic syndrome. Methods. We studied 50 children with nephrotic syndrome and 22 controls. The following surveys were administered: Pediatric Emory RLS questionnaire, Pediatric Daytime Sleepiness Scale, and Pediatric Sleep Questionnaire. Results. Children with nephrotic syndrome were 9.0 ± 4.4 years old, 27 were male, and 27 were in remission. The prevalence of RLS was similar in the nephrotic syndrome cases and controls, whether or not indeterminate cases were considered positive: 14.0% versus 13.6% including indeterminate cases, and 8.0% versus 9.1% excluding indeterminate cases. Conclusion. RLS is not more common in children with glomerular disease compared to healthy controls. PMID:27335958

  6. Restless Legs Syndrome in Pediatric Patients With Nephrotic Syndrome

    PubMed Central

    Cheung, Victoria; Wertenteil, Sara; Sasson, Susan; Vento, Suzanne; Kothare, Sanjeev

    2015-01-01

    Background. Restless legs syndrome (RLS) is a sleep disorder characterized by an urge to move or the presence of unpleasant sensations in the extremities. The prevalence of RLS is higher in children and adults with chronic kidney disease and in adults with glomerular disease. Objective. To determine the prevalence of RLS in children with nephrotic syndrome. Methods. We studied 50 children with nephrotic syndrome and 22 controls. The following surveys were administered: Pediatric Emory RLS questionnaire, Pediatric Daytime Sleepiness Scale, and Pediatric Sleep Questionnaire. Results. Children with nephrotic syndrome were 9.0 ± 4.4 years old, 27 were male, and 27 were in remission. The prevalence of RLS was similar in the nephrotic syndrome cases and controls, whether or not indeterminate cases were considered positive: 14.0% versus 13.6% including indeterminate cases, and 8.0% versus 9.1% excluding indeterminate cases. Conclusion. RLS is not more common in children with glomerular disease compared to healthy controls. PMID:27335958

  7. Aortic Involvement in Pediatric Marfan syndrome: A Review.

    PubMed

    Ekhomu, Omonigho; Naheed, Zahra J

    2015-06-01

    Outlining specific protocols for the management of pediatric patients with Marfan syndrome has been challenging. This is mostly due to a dearth of clinical studies performed in pediatric patients. In Marfan syndrome, the major sources of morbidity and mortality relate to the cardiovascular system. In this review, we focus on aortic involvement seen in pediatric patients with Marfan syndrome, ranging from aortic dilatation to aortic rupture and heart failure. We discuss the histological, morphological, and pathogenetic basis of the cardiac manifestations seen in pediatric Marfan syndrome and use a specific case to depict our experienced range of cardiovascular manifestations. The survival for patients with Marfan syndrome may approach the expected survival for non-affected patients, with optimal management. With this potentiality in mind, we explore possible and actual management considerations for pediatric Marfan syndrome, examining both medical and surgical therapy modalities that can make the possibility of improved survival a reality. PMID:25669767

  8. Case Report: Myelodysplastic syndrome- associated myeloid sarcoma: an unusual clinical presentation of a rare disease.

    PubMed

    Horvath, Emoke; Demian, Smaranda; Nagy, Elod

    2016-01-01

    Myeloid sarcoma results from the extramedullary homing and proliferation of immature myeloid precursors. We present the timeline, events and diagnostic pitfalls related to a 66 year-old male patient's case, admitted to the Hematology Clinic for pancytopenia, fever, weight loss and fatigue. The severe cytopenia and the few blasts observed in his blood smear indicated a bone marrow biopsy. The bone marrow showed hypercellularity and multilineage dysplasia with the presence of 15% myeloblasts. After the biopsy, he promptly developed paraplegia and nuclear magnetic resonance revealed an epidural tumour which was then resected.In the epidural tumour mass blast-like, round cells were observed with a complex immunophenotype, characterized by myeloperoxidase, CD117, CD15, CD99, leucocyte common antigen positivity and a high Ki-67 proliferation index. Considering the main differential diagnostic issues, the final diagnosis was stated as myelodysplastic syndrome-associated myeloid sarcoma. The prognosis was unfavourable, the bone marrow was quickly invaded by proliferating blast cells, and despite chemotherapy attempts, the patient died. PMID:27019694

  9. Case Report: Myelodysplastic syndrome- associated myeloid sarcoma: an unusual clinical presentation of a rare disease

    PubMed Central

    Horvath, Emoke; Demian, Smaranda; Nagy, Elod

    2016-01-01

    Myeloid sarcoma results from the extramedullary homing and proliferation of immature myeloid precursors. We present the timeline, events and diagnostic pitfalls related to a 66 year-old male patient’s case, admitted to the Hematology Clinic for pancytopenia, fever, weight loss and fatigue. The severe cytopenia and the few blasts observed in his blood smear indicated a bone marrow biopsy. The bone marrow showed hypercellularity and multilineage dysplasia with the presence of 15% myeloblasts. After the biopsy, he promptly developed paraplegia and nuclear magnetic resonance revealed an epidural tumour which was then resected.In the epidural tumour mass blast-like, round cells were observed with a complex immunophenotype, characterized by myeloperoxidase, CD117, CD15, CD99, leucocyte common antigen positivity and a high Ki-67 proliferation index. Considering the main differential diagnostic issues, the final diagnosis was stated as myelodysplastic syndrome-associated myeloid sarcoma. The prognosis was unfavourable, the bone marrow was quickly invaded by proliferating blast cells, and despite chemotherapy attempts, the patient died. PMID:27019694

  10. Lenalidomide for myelodysplastic syndromes with del(5q): how long should it last?

    PubMed

    Vozella, Federico; Latagliata, Roberto; Carmosino, Ida; Volpicelli, Paola; Montagna, Chiara; Romano, Angela; Roberto, Amanda; Finsinger, Paola; Mancini, Marco; Breccia, Massimo; Oliva, Esther; Oliva, Esther

    2015-03-01

    Lenalidomide induces in patients with myelodysplastic syndrome (MDS) and del(5q) erythroid and cytogenetic response rates as high as 75% and 50%, respectively. It is still unclear, however, how long lenalidomide treatment should be continued and whether or not the drug could be interrupted. To assess the feasibility of lenalidomide discontinuation, we revised a cohort of 16 low-risk MDS patients with del(5q) treated at our institute in a phase II multicentric Italian study. Among the 12 responding patients, four discontinued lenalidomide while in complete response. All four patients needed during treatment a permanent lenalidomide reduction from 10 to 5 mg/day because of haematological toxicity (three patients) or grade 3 muscular and bone pain (one patient). At lenalidomide discontinuation after 16, 20, 27 and 20 months from the start, respectively, all four patients were in complete hematologic response and three forth in complete cytogenetic response. Three patients are still in response after 36, 30 and 20 months from lenalidomide discontinuation, respectively: The remaining patient relapsed after 20 months, and she is now receiving a new course of lenalidomide. In conclusion, long-lasting remissions are achievable in MDS patients with del(5q) in complete response after lenalidomide discontinuation. PMID:25950027

  11. Incidence of Myelodysplastic Syndrome in UK Petroleum Distribution and Oil Refinery Workers, 1995-2011.

    PubMed

    Sorahan, Tom; Mohammed, Nuredin

    2016-01-01

    The incidence of myelodysplastic syndrome (MDS) experienced by cohorts of 16,467 petroleum distribution workers and 28,554 oil refinery workers has been investigated. Study subjects were all those male employees first employed at one of 476 UK petroleum distribution centres or eight UK oil refineries in the period 1946-1974; all subjects had a minimum of twelve months employment with some employment after 1st January, 1951. Observed numbers (Obs) of MDS cases were compared with expectations based on national incidence rates for the period 1995-2011. The overall standardised registration ratio (SRR) was 73 (Obs = 17) in petroleum distribution workers for the age-range 15-84 years, and 77 (Obs = 21) for the age-range 15-99 years. The overall SRR was 81 (Obs = 29) in oil refinery workers for the age-range 15-84 years, and 83 (Obs = 36) for the age-range 15-99 years. More detailed analyses were carried out in terms of year of registration, period from hire, decade of hire, and duration of employment. The overall SRR findings did not provide clear evidence for the presence of an occupational cancer hazard, and provide no support for the hypothesis that low-level benzene exposure has an important effect on the risks of MDS. PMID:27164123

  12. Impact of TP53 mutation variant allele frequency on phenotype and outcomes in myelodysplastic syndromes.

    PubMed

    Sallman, D A; Komrokji, R; Vaupel, C; Cluzeau, T; Geyer, S M; McGraw, K L; Al Ali, N H; Lancet, J; McGinniss, M J; Nahas, S; Smith, A E; Kulasekararaj, A; Mufti, G; List, A; Hall, J; Padron, E

    2016-03-01

    Although next-generation sequencing has allowed for the detection of somatic mutations in myelodysplastic syndromes (MDS), the clinical relevance of variant allele frequency (VAF) for the majority of mutations is unknown. We profiled TP53 and 20 additional genes in our training set of 219 patients with MDS or secondary acute myeloid leukemia with findings confirmed in a validation cohort. When parsed by VAF, TP53 VAF predicted for complex cytogenetics in both the training (P=0.001) and validation set (P<0.0001). MDS patients with a TP53 VAF > 40% had a median overall survival (OS) of 124 days versus an OS that was not reached in patients with VAF <20% (hazard ratio (HR), 3.52; P=0.01) with validation in an independent cohort (HR, 4.94, P=0.01). TP53 VAF further stratified distinct prognostic groups independent of clinical prognostic scoring systems (P=0.0005). In multivariate analysis, only a TP53 VAF >40% was an independent covariate (HR, 1.61; P<0.0001). In addition, SRSF2 VAF predicted for monocytosis (P=0.003), RUNX1 VAF with thrombocytopenia (P=0.01) and SF3B1 with ringed sideroblasts (P=0.001). Together, our study indicates that VAF should be incorporated in patient management and risk stratification in MDS. PMID:26514544

  13. Reduced DOCK4 expression leads to erythroid dysplasia in myelodysplastic syndromes.

    PubMed

    Sundaravel, Sriram; Duggan, Ryan; Bhagat, Tushar; Ebenezer, David L; Liu, Hui; Yu, Yiting; Bartenstein, Matthias; Unnikrishnan, Madhu; Karmakar, Subhradip; Liu, Ting-Chun; Torregroza, Ingrid; Quenon, Thomas; Anastasi, John; McGraw, Kathy L; Pellagatti, Andrea; Boultwood, Jacqueline; Yajnik, Vijay; Artz, Andrew; Le Beau, Michelle M; Steidl, Ulrich; List, Alan F; Evans, Todd; Verma, Amit; Wickrema, Amittha

    2015-11-17

    Anemia is the predominant clinical manifestation of myelodysplastic syndromes (MDS). Loss or deletion of chromosome 7 is commonly seen in MDS and leads to a poor prognosis. However, the identity of functionally relevant, dysplasia-causing, genes on 7q remains unclear. Dedicator of cytokinesis 4 (DOCK4) is a GTPase exchange factor, and its gene maps to the commonly deleted 7q region. We demonstrate that DOCK4 is underexpressed in MDS bone marrow samples and that the reduced expression is associated with decreased overall survival in patients. We show that depletion of DOCK4 levels leads to erythroid cells with dysplastic morphology both in vivo and in vitro. We established a novel single-cell assay to quantify disrupted F-actin filament network in erythroblasts and demonstrate that reduced expression of DOCK4 leads to disruption of the actin filaments, resulting in erythroid dysplasia that phenocopies the red blood cell (RBC) defects seen in samples from MDS patients. Reexpression of DOCK4 in -7q MDS patient erythroblasts resulted in significant erythropoietic improvements. Mechanisms underlying F-actin disruption revealed that DOCK4 knockdown reduces ras-related C3 botulinum toxin substrate 1 (RAC1) GTPase activation, leading to increased phosphorylation of the actin-stabilizing protein ADDUCIN in MDS samples. These data identify DOCK4 as a putative 7q gene whose reduced expression can lead to erythroid dysplasia. PMID:26578796

  14. SLC7A5 act as a potential leukemic transformation target gene in myelodysplastic syndrome

    PubMed Central

    Ma, Yan; Song, Jing; Chen, Bobin; Xu, Xiaoping; Lin, Guowei

    2016-01-01

    Objective Myelodysplastic syndromes (MDS) are a heterogenous group of clonal hematopoietic stem cell disorders characterized by increased risk of leukemic transformation. This study identifies microRNAs(miRNA) and miRNA targets that might represent leukemic transformation markers for MDS. Methods Based on our previously established nested case-control study cohort of MDS patients, we chose paired patients to undergo Angilent 8 × 15K human miRNA microarrays. Target prediction analysis was administrated using targetscan 5.1 software. We further investigated the function of target gene in MDS cell line using siRNA method, including cell proliferation, cell apoptosis, cell cycle and electron microscope. Results Finally we screened a subset of 7 miRNAs to be significantly differentially expressed between the case (at the end of follow up with leukemic transformation) and control group (at the end of follow up without leukemic transformation). Target prediction analysis revealed SLC7A5 was the common target gene of these 7 miRNAs. Further study on the function of SLC7A5 gene in SKM-1 cell line showed that downregulation of SLC7A5 inhibited SKM-1 cells proliferation, increased apoptosis and caused cell cycle arrest in the G0/G1 stage. Conclusion Our data indicate that SLC7A5 gene may act as a potential leukemic transformation target gene in MDS. PMID:26657287

  15. The role of microRNA in myelodysplastic syndromes: beyond DNA methylation and histone modification.

    PubMed

    Milunović, Vibor; Mandac Rogulj, Inga; Planinc-Peraica, Ana; Bulycheva, Ekaterina; Kolonić Ostojić, Slobodanka

    2016-06-01

    Myelodysplastic syndromes (MDS) are heterogeneous group of hematologic disorders of mostly elderly and based on distinct clinical phenotypes. Current paradigm of their pathogenesis relies on somatic gene mutations combined with the predisposing defective osteohematopoietic niche, but due to the breakout in epigenetic research scientific focus has steered toward two most common epigenetic modifications: methylation mechanisms and histone modification. At the same time, relatively few studies have been undertaken regarding the third epigenetic pathway - microRNAs - in MDS. The main aim of this review is to provide the basics of microRNA biology and function in oncogenesis, showing the complexity of mechanisms behind this single-stranded 22 nucleotides long RNA molecule, with further focus on its implication in MDS pathology and clinical context. By extensive literature search, we have shown enough evidence for their deregulation in MDS. However, few studies have addressed the issue on pathogenic events in MDS and its association with specific microRNAs. Preliminary research in clinical setting has shown the possible utility of microRNAs in terms of prognosis and therapy, although we are only beginning to understand various implications of microRNAs in MDS and further extensive research is warranted to answer multiple questions arising from interconnection of this epigenetic mechanism in MDS. PMID:26773284

  16. Optimal timing of allogeneic hematopoietic stem cell transplantation in patients with myelodysplastic syndrome

    PubMed Central

    Alessandrino, Emilio Paolo; Porta, Matteo G Della; Malcovati, Luca; Jackson, Christopher H; Pascutto, Cristiana; Bacigalupo, Andrea; Teresa van Lint, Maria; Falda, Michele; Bernardi, Massimo; Onida, Francesco; Guidi, Stefano; Iori, Anna Paola; Cerretti, Raffaella; Marenco, Paola; Pioltelli, Pietro; Angelucci, Emanuele; Oneto, Rosi; Ripamonti, Francesco; Rambaldi, Alessandro; Bosi, Alberto; Cazzola, Mario

    2013-01-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) represents the only curative treatment for patients with myelodysplastic syndrome (MDS), but involves non-negligible morbidity and mortality. Registry studies have shown that advanced disease stage at transplantation is associated with inferior overall survival. To define the optimal timing of allogeneic HSCT, we carried out a decision analysis by studying 660 patients who received best supportive care and 449 subjects who underwent transplantation. Risk assessment was based on both the International Prognostic Scoring System (IPSS) and the World Health Organization classification-based Prognostic Scoring System (WPSS). We used a continuous-time multistate Markov model to describe the natural history of disease and evaluate the effect of allogeneic HSCT on survival. This model estimated life expectancy from diagnosis according to treatment policy at different risk stages. Relative to supportive care, estimated life expectancy increased when transplantation was delayed from the initial stages until progression to intermediate-1 IPSS-risk or to intermediate WPSS-risk stage, and then decreased for higher risks. Modeling decision analysis on WPSS versus IPSS allowed better estimation of the optimal timing of transplantation. These observations indicate that allogeneic HSCT offers optimal survival benefits when the procedure is performed before MDS patients progress to advanced disease stages. Am. J. Hematol. 88:581–588, 2013. © 2013 Wiley Periodicals, Inc. PMID:23606215

  17. Complications of 5-azacytidine: Three cases of severe ischemic colitis in elderly patients with myelodysplastic syndrome.

    PubMed

    Melchardt, Thomas; Weiss, Lukas; Pleyer, Lisa; Steinkirchner, Susanne; Auberger, Jutta; Hopfinger, Georg; Greil, Richard; Egle, Alexander

    2013-12-01

    5-Azacytidine (5-AZA) was the first drug to be approved for the treatment of high-risk myelodysplastic syndrome (MDS). The adverse event profile of this drug appears favorable compared with the conventional intensive chemotherapy that is used for MDS or acute myeloid leukemia. However, uncommon adverse events may have remained undetected in the limited number of patients that have been treated to date. The present study describes three cases/66.8 person-years (4,491 cases/100,000 person-years) of severe ischemic colitis in a single center cohort of 95 patients who were consecutively treated using subcutaneous 5-AZA. The results demonstrated a much higher incidence of colitis compared with the rates in the general population or in patients of greater ages and co-morbidities. The present study investigated whether the combination of anemia and constipation due to the co-medication of 5-HT3 receptor antagonists may explain the three cases of ischemic colitis. PMID:24260071

  18. Complications of 5-azacytidine: Three cases of severe ischemic colitis in elderly patients with myelodysplastic syndrome

    PubMed Central

    MELCHARDT, THOMAS; WEISS, LUKAS; PLEYER, LISA; STEINKIRCHNER, SUSANNE; AUBERGER, JUTTA; HOPFINGER, GEORG; GREIL, RICHARD; EGLE, ALEXANDER

    2013-01-01

    5-Azacytidine (5-AZA) was the first drug to be approved for the treatment of high-risk myelodysplastic syndrome (MDS). The adverse event profile of this drug appears favorable compared with the conventional intensive chemotherapy that is used for MDS or acute myeloid leukemia. However, uncommon adverse events may have remained undetected in the limited number of patients that have been treated to date. The present study describes three cases/66.8 person-years (4,491 cases/100,000 person-years) of severe ischemic colitis in a single center cohort of 95 patients who were consecutively treated using subcutaneous 5-AZA. The results demonstrated a much higher incidence of colitis compared with the rates in the general population or in patients of greater ages and co-morbidities. The present study investigated whether the combination of anemia and constipation due to the co-medication of 5-HT3 receptor antagonists may explain the three cases of ischemic colitis. PMID:24260071

  19. Clinical Impact of Hypomethylating Agents in the Treatment of Myelodysplastic Syndromes.

    PubMed

    Finelli, Carlo; Follo, Matilde Y; Stanzani, Marta; Parisi, Sarah; Clissa, Cristina; Mongiorgi, Sara; Barraco, Marilena; Cocco, Lucio

    2016-01-01

    Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic diseases, mainly affecting the elderly, characterized by unilinear or multilinear peripheral cytopenia, bone marrow ineffective haemopoiesis, and a varying risk of progression to acute myeloid leukemia (AML). On the basis of the prognostic score systems currently used, MDS patients are generally classified as having higher risk (HR) or lower risk (LR) MDS. Two drugs, azacitidine (AZA) and decitabine (DAC), defined, because of their proven mechanism of action, as DNA methyltransferase inhibitors (DNMTIs), or hypomethylating agents (HMAs), have proven effective in improving peripheral cytopenias and quality of life, reducing or eliminating transfusion need, delaying leukemic evolution, and (only for AZA) prolonging overall survival (OS). HMAs are currently the first therapeutic choice for MDS patients who are not candidates for allogeneic hematopoietic stem cell transplantation (allo-HSCT). HMAs have also been used before and after allo-HSCT, but their role in this setting needs to be confirmed by larger studies. Although data from several clinical and biological studies might help to identify patients with a higher probability to respond to HMAs, to date this treatment should not be denied to any HR MDS patient. Several attempts have been made to combine HMAs with other therapeutic agents, and these results await confirmation by further studies. PMID:26960675

  20. Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome

    PubMed Central

    Madan, Vikas; Kanojia, Deepika; Li, Jia; Okamoto, Ryoko; Sato-Otsubo, Aiko; Kohlmann, Alexander; Sanada, Masashi; Grossmann, Vera; Sundaresan, Janani; Shiraishi, Yuichi; Miyano, Satoru; Thol, Felicitas; Ganser, Arnold; Yang, Henry; Haferlach, Torsten; Ogawa, Seishi; Koeffler, H. Phillip

    2014-01-01

    Somatic mutations in the spliceosome gene ZRSR2 — located on the X chromosome — are associated with myelodysplastic syndrome (MDS). ZRSR2 is involved in the recognition of 3΄ splice site during the early stages of spliceosome assembly; however, its precise role in RNA splicing has remained unclear. Here, we characterize ZRSR2 as an essential component of the minor spliceosome (U12-dependent) assembly. shRNA mediated knockdown of ZRSR2 leads to impaired splicing of the U12-type introns, and RNA-Sequencing of MDS bone marrow reveals that loss of ZRSR2 activity causes increased mis-splicing. These splicing defects involve retention of the U12-type introns while splicing of the U2-type introns remain mostly unaffected. ZRSR2 deficient cells also exhibit reduced proliferation potential and distinct alterations in myeloid and erythroid differentiation in vitro. These data identify a specific role for ZRSR2 in RNA splicing and highlight dysregulated splicing of U12-type introns as a characteristic feature of ZRSR2 mutations in MDS. PMID:25586593

  1. PAK1 is a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome

    PubMed Central

    Pandolfi, Ashley; Stanley, Robert F.; Yu, Yiting; Bartholdy, Boris; Pendurti, Gopichand; Gritsman, Kira; Boultwood, Jacqueline; Chernoff, Jonathan; Verma, Amit

    2015-01-01

    Poor clinical outcome of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) has been attributed to failure of current chemotherapeutic regimens to target leukemic stem cells. We recently identified p21-activated kinase (PAK1) as a downstream effector molecule of H2.0-like homeobox (HLX), a gene functionally relevant for AML pathogenesis. In this study, we find that inhibition of PAK1 activity by small molecule inhibitors or by RNA interference leads to profound leukemia inhibitory effects both in vitro and in vivo. Inhibition of PAK1 induces differentiation and apoptosis of AML cells through downregulation of the MYC oncogene and a core network of MYC target genes. Importantly, we find that inhibition of PAK1 inhibits primary human leukemic cells including immature leukemic stem cell-enriched populations. Moreover, we find that PAK1 upregulation occurs during disease progression and is relevant for patient survival in MDS. Our studies highlight PAK1 as a novel target in AML and MDS and support the use of PAK1 inhibitors as a therapeutic strategy in these diseases. PMID:26170031

  2. Mutational hierarchies in myelodysplastic syndromes dynamically adapt and evolve upon therapy response and failure.

    PubMed

    Mossner, Maximilian; Jann, Johann-Christoph; Wittig, Janina; Nolte, Florian; Fey, Stephanie; Nowak, Verena; Obländer, Julia; Pressler, Jovita; Palme, Iris; Xanthopoulos, Christina; Boch, Tobias; Metzgeroth, Georgia; Röhl, Henning; Witt, Stephanie H; Dukal, Helene; Klein, Corinna; Schmitt, Steffen; Gelß, Patrick; Platzbecker, Uwe; Balaian, Ekaterina; Fabarius, Alice; Blum, Helmut; Schulze, Torsten J; Meggendorfer, Manja; Haferlach, Claudia; Trumpp, Andreas; Hofmann, Wolf-Karsten; Medyouf, Hind; Nowak, Daniel

    2016-09-01

    Clonal evolution is believed to be a main driver for progression of various types of cancer and implicated in facilitating resistance to drugs. However, the hierarchical organization of malignant clones in the hematopoiesis of myelodysplastic syndromes (MDS) and its impact on response to drug therapy remain poorly understood. Using high-throughput sequencing of patient and xenografted cells, we evaluated the intratumoral heterogeneity (n= 54) and reconstructed mutational trajectories (n = 39) in patients suffering from MDS (n = 52) and chronic myelomonocytic leukemia-1 (n = 2). We identified linear and also branching evolution paths and confirmed on a patient-specific level that somatic mutations in epigenetic regulators and RNA splicing genes frequently constitute isolated disease-initiating events. Using high-throughput exome- and/or deep-sequencing, we analyzed 103 chronologically acquired samples from 22 patients covering a cumulative observation time of 75 years MDS disease progression. Our data revealed highly dynamic shaping of complex oligoclonal architectures, specifically upon treatment with lenalidomide and other drugs. Despite initial clinical response to treatment, patients' marrow persistently remained clonal with rapid outgrowth of founder-, sub-, or even fully independent clones, indicating an increased dynamic rate of clonal turnover. The emergence and disappearance of specific clones frequently correlated with changes of clinical parameters, highlighting their distinct and far-reaching functional properties. Intriguingly, increasingly complex mutational trajectories are frequently accompanied by clinical progression during the course of disease. These data substantiate a need for regular broad molecular monitoring to guide clinical treatment decisions in MDS. PMID:27268087

  3. Myelodysplastic syndrome macrophages have aberrant iron storage and heme oxygenase-1 expression.

    PubMed

    Nybakken, Grant; Gratzinger, Dita

    2016-08-01

    Iron overload and transfusion dependance portend poor risk in myelodysplastic syndromes (MDS); bone marrow macrophages store iron and limit oxidative damage through heme oxygenase-1 (HO1). We assessed iron stores and macrophage HO1 expression in MDS using image analysis of intact diagnostic bone marrow biopsies and qualitative scoring of marrow aspirate iron among 129 cytopenic patients, 67 with MDS and 62 similarly aged patients with benign cytopenias. Using double immunofluorescence and sequential iron and immunohistochemistry staining, we showed that marrow iron colocalizes with HO1 and H-ferritin to CD163 + macrophages. Marrow iron was elevated in MDS independent of transfusion status, a finding of potential utility in distinguishing benign cytopenia from MDS. Among MDS patients only, CD163 + macrophage density and HO1 and H-ferritin expression by CD163 + macrophages increased in tandem with marrow iron. High HO1 was significantly associated with shorter overall survival among MDS patients independent of IPSSR and history of transfusion. PMID:26758041

  4. Pathogenesis of myelodysplastic syndromes: an overview of molecular and non-molecular aspects of the disease

    PubMed Central

    Visconte, Valeria; Tiu, Ramon V.

    2014-01-01

    Myelodysplastic syndromes (MDS) are a group of clonal disorders arising from hematopoietic stem cells generally characterized by inefficient hematopoiesis, dysplasia in one or more myeloid cell lineages, and variable degrees of cytopenias. Most MDS patients are diagnosed in their late 60s to early 70s. The estimated incidence of MDS in the United States and in Europe are 4.3 and 1.8 per 100,000 individuals per year, respectively with lower rates reported in some Asian countries and less well estimated in other parts of the world. Evolution to acute myeloid leukemia can occur in 10-15% of MDS patients. Three drugs are currently approved for the treatment of patients with MDS: immunomodulatory agents (lenalidomide), and hypomethylating therapy [HMT (decitabine and 5-azacytidine)]. All patients will eventually lose their response to therapy, and the survival outcome of MDS patients is poor (median survival of 4.5 months) especially for patients who fail (refractory/relapsed) HMT. The only potential curative treatment for MDS is hematopoietic cell transplantation. Genomic/chromosomal instability and various mechanisms contribute to the pathogenesis and prognosis of the disease. High throughput genetic technologies like single nucleotide polymorphism array analysis and next generation sequencing technologies have uncovered novel genetic alterations and increased our knowledge of MDS pathogenesis. We will review various genetic and non-genetic causes that are involved in the pathogenesis of MDS. PMID:25548754

  5. Oral Clofarabine in the Treatment of Patients With Higher-Risk Myelodysplastic Syndrome

    PubMed Central

    Faderl, Stefan; Garcia-Manero, Guillermo; Estrov, Zeev; Ravandi, Farhad; Borthakur, Gautam; Cortes, Jorge E.; O'Brien, Susan; Gandhi, Varsha; Plunkett, William; Byrd, Anna; Kwari, Monica; Kantarjian, Hagop M.

    2010-01-01

    Purpose Efficacy and toxicity profile of orally administered clofarabine were evaluated in patients with higher-risk myelodysplastic syndrome (MDS). Patients and Methods Thirty-two patients were treated, of whom 22 had intermediate-2 or high-risk disease (International Prognostic Scoring System). Median age was 70 years (range, 53 to 86), nine patients had secondary MDS, and 20 patients experienced prior therapy failure with hypomethylating agents. Three doses of clofarabine were evaluated: 40 mg/m2, 30 mg/m2, and 20 mg/m2 daily for 5 days. Courses were repeated every 4 to 8 weeks. Results Eight patients (25%) achieved complete remission (CR), three had (9%) hematologic improvement (HI), and three had (9%) clinical benefit (CB; overall response rate, 43%). Responses in patients who experience treatment failure with hypomethylating agents included CR in two (10%), HI in two (10%), and CB in two patients (10%). No patients died within 6 weeks of induction. Renal failure occurred in four patients in the context of myelosuppresssion-associated infectious complications. Common adverse events were gastrointestinal and hepatic. Myelosuppression was common, but prolonged myelosuppression (> 42 days) was rare. The toxicity profile was better with lower doses of clofarabine, whereas response rates did not differ significantly. Conclusion Oral clofarabine has achieved a response rate of 43% in patients with higher-risk MDS. The optimal dose and schedule and the appropriate patient population for such therapy remain to be further defined. PMID:20421540

  6. Minimal residual disease monitoring and preemptive immunotherapy in myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Mo, Xiao-Dong; Qin, Ya-Zhen; Zhang, Xiao-Hui; Xu, Lan-Ping; Wang, Yu; Yan, Chen-Hua; Chen, Huan; Chen, Yu-Hong; Han, Wei; Wang, Feng-Rong; Wang, Jing-Zhi; Liu, Kai-Yan; Huang, Xiao-Jun

    2016-08-01

    This study investigated the efficacy of minimal residual disease (MRD) monitoring and MRD-directed preemptive immunotherapy in high-risk myelodysplastic syndrome (MDS) patients who received allogeneic hematopoietic stem cell transplantation (HSCT). MRD assessment consisted of Wilms' tumor gene 1 (WT1) detection with PCR and leukemia-associated immunophenotypic pattern examination with multiparameter flow cytometry (FCM). Post-HSCT, 31 patients were positive for WT1, and 8, for FCM; positivity for WT1 (18.6 vs. 6.1 %, P = 0.040) or FCM (62.5 vs. 3.6 %, P < 0.001) indicated a higher 2-year relapse rate. Twenty-one patients met our combined criteria for MRD, and the presence of MRD was associated with a higher 2-year relapse rate (27.3 vs. 4.5 %, P = 0.003). Preferentially expressed antigen of melanoma (PRAME) expression alone was not an appropriate MRD marker; however, it suggested that the MRD-positive patients may fail to respond to preemptive immunotherapy. In patients positive for both PRAME and MRD, the relapse rate was 60 % despite preemptive immunotherapy. Multivariate analysis confirmed the association between the increased relapse rate and positivity for both PRAME and MRD (hazard ratio = 42.8, P = 0.001). MRD monitoring predicted relapse in high-risk MDS post-HSCT patients, and PRAME- and MRD-positive patients did not benefit from preemptive immunotherapy. PMID:27302479

  7. Molecular and Cellular Mechanisms of Myelodysplastic Syndrome: Implications on Targeted Therapy

    PubMed Central

    Gill, Harinder; Leung, Anskar Y. H.; Kwong, Yok-Lam

    2016-01-01

    Myelodysplastic syndrome (MDS) is a group of heterogeneous clonal hematopoietic stem cell disorders characterized by cytopenia, ineffective hematopoiesis, and progression to secondary acute myeloid leukemia in high-risk cases. Conventional prognostication relies on clinicopathological parameters supplemented by cytogenetic information. However, recent studies have shown that genetic aberrations also have critical impacts on treatment outcome. Moreover, these genetic alterations may themselves be a target for treatment. The mutation landscape in MDS is shaped by gene aberrations involved in DNA methylation (TET2, DNMT3A, IDH1/2), histone modification (ASXL1, EZH2), the RNA splicing machinery (SF3B1, SRSF2, ZRSR2, U2AF1/2), transcription (RUNX1, TP53, BCOR, PHF6, NCOR, CEBPA, GATA2), tyrosine kinase receptor signaling (JAK2, MPL, FLT3, GNAS, KIT), RAS pathways (KRAS, NRAS, CBL, NF1, PTPN11), DNA repair (ATM, BRCC3, DLRE1C, FANCL), and cohesion complexes (STAG2, CTCF, SMC1A, RAD21). A detailed understanding of the pathogenetic mechanisms leading to transformation is critical for designing single-agent or combinatorial approaches in target therapy of MDS. PMID:27023522

  8. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes

    PubMed Central

    Bejar, Rafael; Jaiswal, Siddhartha; Lindsley, R. Coleman; Sekeres, Mikkael A.; Hasserjian, Robert P.; Ebert, Benjamin L.

    2015-01-01

    Recent genetic analyses of large populations have revealed that somatic mutations in hematopoietic cells leading to clonal expansion are commonly acquired during human aging. Clonally restricted hematopoiesis is associated with an increased risk of subsequent diagnosis of myeloid or lymphoid neoplasia and increased all-cause mortality. Although myelodysplastic syndromes (MDS) are defined by cytopenias, dysplastic morphology of blood and marrow cells, and clonal hematopoiesis, most individuals who acquire clonal hematopoiesis during aging will never develop MDS. Therefore, acquisition of somatic mutations that drive clonal expansion in the absence of cytopenias and dysplastic hematopoiesis can be considered clonal hematopoiesis of indeterminate potential (CHIP), analogous to monoclonal gammopathy of undetermined significance and monoclonal B-cell lymphocytosis, which are precursor states for hematologic neoplasms but are usually benign and do not progress. Because mutations are frequently observed in healthy older persons, detection of an MDS-associated somatic mutation in a cytopenic patient without other evidence of MDS may cause diagnostic uncertainty. Here we discuss the nature and prevalence of CHIP, distinction of this state from MDS, and current areas of uncertainty regarding diagnostic criteria for myeloid malignancies. PMID:25931582

  9. Myelodysplastic Syndrome Revealed by Systems Immunology in a Melanoma Patient Undergoing Anti-PD-1 Therapy.

    PubMed

    Greenplate, Allison R; Johnson, Douglas B; Roussel, Mikael; Savona, Michael R; Sosman, Jeffrey A; Puzanov, Igor; Ferrell, P Brent; Irish, Jonathan M

    2016-06-01

    Antibodies aimed at blocking the interaction between programmed cell death-1 (PD-1) and its ligands have shown impressive efficacy in a variety of malignancies and are generally well tolerated. Research has focused intensely on T cells and their interaction with cells within melanoma tumors, while relatively little is understood about the systems immunology of the cells in the blood during checkpoint inhibitor therapy. Longitudinal cytomic analysis using mass cytometry can characterize all the cells in a small sample of blood and has the potential to reveal key shifts in the cellular milieu occurring during treatment. We report a case of advanced melanoma in which mass cytometry detected abnormal myeloid cells resulting from myelodysplastic syndrome (MDS) in the blood following treatment with an anti-PD-1 agent. Myeloid blasts comprised <1% of peripheral blood mononuclear cells (PBMC) 1 month after the start of treatment. Six months after starting therapy, myeloid blasts comprised 5% of PBMCs, and a bone marrow biopsy confirmed refractory anemia with excess blasts-2 (RAEB-2). Longitudinal mass cytometry immunophenotyping comprehensively characterized blast phenotype evolution and revealed elevated PD-1 expression on the surface of nonblast myeloid cells. These findings highlight the clinical significance of cytomic monitoring, indicate that the myeloid compartment should be monitored during checkpoint inhibitor therapy, and emphasize the value of systems immunology in medicine. Cancer Immunol Res; 4(6); 474-80. ©2016 AACR. PMID:26966176

  10. Incidence of Myelodysplastic Syndrome in UK Petroleum Distribution and Oil Refinery Workers, 1995–2011

    PubMed Central

    Sorahan, Tom; Mohammed, Nuredin

    2016-01-01

    The incidence of myelodysplastic syndrome (MDS) experienced by cohorts of 16,467 petroleum distribution workers and 28,554 oil refinery workers has been investigated. Study subjects were all those male employees first employed at one of 476 UK petroleum distribution centres or eight UK oil refineries in the period 1946–1974; all subjects had a minimum of twelve months employment with some employment after 1st January, 1951. Observed numbers (Obs) of MDS cases were compared with expectations based on national incidence rates for the period 1995–2011. The overall standardised registration ratio (SRR) was 73 (Obs = 17) in petroleum distribution workers for the age-range 15–84 years, and 77 (Obs = 21) for the age-range 15–99 years. The overall SRR was 81 (Obs = 29) in oil refinery workers for the age-range 15–84 years, and 83 (Obs = 36) for the age-range 15–99 years. More detailed analyses were carried out in terms of year of registration, period from hire, decade of hire, and duration of employment. The overall SRR findings did not provide clear evidence for the presence of an occupational cancer hazard, and provide no support for the hypothesis that low-level benzene exposure has an important effect on the risks of MDS. PMID:27164123

  11. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet

    PubMed Central

    Malcovati, Luca; Hellström-Lindberg, Eva; Bowen, David; Adès, Lionel; Cermak, Jaroslav; del Cañizo, Consuelo; Della Porta, Matteo G.; Fenaux, Pierre; Gattermann, Norbert; Germing, Ulrich; Jansen, Joop H.; Mittelman, Moshe; Mufti, Ghulam; Platzbecker, Uwe; Sanz, Guillermo F.; Selleslag, Dominik; Skov-Holm, Mette; Stauder, Reinhard; Symeonidis, Argiris; van de Loosdrecht, Arjan A.

    2013-01-01

    Within the myelodysplastic syndrome (MDS) work package of the European LeukemiaNet, an Expert Panel was selected according to the framework elements of the National Institutes of Health Consensus Development Program. A systematic review of the literature was performed that included indexed original papers, indexed reviews and educational papers, and abstracts of conference proceedings. Guidelines were developed on the basis of a list of patient- and therapy-oriented questions, and recommendations were formulated and ranked according to the supporting level of evidence. MDSs should be classified according to the 2008 World Health Organization criteria. An accurate risk assessment requires the evaluation of not only disease-related factors but also of those related to extrahematologic comorbidity. The assessment of individual risk enables the identification of fit patients with a poor prognosis who are candidates for up-front intensive treatments, primarily allogeneic stem cell transplantation. A high proportion of MDS patients are not eligible for potentially curative treatment because of advanced age and/or clinically relevant comorbidities and poor performance status. In these patients, the therapeutic intervention is aimed at preventing cytopenia-related morbidity and preserving quality of life. A number of new agents are being developed for which the available evidence is not sufficient to recommend routine use. The inclusion of patients into prospective clinical trials is strongly recommended. PMID:23980065

  12. ST-Elevation Myocardial Infarction and Myelodysplastic Syndrome with Acute Myeloid Leukemia Transformation

    PubMed Central

    Jao, Geoffrey T.; Knovich, Mary Ann; Savage, Rodney W.; Sane, David C.

    2014-01-01

    Acute myocardial infarction and acute myeloid leukemia are rarely reported as concomitant conditions. The management of ST-elevation myocardial infarction (STEMI) in patients who have acute myeloid leukemia is challenging: the leukemia-related thrombocytopenia, platelet dysfunction, and systemic coagulopathy increase the risk of bleeding, and the administration of thrombolytic agents can be fatal. We report the case of a 76-year-old man who presented emergently with STEMI, myelodysplastic syndrome, and newly recognized acute myeloid leukemia transformation. Standard antiplatelet and anticoagulation therapy were contraindicated by the patient's thrombocytopenia and by his reported ecchymosis and gingival bleeding upon admission. He declined cardiac catheterization, was provided palliative care, and died 2 hours after hospital admission. We searched the English-language medical literature, found 8 relevant reports, and determined that the prognosis for patients with concomitant STEMI and acute myeloid leukemia is clearly worse than that for either individual condition. No guidelines exist to direct the management of STEMI and concomitant acute myeloid leukemia. In 2 reports, dual antiplatelet therapy, anticoagulation, and drug-eluting stent implantation were used without an increased risk of bleeding in the short term, even in the presence of thrombocytopenia. However, we think that a more conservative approach—balloon angioplasty with the provisional use of bare-metal stents—might be safer. Simultaneous chemotherapy for the acute myeloid leukemia is crucial. Older age seems to be a major risk factor: patients too frail for emergent treatment can die within hours or days. PMID:24808792

  13. Reduced DOCK4 expression leads to erythroid dysplasia in myelodysplastic syndromes

    PubMed Central

    Sundaravel, Sriram; Duggan, Ryan; Bhagat, Tushar; Ebenezer, David L.; Liu, Hui; Yu, Yiting; Bartenstein, Matthias; Unnikrishnan, Madhu; Karmakar, Subhradip; Liu, Ting-Chun; Torregroza, Ingrid; Quenon, Thomas; Anastasi, John; McGraw, Kathy L.; Pellagatti, Andrea; Boultwood, Jacqueline; Yajnik, Vijay; Artz, Andrew; Le Beau, Michelle M.; Steidl, Ulrich; List, Alan F.; Evans, Todd; Verma, Amit; Wickrema, Amittha

    2015-01-01

    Anemia is the predominant clinical manifestation of myelodysplastic syndromes (MDS). Loss or deletion of chromosome 7 is commonly seen in MDS and leads to a poor prognosis. However, the identity of functionally relevant, dysplasia-causing, genes on 7q remains unclear. Dedicator of cytokinesis 4 (DOCK4) is a GTPase exchange factor, and its gene maps to the commonly deleted 7q region. We demonstrate that DOCK4 is underexpressed in MDS bone marrow samples and that the reduced expression is associated with decreased overall survival in patients. We show that depletion of DOCK4 levels leads to erythroid cells with dysplastic morphology both in vivo and in vitro. We established a novel single-cell assay to quantify disrupted F-actin filament network in erythroblasts and demonstrate that reduced expression of DOCK4 leads to disruption of the actin filaments, resulting in erythroid dysplasia that phenocopies the red blood cell (RBC) defects seen in samples from MDS patients. Reexpression of DOCK4 in −7q MDS patient erythroblasts resulted in significant erythropoietic improvements. Mechanisms underlying F-actin disruption revealed that DOCK4 knockdown reduces ras-related C3 botulinum toxin substrate 1 (RAC1) GTPase activation, leading to increased phosphorylation of the actin-stabilizing protein ADDUCIN in MDS samples. These data identify DOCK4 as a putative 7q gene whose reduced expression can lead to erythroid dysplasia. PMID:26578796

  14. A nationwide non-interventional epidemiological data registry on myelodysplastic syndromes in Lebanon

    PubMed Central

    Otrock, Zaher K; Chamseddine, Nabil; Salem, Ziad M; Wehbe, Tarek; Al-Ayoubi, Mouna; Dhaini, Moussa; Kattan, Joseph; Mokaddem, Walid; Nasr, Therese Abi; Jradi, Oussama; Farhat, Fadi S; Wehbe, Mahmoud; Haidar, Mohammad H; Kharfan-Dabaja, Mohamed A; Bitar, Nizar; Hajj, Mirna El; Kadri, Adel M; Kamar, Francois G; Yassine, Hanan; Khodr, Hassan; Taher, Ali T; Hakime, Noha; Mahfouz, Rami AR; Serhal, Wassim; Bazarbachi, Ali; Farhat, Hussein Z

    2015-01-01

    Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by peripheral blood cytopenias, blood cells dysplasia, and increased risk for progression to acute leukemia.Physicians should be vigilant in diagnosing MDS and should be aware of the contemporary therapies that are always in progress. Most of the data on MDS epidemiology and management comes from developed countries. The incidence and features of MDS in the Arab countries, among them Lebanon, are not known. We undertook a nationwide epidemiological registry study of all newly diagnosed MDS cases through 2010-2011. Patients were referred by 21 hematologists/oncologists practicing in 17 hospitals and medical centers distributed across the entire country. 58 patients (29 males and 29 females) with confirmed MDS were included. The calculated incidence rate of MDS was 0.71 per 100,000 people. The median age at diagnosis was 73 years (range 16-86). The most common complaints on presentation were fatigue (70.7%), weakness (60.3%) and pallor (43.1%). Most patients were diagnosed as refractory anemia with excess blasts (RAEB; 36.2%) and refractory cytopenia with multilineage dysplasia (RCMD; 32.8%). This paper constitutes the first epidemiological report on the incidence and specific subtypes of MDS in Lebanon. PMID:27069756

  15. Gene Expression and Methylation Pattern in HRK Apoptotic Gene in Myelodysplastic Syndrome

    PubMed Central

    Zaker, Farhad; Amirizadeh, Naser; Nasiri, Nahid; Razavi, Seyed Mohsen; Teimoori-Toolabi, Ladan; Yaghmaie, Marjan; Mehrasa, Roya

    2016-01-01

    Myelodysplastic syndromes (MDSs) are a clonal bone marrow (BM) disease characterized by ineffective hematopoiesis, dysplastic maturation and progression to acute myeloid leukemia (AML). Methylation silencing of HRK has been found in several human malignancies. In this study, we explored the association of HRK methylation status with its expression, clinical parameters and MDS subtypes in MDS patients. To study the methylation status of HRK gene, we applied Methylation Sensitive-High Resolution Melting Curve Analysis (MS-HRM) in MDS patients, as well as healthy controls and EpiTect®PCR Control DNA. Real time RT-PCR was used for gene expression analysis. Methylation frequency in promoter region of HRK in patient samples was 20.37%. Methylation of HRK was significantly related to transcriptional downregulation (P=0.023). The difference in frequency of hypermethylated HRK gene was significant between good (10%) and poor (71.42%) cytogenetic risk groups (P= 0.001), advanced stage MDS patients (66.66%) in comparison with early stage MDS patients (2.56%) (P= 0.00), higher- risk MDS group (61.53%) and lower- risk MDS group (7.31%) (P= 0.00). HRK hypermethylation was associated with advanced- stage MDS and downregulation of HRK gene may play a role in the progression of MDS. PMID:27478805

  16. Abrupt evolution of Philadelphia chromosome-positive acute myeloid leukemia in myelodysplastic syndrome.

    PubMed

    Fukunaga, Akiko; Sakoda, Hiroto; Iwamoto, Yoshihiro; Inano, Shojiro; Sueki, Yuki; Yanagida, Soshi; Arima, Nobuyoshi

    2013-03-01

    Myelodysplastic syndrome (MDS) is a clonal disorder arising from an alteration in multipotent stem cells, which lose the ability of normal proliferation and differentiation. Disease progression occurs in approximately 30% MDS cases. Specific chromosomal alterations seem responsible for each step in the evolution of acute myeloid leukemia (AML). Multiple genetic aberrations occur during the clonal evolution of MDS; however, few studies report the presence of the Philadelphia (Ph) chromosome. We report a rare case of Ph-positive AML, which evolved during the course of low-risk MDS. The patient, a 76-year-old man with mild leukocytopenia, was diagnosed with MDS, refractory neutropenia (RN). After 1.5 yr, his peripheral blood and bone marrow were suddenly occupied by immature basophils and myeloblasts, indicating the onset of AML. A bone marrow smear showed multilineage dysplasia, consistent with MDS evolution. Chromosomal analysis showed an additional t(9;22)(q34;q11) translocation. Because progression occurred concurrently with emergence of the Ph chromosome, we diagnosed this case as Ph-positive AML with basophilia arising from the clonal evolution of MDS. The patient was initially treated with nilotinib. A hematological response was soon achieved with disappearance of the Ph chromosome in the bone marrow. Emergence of Ph-positive AML in the course of low-risk MDS has rarely been reported. We report this case as a rare clinical course of MDS. PMID:23240925

  17. Current State of the Art: Management of Higher Risk Myelodysplastic Syndromes.

    PubMed

    Komrokji, Rami S

    2016-08-01

    The higher risk myelodysplastic syndrome (MDS) patients, defined by the International Prognostic Scoring System (IPSS) as intermediate-2 or high-risk groups, compromise a third of MDS patients who have an expected survival of less than 1.5 years. Our ability to better define higher risk MDS improved with the proposal of new clinical risk models such as the revised IPSS and by integration of molecular data, including somatic gene mutations. Allogeneic hematopoietic stem-cell transplantation (AHSCT) remains the only curative option. In higher risk MDS patients, proceeding early with AHSCT is associated with maximum survival gain. The decision to pursue AHSCT is individualized according to disease risk, comorbidities, and functional status. The role of therapy before AHSCT remains controversial, and the role of post-AHSCT maintenance is evolving. Hypomethylating agents are the only medications that alter the natural history of the disease. Azacitidine is the only drug reported to improve overall survival in higher risk MDS patients. Appropriate use and assessment of response is key for assuring patients benefit of such limited options. Treatment after failure of hypomethylating agents is an unmet need. The role of detectable somatic gene mutations in prognosis and tailoring therapy continue to emerge. PMID:27521322

  18. Influence of functional polymorphisms in DNA repair genes of myelodysplastic syndrome.

    PubMed

    Ribeiro, Howard Lopes; Soares Maia, Allan Rodrigo; Costa, Marília Braga; Farias, Izabelle Rocha; de Paula Borges, Daniela; de Oliveira, Roberta Taiane Germano; de Sousa, Juliana Cordeiro; Magalhães, Silvia Maria Meira; Pinheiro, Ronald Feitosa

    2016-09-01

    Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell (HSC) malignances characterized by peripheral cytopenias and predisposition to acute myeloid leukemia transformation. Several studies show that the MDS pathogenesis is a complex and heterogeneous process that involves multiple steps through a sequence of genetic lesions in the DNA which lead to functional changes in the cell and the emergence and subsequent evolution of pre-malignant clone. Double strand breaks (DSB) lesions are the most severe type of DNA damage in HSCs, which, if not properly repaired, might contribute to the development of chromosomal abnormalities, which in turn may lead to leukemia development. We assessed the mRNA expression levels of ATM, BRCA1, BRCA2, RAD51, XRCC5, XRCC6 and LIG4 genes in bone marrow samples of 47 MDS patients in order to evaluate the association with functional polymorphisms rs228593, rs4793191, rs9567623, rs1801320, rs3835, rs2267437 and rs1805388, respectively, and try to detect clinical associations. We found that the rs228593, rs2267437 and rs1805388 functional polymorphisms probably alter the level of expression of the ATM, XRCC6 and LIG4 genes, respectively, being important in the maintenance of genomic instability in MDS. PMID:27497341

  19. Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome.

    PubMed

    Madan, Vikas; Kanojia, Deepika; Li, Jia; Okamoto, Ryoko; Sato-Otsubo, Aiko; Kohlmann, Alexander; Sanada, Masashi; Grossmann, Vera; Sundaresan, Janani; Shiraishi, Yuichi; Miyano, Satoru; Thol, Felicitas; Ganser, Arnold; Yang, Henry; Haferlach, Torsten; Ogawa, Seishi; Koeffler, H Phillip

    2015-01-01

    Somatic mutations in the spliceosome gene ZRSR2-located on the X chromosome-are associated with myelodysplastic syndrome (MDS). ZRSR2 is involved in the recognition of 3'-splice site during the early stages of spliceosome assembly; however, its precise role in RNA splicing has remained unclear. Here we characterize ZRSR2 as an essential component of the minor spliceosome (U12 dependent) assembly. shRNA-mediated knockdown of ZRSR2 leads to impaired splicing of the U12-type introns and RNA-sequencing of MDS bone marrow reveals that loss of ZRSR2 activity causes increased mis-splicing. These splicing defects involve retention of the U12-type introns, while splicing of the U2-type introns remain mostly unaffected. ZRSR2-deficient cells also exhibit reduced proliferation potential and distinct alterations in myeloid and erythroid differentiation in vitro. These data identify a specific role for ZRSR2 in RNA splicing and highlight dysregulated splicing of U12-type introns as a characteristic feature of ZRSR2 mutations in MDS. PMID:25586593

  20. Chronic GVHD induced GVL effect after unmanipulated haploidentical hematopoietic SCT for AML and myelodysplastic syndrome.

    PubMed

    Mo, X-D; Xu, L-P; Zhang, X-H; Liu, D-H; Wang, Y; Chen, H; Yan, C-H; Chen, Y-H; Han, W; Wang, F-R; Wang, J-Z; Liu, K-Y; Huang, X-J

    2015-01-01

    The aim of this study was to investigate the impact of occurrence of chronic GVHD (cGVHD) and its severity on transplantation outcomes in a consecutive cohort of AML and myelodysplastic syndrome (MDS) patients who received unmanipulated haploidentical hematopoietic SCT (haplo-HSCT; n=324). The cumulative incidence of relapse was significantly decreased in patients with cGVHD compared with the non-cGVHD group (1 year: 3.2% vs 11.9%, P=0.002; 3 years: 6.0% vs 16.3%, P=0.002), particularly in those with mild cGVHD. The cumulative incidence of non-relapse mortality was comparable between patients with and without cGVHD. The probabilities of disease-free survival (DFS) were significantly better in patients with cGVHD than in those in the non-cGVHD group (1 year: 90.5% vs 78.5%, P=0.002; 3 years: 86.5% vs 71.5%, P<0.001), particularly in those with mild or moderate cGVHD; however, no significant impact of severe cGVHD on DFS was seen. Our findings highlight the close relationship between cGVHD and the immune-mediated GVL effect in patients with AML and MDS receiving unmanipulated haplo-HSCT; however, only mild or moderate cGVHD was associated with a lower risk of relapse translating into improved DFS. PMID:25387095

  1. Treatment of pyoderma gangrenosum with thalidomide in a myelodysplastic syndrome case

    PubMed Central

    Malkan, Umit Yavuz; Gunes, Gursel; Eliacik, Eylem; Haznedaroglu, Ibrahim Celalettin

    2016-01-01

    Thalidomide may be used as a treatment option for pyoderma gangrenosum (PG) and myelodysplastic syndrome (MDS). Herein, we aimed to report a patient who was treated well with thalidomide and whose diagnosis was PG with MDS. A 61-year-old man with painless ecchymotic lesions in his right upper extremity was admitted to the hospital in Isparta, Turkey, in January 2015. The lesions were diagnosed as PG. In his anamnesis, it was found that he was diagnosed with MDS 6 years ago and had been treated with cyclosporine at 2×100 mg for 5 years, which was stopped in January 2015. Aspiration from liver lesion revealed the presence of Mycobacterium tuberculosis, so antituberculosis treatment was started. Bone marrow investigation revealed MDS-refractory anemia with excess blasts (7%). For lesions in bilateral upper extremities, thalidomide treatment was started at 50 mg/d. After 1 month from the initiation of thalidomide treatment, the lesions in upper extremities had disappeared. In the literature, there are some reports of patients with PG who were successfully treated with thalidomide. Our patient is a complicated case who simultaneously has MDS, PG, and tuberculosis infection. The reason for thalidomide usage in our patient was the need of immune modulation without immune suppression. Our patient has tolerated the drug well, and excellent response was obtained after 1 month of initiation of thalidomide treatment. To conclude, thalidomide is a very effective drug acting as an immune modulator, which is useful in the clinical management of both MDS and PG. PMID:27051318

  2. Treatment of pyoderma gangrenosum with thalidomide in a myelodysplastic syndrome case.

    PubMed

    Malkan, Umit Yavuz; Gunes, Gursel; Eliacik, Eylem; Haznedaroglu, Ibrahim Celalettin

    2016-01-01

    Thalidomide may be used as a treatment option for pyoderma gangrenosum (PG) and myelodysplastic syndrome (MDS). Herein, we aimed to report a patient who was treated well with thalidomide and whose diagnosis was PG with MDS. A 61-year-old man with painless ecchymotic lesions in his right upper extremity was admitted to the hospital in Isparta, Turkey, in January 2015. The lesions were diagnosed as PG. In his anamnesis, it was found that he was diagnosed with MDS 6 years ago and had been treated with cyclosporine at 2×100 mg for 5 years, which was stopped in January 2015. Aspiration from liver lesion revealed the presence of Mycobacterium tuberculosis, so antituberculosis treatment was started. Bone marrow investigation revealed MDS-refractory anemia with excess blasts (7%). For lesions in bilateral upper extremities, thalidomide treatment was started at 50 mg/d. After 1 month from the initiation of thalidomide treatment, the lesions in upper extremities had disappeared. In the literature, there are some reports of patients with PG who were successfully treated with thalidomide. Our patient is a complicated case who simultaneously has MDS, PG, and tuberculosis infection. The reason for thalidomide usage in our patient was the need of immune modulation without immune suppression. Our patient has tolerated the drug well, and excellent response was obtained after 1 month of initiation of thalidomide treatment. To conclude, thalidomide is a very effective drug acting as an immune modulator, which is useful in the clinical management of both MDS and PG. PMID:27051318

  3. Outcome of High-Risk Myelodysplastic Syndrome After Azacitidine Treatment Failure

    PubMed Central

    Prébet, Thomas; Gore, Steven D.; Esterni, Benjamin; Gardin, Claude; Itzykson, Raphael; Thepot, Sylvain; Dreyfus, François; Rauzy, Odile Beyne; Recher, Christian; Adès, Lionel; Quesnel, Bruno; Beach, C.L.; Fenaux, Pierre; Vey, Norbert

    2011-01-01

    Purpose Azacitidine (AZA) is the current standard of care for high-risk (ie, International Prognostic Scoring System high or intermediate 2) myelodysplastic syndrome (MDS), but most patients will experience primary or secondary treatment failure. The outcome of these patients has not yet been described. Patients and Methods Overall, 435 patients with high-risk MDS and former refractory anemia with excess blasts in transformation (RAEB-T) were evaluated for outcome after AZA failure. The cohort of patients included four data sets (ie, AZA001, J9950, and J0443 trials and the French compassionate use program). Results The median follow-up after AZA failure was 15 months. The median overall survival was 5.6 months, and the 2-year survival probability was 15%. Increasing age, male sex, high-risk cytogenetics, higher bone marrow blast count, and the absence of prior hematologic response to AZA were associated with significantly worse survival in multivariate analysis. Data on treatment administered after AZA failure were available for 270 patients. Allogeneic stem-cell transplantation and investigational agents were associated with a better outcome when compared with conventional clinical care. Conclusion Outcome after AZA failure is poor. Our results should serve as a basis for designing second-line clinical trials in this population. PMID:21788559

  4. Awareness of acute myeloid leukaemia risk induced by diagnosis of a myelodysplastic syndrome.

    PubMed

    Ousseine, Youssoufa M; Butow, Phyllis N; Julian-Reynier, Claire; Dring, Rebecca; Festy, Patrick; Fenaux, Pierre; Vey, Norbert; Mancini, Julien

    2016-07-01

    Myelodysplastic syndromes (MDS) can evolve to acute myeloid leukaemia (AML) in approximately 30% of cases. Knowing their AML risk is important for patients because it might impact adherence to care and psychological health. The aim of this study was to evaluate the awareness of AML risk among MDS patients and to study the factors associated with this awareness. A self-administered questionnaire was mailed to all members of French and Australian patients' national MDS associations. Data of 301 patients were analysed. Patients were satisfied with the information they had received, but 33.2% did not know that they had an increased risk of developing AML. Younger age, higher-risk MDS treatment, preferences for health-related information and satisfaction with information provided about treatment were the factors independently associated with awareness of AML risk. Compared to unaware patients, patients knowing their risk were more likely to participate in a hypothetical clinical trial (83.0% vs 72.4%, p=0.043). More efforts are needed to provide more systematic information about AML risk to patients wishing to know it. More research is needed to study if increasing awareness can lead to more active engagement of MDS patients in their care and can increase the rate of clinical trial participation. PMID:27173089

  5. Durable long-term responses in patients with myelodysplastic syndromes treated with lenalidomide.

    PubMed

    Kurtin, Sandra E; List, Alan F

    2009-06-01

    Lenalidomide has proven efficacy and safety and has been shown to reduce transfusion requirements and reverse cytogenetic abnormalities in lower-risk myelodysplastic syndromes (MDS). However, long-term follow-up data have not yet been reported. Here, we describe 6 patients with International Prognostic Scoring System low- or intermediate-1-risk MDS who began lenalidomide therapy between April 2002 and June 2003 as part of the MDS-001 study and who have maintained long-term therapy. Five of these patients had an ongoing requirement for red blood cell transfusions despite previous treatment with recombinant erythropoietin. One patient began lenalidomide therapy because of progressive and symptomatic anemia. To date, all patients maintained long-term transfusion independence (over 4.5 years) while receiving oral lenalidomide therapy, including 5 patients who remain on therapy. Sustained erythroid response was reported despite persistence of the deletion 5q [del(5q)] abnormality in 3 of the 4 patients with del(5q) at study entry. Side effects were largely predictable and manageable. The favorable outcomes presented here show that lenalidomide can induce durable erythroid responses with sustained transfusion independence that can exceed 6 years in patients with lower-risk MDS. PMID:19525184

  6. Management of lower-risk myelodysplastic syndromes: the art and evidence.

    PubMed

    Komrokji, Rami S; Sekeres, Mikkael A; List, Alan F

    2011-06-01

    Myelodysplastic syndromes (MDS) represent a spectrum of bone marrow failure with variable outcome. Patients with "lower-risk" disease have an expected median survival measured in years, and a low risk of leukemia progression. Patients with "higher-risk" MDS, on the other hand, have expected survival measured in months without treatment and rapid leukemia progression. The outcome of those distinct groups can be explained by different underlying disease biology. In clinical practice, patients are stratified into risk groups based on prognostic models, most commonly the International Prognostic Scoring System (IPSS). In higher-risk disease, the standard of care is hypomethylating agents to extend survival and suppress leukemia potential, and consideration of allogeneic stem cell transplantation, which remains the only curative option. Patients classified as having lower-risk disease begin treatment with management focused on ameliorating hematologic deficits, related symptoms, or both. This review of lower-risk MDS highlights the biology of the disease and models for risk stratification. We use a case-based format to discuss current options for treatment, including erythropoiesis-stimulating agents, hypomethylating agents, lenalidomide, immunosuppressive therapy, supportive care, and investigational agents. PMID:21442178

  7. The prevalence of chromosomal aberrations associated with myelodysplastic syndromes in China.

    PubMed

    Hu, Qinyong; Chu, Yuxin; Song, Qibin; Yao, Yi; Yang, Weihong; Huang, Shiang

    2016-08-01

    This study aims to investigate the prevalence and distribution of diverse chromosomal aberrations associated with myelodysplastic syndromes (MDS) in China. Bone marrow samples were collected from multiple cities in China. Metaphase cytogenetic (MC) analysis and fluorescence in situ hybridization (FISH) were initially used to test chromosomal lesions. Affymetrix CytoScan 750 K genechip platform performed a genome-wide detection of chromosomal aberrations. Chromosomal gain was identified in 76 patients; the most prevalent was trisomy 8(17.9 %). New chromosomal gain was detected on chromosome 9, 19p, and X. Chromosomal loss was detected in 101 patients. The most frequent was loss 5q (21.0 %). Some loss and gain were not identified by MC or FISH but identified by genechip. UPD was solely identified by genechip in 51 patients; the most prevalent were UPD 7q (4.94 %) and UPD 17p (4.32 %). Furthermore, complex chromosomal aberrations were detected in 56 patients. In conclusion, Affymetrix CytoScan 750 K genechip was more precise than MC and FISH in detection of cryptic chromosomal aberrations relevant to MDS. Analysis of the prevalence and distribution of diverse chromosomal aberrations in China may improve strategies for MDS diagnosis and therapies. PMID:27225263

  8. Proposal of criteria for dyserythropoiesis in the diagnosis of myelodysplastic syndromes.

    PubMed

    Kawai, Nobutaka; Matsuda, Akira; Jinnai, Itsuro; Ichimura, Takaya; Kayano, Hidekazu; Okamura, Daisuke; Ishikawa, Maho; Maeda, Tomoya; Hata, Tomoko; Miyazaki, Yasushi; Asou, Norio; Bessho, Masami; Tomonaga, Masao

    2016-02-01

    The percentage manifesting dysplasia in bone marrow needed to qualify as significant is ≥10 % in each lineage. However, detailed analyses of this threshold have not been reported. Here, we analyzed dyserythropoiesis (dysE) in 109 myelodysplastic syndromes (MDS) patients with 21 immune thrombocytopenia (ITP)/12 hemolytic anemia (HA) patients as a control. In present study, mild megaloblastic erythroblasts were specifically named 'red cell with abnormal chromatin clumping (RCACC)'. RCACC ≥10 % in erythroblasts was observed in 29 % of ITP patients and 58 % of HA patients. The numbers of MDS patients with RCACC in erythroblasts <10, 10-19 and ≥20 % were 1, 3, and 105, respectively. We analyzed dysE criteria according to the WHO classification (original WHO dysE). Most of our MDS patients (98 %) had original WHO dysE ≥20 %. The ITP patients with original WHO dysE ≥10 % was 48 %, and there were no ITP patients had original WHO dysE ≥20 %. Sixty-seven percent of HA patients had original WHO dysE ≥10 %, and three patients (25 %) had original WHO dysE ≥20 %. Raising the threshold of the original WHO dysE from 10 to 20 or 30 % may provide more suitable criteria. If RCACC is not included in dysE criteria, we think that '10 %' is a suitable threshold for the determination of dyserythropoiesis. PMID:26608365

  9. Iodine I 131 Monoclonal Antibody BC8, Fludarabine Phosphate, Cyclophosphamide, Total-Body Irradiation and Donor Bone Marrow Transplant in Treating Patients With Advanced Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or High-Risk Myelodysplastic Syndrome

    ClinicalTrials.gov

    2016-07-18

    Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Chronic Myelomonocytic Leukemia; Previously Treated Myelodysplastic Syndrome; Refractory Anemia With Excess Blasts; Refractory Anemia With Ring Sideroblasts; Refractory Cytopenia With Multilineage Dysplasia; Refractory Cytopenia With Multilineage Dysplasia and Ring Sideroblasts

  10. Donor Umbilical Cord Blood Transplant With or Without Ex-vivo Expanded Cord Blood Progenitor Cells in Treating Patients With Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia, or Myelodysplastic Syndromes

    ClinicalTrials.gov

    2016-08-10

    Acute Biphenotypic Leukemia; Acute Lymphoblastic Leukemia in Remission; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Acute Myeloid Leukemia in Remission; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Mixed Phenotype Acute Leukemia; Myelodysplastic Syndrome; Pancytopenia; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Secondary Acute Myeloid Leukemia

  11. Myelodysplastic/ Myeloproliferative Neoplasms Treatment

    MedlinePlus

    ... Myeloproliferative Neoplasms Treatment Myelodysplastic/ Myeloproliferative Neoplasms Treatment Myelodysplastic/ Myeloproliferative Neoplasms Treatment (PDQ®)–Patient Version General Information About Myelodysplastic/ ...

  12. Certain Autoimmune Manifestations Are Associated With Distinctive Karyotypes and Outcomes in Patients With Myelodysplastic Syndrome

    PubMed Central

    Lee, Sang Jin; Park, Jin Kyun; Lee, Eun Young; Joo, Sang Hyun; Jung, Kyeong Cheon; Lee, Eun Bong; Song, Yeong Wook; Yoon, Sung-Soo

    2016-01-01

    Abstract Autoimmune manifestations (AIMs) are common in patients with myelodysplastic syndrome (MDS). This study aimed to investigate whether AIMs are associated with a specific cytogenetic abnormalities and worse survival in patients with MDS. A total of 67 MDS patients with AIMs and 134 age- and sex-matched MDS patients without AIMs, all of whom received medical care at Seoul National University Hospital from January 2000 through July 2014, were enrolled. The clinical features, chromosomal abnormalities, and outcomes were examined. The effect of AIMs on mortality was estimated after adjusting for age, sex, and the International Prognostic Scoring System. The mean age (±SD) at the time of MDS diagnosis was 54.5 ± 17.1 years, and 44.8% of patients were male. Neutrophilic dermatosis (ND; Sweet syndrome and pyoderma gangrenosum) was the most prevalent AIM (n = 24 36%]), followed by Behcet disease (10 [15%]), rheumatoid arthritis (9 [13%]), vasculitis (8 [12%]), myositis (3 [4%]), spondyloarthropathy (3 [4%]), and systemic lupus erythematous (2 [3%]). ND and vasculitis occurred at the time of MDS diagnosis, whereas other AIMs occurred years after MDS diagnosis. Deletion of 5q was associated with ND (P = 0.001), whereas trisomy 8 was associated with Behcet disease (P = 0.015). Strikingly, ND was associated with a 1.8-fold increase in mortality (95% CI 1.033–3.093; P = 0.038). Certain AIMs in MDS patients are associated with distinctive karyotypes and worse survival. A larger study is needed to confirm whether the presence of AIMs influences disease outcome in MDS. PMID:27043672

  13. Polycystic Ovary Syndrome in the Pediatric Population

    PubMed Central

    2010-01-01

    Abstract Polycystic ovary syndrome (PCOS) is a common disorder characterized by hyperandrogenism and disordered gonadotropin secretion, often associated with insulin resistance. The syndrome, which modulates both hormonal and metabolic processes, is the most common endocrinopathy in reproductive-age women and increases a woman's risk of infertility, endometrial pathology, and cardiometabolic disease. As it is currently defined, PCOS most likely encompasses several distinct diseases with similar clinical phenotypes but different underlying pathophysiological processes. However, hyperandrogenism remains the syndrome's clinical hallmark. The clinical manifestations of PCOS often emerge during childhood or in the peripubertal years, suggesting that the syndrome is influenced by fetal programming and/or early postnatal events. However, given that the full clinical spectrum of PCOS does not typically appear until puberty, a “two-hit” hypothesis has been proposed: (1) a girl develops hyperandrogenism via one or more of many different potential mechanisms; (2) the preexisting hyperandrogenism subsequently disturbs the hypothalamic–pituitary–ovarian axis, resulting in ovulatory dysfunction and sustained hyperandrogenism. No consensus guidelines exist regarding the diagnosis and management of PCOS in the pediatric population; however, because the syndrome is a diagnosis of exclusion, the clinical evaluation of girls suspected of having PCOS is aimed at excluding other causes of androgen excess and menstrual dysfunction. For the syndrome's management, emphasis is placed on lifestyle and symptom-directed treatment. PMID:20939704

  14. Reduced-toxicity conditioning with treosulfan and fludarabine in allogeneic hematopoietic stem cell transplantation for myelodysplastic syndromes: final results of an international prospective phase II trial

    PubMed Central

    Ruutu, Tapani; Volin, Liisa; Beelen, Dietrich W.; Trenschel, Rudolf; Finke, Juergen; Schnitzler, Marc; Holowiecki, Jerzy; Giebel, Sebastian; Markiewicz, Miroslaw; Uharek, Lutz; Blau, Igor W.; Kienast, Joachim; Stelljes, Matthias; Larsson, Kajsa; Zander, Axel R.; Gramatzki, Martin; Repp, Roland; Einsele, Hermann; Stuhler, Gernot; Baumgart, Joachim; Mylius, Heidrun A.; Pichlmeier, Uwe; Freund, Mathias; Casper, Jochen

    2011-01-01

    Background An alternative reduced-toxicity conditioning regimen for allogeneic transplantation, based on treosulfan and fludarabine, has recently been identified. The rationale for this study was to investigate the efficacy and safety of this regimen prospectively in patients with a primary myelodysplastic syndrome. Design and Methods A total of 45 patients with primary myelodysplastic syndromes were conditioned with 3×14 g/m2 treosulfan and 5×30 mg/m2 fludarabine followed by allogeneic hematopoietic stem cell transplantation. Subtypes of myelodysplastic syndromes were refractory anemia with excess blasts-2 (44%), refractory cytopenia with multilineage dysplasia (27%), refractory anemia (9%), refractory anemia with ringed sideroblasts (4%), refractory cytopenia with multilineage dysplasia and ringed sideroblasts (4%), refractory anemia with excess blasts-1 (2%), and myelodysplastic syndrome with isolated del (5q) (2%). The myelodysplastic syndrome was unclassified in 7% of the patients. Forty-seven percent of the patients had a favorable karyotype, 29% an unfavorable one, and 18% an intermediate karyotype. Patients were evaluated for engraftment, adverse events, graft-versus-host disease, non-relapse mortality, relapse incidence, overall survival and disease-free survival. Results All but one patient showed primary engraftment of neutrophils after a median of 17 days. Non-hematologic adverse events of grade III–IV in severity included mainly infections and gastrointestinal symptoms (80% and 22% of the patients, respectively). Acute graft-versus-host disease grade II–IV developed in 24%, and extensive chronic graft-versus-host disease in 28% of the patients. After a median follow-up of 780 days, the 2-year overall and disease-free survival estimates were 71% and 67%, respectively. The 2-year cumulative incidences of non-relapse mortality and relapse were 17% and 16%, respectively. Conclusions Our safety and efficacy data suggest that treosulfan

  15. Screening for hotspot mutations in PI3K, JAK2, FLT3 and NPM1 in patients with myelodysplastic syndromes

    PubMed Central

    Machado-Neto, João Agostinho; Traina, Fabiola; Lazarini, Mariana; de Melo Campos, Paula; Pagnano, Katia Borgia Barbosa; Lorand-Metze, Irene; Costa, Fernando Ferreira; Olalla Saad, Sara T

    2011-01-01

    INTRODUCTION: Myelodysplastic syndromes encompass a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, refractory cytopenia and a tendency to progress toward acute myeloid leukemia. The accumulation of genetic alterations is closely associated with the progression of myelodysplastic syndromes toward acute myeloid leukemia. OBJECTIVE: To investigate the presence of mutations in the points most frequent for mutations (hotspot mutations) in phosphatidylinositol-3-kinase (PI3K), Janus kinase 2 (JAK2), FMS-like tyrosine kinase 3 (FLT3) and nucleophosmin (NPM1), which are involved in leukemia and other cancers, in a population of Brazilian MDS patients. METHODS: Fifty-one myelodysplastic syndromes patients were included in the study. According to French-American-British classification, the patients were distributed as follows: 31 with refractory anemia, 8 with refractory anemia with ringed sideroblasts, 7 with refractory anemia with excess blasts, 3 with refractory anemia with excess blasts in transformation and 2 with chronic myelomonocytic leukemia. Bone marrow samples were obtained and screened for the presence of hotspot mutations using analysis based on amplification with the polymerase chain reaction, sequencing, fragment size polymorphisms or restriction enzyme digestion. All patients were screened for mutations at the time of diagnosis, and 5 patients were also screened at the time of disease progression. RESULTS: In the genes studied, no mutations were detected in the patients at the time of diagnosis. One patient with chronic myelomonocytic leukemia was heterozygous for a Janus kinase 2 mutation after disease progression. CONCLUSIONS: These results show that hotspot mutations in the PI3K, JAK2, FLT3 and NPM1 genes are not common in MDS patients; nevertheless, JAK2 mutations may be present in myelodysplasia during disease progression. PMID:21789382

  16. p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q)

    PubMed Central

    Saft, Leonie; Karimi, Mohsen; Ghaderi, Mehran; Matolcsy, András; Mufti, Ghulam J.; Kulasekararaj, Austin; Göhring, Gudrun; Giagounidis, Aristoteles; Selleslag, Dominik; Muus, Petra; Sanz, Guillermo; Mittelman, Moshe; Bowen, David; Porwit, Anna; Fu, Tommy; Backstrom, Jay; Fenaux, Pierre; MacBeth, Kyle J.; Hellström-Lindberg, Eva

    2014-01-01

    Del(5q) myelodysplastic syndromes defined by the International Prognostic Scoring System as low- or intermediate-1-risk (lower-risk) are considered to have an indolent course; however, recent data have identified a subgroup of these patients with more aggressive disease and poorer outcomes. Using deep sequencing technology, we previously demonstrated that 18% of patients with lower-risk del(5q) myelodysplastic syndromes carry TP53 mutated subclones rendering them at higher risk of progression. In this study, bone marrow biopsies from 85 patients treated with lenalidomide in the MDS-004 clinical trial were retrospectively assessed for p53 expression by immunohistochemistry in association with outcome. Strong p53 expression in ≥1% of bone marrow progenitor cells, observed in 35% (30 of 85) of patients, was significantly associated with higher acute myeloid leukemia risk (P=0.0006), shorter overall survival (P=0.0175), and a lower cytogenetic response rate (P=0.009), but not with achievement or duration of 26-week transfusion independence response. In a multivariate analysis, p53-positive immunohistochemistry was the strongest independent predictor of transformation to acute myeloid leukemia (P=0.0035). Pyrosequencing analysis of laser-microdissected cells with strong p53 expression confirmed the TP53 mutation, whereas cells with moderate expression predominantly had wild-type p53. This study validates p53 immunohistochemistry as a strong and clinically useful predictive tool in patients with lower-risk del(5q) myelodysplastic syndromes. This study was based on data from the MDS 004 trial (clinicaltrials.gov identifier: NCT00179621). PMID:24682512

  17. p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q).

    PubMed

    Saft, Leonie; Karimi, Mohsen; Ghaderi, Mehran; Matolcsy, András; Mufti, Ghulam J; Kulasekararaj, Austin; Göhring, Gudrun; Giagounidis, Aristoteles; Selleslag, Dominik; Muus, Petra; Sanz, Guillermo; Mittelman, Moshe; Bowen, David; Porwit, Anna; Fu, Tommy; Backstrom, Jay; Fenaux, Pierre; MacBeth, Kyle J; Hellström-Lindberg, Eva

    2014-06-01

    Del(5q) myelodysplastic syndromes defined by the International Prognostic Scoring System as low- or intermediate-1-risk (lower-risk) are considered to have an indolent course; however, recent data have identified a subgroup of these patients with more aggressive disease and poorer outcomes. Using deep sequencing technology, we previously demonstrated that 18% of patients with lower-risk del(5q) myelodysplastic syndromes carry TP53 mutated subclones rendering them at higher risk of progression. In this study, bone marrow biopsies from 85 patients treated with lenalidomide in the MDS-004 clinical trial were retrospectively assessed for p53 expression by immunohistochemistry in association with outcome. Strong p53 expression in ≥ 1% of bone marrow progenitor cells, observed in 35% (30 of 85) of patients, was significantly associated with higher acute myeloid leukemia risk (P=0.0006), shorter overall survival (P=0.0175), and a lower cytogenetic response rate (P=0.009), but not with achievement or duration of 26-week transfusion independence response. In a multivariate analysis, p53-positive immunohistochemistry was the strongest independent predictor of transformation to acute myeloid leukemia (P=0.0035). Pyrosequencing analysis of laser-microdissected cells with strong p53 expression confirmed the TP53 mutation, whereas cells with moderate expression predominantly had wild-type p53. This study validates p53 immunohistochemistry as a strong and clinically useful predictive tool in patients with lower-risk del(5q) myelodysplastic syndromes. This study was based on data from the MDS 004 trial (clinicaltrials.gov identifier: NCT00179621). PMID:24682512

  18. [Investigation of FLT3-ITD and NPM1 mutations in patients with myelodysplastic syndrome and mixed myeloid diseases].

    PubMed

    Gritsaev, S V; Martynkevich, I S; Ivanova, M P; Moskalenko, M V; Aksenova, V Iu; Tiranova, S A; Abdulkadyrov, K M

    2010-01-01

    Two FLT3-ITD mutations, one FLT3-TKD) and five NPM1 mutations were detected in 7 patients with de novo myelodysplastic syndrome (MDS) out of 44 cases of MDS and MDS/mixed myeloid diseases. Expression of one of the three investigated mutations was identified: 4 in gene NPM1 (9.1%) and 2--FLT3-ITD (4.5%); simultaneous FLT3-ITD and NPM1 mutation--1 (2.3%); no progression in NPM1 within 9-20 months--3, although with chromosome 7 damage--2. It was suggested that NPM1 mutation without complex karyotype may serve as marker of relatively favorable course. PMID:21395122

  19. The sudden onset of mastocytosis in the course of venom-induced anaphylactic reaction in a patient with myelodysplastic syndrome.

    PubMed

    Rybicka, Malwina; Helbig, Grzegorz; Woźniczka, Krzysztof; Kopera, Małgorzata; Pająk, Jacek; Kyrcz-Krzemień, Sławomira

    2015-01-01

    Mastocytosis is a disease resulting from a proliferation of clonal, abnormal mast cells in tissues and organs, defined as Philadelphia-negative myeloproliferative neoplasm. We present a male patient with clinically, morphologically and immunohistochemically confirmed mastocytosis with preceding myelodysplastic syndrome, occurred after wasp bite in the course of anaphylactic reaction. The propensity to hymenoptera venom-induced anaphylaxis and the presence of an increased population of atypical mast cells in bone marrow found after anaphylactic shock may suggest the possible relationship between hymenoptera venom allergy and anaphylaxis and the development of mastocytosis of unusual course in a predisposed person. PMID:26181160

  20. Patterns of erythropoiesis-stimulating agent use among Medicare beneficiaries with myelodysplastic syndromes and consistency with clinical guidelines.

    PubMed

    Davidoff, Amy J; Weiss, Sheila R; Baer, Maria R; Ke, Xuehua; Hendrick, Franklin; Zeidan, Amer; Gore, Steven D

    2013-06-01

    Erythropoiesis-stimulating agents (ESA) are used commonly to reduce symptomatic anemia in patients with myelodysplastic syndromes (MDS). We assessed population-based patterns of ESA use relative to treatment guidelines using data from the Surveillance, Epidemiology, and End Results (SEER) registries, with linked Medicare claims providing detailed treatment data from 2001 through 2005. The study found widespread use (62%) of ESA in Medicare beneficiaries with MDS. Similar ESA use rates regardless of risk status, low frequency (45%) of serum erythropoietin determination prior to ESA initiation, and high prevalence (60.4%) of short-duration ESA episodes suggest clinically important discrepancies between actual practice and guideline-recommended therapy. PMID:23523473

  1. Prevalence, severity and correlates of fatigue in newly diagnosed patients with myelodysplastic syndromes.

    PubMed

    Efficace, Fabio; Gaidano, Gianluca; Breccia, Massimo; Criscuolo, Marianna; Cottone, Francesco; Caocci, Giovanni; Bowen, David; Lübbert, Michael; Angelucci, Emanuele; Stauder, Reinhard; Selleslag, Dominik; Platzbecker, Uwe; Sanpaolo, Grazia; Jonasova, Anna; Buccisano, Francesco; Specchia, Giorgina; Palumbo, Giuseppe A; Niscola, Pasquale; Wan, Chonghua; Zhang, Huiyong; Fenu, Susanna; Klimek, Virginia; Beyne-Rauzy, Odile; Nguyen, Khanh; Mandelli, Franco

    2015-02-01

    The primary objective of this study was to investigate factors associated with fatigue severity in newly diagnosed patients with higher-risk myelodysplastic syndromes (MDS). The secondary objectives were to assess symptom prevalence and to examine the relationships between fatigue, quality of life (QoL) and overall symptom burden in these patients. The analyses were conducted in 280 higher-risk MDS patients. Pre-treatment patient-reported fatigue was evaluated with the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale and QoL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). Female gender (P = 0·018), poor performance status (i.e., ECOG of 2-4) (P < 0·001) and lower levels of haemoglobin (Hb) (P = 0·026) were independently associated with higher fatigue severity. The three most prevalent symptoms were as follows: fatigue (92%), dyspnoea (63%) and pain (55%). Patients with higher levels of fatigue also had greater overall symptom burdens. The mean global QoL scores of patients with the highest versus those with the lowest levels of fatigue were 29·2 [standard deviation (SD), 18·3] and 69·0 (SD, 18·8), respectively and this difference was four times the magnitude of a clinically meaningful difference. Patient-reported fatigue severity revealed the effects of disease burden on overall QoL more accurately than did degree of anaemia. Special attention should be given to the female patients in the management of fatigue. PMID:25272332

  2. Decitabine Can Be Safely Reduced after Achievement of Best Objective Response in Patients with Myelodysplastic Syndrome

    PubMed Central

    Ghanem, Hady; Cornelison, A. Megan; Garcia-Manero, Guillermo; Kantarjian, Hagop; Ravandi, Farhad; Kadia, Tapan; Cortes, Jorge; O’Brien, Susan; Brandt, Mark; Borthakur, Gautam; Jabbour, Elias

    2014-01-01

    Decitabine is standard therapy in patients with myelodysplastic syndrome (MDS). Current recommendations suggest a dose of 20 mg/m2 IV daily for 5 days every 4 weeks. However, this therapy is associated with frequent grade 3–4 hematologic toxicity, requiring dose reductions (DR) and/or dose delays (DD). We investigated the outcome of 122 MDS patients who had DD/DR of frontline decitabine therapy. Sixty five patients (53%) had DR by at least 25% or DD (defined as a delay beyond 5 weeks between cycles). Thirty-five patients (29%) underwent DD/DR after achieving best objective response (BOR), 30 patients (25%) before BOR and 57 (54%) had no DD/DR. There was a trend for more durable responses in favor of patients requiring DD/DR after the achievement of BOR (median not reached) (p=0.161). Overall survival rates were significantly higher for patients who had DD/DR after BOR compared to those who had DD/DR prior to BOR or those with no DD/DR (30 v/s 22 v/s 11 months, respectively, p<0.001). Progression-free survival rates also trended higher for those with DD/DR after BOR (median not reached) compared to those who required DD/DR before (median of 15 months) (p=0.285). In conclusion, DD/DR may be safely accomplished once the patient has achieved BOR (preferably complete remission) without impacting outcome. Prospective evaluation of an approach conceiving a loading dose for induction of a best objective response followed by a maintenance schedule is to be considered. PMID:23969308

  3. Targeting of the bone marrow microenvironment improves outcome in a murine model of myelodysplastic syndrome

    PubMed Central

    Balderman, Sophia R.; Li, Allison J.; Hoffman, Corey M.; Frisch, Benjamin J.; Goodman, Alexandra N.; LaMere, Mark W.; Georger, Mary A.; Evans, Andrew G.; Liesveld, Jane L.; Becker, Michael W.

    2016-01-01

    In vitro evidence suggests that the bone marrow microenvironment (BMME) is altered in myelodysplastic syndromes (MDSs). Here, we study the BMME in MDS in vivo using a transgenic murine model of MDS with hematopoietic expression of the translocation product NUP98-HOXD13 (NHD13). This model exhibits a prolonged period of cytopenias prior to transformation to leukemia and is therefore ideal to interrogate the role of the BMME in MDS. In this model, hematopoietic stem and progenitor cells (HSPCs) were decreased in NHD13 mice by flow cytometric analysis. The reduction in the total phenotypic HSPC pool in NHD13 mice was confirmed functionally with transplantation assays. Marrow microenvironmental cellular components of the NHD13 BMME were found to be abnormal, including increases in endothelial cells and in dysfunctional mesenchymal and osteoblastic populations, whereas megakaryocytes were decreased. Both CC chemokine ligand 3 and vascular endothelial growth factor, previously shown to be increased in human MDS, were increased in NHD13 mice. To assess whether the BMME contributes to disease progression in NHD13 mice, we performed transplantation of NHD13 marrow into NHD13 mice or their wild-type (WT) littermates. WT recipients as compared with NHD13 recipients of NHD13 marrow had a lower rate of the combined outcome of progression to leukemia and death. Moreover, hematopoietic function was superior in a WT BMME as compared with an NHD13 BMME. Our data therefore demonstrate a contributory role of the BMME to disease progression in MDS and support a therapeutic strategy whereby manipulation of the MDS microenvironment may improve hematopoietic function and overall survival. PMID:26637787

  4. Influence of patient and provider characteristics on quality of care for the myelodysplastic syndromes.

    PubMed

    Abel, Gregory A; Cronin, Angel M; Odejide, Oreofe O; Uno, Hajime; Stone, Richard M; Steensma, David P

    2016-06-01

    Little is known about quality of care for patients with myelodysplastic syndromes (MDS), or patient and provider factors that influence quality. We identified Medicare enrollees diagnosed with MDS between 2006 and 2011, and analysed linked claims for performance on two widely-accepted quality measures: diagnostic bone marrow cytogenetic testing (diagnostic quality) and pre-treatment iron assessment for patients receiving an erythropoiesis-stimulating agent (ESA; treatment quality). A total of 4575 patients met the criteria for diagnostic quality measurement, and 3379 for treatment quality measurement. In the diagnostic cohort, 74% had a claim for marrow cytogenetic testing 3 months before to 3 months after diagnosis. In multivariate models, younger age (P < 0·001), treatment at a higher-volume MDS centre (P < 0·001), and claims for pancytopenia (P < 0·001) were all associated with higher levels of testing. A borderline result was observed for diagnostic year, with improvement over time (P = 0·06). In the treatment cohort, 56% had evidence of pre-ESA iron assessment, with higher rates for later years of diagnosis (P < 0·001), higher household income (P = 0·03), and those treated at higher-volume centres (P = 0·01). In this large cohort of patients with MDS, quality of care was suboptimal overall, but worse in several specific subgroups. These data suggest that targeted educational and/or process-focused interventions are warranted. PMID:26913376

  5. Impact of socioeconomic status on disease phenotype, genomic landscape and outcomes in myelodysplastic syndromes.

    PubMed

    Mastaglio, Francesca; Bedair, Khaled; Papaemmanuil, Elli; Groves, Michael J; Hyslop, Ann; Keenan, Norene; Hothersall, Eleanor J; Campbell, Peter J; Bowen, David T; Tauro, Sudhir

    2016-07-01

    Genetic and epigenetic alterations contribute to the biological and clinical characteristics of myelodysplastic syndromes (MDS), but a role for socioeconomic environment remains unclear. Here, socioeconomic status (SES) for 283 MDS patients was estimated using the Scottish Index of Multiple Deprivation tool. Indices were assigned to quintile categorical indicators ranked from SES1 (lowest) to SES5 (highest). Clinicopathological features and outcomes between SES quintiles containing 15%, 20%, 19%, 30% and 16% of patients were compared. Prognostic scores identified lower-risk MDS in 82% of patients, with higher-risk disease in 18%. SES quintiles did not associate with age, gender, cytogenetics, International Prognostic scores or, in sub-analysis (n = 95), driver mutations. The odds ratio of a diagnosis of refractory anaemia was greater than other MDS sub-types in SES5 (OR 1·9, P = 0·024). Most patients (91%) exclusively received supportive care. SES did not associate with leukaemic transformation or cause of death. Cox regression models confirmed male gender (P < 0·05), disease-risk (P < 0·0001) and age (P < 0·01) as independent predictors of leukaemia-free survival, with leukaemic transformation an additional determinant of overall survival (P = 0·07). Thus, if access to healthcare is equitable, SES does not determine disease biology or survival in MDS patients receiving supportive treatment; additional studies are required to determine whether outcomes following disease-modifying therapies are influenced by SES. PMID:27098194

  6. Allogeneic transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia

    PubMed Central

    Litzow, Mark R.; Tarima, Sergey; Pérez, Waleska S.; Bolwell, Brian J.; Cairo, Mitchell S.; Camitta, Bruce M.; Cutler, Corey S.; de Lima, Marcos; DiPersio, John F.; Gale, Robert Peter; Keating, Armand; Lazarus, Hillard M.; Luger, Selina; Marks, David I.; Maziarz, Richard T.; McCarthy, Philip L.; Pasquini, Marcelo C.; Phillips, Gordon L.; Rizzo, J. Douglas; Sierra, Jorge; Tallman, Martin S.

    2010-01-01

    Therapy-related myelodysplastic syndromes (t-MDSs) and acute myeloid leukemia (t-AML) have a poor prognosis with conventional therapy. Encouraging results are reported after allogeneic transplantation. We analyzed outcomes in 868 persons with t-AML (n = 545) or t-MDS (n = 323) receiving allogeneic transplants from 1990 to 2004. A myeloablative regimen was used for conditioning in 77%. Treatment-related mortality (TRM) and relapse were 41% (95% confidence interval [CI], 38-44) and 27% (24-30) at 1 year and 48% (44-51) and 31% (28-34) at 5 years, respectively. Disease-free (DFS) and overall survival (OS) were 32% (95% CI, 29-36) and 37% (34-41) at 1 year and 21% (18-24) and 22% (19-26) at 5 years, respectively. In multivariate analysis, 4 risk factors had adverse impacts on DFS and OS: (1) age older than 35 years; (2) poor-risk cytogenetics; (3) t-AML not in remission or advanced t-MDS; and (4) donor other than an HLA-identical sibling or a partially or well-matched unrelated donor. Five-year survival for subjects with none, 1, 2, 3, or 4 of these risk factors was 50% (95% CI, 38-61), 26% (20-31), 21% (16-26), 10% (5-15), and 4% (0-16), respectively (P < .001). These data permit a more precise prediction of outcome and identify subjects most likely to benefit from allogeneic transplantation. PMID:20032503

  7. APG101 efficiently rescues erythropoiesis in lower risk myelodysplastic syndromes with severe impairment of hematopoiesis

    PubMed Central

    Rouquette, Alexandra; Deudon, Celine; Willems, Lise; Chapuis, Nicolas; Mathis, Stephanie; Kunz, Claudia; Fricke, Harald; Kosmider, Olivier; Bardet, Valerie; Fontenay, Michaela

    2016-01-01

    CD95, a member of the death receptor family initiates a caspase-dependent apoptosis, when activated by its ligand CD95L, thought to negatively regulate erythrocyte production in the bone marrow. We have previously shown that CD95 is overexpressed in two thirds of patients with a lower risk myelodysplastic syndrome (MDS) and that resistance to erythropoiesis-stimulating agents (ESA) is linked to poor residual erythropoiesis. In the present study, we show that CD95 overexpression and previous transfusion are independent predictive factors of ESA resistance. To investigate an alternative therapeutic strategy of anemia in ESA-resistant patients, we have conducted a preclinical study of the effects of APG101, a fusion protein consisting of the extracellular domain of human CD95 and the Fc region of human IgG1 on MDS erythropoiesis in vitro. APG101 increases the number of burst-forming unit-erythroid (BFU-E) progenitors derived from CD34+ progenitors in liquid culture and improves overall proliferation rate of erythroid precursors by inhibiting apoptosis. APG101 rescues BFU-E growth in MDS patients presenting with attrition of erythroid progenitors at baseline, independently of CD95 or CD95L expression level. Our data show that overexpression of CD95 at diagnosis is a hallmark of ESA resistance and that severe impairment of erythropoiesis is predictive of erythroid response to APG101 in vitro. These data provide a rationale for further clinical investigation of APG101 in an attempt to treat anemia in lower risk MDS patients. PMID:26910909

  8. Phase I Study of Oral Azacitidine in Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Acute Myeloid Leukemia

    PubMed Central

    Garcia-Manero, Guillermo; Gore, Steven D.; Cogle, Christopher; Ward, Renee; Shi, Tao; MacBeth, Kyle J.; Laille, Eric; Giordano, Heidi; Sakoian, Sarah; Jabbour, Elias; Kantarjian, Hagop; Skikne, Barry

    2011-01-01

    Purpose To determine the maximum-tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and clinical activity of an oral formulation of azacitidine in patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). Patients and Methods Patients received 1 cycle of subcutaneous (SC) azacitidine (75 mg/m2) on the first 7 days of cycle 1, followed by oral azacitidine daily (120 to 600 mg) on the first 7 days of each additional 28-day cycle. Pharmacokinetic and pharmacodynamic profiles were evaluated during cycles 1 and 2. Adverse events and hematologic responses were recorded. Cross-over to SC azacitidine was permitted for nonresponders who received ≥ 6 cycles of oral azacitidine. Results Overall, 41 patients received SC and oral azacitidine (MDSs, n = 29; CMML, n = 4; AML, n = 8). Dose-limiting toxicity (grade 3/4 diarrhea) occurred at the 600-mg dose and MTD was 480 mg. Most common grade 3/4 adverse events were diarrhea (12.2%), nausea (7.3%), vomiting (7.3%), febrile neutropenia (19.5%), and fatigue (9.8%). Azacitidine exposure increased with escalating oral doses. Mean relative oral bioavailability ranged from 6.3% to 20%. Oral and SC azacitidine decreased DNA methylation in blood, with maximum effect at day 15 of each cycle. Hematologic responses occurred in patients with MDSs and CMML. Overall response rate (ie, complete remission, hematologic improvement, or RBC or platelet transfusion independence) was 35% in previously treated patients and 73% in previously untreated patients. Conclusion Oral azacitidine was bioavailable and demonstrated biologic and clinical activity in patients with MDSs and CMML. PMID:21576646

  9. Cost-effectiveness in Canada of azacitidine for the treatment of higher-risk myelodysplastic syndromes

    PubMed Central

    Levy, A.R.; Zou, D.; Risebrough, N.; Buckstein, R.; Kim, T.; Brereton, N.

    2014-01-01

    Objective Our goal was to determine the economic value of azacitidine in Canada compared with conventional care regimens (ccrs), including best supportive care (bsc) and low- or standard-dose chemotherapy plus bsc in the treatment of higher-risk myelodysplastic syndromes (mdss) and acute myeloid leukemia (aml) with 20%–30% blasts. Methods The cost–utility model is a lifetime probabilistic Markov model with a 35-day cycle length consisting of 3 health states: mds; transformation to aml with more than 30% blasts; and death. A third-party public payer perspective was adopted. Overall survival was extrapolated beyond the time horizon of the aza-001 trial comparing azacitidine with ccr. Resource use was determined through a questionnaire completed by Canadian hematologists. Utility values were obtained from two studies in which EQ-5D health questionnaire values were mapped from the European Organization for Research and Treatment of Cancer qlq-C30 survey, and SF-6D scores were mapped from the Short Form 12, elicited from 191 and 43 patients in two different trials. Results In the base case, azacitidine had an incremental cost-effectiveness ratio (icer) of $86,182 (95% confidence limits: $69,920, $107,157) per quality-adjusted life year (qaly) gained relative to ccr. Comparing azacitidine with bsc, low-dose chemotherapy plus bsc, and standard-dose chemotherapy plus bsc, the icers were, respectively, $86,973, $84,829, and $2,152 per qaly gained. Results were most sensitive to the utility for azacitidine after 6 months of treatment and to overall survival. Conclusions The prolonged 9-month median overall survival with azacitidine relative to ccr fills a gap w hen treating patients with higher-risk mds and aml with 20%–30% blasts. The economic value of azacitidine is within the threshold of willingness-to-pay for third-party public payers for oncology treatments in Canada. PMID:24523619

  10. Tumor suppressor microRNAs are downregulated in myelodysplastic syndrome with spliceosome mutations

    PubMed Central

    Aslan, Derya; Garde, Christian; Nygaard, Mette Katrine; Helbo, Alexandra Søgaard; Dimopoulos, Konstantinos; Hansen, Jakob Werner; Severinsen, Marianne Tang; Treppendahl, Marianne Bach; Sjø, Lene Dissing; Grønbæk, Kirsten; Kristensen, Lasse Sommer

    2016-01-01

    Spliceosome mutations are frequently observed in patients with myelodysplastic syndromes (MDS). However, it is largely unknown how these mutations contribute to the disease. MicroRNAs (miRNAs) are small noncoding RNAs, which have been implicated in most human cancers due to their role in post transcriptional gene regulation. The aim of this study was to analyze the impact of spliceosome mutations on the expression of miRNAs in a cohort of 34 MDS patients. In total, the expression of 76 miRNAs, including mirtrons and splice site overlapping miRNAs, was accurately quantified using reverse transcriptase quantitative PCR. The majority of the studied miRNAs have previously been implicated in MDS. Stably expressed miRNA genes for normalization of the data were identified using GeNorm and NormFinder algorithms. High-resolution melting assays covering all mutational hotspots within SF3B1, SRSF2, and U2AF1 (U2AF35) were developed, and all detected mutations were confirmed by Sanger sequencing. Overall, canonical miRNAs were downregulated in spliceosome mutated samples compared to wild-type (P = 0.002), and samples from spliceosome mutated patients clustered together in hierarchical cluster analyses. Among the most downregulated miRNAs were several tumor-suppressor miRNAs, including several let-7 family members, miR-423, and miR-103a. Finally, we observed that the predicted targets of the most downregulated miRNAs were involved in apoptosis, hematopoiesis, and acute myeloid leukemia among other cancer- and metabolic pathways. Our data indicate that spliceosome mutations may play an important role in MDS pathophysiology by affecting the expression of tumor suppressor miRNA genes involved in the development and progression of MDS. PMID:26848861

  11. A calcium- and calpain-dependent pathway determines the response to lenalidomide in myelodysplastic syndromes.

    PubMed

    Fang, Jing; Liu, Xiaona; Bolanos, Lyndsey; Barker, Brenden; Rigolino, Carmela; Cortelezzi, Agostino; Oliva, Esther N; Cuzzola, Maria; Grimes, H Leighton; Fontanillo, Celia; Komurov, Kakajan; MacBeth, Kyle; Starczynowski, Daniel T

    2016-07-01

    Despite the high response rates of individuals with myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)) to treatment with lenalidomide (LEN) and the recent identification of cereblon (CRBN) as the molecular target of LEN, the cellular mechanism by which LEN eliminates MDS clones remains elusive. Here we performed an RNA interference screen to delineate gene regulatory networks that mediate LEN responsiveness in an MDS cell line, MDSL. We identified GPR68, which encodes a G-protein-coupled receptor that has been implicated in calcium metabolism, as the top candidate gene for modulating sensitivity to LEN. LEN induced GPR68 expression via IKAROS family zinc finger 1 (IKZF1), resulting in increased cytosolic calcium levels and activation of a calcium-dependent calpain, CAPN1, which were requisite steps for induction of apoptosis in MDS cells and in acute myeloid leukemia (AML) cells. In contrast, deletion of GPR68 or inhibition of calcium and calpain activation suppressed LEN-induced cytotoxicity. Moreover, expression of calpastatin (CAST), an endogenous CAPN1 inhibitor that is encoded by a gene (CAST) deleted in del(5q) MDS, correlated with LEN responsiveness in patients with del(5q) MDS. Depletion of CAST restored responsiveness of LEN-resistant non-del(5q) MDS cells and AML cells, providing an explanation for the superior responses of patients with del(5q) MDS to LEN treatment. Our study describes a cellular mechanism by which LEN, acting through CRBN and IKZF1, has cytotoxic effects in MDS and AML that depend on a calcium- and calpain-dependent pathway. PMID:27294874

  12. Effect of lenalidomide treatment on clonal architecture of myelodysplastic syndromes without 5q deletion.

    PubMed

    Chesnais, Virginie; Renneville, Aline; Toma, Andrea; Lambert, Jérôme; Passet, Marie; Dumont, Florent; Chevret, Sylvie; Lejeune, Julie; Raimbault, Anna; Stamatoullas, Aspasia; Rose, Christian; Beyne-Rauzy, Odile; Delaunay, Jacques; Solary, Eric; Fenaux, Pierre; Dreyfus, François; Preudhomme, Claude; Kosmider, Olivier; Fontenay, Michaela

    2016-02-11

    Non-del(5q) transfusion-dependent low/intermediate-1 myelodysplastic syndrome (MDS) patients achieve an erythroid response with lenalidomide in 25% of cases. Addition of an erythropoiesis-stimulating agent could improve response rate. The impact of recurrent somatic mutations identified in the diseased clone in response to lenalidomide and the drug's effects on clonal evolution remain unknown. We investigated recurrent mutations by next-generation sequencing in 94 non-del(5q) MDS patients randomized in the GFM-Len-Epo-08 clinical trial to lenalidomide or lenalidomide plus epoetin β. Clonal evolution was analyzed after 4 cycles of treatment in 42 cases and reanalyzed at later time points in 18 cases. The fate of clonal architecture of single CD34(+)CD38(-) hematopoietic stem cells was also determined in 5 cases. Mutation frequency was >10%: SF3B1 (74.5%), TET2 (45.7%), DNMT3A (20.2%), and ASXL1 (19.1%). Analysis of variant allele frequencies indicated a decrease of major mutations in 15 of 20 responders compared with 10 of 22 nonresponders after 4 cycles. The decrease in the variant allele frequency of major mutations was more significant in responders than in nonresponders (P < .001). Genotyping of single CD34(+)CD38(-) cell-derived colonies showed that the decrease in the size of dominant subclones could be associated with the rise of founding clones or of hematopoietic stem cells devoid of recurrent mutations. These effects remained transient, and disease escape was associated with the re-emergence of the dominant subclones. In conclusion, we show that, although the drug initially modulates the distribution of subclones, loss of treatment efficacy coincides with the re-expansion of the dominant subclone. This trial was registered at www.clinicaltrials.gov as #NCT01718379. PMID:26626993

  13. SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts

    PubMed Central

    Karimi, Mohsen; Papaemmanuil, Elli; Ambaglio, Ilaria; Jädersten, Martin; Jansson, Monika; Elena, Chiara; Gallì, Anna; Walldin, Gunilla; Della Porta, Matteo G.; Raaschou-Jensen, Klas; Travaglino, Erica; Kallenbach, Klaus; Pietra, Daniela; Ljungström, Viktor; Conte, Simona; Boveri, Emanuela; Invernizzi, Rosangela; Rosenquist, Richard; Campbell, Peter J.; Cazzola, Mario; Hellström Lindberg, Eva

    2015-01-01

    Refractory anemia with ring sideroblasts (RARS) is a myelodysplastic syndrome (MDS) characterized by isolated erythroid dysplasia and 15% or more bone marrow ring sideroblasts. Ring sideroblasts are found also in other MDS subtypes, such as refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). A high prevalence of somatic mutations of SF3B1 was reported in these conditions. To identify mutation patterns that affect disease phenotype and clinical outcome, we performed a comprehensive mutation analysis in 293 patients with myeloid neoplasm and 1% or more ring sideroblasts. SF3B1 mutations were detected in 129 of 159 cases (81%) of RARS or RCMD-RS. Among other patients with ring sideroblasts, lower prevalence of SF3B1 mutations and higher prevalence of mutations in other splicing factor genes were observed (P < .001). In multivariable analyses, patients with SF3B1 mutations showed significantly better overall survival (hazard ratio [HR], .37; P = .003) and lower cumulative incidence of disease progression (HR = 0.31; P = .018) compared with SF3B1-unmutated cases. The independent prognostic value of SF3B1 mutation was retained in MDS without excess blasts, as well as in sideroblastic categories (RARS and RCMD-RS). Among SF3B1-mutated patients, coexisting mutations in DNA methylation genes were associated with multilineage dysplasia (P = .015) but had no effect on clinical outcome. TP53 mutations were frequently detected in patients without SF3B1 mutation, and were associated with poor outcome. Thus, SF3B1 mutation identifies a distinct MDS subtype that is unlikely to develop detrimental subclonal mutations and is characterized by indolent clinical course and favorable outcome. PMID:25957392

  14. SF3B1 haploinsufficiency leads to formation of ring sideroblasts in myelodysplastic syndromes

    PubMed Central

    Visconte, Valeria; Rogers, Heesun J.; Singh, Jarnail; Barnard, John; Bupathi, Manoj; Traina, Fabiola; McMahon, James; Makishima, Hideki; Szpurka, Hadrian; Jankowska, Anna; Jerez, Andres; Sekeres, Mikkael A.; Saunthararajah, Yogen; Advani, Anjali S.; Copelan, Edward; Koseki, Haruhiko; Isono, Kyoichi; Padgett, Richard A.; Osman, Sami; Koide, Kazunori; O'Keefe, Christine; Maciejewski, Jaroslaw P.

    2012-01-01

    Whole exome/genome sequencing has been fundamental in the identification of somatic mutations in the spliceosome machinery in myelodysplastic syndromes (MDSs) and other hematologic disorders. SF3B1, splicing factor 3b subunit 1 is mutated in 60%-80% of refractory anemia with ring sideroblasts (RARS) and RARS associated with thrombocytosis (RARS-T), 2 distinct subtypes of MDS and MDS/myeloproliferative neoplasms (MDSs/MPNs). An idiosyncratic feature of RARS/RARS-T is the presence of abnormal sideroblasts characterized by iron overload in the mitochondria, called RS. Based on the high frequency of mutations of SF3B1 in RARS/RARS-T, we investigated the consequences of SF3B1 alterations. Ultrastructurally, SF3B1 mutants showed altered iron distribution characterized by coarse iron deposits compared with wild-type RARS patients by transmission electron microscopy. SF3B1 knockdown experiments in K562 cells resulted in down-regulation of U2-type intron-splicing by RT-PCR. RNA-sequencing analysis of SF3B1 mutants showed differentially used genes relevant in MDS pathogenesis, such as ASXL1, CBL, EZH, and RUNX families. A SF3B pharmacologic inhibitor, meayamycin, induced the formation of RS in healthy BM cells. Further, BM aspirates of Sf3b1 heterozygous knockout mice showed RS by Prussian blue. In conclusion, we report the first experimental evidence of the association between SF3B1 and RS phenotype. Our data suggest that SF3B1 haploinsufficiency leads to RS formation. PMID:22826563

  15. Effect of lenalidomide treatment on clonal architecture of myelodysplastic syndromes without 5q deletion

    PubMed Central

    Chesnais, Virginie; Renneville, Aline; Toma, Andrea; Lambert, Jérôme; Passet, Marie; Dumont, Florent; Chevret, Sylvie; Lejeune, Julie; Raimbault, Anna; Stamatoullas, Aspasia; Rose, Christian; Beyne-Rauzy, Odile; Delaunay, Jacques; Solary, Eric; Fenaux, Pierre; Dreyfus, François; Preudhomme, Claude; Kosmider, Olivier

    2016-01-01

    Non-del(5q) transfusion-dependent low/intermediate-1 myelodysplastic syndrome (MDS) patients achieve an erythroid response with lenalidomide in 25% of cases. Addition of an erythropoiesis-stimulating agent could improve response rate. The impact of recurrent somatic mutations identified in the diseased clone in response to lenalidomide and the drug’s effects on clonal evolution remain unknown. We investigated recurrent mutations by next-generation sequencing in 94 non-del(5q) MDS patients randomized in the GFM-Len-Epo-08 clinical trial to lenalidomide or lenalidomide plus epoetin β. Clonal evolution was analyzed after 4 cycles of treatment in 42 cases and reanalyzed at later time points in 18 cases. The fate of clonal architecture of single CD34+CD38− hematopoietic stem cells was also determined in 5 cases. Mutation frequency was >10%: SF3B1 (74.5%), TET2 (45.7%), DNMT3A (20.2%), and ASXL1 (19.1%). Analysis of variant allele frequencies indicated a decrease of major mutations in 15 of 20 responders compared with 10 of 22 nonresponders after 4 cycles. The decrease in the variant allele frequency of major mutations was more significant in responders than in nonresponders (P < .001). Genotyping of single CD34+CD38− cell–derived colonies showed that the decrease in the size of dominant subclones could be associated with the rise of founding clones or of hematopoietic stem cells devoid of recurrent mutations. These effects remained transient, and disease escape was associated with the re-emergence of the dominant subclones. In conclusion, we show that, although the drug initially modulates the distribution of subclones, loss of treatment efficacy coincides with the re-expansion of the dominant subclone. This trial was registered at www.clinicaltrials.gov as #NCT01718379. PMID:26626993

  16. Epigenetic control of NF-κB-dependent FAS gene transcription during progression of myelodysplastic syndromes.

    PubMed

    Ettou, Sandrine; Humbrecht, Catherine; Benet, Blandine; Billot, Katy; d'Allard, Diane; Mariot, Virginie; Goodhardt, Michele; Kosmider, Olivier; Mayeux, Patrick; Solary, Eric; Fontenay, Michaela

    2013-07-01

    The death domain containing TNF receptor 6 (CD95/Fas) is a direct target for the NF-κB transcription factor and is repressed in solid tumors such as colon carcinomas. Previously, we reported that the Fas death receptor, while overexpressed in low-risk myelodysplastic syndromes (MDS), becomes undetectable on CD34(+) progenitors when the disease progresses to secondary acute myeloid leukemia (AML). This study determined the interplay between NF-κB and Fas during MDS progression. We first observed that Fas was induced by TNF-α in the HL60 cell line. In these cells, p65 (RELA) was associated with the FAS promoter, and inhibition of the NF-κB pathway by an IKKα inhibitor (BAY11-7082) or lentiviral expression of a nondegradable mutant of IκBα (IκSR) blocked Fas expression. In contrast, TNF-α failed to induce Fas expression in the colon carcinoma cell line SW480, due to hypermethylation of the FAS promoter. Azacitidine rescued p65 binding on FAS promoter in vitro, and subsequently Fas expression in SW480 cells. Furthermore, inhibition of the NF-κB pathway decreased the expression of Fas in MDS CD45(lo)CD34(+) bone marrow cells. However, despite the nuclear expression of p65, Fas was often low on CD45(lo)CD34(+) AML cells. TNF-α failed to stimulate its expression, while azacitidine efficiently rescued p65 binding and Fas reexpression. Overall, these data suggest that DNA methylation at NF-κB sites is responsible for FAS gene silencing. PMID:23604035

  17. Vatalanib population pharmacokinetics in patients with myelodysplastic syndrome: CALGB 10105 (Alliance)

    PubMed Central

    Wang, Xiaofeng; Owzar, Kouros; Gupta, Pankaj; Larson, Richard A; Mulkey, Flora; Miller, Antonius A; Lewis, Lionel D; Hurd, David; Vij, Ravi; Ratain, Mark J; Murry, Daryl J

    2014-01-01

    Aims Vatalanib is an oral anti-angiogenesis agent that inhibits vascular endothelial growth factor receptor tyrosine kinases, which in patients showed auto induction of metabolism and variability in pharmacokinetic (PK) disposition. The objective was to characterize the population PK and time-dependent change in vatalanib clearance and assess exposure–toxicity relationship in patients with myelodysplastic syndrome (MDS). Methods This was an open-label phase II study of vatalanib in MDS patients receiving 750–1250 mg once daily in 28-day cycles. Serial blood samples were obtained and plasma vatalanib concentrations measured by HPLC. Population PK analysis was performed using nonmem 7.2 with FO estimation since FOCE failed. The final model was evaluated using goodness-of-fit plots, bootstrap analysis, and visual predictive check. Results Pharmacokinetic data were complete for 137 patients (86 M, 51 F), of median age 70 years (range 20–91). A one-compartment model with lagged first-order absorption and time-dependent change in oral clearance was fitted to the vatalanib plasma concentration versus time data. The population means for pre-induction and post-induction oral clearance were 24.1 l h–1 (range: 9.6–45.5) and 54.9 l h–1 (range: 39.8–75.6), respectively. The apparent oral clearance increased 2.3-fold, (range: 1.7–4.1-fold) from first dose to steady state. Our data did not identify a significant relationship of the predefined covariates with vatalanib pharmacokinetics, although power to detect such a relationship was limited. Conclusions Vatalanib pharmacokinetics were highly variable and the extent of auto induction was not determined to correlate with any of the pre-defined covariates. PMID:24838014

  18. Somatic Mutations Predict Poor Outcome in Patients With Myelodysplastic Syndrome After Hematopoietic Stem-Cell Transplantation

    PubMed Central

    Bejar, Rafael; Stevenson, Kristen E.; Caughey, Bennett; Lindsley, R. Coleman; Mar, Brenton G.; Stojanov, Petar; Getz, Gad; Steensma, David P.; Ritz, Jerome; Soiffer, Robert; Antin, Joseph H.; Alyea, Edwin; Armand, Philippe; Ho, Vincent; Koreth, John; Neuberg, Donna; Cutler, Corey S.; Ebert, Benjamin L.

    2014-01-01

    Purpose Recurrently mutated genes in myelodysplastic syndrome (MDS) are pathogenic drivers and powerfully associated with clinical phenotype and prognosis. Whether these types of mutations predict outcome after allogeneic hematopoietic stem-cell transplantation (HSCT) in patients with MDS is not known. Patients and Methods We used massively parallel sequencing to examine tumor samples collected from 87 patients with MDS before HSCT for coding mutations in 40 recurrently mutated MDS genes. Results Mutations were identified in 92% of patients, most frequently in the ASXL1 (29%), TP53 (21%), DNMT3A (18%), and RUNX1 (16%) genes. In univariable analyses, only TP53 mutations were associated with shorter overall (OS; hazard ratio [HR], 3.74; P < .001) and progression-free survival (HR, 3.97; P < .001). After adjustment for clinical variables associated with these end points, mutations in TP53 (HR, 2.30; P = .027), TET2 (HR, 2.40; P = .033), and DNMT3A (HR, 2.08; P = .049) were associated with decreased OS. In multivariable analysis including clinical variables, complex karyotype status, and candidate genes, mutations in TP53 (HR, 4.22; P ≤ .001) and TET2 (HR, 1.68; P = .037) were each independently associated with shorter OS. Nearly one half of patients (46%) carried a mutation in TP53, DNMT3A, or TET2 and accounted for 64% of deaths. Three-year OS in patients without these mutations was 59% (95% CI, 43% to 72%), versus 19% (95% CI, 9% to 33%) in patients with these mutations. Conclusion Mutations in TP53, TET2, or DNMT3A identify patients with MDS with shorter OS after HSCT. PMID:25092778

  19. TP53 overexpression is an independent adverse prognostic factor in de novo myelodysplastic syndromes with fibrosis.

    PubMed

    Loghavi, Sanam; Al-Ibraheemi, Alyaa; Zuo, Zhuang; Garcia-Manero, Guillermo; Yabe, Mariko; Wang, Sa A; Kantarjian, Hagop M; Yin, Cameron C; Miranda, Roberto N; Luthra, Raja; Medeiros, L Jeffrey; Bueso-Ramos, Carlos E; Khoury, Joseph D

    2015-10-01

    Bone marrow (BM) fibrosis is associated with poor prognosis in patients with de novo myelodysplastic syndromes (MDS). TP53 mutations and TP53 (p53) overexpression in MDS are also associated with poor patient outcomes. The prevalence and significance of TP53 mutations and TP53 overexpression in MDS with fibrosis are unknown. We studied 67 patients with de novo MDS demonstrating moderate to severe reticulin fibrosis (MDS-F). Expression of TP53 was evaluated in BM core biopsy specimens using dual-colour CD34/TP53 immunohistochemistry with computer-assisted image analysis. Mutation analysis was performed using next-generation sequencing, or Sanger sequencing methods. TP53 mutations were present in 47·1% of cases. TP53 mutation was significantly associated with TP53 expression (P = 0·0294). High levels of TP53 expression (3 +  in ≥10% cells) were associated with higher BM blast counts (P = 0·0149); alterations of chromosomes 5 (P = 0·0009) or 7 (P = 0·0141); complex karyotype (P = 0·0002); high- and very-high risk IPSS-R groups (P = 0·009); and TP53 mutations (P = 0·0003). High TP53 expression independently predicted shorter overall survival (OS) by multivariate analysis (P = <0·001). Expression of TP53 by CD34-positive cells was associated with shorter OS and leukaemia-free survival (P = 0·0428). TP53 overexpression is a predictor of poor outcome in patients with MDS-F. PMID:26123119

  20. Management and supportive care measures for adverse events in patients with myelodysplastic syndromes treated with azacitidine*

    PubMed Central

    Santini, Valeria; Fenaux, Pierre; Mufti, Ghulam J.; Hellström-Lindberg, Eva; Silverman, Lewis R.; List, Alan; Gore, Steven D.; Seymour, John F.; Backstrom, Jay; Beach, Charles L.

    2013-01-01

    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. PMID

  1. Review of Stem-Cell Transplantation for Myelodysplastic Syndromes in Older Patients in the Context of the Decision Memo for Allogeneic Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome Emanating From the Centers for Medicare and Medicaid Services

    PubMed Central

    Giralt, Sergio A.; Horowitz, Mary; Weisdorf, Daniel; Cutler, Corey

    2011-01-01

    Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem-cell disorders that result in varying degrees of cytopenia and risk of transformation into acute leukemia. Allogeneic stem-cell transplantation (SCT) is the only known cure for this disease. The treatment is routinely used for younger patients, but only a minority of patients older than the age of 60 undergo this procedure. The overall MDS incidence is 3.3 per 100,000, but the incidence in patients older than age 70 is between 15 and 50 per 100,000. The median age at presentation is 76 years. Medicare-age patients 65 or older represent 80% of the total population receiving an MDS diagnosis. In the United States, one of the obstacles to SCT for older patients with MDS has been lack of third party reimbursement. On August 4, 2010, the Centers for Medicare and Medicaid Services released their Decision Memo for Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Myelodysplastic Syndrome. This memo states: “Allogeneic HSCT for MDS is covered by Medicare only for beneficiaries with MDS participating in an approved clinical study that meets the criteria below…. ” In this review, we will summarize what is known regarding the role of allogeneic SCT in older patients as well as other elements that should be included within clinical trials that can provide the evidence necessary to demonstrate that allogeneic SCT should be a covered benefit for Medicare beneficiaries. PMID:21220586

  2. Antiretroviral activity of 5-azacytidine during treatment of a HTLV-1 positive myelodysplastic syndrome with autoimmune manifestations

    PubMed Central

    2012-01-01

    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. PMID:22214262

  3. Fludarabine Phosphate and Total Body Irradiation Followed by a Donor Peripheral Stem Cell Transplant in Treating Patients With Myelodysplastic Syndromes or Myeloproliferative Disorders

    ClinicalTrials.gov

    2016-05-19

    Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndrome; Essential Thrombocythemia; Myeloproliferative Neoplasm; Paroxysmal Nocturnal Hemoglobinuria; Polycythemia Vera; Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase; Primary Myelofibrosis; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Ring Sideroblasts; Refractory Cytopenia With Multilineage Dysplasia; Refractory Cytopenia With Multilineage Dysplasia and Ring Sideroblasts

  4. Pediatric complex regional pain syndrome: a review.

    PubMed

    Weissmann, Rotem; Uziel, Yosef

    2016-01-01

    Complex regional pain syndrome (CRPS) is a chronic, intensified localized pain condition that can affect children and adolescents as well as adults, but is more common among adolescent girls. Symptoms include limb pain; allodynia; hyperalgesia; swelling and/or changes in skin color of the affected limb; dry, mottled skin; hyperhidrosis and trophic changes of the nails and hair. The exact mechanism of CRPS is unknown, although several different mechanisms have been suggested. The diagnosis is clinical, with the aid of the adult criteria for CRPS. Standard care consists of a multidisciplinary approach with the implementation of intensive physical therapy in conjunction with psychological counseling. Pharmacological treatments may aid in reducing pain in order to allow the patient to participate fully in intensive physiotherapy. The prognosis in pediatric CRPS is favorable. PMID:27130211

  5. A Meta-Analysis of the Relationship between Cigarette Smoking and Incidence of Myelodysplastic Syndromes

    PubMed Central

    Tong, Hongyan; Hu, Chao; Yin, Xiufeng; Yu, Mengxia; Yang, Jun; Jin, Jie

    2013-01-01

    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. PMID:23805315

  6. Recombinant human erythropoietin in very elderly patients with myelodysplastic syndromes: results from a retrospective study.

    PubMed

    Tatarelli, Caterina; Piccioni, Anna Lina; Maurillo, Luca; Naso, Virginia; Battistini, Roberta; D'Andrea, Mariella; Criscuolo, Marianna; Nobile, Carolina; Villivà, Nicoletta; Mancini, Stefano; Neri, Benedetta; Breccia, Massimo; Fenu, Susanna; Buccisano, Francesco; Voso, Maria Teresa; Latagliata, Roberto; Aloe Spiriti, Maria Antonietta

    2014-08-01

    Myelodysplastic syndromes (MDS) are common in elderly patients. Recombinant human erythro-poietin (rHuEPO) has been widely used to treat anemia in lower risk MDS patients, but few data are known about rHuEPO treatment in the very elderly patient group. In order to investigate the role of rHuEPO treatment in terms of response, overall survival (OS), and toxicity in a very elderly MDS patient group, 93 MDS patients treated with rHuEPO when aged ≥80 years were selected among MDS cases enrolled in a retrospective multicenter study by the cooperative group Gruppo Romano Mielodisplasie (GROM) from Jan 2002 to Dec 2010. At baseline, median age was 82.7 (range 80-99.1) with a median hemoglobin (Hb) level of 9 g/dl (range 6-10.8). The initial dose of rHuEPO was standard (epoetin alpha 40,000 IU/week or epoetin beta 30,000 IU/week) in 59 (63.4 %) patients or high in 34 (36.6 %) (epoetin alpha 80,000 IU/week) patients. We observed an erythroid response (ER) in 59 (63.4 %) patients. No thrombotic event was reported. Independent predictive factors for ER were low transfusion requirement before treatment (p = 0.004), ferritin <200 ng/ml (p = 0.017), Hb >8 g/dl (p = 0.034), and a high-dose rHuEPO treatment (p = 0.032). Median OS from rHuEPO start was 49.3 months (95 % CI 27.5-68.4) in responders versus 30.6 months (95 % CI 7.3-53.8) in resistant patients (p = 0.185). In conclusion, rHuEPO treatment is safe and effective also in the very elderly MDS patients. However, further larger studies are warranted to evaluate if EPO treatment could be worthwhile in terms of quality of life and cost-efficacy in very old patients. PMID:24647684

  7. [Correlation of laboratory indexes with prognosis in patients with myelodysplastic syndrome].

    PubMed

    Li, Wen-Wen; Li, Yan; Wang, Xiao-Min

    2012-02-01

    The myelodysplastic syndrome (MDS) is a group of hematopoietic stem cell-clonal disease. The International Prognostic Scoring System (IPSS) is mainly used for its prognostic classification, but still remains some unrepeatable results in the same group of patients with MDS. This study was aimed to compare the levels of peripheral blood mean corpuscular volume (MCV), serum lactate dehydrogenase (LDH), β2-microglobulin (β2-MG), ferroprotein (SF), Vit B12 in patients with MDS classified by IPSS and to explore the relationship between the prognosis and laboratory indexes above mentioned in MDS patients. 116 patients with MDS were divided into 4 group: low-risk, intermediate risk-I, intermediate risk-II and high-risk according to IPSS. The index of MCV, serum LDH, β2-MG, SF and Vit B12 in MDS patients prior treatment and in normal control group were detected. Data with normal group and each groups of MDS were compared. The results showed that the levels of MCV, LDH, β2-MG, SF were Vit B12 in patients with MDS were significantly higher than those in normal control group (P < 0.05). There were significant differences of serum LDH among the 4 groups of MDS (P < 0.05), and the levels of serum LDH increased in turn: low-risk, intermediate risk I, intermediate risk II and high-risk. Serum β2-MG level in the high-risk group was significantly higher than that in the groups of low risk, intermediate risk I and intermediate risk II (P < 0.05), the difference among the latter three groups was not statistically significant (P > 0.05). There were no significant differences in MCV, SF and Vit B12 levels of all groups compared with each other. It is concluded that the level of serum LDH and β2-MG seems to have a certain correlation with the progress and prognosis of the MDS, which may be useful for predicting the prognosis of the MDS besides IPSS scoring system. PMID:22391179

  8. The Systemic Profile of Soluble Immune Mediators in Patients with Myelodysplastic Syndromes

    PubMed Central

    Kittang, Astrid Olsnes; Sand, Kristoffer; Brenner, Annette Katharina; Rye, Kristin Paulsen; Bruserud, Øystein

    2016-01-01

    Introduction: Myelodysplastic syndromes (MDS) are characterized by bone marrow failure due to disturbed bone marrow maturation. MDS is associated with increased risk of transformation to acute myeloid leukemia (AML) and features of immunological dysregulation. Materials and methods: Serum levels of 47 soluble immune mediators were examined in samples derived from 49 MDS patients (35 low-risk and 14 high-risk) and 23 healthy adults. Our patients represent an unselected population-based cohort. The mediators included cytokines, soluble adhesion proteins, matrix metalloproteases, and tissue inhibitors of proteases. Levels were determined using Luminex assays. Patients were classified as low- and high-risk based on the international prognostic scoring system (IPSS) score. Results: When comparing the serum levels of single mediators the MDS patients showed a relatively wide variation range for several mediators compared with healthy adults, especially interleukin 6 (IL-6), IL-8/CXCL8, CCL3, and CCL4. The high-risk patients had lower levels of epidermal growth factor (EGF), cluster of differentiation 40 ligand (CD40L), CCL5, CCL11, CXCL5, matrix metalloproteinase 1 (MMP-1), MMP-9, and tissue inhibitor of metalloproteinases 2 (TIMP-2) compared with low-risk patients. Unsupervised hierarchical cluster analysis visualized marked serum mediator profile differences between MDS patients; based on this analysis three patient subsets could be identified. The healthy adults were also included in this analysis and, as expected, they formed their own separate cluster, except for one outlier. Both low- and high-risk patients showed considerable heterogeneity with regard to serum profile, and this heterogeneity seems stable over time (one year follow-up). Finally, very few mediators differed between low- and high-risk patients, but hierarchical clustering based both on all mediators, as well as five selected mediators (EGF, CCL11, TIMP-2, MMP-1, and MMP-9) identified subsets of

  9. Evaluation of noncytotoxic DNMT1-depleting therapy in patients with myelodysplastic syndromes

    PubMed Central

    Saunthararajah, Yogen; Sekeres, Mikkael; Advani, Anjali; Mahfouz, Reda; Durkin, Lisa; Radivoyevitch, Tomas; Englehaupt, Ricki; Juersivich, Joy; Cooper, Kathleen; Husseinzadeh, Holleh; Przychodzen, Bartlomiej; Rump, Matthew; Hobson, Sean; Earl, Marc; Sobecks, Ronald; Dean, Robert; Reu, Frederic; Tiu, Ramon; Hamilton, Betty; Copelan, Edward; Lichtin, Alan; Hsi, Eric; Kalaycio, Matt; Maciejewski, Jaroslaw

    2015-01-01

    BACKGROUND. Mutational inactivation in cancer of key apoptotic pathway components, such as TP53/p53, undermines cytotoxic therapies that aim to increase apoptosis. Accordingly, TP53 mutations are reproducibly associated with poor treatment outcomes. Moreover, cytotoxic treatments destroy normal stem cells with intact p53 systems, a problem especially for myeloid neoplasms, as these cells reverse the low blood counts that cause morbidity and death. Preclinical studies suggest that noncytotoxic concentrations of the DNA methyltransferase 1 (DNMT1) inhibitor decitabine produce p53-independent cell-cycle exits by reversing aberrant epigenetic repression of proliferation-terminating (MYC-antagonizing) differentiation genes in cancer cells. METHODS. In this clinical trial, patients with myelodysplastic syndrome (n = 25) received reduced decitabine dosages (0.1–0.2 mg/kg/day compared with the FDA-approved 20–45 mg/m2/day dosage, a 75%–90% reduction) to avoid cytotoxicity. These well-tolerated doses were frequently administered 1–3 days per week, instead of pulse cycled for 3 to 5 days over a 4- to 6-week period, to increase the probability that cancer S-phase entries would coincide with drug exposure, which is required for S-phase–dependent DNMT1 depletion. RESULTS. The median subject age was 73 years (range, 46–85 years), 9 subjects had relapsed disease or were refractory to 5-azacytidine and/or lenalidomide, and 3 had received intensive chemoradiation to treat other cancers. Adverse events were related to neutropenia present at baseline: neutropenic fever (13 of 25 subjects) and septic death (1 of 25 subjects). Blood count improvements meeting the International Working Group criteria for response occurred in 11 of 25 (44%) subjects and were highly durable. Treatment-induced freedom from transfusion lasted a median of 1,025 days (range, 186–1,152 days; 3 ongoing), and 20% of subjects were treated for more than 3 years. Mutations and/or deletions of key

  10. Gastrointestinal microbiome signatures of pediatric patients with irritable bowel syndrome

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The intestinal microbiomes of healthy children and pediatric patients with irritable bowel syndrome (IBS) are not well defined. Studies in adults have indicated that the gastrointestinal microbiota could be involved in IBS. We analyzed 71 samples from 22 children with IBS (pediatric Rome III criteri...

  11. Monoclonal Antibody Therapy in Treating Patients With Ovarian Epithelial Cancer, Melanoma, Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-01-09

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Recurrent Melanoma; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Stage IV Melanoma; Stage IV Non-small Cell Lung Cancer

  12. MS-275 and GM-CSF in Treating Patients With Myelodysplastic Syndrome and/or Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphocytic Leukemia

    ClinicalTrials.gov

    2013-01-08

    Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Ringed Sideroblasts; Refractory Cytopenia With Multilineage Dysplasia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

  13. Vorinostat, Cytarabine, and Etoposide in Treating Patients With Relapsed and/or Refractory Acute Leukemia or Myelodysplastic Syndromes or Myeloproliferative Disorders

    ClinicalTrials.gov

    2013-05-01

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Acute Promyelocytic Leukemia (M3); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Polycythemia Vera; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

  14. Clinical activity and safety of the dual pathway inhibitor rigosertib for higher risk myelodysplastic syndromes following DNA methyltransferase inhibitor therapy.

    PubMed

    Silverman, Lewis R; Greenberg, Peter; Raza, Azra; Olnes, Matthew J; Holland, James F; Reddy, Premkumar; Maniar, Manoj; Wilhelm, Francois

    2015-06-01

    Rigosertib (ON 01910.Na) is an inhibitor of the phosphoinositide 3-kinase and polo-like kinase pathways that induces mitotic arrest and apoptosis in neoplastic cells, while sparing normal cells. Our purpose is to summarize the clinical activity and safety of intravenous (IV) rigosertib delivered by an external ambulatory infusion pump in patients with refractory anemia with excess blasts-1, -2, or, -t myelodysplastic syndromes (MDS) following prior treatment with DNA methyltransferase (DNMT) inhibitors. A total of 39 patients with MDS who fulfilled these criteria were enrolled in four phase 1-2 clinical trials of IV rigosertib. Thirty five (88%) had higher risk disease according to the Revised International Prognostic Scoring System. Median overall survival for this group of 39 patients was 35 weeks. Of 30 evaluable patients with follow-up bone marrow biopsies, 12 (40%) achieved complete (n = 5) or partial (n = 7) bone marrow blast responses. In addition, 15 patients achieved stabilization of bone marrow blasts. One patient with a complete bone marrow response also achieved a complete cytogenetic response. A second patient with stable bone marrow blasts achieved a partial cytogenetic response. Two of the responding patients and three patients with stable disease had hematological improvements. Rigosertib-induced bone marrow blast decreases and stability appeared to be predictive of prolonged survival. IV rigosertib had a favorable safety profile without significant myelosuppression. Most common drug-related toxicities included fatigue, diarrhea, nausea, dysuria, and hematuria. In summary, IV rigosertib is well tolerated and has clinical activity in patients with higher risk MDS following DNMT inhibitor treatment. A multinational pivotal phase 3 randomized clinical trial of rigosertib versus best supportive care for patients with MDS with excess blasts following prior treatment with DNMT inhibitors (ONTIME: ON 01910.Na Trial In Myelodysplastic SyndromE) has recently

  15. The Effect of Decitabine Dose Modification and Myelosuppression on Response and Survival in Patients With Myelodysplastic Syndromes

    PubMed Central

    Jabbour, Elias; Garcia-Manero, Guillermo; Cornelison, A. Megan; Cortes, Jorge E.; Ravandi, Farhad; Daver, Naval; Kadia, Tapan; Teng, Angela; Kantarjian, Hagop

    2014-01-01

    Myelosuppression in myelodysplastic syndromes (MDS) is associated with the hypomethylating agent decitabine. A retrospective pooled analysis of 2 decitabine clinical trials in patients with MDS conducted Cox regression analyses of red blood cell or platelet dependence, myelosuppression, dose modification, cycle delay or dose reduction, and survival effects. In 182 patients, baseline platelet dependence was a predictor for dose modification, reduction, or delay, and death (modification: P = .006, hazard ratio [HR] = 2.04; reduction/delay: P = .011, HR = 2.00; death: P = .003, HR = 1.94). Patients with dose modifications had significantly higher overall response rates versus those with none (22% vs 10%; P = .015). Patients with no dose modifications had faster progression to AML versus patients with dose modifications (P = .004). Without dose modifications, patients tended to drop out due to disease progression or other reasons. Decitabine dose modifications on treatment may indicate response to treatment. PMID:24844364

  16. Effectiveness and safety of different azacitidine dosage regimens in patients with myelodysplastic syndromes or acute myeloid leukemia.

    PubMed

    García-Delgado, Regina; de Miguel, Dunia; Bailén, Alicia; González, José Ramón; Bargay, Joan; Falantes, José F; Andreu, Rafael; Ramos, Fernando; Tormo, Mar; Brunet, Salut; Figueredo, Antonio; Casaño, Javier; Medina, Angeles; Badiella, Llorenç; Jurado, Antonio Fernández; Sanz, Guillermo

    2014-07-01

    We investigated the effectiveness and tolerability of azacitidine in patients with World Health Organization-defined myelodysplastic syndromes, or acute myeloid leukemia with 20-30% bone marrow blasts. Patients were treated with azacitidine, with one of three dosage regimens: for 5 days (AZA 5); 7 days including a 2-day break (AZA 5-2-2); or 7 days (AZA 7); all 28-day cycles. Overall response rates were 39.4%, 67.9%, and 51.3%, respectively, and median overall survival (OS) durations were 13.2, 19.1, and 14.9 months. Neutropenia was the most common grade 3-4 adverse event. These results suggest better effectiveness-tolerability profiles for 7-day schedules. PMID:24795069

  17. On the potential role of DNMT1 in acute myeloid leukemia and myelodysplastic syndromes: not another mutated epigenetic driver.

    PubMed

    Benetatos, Leonidas; Vartholomatos, Georgios

    2016-10-01

    DNA methylation is the most common epigenetic modification in the mammalian genome. DNA methylation is governed by the DNA methyltransferases mainly DNMT1, DNMT3A, and DNMT3B. DNMT1 methylates hemimethylated DNA ensuring accurate DNA methylation maintenance. DNMT1 is involved in the proper differentiation of hematopoietic stem cells (HSCs) through the interaction with effector molecules. DNMT1 is deregulated in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) as early as the leukemic stem cell stage. Through the interaction with fundamental transcription factors, non-coding RNAs, fusion oncogenes and by modulating core members of signaling pathways, it can affect leukemic cells biology. DNMT1 action might be also catalytic-independent highlighting a methylation-independent mode of action. In this review, we have gathered some current facts of DNMT1 role in AML and MDS and we also propose some perspectives for future studies. PMID:26983918

  18. Random-start controlled ovarian stimulation for emergency fertility preservation in a patient with myelodysplastic syndrome: a case report

    PubMed Central

    Cai, H.; Shen, H.

    2016-01-01

    This study reports a case of a gonadotropin-releasing hormone agonist trigger in a young female with myelodysplastic syndrome (MDS) who underwent fertility preservation using random-start controlled ovarian stimulation. This method involves the stimulation of the ovary regardless of a patient's menstrual-cycle phase. A review of the related literature is also provided. A 17-year-old patient was diagnosed with MDS and required initiation of peripheral blood stem cell transplantation within a maximum of 3 weeks and was in the luteal phase of the menstrual cycle when the possibility of attempting preservation of fertility was presented to her. She opted for a random-start controlled ovarian stimulation with gonadotropins. With successful hemorrhagic prophylaxis, 17 oocytes were retrieved including 10 mature and 7 immature oocytes. Of the immature oocytes, 3 were successfully matured in vitro and a vitrification protocol was used to freeze the 13 mature oocytes. PMID:27191608

  19. Stem cell transplantation in 6 children with parvovirus B19- induced severe aplastic anaemia or myelodysplastic syndrome.

    PubMed

    Urban, C; Lackner, H; Müller, E; Benesch, M; Strenger, V; Sovinz, P; Schwinger, W

    2011-11-01

    Parvovirus B19 (PVB19) induced severe aplastic anaemia (SAA) or myelodysplastic syndrome (MDS) is rare, and haematopoietic stem cell transplantation (HSCT) in this condition has not been reported so far. 6 children with SAA (n=4) or MDS (n=2) caused by acute PVB19 infection underwent HSCT under the protection of intravenous immunoglobulines. The 4 children with SAA received matched HLA bone marrow from a sibling (n=3) or peripheral unrelated blood stem cells (n=1). 1 patient had delayed erythrocyte engraftment, whereas 3 patients had an uneventful transplantation course. HSCT in one of the 2 children with MDS was complicated by poor graft function, the other patient engrafted without complications. In conclusion, HSCT in children with PVB19 induced SAA or MDS is feasible, even though some patients may develop delayed engraftment or prolonged poor graft function. PMID:22052631

  20. Which Patients Should Undergo Allogeneic Stem Cell Transplantation for Myelodysplastic Syndromes, and When Should We Do It?

    PubMed

    Oran, Betul

    2015-06-01

    Allogeneic hematopoietic stem cell transplantation (SCT) can cure a proportion of patients with myelodysplastic syndromes (MDS). However, treatment related toxicities, graft versus host disease, infectious complications and relapse remain major problems post transplant. Further, recent new developments with innovative drugs including hypomethylating agents (HMA) have extended the therapeutic alternatives for our patients. Nevertheless, with the introduction of reduced-intensity conditioning and thereby reducing early mortality, transplant numbers in MDS patients have significantly increased recently. In the absence of prospective randomized trials emphasis should be put on patient selection and optimization of the pre- and post-transplant treatment in order to achieve long-term disease control and at the same time maintain an adequate quality of life. With better understanding of disease biology and prognosis and with different types of conditioning regimens as well as different graft sources, a transplant strategy should be tailored to the individual host to maximize the benefits of this procedure. PMID:26297277

  1. Early Discharge and Outpatients Care in Patients With Myelodysplastic Syndrome or Acute Myeloid Leukemia Previously Treated With Intensive Chemotherapy

    ClinicalTrials.gov

    2015-02-05

    Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia

  2. Pyoderma gangrenosum complicated with myelodysplastic syndrome followed by rapidly progressing pyothorax-associated lymphoma: a case report.

    PubMed

    Goto, Akiko; Yamamoto, Satoshi; Notoya, Atsushi; Takada, Akio; Mukai, Masaya

    2006-07-01

    This report describes a patient with pyoderma gangrenosum (PG) complicated with myelodysplastic syndrome (MDS) followed by rapidly progressing pyothorax-associated lymphoma (PAL). A 74-year-old man was admitted with cutaneous gangrene associated with MDS. We diagnosed him as having PG, and high-dose oral prednisolone was started. Two months after admission he developed lymphoma rapidly. The patient died in spite of radiation therapy. On autopsy, the pathological diagnosis was diffuse large cell lymphoma. Epstein-Barr virus (EBV)-encoded RNA, and EBV-encoded nuclear antigen (EBNA) were detected in lymphoma cells. This case suggested that immunosuppressive therapy might favour the clonal proliferation of EBV-infected cells. PMID:16892654

  3. Decitabine Followed by Idarubicin and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndromes

    ClinicalTrials.gov

    2013-10-09

    Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts

  4. Monoclonal antibody panels for acute leukemia and myelodysplastic syndrome diagnosis. Results of a co-operative quality control group.

    PubMed

    Basso, G; Bernasconi, P; Chianese, R; Crovetti, G; Garbaccio, G; Iavarone, A; Pautasso, M; Santagostino, A; Stacchini, A

    2001-01-01

    The need for standardization criteria and result reproducibility in immunophenotyping hematological diseases has increased along with their clinical importance. Our group "Policentric Study Group on Immunological Markers", is composed of 40 laboratories. Its aim, over recent years, has been to find a standardized way of immunophenotypic analysis applicable to various hematological diseases. The objective of this study is to contribute to the debate concerning standardization of monoclonal antibody panels and immunophenotypic analysis procedures in acute leukemia (AL) and myelodysplastic syndrome (MDS), with the following targets: to improve interlaboratory reproducibility of the immunophenotyping data, and interpretative results; to study, with improved feasibility, correlation between immunophenotype and clinical or biological findings on a large number of AL and MDS cases; to verify the utility of the proposed monoclonal antibody panels for proper AL and MDS classification, and to detect minimal residual disease. In the field of AL and MDS our experience is based on about 1800 and 700 cases respectively analyzed over the last five years. Starting from these experiences and data of the literature we have elaborated the proposed panels of monoclonal antibodies and the methods of analysis. We have suggested a standardized immunophenotypic approach to study AL and MDS. In particular our work has focused on the gating strategy. This aims at drawing a gate of analysis having high purity and recovery, and on the choice of monoclonal antibody combinations for multiparametric analysis, particularly the normal antigen expression on each step of lineage differentiation or their clinically relevant aberrant expressions. A standardized criteria has become a necessary starting point in any kind of analytical process. In the field of acute leukemias and myelodysplastic syndromes the work of this polycentric group has focused on the pre-analytical and analytical steps to be

  5. Red ear syndrome: literature review and a pediatric case report.

    PubMed

    Moitri, Misha O; Banglawala, Sarfaraz M; Archibald, Jason

    2015-03-01

    Red ear syndrome (RES) is characterized by recurrent unilateral or bilateral painful attacks of the external ear, accompanied by ear redness, burning, or warmth. Proposed etiologies of this rare condition include dysregulation of sympathetic outflow, upper cervical pathology, glossopharyngeal and trigeminal neuralgia, TMJ dysfunction, thalamic syndrome, and primary headache syndromes. Idiopathic cases also exist in the literature. Pediatric cases are particularly rare and more commonly associated with migraine. Given the various potential etiologies, no single treatment is effective in all cases. This paper summarizes the current understanding and management of RES, and describes a case of idiopathic pediatric RES. PMID:25583087

  6. Biological Therapy in Treating Patients With Advanced Myelodysplastic Syndrome, Acute or Chronic Myeloid Leukemia, or Acute Lymphoblastic Leukemia Who Are Undergoing Stem Cell Transplantation

    ClinicalTrials.gov

    2013-07-03

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; Essential Thrombocythemia; Polycythemia Vera; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; T-cell Adult Acute Lymphoblastic Leukemia; T-cell Childhood Acute Lymphoblastic Leukemia

  7. Three cases of triple A syndrome (Allgrove syndrome) in pediatric surgeons' view.

    PubMed

    Erginel, Başak; Gün, Feryal; Kocaman, Hakan; Çelik, Alaadin; Salman, Tansu

    2016-04-01

    Triple A syndrome, also known as Allgrove syndrome, is a rare disease, and presents mainly in children. Its cardinal symptoms are achalasia, alacrima, and adrenocorticotropic hormone (ACTH) insensitivity. We report three cases of Triple A syndrome. Our aim is to inform pediatric surgeons about the existence of this rare syndrome and to highlight the need for suspicion of alacrima and ACTH insensitivity in cases of pediatric achalasia. Triple A syndrome should be considered in patients presenting with achalasia. Alacrima should be investigated by a Schirmer test, and adrenal dysfunction should be tested in cases of suspected triple A. PMID:27385299

  8. Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable

    MedlinePlus

    ... Myeloproliferative Neoplasms Treatment Myelodysplastic/ Myeloproliferative Neoplasms Treatment Myelodysplastic/ Myeloproliferative Neoplasms Treatment (PDQ®)–Patient Version General Information About Myelodysplastic/ ...

  9. Tanespimycin and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia, Chronic Myelomonocytic Leukemia, or Myelodysplastic Syndromes

    ClinicalTrials.gov

    2013-09-27

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Blastic Phase Chronic Myelogenous Leukemia; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

  10. Lenalidomide treatment induced the normalization of marker protein levels in blood plasma of patients with 5q-myelodysplastic syndrome.

    PubMed

    Messingerová, Lucia; Jonášová, Anna; Barančik, Miroslav; Poleková, Lenka; Šereš, Mário; Gibalová, Lenka; Breier, Albert; Sulová, Zdena

    2015-10-01

    A specific type of myelodysplastic syndrome (MDS) is associated with isolated deletion on the long arm of chromosome 5, i.e., 5q-syndrome (del(5q)). The treatment approaches for MDS del(5q) include the immunomodulating drug lenalidomide (LEN). Thirteen MDS del(5q) patients were included in this study. We found elevated activities of lactate dehydrogenase (LDH) and matrix metalloproteinase 9 (MMP-9) in the blood plasma of MDS del(5q) patients as compared with healthy controls. This was stabilized to control values after LEN treatment. Similar behavior we registered also for the thioredoxin and calnexin contents in BP. Peripheral blood mononuclear cells (PBMC) from patients with MDS del(5q) prior to and after treatment with LEN did not exhibit any detectable amount of P-glycoprotein (P-gp) gene transcript. However, we detected a measurable amount of multidrug resistance associated protein 1 (MRP1) mRNA in PBMCs from three patients prior to LEN treatment and in one patient during LEN treatment but it was not present prior to treatment. These data indicated on usefulness of applied protein markers estimation for monitoring of MDS del(5q) patient treatment effectiveness by LEN. Expression of MRP1 seems to be independent on LEN treatment and reflects probably the molecular variability in the ethiopathogenesis of MDS del(5q). PMID:26001289