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Sample records for positive chronic myeloproliferative

  1. Chronic Myeloproliferative Neoplasms Treatment

    MedlinePlus

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

  2. Treatment Options for Chronic Myeloproliferative Neoplasms

    MedlinePlus

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

  3. Treatment Option Overview (Chronic Myeloproliferative Neoplasms)

    MedlinePlus

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

  4. General Information about Chronic Myeloproliferative Neoplasms

    MedlinePlus

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

  5. Tipifarnib in Treating Patients With Chronic Myeloid Leukemia, Chronic Myelomonocytic Leukemia, or Undifferentiated Myeloproliferative Disorders

    ClinicalTrials.gov

    2017-05-08

    Accelerated Phase of Disease; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Chronic Myelomonocytic Leukemia; Chronic Phase of Disease; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Recurrent Disease

  6. Philadelphia-negative chronic myeloproliferative neoplasms

    PubMed Central

    Bittencourt, Rosane Isabel; Vassallo, Jose; Chauffaille, Maria de Lourdes Lopes Ferrari; Xavier, Sandra Guerra; Pagnano, Katia Borgia; Nascimento, Ana Clara Kneese; De Souza, Carmino Antonio; Chiattone, Carlos Sergio

    2012-01-01

    Chronic myeloproliferative diseases without the Philadelphia chromosome marker (Ph-), although first described 60 years ago, only became the subject of interest after the turn of the millennium. In 2001, the World Health Organization (WHO) defined the classification of this group of diseases and in 2008 they were renamed myeloproliferative neoplasms based on morphological, cytogenetic and molecular features. In 2005, the identification of a recurrent molecular abnormality characterized by a gain of function with a mutation in the gene encoding Janus kinase 2 (JAK2) paved the way for greater knowledge of the pathophysiology of myeloproliferative neoplasms. The JAK2 mutation is found in 90-98% of polycythemia vera and in about 50% essential thrombocytosis and primary myelofibrosis. In addition to the JAK2 mutation, other mutations involving TET2 (ten-eleven translocation), LNK (a membrane-bound adaptor protein); IDH1/2 (isocitrate dehydrogenase 1/2 enzyme); ASXL1 (additional sex combs-like 1) genes were found in myeloproliferative neoplasms thus showing the importance of identifying molecular genetic alterations to confirm diagnosis, guide treatment and improve our understanding of the biology of these diseases. Currently, polycythemia vera, essential thrombocytosis, myelofibrosis, chronic neutrophilic leukemia, chronic eosinophilic leukemia and mastocytosis are included in this group of myeloproliferative neoplasms, but are considered different situations with individualized diagnostic methods and treatment. This review updates pathogenic aspects, molecular genetic alterations, the fundamental criteria for diagnosis and the best approach for each of these entities. PMID:23049404

  7. Chronic myelomonocytic leukemia: myelodysplastic or myeloproliferative?

    PubMed

    Itzykson, Raphael; Itzkson, Raphael; Fenaux, Pierre; Solary, Eric

    2013-12-01

    Chronic myelomonocytic leukemia (CMML) is a clonal disease of the hematopoietic stem cell that provokes a stable increase in peripheral blood monocyte count. The World Health Organisation classification appropriately underlines that the disease combines dysplastic and proliferative features. The percentage of blast cells in the blood and bone marrow distinguishes CMML-1 from CMML-2. The disease is usually diagnosed after the age of 50, with a strong male predominance. Inconstant and non-specific cytogenetic aberrations have a negative prognostic impact. Recurrent gene mutations affect mainly the TET2, SRSF2, and ASXL1 genes. Median survival is 3 years, with patients dying from progression to AML (20-30%) or from cytopenias. ASXL1 is the only gene whose mutation predicts outcome and can be included within a prognostic score. Allogeneic stem cell transplantation is possibly curative but rarely feasible. Hydroxyurea, which is the conventional cytoreductive agent, is used in myeloproliferative forms, and demethylating agents could be efficient in the most aggressive forms of the disease. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. RAS gene mutations in acute and chronic myelocytic leukemias, chronic myeloproliferative disorders, and myelodysplastic syndromes

    SciTech Connect

    Janssen, J.W.G.; Steenvoorden, A.C.M.; Lyons, J.; Anger, B.; Boehlke, J.U.; Bos, J.L.; Seliger, H.; Bartram, C.R.

    1987-12-01

    The authors report on investigations aimed at detecting mutated RAS genes in a variety of preleukemic disorders and leukemias of myeloid origin. DNA transfection analyses (tumorigenicity assay) and hybridization to mutation-specific oligonucleotide probes established NRAS mutations in codon 12 or 61 of 4/9 acute myelocytic leukemias (AML) and three AML lines. Leukemic cells of another AML patient showed HRAS gene activation. By using a rapid and sensitive dot-blot screening procedure based on the combination of in vitro amplification of RAS-specific sequences and oligonucleotide hybridization they additionally screened 15 myelodysplastic syndromes, 26 Philadelphia chromosome-positive chronic myelocytic leukemias in chronic or acute phase, and 19 other chronic myeloproliferative disorders. A mutation within NRAS codon 12 could thus be demonstrated in a patient with idiopathic myelofibrosis and in another with chronic myelomonocytic leukemia. Moreover, mutated NRAS sequences were detected in lymphocytes, in granulocytes, as well as in monocytes/macrophages of the latter case.

  9. Pulmonary hypertension in patients with chronic myeloproliferative disorders.

    PubMed

    Adir, Yochai; Elia, Davide; Harari, Sergio

    2015-09-01

    Pulmonary hypertension (PH) is a major complication of several haematological disorders. Chronic myeloproliferative diseases (CMPDs) associated with pulmonary hypertension have been included in group five of the clinical classification for pulmonary hypertension, corresponding to pulmonary hypertension for which the aetiology is unclear and/or multifactorial. The aim of this review is to discuss the epidemiology, pathogenic mechanism and treatment approaches of the more common forms of pulmonary hypertension in the context of CMPD's: chronic thromboembolic pulmonary hypertension, precapillary pulmonary hypertension and drug-induced PH. Copyright ©ERS 2015.

  10. Single chromosomal abnormalities in Philadelphia-negative chronic myeloproliferative disorders.

    PubMed

    Panani, Anna D

    2007-01-01

    In Philadelphia-negative chronic myeloproliferative disorders (CMPD), increased proliferation with effective maturation of the myeloid lineage is present, while peripheral leukocytosis, thrombocytosis or elevated red blood cell mass are found. This group of disorders includes polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). Furthermore, cases that cannot be clearly defined are regarded as unclassified CMPD. In Philadelphia-negative CMPD, recurrent cytogenetic abnormalities occur, but no specific abnormality has been defined to date. Chromosomal abnormalities detected in a neoplastic disease as a sole anomaly are of major importance, possibly constituting primary changes implicated in the initiation or progression of the neoplastic process. The aim of this study was to investigate the frequency and the type of single chromosomal changes in Philadelphia-negative CMPD patients. By conventional cytogenetics, 245 Philadelphia-negative CMPD cases at diagnosis were investigated for the frequency and the type of single chromosomal aberrations. Seventeen patients presented single chromosomal changes. These aberrations were, according to frequency, +8 (in 3 PV cases, 2 IMF and 2 unclassified myeloproliferative diseases), +13 in 3 cases (IMF, ET and unclassified myeloproliferative disease), monosomy 10 in 2 PV cases, monosomy 14 in one ET patient, +3, -4 and del(11)(q13) in 1 unclassified myeloproliferative disease each and monosomy 7 in 1 IMF case. It is unclear whether these abnormalities found at the time of diagnosis play a role in CMPD. However, since an isolated chromosomal abnormality may be implicated in the initiation of the neoplastic process, the documentation of more cases of CMPD with single abnormalities at the time of diagnosis would facilitate the identification of candidate genes involved in the neoplastic process.

  11. Multicenter Retrospective Analysis of Turkish Patients with Chronic Myeloproliferative Neoplasms

    PubMed Central

    Soyer, Nur; Haznedaroğlu, İbrahim C.; Cömert, Melda; Çekdemir, Demet; Yılmaz, Mehmet; Ünal, Ali; Çağlıyan, Gülsüm; Bilgir, Oktay; İlhan, Osman; Özdemirkıran, Füsun; Kaya, Emin; Şahin, Fahri; Vural, Filiz; Saydam, Güray

    2017-01-01

    Objective: Chronic myeloproliferative neoplasms (CMPNs) that include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are Philadelphia-negative malignancies characterized by a clonal proliferation of one or several lineages. The aim of this report was to determine the demographic features, disease characteristics, treatment strategies, and survival rates of patients with CMPNs in Turkey. Materials and Methods: Across all of Turkey, 9 centers were enrolled in the study. We retrospectively evaluated 708 CMPN patients’ results including 390 with ET, 213 with PV, and 105 with PMF. Results: The JAK2V617F mutation was found positive in 86% of patients with PV, in 51.5% of patients with ET, and in 50.4% of patients with PMF. Thrombosis and bleeding at diagnosis occurred in 20.6% and 7.5% of PV patients, 15.1% and 9% of ET patients, and 9.5% and 10.4% of PMF patients, respectively. Six hundred and eight patients (85.9%) received cytoreductive therapy. The most commonly used drug was hydroxyurea (89.6%). Leukemic and fibrotic transformations occurred at rates of 0.6% and 13.2%. The estimated overall survival in PV, ET, and PMF patients was 89.7%, 85%, and 82.5% at 10 years, respectively. There were no significant differences between survival in ET, PV, and PMF patients at 10 years. Conclusion: Our patients’ results are generally compatible with the literature findings, except for the relatively high survival rate in PMF patients. Hydroxyurea was the most commonly used cytoreductive therapy. Our study reflects the demographic features, patient characteristics, treatments, and survival rates of Turkish CMPN patients. PMID:27094252

  12. Genomic aberrations of myeloproliferative and myelodysplastic/myeloproliferative neoplasms in chronic phase and during disease progression.

    PubMed

    Hahm, C; Huh, H J; Mun, Y C; Seong, C M; Chung, W S; Huh, J

    2015-04-01

    Myeloproliferative neoplasms (MPN) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) may transform into secondary myelofibrosis (MF) or evolve into acute myeloid leukemia (AML). The genetic mechanisms underlying disease progression in MPN and MDS/MPN patients remain unclear. The purpose of this study was to investigate sequential genomic aberrations identified by single nucleotide polymorphism array (SNP-A)-based karyotyping that can detect cryptic aberrations or copy neutral loss of heterozygosity (CN-LOH) in the chronic phase and during disease progression of MPN and MDS/MPN patients. The study group included 13 MPN and four MDS/MPN patients (seven polycythemia vera (PV); four essential thrombocythemia (ET); two MPN-unclassifiable (MPN-U); one chronic myelomonocytic leukemia (CMML); one atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML); and two MDS/MPN-unclassifiable (MDS/MPN-U)). Among them, five patients (two PV, two MPN-U, and one MDS/MPN-U) progressed to MF and three patients (one CMML, one aCML, and one MDS/MPN-U) transformed to AML. The median follow-up period was 70 months (range, 7-152). Whole-genome SNP-A (SNP 6.0; Affymetrix, Santa Clara, CA, USA)-based karyotyping and JAK2 mutation analysis were performed according to the manufacturer's instructions. SNP-A showed 19 kinds of genomic aberrations, including seven gains, eight deletions, and four CN-LOH. CN-LOH of 9p involving JAK2 was the most common aberration, followed by 5q deletion and 9p gain. The incidence of genomic changes identified by SNP was not different in patients with disease progression (75%), compared with those without disease progression (56%) (P = 0.4). However, when excluding 9p CN-LOH, the incidence of genomic changes was significantly higher in patients with disease progression than in patients without disease progression (63% and 0%, respectively, P = 0.01). Among eight patients with disease progression, two patients (two MPN-U) showed abnormal SNP-A results

  13. Gene mutations differently impact the prognosis of the myelodysplastic and myeloproliferative classes of chronic myelomonocytic leukemia.

    PubMed

    Cervera, Nathalie; Itzykson, Raphael; Coppin, Emilie; Prebet, Thomas; Murati, Anne; Legall, Stevan; Vey, Norbert; Solary, Eric; Birnbaum, Daniel; Gelsi-Boyer, Véronique

    2014-06-01

    Initially classified in the myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML) is currently considered as a MDS/myeloproliferative neoplasm. Two classes-myelodysplastic and myeloproliferative-have been distinguished upon the level of the white blood cell count (threshold 13 G/L). We analyzed mutations in 19 genes reported in CMML to determine if and how these mutations impacted the respective prognosis of the two classes. We defined four major mutated pathways (DNA methylation, ASXL1, splicing, and signaling) and determined their prognostic impact. The number of mutated pathways impacted overall survival in the myelodysplastic class but not in the myeloproliferative class. The myeloproliferative class had a worse prognosis than the myelodysplastic class and was impacted by RUNX1 mutations only. Our results argue for a reclassification of CMML based on the myelodysplastic/myeloproliferative status. © 2014 Wiley Periodicals, Inc.

  14. Evaluation of the association between the JAK2 46/1 haplotype and chronic myeloproliferative neoplasms in a Brazilian population

    PubMed Central

    Silva, Sarah Pagliarini- e-; Santos, Bruna Cunha; de Figueiredo Pereira, Elizangela Mendes; Ferreira, Mari Ellen; Baraldi, Elaine Cristina; Sell, Ana Maria; Visentainer, Jeane Eliete Laguila

    2013-01-01

    OBJECTIVE: The JAK2 46/1 haplotype has recently been described as a major contributing factor to the development of myeloproliferative neoplasm, whether positive or negative for the JAK2 V617F mutation. The G allele, identified by a single-nucleotide polymorphism known as JAK2 rs10974944, is part of the JAK2 46/1 haplotype. The aim of this study was to verify the association between the presence of the G allele and the development of BCR-ABL-negative chronic myeloproliferative neoplasms in our population. METHODS: Blood and oral mucosa swab samples were obtained from 56 patients of two local Brazilian hospitals who had previously been diagnosed with BCR-ABL-negative chronic myeloproliferative neoplasms. Blood samples from 90 local blood donors were used as controls. The presence of the G allele was assessed using a PCR-RFLP assay after extracting DNA from the samples. RESULTS: The presence of the G allele was strongly associated with the presence of BCR-ABL-negative chronic myeloproliferative neoplasms (p = 0.0001; OR = 2.674; 95% CI = 1.630−4.385) in the studied population. CONCLUSION: In agreement with previous reports, the JAK2 46/1 haplotype, represented in this study by the presence of the G allele, is an important predisposing factor in the oncogenetic development of these neoplasms in our population. PMID:23420150

  15. Incidence of pulmonary hypertension in patients with chronic myeloproliferative disorders.

    PubMed Central

    Gupta, Ranju; Perumandla, Sirisha; Patsiornik, Yelena; Niranjan, Selvanayagam; Ohri, Anju

    2006-01-01

    STUDY OBJECTIVE: To assess the incidence of pulmonary hypertension (PH) in patients with chronic myeloproliferative disorders (CMPD). METHOD: Twenty-seven patients with a diagnosis of CMPD were included in the study. Patients were excluded if they had a secondary cause of PH. Diagnosis of PH was established if right ventricular systolic pressure (RVSP) by transthoracic echocardiography (TTE) was >35 mmHg. RESULTS: Diagnosis of PH was established in 14 out of 27 patients. Two patients were excluded from analysis because of poor ejection fraction on TTE, resulting in a final diagnosis of PH in 12 of 25 (48%) patients. Of these 25 patients, seven of nine with essential thrombocytosis (ET), five of 14 with polycythemia vera (PV), and 0 out of two with chronic myeloid leukemia (CML) had PH. All patients were asymptomatic at the time of their most recent visit. There was no relationship between PH and age at diagnosis, duration of disease, platelet count and hematocrit at diagnosis or during follow-up, both for the entire cohort or for specific diagnosis of ET or PV. CONCLUSION: Pulmonary hypertension appears to be common in patients with CMPD. Further studies are needed to evaluate the impact of treatment on PH and long-term survival in these patients. PMID:17128687

  16. Pathogenesis of Myeloproliferative Neoplasms: Role and Mechanisms of Chronic Inflammation.

    PubMed

    Hermouet, Sylvie; Bigot-Corbel, Edith; Gardie, Betty

    2015-01-01

    Myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal diseases characterized by the excessive and chronic production of mature cells from one or several of the myeloid lineages. Recent advances in the biology of MPNs have greatly facilitated their molecular diagnosis since most patients present with mutation(s) in the JAK2, MPL, or CALR genes. Yet the roles played by these mutations in the pathogenesis and main complications of the different subtypes of MPNs are not fully elucidated. Importantly, chronic inflammation has long been associated with MPN disease and some of the symptoms and complications can be linked to inflammation. Moreover, the JAK inhibitor clinical trials showed that the reduction of symptoms linked to inflammation was beneficial to patients even in the absence of significant decrease in the JAK2-V617F mutant load. These observations suggested that part of the inflammation observed in patients with JAK2-mutated MPNs may not be the consequence of JAK2 mutation. The aim of this paper is to review the different aspects of inflammation in MPNs, the molecular mechanisms involved, the role of specific genetic defects, and the evidence that increased production of certain cytokines depends or not on MPN-associated mutations, and to discuss possible nongenetic causes of inflammation.

  17. Pathogenesis of Myeloproliferative Neoplasms: Role and Mechanisms of Chronic Inflammation

    PubMed Central

    Hermouet, Sylvie; Bigot-Corbel, Edith; Gardie, Betty

    2015-01-01

    Myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal diseases characterized by the excessive and chronic production of mature cells from one or several of the myeloid lineages. Recent advances in the biology of MPNs have greatly facilitated their molecular diagnosis since most patients present with mutation(s) in the JAK2, MPL, or CALR genes. Yet the roles played by these mutations in the pathogenesis and main complications of the different subtypes of MPNs are not fully elucidated. Importantly, chronic inflammation has long been associated with MPN disease and some of the symptoms and complications can be linked to inflammation. Moreover, the JAK inhibitor clinical trials showed that the reduction of symptoms linked to inflammation was beneficial to patients even in the absence of significant decrease in the JAK2-V617F mutant load. These observations suggested that part of the inflammation observed in patients with JAK2-mutated MPNs may not be the consequence of JAK2 mutation. The aim of this paper is to review the different aspects of inflammation in MPNs, the molecular mechanisms involved, the role of specific genetic defects, and the evidence that increased production of certain cytokines depends or not on MPN-associated mutations, and to discuss possible nongenetic causes of inflammation. PMID:26538820

  18. Clinical Features of 294 Turkish Patients with Chronic Myeloproliferative Neoplasms

    PubMed Central

    Andıç, Neslihan; Ünübol, Mustafa; Yağcı, Eren; Akay, Olga Meltem; Yavaşoğlu, İrfan; Kadıköylü, Vefki Gürhan; Bolaman, Ali Zahit

    2016-01-01

    Objective: Myeloproliferative neoplasms (MPNs) share common clonal stem cells but show significant differences in their clinical courses. The aim of this retrospective study was to evaluate thrombotic and hemorrhagic complications, JAK2 status, gastrointestinal and cardiac changes, treatment modalities, and survival in MPNs in Turkish patients. Materials and Methods: Medical files of 294 patients [112 essential thrombocythemia (ET), 117 polycythemia vera (PV), 46 primary myelofibrosis, and 19 unclassified MPN cases] from 2 different universities in Turkey were examined. Results: Older age, higher leukocyte count at diagnosis, and JAK2 mutation positivity were risk factors for thrombosis. Platelet count over 1000x109/L was a risk factor for hemorrhagic episodes. Hydroxyurea treatment was not related to leukemic transformation. Median follow-up time was 50 months (quartiles: 22.2-81.75) in these patients. Patients with primary myelofibrosis had the shortest survival of 137 months when compared with 179 months for ET and 231 months for PV. Leukemic transformation, thromboembolic events, age over 60 years, and anemia were found to be the factors affecting survival. Conclusion: Thromboembolic complications are the most important preventable risk factors for morbidity and mortality in MPNs. Drug management in MPNs is done according to hemoglobin and platelet counts. Based on the current study population our results support the idea that leukocytosis and JAK2 positivity are more important risk factors for thrombosis than hemoglobin and platelet values. PMID:27094255

  19. The simultaneous occurrence of multiple myeloma and JAK2 positive myeloproliferative neoplasms - Report on two cases

    PubMed Central

    Badelita, S; Dobrea, C; Colita, A; Dogaru, M; Dragomir, M; Jardan, C; Coriu, D

    2015-01-01

    Multiple myeloma and JAK2 positive chronic myeloproliferative neoplasms are hematologic malignancies with a completely different cellular origin. Two cases of simultaneous occurrence of multiple myeloma, one with primary myelofibrosis and another one with essential thrombocythemia are reported in this article. In such cases, an accurate diagnosis requires a molecular testing, including gene sequencing and differential diagnosis of pancytosis associated with splenic amyloidosis. In general, in such cases, of two coexisting malignant hematologic diseases, the treatment of the most aggressive one is recommended. For our two cases, it was decided to start a Velcade based therapy. The main concern was the medullar toxicity, especially when a multiple myeloma was associated with a primary myelofibrosis. Abbreviations:JAK2 = Janus kinase 2 gene, PMF = primary myelofibrosis, MPNs = myeloproliferative neoplasms, ET = essential thrombocythemia, PV = polycythemia vera, MM = multiple myeloma, WBC = white blood cells, Hb = haemoglobin, Ht = haematocrit, Plt = platelets, BMB = bone marrow biopsy, CBC = blood cell count, CT = computerized tomography, LAP = leukocyte alkaline phosphatase, MGUS = monoclonal gammopathy of undetermined significance. PMID:25914740

  20. The effect of chronic hypocholesterolemia in myeloproliferative disease on the distribution of plasma and erythrocyte tocopherol.

    PubMed

    Gilbert, H S; Stump, D D; Ginsberg, H; Roth, E F

    1984-07-01

    The presence of hypocholesterolemia and increased erythrocyte lipid peroxidation susceptibility in myeloproliferative disorders raised the possibility of coexistent tocopherol deficiency. Plasma and red blood cell (RBC) alpha-tocopherol, beta- + gamma-tocopherol, and free cholesterol were determined simultaneously by high performance liquid chromatography in 22 patients and 26 controls. Plasma alpha-tocopherol was correlated most highly with plasma free cholesterol and secondarily with RBC alpha-tocopherol in both groups. Plasma-free cholesterol and alpha-tocopherol were significantly reduced in myeloproliferative disease, although the ratio between the two remained normal. Erythrocyte tocopherol and free cholesterol concentrations were normal in myeloproliferative disease. High relative retention of tocopherol by erythrocytes was most pronounced in patients with the lowest plasma alpha-tocopherol and free cholesterol levels. The normal RBC tocopherol levels in these patients with chronic hypocholesterolemia indicate that the observed increase in RBC peroxidation susceptibility is not explainable by a deficiency of RBC vitamin E.

  1. Janus kinase 2 mutations in cases with BCR-ABL-negative chronic myeloproliferative disorders from Turkey

    PubMed Central

    Yildiz, Ismail; Yokuş, Osman; Gedik, Habip

    2017-01-01

    Objective: We aimed to investigate the frequency of Janus kinase 2 (JAK2) mutations in cases with chronic myeloproliferative disorders (CMDs), and the relationship between the presence of JAK2 mutation and leukocytosis and splenomegaly, retrospectively. Materials and Methods: Patients, who were diagnosed with BCR-ABL-negative CMDs according to diagnosis criteria of the World Health Organization and followed up at the hematology clinic between 2013 and 2015, were investigated in terms of the frequency of JAK2 mutation in cases with CMDs, and the relationship between the presence of JAK2 mutation and leukocytosis and splenomegaly, retrospectively. Results: In total, 100 patients, who were diagnosed with BCR-ABL-negative CMDs, were evaluated retrospectively. The mean age of the patients with JAK2 positivity was significantly higher compared to patients with negative. JAK2-positivity rates in the age groups were significantly different. Gender, diagnosis, splenomegaly, and leukocytosis were not statistically different for JAK2 positivity between the groups. Conclusion: JAK2 V617F mutation is more commonly seen in older age as a risk for complications related to CDMS. Splenomegaly and leukocytosis are not associated with JAK2 V617F mutation. PMID:28182037

  2. Development of paroxysmal nocturnal hemoglobinuria in CALR-positive myeloproliferative neoplasm

    PubMed Central

    Fraiman, Yarden S; Cuka, Nathan; Batista, Denise; Vuica-Ross, Milena; Moliterno, Alison R

    2016-01-01

    Paroxysmal nocturnal hemoglobinuria (PNH), a disease characterized by intravascular hemolysis, thrombosis, and bone marrow failure, is associated with mutations in the PIG-A gene, resulting in a deficiency of glycosylphosphatidylinositol-anchored proteins. Many hypotheses have been posed as to whether PNH and PIG-A mutations result in an intrinsic survival benefit of CD55−/CD59− cells or an extrinsic permissive environment that allows for their clonal expansion within the bone marrow compartment. Recent data have identified the concurrence of PIG-A mutations with additional genetic mutations associated with myeloproliferative disorders, suggesting that some presentations of PNH are the result of a stepwise progression of genetic mutations similar to other myelodysplastic or myeloproliferative syndromes. We report for the first time in the literature the development of clinically significant PNH in a patient with JAK2V617F-negative, CALR-positive essential thrombocythemia, providing further support to the hypothesis that the development of PNH is associated with the accumulation of multiple genetic mutations that create an intrinsic survival benefit for clonal expansion. This case study additionally highlights the utility of genomic testing in diagnosis and the understanding of disease progression in the clinical setting. PMID:27313483

  3. Correlation between JAK2 allele burden and pulmonary arterial hypertension and hematological parameters in Philadelphia negative JAK2 positive myeloproliferative neoplasms. An Egyptian experience.

    PubMed

    Mattar, Mervat M; Morad, Mohammed Abdel Kader; El Husseiny, Noha M; Ali, Noha H; El Demerdash, Doaa M

    2016-10-01

    Myeloproliferative neoplasms are characterized by a common stem cell-derived clonal proliferation, but are phenotypically diverse. JAK2 is mutated (V617F) in more than 90 % of patients with polycythemia vera (PV) and approximately 60 % of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). Pulmonary arterial hypertension (PAH) is a major complication of several hematological disorders. Chronic myeloproliferative disorders associated with PAH have been included in group five for which the etiology is unclear and/or multifactorial. The aim of this study is to screen Egyptian Philadelphia negative JAK2 positive myeloproliferative neoplasm patients for the presence of PAH and its correlation with JAK2 allele burden. We also made a review for correlation of JAK2 allele with hematological parameters comparing our results to others. We enrolled 60 patients with Philadelphia negative myeloproliferative neoplasms. All patients enrolled in the study were subjected to laboratory and imaging workup in the form of CBC, liver, kidney profile, bone marrow examination, abdominal ultrasonography, and transthoracic echocardiography. Our results revealed that 7 patients out of 60 (11.67 %) had pulmonary arterial hypertension, 3 patients with PMF, 2 patients with PRV, and 2 patients with ET, and its correlation with JAK2 allele burden was not statistically significant. Correlation analysis between JAK2 V617F allele burden and other parameters revealed: statistical significant correlation with age, HB, HCT, PLT, UA, LDH, and splenic diameter but insignificant correlation with WBCs and PAH. Pulmonary arterial hypertension prevalence in our study was 11.67 % and no significant correlation with JAK 2 allele burden. Our study is the largest one up to our knowledge that studies the association between its prevalence and JAK2 burden.

  4. JAK2 Exon 14 Deletion in Patients with Chronic Myeloproliferative Neoplasms

    PubMed Central

    Ma, Wanlong; Kantarjian, Hagop; Zhang, Xi; Wang, Xiuqiang; Zhang, Zhong; Yeh, Chen-Hsiung; O'Brien, Susan; Giles, Francis; Bruey, Jean Marie; Albitar, Maher

    2010-01-01

    Background The JAK2 V617F mutation in exon 14 is the most common mutation in chronic myeloproliferative neoplasms (MPNs); deletion of the entire exon 14 is rarely detected. In our previous study of >10,000 samples from patients with suspected MPNs tested for JAK2 mutations by reverse transcription-PCR (RT-PCR) with direct sequencing, complete deletion of exon 14 (Δexon14) constituted <1% of JAK2 mutations. This appears to be an alternative splicing mutation, not detectable with DNA-based testing. Methodology/Principal Findings We investigated the possibility that MPN patients may express the JAK2 Δexon14 at low levels (<15% of total transcript) not routinely detectable by RT-PCR with direct sequencing. Using a sensitive RT-PCR–based fluorescent fragment analysis method to quantify JAK2 Δexon14 mRNA expression relative to wild-type, we tested 61 patients with confirmed MPNs, 183 with suspected MPNs (93 V617F-positive, 90 V617F-negative), and 46 healthy control subjects. The Δexon14 variant was detected in 9 of the 61 (15%) confirmed MPN patients, accounting for 3.96% to 33.85% (mean  = 12.04%) of total JAK2 transcript. This variant was also detected in 51 of the 183 patients with suspected MPNs (27%), including 20 of the 93 (22%) with V617F (mean [range] expression  = 5.41% [2.13%–26.22%]) and 31 of the 90 (34%) without V617F (mean [range] expression  = 3.88% [2.08%–12.22%]). Immunoprecipitation studies demonstrated that patients expressing Δexon14 mRNA expressed a corresponding truncated JAK2 protein. The Δexon14 variant was not detected in the 46 control subjects. Conclusions/Significance These data suggest that expression of the JAK2 Δexon14 splice variant, leading to a truncated JAK2 protein, is common in patients with MPNs. This alternatively spliced transcript appears to be more frequent in MPN patients without V617F mutation, in whom it might contribute to leukemogenesis. This mutation is missed if DNA rather than RNA is used for

  5. Myelodysplastic/ Myeloproliferative Neoplasms Treatment

    MedlinePlus

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

  6. Germline and somatic JAK2 mutations and susceptibility to chronic myeloproliferative neoplasms

    PubMed Central

    2009-01-01

    Myeloproliferative neoplasms (MPNs) are a group of closely related stem-cell-derived clonal proliferative diseases. Most cases are sporadic but first-degree relatives of MPN patients have a five- to seven-fold increased risk for developing an MPN. The tumors of most patients carry a mutation in the Janus kinase 2 gene (JAK2V617F). Recently, three groups have described a strong association of JAK2 germline polymorphisms with MPN in patients positive for JAK2V617F. The somatic mutation occurs primarily on one particular germline JAK2 haplotype, which may account for as much as 50% of the risk to first-degree relatives. This finding provides new directions for unraveling the pathogenesis of MPN. PMID:19490586

  7. Myeloproliferative Neoplasms (MPNs) Patient Registry

    ClinicalTrials.gov

    2016-04-28

    Primary Myelofibrosis; Polycythemia Vera; Essential Thrombocythemia; Mastocytosis; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative; Leukemia, Myelomonocytic, Juvenile; Chronic Eosinophilic Leukemia-not Otherwise Specified; Myelodysplastic-Myeloproliferative Diseases; Neoplasms; Leukemia, Myelomonocytic, Chronic

  8. An addition to geographic hematology: chronic myeloproliferative diseases are infrequent in Mexican Mestizos.

    PubMed

    Ruiz-Argüelles, Guillermo J; López-Martínez, Briceida; Lobato-Mendizábal, Eduardo; Ruiz-Delgado, Guillermo J

    2002-06-01

    The chronic myeloproliferative diseases (CMPDs) include chronic myelogenous leukemia (CML), primary (essential) thrombocythemia (PT), agnogenic myeloid metaplasia (AMM), and polycythemia vera (PV). Certain hematological malignancies have a different prevalence in our country than in countries with Caucasian populations. Data indicate that the prevalence of CML in our country is similar to that found in Caucasians; however, the prevalence of the other CMPDs has not been studied. In a total of 8069 individuals studied between June 1983 and March 2001 in the Centro de Hematologia y Medicina Interna de Puebla, we assessed the prevalence of CML, PT, AMM, and PV. Some of the clinical features of these individuals were also assessed. Forty-nine patients with CML, 14 with PT, 7 with AMM, and 3 with PV were identified. The clinical presentations of these CMPDs were not different from those described in Caucasians. We found that CML was more than 3 times more frequent than PT, that both PV and AMM were exceptional, and that PT, AMM, and PV were significantly less frequent in Mexican than in Caucasian populations (P < .01).

  9. Molecular mimicry in the chronic myeloproliferative disorders: reciprocity between quantitative JAK2 V617F and Mpl expression

    PubMed Central

    Moliterno, Alison R.; Williams, Donna M.; Rogers, Ophelia; Spivak, Jerry L.

    2006-01-01

    An activating JAK2 mutation (JAK2 V617F) is present in the chronic myeloproliferative disorders (MPDs), polycythemia vera (PV), idiopathic myelofibrosis (IMF), and essential thrombocytosis (ET). JAK2 is also a chaperone for Mpl and responsible for its cell-surface expression. We observed a reciprocal relationship between neutrophil JAK2 V617F allele percentage and platelet Mpl expression in JAK2 V617F–positive PV, IMF, and ET patients. However, severely impaired platelet Mpl expression was present in JAK2 V617F–negative MPD patients. While JAK2 V617F allele status did not necessarily correlate with the clinical MPD phenotype, the degree of impaired platelet Mpl expression did. We conclude that multiple molecular abnormalities are involved in the pathogenesis of the MPDs and that aberrant Mpl expression may be a common denominator of aberrant signaling in both the JAK2 V617F–positive and JAK2 V617F–negative MPDs. PMID:16912229

  10. TNFα facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms

    PubMed Central

    Aichberger, Karl J.; Luty, Samuel B.; Bumm, Thomas G.; Petersen, Curtis L.; Doratotaj, Shirin; Vasudevan, Kavin B.; LaTocha, Dorian H.; Yang, Fei; Press, Richard D.; Loriaux, Marc M.; Pahl, Heike L.; Silver, Richard T.; Agarwal, Anupriya; O'Hare, Thomas; Druker, Brian J.; Bagby, Grover C.

    2011-01-01

    Proinflammatory cytokines such as TNFα are elevated in patients with myeloproliferative neoplasms (MPN), but their contribution to disease pathogenesis is unknown. Here we reveal a central role for TNFα in promoting clonal dominance of JAK2V617F expressing cells in MPN. We show that JAK2V617F kinase regulates TNFα expression in cell lines and primary MPN cells and TNFα expression is correlated with JAK2V617F allele burden. In clonogenic assays, normal controls show reduced colony formation in the presence of TNFα while colony formation by JAK2V617F-positive progenitor cells is resistant or stimulated by exposure to TNFα. Ectopic JAK2V617F expression confers TNFα resistance to normal murine progenitor cells and overcomes inherent TNFα hypersensitivity of Fanconi anemia complementation group C deficient progenitors. Lastly, absence of TNFα limits clonal expansion and attenuates disease in a murine model of JAK2V617F-positive MPN. Altogether our data are consistent with a model where JAK2V617F promotes clonal selection by conferring TNFα resistance to a preneoplastic TNFα sensitive cell, while simultaneously generating a TNFα-rich environment. Mutations that confer resistance to environmental stem cell stressors are a recognized mechanism of clonal selection and leukemogenesis in bone marrow failure syndromes and our data suggest that this mechanism is also critical to clonal selection in MPN. PMID:21860020

  11. Neutrophil extracellular trap formation and circulating nucleosomes in patients with chronic myeloproliferative neoplasms

    PubMed Central

    Marin Oyarzún, Cecilia P.; Carestia, Agostina; Lev, Paola R.; Glembotsky, Ana C.; Castro Ríos, Miguel A.; Moiraghi, Beatriz; Molinas, Felisa C.; Marta, Rosana F.; Schattner, Mirta; Heller, Paula G.

    2016-01-01

    The mechanisms underlying increased thrombotic risk in chronic myeloproliferative neoplasms (MPN) are incompletely understood. We assessed whether neutrophil extracellular traps (NETs), which promote thrombosis, contribute to the procoagulant state in essential thrombocythemia, polycythemia vera and myelofibrosis (MF) patients. Although MPN neutrophils showed increased basal reactive oxygen species (ROS), enhanced NETosis by unstimulated neutrophils was an infrequent finding, whereas PMA-triggered NETosis was impaired, particularly in MF, due to decreased PMA-triggered ROS production. Elevated circulating nucleosomes were a prominent finding and were higher in patients with advanced disease, which may have potential prognostic implication. Histone-MPO complexes, proposed as specific NET biomarker, were seldomly detected, suggesting NETs may not be the main source of nucleosomes in most patients, whereas their correlation with high LDH points to increased cell turn-over as a plausible origin. Lack of association of nucleosomes or NETs with thrombosis or activation markers does not support their use as predictors of thrombosis although prospective studies in a larger cohort may help define their potential contribution to MPN thrombosis. These results do not provide evidence for relevant in vivo NETosis in MPN patients under steady state conditions, although availability of standardized NET biomarkers may contribute to further research in this field. PMID:27958278

  12. Novel Insights into the Biology and Treatment of Chronic Myeloproliferative Neoplasms*

    PubMed Central

    Mughal, Tariq I.; Barbui, Tiziano; Abdel-Wahab, Omar; Kralovics, Robert; Jamieson, Catriona; Kvasnicka, Hans-Michael; Mullaly, Ann; Rampal, Raajit; Mesa, Ruben; Kiladjian, Jean-Jacques; Deininger, Michael; Prchal, Joseph; Hehlmann, Rüdiger; Saglio, Giuseppe; Van Etten, Richard A.

    2016-01-01

    Myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoiesis characterized by a high frequency of genetic alterations and include chronic myeloid leukemia (CML) and the BCR-ABL1-negative MPNs. Herein we summarize recent advances and controversies in our understanding of the biology and therapy of these disorders, as discussed at the 8th post-American Society of Hematology CML-MPN workshop. The principal areas addressed include the breakthrough discovery of CALR mutations in patients with JAK2/MPL wild type MPN, candidate therapies based on novel genetic findings in leukemic transformation and new therapeutic targets in MPNs, and an appraisal of bone marrow histopathology in MPNs with a focus on the potential new clinical entity of “ masked ” polycythemia vera. An update on clinical trials of Janus kinase (JAK) inhibitors is presented as well as current understanding regarding the definitions and mechanisms of resistance to JAK inhibitors, and updated information on the safety and efficacy of discontinuation of tyrosine kinase inhibitors in patients with CML. PMID:25330439

  13. The role of JAK1/2 inhibitors in the treatment of chronic myeloproliferative neoplasms.

    PubMed

    Keohane, Clodagh; Mesa, Ruben; Harrison, Claire

    2013-01-01

    In 2005, the description of the JAK2V617F mutation for the first time provided a molecular key to enable more rapid diagnosis and target for novel therapeutics in the myeloproliferative neoplasms. In 2007, the first-in-class agent INC18424, ruxolitinib, JAKafi, or JAKAVI was first tested in patients with intermediate-risk 2 or high-risk myelofibrosis regardless of whether they possessed the JAK2V617F mutation. Patients treated with this agent had major reduction in splenomegaly as well as impressive reduction, and in some cases resolution, of symptoms. This study was followed by the two Controlled Myelofibrosis Study with Oral JAK Inhibitor Therapy (COMFORT) trials (the first-ever phase III trials in myelofibrosis), which confirmed results in these aspects were superior to either placebo or standard care, and updated results show a survival advantage with this therapy. This paper discusses these results and data from other JAK inhibitors while speculating on the future of these therapies. It also reflects on the fact that the true targets and agents' mode of action are uncertain. Unlike targeted therapy for chronic myeloid leukemia (CML), these agents do not deliver molecular remission, and it is not clear whether their predominant benefit is mediated via JAK2, JAK1, or both. Nonetheless, the advent of the JAK inhibitor is a welcome advance and has made a dramatic improvement to the therapeutic landscape of these conditions.

  14. [Budd-Chiari syndrome associated with chronic myeloproliferative syndromes: analysis of 6 cases].

    PubMed

    Cobo, F; Cervantes, F; García-Pagán, J C; Bosch, J; Rozman, C; Montserrat, E

    1996-11-16

    The chronic myeloproliferative disorders (CMPD) are considered the main etiology of Budd-Chiari syndrome in Western countries. Moreover, an occult CMPD has been recently identified in most patients with idiopathic hepatic vein thrombosis. In order to determine the frequency of the association between the above entities and to analyze the clinical and hematologic features of such patients, fourteen cases of Budd-Chiari syndrome diagnosed at a single institution over a five year period were reviewed. In 6 patients a CMPD was identified, with this being the first cause of the syndrome. Median age of the later six patients was 32 years (range: 14-54), and 4 were females. In all cases the CMPD was suspected due to the presence of hematological abnormalities, including a high hematocrit (5 cases), leucocytosis (4 cases) and thrombocytosis (3 cases). Five patients had polycythemia vera (PV) and one idiopathic myelofibrosis. In an additional Budd-Chiari patient with polycythemia, PV was ruled out on the basis of high serum erythropoietin and the absence of endogenous growth of erythroid colonies in the hematopoietic progenitor culture. The CMPD treatment included phlebotomies and hydroxiurea, whereas the Budd-Chiari syndrome was treated in most patients with transjugular intrahepatic portosystemic stent-shunt. One patient died from a gastrointestinal hemorrhage at 48 months from Budd-Chiari diagnosis, and the remaining five are alive after a median follow-up of 28 months.

  15. Open Label, Phase II Study to Evaluate Efficacy and Safety of Oral Nilotinib in Philadelphia Positive (Ph+) Chronic Myelogenous Leukemia (CML) Pediatric Patients.

    ClinicalTrials.gov

    2017-03-20

    Leukemia; Leukemia,Pediatric; Leukemia, Myleiod; Leukemia, Mylegenous, Chronic; Leukemia, Mylegenous, Accelerated; BCR-ABL Positive; Myeloproliferative Disorder; Bone Marrow Disease; Hematologic Diseases; Neoplastic Processes; Imatinib; Dasatinib; Enzyme Inhibitor; Protein Kinase Inhibitor

  16. Telomere length is severely and similarly reduced in JAK2V617F-positive and -negative myeloproliferative neoplasms

    PubMed Central

    Bernard, L; Belisle, C; Mollica, L; Provost, S; Roy, D-C; Gilliland, DG; Levine, RL; Busque, L

    2015-01-01

    Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders characterized by chronic proliferation of hematopoietic progenitors. We studied the telomere length (TL) of 335 MPN patients and 93 gender- and age-matched controls using a quantitative PCR method (relative TL calculated as the ratio of the amount of telomere DNA vs single-copy DNA: T/S ratio). TL was markedly reduced in MPN patients compared with controls (T/S 0.561 vs 0.990, P<0.001). In JAK2V617F MPN patients, TL correlated inversely with allelic burden (P<0.001). Patients homozygous for the mutation (allelic burden 90–100%) had the shortest TL, even when compared with patients with lower allele burdens consistent with a dominant heterozygous population (allelic burden 55–65%) (T/S 0.367 vs 0.497, P = 0.037). This suggests that the high degree of proliferation of the MPN clone reduces TL and suggests the possibility that TL shortening may be indicative of progressive genomic instability during MPN progression. The TL of JAK2V617F-negative MPN patients was similar to JAK2V617F-positive counterparts (T/S 0.527 vs 0.507, P = 0.603), suggesting that the yet-to-be-discovered causative mutation(s) impact the mutated stem cell similarly to JAK2V617F, and that TL measurement may prove useful in the diagnostic workup of JAK2V617F-negative MPN. PMID:19005480

  17. Topotecan Hydrochloride and Carboplatin With or Without Veliparib in Treating Advanced Myeloproliferative Disorders and Acute Myeloid Leukemia or Chronic Myelomonocytic Leukemia

    ClinicalTrials.gov

    2017-09-21

    Acute Myeloid Leukemia; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Chronic Myelomonocytic Leukemia; Essential Thrombocythemia; Myelodysplastic/Myeloproliferative Neoplasm; Myelofibrosis; Polycythemia Vera; Recurrent Adult Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia

  18. Disruption of the estrogen receptor β gene in mice causes myeloproliferative disease resembling chronic myeloid leukemia with lymphoid blast crisis

    PubMed Central

    Shim, Gil-Jin; Wang, Ling; Andersson, Sandra; Nagy, Noémi; Kis, Loránd Levente; Zhang, Qinghong; Mäkelä, Sari; Warner, Margaret; Gustafsson, Jan-Åke

    2003-01-01

    Proliferation of pluripotent, bone marrow stem cells, which develop to lymphoid and myeloid progenitors, is negatively regulated by estrogen. Although in estrogen deficiency and in estrogen receptor knockout mice there is significant alteration in bone marrow hematopoiesis, the effects of aging on estrogen receptor deficiencies in mice have not been investigated yet. In this study we show that by 1.5 years of age, estrogen receptor β knockout (ERβ–/–) mice develop pronounced splenomegaly that is much more severe in females than in males. Further characterization of these mice revealed myelogenous hyperplasia in bone marrow, an increase in the number of granulocytes and B lymphocytes in blood, lymphadenopathy, and infiltration of leukocytes in the liver and lung. Analysis by flow cytometry of the bone marrow cells revealed that the percentage and total number of Gr-1hi/Mac-1hi-positive granulocytes were increased by 15–30% and 100%, respectively. The numbers of B cells in the bone marrow and spleen were significantly higher in ERβ–/– mice than in WT littermates. Some of the ERβ–/– mice also had a severe lymphoproliferative phenotype. Thus the absence of ERβ results in a myeloproliferative disease resembling human chronic myeloid leukemia with lymphoid blast crisis. Our results indicate a previously unknown role for ERβ in regulating the differentiation of pluripotent hematopoietic progenitor cells and suggest that the ERβ–/– mouse is a potential model for myeloid and lymphoid leukemia. Furthermore, we suggest that ERβ agonists might have clinical value in the treatment of leukemia. PMID:12740446

  19. Analyses of critical target cell responses during preclinical phases of evolving chronic radiation-induced myeloproliferative disease-exploitation of a unique canine model

    SciTech Connect

    Seed, T.M.; Kaspar, L.V.; Tolle, D.V.; Fritz, T.E.; Frazier, M.E.

    1988-01-01

    This document briefly summarizes and highlights ongoing studies on the cellular and molecular processes involved in the induction and progression of myeloid leukemia in dogs chronically exposed to low daily doses of wholebody gamma irradiation. Under such conditions, select groups of dogs exhibit extremely high frequencies of myeloproliferative disease (MPD) (i.e., /congruent/50%) of which myeloid leukemia is most prominent. 2 figs.

  20. GM-CSF Autoantibody-positive Pulmonary Alveolar Proteinosis with Simultaneous Myeloproliferative Neoplasm

    PubMed Central

    Imoto, Naoto; Harunori, Nakashima; Furukawa, Katsuya; Tange, Naoyuki; Murase, Atsushi; Hayakawa, Masaya; Ichihara, Masatoshi; Iwata, Yosuke; Kosugi, Hiroshi

    2017-01-01

    Pulmonary alveolar proteinosis (PAP) is classified as autoimmune, secondary, or genetic. We herein describe a 69-year-old man with autoimmune PAP, simultaneously diagnosed with myeloproliferative neoplasm (MPN). Two years after the diagnosis, the MPN progressed to acute myeloid leukemia, and the patient died from an alveolar hemorrhage during remission induction chemotherapy. Throughout the clinical course, no progression of PAP was observed, despite the progression to leukemia. There are few reports of autoimmune PAP with hematological malignancy, and this case demonstrated that an evaluation for GM-CSF autoantibodies is important for distinguishing the autoimmune and secondary forms of PAP, even if the patient has hematological malignancy. PMID:28202867

  1. Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable

    MedlinePlus

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

  2. Gender and Vascular Complications in the JAK2 V617F-Positive Myeloproliferative Neoplasms

    PubMed Central

    Stein, Brady L.; Rademaker, Alfred; Spivak, Jerry L.; Moliterno, Alison R.

    2011-01-01

    We previously found that gender influenced the JAK2 V617F allele burden, but it is unknown whether this gender difference in molecular epidemiology influences complications in the myeloproliferative neoplasms (MPNs). Historically, vascular complications represented the most common cause of mortality in polycythemia vera and essential thrombocytosis and contributed to morbidity in primary myelofibrosis. To determine the influence of gender on vascular complications, we retrospectively analyzed associations between gender and vascular complications. Despite their younger age, less prevalent dyslipidemia or smoking history, lower white blood counts, and lower JAK2 V617F allele burden, women had higher rates of abdominal venous thrombosis and comparable rates of all vascular complications. Vascular risk is currently not easily stratified by MPN-disease burden or traditional risk factors. Our analysis contributes to growing literature emphasizing gender differences in the MPN and further supports the important impact of individual and host variation on MPN clinical manifestations, and especially vascular risk. PMID:22084670

  3. [FIP1L1-PDGFRА-positive myeloproliferative disease with eosinophilia: A rare case with multiple organ dysfunction and a response to tyrosine kinase inhibitor therapy].

    PubMed

    Nemchenko, I S; Turkina, A G; Chelysheva, E Yu; Galstyan, G M; Kovrigina, A M; Khuazheva, N K; Savchenko, V G

    2015-01-01

    The described case of FIP1L1-PDGFRА-positive myeloproliferative disease is characterized by an atypical aggressive course to develop severe specific complications as injuries to the brain, heart, lung, and intestine. Pathogenetic therapy with imatinib could stabilize a patient's state, but failed to produce a complete hematological response. Switching from imatinib to dasatinib could produce sustained clinical, hematological, and molecular remissions.

  4. The Hepatocyte Growth Factor (HGF)/Met Axis: A Neglected Target in the Treatment of Chronic Myeloproliferative Neoplasms?

    PubMed Central

    Boissinot, Marjorie; Vilaine, Mathias; Hermouet, Sylvie

    2014-01-01

    Met is the receptor of hepatocyte growth factor (HGF), a cytoprotective cytokine. Disturbing the equilibrium between Met and its ligand may lead to inappropriate cell survival, accumulation of genetic abnormalities and eventually, malignancy. Abnormal activation of the HGF/Met axis is established in solid tumours and in chronic haematological malignancies, including myeloma, acute myeloid leukaemia, chronic myelogenous leukaemia (CML), and myeloproliferative neoplasms (MPNs). The molecular mechanisms potentially responsible for the abnormal activation of HGF/Met pathways are described and discussed. Importantly, inCML and in MPNs, the production of HGF is independent of Bcr-Abl and JAK2V617F, the main molecular markers of these diseases. In vitro studies showed that blocking HGF/Met function with neutralizing antibodies or Met inhibitors significantly impairs the growth of JAK2V617F-mutated cells. With personalised medicine and curative treatment in view, blocking activation of HGF/Met could be a useful addition in the treatment of CML and MPNs for those patients with high HGF/MET expression not controlled by current treatments (Bcr-Abl inhibitors in CML; phlebotomy, hydroxurea, JAK inhibitors in MPNs). PMID:25119536

  5. JAK2 V617F detected in two B-cell chronic lymphocytic leukemia patients without coexisting Philadelphia chromosome-negative myeloproliferative neoplasms: A report of two cases

    PubMed Central

    YANG, YI-NING; QIN, YOU-WEN; WANG, CHUN

    2014-01-01

    The JAK2 V617F mutation has been observed in patients with Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-MPNs), including polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis. This mutation has also been observed in a small number of other myeloid malignancies, such as acute myeloid leukemia, chronic myeloid leukemia and myelodysplastic syndrome. The JAK2 V617F allele has rarely been evaluated in lymphoproliferative disorders. In total, 28 JAK2 V617F-positive B-cell lymphocytic leukemia (B-CLL) patients have previously been reported and all presented with Ph-MPN concomitantly. However, following investigation of the JAK2 V617F mutation in 63 B-CLL patients at the Shanghai First People’s Hospital (Shanghai, China) between January 2008 and December 2012 via allele-specific polymerase chain reaction, two B-CLL patients without a history of Ph-MPN were identified to carry the JAK2 V617F allele. PMID:25013507

  6. Advances in the biology and therapy of chronic myeloid leukemia: proceedings from the 6th Post-ASH International Chronic Myeloid Leukemia and Myeloproliferative Neoplasms Workshop.

    PubMed

    Van Etten, Richard A; Mauro, Michael; Radich, Jerald P; Goldman, John M; Saglio, Giuseppe; Jamieson, Catriona; Soverini, Simona; Gambacorti-Passerini, Carlo; Hehlmann, Rüdiger; Martinelli, Giovanni; Perrotti, Danilo; Scadden, David T; Skorski, Tomasz; Tefferi, Ayalew; Mughal, Tariq I

    2013-06-01

    Following the 53rd annual meeting of the American Society of Hematology (ASH) in San Diego in December 2011, a group of clinical and laboratory investigators convened for the 6th Post-ASH International Workshop on Chronic Myeloid Leukemia (CML) and Myeloproliferative Neoplasms (MPN). The Workshop took place on 13-14 December at the Estancia, La Jolla, California, USA. This report summarizes the most recent advances in the biology and therapy of CML that were presented at the ASH meeting and discussed at the Workshop. Preclinical studies focused on the CML stem cell and its niche, and on early results of deep sequencing of CML genomes. Clinical advances include updates on second- and third-generation tyrosine kinase inhibitors (TKIs), molecular monitoring, TKI discontinuation studies and new therapeutic agents. A report summarizing the pertinent advances in MPN has been published separately.

  7. von Willebrand factor is the most reliable immunohistochemical marker for megakaryocytes of myelodysplastic syndrome and chronic myeloproliferative disorders.

    PubMed

    Chuang, S S; Jung, Y C; Li, C Y; Yung, Y C

    2000-04-01

    To find the best immunohistochemical marker for megakaryocytes in normal marrow, myelodysplastic syndrome (MDS), and chronic myeloproliferative disorders (CMPD), 57 marrow biopsy specimens were studied semiquantitatively with immunohistochemical methods using a panel of 7 antibodies. The staining intensity was graded 0 to 3 for scoring 100 consecutive megakaryocytes in each stained section. The final score for each stain was the sum of these 100 megakaryocytes individually multiplied by their corresponding grade. In normal marrow (11 cases), the average scores for antivon Willebrand factor (vWF) and Ulex europaeus agglutinin-1 (UEA-1) were 177.1 and 195.1, respectively. The scores for the other 5 markers, including anti-platelet-derived growth factor-BB, 2 anti-transforming growth factor-beta 3, anti-CD61, and anti-CD79a ranged from 96.1 to 124.1. In MDS (27 cases), the scores were 200.8 (vWF), 152.6 (UEA-1), and 28.7 to 98.5 (others). In CMPD (19 cases), the scores were 220.5 (vWF), 179.2 (UAE-1), and 64.8 to 101.2 (others). These results show that vWF and UEA-1 are good immunohistochemical markers for megakaryocytes in normal marrow, and vWF is the best marker in MDS and CMPD. For routine practice, vWF is the most reliable marker for identifying atypical megakaryocytes, especially in the cases of 5q-syndrome and agnogenic myeloid metaplasia.

  8. The Impact of Mean Platelet Volume (MPV) and JAK-2 Mutation on Thrombosis in Chronic Myeloproliferative Diseases.

    PubMed

    Ayer, Mesut; Menken, İlhan; Yamak, Mehmet; Ayer, Fatma Aylin; Kırkızlar, Onur; Burak Aktuğlu, M

    2017-06-01

    Thrombosis and bleeding are the main complications of chronic myeloproliferative diseases. Mean platelet volume (MPV) is an important indicator of the platelet activation. The aim of the present study was to assess the interrelationships between MPV, JAK-2 gene mutation and thromboembolic events in patients with ET and PV. Patients with ET (n = 60) and PV (n = 46) were compared to the secondary erythrocytosis group (n = 19); and a control group of age and sex matched healthy volunteers (n = 52). Besides demographic, clinical and laboratory data; thrombotic and hemorrhagic events were recorded for each patient. Platelet counts, MPV and JAK2 mutations were studied; and their relation with thromboembolic events were investigated using SPSS program for statistical analysis. There was no significant difference between groups regarding age (p = 0.188). Mean platelet count was significantly higher in ET group than other groups (p < 0.0001). Mean platelet count in PV group was significantly higher than control (p < 0.0001) and secondary erythrocytosis groups (p < 0.0001). In the ET group, MPV values were significantly lower than the control group and PV group. In the ET group, those with thromboembolia had lower platelet counts. There was no relation between MPV and thromboembolic event rate in PV, ET and secondary erithrocytosis groups; while no event was recorded in the control group. There was no relation between thromboembolic event rate and JAK 2 mutation. The association of JAK-2 mutation and high MPV especially in ET and PV groups does not contribute to the thromboembolic events.

  9. General Information about Myelodysplastic/Myeloproliferative Neoplasms

    MedlinePlus

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

  10. Treatment Options for Myelodysplastic/Myeloproliferative Neoplasms

    MedlinePlus

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

  11. Treatment Option Overview (Myelodysplastic/Myeloproliferative Neoplasms)

    MedlinePlus

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

  12. Nuclear magnetic resonance investigation of erythrocyte membranes in chronic myeloproliferative disorders.

    PubMed

    Morariu, V V; Petrov, L

    1986-07-01

    The temperature dependence of the apparent water diffusional exchange through erythrocyte membranes in cases of policitemia vera, chronic granulocytic leukemia and primary myelofibrosis was measured by using a nuclear magnetic resonance method in the presence of Mn2+. The thermal transition shifted to lower temperatures in all cases, regardless of the stage of the disease, suggesting a structural alteration of the membrane. The shift of transition indirectly suggests a lower penetration of the erythrocytes by Mn2+. The water exchange time at 37 degrees C also increased, mainly in the blast crisis; it seems to have a prognostic value of some clinical interest. No simple correlation of the water exchange and the following clinical investigations was observed: the white count, the percentage of promyelocites and myeloblasts, the sedimentation rate of blood, the osmotic fragility of erythrocytes, the total concentration of proteins, albumin and immunoglobulins, respectively, in plasma.

  13. The role of the JAK2 GGCC haplotype and the TET2 gene in familial myeloproliferative neoplasms

    PubMed Central

    Olcaydu, Damla; Rumi, Elisa; Harutyunyan, Ashot; Passamonti, Francesco; Pietra, Daniela; Pascutto, Cristiana; Berg, Tiina; Jäger, Roland; Hammond, Emma; Cazzola, Mario; Kralovics, Robert

    2011-01-01

    Background Myeloproliferative neoplasms constitute a group of diverse chronic myeloid malignancies that share pathogenic features such as acquired mutations in the JAK2, TET2, CBL and MPL genes. There are recent reports that a JAK2 gene haplotype (GGCC or 46/1) confers susceptibility to JAK2 mutation-positive myeloproliferative neoplasms. The aim of this study was to examine the role of the JAK2 GGCC haplotype and germline mutations of TET2, CBL and MPL in familial myeloproliferative neoplasms. Design and Methods We investigated patients with familial (n=88) or sporadic (n=684) myeloproliferative neoplasms, and a control population (n=203) from the same demographic area in Italy. Association analysis was performed using tagged single nucleotide polymorphisms (rs10974944 and rs12343867) of the JAK2 haplotype. Sequence analysis of TET2, CBL and MPL was conducted in the 88 patients with familial myeloproliferative neoplasms. Results Association analysis revealed no difference in haplotype frequency between familial and sporadic cases of myeloproliferative neoplasms (P=0.6529). No germline mutations in TET2, CBL or MPL that segregate with the disease phenotype were identified. As we observed variability in somatic mutations in the affected members of a pedigree with myeloproliferative neoplasms, we postulated that somatic mutagenesis is increased in familial myeloproliferative neoplasms. Accordingly, we compared the incidence of malignant disorders between sporadic and familial patients. Although the overall incidence of malignant disorders did not differ significantly between cases of familial and sporadic myeloproliferative neoplasms, malignancies were more frequent in patients with familial disease aged between 50 to 70 years (P=0.0198) than in patients in the same age range with sporadic myeloproliferative neoplasms. Conclusions We conclude that the JAK2 GGCC haplotype and germline mutations of TET2, CBL or MPL do not explain familial clustering of

  14. Association of Oesophageal Varices and Splanchnic Vein Thromboses in Patients with JAK2-Positive Myeloproliferative Neoplasms: Presentation of Two Cases and Data from a Retrospective Analysis

    PubMed Central

    Link, Cornelia S.; Platzbecker, Uwe; Kroschinsky, Frank; Pannach, Sven; Thiede, Christian; Platzek, Ivan; Ehninger, Gerhard; Schuler, Markus K.

    2013-01-01

    Background Oesophageal varices and gastrointestinal bleeding are common complications of liver cirrhosis. More rarely, oesophageal varices occur in patients with non-cirrhotic portal hypertension that results from thromboses of portal or splanchnic veins. Case Report We describe 2 young men who initially presented with varices as a result of portal vein thromboses. In the clinical follow-up, both were tested positive for a JAK2 mutation and consequently diagnosed with myeloproliferative neoplasms (MPNs). In an attempt to characterise the frequency of gastrointestinal complications in patients with JAK2-positive MPNs, we retrospectively analysed all known affected patients from our clinic for the diagnosis of portal vein thromboses and oesophageal varices. Strikingly, 48% of those who had received an oesophagogastroduodenoscopy had detectable oesophageal or gastric varices, and 82% of those suffered from portal or splanchnic vein thromboses. Conclusion While the association between JAK2, myeloproliferative disease and thrombotic events is well established, patients with idiopathic oesophageal varices are not regularly tested for JAK2 mutations. However, the occurrence of oesophageal varices may be the first presenting symptom of a MPN with a JAK2 mutation, and affected patients may profit from a close haematological monitoring to assure the early detection of developing MPN. PMID:23898274

  15. Myelodysplastic/ Myeloproliferative Neoplasms Treatment (PDQ®)—Health Professional Version

    Cancer.gov

    Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are composed of three major myeloid disorders: chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), and atypical chronic myeloid leukemia (aCML). Learn about the clinical features and treatment of these leukemias.

  16. Oncogenes in myeloproliferative disorders.

    PubMed

    Tefferi, Ayalew; Gilliland, D Gary

    2007-03-01

    Myeloproliferative disorders (MPDs) constitute a group of hematopoietic malignancies that feature enhanced proliferation and survival of one or more myeloid lineage cells. William Dameshek is credited for introducing the term "MPDs" in 1951 when he used it to group chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) under one clinicopathologic category. Since then, other myeloid neoplasms have been added to the MPD member list: chronic neutrophilic (CNL), eosinophilic (CEL) and myelomonocytic (CMML) leukemias; juvenile myelomonocytic leukemia (JMML); hypereosinophilic syndrome (HES); systemic mastocytosis (SM); and others. Collectively, MPDs are stem cell-derived clonal proliferative diseases whose shared and diverse phenotypic characteristics can be attributed to dysregulated signal transduction--a consequence of acquired somatic mutations. The most recognized among the latter is BCR-ABL, the disease-causing mutation in CML. Other mutations of putative pathogenetic relevance in MPDs include: JAK2V617F in PV, ET, and PMF; JAK2 exon 12 mutations in PV; MPLW515L/K in PMF and ET; KITD816V in SM; FIP1L1-PDGFRA in CEL-SM; rearrangements of PDGFRB in CEL-CMML and FGFR1 in stem cell leukemia-lymphoma syndrome; and RAS/PTPN11/NF1 mutations in JMML. This increasing repertoire of mutant molecules has streamlined translational research and molecularly targeted drug development in MPDs.

  17. Myeloproliferative disease in a cat

    SciTech Connect

    Yates, R.W.; Weller, R.E.; Feldman, B.F.

    1984-10-01

    Myeloproliferative disorders, a complex of cytologic abnormalities arising in the bone marrow, are among domestic animals most frequently recognized in cats but are relatively uncommon. A 4-year-old female Siamese, with splenomegaly and weight loss, was listless, anorectic, pale and dehydrated. A hemogram showed severe, macrocytic normochromic anemia, leukocytosis and reticulocytosis, with abnormally high numbers of nucleated RBC and undifferentiated blast cells. Bone marrow smears contained predominantly undifferentiated blast cells, RBC precursors and myeloblasts. The fluorescent antibody test for FeLV was positive. The cat died 66 days later despite a blood transfusion and chemotherapy. Necropsy confirmed a diagnosis of myeloproliferative disease, with hepatic and splenic invasion. 15 references, 5 figures, 1 table.

  18. TET2, ASXL1, IDH1, and IDH2 Single Nucleotide Polymorphisms in Turkish Patients with Chronic Myeloproliferative Neoplasms

    PubMed Central

    Soyer, Nur; Tezcanlı Kaymaz, Burçin; Cömert Özkan, Melda; Aktan, Çağdaş; Küçükaslan, Ali Şahin; Şahin, Fahri; Kosova, Buket; Saydam, Güray

    2017-01-01

    We aimed to determine the genotype distribution, allele frequency, and prognostic impact of IDH1/2, TET2, and ASXL1 single nucleotide polymorphisms (SNPs) in myeloproliferative neoplasms (MPNs). TET2 (rs763480), ASXL1 (rs2208131), and IDH1 (rs11554137) variant homozygous genotype frequencies were found at rates of 1.5%, 9.2%, and 2.3%, respectively. No IDH2 SNP was identified. IDH1 and TET2 frequencies were 5% in essential thrombocythemia (ET) and 1.7% in ET and 5% in primary myelofibrosis (PMF), respectively. ASXL1 frequencies were 8.3%-10% in MPN subgroups. The TET2 mutant allele T and ASXL1 mutant allele G had the highest frequencies with 0.272 in the PMF and 0.322 in the polycythemia vera (PV) group, respectively. There was no impact of the SNPs on prognosis. IDH1 frequency in MPNs was found similar to the literature. ASXL1 frequencies were similar between ET, PV, and PMF patients. The ASXL1 and TET2 allele frequencies of the Turkish population are similar to those of the European population. The role of SNPs in MPNs might be further evaluated in larger multicenter studies. PMID:28218607

  19. Eosinophilic Myeloproliferative Disorders

    PubMed Central

    Klion, Amy D.

    2014-01-01

    Despite recent attempts to define and classify patients with marked eosinophilia and features consistent with myeloproliferative disease, areas of controversy remain. These are particularly apparent in situations in which multiple lineages are involved in a clonal process and clinical manifestations are overlapping. Although the introduction of new molecular diagnostics and targeted therapies has begun to clarify the boundaries between some of these disorders, several questions remain with respect to the classification of patients with myeloproliferative hypereosinophilic syndrome (HES) of unknown etiology. PMID:22160043

  20. MMP2 gene-735 C/T and MMP9 gene -1562 C/T polymorphisms in JAK2V617F positive myeloproliferative disorders.

    PubMed

    Sag, Sebnem Ozemri; Gorukmez, Ozlem; Ture, Mehmet; Gorukmez, Orhan; Topak, Ali; Sahinturk, Serdar; Ocakoglu, Gokhan; Gulten, Tuna; Ali, Ridvan; Yakut, Tahsin

    2015-01-01

    Myeloproliferative disorders (MPDs) are clonal hematologic malignancies originating at the level of the pluripotent hematopoietic stem cell. Matrix metalloproteases (MMPs) are proteolytic enzymes that contribute to all stages of malignancy progression. Genetic variants in the MMP genes may influence the biological function of these enzymes and change their role in carcinogenesis and progression. To our knowledge, this is the first investigation of associations between the -735 C/T and -1562 C/T polymorphisms in the MMP2 and MMP9 genes, respectively, and the risk of essential thrombocytosis (ET), and polycythemia vera (PV). The case-control study included JAK2V617F mutation positive 102 ET and PV patients and 111 controls. Polymorphisms were determined by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and electrophoresis. No statistically significant differences were detected between patient (ET+PV) and control groups regarding genotype distribution for MMP2 gene-735 C/T and MMP9 gene -1562 C/T polymorphisms and C/T allele frequency (p>0.050). Statistically borderline significance was observed between PV and control groups regarding genotype distribution for the MMP9 gene -1562 C/T polymorphism (p=0.050, OR=2.26, 95%Cl=0.99-5.16). Consequently this study supported that CC genotype of MMP9 gene -1562 C/T polymorphism may be related with PV even if with borderline significance.

  1. A germline JAK2 SNP is associated with predisposition to the development of JAK2V617F-positive myeloproliferative neoplasms

    PubMed Central

    Kilpivaara, Outi; Mukherjee, Semanti; Schram, Alison M; Wadleigh, Martha; Mullally, Ann; Ebert, Benjamin L; Bass, Adam; Marubayashi, Sachie; Heguy, Adriana; Garcia-Manero, Guillermo; Kantarjian, Hagop; Offit, Kenneth; Stone, Richard M; Gilliland, D Gary; Klein, Robert J; Levine, Ross L

    2013-01-01

    Polycythemia vera, essential thrombocythemia and primary myelofibrosis are myeloproliferative neoplasms (MPN) characterized by multilineage clonal hematopoiesis1–5. Given that the identical somatic activating mutation in the JAK2 tyrosine kinase gene (JAK2V617F) is observed in most individuals with polycythemia vera, essential thrombocythemia and primary myelofibrosis6–10, there likely are additional genetic events that contribute to the pathogenesis of these phenotypically distinct disorders. Moreover, family members of individuals with MPN are at higher risk for the development of MPN, consistent with the existence of MPN predisposition loci11. We hypothesized that germline variation contributes to MPN predisposition and phenotypic pleiotropy. Genome-wide analysis identified an allele in the JAK2 locus (rs10974944) that predisposes to the development of JAK2V617F-positive MPN, as well as three previously unknown MPN modifier loci. We found that JAK2V617F is preferentially acquired in cis with the predisposition allele. These data suggest that germline variation is an important contributor to MPN phenotype and predisposition. PMID:19287384

  2. The hematopoietic stem cell compartment of JAK2V617F-positive myeloproliferative disorders is a reflection of disease heterogeneity.

    PubMed

    James, Chloe; Mazurier, Frederic; Dupont, Sabrina; Chaligne, Ronan; Lamrissi-Garcia, Isabelle; Tulliez, Micheline; Lippert, Eric; Mahon, François-Xavier; Pasquet, Jean-Max; Etienne, Gabriel; Delhommeau, François; Giraudier, Stephane; Vainchenker, William; de Verneuil, Hubert

    2008-09-15

    The JAK2V617F somatic point mutation has been described in patients with myeloproliferative disorders (MPDs). Despite this progress, it remains unknown how a single JAK2 mutation causes 3 different MPD phenotypes, polycythemia vera (PV), essential thrombocythemia, and primitive myelofibrosis (PMF). Using an in vivo xenotransplantation assay in nonobese diabetic-severe combined immunodeficient (NOD/SCID) mice, we tested whether disease heterogeneity was associated with quantitative or qualitative differences in the hematopoietic stem cell (HSC) compartment. We show that the HSC compartment of PV and PMF patients contains JAK2V617F-positive long-term, multipotent, and self-renewing cells. However, the proportion of JAK2V617F and JAK2 wild-type SCID repopulating cells was dramatically different in these diseases, without major modifications of the self-renewal and proliferation capacities for JAK2V617F SCID repopulating cells. These experiments provide new insights into the pathogenesis of JAK2V617F MPD and demonstrate that a JAK2 inhibitor needs to target the HSC compartment for optimal disease control in classical MPD.

  3. 3-AP and Fludarabine in Treating Patients With Myeloproliferative Disorders, Chronic Myelomonocytic Leukemia, or Accelerated Phase or Blastic Phase Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2014-12-16

    Accelerated Phase Chronic Myelogenous Leukemia; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Essential Thrombocythemia; Philadelphia Chromosome Negative Chronic Myelogenous Leukemia; Polycythemia Vera; Primary Myelofibrosis; Relapsing Chronic Myelogenous Leukemia

  4. A Phase I Study of Topotecan, Carboplatin and the PARP Inhibitor Veliparib in Acute Leukemias, Aggressive Myeloproliferative Neoplasms, and Chronic Myelomonocytic Leukemia.

    PubMed

    Pratz, Keith W; Rudek, Michelle A; Gojo, Ivana; Litzow, Mark R; McDevitt, Michael A; Ji, Jiuping; Karnitz, Larry M; Herman, James G; Kinders, Robert J; Smith, B Douglas; Gore, Steven D; Carraway, Hetty E; Showel, Margaret M; Gladstone, Douglas E; Levis, Mark J; Tsai, Hua-Ling; Rosner, Gary; Chen, Alice; Kaufmann, Scott H; Karp, Judith E

    2017-02-15

    Purpose: The PARP inhibitor veliparib delays DNA repair and potentiates cytotoxicity of multiple classes of chemotherapy drugs, including topoisomerase I inhibitors and platinating agents. This study evaluated veliparib incorporation into leukemia induction therapy using a previously described topotecan/carboplatin backbone.Experimental Design: Employing a 3+3 trial design, we administered escalating doses of veliparib combined with topotecan + carboplatin in relapsed or refractory acute leukemias, aggressive myeloproliferative neoplasms (MPN), and chronic myelomonocytic leukemia (CMML).Results: A total of 99 patients received veliparib 10-100 mg orally twice daily on days 1-8, 1-14, or 1-21 along with continuous infusion topotecan 1.0-1.2 mg/m(2)/d + carboplatin 120-150 mg/m(2)/d on days 3-7. The MTD was veliparib 80 mg twice daily for up to 21 days with topotecan 1.2 mg/m(2)/d + carboplatin 150 mg/m(2)/d. Mucositis was dose limiting and correlated with high veliparib concentrations. The response rate was 33% overall (33/99: 14 CR, 11 CRi, 8 PR) but was 64% (14/22) for patients with antecedent or associated aggressive MPNs or CMML. Leukemias with baseline DNA repair defects, as evidenced by impaired DNA damage-induced FANCD2 monoubiquitination, had improved survival [HR = 0.56 (95% confidence interval, 0.27-0.92)]. A single 80-mg dose of veliparib, as well as veliparib in combination with topotecan + carboplatin, induced DNA damage as manifested by histone H2AX phosphorylation in CD34(+) leukemia cells, with greater phosphorylation in cells from responders.Conclusions: The veliparib/topotecan/carboplatin combination warrants further investigation, particularly in patients with aggressive MPNs, CMML, and MPN- or CMML-related acute leukemias. Clin Cancer Res; 23(4); 899-907. ©2016 AACR. ©2016 American Association for Cancer Research.

  5. Telomere shortening in Ph-negative chronic myeloproliferative neoplasms: a biological marker of polycythemia vera and myelofibrosis, regardless of hydroxycarbamide therapy.

    PubMed

    Ruella, Marco; Salmoiraghi, Silvia; Risso, Alessandra; Carobbio, Alessandra; Buttiglieri, Stefano; Spatola, Tiziana; Sivera, Piera; Ricca, Irene; Barbui, Tiziano; Tarella, Corrado; Rambaldi, Alessandro

    2013-07-01

    The purpose of this study was to investigate telomere length (TL) in Ph-negative chronic myeloproliferative neoplasms (Ph-neg-CMNs), and the possible association of TL with disease progression and hydroxycarbamide (HU) treatment. TL was analyzed in peripheral blood samples from 239 patients with Ph-neg-CMNs, including polycythemia vera (PV), essential thrombocythemia and myelofibrosis (MF), and compared with age-matched healthy control subjects (CTR), along with some cases of secondary erythrocytosis (SE). More than half of the patients with CMN received at least 1 year of cytoreduction, mainly HU, before TL analysis. JAK2 mutation analysis was performed as well. TL was significantly shortened in patients with CMN compared with CTR (p < 0.0001). PV and MF showed the most pronounced decrease (p < 0.0001), whereas both essential thrombocythemia and SE showed no significant difference in TL compared with CTR. A short TL correlated with JAK2-V617F allele burden greater than 50% (p = 0.0025), age (p = 0.0132) and diagnosis of PV (p = 0.0122). No correlation was found with disease duration, history of thrombosis, cytoreductive treatment, antiaggregation agents, adverse cytogenetics, phlebotomies, or time to evolution to MF. In summary, TL is distinctly shortened in PV and MF, and it inversely correlates with JAK2V617F allele burden. In addition, HU is unlikely to contribute to telomere erosion. Lastly, PV and SE significantly differ in TL. Therefore, TL could be an additional diagnostic marker to identify and monitor Ph-neg-CMN patients.

  6. IRS2 silencing increases apoptosis and potentiates the effects of ruxolitinib in JAK2V617F-positive myeloproliferative neoplasms

    PubMed Central

    de Melo Campos, Paula; Machado-Neto, João A.; Eide, Christopher A.; Savage, Samantha L.; Scopim-Ribeiro, Renata; da Silva Souza Duarte, Adriana; Favaro, Patricia; Lorand-Metze, Irene; Costa, Fernando F.; Tognon, Cristina E.; Druker, Brian J.; Saad, Sara T. Olalla; Traina, Fabiola

    2016-01-01

    The recurrent V617F mutation in JAK2 (JAK2V617F) has emerged as the primary contributor to the pathogenesis of myeloproliferative neoplasms (MPN). However, the lack of complete response in most patients treated with the JAK1/2 inhibitor, ruxolitinib, indicates the need for identifying pathways that cooperate with JAK2. Activated JAK2 was found to be associated with the insulin receptor substrate 2 (IRS2) in non-hematological cells. We identified JAK2/IRS2 binding in JAK2V617F HEL cells, but not in the JAK2WT U937 cell line. In HEL cells, IRS2 silencing decreased STAT5 phosphorylation, reduced cell viability and increased apoptosis; these effects were enhanced when IRS2 silencing was combined with ruxolitinib. In U937 cells, IRS2 silencing neither reduced cell viability nor induced apoptosis. IRS1/2 pharmacological inhibition in primary MPN samples reduced cell viability in JAK2V617F-positive but not JAK2WT specimens; combination with ruxolitinib had additive effects. IRS2 expression was significantly higher in CD34+ cells from essential thrombocythemia patients compared to healthy donors, and in JAK2V617F MPN patients when compared to JAK2WT. Our data indicate that IRS2 is a binding partner of JAK2V617F in MPN. IRS2 contributes to increased cell viability and reduced apoptosis in JAK2-mutated cells. Combined pharmacological inhibition of IRS2 and JAK2 may have a potential clinical application in MPN. PMID:26755644

  7. A novel assay to detect calreticulin mutations in myeloproliferative neoplasms

    PubMed Central

    Rosso, Valentina; Petiti, Jessica; Bracco, Enrico; Pedrola, Roberto; Carnuccio, Francesca; Signorino, Elisabetta; Carturan, Sonia; Calabrese, Chiara; Bot-Sartor, Giada; Ronconi, Michela; Serra, Anna; Saglio, Giuseppe; Frassoni, Francesco; Cilloni, Daniela

    2017-01-01

    The myeloproliferative neoplasms are chronic myeloid cancers divided in Philadelphia positive (Ph+), chronic myeloid leukemia, or negative: polycythemia vera (PV) essential thrombocythemia (ET), and primary myelofibrosis (PMF). Most Ph negative cases have an activating JAK2 or MPL mutation. Recently, somatic mutations in the calreticulin gene (CALR) were detected in 56–88% of JAK2/MPL-negative patients affected by ET or PMF. The most frequent mutations in CARL gene are type-1 and 2. Currently, CALR mutations are evaluated by sanger sequencing. The evaluation of CARL mutations increases the diagnostic accuracy in patients without other molecular markers and could represent a new therapeutic target for molecular drugs. We developed a novel detection assay in order to identify type-1 and 2 CALR mutations by PNA directed PCR clamping. Seventy-five patients affected by myeloproliferative neoplasms and seven controls were examined by direct DNA sequencing and by PNA directed PCR clamping. The assay resulted to be more sensitive, specific and cheaper than sanger sequencing and it could be applied even in laboratory not equipped for more sophisticated analysis. Interestingly, we report here a case carrying both type 1 and type2 mutations in CALR gene. PMID:28031530

  8. Imaging features of myeloproliferative neoplasms.

    PubMed

    Murphy, I G; Mitchell, E L; Raso-Barnett, L; Godfrey, A L; Godfrey, E M

    2017-10-01

    Myeloproliferative neoplasms (MPNs) are a heterogeneous group of haematological disorders including polycythaemia vera (PV), essential thrombocythaemia (ET), primary myelofibrosis (PMF), and chronic myeloid leukaemia (CML). These disorders show large overlap in genetic and clinical presentations, and can have many different imaging manifestations. Unusual thromboses, embolic events throughout the systemic or pulmonary vasculature, or osseous findings can often be clues to the underlying disease. There is limited literature about the imaging features of these disorders, and this may result in under-diagnosis. Multiple treatments are available for symptom control, and the development of multiple new pharmacological inhibitors has significantly improved morbidity and prognosis. Knowledge of these conditions may enable the radiologist to suggest an MPN as a possible underlying cause for certain imaging findings, particularly unexplained splanchnic venous thrombosis, i.e. in the absence of chronic liver disease or pancreatitis. The aim of the present review is to outline using examples the different categories of MPN and illustrate the variety of radiological findings associated with these diseases. Copyright © 2017 The Royal College of Radiologists. All rights reserved.

  9. Myeloproliferative neoplasm stem cells.

    PubMed

    Mead, Adam J; Mullally, Ann

    2017-03-23

    Myeloproliferative neoplasms (MPNs) arise in the hematopoietic stem cell (HSC) compartment as a result of the acquisition of somatic mutations in a single HSC that provides a selective advantage to mutant HSC over normal HSC and promotes myeloid differentiation to engender a myeloproliferative phenotype. This population of somatically mutated HSC, which initiates and sustains MPNs, is termed MPN stem cells. In >95% of cases, mutations that drive the development of an MPN phenotype occur in a mutually exclusive manner in 1 of 3 genes: JAK2, CALR, or MPL The thrombopoietin receptor, MPL, is the key cytokine receptor in MPN development, and these mutations all activate MPL-JAK-STAT signaling in MPN stem cells. Despite common biological features, MPNs display diverse disease phenotypes as a result of both constitutional and acquired factors that influence MPN stem cells, and likely also as a result of heterogeneity in the HSC in which MPN-initiating mutations arise. As the MPN clone expands, it exerts cell-extrinsic effects on components of the bone marrow niche that can favor the survival and expansion of MPN stem cells over normal HSC, further sustaining and driving malignant hematopoiesis. Although developed as targeted therapies for MPNs, current JAK2 inhibitors do not preferentially target MPN stem cells, and as a result, rarely induce molecular remissions in MPN patients. As the understanding of the molecular mechanisms underlying the clonal dominance of MPN stem cells advances, this will help facilitate the development of therapies that preferentially target MPN stem cells over normal HSC.

  10. Thrombocytosis associated with a myeloproliferative disorder in a dog

    SciTech Connect

    Degen, M.A.; Feldman, B.F.; Turrel, J.M.; Goding, B.; Kitchell, B.; Mandell, C.P. )

    1989-05-15

    A dog with a myeloproliferative disorder and thrombocytosis had clinical signs that were consistent with a diagnosis of essential thrombocythemia. The dog was treated with aspirin, radioactive phosphorus, and melphalan. Eighteen months after referral, the disorder progressed to chronic granulocytic leukemia, and treatment was switched to hydroxyurea. Fourteen months later, the dog was euthanatized because of uncontrollable atrial fibrillation.

  11. Chronic Wasting Disease Positive Tissue Bank

    USGS Publications Warehouse

    Wright, Scott D.

    2007-01-01

    In 2005, the USGS National Wildlife Health Center entered into an agreement with the Wyoming Game and Fish Department and the Department of Veterinary Sciences at the University of Wyoming to produce a collection of positive tissues from cervids intentionally infected with chronic wasting disease. This agreement was facilitated through the University of Wyoming Cooperative Fish and Wildlife Unit. Also, the investigators on this project sampled the animals incrementally over 2 years to show changes over time, and examined tissues from the animals by immunohistochemistry. CWD positive tissues are catalogued by species, sample site and time of infection. These data and more will soon be published.

  12. Myeloproliferative Neoplasms in Children

    PubMed Central

    Hofmann, Inga

    2015-01-01

    Myeloproliferative neoplasms (MPN) are a group of clonal hematopoietic stem cell disorders characterized by aberrant proliferation of one or more myeloid lineages often with increased immature cells in the peripheral blood. The three classical BCR-ABL-negative MPNs are: 1) polycythemia vera (PV), 2) essential thrombocythemia (ET), and 3) primary myelofibrosis (PMF), which are typically disorders of older adults and are exceedingly rare in children. The diagnostic criteria for MPNs remain largely defined by clinical, laboratory and histopathology assessments in adults, but they have been applied to the pediatric population. The discovery of the JAK2 V617F mutation, and more recently, MPL and CALR mutations, are major landmarks in the understanding of MPNs. Nevertheless, they rarely occur in children, posing a significant diagnostic challenge given the lack of an objective, clonal marker. Therefore, in pediatric patients, the diagnosis must rely heavily on clinical and laboratory factors, and exclusion of secondary disorders to make an accurate diagnosis of MPN. This review focuses on the clinical presentation, diagnostic work up, differential diagnosis, treatment and prognosis of the classical BCR-ABL-negative MPNs (PV, ET and PMF) in children and highlights key differences to the adult diseases. Particular attention will be given to pediatric PMF, as it is the only disorder of this group that is observed in infants and young children, and in many ways appears to be a unique entity compared to adult PMF. PMID:26609329

  13. Genomics of Myeloproliferative Neoplasms.

    PubMed

    Zoi, Katerina; Cross, Nicholas C P

    2017-03-20

    Myeloproliferative neoplasms (MPNs) are a group of related clonal hematologic disorders characterized by excess accumulation of one or more myeloid cell lineages and a tendency to transform to acute myeloid leukemia. Deregulated JAK2 signaling has emerged as the central phenotypic driver of BCR -ABL1-negative MPNs and a unifying therapeutic target. In addition, MPNs show unexpected layers of genetic complexity, with multiple abnormalities associated with disease progression, interactions between inherited factors and phenotype driver mutations, and effects related to the order in which mutations are acquired. Although morphology and clinical laboratory analysis continue to play an important role in defining these conditions, genomic analysis is providing a platform for better disease definition, more accurate diagnosis, direction of therapy, and refined prognostication. There is an emerging consensus with regard to many prognostic factors, but there is a clear need to synthesize genomic findings into robust, clinically actionable and widely accepted scoring systems as well as the need to standardize the laboratory methodologies that are used.

  14. Enhancing Targeted Therapy for Myeloproliferative Neoplasms

    DTIC Science & Technology

    2013-10-01

    Myeloproliferative Neoplasms PRINCIPAL INVESTIGATOR: Gary W. Reuther CONTRACTING...2. REPORT TYPE Annual 3. DATES COVERED 30 2012-2 2013 4. TITLE AND SUBTITLE Enhancing Targeted Therapy for Myeloproliferative Neoplasms ...AVAILABILITY STATEMENT Approved for Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Myeloproliferative neoplasms

  15. Enhancing Targeted Therapy for Myeloproliferative Neoplasms

    DTIC Science & Technology

    2014-12-01

    1 AWARD NUMBER: W81XWH-12-1-0450 TITLE: Enhancing Targeted Therapy for Myeloproliferative Neoplasms PRINCIPAL...TYPE Final 3. DATES COVERED 30 Sep 2012 - 29 Sep 20144 4. TITLE AND SUBTITLE Enhancing Targeted Therapy for Myeloproliferative Neoplasms ... Myeloproliferative neoplasms (MPNs) are blood cancers that affect almost 300,000 people in the United States. MPN drugs (JAK inhibitors) do not effectively

  16. [Utility of bone marrow biopsy in the diagnosis of myeloproliferative neoplasm].

    PubMed

    Tovar-Bobadilla, José Leonard; Ortiz-Hidalgo, Carlos

    2016-01-01

    A diagnostic approach of myeloproliferative neoplasms, according to the 2008 WHO classification system for hematological malignancies, has to consider clinical, molecular, and cytogenetic information as well as bone marrow histology. A diagnosis of chronic myeloid leukemia requires the presence of BCR-ABL-1, and the Philadelphia chromosome-negative (Ph-1-negative) myeloproliferative neoplasms constitute three main subtypes, including primary myelofibrosis, polycythemia rubra vera, and essential thrombocythemia. These three Ph-1-negative myeloproliferative neoplasms share many pathogenic characteristic such as JAK2 mutations; however, they differ in prognosis, progression to myelofibrosis, and risk of leukemic transformation. There are currently various major points of interest in bone marrow examination in myeloproliferative neoplasms. One is the morphology of megakaryocytes, which are the hallmark of Ph-1-negative myeloproliferative neoplasms and play a crucial role in separating the different subtypes of myeloproliferative neoplasms. Another is reticulin fibrosis or collagen fibrosis, which may only be detected on a bone marrow biopsy specimen by reticulin and trichrome stains, respectively, and immunohistochemistry and certain molecular techniques may be applied in bone marrow biopsies as supporting evidence of certain features of myeloproliferative neoplasms.

  17. Drugs Approved for Myeloproliferative Neoplasms

    Cancer.gov

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for myeloproliferative neoplasms. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters. The drug names link to NCI's Cancer Drug Information summaries.

  18. Clinical management of myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes

    PubMed Central

    Clara, Joseph A.; Sallman, David A.; Padron, Eric

    2016-01-01

    The myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) are a unique group of hematologic malignancies characterized by concomitant myelodysplastic and myeloproliferative features. According to the 2008 WHO classification, the category includes atypical chronic myeloid leukemia (aCML), chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), MDS/MPN-unclassifiable (MDS/MPN-U), and the provisional entity refractory anemia with ring sideroblasts and thrombocytosis (RARS-T). Although diagnosis currently remains based on clinicopathologic features, the incorporation of next-generation platforms has allowed for the recent molecular characterization of these diseases which has revealed unique and complex mutational profiles that support their distinct biology and is anticipated to soon play an integral role in diagnosis, prognostication, and treatment. Future goals of research should include the development of disease-modifying therapies, and further genetic understanding of the category will likely form the foundation of these efforts. PMID:27807503

  19. Calreticulin Exon 9 Mutations in Myeloproliferative Neoplasms

    PubMed Central

    Kim, Yu-Kyung

    2015-01-01

    Background Calreticulin (CALR) mutations were recently discovered in patients with myeloproliferative neoplasms (MPNs). We studied the frequency and type of CALR mutations and their hematological characteristics. Methods A total of 168 MPN patients (36 polycythemia vera [PV], 114 essential thrombocythemia [ET], and 18 primary myelofibrosis [PMF] cases) were included in the study. CALR mutation was analyzed by the direct sequencing method. Results CALR mutations were detected in 21.9% of ET and 16.7% of PMF patients, which accounted for 58.5% and 33.3% of ET and PMF patients without Janus kinase 2 (JAK2) or myeloproliferative leukemia virus oncogenes (MPL) mutations, respectively. A total of five types of mutation were detected, among which, L367fs*46 (53.6%) and K385fs*47 (35.7%) were found to be the most common. ET patients with CALR mutation had lower leukocyte counts and ages compared with JAK2-mutated ET patients. Conclusion Genotyping for CALR could be a useful diagnostic tool for JAK2-or MPL-negative ET or PMF patients. CALR mutation may be a distinct disease group, with different hematological characteristics than that of JAK2-positive patients. PMID:25553276

  20. Prospect of JAK2 inhibitor therapy in myeloproliferative neoplasms

    PubMed Central

    Atallah, Ehab; Verstovsek, Srdan

    2016-01-01

    The discovery of the Janus kinase (JAK)2 V617F mutation in patients with myeloproliferative neoplasms was a major milestone in understanding the biology of those disorders. Several groups simultaneously reported on the high incidence of this mutation in patients with myeloproliferative neoplasms: almost all patients with polycythemia vera harbor the mutation and about 50% of patients with essential thrombocythemia and primary myelofibrosis have the mutation, making the development of JAK2 tyrosine kinase inhibitors an attractive therapeutic goal. In addition, inhibition of JAK2 kinase may have a therapeutic role in other hematologic malignancies, such as chronic myeloid leukemia or lymphoma. A number of molecules that inhibit JAK2 kinase have been described in the literature, and several are being evaluated in a clinical setting. Here, we summarize current clinical experience with JAK2 inhibitors. PMID:19445582

  1. Reclaiming a Positive Identity in Chronic Illness through Artistic Occupation.

    ERIC Educational Resources Information Center

    Reynolds, Frances

    2003-01-01

    A study of 10 chronically ill women showed how they positively reconstructed self and identity through engaging in textile artwork. Findings suggest that meaningful artistic occupation may provide a source of positive identity for people with chronic illness. (Contains 24 references.) (JOW)

  2. Incidence and patient survival of myeloproliferative neoplasms and myelodysplastic/myeloproliferative neoplasms in the United States, 2001-2012

    PubMed Central

    Srour, Samer A.; Devesa, Susan S.; Morton, Lindsay M.; Check, David P.; Curtis, Rochelle E.; Linet, Martha S.; Dores, Graça M.

    2016-01-01

    Summary Descriptive epidemiological information on myeloproliferative neoplasms (MPNs) and myelodysplastic (MDS)/MPNs is largely derived from single institution and European population-based studies. Data obtained following adoption of the World Health Organization classification of haematopoietic neoplasms and JAK2 V617F mutation testing are sparse. Using population-based data, we comprehensively assessed subtype-specific MPN and MDS/MPN incidence rates (IRs), IR ratios (IRRs) and relative survival (RS) in the United States (2001-2012). IRs were highest for polycythaemia vera (PV) (IR=10.9) and essential thrombocythaemia (ET) (IR=9.6). Except for ET and mastocytosis, overall IRs were significantly higher among males (IRRs=1.4-2.3). All evaluable MPNs were associated with lower IRs among Hispanic whites than non-Hispanic whites (NHWs), with the exception of BCR-ABL1-positive chronic myeloid leukaemia (CML), chronic eosinophilic leukaemia (CEL) and juvenile myelomonocytic leukaemia. Except for CEL, Asians/Pacific Islanders had significantly lower MPN IRs than NHWs. ET, MPN-unclassifiable and CEL IRs were 18%, 19% and 60% higher, respectively, among blacks than NHWs. Five-year RS was more favourable for younger (<60 years) than older individuals and for women compared with men, except for PV at older ages. RS was highest (>90%) for younger PV and ET patients and lowest (<20%) for older chronic myelomonocytic leukaemia and atypical BCR-ABL1-negative CML patients. Varying MPN and MDS/MPN incidence patterns by subtype support distinct aetiologies and/or susceptible populations. Decreased survival rates as compared to that expected in the general population were associated with every MPN subtype, highlighting the need for new treatments, particularly among older individuals. PMID:27061824

  3. The Role of MicroRNAs in Myeloproliferative Neoplasia

    PubMed Central

    Alizadeh, Shaban; Azizi, Seyed Ghader; Soleimani, Masoud; Farshi, Yadollah; Kashani Khatib, Zahra

    2016-01-01

    MiRs are 17-25 nucleotide non-coding RNAs. These RNAs target approximately 80% of protein coding mRNAs. MiRs control gene expression and altered expression of them affects the development of cancer. MiRs can function as tumor suppressor via down-regulation of proto-oncogenes and may function as oncogenes by suppressing tumor suppressors. Myeloproliferative neoplasias (formerly known as chronic myeloproliferative disorders) form a class of hematologic malignancies demonstrating the expansion of stem cells in one or more hematopoietic cell lines. CML results from an acquired translocation known as BCR-ABL (Philadelphia chromosome). JAK2V617F mutation is present in over 95% of PV, 55% of ET and 65% of PMF cases. Aberrant expression of miR is associated with myeloproliferative neoplasias, pathogenesis, disease progress and response to treatment. MiRs can also be potential therapeutic targets. CML is mainly treated by tyrosine kinase inhibitors such as Imatinib. In addition, altered function of miRs may be used as a prognostic factor in treatment. Resistance to Imatinib is currently a major clinical problem. The role of a number of miRs has been demonstrated in this resistance. Changing expression pattern of miRs can be effective in response to treatment and inhibition of drug resistance. In this paper, we set out to evaluate the effect of miRs in pathogenesis and treatment of MPN. PMID:27489593

  4. Transition Planning for Students with Chronic Health Conditions. Position Statement

    ERIC Educational Resources Information Center

    Baszler, Rita; Rochkes, Laura; Dolatowski, Rosemary; Mendes, Irene; Yow, Barbara; Butler, Sarah; Fekaris, Nina

    2014-01-01

    It is the position of the National Association of School Nurses (NASN) that all children with chronic health conditions should receive coordinated and deliberate transition planning to maximize lifelong functioning and well-being. Transition planning refers to a coordinated set of activities to assist students with chronic health conditions to…

  5. Myelodysplasia and myeloproliferative disorders in children.

    PubMed

    McKenna, Robert W

    2004-12-01

    Myelodysplastic syndromes (MDSs) are uncommon in pediatric patients; they account for less than 10% of hematopoietic malignancies. In about one third of children with MDSs there is a predisposing genetic condition. MDS in children is more difficult to classify using criteria applied to cases in adult populations, and there are often features present that bridge those of MDS and chronic myeloproliferative diseases. Two groups of MDSs are found in children: juvenile myelomonocytic leukemia, which is unique to infants and young children, and adult-type MDS. A high percentage of children with MDS have bone marrow cytogenetic abnormalities; monosomy 7 is the most common. Patients less than 1 year of age at diagnosis have a significantly better survival than older children. A low platelet count, elevated hemoglobin F (>15%), and complex cytogenetic abnormalities are unfavorable prognostic indicators. MDSs must be distinguished from the same nonneoplastic causes of myelodysplasia that occur in adults, but in addition there are a number of congenital disorders of hematopoiesis and inherited metabolic diseases that affect hematopoiesis in children.

  6. Chronic Health Conditions Managed by School Nurses. Position Statement. Revised

    ERIC Educational Resources Information Center

    Morgitan, Judith; Bushmiaer, Margo; DeSisto, Marie C.; Duff, Carolyn; Lambert, C. Patrice; Murphy, M. Kathleen; Roland, Sharon; Selser, Kendra; Wyckoff, Leah; White, Kelly

    2012-01-01

    It is the position of the National Association of School Nurses that students with chronic health conditions have access to a full-time registered professional school nurse (hereinafter referred to as school nurse). School districts should include school nurse positions in their full-time instructional support personnel to provide health services…

  7. JAK2V617F somatic mutation in the general population: myeloproliferative neoplasm development and progression rate

    PubMed Central

    Nielsen, Camilla; Bojesen, Stig E.; Nordestgaard, Børge G.; Kofoed, Klaus F.; Birgens, Henrik S.

    2014-01-01

    Clinical significance of the JAK2V617F mutation in patients with a myeloproliferative neoplasm has been the target of intensive research in recent years. However, there is considerably uncertainty about prognosis in JAK2V617F positive individuals without overt signs of myeloproliferative disease. In this study, we tested the hypothesis that increased JAK2V617F somatic mutation burden is associated with myeloproliferative neoplasm progression rate in the general population. Among 49,488 individuals from the Copenhagen General Population Study, 63 (0.1%) tested positive for the JAK2V617F mutation in the time period 2003–2008. Of these, 48 were available for re-examination in 2012. Level of JAK2V617F mutation burden was associated with myeloproliferative neoplasm progression rate, consistent with a biological continuum of increasing JAK2V617F mutation burden across increasing severity of myeloproliferative neoplasm from no disease (n=8 at re-examination) through essential thrombocythemia (n=20) and polycythemia vera (n=13) to primary myelofibrosis (n=7). Among those diagnosed with a myeloproliferative neoplasm only at re-examination in 2012, in the preceding years JAK2V617F mutation burden increased by 0.55% per year, erythrocyte volume fraction increased by 1.19% per year, and erythrocyte mean corpuscular volume increased by 1.25% per year, while there was no change in platelet count or erythropoietin levels. Furthermore, we established a JAK2V617F mutation burden cut-off point of 2% indicative of disease versus no disease; however, individuals with a mutation burden below 2% may suffer from a latent form of myeloproliferative disease revealed by a slightly larger spleen and/or slightly higher lactic acid dehydrogenase concentration compared to controls. Of all 63 JAK2V617F positive individuals, 48 were eventually diagnosed with a myeloproliferative neoplasm. PMID:24907356

  8. Molecular diagnostics of myeloproliferative neoplasms.

    PubMed

    Langabeer, Stephen E; Andrikovics, Hajnalka; Asp, Julia; Bellosillo, Beatriz; Carillo, Serge; Haslam, Karl; Kjaer, Lasse; Lippert, Eric; Mansier, Olivier; Oppliger Leibundgut, Elisabeth; Percy, Melanie J; Porret, Naomi; Palmqvist, Lars; Schwarz, Jiri; McMullin, Mary F; Schnittger, Susanne; Pallisgaard, Niels; Hermouet, Sylvie

    2015-10-01

    Since the discovery of the JAK2 V617F mutation in the majority of the myeloproliferative neoplasms (MPN) of polycythemia vera, essential thrombocythemia and primary myelofibrosis ten years ago, further MPN-specific mutational events, notably in JAK2 exon 12, MPL exon 10 and CALR exon 9 have been identified. These discoveries have been rapidly incorporated into evolving molecular diagnostic algorithms. Whilst many of these mutations appear to have prognostic implications, establishing MPN diagnosis is of immediate clinical importance with selection, implementation and the continual evaluation of the appropriate laboratory methodology to achieve this diagnosis similarly vital. The advantages and limitations of these approaches in identifying and quantitating the common MPN-associated mutations are considered herein with particular regard to their clinical utility. The evolution of molecular diagnostic applications and platforms has occurred in parallel with the discovery of MPN-associated mutations, and it therefore appears likely that emerging technologies such as next-generation sequencing and digital PCR will in the future play an increasing role in the molecular diagnosis of MPN.

  9. Inherited predisposition to myeloproliferative neoplasms

    PubMed Central

    Jones, Amy V.

    2013-01-01

    Myeloproliferative neoplasms (MPNs) are haematological disorders characterized by an overproduction of mature myeloid cells with a tendency to transform to acute myeloid leukaemia. Clonal proliferation of myeloid progenitor cells is driven by somatically acquired mutations, most notably JAK2 V617F, but there are important features relating to pathogenesis and phenotypic diversity that cannot be explained by acquired mutations alone. In this review we consider what is currently known about the role that inherited factors play in the development and biology of both sporadic and familial forms of MPN. Although most MPN cases appear to be sporadic, familial predisposition has been recognized for many years in a subset of cases and epidemiological studies have indicated the presence of common susceptibility alleles. Currently the JAK2 46/1 haplotype (also referred to as ‘GGCC’) is the strongest known predisposition factor for sporadic MPNs carrying a JAK2 V617F mutation, explaining a large proportion of the heritability of this disorder. Less is known about what genetic variants predispose to MPNs that lack JAK2 V617F, but there have been recent reports of interesting associations in biologically plausible candidates, and more loci are set to emerge with the application of systematic genome-wide association methodologies. Several highly penetrant predisposition variants that affect erythropoietin signalling, thrombopoietin signalling or oxygen sensing have been characterized in families with nonclonal hereditary erythrocytosis or thrombocytosis, but much less is known about familial predisposition to true clonal MPN. The heterogeneous pattern of inheritance and presumed genetic heterogeneity in these families makes analysis difficult, but whole exome or genome sequencing should provide novel insights into these elusive disorders. PMID:23926457

  10. Global coagulation in myeloproliferative neoplasms.

    PubMed

    Tripodi, Armando; Chantarangkul, Veena; Gianniello, Francesca; Clerici, Marigrazia; Lemma, Laura; Padovan, Lidia; Gatti, Loredana; Mannucci, Pier Mannuccio; Peyvandi, Flora

    2013-12-01

    In spite of their recognized risk of thrombosis, patients with myeloproliferative neoplasms (MPN) show little or no abnormalities of traditional coagulation tests, perhaps because these are unable to represent the balance between pro- and anticoagulants nor the effect of platelets and blood cells. We investigated whether global tests such as thrombin generation in platelet-rich plasma (PRP) or thromboelastometry in whole blood were able to detect signs of procoagulant imbalance in MPN. The endogenous thrombin potential (ETP) of 111 patients and 89 controls was measured in PRP with platelet count adjusted to the original patient- or control-count. Testing was performed with and without thrombomodulin (the physiological protein C activator) and results were expressed as ETP ratios (with/without thrombomodulin). High ETP ratios reflect resistance to thrombomodulin and were taken as indexes of procoagulant imbalance. Patients were also investigated by thromboelastometry that provides such parameters as the clot formation time (CFT) and maximal clot firmness (MCF). Short CFT or high MCF were taken as indexes of procoagulant imbalance. ETP ratios were higher in patients than in controls and were directly correlated with platelet counts and inversely with the plasma levels of free protein S, protein C and antithrombin. Patients on hydroxyurea had lower ETP ratios than those on other treatments. CFT was shorter and MCF was greater in patients than controls; CFT and MCF were correlated with platelet counts. In conclusion, patients with MPN display a procoagulant imbalance detectable by thrombin generation and thromboelastometry. These tests might be useful in the frame of clinical trials to assess their association with the occurrence of thrombosis and with the effect of therapeutic strategies in MPN.

  11. Calreticulin Mutations in Myeloproliferative Neoplasms

    PubMed Central

    Lavi, Noa

    2014-01-01

    With the discovery of the JAK2V617F mutation in patients with Philadelphia chromosome-negative (Ph−) myeloproliferative neoplasms (MPNs) in 2005, major advances have been made in the diagnosis of MPNs, in understanding of their pathogenesis involving the JAK/STAT pathway, and finally in the development of novel therapies targeting this pathway. Nevertheless, it remains unknown which mutations exist in approximately one-third of patients with non-mutated JAK2 or MPL essential thrombocythemia (ET) and primary myelofibrosis (PMF). At the end of 2013, two studies identified recurrent mutations in the gene encoding calreticulin (CALR) using whole-exome sequencing. These mutations were revealed in the majority of ET and PMF patients with non-mutated JAK2 or MPL but not in polycythemia vera patients. Somatic 52-bp deletions (type 1 mutations) and recurrent 5-bp insertions (type 2 mutations) in exon 9 of the CALR gene (the last exon encoding the C-terminal amino acids of the protein calreticulin) were detected and found always to generate frameshift mutations. All detected mutant calreticulin proteins shared a novel amino acid sequence at the C-terminal. Mutations in CALR are acquired early in the clonal history of the disease, and they cause activation of JAK/STAT signaling. The CALR mutations are the second most frequent mutations in Ph− MPN patients after the JAK2V617F mutation, and their detection has significantly improved the diagnostic approach for ET and PMF. The characteristics of the CALR mutations as well as their diagnostic, clinical, and pathogenesis implications are discussed in this review. PMID:25386351

  12. The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos.

    PubMed

    Tefferi, Ayalew; Thiele, Juergen; Vardiman, James W

    2009-09-01

    The first formal classification of chronic myeloid neoplasms is credited to William Dameshek, who in 1951 described the concept of "myeloproliferative disorders (MPD)" by grouping together chronic myelogenous leukemia, polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The 2001 World Health Organization (WHO) classification of myeloid malignancies included these MPDs under the broader category of chronic myeloproliferative diseases (CMPD), which also included chronic neutrophilic leukemia, chronic eosinophilic leukemia/hypereosinophilic syndrome (CEL/HES), and "CMPD, unclassifiable." The revised 2008 WHO classification system featured the following changes: 1) the term "CMPD" was replaced by "myeloproliferative neoplasm (MPN)," 2) mast cell disease was formally included under the category of MPN, and 3) the subcategory of CEL/HES was reorganized into "CEL not otherwise specified (CEL-NOS)" and "myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1"; CEL-NOS remained a subcategory of "MPN," whereas the latter neoplasms were now assigned a new category of their own. Furthermore, diagnostic criteria for PV, ET, and PMF were revised by incorporating recently described molecular markers (eg, JAK2 and MPL mutations) as well as underscoring the role of histology in differentiating reactive from clonal myeloproliferations. As a result, red cell mass measurement is no longer necessary for the diagnosis of PV, and ET can now be diagnosed at a lower platelet count threshold. The revised WHO document continues to promote the recognition of histologic categories as a necessary first step toward the genetic characterization of myeloid malignancies.

  13. 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

  14. Obesity and related risk of myeloproliferative neoplasms among israeli adolescents.

    PubMed

    Leiba, Adi; Duek, Adrian; Afek, Arnon; Derazne, Estela; Leiba, Merav

    2017-07-01

    Obesity has been associated with various malignancies, but a clear association between overweight and myeloproliferative neoplasms (MPN) has not been established. This study assessed the association between adolescent obesity and future risk for MPN. Data on 2,516,256 Israeli adolescents, who underwent a compulsory general health examination at ages 16 to 19, between 1967 and 2011, were linked to the National Cancer Registry in this nationwide, population-based cohort study. Cox proportional hazards models were used to estimate the hazard ratio (HR) for MPN associated with BMI measured at adolescence. The mean follow-up of 19.86 ± 12.15 years reflected 49,977,521 person years, during which 433 examinees developed MPN, primarily chronic myelogenous leukemia, polycythemia vera, and essential thrombocythemia. Obesity (BMI ≥ 95th percentile) in adolescence significantly predicted increased risk of MPN with HR (adjusted for sex) of 1.81 (95% confidence interval 1.13-2.92, P = 0.014). Adolescent obesity might be related to an increased incidence of myeloproliferative neoplasms. © 2017 The Obesity Society.

  15. Hematopoietic Neoplasias in Horses: Myeloproliferative and Lymphoproliferative Disorders

    PubMed Central

    MUÑOZ, Ana; RIBER, Cristina; TRIGO, Pablo; CASTEJÓN, Francisco

    2010-01-01

    Leukemia, i.e., the neoplasia of one or more cell lines of the bone marrow, although less common than in other species, it is also reported in horses. Leukemia can be classified according to the affected cells (myeloproliferative or lymphoproliferative disorders), evolution of clinical signs (acute or chronic) and the presence or lack of abnormal cells in peripheral blood (leukemic, subleukemic and aleukemic leukemia). The main myeloproliferative disorders in horses are malignant histiocytosis and myeloid leukemia, the latter being classified as monocytic and myelomonocytic, granulocytic, primary erythrocytosis or polycythemia vera and megakaryocytic leukemia. The most common lymphoproliferative disorders in horses are lymphoid leukemia, plasma cell or multiple myeloma and lymphoma. Lymphoma is the most common hematopoietic neoplasia in horses and usually involves lymphoid organs, without leukemia, although bone marrow may be affected after metastasis. Lymphoma could be classified according to the organs involved and four main clinical categories have been established: generalized-multicentric, alimentary-gastrointestinal, mediastinal-thymic-thoracic and cutaneous. The clinical signs, hematological and clinical pathological findings, results of bone marrow aspirates, involvement of other organs, prognosis and treatment, if applicable, are presented for each type of neoplasia. This paper aims to provide a guide for equine practitioners when approaching to clinical cases with suspicion of hematopoietic neoplasia. PMID:24833969

  16. Ptch2 loss drives myeloproliferation and myeloproliferative neoplasm progression

    PubMed Central

    Klein, Claudius; Zwick, Anabel; Kissel, Sandra; Forster, Christine Ulrike; Pfeifer, Dietmar; Follo, Marie; Illert, Anna Lena; Decker, Sarah; Benkler, Thomas; Pahl, Heike; Oostendorp, Robert A.J.; Aumann, Konrad; Duyster, Justus

    2016-01-01

    JAK2V617F+ myeloproliferative neoplasms (MPNs) frequently progress into leukemias, but the factors driving this process are not understood. Here, we find excess Hedgehog (HH) ligand secretion and loss of PTCH2 in myeloproliferative disease, which drives canonical and noncanonical HH-signaling. Interestingly, Ptch2−/− mice mimic dual pathway activation and develop a MPN-phenotype with leukocytosis (neutrophils and monocytes), strong progenitor and LKS mobilization, splenomegaly, anemia, and loss of lymphoid lineages. HSCs exhibit increased cell cycling with improved stress hematopoiesis after 5-FU treatment, and this results in HSC exhaustion over time. Cytopenias, LKS loss, and mobilization are all caused by loss of Ptch2 in the niche, whereas hematopoietic loss of Ptch2 drives leukocytosis and promotes LKS maintenance and replating capacity in vitro. Ptch2−/− niche cells show hyperactive noncanonical HH signaling, resulting in reduced production of essential HSC regulators (Scf, Cxcl12, and Jag1) and depletion of osteoblasts. Interestingly, Ptch2 loss in either the niche or in hematopoietic cells dramatically accelerated human JAK2V617F-driven pathogenesis, causing transformation of nonlethal chronic MPNs into aggressive lethal leukemias with >30% blasts in the peripheral blood. Our findings suggest HH ligand inhibitors as possible drug candidates that act on hematopoiesis and the niche to prevent transformation of MPNs into leukemias. PMID:26834157

  17. Treatment for Chronic Pain in Patients With Advanced Cancer

    ClinicalTrials.gov

    2016-11-25

    Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Pain; Precancerous/Nonmalignant Condition; Small Intestine Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  18. A phase II trial of sequential ribonucleotide reductase inhibition in aggressive myeloproliferative neoplasms

    PubMed Central

    Zeidner, Joshua F.; Karp, Judith E.; Blackford, Amanda L.; Smith, B. Douglas; Gojo, Ivana; Gore, Steven D.; Levis, Mark J.; Carraway, Hetty E.; Greer, Jacqueline M.; Ivy, S. Percy; Pratz, Keith W.; McDevitt, Michael A.

    2014-01-01

    Myeloproliferative neoplasms are a varied group of disorders that can have prolonged chronic phases, but eventually accelerate and can transform into a secondary acute myeloid leukemia that is ultimately fatal. Triapine is a novel inhibitor of the M2 subunit of ribonucleotide reductase. Sequential inhibition of ribonucleotide reductase with triapine and an M1 ribonucleotide reductase inhibitor (fludarabine) was noted to be safe, and led to a 29% complete plus partial response rate in myeloproliferative neoplasms. This article reports the findings of a phase II trial of triapine (105 mg/m2/day) followed by fludarabine (30 mg/m2/day) daily for 5 consecutive days in 37 patients with accelerated myeloproliferative neoplasms and secondary acute myeloid leukemia. The overall response rate was 49% (18/37), with a complete remission rate of 24% (9/37). Overall response rates and complete remissions were seen in all disease subsets, including secondary acute myeloid leukemia, in which the overall response rate and complete remission rate were 48% and 33%, respectively. All patients with known JAK2 V617F mutations (6/6) responded. The median overall survival of the entire cohort was 6.9 months, with a median overall survival of both overall responders and complete responders of 10.6 months. These data further demonstrate the promise of sequential inhibition of ribonucleotide reductase in patients with accelerated myeloproliferative neoplasms and secondary acute myeloid leukemia. This study was registered with clinicaltrials.gov (NCT00381550). PMID:24362550

  19. Chronic pain and the adaptive significance of positive emotions.

    PubMed

    Ong, Anthony D; Zautra, Alex J; Reid, M Carrington

    2015-04-01

    The February-March 2014 special issue of the American Psychologist featured articles summarizing select contributions from the field of psychology to the assessment and treatment of chronic pain. The articles examined a range of psychosocial and family factors that influence individual adjustment and contribute to disparities in pain care. The reviews also considered the psychological correlates and neurophysiological mechanisms of specific pain treatments, including cognitive-behavioral therapy, hypnosis, acceptance and commitment therapy, mindfulness, and meditation. Although a number of articles emphasized the role that negative states of mind play in pain outcomes, positive emotions were given only brief mention. Here, we provide a rationale for the inclusion of positive emotions in chronic pain research.

  20. [Pathogenesis of thrombotic and hemorrhagic complications in myeloproliferative and myelodysplastic syndromes].

    PubMed

    Vlădăreanu, Ana-Maria; Popov, Viola; Bumbea, H; Ciufu, Cristina; Vasilache, Veronica; Petre, Anca; Onisâi, Minodora

    2011-01-01

    Chronic myeloproliferative disorders (CMD) and Myelodisplastic Syndromes (MDS) represents a group of clonal pluripotent stem-cell pathologies. During their natural history, the clinical picture reveals both thrombosis and hemorrhage. The thrombosis could affect the microvessels, and also the large vessels, including even less usual territories (suprahepatic veins, porta vein, pulmonary vein). There are many factors contributing to thrombosis in myeloproliferative chronic disorders--the associated comorbidities, the numeric alterations of blood elements and also the disorders of the platelet's function. Thus, there were described quantitative and qualitative anomalies of platelet's receptors: GP Ib, GP IIb/IIIa, GP IV, GP VI, thrombopoietin receptor of the platelet cMPL, the increase of platelet activation; the increase of P selectin and thrombospondin and the increase on GP IIb/IIIa expression--they were all correlated with thrombosis. An important role has been attributed to JAK2 mutation, which affects the platelet receptor for thrombopoietin cMPL. Regarding the hemorrhage in chronic myeloproliferative syndrome, it is favored by many disorders in platelet's function, such as: the decrease of von Willebrand factor's receptor of the platelet, which leads to acquired Bernard Soulier syndrome; quantitative and qualitative disorders of dense granules of the platelet, decrease of the secretion and platelet aggregation after epinephrine, ADP and collagen stimulation. It was also described the acquired von Willebrand syndrome, most frequently type 2.

  1. Atypical Chronic Myelogenous Leukemia

    MedlinePlus

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

  2. 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

    2017-09-01

    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

  3. Diagnosis of vitamin B12 deficiency in patients with myeloproliferative disorders.

    PubMed

    Cinemre, Hakan; Serinkan Cinemre, Behice F; Çekdemir, Demet; Aydemir, Birsen; Tamer, Ali; Yazar, Hayrullah

    2015-04-01

    Myeloproliferative disorders are characterized by proliferation of 1 or more lineage of hematologic cells. Rapid proliferation of cells may lead to depletion of vitamin B12, which may be falsely elevated by conventional assays in these disorders. We evaluated vitamin B12 status with conventional vitamin B12 assay and levels of serum methylmalonic acid (MMA), serum holotranscobalamin (holoTC), and plasma homocysteine in myeloproliferative disorders. In 58 patients who had myeloproliferative disorders and normal serum creatinine levels, we measured levels of vitamin B12, MMA, holoTC, and homocysteine. Correlations were evaluated between these tests, with MMA as the reference standard for vitamin B12 deficiency. Prevalence of vitamin B12 deficiency was 69%, despite high serum vitamin B12 levels. Levels of holoTC of 40.6 pmol/L or less and homocysteine of greater than 14 mol/L were the best cutoff levels with sensitivity values of 75% and 70%, specificity values of 80% and 68%, and positive predictive values of 88% and 80%. Logistic regression showed that cutoff values of holoTC of 40.6 pmol/L or less and homocysteine of greater than 14 mol/L resulted in odds ratio 15.5 for low versus high holoTC, and odds ratio 5.4 for high versus low homocysteine, to confirm vitamin B12 deficiency. Patients who had myeloproliferative disorders had a high prevalence of vitamin B12 deficiency, despite high serum vitamin B12 levels. Therefore, vitamin B12 status should be evaluated in patients with myeloproliferative disorders. Holotranscobalamin level may be the best initial test and may replace vitamin B12 assay to accompany MMA and homocysteine levels.

  4. JAK2 Allele Burden in the Myeloproliferative Neoplasms: Effects on Phenotype, Prognosis and Change with Treatment

    PubMed Central

    Vannucchi, Alessandro M.; Pieri, Lisa; Guglielmelli, Paola

    2011-01-01

    The field of Philadelphia-chromosome-negative chronic myeloproliferative neoplasms (MPNs) has recently witnessed tremendous advances in the basic knowledge of disease pathophysiology that followed the identification of mutations in JAK2 and MPL. These discoveries led to a revision of the criteria employed for diagnosis by the World Health Organization. The prognostic role of the JAK2V617F mutation and of its allelic burden has been the objective of intensive research using a variety of cellular and animal models as well as in large series of patients. While a definitive position cannot yet been taken on all of the issues, there is a consensus that the presence of higher V617F allele burden, that is on the basis of a stronger activation of intracellular signalling pathways, is associated with the clinical phenotype of polycythemia vera and with defined haematological and clinical markers indicative of a more aggressive phenotype. On the other hand, a low allele burden in myelofibrosis is associated with reduced survival. Finally, a significant reduction of JAK2 V617F allele burden has been demonstrated in patients treated with interferon, while the effects of novel JAK1 and JAK2 inhibitors have not yet been fully ascertained. PMID:23556073

  5. Myeloproliferative neoplasms: A decade of discoveries and treatment advances.

    PubMed

    Tefferi, Ayalew

    2016-01-01

    Myeloproliferative neoplasms (MPN) are clonal stem cell diseases, first conceptualized in 1951 by William Dameshek, and historically included chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). In 1960, Nowell and Hungerford discovered an invariable association between the Philadelphia chromosome (subsequently shown to harbor the causal BCR-ABL1 mutation) and CML; accordingly, the term MPN is primarily reserved for PV, ET, and PMF, although it includes other related clinicopathologic entities, according to the World Health Organization (WHO) classification system. In 2005, William Vainchenker and others described a Janus kinase 2 mutation (JAK2V617F) in MPN and this was followed by a series of additional descriptions of mutations that directly or indirectly activate JAK-STAT: JAK2 exon 12, myeloproliferative leukemia virus oncogene (MPL) and calreticulin (CALR) mutations. The discovery of these, mostly mutually exclusive, "driver" mutations has contributed to revisions of the WHO diagnostic criteria and risk stratification in MPN. Mutations other than JAK2, CALR and MPL have also been described in MPN and shown to provide additional prognostic information. From the standpoint of treatment, over the last 50 years, Louis Wasserman from the Unites States and Tiziano Barbui from Italy had skillfully organized and led a number of important clinical trials, whose results form the basis for current treatment strategies in MPN. More recently, allogeneic stem cell transplant, as a potentially curative treatment modality, and JAK inhibitors, as palliative drugs, have been added to the overall therapeutic armamentarium in myelofibrosis. In the current review, I will summarize the important advances made in the last 10 years regarding the science and practice of MPN.

  6. Noninvasive Positive Pressure Ventilation in Chronic Heart Failure

    PubMed Central

    Han, Yi

    2016-01-01

    Instruction and Objectives. Noninvasive positive pressure ventilation (NPPV) alleviates sleep-disordered breathing (SDB) and it may improve cardiac function in SDB patients. Because large randomized controlled trials directly evaluating the impact of NPPV on cardiac function are lacking, we conducted a meta-analysis of published data on effectiveness of NPPV in improving cardiac function in patients with chronic heart failure regardless of SDB presence. Methods. Controlled trials were identified in PubMed, OVID, and EMBASE databases. Both fixed and randomized models were used in meta-analysis with primary outcomes of left ventricular ejection fraction (LVEF). Results. Nineteen studies were included with a total of 843 patients. Compared to standard medical treatment (SMT) plus sham-NPPV or SMT only, NPPV plus SMT was associated with improvement in LVEF (weighted mean difference 5.34, 95% CI, [3.85,6.82]; P < 0.00001) and plasma brain natriuretic peptide (BNP) level (weighted mean difference −117.37, 95% CI, [−227.22, −7.52]; P = 0.04) and no influence on overall mortality (RR 1.00, 95% CI, [0.96,1.04]; P = 0.95). Conclusions. In the present meta-analysis, use of NPPV plus SMT improved LVEF and reduced plasma BNP level but did not improve overall mortality in patients with chronic heart failure. PMID:27891061

  7. An International MDS/MPN Working Group’s perspective and recommendations on molecular pathogenesis, diagnosis and clinical characterization of myelodysplastic/myeloproliferative neoplasms

    PubMed Central

    Mughal, Tariq I.; Cross, Nicholas C.P.; Padron, Eric; Tiu, Ramon V.; Savona, Michael; Malcovati, Luca; Tibes, Raoul; Komrokji, Rami S.; Kiladjian, Jean-Jacques; Garcia-Manero, Guillermo; Orazi, Attilio; Mesa, Ruben; Maciejewski, Jaroslaw P.; Fenaux, Pierre; Itzykson, Raphael; Mufti, Ghulam; Solary, Eric; List, Alan F.

    2015-01-01

    In the 2008 WHO classification, chronic myeloid malignancies that share both myelodysplastic and myeloproliferative features define the myelodysplastic/myeloproliferative group, which includes chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, atypical chronic myeloid leukemia, refractory anemia with ring sideroblasts and thrombocytosis, and myelodysplastic/myeloproliferative unclassified. With the notable exception of refractory anemia with ring sideroblasts and thrombocytosis, there is much overlap among the various subtypes at the molecular and clinical levels, and a better definition of these entities, an understanding of their biology and an identification of subtype-specific molecular or cellular markers are needed. To address some of these challenges, a panel comprised of laboratory and clinical experts in myelodysplastic/myeloproliferative was established, and four independent academic MDS/MPN workshops were held on: 9th March 2013, in Miami, Florida, USA; 6th December 2013, in New Orleans, Louisiana, USA; 13th June 2014 in Milan, Italy; and 5th December 2014 in San Francisco, USA. During these meetings, the current understanding of these malignancies and matters of biology, diagnosis and management were discussed. This perspective and the recommendations on molecular pathogenesis, diagnosis and clinical characterization for adult onset myelodysplastic/myeloproliferative is the result of a collaborative project endorsed and supported by the MDS Foundation. PMID:26341525

  8. Early relapse of JAK2 V617F-positive chronic neutrophilic leukemia with central nervous system infiltration after unrelated bone marrow transplantation.

    PubMed

    Kako, Shinichi; Kanda, Yoshinobu; Sato, Tomohiko; Goyama, Susumu; Noda, Naohiro; Shoda, Eriko; Oshima, Kumi; Inoue, Morihiro; Izutsu, Koji; Watanabe, Takuro; Motokura, Toru; Chiba, Shigeru; Fukayama, Masashi; Kurokawa, Mineo

    2007-05-01

    Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative disorder characterized by a proliferation mainly of mature neutrophils. The prognosis is generally poor and an optimal therapeutic strategy remains to be determined. Allogeneic hematopoietic stem cell transplantation (HSCT) is expected to be the only curative therapy so far. We report a 46-year-old male with progressive CNL who underwent bone marrow transplantation from an HLA-matched unrelated donor. After engraftment was achieved on day 35, relapse of CNL was confirmed on day 50. The progression of CNL was very rapid afterward and infiltration to the central nervous system was observed. The Janus Kinase 2 (JAK2) V617F homozygous mutation was detected from the peripheral blood or bone marrow samples throughout the clinical course. From comparison with reports of successful HSCT for CNL in the literature, it was inferred that HSCT should be performed in a stable status before progression. Furthermore, JAK2 V617F-positive CNL may contain an aggressive disease entity in contrast to previous reports. Accumulation of experiences is required to establish a definite role of HSCT in the treatment of CNL and a prognostic significance of JAK2 mutation in CNL.

  9. Therapeutic plateletpheresis in a case of symptomatic thrombocytosis in chronic myeloid leukemia.

    PubMed

    Thakral, Beenu; Saluja, Karan; Malhotra, Pankaj; Sharma, Ratti Ram; Marwaha, Neelam; Varma, Subhash

    2004-12-01

    Extreme thrombocytosis is a frequent feature in myeloproliferative disorders which can predispose a person to thrombotic complications. As opposed to other myeloproliferative disorders, symptomatic thrombocytosis is rare in chronic myeloid leukemia. We describe a second case report of chronic myeloid leukemia (Ph chromosome positive) in a patient in chronic phase on hydroxyurea who presented with sudden onset digital cyanosis of the left hand, giddiness, headache and malaise due to extreme thrombocytosis. A 67% global reduction in the platelet count from 1553 x 10(9)/L to 513 x 10(9)/L after two therapeutic plateletpheresis procedures was seen. There was simultaneous improvement in all symptoms except cyanosis on the tip of the middle finger that progressed to dry gangrene. Dramatic reduction in the platelet count and ablation of symptoms by therapeutic plateletpheresis is an effective therapy and should begin as soon as possible.

  10. Effect of mutation order on myeloproliferative neoplasms.

    PubMed

    Ortmann, Christina A; Kent, David G; Nangalia, Jyoti; Silber, Yvonne; Wedge, David C; Grinfeld, Jacob; Baxter, E Joanna; Massie, Charles E; Papaemmanuil, Elli; Menon, Suraj; Godfrey, Anna L; Dimitropoulou, Danai; Guglielmelli, Paola; Bellosillo, Beatriz; Besses, Carles; Döhner, Konstanze; Harrison, Claire N; Vassiliou, George S; Vannucchi, Alessandro; Campbell, Peter J; Green, Anthony R

    2015-02-12

    Cancers result from the accumulation of somatic mutations, and their properties are thought to reflect the sum of these mutations. However, little is known about the effect of the order in which mutations are acquired. We determined mutation order in patients with myeloproliferative neoplasms by genotyping hematopoietic colonies or by means of next-generation sequencing. Stem cells and progenitor cells were isolated to study the effect of mutation order on mature and immature hematopoietic cells. The age at which a patient presented with a myeloproliferative neoplasm, acquisition of JAK2 V617F homozygosity, and the balance of immature progenitors were all influenced by mutation order. As compared with patients in whom the TET2 mutation was acquired first (hereafter referred to as "TET2-first patients"), patients in whom the Janus kinase 2 (JAK2) mutation was acquired first ("JAK2-first patients") had a greater likelihood of presenting with polycythemia vera than with essential thrombocythemia, an increased risk of thrombosis, and an increased sensitivity of JAK2-mutant progenitors to ruxolitinib in vitro. Mutation order influenced the proliferative response to JAK2 V617F and the capacity of double-mutant hematopoietic cells and progenitor cells to generate colony-forming cells. Moreover, the hematopoietic stem-and-progenitor-cell compartment was dominated by TET2 single-mutant cells in TET2-first patients but by JAK2-TET2 double-mutant cells in JAK2-first patients. Prior mutation of TET2 altered the transcriptional consequences of JAK2 V617F in a cell-intrinsic manner and prevented JAK2 V617F from up-regulating genes associated with proliferation. The order in which JAK2 and TET2 mutations were acquired influenced clinical features, the response to targeted therapy, the biology of stem and progenitor cells, and clonal evolution in patients with myeloproliferative neoplasms. (Funded by Leukemia and Lymphoma Research and others.).

  11. Myeloproliferative neoplasms in five multiple sclerosis patients☆

    PubMed Central

    Thorsteinsdottir, Sigrun; Bjerrum, Ole Weis; Hasselbalch, Hans Carl

    2013-01-01

    The concurrence of myeloproliferative neoplasms (MPNs) and multiple sclerosis (MS) is unusual. We report five patients from a localized geographic area in Denmark with both MS and MPN; all the patients were diagnosed with MPNs in the years 2007–2012. We describe the patients' history and treatment. A potential link between MS and MPNs has not been previously recognized. This observation calls attention to potential environmental factors and/or previously unrecognized genetic factors predisposing these patients to both MS and MPNs. PMID:24371783

  12. A BCR-ABL Kinase Activity-Independent Signaling Pathway in Chronic Myelogenous Leukemia

    DTIC Science & Technology

    2008-02-01

    myeloproliferative disease in mice receiving P210 bcr/abl-transduced bone marrow. Blood. 1998;92:3780-3792. 17. Zhang X, Ren R. Bcr-Abl efficiently induces a... myeloproliferative disease and production of excess interleukin-3 and granulocyte-macrophage colony-stimulating factor in mice: a novel model for chronic...Xu L, et al. Efficient and rapid induction of a chronic myelogenous leukemia-like myeloproliferative disease in mice receiving P210 bcr/abl-transduced

  13. Myeloproliferative neoplasms working group consensus recommendations for diagnosis and management of primary myelofibrosis, polycythemia vera, and essential thrombocythemia

    PubMed Central

    Agarwal, M. B.; Malhotra, Hemant; Chakrabarti, Prantar; Varma, Neelam; Mathews, Vikram; Bhattacharyya, Jina; Seth, Tulika; Gayathri, K.; Menon, Hari; Subramanian, P. G.; Sharma, Ajay; Bhattacharyya, Maitreyee; Mehta, Jay; Vaid, A. K.; Shah, Sandeep; Aggarwal, Shyam; Gogoi, P. K.; Nair, Reena; Agarwal, Usha; Varma, Subhash; Prasad, S. V. S. S.; Manipadam, Marie Therese

    2015-01-01

    According to the 2008 revision of the World Health Organization (WHO) classification of myeloid malignancies, philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) include clonal, hematologic disorders such as polycythemia vera, primary myelofibrosis, and essential thrombocythemia.Recent years have witnessed major advances in the understanding of the molecular pathophysiology of these rare subgroups of chronic, myeloproliferative disorders. Identification of somatic mutations in genes associated with pathogenesis and evolution of these myeloproliferative conditions (Janus Kinase 2; myeloproliferative leukemia virus gene; calreticulin) led to substantial changes in the international guidelines for diagnosis and treatment of Ph-negative MPN during the last few years.The MPN-Working Group (MPN-WG), a panel of hematologists with expertise in MPN diagnosis and treatment from various parts of India, examined applicability of this latest clinical and scientific evidence in the context of hematology practice in India.This manuscript summarizes the consensus recommendations formulated by the MPN-WG that can be followed as a guideline for management of patients with Ph-negative MPN in the context of clinical practice in India. PMID:25810569

  14. [Domiciliary noninvasive positive pressure ventilation in chronic alveolar hypoventilation].

    PubMed

    Casas, J P; Robles, A M; Pereyra, M A; Abbona, H L; López, A M

    2000-01-01

    Effectiveness of treatment with domiciliary nocturnal noninvasive positive pressure ventilation is analyzed in a group of patients with chronic alveolar hypoventilation of different etiologies. It was applied with two levels of pressure (BiPAP) via nasal mask. Criteria for evaluation were symptomatology and improvement in gas exchange. Data were analyzed by Student t tests. A total of 13 patients were included, mean age 55.7 range 20 to 76 years (5 male 8 female). Main diagnosis was tuberculosis in 6, four of them having had surgical procedure (thoracoplasty 2, frenicectomy 1 and neumonectomy 1), myopathy 3 (myasthenia gravis 1, muscular dystrophy 1 and diaphragmatic paralysis 1), obesity-hypoventilation syndrome 1, escoliosis 1, bronchiectasis 1 and cystic fibrosis 1. These last two patients were on waiting list for lung transplantation. At the moment of consultation, the symptoms were: dysnea 13/13 (100%), astenia 13/13 (100%), hypersomnolency 10/13 (77%), cephalea 9/13 (69%), leg edema 6/13 (46%), loss of memory 6/13 (46%). Regarding gas exchange, they showed hypoxemia and hypercapnia. Mean follow up was of 2.2 years (range 6 months to 4 years). Within the year, all 13 patients became less dyspneic. Astenia, hypersomnolency, cephalea, leg edema and memory loss disappeared. Improvement in gas exchange was: PaO2/FiO2 from 269 +/- 65.4 (basal) to 336.7 +/- 75.3 post-treatment (p = 0.0018). PaCO2 from 70.77 +/- 25.48 mmHg (basal) to 46.77 +/- 8.14 mmHg (p = 0.0013). Ventilatory support was discontinued en 5 patients: three because of pneumonia requiring intubation and conventional mechanical ventilation, two of them died and one is still with tracheostomy; One patient with bronchiectasis and one with cystic fibrosis were transplanted. The remaining eight patients are stable. In conclusion, chronic alveolar hypoventilation can be effectively treated with domiciliary nocturnal noninvasive ventilation. Long term improvement in symptomatology and arterial blood gases

  15. Oscillatory Positive Expiratory Pressure in Chronic Obstructive Pulmonary Disease.

    PubMed

    Svenningsen, Sarah; Paulin, Gregory A; Sheikh, Khadija; Guo, Fumin; Hasany, Aasim; Kirby, Miranda; Rezai, Roya Etemad; McCormack, David G; Parraga, Grace

    2016-01-01

    Evidence-based guidance for the use of airway clearance techniques (ACT) in chronic obstructive pulmonary disease (COPD) is lacking in-part because well-established measurements of pulmonary function such as the forced expiratory volume in 1s (FEV1) are relatively insensitive to ACT. The objective of this crossover study was to evaluate daily use of an oscillatory positive expiratory pressure (oPEP) device for 21-28 days in COPD patients who were self-identified as sputum-producers or non-sputum-producers. COPD volunteers provided written informed consent to daily oPEP use in a randomized crossover fashion. Participants completed baseline, crossover and study-end pulmonary function tests, St. George's Respiratory Questionnaire (SGRQ), Patient Evaluation Questionnaire (PEQ), Six-Minute Walk Test and (3)He magnetic resonance imaging (MRI) for the measurement of ventilation abnormalities using the ventilation defect percent (VDP). Fourteen COPD patients, self-identified as sputum-producers and 13 COPD-non-sputum-producers completed the study. Post-oPEP, the PEQ-ease-bringing-up-sputum was improved for sputum-producers (p = 0.005) and non-sputum-producers (p = 0.04), the magnitude of which was greater for sputum-producers (p = 0.03). There were significant post-oPEP improvements for sputum-producers only for FVC (p = 0.01), 6MWD (p = 0.04), SGRQ total score (p = 0.01) as well as PEQ-patient-global-assessment (p = 0.02). Clinically relevant post-oPEP improvements for PEQ-ease-bringing-up-sputum/PEQ-patient-global-assessment/SGRQ/VDP were observed in 8/7/9/6 of 14 sputum-producers and 2/0/3/3 of 13 non-sputum-producers. The post-oPEP change in (3)He MRI VDP was related to the change in PEQ-ease-bringing-up-sputum (r = 0.65, p = 0.0004) and FEV1 (r = -0.50, p = 0.009). In COPD patients with chronic sputum production, PEQ and SGRQ scores, FVC and 6MWD improved post-oPEP. FEV1 and PEQ-ease-bringing-up-sputum improvements were related to improved ventilation providing

  16. Position-dependent, hyperexcitable patellar reflex dynamics in chronic stroke.

    PubMed

    Yang, Chung-Yong; Guo, Xin; Ren, Yupeng; Kang, Sang Hoon; Zhang, Li-Qun

    2013-02-01

    To quantify tendon tap response (TTR) properties and their position dependence using multiple neuromechanical parameters, and to analyze correlations among neuromechanical and clinical measures. Hyperexcitable dynamics of TTR were investigated in a case-control manner. An instrumented hammer was used to induce the patellar deep tendon reflex (DTR), with reflex-mediated electromyography and torque responses measured across a range of knee flexion. Research laboratory in a rehabilitation hospital. Chronic hemiplegic stroke survivors (n=9) and healthy subjects (n=13). Not applicable. Neuromechanical measures (system gain, contraction rate, half-relaxation rate, reflex loop delay, peak reflex torque, peak reflex electromyography, and reflex threshold in tapping force) were measured to characterize neuromuscular properties of patellar TTR. Clinical measurements were taken using the DTR scale and the Modified Ashworth Scale. The system gain, contraction rate, half-relaxation rate, and peak reflex-mediated torque in the stroke group were generally higher, whereas the reflex threshold in the stroke group was significantly lower than their counterparts in the control group across 45° to 90° of knee flexion (P<.05). The 4 parameters were significantly higher at 60° and 75° of flexion than at 15°, 30°, 45°, and 90°, and their correlations with the 2 clinical scales at 60°, 75°, and 90° of flexion were also significantly higher than those at 15°, 30°, and 45° (P<.05). The results showed hyperexcitability of TTR in stroke, quantified using a number of neuromechanical measures. Those measures peak around 60° to 75° of knee flexion and were correlated with clinical scales. Copyright © 2013 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

  17. Effect of Mutation Order on Myeloproliferative Neoplasms

    PubMed Central

    Nangalia, Jyoti; Silber, Yvonne; Wedge, David C.; Grinfeld, Jacob; Baxter, E. Joanna; Massie, Charles E.; Papaemmanuil, Elli; Menon, Suraj; Godfrey, Anna L.; Dimitropoulou, Danai; Guglielmelli, Paola; Bellosillo, Beatriz; Besses, Carles; Döhner, Konstanze; Harrison, Claire N.; Vassiliou, George S.; Vannucchi, Alessandro; Campbell, Peter J.; Green, Anthony R.

    2015-01-01

    BACKGROUND Cancers result from the accumulation of somatic mutations, and their properties are thought to reflect the sum of these mutations. However, little is known about the effect of the order in which mutations are acquired. METHODS We determined mutation order in patients with myeloproliferative neoplasms by genotyping hematopoietic colonies or by means of next-generation sequencing. Stem cells and progenitor cells were isolated to study the effect of mutation order on mature and immature hematopoietic cells. RESULTS The age at which a patient presented with a myeloproliferative neoplasm, acquisition of JAK2 V617F homozygosity, and the balance of immature progenitors were all influenced by mutation order. As compared with patients in whom the TET2 mutation was acquired first (hereafter referred to as “TET2-first patients”), patients in whom the Janus kinase 2 (JAK2) mutation was acquired first (“JAK2-first patients”) had a greater likelihood of presenting with polycythemia vera than with essential thrombocythemia, an increased risk of thrombosis, and an increased sensitivity of JAK2-mutant progenitors to ruxolitinib in vitro. Mutation order influenced the proliferative response to JAK2 V617F and the capacity of double-mutant hematopoietic cells and progenitor cells to generate colony-forming cells. Moreover, the hematopoietic stem-and-progenitor-cell compartment was dominated by TET2 single-mutant cells in TET2-first patients but by JAK2–TET2 double-mutant cells in JAK2-first patients. Prior mutation of TET2 altered the transcriptional consequences of JAK2 V617F in a cell-intrinsic manner and prevented JAK2 V617F from up-regulating genes associated with proliferation. CONCLUSIONS The order in which JAK2 and TET2 mutations were acquired influenced clinical features, the response to targeted therapy, the biology of stem and progenitor cells, and clonal evolution in patients with myeloproliferative neoplasms. (Funded by Leukemia and Lymphoma Research

  18. Positive emotions and brain reward circuits in chronic pain.

    PubMed

    Navratilova, Edita; Morimura, Kozo; Xie, Jennifer Y; Atcherley, Christopher W; Ossipov, Michael H; Porreca, Frank

    2016-06-01

    Chronic pain is an important public health problem that negatively impacts the quality of life of affected individuals and exacts enormous socioeconomic costs. Chronic pain is often accompanied by comorbid emotional disorders including anxiety, depression, and possibly anhedonia. The neural circuits underlying the intersection of pain and pleasure are not well understood. We summarize recent human and animal investigations and demonstrate that aversive aspects of pain are encoded in brain regions overlapping with areas processing reward and motivation. We highlight findings revealing anatomical and functional alterations of reward/motivation circuits in chronic pain. Finally, we review supporting evidence for the concept that pain relief is rewarding and activates brain reward/motivation circuits. Adaptations in brain reward circuits may be fundamental to the pathology of chronic pain. Knowledge of brain reward processing in the context of pain could lead to the development of new therapeutics for the treatment of emotional aspects of pain and comorbid conditions. © 2016 Wiley Periodicals, Inc.

  19. Positive emotions and brain reward circuits in chronic pain

    PubMed Central

    Navratilova, Edita; Morimura, Kozo; Xie, Jennifer Y.; Atcherley, Christopher W.; Ossipov, Michael H.; Porreca, Frank

    2016-01-01

    Chronic pain is an important public health problem that negatively impacts quality of life of affected individuals and exacts enormous socio-economic costs. Chronic pain is often accompanied by comorbid emotional disorders including anxiety, depression and possibly anhedonia. The neural circuits underlying the intersection of pain and pleasure are not well understood. We summarize recent human and animal investigations demonstrating that aversive aspects of pain are encoded in brain regions overlapping with areas processing reward and motivation. We highlight findings revealing anatomical and functional alterations of reward/motivation circuits in chronic pain. Finally, we review supporting evidence for the concept that pain relief is rewarding and activates brain reward/motivation circuits. Adaptations in brain reward circuits may be fundamental to the pathology of chronic pain. Knowledge of brain reward processing in the context of pain could lead to the development of new therapeutics for the treatment of emotional aspects of pain and comorbid conditions. PMID:26788716

  20. Molecular determinants of pathogenesis and clinical phenotype in myeloproliferative neoplasms

    PubMed Central

    Grinfeld, Jacob; Nangalia, Jyoti; Green, Anthony R.

    2017-01-01

    The myeloproliferative neoplasms are a heterogeneous group of clonal disorders characterized by the overproduction of mature cells in the peripheral blood, together with an increased risk of thrombosis and progression to acute myeloid leukemia. The majority of patients with Philadelphia-chromosome negative myeloproliferative neoplasms harbor somatic mutations in Janus kinase 2, leading to constitutive activation. Acquired mutations in calreticulin or myeloproliferative leukemia virus oncogene are found in a significant number of patients with essential thrombocythemia or myelofibrosis, and mutations in numerous epigenetic regulators and spliceosome components are also seen. Although the cellular and molecular consequences of many of these mutations remain unclear, it seems likely that they interact with germline and microenvironmental factors to influence disease pathogenesis. This review will focus on the determinants of specific myeloproliferative neoplasm phenotypes as well as on how an improved understanding of molecular mechanisms can inform our understanding of the disease entities themselves. PMID:27909216

  1. [Deep vein thrombosis revealing myeloproliferative syndrome in two adolescents].

    PubMed

    Bertrand, A; Heissat, S; Caron, N; Viremouneix, L; Pracros, J-P; Javouhey, E; Lachaux, A; Mialou, V

    2014-05-01

    Deep vein thrombosis occurs in 30% of patients with essential thrombocythemia, but rarely at initial diagnosis. We report two pediatric patients with essential thrombocythemia revealed by atypical deep vein thrombosis. First, a 16-year-old girl presented Budd-Chiari syndrome revealed by a hemorrhagic shock. Clinical exam revealed isolated splenomegaly. A search for thrombophilia found a factor V Leiden homozygous mutation and a Jak2 mutation. Bone marrow biopsy confirmed the diagnosis of a myeloproliferative disorder. The second case, a 17-year-old girl, had a routine examination by her physician that revealed splenomegaly. Ultrasonography displayed thrombus in the splenic and portal vein. An isolated Jak2 mutation was found and a myeloproliferative disorder was confirmed by bone marrow biopsy. The diagnosis of myeloproliferative disorder was made in both patients presenting atypical venous thrombosis with a Jak2 mutation and confirmed by bone marrow biopsy. These initial presentations of myeloproliferative disorders are rare in childhood and possibly underdiagnosed.

  2. Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms

    PubMed Central

    Rampal, Raajit; Ahn, Jihae; Abdel-Wahab, Omar; Nahas, Michelle; Wang, Kai; Lipson, Doron; Otto, Geoff A.; Yelensky, Roman; Hricik, Todd; McKenney, Anna Sophia; Chiosis, Gabriela; Chung, Young Rock; Pandey, Suveg; van den Brink, Marcel R. M.; Armstrong, Scott A.; Dogan, Ahmet; Intlekofer, Andrew; Manshouri, Taghi; Park, Christopher Y.; Verstovsek, Srdan; Rapaport, Franck; Stephens, Philip J.; Miller, Vincent A.; Levine, Ross L.

    2014-01-01

    Patients with myeloproliferative neoplasms (MPNs) are at significant, cumulative risk of leukemic transformation to acute myeloid leukemia (AML), which is associated with adverse clinical outcome and resistance to standard AML therapies. We performed genomic profiling of post-MPN AML samples; these studies demonstrate somatic tumor protein 53 (TP53) mutations are common in JAK2V617F-mutant, post-MPN AML but not in chronic-phase MPN and lead to clonal dominance of JAK2V617F/TP53-mutant leukemic cells. Consistent with these data, expression of JAK2V617F combined with Tp53 loss led to fully penetrant AML in vivo. JAK2V617F-mutant, Tp53-deficient AML was characterized by an expanded megakaryocyte erythroid progenitor population that was able to propagate the disease in secondary recipients. In vitro studies revealed that post-MPN AML cells were sensitive to decitabine, the JAK1/2 inhibitor ruxolitinib, or the heat shock protein 90 inhibitor 8-(6-iodobenzo[d][1.3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purine-6-amine (PU-H71). Treatment with ruxolitinib or PU-H71 improved survival of mice engrafted with JAK2V617F-mutant, Tp53-deficient AML, demonstrating therapeutic efficacy for these targeted therapies and providing a rationale for testing these therapies in post-MPN AML. PMID:25516983

  3. Myeloproliferative neoplasms: updates on molecular pathophysiology, diagnosis and treatment strategies.

    PubMed

    Takenaka, Katsuto

    Myeloproliferative neoplasms (MPNs) are chronic hematopoietic stem cell disorders, including polycythemia vera, essential thrombocytosis, and primary myelofibrosis. The JAK2V617F mutation was identified in 2005, followed by the discovery of the JAK2 exon12, MPNW515 mutation, and CALR mutation. About 90% of patients with BCR/ABL negative MPNs have been shown to have one of these driver mutations. In addition, mutations in epigenetic regulators and RNA splicing genes were found to co-exist with driver mutations and to play critical roles in the disease progression of MPNs. Currently, evaluations of these gene mutations are essential for the diagnosis of MPNs, and are also necessary for estimating the clinical course and the risk of disease progression. Guidelines for the management of MPNs were based on the results of large clinical trials. Furthermore, recent advancements in understanding the pathogenesis of MPNs are anticipated to promote the development of MPN-targeted therapies such as JAK2 inhibitors. Clinical trials for patients with PMF and PV have confirmed the efficacies of JAK2 inhibitors.

  4. Cytokine Regulation of Microenvironmental Cells in Myeloproliferative Neoplasms

    PubMed Central

    Hoermann, Gregor; Greiner, Georg; Valent, Peter

    2015-01-01

    The term myeloproliferative neoplasms (MPN) refers to a heterogeneous group of diseases including not only polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), but also chronic myeloid leukemia (CML), and systemic mastocytosis (SM). Despite the clinical and biological differences between these diseases, common pathophysiological mechanisms have been identified in MPN. First, aberrant tyrosine kinase signaling due to somatic mutations in certain driver genes is common to these MPN. Second, alterations of the bone marrow microenvironment are found in all MPN types and have been implicated in the pathogenesis of the diseases. Finally, elevated levels of proinflammatory and microenvironment-regulating cytokines are commonly found in all MPN-variants. In this paper, we review the effects of MPN-related oncogenes on cytokine expression and release and describe common as well as distinct pathogenetic mechanisms underlying microenvironmental changes in various MPN. Furthermore, targeting of the microenvironment in MPN is discussed. Such novel therapies may enhance the efficacy and may overcome resistance to established tyrosine kinase inhibitor treatment in these patients. Nevertheless, additional basic studies on the complex interplay of neoplastic and stromal cells are required in order to optimize targeting strategies and to translate these concepts into clinical application. PMID:26543328

  5. Assessment of platelet activation in myeloproliferative disorders with complementary techniques.

    PubMed

    Bermejo, Emilse; Alberto, Maria F; Meschengieser, Susana S; Lazzari, Maria A

    2004-04-01

    Bleeding and thrombosis in myeloproliferative disorders (MPD) are common events, sometimes both are present in the same patient during the course of the disease. Platelet activation in patients with MPD is often suggested. The present study analyses the presence of circulating activated platelets, using simultaneously flow cytometry and aggregometric studies in MPD. We studied 28 patients: 13 with polycythaemia vera, seven with essential thrombocythaemia, and eight chronic myeloid leukaemia. We performed functional tests, aggregation and adenosine triphosphate (ATP) release and flow cytometric assays (mepacrine staining and platelet activation markers CD62, CD63 and fibrinogen binding (B-FG)). Twenty-one MPD samples (75%) had reduced aggregation and ATP release. Acquired delta-SPD was detected in 11 of 28 MPD patients (39%), and we found no association between reduced mepacrine labelling and abnormal ATP release. High levels of activation markers were obtained: CD62 in 19 of 28 patients (68%), CD63 in 13 of 28 patients (46%) and B-FG in 19 of 28 patients (68%). The most prevalent abnormality was a reduced aggregation and ATP release. The lack of association between ATP release and mepacrine labelling suggests that other mechanisms, besides the deficit of intraplatelet ATP/adenosine diphosphate, might occur. High levels of activation markers were also observed. We conclude that both tests are complementary and necessary to understand the functional status of platelets in MPD.

  6. An Exploration of Positive Identity Development in Women Living with Chronic Pain

    ERIC Educational Resources Information Center

    Sharpe, Hillary; Alderson, Kevin; Collins, Sandra

    2013-01-01

    We explored the concept of living positively with chronic pain using a mixed-methods design that relied primarily on hermeneutic phenomenology. Ten women described their experiences of developing a positive identity while contending with chronic pain. Throughout their journeys, the women interviewed experienced a number of key themes including:…

  7. Does an elevated serum vitamin B(12) level mask actual vitamin B(12) deficiency in myeloproliferative disorders?

    PubMed

    Gauchan, Dron; Joshi, Nitin; Gill, Amandeep Singh; Patel, Vishal; Debari, Vincent A; Guron, Gunwant; Maroules, Michael

    2012-08-01

    Elevation of the methylmalonic acid level is a sensitive marker of vitamin B(12) deficiency. Our cross-sectional observational study of 33 patients with myeloproliferative disorders found that 9 patients, 27.27% had occult deficiency despite having normal to elevated serum vitamin B(12) levels. Early detection of vitamin B(12) deficiency by using the methylmalonic acid measurement may prevent significant neurologic and hematologic complications in patients with myeloproliferative disorders. In patients with myeloproliferative disorders, normal to high serum vitamin B(12) concentrations have often been reported. The primary objective of this study was to determine whether normal or elevated serum vitamin B(12) levels in myeloproliferative disorders might actually mask the true underlying vitamin B(12) deficiency in some patients. Thirty-three patients (12 men, 21 women; mean age, 70.55 years [range, 37-90 years]) with polycythemia vera (n = 13), essential thrombocythemia (n = 12), chronic myelogenous leukemia (n = 5), and idiopathic myelofibrosis (IMF) (n = 3) were accrued over a period of 1 year, from March 2009 to February 2010. From all of the subjects, serum vitamin B(12) level, methylmalonic acid level, a basic complete blood cell count panel, and liver and renal function tests were obtained. Normal to elevated serum vitamin B(12) levels were recorded in all the patients. However, elevated serum methylmalonic acid levels were found in 9 (27.27%) patients, with a prevalence of 2 patients with polycythemia vera, 23% in polycythemia vera, 4 patients with essential thrombocythemia, 33.3% in essential thrombocythemia, 1 patient with chronic myelogenous leukemia, 20% in chronic myelogenous leukemia, and 2 patients with idiopathic myelofibrosis, 66.7% in IMF. Our data suggest that 27.27% of the total enrolled patients had occult vitamin B(12) deficiency despite normal to elevated vitamin B(12) levels on regular serum vitamin B(12) testing.

  8. [Vocational rehabilitation in chronic mental illness. The current position].

    PubMed

    Pfammatter, M; Hoffmann, H; Kupper, Z; Brenner, H D

    2000-02-01

    Vocational rehabilitation has long been of central importance in the comprehensive treatment of the psychiatrically disabled. This is reflected by the creation of a broad spectrum of vocational rehabilitation programs, ranging from inpatient and outpatient work therapy and sheltered employment to supported employment programs within the competitive labour market. Evaluation studies have shown that although sheltered vocational rehabilitation programs effect a significant rise in the work activity, rate of employment, job tenure and income of people with chronic mental illness in the alternative labour market, these programmes do not substantially increase job placement in the competitive labour market. By contrast, supported employment programs have proven more successful in achieving a higher integration rate in the competitive labour market for the chronically mentally ill. As opposed to the well-developed alternative labour market, supported employment programs are not broadly disseminated in German-speaking countries. Furthermore, vocational rehabilitation in general suffers from a lack of systematic evaluation and thus from inadequate scientific foundation.

  9. Predomination of IL-17-producing tryptase-positive/chymase-positive mast cells in azoospermic chronic testicular inflammation.

    PubMed

    Chen, S-J; Duan, Y-G; Haidl, G; Allam, J-P

    2016-08-01

    Chronic testicular inflammation and infection have been regarded as important factors in the pathogenesis of azoospermia. As key effector cells in innate and adaptive immune system, mast cells (MCs) were observed in inflammation and autoimmune disease. Furthermore, increased expression of tryptase-positive MCs has been reported in testicular disorders associated with male infertility/subfertility. However, little is known about the potential relationship between MCs and chronic testicular inflammation in azoospermic patients. Moreover, the preferential expression of MCs' subtypes in testis of these patients is still far from being understood. Thus, this study aimed to investigate characteristics of testicular MCs as well as their subtypes in azoospermic men with chronic testicular inflammation (AZI, n = 5) by immunohistochemical techniques. Our results showed significant increase of MCs in AZI, and more importantly, considerable numbers of tryptase-positive/chymase-positive MCs could also be demonstrated in AZI, when compared to control groups representing azoospermia without chronic testicular inflammation (AZW, n = 5) and normal spermatogenesis (NT, n = 5) respectively. Most interestingly, immunofluorescence staining revealed autoimmune-associated interleukin (IL)-17-producing MCs in AZI, whereas co-expression of MC markers with tumour necrosis factor (TNF)-α, IL-10 and IL-1β could not be detected. In conclusion, AZI is associated with significant increase of tryptase-positive/chymase-positive MCs expressing IL-17, and these MCs might contribute to the pathogenesis of AZI.

  10. IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms

    PubMed Central

    Mager, Lukas F.; Riether, Carsten; Schürch, Christian M.; Banz, Yara; Wasmer, Marie-Hélène; Stuber, Regula; Theocharides, Alexandre P.; Li, Xiaohong; Xia, Yu; Saito, Hirohisa; Nakae, Susumu; Baerlocher, Gabriela M.; Manz, Markus G.; McCoy, Kathy D.; Macpherson, Andrew J.; Ochsenbein, Adrian F.; Beutler, Bruce; Krebs, Philippe

    2015-01-01

    Myeloproliferative neoplasms (MPNs) are characterized by the clonal expansion of one or more myeloid cell lineage. In most cases, proliferation of the malignant clone is ascribed to defined genetic alterations. MPNs are also associated with aberrant expression and activity of multiple cytokines; however, the mechanisms by which these cytokines contribute to disease pathogenesis are poorly understood. Here, we reveal a non-redundant role for steady-state IL-33 in supporting dysregulated myelopoiesis in a murine model of MPN. Genetic ablation of the IL-33 signaling pathway was sufficient and necessary to restore normal hematopoiesis and abrogate MPN-like disease in animals lacking the inositol phosphatase SHIP. Stromal cell–derived IL-33 stimulated the secretion of cytokines and growth factors by myeloid and non-hematopoietic cells of the BM, resulting in myeloproliferation in SHIP-deficient animals. Additionally, in the transgenic JAK2V617F model, the onset of MPN was delayed in animals lacking IL-33 in radio-resistant cells. In human BM, we detected increased numbers of IL-33–expressing cells, specifically in biopsies from MPN patients. Exogenous IL-33 promoted cytokine production and colony formation by primary CD34+ MPN stem/progenitor cells from patients. Moreover, IL-33 improved the survival of JAK2V617F-positive cell lines. Together, these data indicate a central role for IL-33 signaling in the pathogenesis of MPNs. PMID:26011644

  11. The Hematopoietic Niche in Myeloproliferative Neoplasms

    PubMed Central

    Schmitt-Graeff, Annette H.; Nitschke, Roland; Zeiser, Robert

    2015-01-01

    Specialized microanatomical areas of the bone marrow provide the signals that are mandatory for the maintenance and regulation of hematopoietic stem cells (HSCs) and progenitor cells. A complex microenvironment adjacent to the marrow vasculature (vascular niche) and close to the endosteum (endosteal niche) harbors multiple cell types including mesenchymal stromal cells and their derivatives such as CAR cells expressing high levels of chemokines C-X-C motif ligand 12 and early osteoblastic lineage cells, endothelial cells, and megakaryocytes. The characterization of the cellular and molecular networks operating in the HSC niche has opened new perspectives for the understanding of the bidirectional cross-talk between HSCs and stromal cell populations in normal and malignant conditions. A structural and functional remodeling of the niche may contribute to the development of myeloproliferative neoplasms (MPN). Malignant HSCs may alter the function and survival of MSCs that do not belong to the neoplastic clone. For example, a regression of nestin+ MSCs by apoptosis has been attributed to neuroglial damage in MPN. Nonneoplastic MSCs in turn can promote aggressiveness and drug resistance of malignant cells. In the future, strategies to counteract the pathological interaction between the niche and neoplastic HSCs may offer additional treatment strategies for MPN patients. PMID:26696752

  12. CALR mutation characterization in myeloproliferative neoplasms

    PubMed Central

    Bilbao-Sieyro, Cristina; Florido, Yanira; Gómez-Casares, María Teresa

    2016-01-01

    Identification of somatic frameshift mutations in exon 9 of the calreticulin gene (CALR) in myeloproliferative neoplasms (MPNs) in December of 2013 has been a remarkable finding. It has provided a new molecular diagnostic marker, particularly in essential thrombocythemia (ET) and primary myelofibrosis (PMF), where is the second most common altered gene after JAK2V617F. There are two main types of CALR mutants, type 1 and type 2, and there is evidence about their distinct clinical/prognostic implications, for instances, it is believed that favorable outcome might be restricted to type-1 in PMF. By using reasoned approaches, very recent publications have supported classifying the alternative mutants in type-1-like or type-2-like. If further studies confirm these results, new considerations may be taken into account in the molecular diagnosis of MPNs. This implies that precise mutation characterization must be performed and caution should be taken in screening technique selection. In this Editorial we summarize the current information regarding all this issues. PMID:27384487

  13. Guidelines for the management of myeloproliferative neoplasms

    PubMed Central

    Choi, Chul Won; Bang, Soo-Mee; Jang, Seongsoo; Jung, Chul Won; Kim, Hee-Jin; Kim, Ho Young; Kim, Soo-Jeong; Kim, Yeo-Kyeoung; Park, Jinny; Won, Jong-Ho

    2015-01-01

    Polycythemia vera, essential thrombocythemia, and primary myelofibrosis are collectively known as ‘Philadelphia-negative classical myeloproliferative neoplasms (MPNs).’ The discovery of new genetic aberrations such as Janus kinase 2 (JAK2) have enhanced our understanding of the pathophysiology of MPNs. Currently, the JAK2 mutation is not only a standard criterion for diagnosis but is also a new target for drug development. The JAK1/2 inhibitor, ruxolitinib, was the first JAK inhibitor approved for patients with intermediate- to high-risk myelofibrosis and its effects in improving symptoms and survival benefits were demonstrated by randomized controlled trials. In 2011, the Korean Society of Hematology MPN Working Party devised diagnostic and therapeutic guidelines for Korean MPN patients. Subsequently, other genetic mutations have been discovered and many kinds of new drugs are now under clinical investigation. In view of recent developments, we have revised the guidelines for the diagnosis and management of MPN based on published evidence and the experiences of the expert panel. Here we describe the epidemiology, new genetic mutations, and novel therapeutic options as well as diagnostic criteria and standard treatment strategies for MPN patients in Korea. PMID:26552452

  14. Targeting myeloproliferative neoplasms with JAK inhibitors.

    PubMed

    Pardanani, Animesh; Tefferi, Ayalew

    2011-03-01

    The discovery of JAK2V617F and other JAK-STAT-activating mutations in BCR-ABL1-negative myeloproliferative neoplasms (MPN) has led to the development of small-molecule ATP-mimetics that inhibit wild-type and mutant JAK. Here, we review the current experience with JAK inhibitors used for the treatment of myelofibrosis and polycythemia vera/essential thrombocythemia. Consistent with the clonal complexity of MPN, JAK inhibitors have not thus far shown disease-modifying activity; treatment with these agents has however shown clinically meaningful benefits, particularly decreased splenomegaly and improvement in constitutional symptoms, in myelofibrosis patients. Although these benefits accrue with both JAK-2 (TG101348) and JAK-1/2 (INCB018424, CYT387) inhibitors, the mode of action (predominant anticlonal versus anticytokine activity) may be different between the two groups. It is possible that an optimal balance between JAK-1-inhibitory and JAK-2-inhibitory activities may broaden the therapeutic activity (i.e. anemia improvement), as has been preliminarily seen (CYT387). Although JAK inhibitors have important benefits in myelofibrosis therapy, their role in polycythemia vera/essential thrombocythemia treatment is still being defined. The optimal dosing strategy and feasibility for combination with other therapeutic agents remains to be established. Another challenge is the identification of robust primary end-points that will support labeling claims for JAK inhibitors for the aforementioned indications.

  15. [Precursors of acute leukemia: myelodysplastic syndromes and myeloproliferative neoplasms].

    PubMed

    Kreipe, H H

    2011-11-01

    Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) represent neoplastic proliferations of hematopoietic stem cells, which may progress to loss of differentiation and acute myeloid leukemia (AML). Transitions between MDSs and MPNs as well as combinations between both disorders occur and MPNs may acquire dysplastic features combined with cytopenia. Myelodysplastic/myeloproliferative neoplasms show dysplastic and myeloproliferative properties and have in common genetic aberrations at the stem cell level (TET2, ASXL 1, CBL, IDH 1, IDH 2, EZH2, p53, Runx1), which may be found in one cell or may affect different hematopoietic stem cells, expanding in parallel. Progress to AML follows a linear clonal evolution only in a subset of cases. Alternatively AML derives from secondary clones, devoid of any marker mutation or originates from a common aberrant progenitor cell which shares other but not the JAK2 ( V617F ) mutation.

  16. Molecular similarity between myelodysplastic form of chronic myelomonocytic leukemia and refractory anemia with ring sideroblasts.

    PubMed

    Gelsi-Boyer, Véronique; Cervera, Nathalie; Bertucci, François; Brecqueville, Mandy; Finetti, Pascal; Murati, Anne; Arnoulet, Christine; Mozziconacci, Marie-Joelle; Mills, Ken I; Cross, Nicholas C P; Vey, Norbert; Birnbaum, Daniel

    2013-04-01

    Chronic myelomonocytic leukemia is similar to but a separate entity from both myeloproliferative neoplasms and myelodysplastic syndromes, and shows either myeloproliferative or myelodysplastic features. We ask whether this distinction may have a molecular basis. We established the gene expression profiles of 39 samples of chronic myelomonocytic leukemia (including 12 CD34-positive) and 32 CD34-positive samples of myelodysplastic syndromes by using Affymetrix microarrays, and studied the status of 18 genes by Sanger sequencing and array-comparative genomic hybridization in 53 samples. Analysis of 12 mRNAS from chronic myelomonocytic leukemia established a gene expression signature of 122 probe sets differentially expressed between proliferative and dysplastic cases of chronic myelomonocytic leukemia. As compared to proliferative cases, dysplastic cases over-expressed genes involved in red blood cell biology. When applied to 32 myelodysplastic syndromes, this gene expression signature was able to discriminate refractory anemias with ring sideroblasts from refractory anemias with excess of blasts. By comparing mRNAS from these two forms of myelodysplastic syndromes we derived a second gene expression signature. This signature separated the myelodysplastic and myeloproliferative forms of chronic myelomonocytic leukemias. These results were validated using two independent gene expression data sets. We found that myelodysplastic chronic myelomonocytic leukemias are characterized by mutations in transcription/epigenetic regulators (ASXL1, RUNX1, TET2) and splicing genes (SRSF2) and the absence of mutations in signaling genes. Myelodysplastic chronic myelomonocytic leukemias and refractory anemias with ring sideroblasts share a common expression program suggesting they are part of a continuum, which is not totally explained by their similar but not, however, identical mutation spectrum.

  17. Molecular similarity between myelodysplastic form of chronic myelomonocytic leukemia and refractory anemia with ring sideroblasts

    PubMed Central

    Gelsi-Boyer, Véronique; Cervera, Nathalie; Bertucci, François; Brecqueville, Mandy; Finetti, Pascal; Murati, Anne; Arnoulet, Christine; Mozziconacci, Marie-Joelle; Mills, Ken I.; Cross, Nicholas C. P.; Vey, Norbert; Birnbaum, Daniel

    2013-01-01

    Chronic myelomonocytic leukemia is similar to but a separate entity from both myeloproliferative neoplasms and myelodysplastic syndromes, and shows either myeloproliferative or myelodysplastic features. We ask whether this distinction may have a molecular basis. We established the gene expression profiles of 39 samples of chronic myelomonocytic leukemia (including 12 CD34-positive) and 32 CD34-positive samples of myelodysplastic syndromes by using Affymetrix microarrays, and studied the status of 18 genes by Sanger sequencing and array-comparative genomic hybridization in 53 samples. Analysis of 12 mRNAS from chronic myelomonocytic leukemia established a gene expression signature of 122 probe sets differentially expressed between proliferative and dysplastic cases of chronic myelomonocytic leukemia. As compared to proliferative cases, dysplastic cases over-expressed genes involved in red blood cell biology. When applied to 32 myelodysplastic syndromes, this gene expression signature was able to discriminate refractory anemias with ring sideroblasts from refractory anemias with excess of blasts. By comparing mRNAS from these two forms of myelodysplastic syndromes we derived a second gene expression signature. This signature separated the myelodysplastic and myeloproliferative forms of chronic myelomonocytic leukemias. These results were validated using two independent gene expression data sets. We found that myelodysplastic chronic myelomonocytic leukemias are characterized by mutations in transcription/epigenetic regulators (ASXL1, RUNX1, TET2) and splicing genes (SRSF2) and the absence of mutations in signaling genes. Myelodysplastic chronic myelomonocytic leukemias and refractory anemias with ring sideroblasts share a common expression program suggesting they are part of a continuum, which is not totally explained by their similar but not, however, identical mutation spectrum. PMID:23065512

  18. Somatic CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2

    PubMed Central

    Baxter, E.J.; Nice, F.L.; Gundem, G.; Wedge, D.C.; Avezov, E.; Li, J.; Kollmann, K.; Kent, D.G.; Aziz, A.; Godfrey, A.L.; Hinton, J.; Martincorena, I.; Van Loo, P.; Jones, A.V.; Guglielmelli, P.; Tarpey, P.; Harding, H.P.; Fitzpatrick, J.D.; Goudie, C.T.; Ortmann, C.A.; Loughran, S.J.; Raine, K.; Jones, D.R.; Butler, A.P.; Teague, J.W.; O’Meara, S.; McLaren, S.; Bianchi, M.; Silber, Y.; Dimitropoulou, D.; Bloxham, D.; Mudie, L.; Maddison, M.; Robinson, B.; Keohane, C.; Maclean, C.; Hill, K.; Orchard, K.; Tauro, S.; Du, M.-Q.; Greaves, M.; Bowen, D.; Huntly, B.J.P.; Harrison, C.N.; Cross, N.C.P.; Ron, D.; Vannucchi, A.M.; Papaemmanuil, E.; Campbell, P.J.; Green, A.R.

    2014-01-01

    BACKGROUND Somatic mutations in the Janus kinase 2 gene (JAK2) occur in many myeloproliferative neoplasms, but the molecular pathogenesis of myeloproliferative neoplasms with nonmutated JAK2 is obscure, and the diagnosis of these neoplasms remains a challenge. METHODS We performed exome sequencing of samples obtained from 151 patients with myeloproliferative neoplasms. The mutation status of the gene encoding calreticulin (CALR) was assessed in an additional 1345 hematologic cancers, 1517 other cancers, and 550 controls. We established phylogenetic trees using hematopoietic colonies. We assessed calreticulin subcellular localization using immunofluorescence and flow cytometry. RESULTS Exome sequencing identified 1498 mutations in 151 patients, with medians of 6.5, 6.5, and 13.0 mutations per patient in samples of polycythemia vera, essential thrombocythemia, and myelofibrosis, respectively. Somatic CALR mutations were found in 70 to 84% of samples of myeloproliferative neoplasms with nonmutated JAK2, in 8% of myelodysplasia samples, in occasional samples of other myeloid cancers, and in none of the other cancers. A total of 148 CALR mutations were identified with 19 distinct variants. Mutations were located in exon 9 and generated a +1 base-pair frameshift, which would result in a mutant protein with a novel C-terminal. Mutant calreticulin was observed in the endoplasmic reticulum without increased cell-surface or Golgi accumulation. Patients with myeloproliferative neoplasms carrying CALR mutations presented with higher platelet counts and lower hemoglobin levels than patients with mutated JAK2. Mutation of CALR was detected in hematopoietic stem and progenitor cells. Clonal analyses showed CALR mutations in the earliest phylogenetic node, a finding consistent with its role as an initiating mutation in some patients. CONCLUSIONS Somatic mutations in the endoplasmic reticulum chaperone CALR were found in a majority of patients with myeloproliferative neoplasms with

  19. Positive Airway Pressure Therapies and Hospitalization in Chronic Obstructive Pulmonary Disease.

    PubMed

    Vasquez, Monica M; McClure, Leslie A; Sherrill, Duane L; Patel, Sanjay R; Krishnan, Jerry; Guerra, Stefano; Parthasarathy, Sairam

    2017-07-01

    Hospitalization of patients with chronic obstructive pulmonary disease creates a huge healthcare burden. Positive airway pressure therapy is sometimes used in patients with chronic obstructive pulmonary disease, but the possible impact on hospitalization risk remains controversial. We studied the hospitalization risk of patients with chronic obstructive pulmonary disease before and after initiation of various positive airway pressure therapies in a "real-world" bioinformatics study. We performed a retrospective analysis of administrative claims data of hospitalizations in patients with chronic obstructive pulmonary disease who received or did not receive positive airway pressure therapy: continuous positive airway pressure, bilevel positive airway pressure, and noninvasive positive pressure ventilation using a home ventilator. The majority of 1,881,652 patients with chronic obstructive pulmonary disease (92.5%) were not receiving any form of positive airway pressure therapy. Prescription of bilevel positive airway pressure (1.5%), continuous positive airway pressure (5.6%), and noninvasive positive pressure ventilation (<1%) in patients with chronic obstructive pulmonary disease demonstrated geographic-, sex-, and age-related variability. After adjusting for confounders and propensity score, noninvasive positive pressure ventilation (odds ratio [OR], 0.19; 95% confidence interval [CI], 0.13-0.27), bilevel positive airway pressure (OR, 0.42; 95% CI, 0.39-0.45), and continuous positive airway pressure (OR, 0.70; 95% CI, 0.67-0.72) were individually associated with lower hospitalization risk in the 6 months post-treatment when compared with the 6 months pretreatment but not when compared with the baseline period between 12 and 6 months before treatment initiation. Stratified analysis suggests that comorbid sleep-disordered breathing, chronic respiratory failure, heart failure, and age less than 65 years were associated with greater benefits from positive airway

  20. Emerging treatments for classical myeloproliferative neoplasms.

    PubMed

    Vannucchi, Alessandro M; Harrison, Claire N

    2017-02-09

    There has been a major revolution in the management of patients with myeloproliferative neoplasms (MPN), and in particular those with myelofibrosis and extensive splenomegaly and symptomatic burden, after the introduction of the JAK1 and JAK2 inhibitor ruxolitinib. The drug also has been approved as second-line therapy for polycythemia vera (PV). However, the therapeutic armamentarium for MPN is still largely inadequate for coping with patients' major unmet needs, which include normalization of life span (myelofibrosis and some patients with PV), reduction of cardiovascular complications (mainly PV and essential thrombocythemia), prevention of hematological progression, and improved quality of life (all MPN). In fact, none of the available drugs has shown clear evidence of disease-modifying activity, even if some patients treated with interferon and ruxolitinib showed reduction of mutated allele burden, and ruxolitinib might extend survival of patients with higher-risk myelofibrosis. Raised awareness of the molecular abnormalities and cellular pathways involved in the pathogenesis of MPN is facilitating the development of clinical trials with novel target drugs, either alone or in combination with ruxolitinib. Although for most of these molecules a convincing preclinical rationale was provided, the results of early phase 1 and 2 clinical trials have been quite disappointing to date, and toxicities sometimes have been limiting. In this review, we critically illustrate the current landscape of novel therapies that are under evaluation for patients with MPN on the basis of current guidelines, patient risk stratification criteria, and previous experience, looking ahead to the chance of a cure for these disorders.

  1. Somatic mutations of calreticulin in myeloproliferative neoplasms.

    PubMed

    Klampfl, Thorsten; Gisslinger, Heinz; Harutyunyan, Ashot S; Nivarthi, Harini; Rumi, Elisa; Milosevic, Jelena D; Them, Nicole C C; Berg, Tiina; Gisslinger, Bettina; Pietra, Daniela; Chen, Doris; Vladimer, Gregory I; Bagienski, Klaudia; Milanesi, Chiara; Casetti, Ilaria Carola; Sant'Antonio, Emanuela; Ferretti, Virginia; Elena, Chiara; Schischlik, Fiorella; Cleary, Ciara; Six, Melanie; Schalling, Martin; Schönegger, Andreas; Bock, Christoph; Malcovati, Luca; Pascutto, Cristiana; Superti-Furga, Giulio; Cazzola, Mario; Kralovics, Robert

    2013-12-19

    Approximately 50 to 60% of patients with essential thrombocythemia or primary myelofibrosis carry a mutation in the Janus kinase 2 gene (JAK2), and an additional 5 to 10% have activating mutations in the thrombopoietin receptor gene (MPL). So far, no specific molecular marker has been identified in the remaining 30 to 45% of patients. We performed whole-exome sequencing to identify somatically acquired mutations in six patients who had primary myelofibrosis without mutations in JAK2 or MPL. Resequencing of CALR, encoding calreticulin, was then performed in cohorts of patients with myeloid neoplasms. Somatic insertions or deletions in exon 9 of CALR were detected in all patients who underwent whole-exome sequencing. Resequencing in 1107 samples from patients with myeloproliferative neoplasms showed that CALR mutations were absent in polycythemia vera. In essential thrombocythemia and primary myelofibrosis, CALR mutations and JAK2 and MPL mutations were mutually exclusive. Among patients with essential thrombocythemia or primary myelofibrosis with nonmutated JAK2 or MPL, CALR mutations were detected in 67% of those with essential thrombocythemia and 88% of those with primary myelofibrosis. A total of 36 types of insertions or deletions were identified that all cause a frameshift to the same alternative reading frame and generate a novel C-terminal peptide in the mutant calreticulin. Overexpression of the most frequent CALR deletion caused cytokine-independent growth in vitro owing to the activation of signal transducer and activator of transcription 5 (STAT5) by means of an unknown mechanism. Patients with mutated CALR had a lower risk of thrombosis and longer overall survival than patients with mutated JAK2. Most patients with essential thrombocythemia or primary myelofibrosis that was not associated with a JAK2 or MPL alteration carried a somatic mutation in CALR. The clinical course in these patients was more indolent than that in patients with the JAK2 V617F

  2. Myeloproliferative neoplasms: Current molecular biology and genetics.

    PubMed

    Saeidi, Kolsoum

    2016-02-01

    Myeloproliferative neoplasms (MPNs) are clonal disorders characterized by increased production of mature blood cells. Philadelphia chromosome-negative MPNs (Ph-MPNs) consist of polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). A number of stem cell derived mutations have been identified in the past 10 years. These findings showed that JAK2V617F, as a diagnostic marker involving JAK2 exon 14 with a high frequency, is the best molecular characterization of Ph-MPNs. Somatic mutations in an endoplasmic reticulum chaperone, named calreticulin (CALR), is the second most common mutation in patients with ET and PMF after JAK2 V617F mutation. Discovery of CALR mutations led to the increased molecular diagnostic of ET and PMF up to 90%. It has been shown that JAK2V617F is not the unique event in disease pathogenesis. Some other genes' location such as TET oncogene family member 2 (TET2), additional sex combs-like 1 (ASXL1), casitas B-lineage lymphoma proto-oncogene (CBL), isocitrate dehydrogenase 1/2 (IDH1/IDH2), IKAROS family zinc finger 1 (IKZF1), DNA methyltransferase 3A (DNMT3A), suppressor of cytokine signaling (SOCS), enhancer of zeste homolog 2 (EZH2), tumor protein p53 (TP53), runt-related transcription factor 1 (RUNX1) and high mobility group AT-hook 2 (HMGA2) have also identified to be involved in MPNs phenotypes. Here, current molecular biology and genetic mechanisms involved in MNPs with a focus on the aforementioned factors is presented.

  3. Calreticulin (CALR) mutation in myeloproliferative neoplasms (MPNs)

    PubMed Central

    Luo, Wenyi

    2015-01-01

    As a heterogeneous group of disease, myeloproliferative neoplasms (MPNs) have confused hematologists and hematopathologists with their protean clinical presentations and myriads of morphologies. A thought of classifying MPNs based on molecular alterations has gained popularity because there is increasing evidence that molecular or chromosomal alterations have a better correlation with clinical presentation, response to therapies, and prognosis than conventional morphological classification. This type of efforts has been facilitated by the advancement of molecular technologies. A significant number of gene mutations have been identified in MPNs with JAK2 and MPL being the major ones. However, a significant gap is present in that many cases of MPNs do not harbor any of these mutations. This gap is recently filled by the discovery of Calreticulin (CALR) mutation in MPNs without JAK2 or MPL mutation and since then, the clinical and molecular correlation in MPNs has become a hot research topic. There seems to be a fairly consistent correlation between CALR mutation and certain hematological parameters such as a high platelet count and a better prognosis in MPNs with CALR mutation. However, controversies are present regarding the risks of thrombosis, interactions of CALR with other gene mutation, the role of CALR in the pathogenesis, and the optimal treatment strategies. In addition, there are many questions remain to be answered, which all boiled down to the molecular mechanisms by which CALR causes or contributes to MPNs. Here, we summarized current published literatures on CALR mutations in MPNs with an emphasis on the clinical-molecular correlation. We also discussed the controversies and questions remain to be answered. PMID:27358884

  4. Targeting glutamine metabolism in myeloproliferative neoplasms

    PubMed Central

    Zhan, Huichun; Ciano, Kristen; Dong, Katherine; Zucker, Stanley

    2016-01-01

    JAK2V617F mutation can be detected in the majority of myeloproliferative neoplasm (MPN) patients. The JAK2 inhibitor Ruxolitinib is the first FDA-approved treatment for MPNs. However, its use is limited by various dose related toxicities. Here, we studied the metabolic state and glutamine metabolism of BaF3-hEPOR-JAK2V617F and BaF3-hEPOR-JAK2WT cells. We found that the JAK2V617F-mutant cells were associated with increased oxygen consumption rate and extracellular acidification rate than the JAK2WT cells and there was an increased glutamine metabolism in JAK2V617F-mutant cells compared to wild-type cells. Glutaminase (GLS), the key enzyme in gluta-mine metabolism, was upregulated in the JAK2V617F-mutant BaF3 cells compared to the JAK2WT BaF3 cells. In MPN patient peripheral blood CD34+ cells, GLS expression was increased in JAK2V617F-mutant progenitor cells compared to JAK2 wild-type progenitor cells from the same patients and GLS levels were increased at the time of disease progression compared to at earlier time points. Moreover, GLS inhibitor increased the growth inhibitory effect of Ruxolitinib in both JAK2V617F-mutant cell lines and peripheral blood CD34+ cells from MPN patients. Therefore, GLS inhibitor should be further explored to enhance the therapeutic effectiveness of JAK2 inhibitor and allow the administration of lower doses of the drug to avoid its toxicity. PMID:26227854

  5. Genetic–pathologic characterization of myeloproliferative neoplasms

    PubMed Central

    Kim, Yonggoo; Park, Joonhong; Jo, Irene; Lee, Gun Dong; Kim, Jiyeon; Kwon, Ahlm; Choi, Hayoung; Jang, Woori; Chae, Hyojin; Han, Kyungja; Eom, Ki-Seong; Cho, Byung-Sik; Lee, Sung-Eun; Yang, Jinyoung; Shin, Seung-Hwan; Kim, Hyunjung; Ko, Yoon Ho; Park, Haeil; Jin, Jong Youl; Lee, Seungok; Jekarl, Dong Wook; Yahng, Seung-Ah; Kim, Myungshin

    2016-01-01

    Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by the proliferation of one or more myeloid lineages. The current study demonstrates that three driver mutations were detected in 82.6% of 407 MPNs with a mutation distribution of JAK2 in 275 (67.6%), CALR in 55 (13.5%) and MPL in 6 (1.5%). The mutations were mutually exclusive in principle except in one patient with both CALR and MPL mutations. The driver mutation directed the pathologic features of MPNs, including lineage hyperplasia, laboratory findings and clinical presentation. JAK2-mutated MPN showed erythroid, granulocytic and/or megakaryocytic hyperplasia whereas CALR- and MPL-mutated MPNs displayed granulocytic and/or megakaryocytic hyperplasia. The lineage hyperplasia was closely associated with a higher mutant allele burden and peripheral cytosis. These findings corroborated that the lineage hyperplasia consisted of clonal proliferation of each hematopoietic lineage acquiring driver mutations. Our study has also demonstrated that bone marrow (BM) fibrosis was associated with disease progression. Patients with overt fibrosis (grade ⩾2) presented an increased mutant allele burden (P<0.001), an increase in chromosomal abnormalities (P<0.001) and a poor prognosis (P<0.001). Moreover, among patients with overt fibrosis, all patients with wild-type JAK2/CALR/MPL (triple-negative) showed genomic alterations by genome-wide microarray study and revealed the poorest overall survival, followed by JAK2-mutated MPNs. The genetic–pathologic characteristics provided the information for understanding disease pathogenesis and the progression of MPNs. The prognostic significance of the driver mutation and BM fibrosis suggests the necessity of a prospective therapeutic strategy to improve the clinical outcome. PMID:27444979

  6. The expression of Death Inducer-Obliterator (DIDO) variants in Myeloproliferative Neoplasms.

    PubMed

    Berzoti-Coelho, Maria Gabriela; Ferreira, Aline Fernanda; de Souza Nunes, Natalia; Pinto, Mariana Tomazini; Júnior, Maurício Cristiano Rocha; Simões, Belinda Pinto; Martínez-A, Carlos; Souto, Elizabeth Xisto; Panepucci, Rodrigo Alexandre; Covas, Dimas Tadeu; Kashima, Simone; Castro, Fabíola Attié

    2016-07-01

    Chronic Myeloid Leukemia (CML), Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF) are Myeloproliferative Neoplasms (MPN) characterized by clonal myeloproliferation without cell maturation impairment. CML pathogenesis is associated with the Ph chromosome leading to BCR-ABL tyrosine-kinase constitutive expression. The Ph negative MPN (PV, ET and PMF) are characterized by the mutation JAK2(V617F) of the JAK2 protein in the auto-inhibitory JH2 domain, which is found in most PV patients and in approximately half of ET and PMF patients. Considerable effort is being made to understand the role of JAK2(V617F) at the MPN initiation and to clarify the pathogenesis and apoptosis resistance in CML, PV, ET and PMF patients. In the present investigation, we evaluated the Death Inducer-Obliterator (DIDO) (variants DIDO 1, 2 and 3) levels in CML, PV, ET and PMF patients. Our data reported the DIDO 1, 2 and 3 differential expressions in Myeloproliferative Neoplasms. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. UHMS position statement: topical oxygen for chronic wounds.

    PubMed

    Feldmeier, J J; Hopf, H W; Warriner, R A; Fife, C E; Gesell, L B; Bennett, M

    2005-01-01

    A small body of literature has been published reporting the application of topical oxygen for chronic non-healing wounds . Frequently, and erroneously, this form of oxygen administration has been referred to as "topical hyperbaric oxygen therapy" or even more erroneously "hyperbaric oxygen therapy." The advocates of topical oxygen claim several advantages over systemic hyperbaric oxygen including decreased cost, increased safety, decreased complications and putative physiologic effects including decreased free radical formation and more efficient delivery of oxygen to the wound surface. With topical oxygen an airtight chamber or polyethylene bag is sealed around a limb or the trunk by either a constriction/tourniquet device or by tape and high flow (usually 10 liters per minute) oxygen is introduced into the bag and over the wound. Pressures just over 1.0 atmospheres absolute (atm abs) (typically 1.004 to 1.013 atm abs) are recommended because higher pressures could decrease arterial/capillary inflow. The premise for topical oxygen, the diffusion of oxygen into the wound adequate to enhance healing, is attractive (though not proven) and its delivery is certainly less complex and expensive than hyperbaric oxygen. When discussing the physiology of topical oxygen, its proponents frequently reference studies of systemic hyperbaric oxygen suggesting that mechanisms are equally applicable to both topical and systemic high pressure oxygen delivery. In fact, however, the two are very different. To date, mechanisms of action whereby topical oxygen might be effective have not been defined or substantiated. Conversely, cellular toxicities due to extended courses of topical oxygen have been reported, although, again these data are not conclusive, and no mechanism for toxicity has been examined scientifically. Generally, collagen production and fibroblast proliferation are considered evidence of improved healing, and these are both enhanced by hyperbaric oxygen therapy

  8. Molecular Pathogenesis of Myeloproliferative Neoplasms: Influence of Age and Gender.

    PubMed

    Patterson-Fortin, Jeffrey; Moliterno, Alison R

    2017-09-25

    The myeloproliferative neoplasms polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) display distinct clinical and pathologic features but are characterized by mutations in JAK2, MPL, and CALR leading to activation of the JAK-STAT pathway. This review addresses the pathogenesis and mechanisms of these mutant alleles and the unique interactions of both of age and gender.

  9. Genetics Home Reference: 8p11 myeloproliferative syndrome

    MedlinePlus

    ... to view the expand/collapse boxes. Description 8p11 myeloproliferative syndrome is a blood cancer that involves different types of blood cells . Blood ... Hodgkin's Lymphoma KidsHealth from Nemours: Leukemia MalaCards: 8p11 ... associated with FGFR1 rearrangement Patient Support and Advocacy ...

  10. Calreticulin Mutations in Myeloproliferative Neoplasms: Comparison of Three Diagnostic Methods

    PubMed Central

    Park, Ji-Hye; Sevin, Margaux; Ramla, Selim; Truffot, Aurélie; Verrier, Tiffany; Bouchot, Dominique; Courtois, Martine; Bas, Mathilde; Benali, Sonia; Bailly, François; Favre, Bernardine; Guy, Julien; Martin, Laurent; Maynadié, Marc; Carillo, Serge; Girodon, François

    2015-01-01

    Calreticulin (CALR) mutations have recently been reported in 70–84% of JAK2V617F-negative myeloproliferative neoplasms (MPN), and this detection has become necessary to improve the diagnosis of MPN. In a large single-centre cohort of 298 patients suffering from Essential Thrombocythemia (ET), the JAK2V617F, CALR and MPL mutations were noted in 179 (60%), 56 (18.5%) and 13 (4.5%) respectively. For the detection of the CALR mutations, three methods were compared in parallel: high-resolution melting-curve analysis (HRM), product-sizing analysis and Sanger sequencing. The sensitivity for the HRM, product-sizing analysis and Sanger sequencing was 96.4%, 98.2% and 89.3% respectively, whereas the specificity was 96.3%, 100% and 100%. In our cohort, the product-sizing analysis was the most sensitive method and was the easiest to interpret, while the HRM was sometimes difficult to interpret. In contrast, when large series of samples were tested, HRM provided results more quickly than did the other methods, which required more time. Finally, the sequencing method, which is the reference method, had the lowest sensitivity but can be used to describe the type of mutation precisely. Altogether, our results suggest that in routine laboratory practice, product-sizing analysis is globally similar to HRM for the detection of CALR mutations, and that both may be used as first-line screening tests. If the results are positive, Sanger sequencing can be used to confirm the mutation and to determine its type. Product-sizing analysis provides sensitive and specific results, moreover, with the quantitative measurement of CALR, which might be useful to monitor specific treatments. PMID:26501981

  11. The natural history and treatment outcome of blast phase BCR-ABL− myeloproliferative neoplasms

    PubMed Central

    Tam, Constantine S.; Nussenzveig, Roberto M.; Popat, Uday; Bueso-Ramos, Carlos E.; Thomas, Deborah A.; Cortes, Jorge A.; Champlin, Richard E.; Ciurea, Stefan E.; Manshouri, Taghi; Pierce, Sherry M.; Kantarjian, Hagop M.

    2008-01-01

    We analyzed the outcomes of 74 patients diagnosed with BCR-ABL− myeloproliferative neoplasms in blast phase receiving induction chemotherapy (55%), low-intensity therapy (16%), stem cell transplantation (SCT; 3%), or supportive care (26%). Median survival from the date of blastic transformation was 5 months. Patients receiving supportive therapy had a median survival of 6 weeks. Complete remission with or without blood recovery was achieved in 46% of patients receiving induction chemotherapy, but remissions were not durable with a median progression-free survival of only 5 months. Eight patients received SCT either as first therapy or after responding to antileukemia therapy. These patients had a markedly superior survival, with 73% alive at a median follow-up of 31 months. JAK2V617F kinetics were assessed in 16 patients: 0 of 4 negative patients became positive at transformation, and among 12 positive patients, 1 had an increase in JAK2V617F% at transformation, 7 had a substantial decrease, and 4 had stable levels. Myeloproliferative neoplasm blast phase is associated with a dismal prognosis. Responses to chemotherapy can be achieved but are not durable. Long-term survivors had all received SCT either as first therapy or in first remission. PMID:18566326

  12. Refractory ascites in the chronic myeloproliferative syndrome: A case report

    SciTech Connect

    Jacobs, P.; Wood, L.; Robson, S. )

    1991-06-01

    In a patient with myelofibrosis, tense ascites refractory to conventional therapy resulted from extensive seeding of the peritoneum with colonies of extramedullary haematopoiesis. Whole abdominal radiation was found to be effective and well tolerated, and brought about prompt and lasting resorption of the exudate, with weight reduction and improvement in performance status from 50% to 90% on the Karnofsky rating.

  13. Multicenter Retrospective Analysis of Turkish Patients with Chronic Myeloproliferative Neoplasms.

    PubMed

    Soyer, Nur; Haznedaroğlu, İbrahim C; Cömert, Melda; Çekdemir, Demet; Yılmaz, Mehmet; Ünal, Ali; Çağlıyan, Gülsüm; Bilgir, Oktay; İlhan, Osman; Özdemirkıran, Füsun; Kaya, Emin; Şahin, Fahri; Vural, Filiz; Saydam, Güray

    2017-03-01

    Amaç: Polisitemia vera (PV), esansiyel trombositemi (ET) ve primer miyelofibrozu (PMF) içeren kronik miyeloproliferatif neoplaziler (KMPN), bir ya da birden fazla serinin klonal proliferasyonu ile karakterize Philadelphia kromozomu negatif olan malignitelerdir. Bu çalışmanın amacı, Türkiye’de KMPN’li hastaların demografik özellikleri, hastalık karakteristikleri, tedavi stratejileri ve yaşam oranlarını belirlemektir. Gereç ve Yöntemler: Türkiye’nin her yanından 9 merkez çalışmaya katıldı. Biz geriye dönük olarak ET’li 390, PV’li 213 ve PMF’li 105 hasta olmak üzere toplam 708 KMPN’li hastanın verisini değerlendirdik. Bulgular: JAK-2 mutasyonu PV’li hastaların %86’sında, ET’li hastaların %51,5’inde ve PMF’li hastaların %50,4’ünde pozitif bulundu. Tanıda tromboz ve kanama, PV’li hastaların sırasıyla %20,6 ve %7,5’inde, ET’li hastaların %15,1 ve %9’unda ve PMF’li hastaların %9,5 ve %10,4’ünde saptandı. Altı yüz sekiz hasta (%85,9) sitoredüktif tedavi almıştı. En sık kullanılan ilaç hidroksiüre (%89,6) idi. Lösemik ve fibrotik transformasyon sıklığı %0,6 ve %13,2 idi. 10 yıllık hesaplanan toplam sağkalım PV, ET ve PMF hastalarında sırasıyla %89,7, %85 ve %82,5 idi. 10 yıllık toplam sağkalım açısından ET, PV ve PMF hastalarında anlamlı fark yoktu. Sonuç: Sonuçlarımız, PMF hastalarının yüksek sağkalımı hariç literatürle benzerdir. Hidroksiüre ülkemizdeki en sık kullanılan sitoredüktif ajandır. Bizim çalışmamız, Türk KMPN hastalarının demografik özelliklerini, hastaların karakteristiklerini, tedavilerini ve sağkalım oranlarını yansıtmaktadır.

  14. Individuals with chronic hemiparetic stroke can correctly match forearm positions within a single arm.

    PubMed

    Gurari, Netta; Drogos, Justin M; Dewald, Julius P A

    2017-01-01

    Previous studies determined, using between arms position matching assessments, that at least one-half of individuals with stroke have an impaired position sense. We investigated whether individuals with chronic stroke who have impairments mirroring arm positions also have impairments identifying the location of each arm in space. Participants with chronic hemiparetic stroke and age-matched participants without neurological impairments (controls) performed a between forearms position matching task based on a clinical assessment and a single forearm position matching task, using passive and active movements, based on a robotic assessment. 12 out of our 14 participants with stroke who had clinically determined between forearms position matching impairments had greater errors than the controls in both their paretic and non-paretic arm when matching positions during passive movements; yet stroke participants performed comparable to the controls during active movements. Many individuals with chronic stroke may have impairments matching positions in both their paretic and non-paretic arm if their arm is moved for them, yet not within either arm if these individuals control their own movements. The neural mechanisms governing arm location perception in the stroke population may differ depending on whether arm movements are made passively versus actively. Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  15. Individuals with chronic hemiparetic stroke can correctly match forearm positions within a single arm

    PubMed Central

    Gurari, Netta; Drogos, Justin M.; Dewald, Julius P.A.

    2017-01-01

    Objective Previous studies determined, using between arms position matching assessments, that at least one-half of individuals with stroke have an impaired position sense. We investigated whether individuals with chronic stroke who have impairments mirroring arm positions also have impairments identifying the location of each arm in space. Methods Participants with chronic hemiparetic stroke and age-matched participants without neurological impairments (controls) performed a between forearms position matching task based on a clinical assessment and a single forearm position matching task, using passive and active movements, based on a robotic assessment. Results 12 out of our 14 participants with stroke who had clinically determined between forearms position matching impairments had greater errors than the controls in both their paretic and non-paretic arm when matching positions during passive movements; yet stroke participants performed comparable to the controls during active movements. Conclusions Many individuals with chronic stroke may have impairments matching positions in both their paretic and non-paretic arm if their arm is moved for them, yet not within either arm if these individuals control their own movements. Significance The neural mechanisms governing arm location perception in the stroke population may differ depending on whether arm movements are made passively versus actively. PMID:27866116

  16. [Recurrent deep vein thrombosis and myeloproliferative syndrom: emergence of JAK2 mutation five years after the initial event].

    PubMed

    Salort, A; Seinturier, C; Molina, L; Lévèque, P; Imbert, B; Pernod, G

    2014-05-01

    JAK 2 mutation is the molecular event responsible for 95% of polycythemia cases and 50% of thrombocythemia vera and myelofibrosis cases. It can be used as a tool for the diagnosis of myeloproliferative disorders. We report a case illustrating the fact that a negative result does not definitively eliminate the diagnosis. A 40-year old woman, with a medical history of familial deep vein thrombosis, developed thrombosis of the inferior vena cava with extension to the suprahepatic veins and pulmonary embolism. No constitutional or acquired thrombophilia was diagnosed; search for JAK 2 mutation was negative. The patient was treated with fluindione. Five years later, she relapsed with popliteo-femoral and vena cava deep vein thrombosis. The etiological work-up included a PET scan which revealed diffuse uptake in bones and suspected neoplasic bone marrow invasion. Progenitor cell cultures were positive and JAK 2 mutation was confirmed. The bone marrow aspirate had the cytologic appearance of a myeloproliferative disorder. This case illustrates the fact that JAK 2 mutation can be identified several years after onset of a latent myeloproliferative disorder. Cases with a high clinical likelihood should lead to renewed search for this mutation. Secondary discovery of this mutation can be explained by a higher proportion of mutation expressing clones. Copyright © 2014. Published by Elsevier Masson SAS.

  17. [Two cases of chronic atelectasis that improved through use of nasal continuous positive pressure].

    PubMed

    Tsuchiya, Michiko; Katsuki, Yuko; Enokibori, Toru; Ninomiya, Kiyoshi; Fujimura, Naoki

    2007-06-01

    We observed improvements in two cases of chronic atelectasis through use of nasal continuous positive airway pressure (nCPAP). Case 1 suffered from middle lobe syndrome accompanied by chronic atelectasis resistant to medical treatment. Case 2 suffered from respiratory failure caused by chronic atelectasis and airway infection complications thereof following a total pneumonectomy and post-pneumonectomy syndrome. The patient was placed on artificial ventilation, and atelectasis was improved by maintaining PEEP and airflow to the atelectatic region. Following extubation we obtained good pneumatization using nCPAP. nCPAP has been reported as effective not only in cases of sleep apnea, but also for cardiogenic pulmonary edema and post-operative atelectasis; we believe it holds great promise for chronic atelectasis as well.

  18. Imatinib-induced thyroiditis in Philadelphia chromosome-positive chronic myeloid leukemia

    PubMed Central

    Singh, Surjit; Sharma, Pramod Kumar

    2016-01-01

    Here, we present a case of chronic myeloid leukemia for which imatinib therapy was initated. Triiodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone was normal, and thyroid microsomal autoantibodies (TMA) were positive and patient was diagnosed as thyroiditis treated with corticosteroids for 1½ months which lead to resolution. PMID:27756963

  19. Natural killer T cells: innate lymphocytes positioned as a bridge between acute and chronic inflammation?

    PubMed Central

    Fox, Lisa; Hegde, Subramanya

    2010-01-01

    Natural killer T cells are an innate population of T lymphocytes that recognize antigens derived from host lipids and glycolipids. In this review, we focus on how these unique T cells are positioned to influence both acute and chronic inflammatory processes through their early recruitment to sites of inflammation, interactions with myeloid antigen presenting cells, and recognition of lipids associated with inflammation. PMID:20850561

  20. Systematic review of positive youth development programs for adolescents with chronic illness.

    PubMed

    Maslow, Gary R; Chung, Richard J

    2013-05-01

    The Positive Youth Development (PYD) framework has been successfully used to support at-risk youth. However, its effectiveness in fostering positive outcomes for adolescents with chronic illness has not been established. We performed a systematic review of PYD-consistent programs for adolescents with chronic illness. Data sources included PubMed, CINAHL, and PsychINFO. Guided by an analytic framework, we searched for studies of PYD-consistent programs serving adolescents and young adults aged 13 through 24 with chronic illness. References were screened iteratively with increasing depth until a focused cohort was obtained and reviewed in full. The authors separately reviewed the studies using structured analysis forms. Relevant study details were abstracted during the review process. Fifteen studies describing 14 programs were included in the analysis. Three comprehensive programs included all 3 core components of a PYD program, including opportunities for youth leadership, skill building, and sustained connections between youth and adults. Four programs were primarily mentoring programs, and 7 others focused on youth leadership. Programs served youth with a variety of chronic illnesses. The quality and type of evaluation varied considerably, with most reporting psychosocial outcomes but only a few including medical outcomes. The PYD-consistent programs identified in this review can serve as models for the development of youth development programs for adolescents with chronic illness. Additional study is needed to evaluate such programs rigorously with respect to both psychosocial and health-related outcomes. PYD-consistent programs have the potential to reach youth with chronic illness and promote positive adult outcomes broadly.

  1. JAK/STAT Pathways in Cytokine Signaling and Myeloproliferative Disorders

    PubMed Central

    Jatiani, Shashidhar S.; Baker, Stacey J.; Silverman, Lewis R.; Reddy, E. Premkumar

    2010-01-01

    Hematopoiesis is the cumulative result of intricately regulated signaling pathways that are mediated by cytokines and their receptors. Studies conducted over the past 10 to 15 years have revealed that hematopoietic cytokine receptor signaling is largely mediated by a family of tyrosine kinases termed Janus kinases (JAKs) and their downstream transcription factors, termed STATs (signal transducers and activators of transcription). Aberrations in these pathways, such as those caused by the recently identified JAK2V617F mutation and translocations of the JAK2 gene, are underlying causes of leukemias and other myeloproliferative disorders. This review discusses the role of JAK/STAT signaling in normal hematopoiesis as well as genetic abnormalities associated with myeloproliferative and myelodisplastic syndromes. This review also summarizes the status of several small molecule JAK2 inhibitors that are currently at various stages of clinical development. Several of these compounds appear to improve the quality of life of patients with myeloproliferative disorders by palliation of disease-related symptoms. However, to date, these agents do not seem to significantly affect bone marrow fibrosis, alter marrow histopathology, reverse cytopenias, reduce red cell transfusion requirements, or significantly reduce allele burden. These results suggest the possibility that additional mutational events might be associated with the development of these neoplasms, and indicate the need for combination therapies as the nature and significance of these additional molecular events is better understood. PMID:21442038

  2. Adaptive splenic radiotherapy for symptomatic splenomegaly management in myeloproliferative disorders.

    PubMed

    Sager, Omer; Beyzadeoglu, Murat; Dincoglan, Ferrat; Demiral, Selcuk; Uysal, Bora; Gamsiz, Hakan; Akin, Mustafa; Gundem, Esin; Dirican, Bahar

    2015-01-01

    Symptomatic, massive splenomegaly is a debilitating complication of myeloproliferative disorders. In the study, we evaluated the use of a contemporary, individualized radiotherapeutic approach for splenic irradiation, including 3-dimensional computed tomography-based treatment planning, individualized treatment margins based on splenic motion assessment, online setup verification with volumetric image guidance at each fraction, and adaptive radiation treatment planning to account for changes in splenic size during the fractionated radiotherapy course. Between December 2008 and January 2014, 18 patients (13 males, 5 females) with myeloproliferative disorders referred to Gulhane Military Medical Academy Radiation Oncology Department underwent 22 courses of splenic irradiation using 3-dimensional computed tomography-based treatment planning and volumetric image guidance for palliation of symptomatic splenomegaly. Median age was 64 years (range 28-79). Significant pain relief was achieved in 20 of the 22 splenic irradiation courses (90.9%). Improvement in hematological parameters was achieved in 8 of the 11 splenic irradiation courses applied for cytopenia (72.7%). At least a 50% reduction in splenic size was achieved in 18 of the 22 splenic irradiation courses (81.8%). Toxicity was manageable with supportive treatment including antiemetics and platelet or red blood cell transfusions. Splenic irradiation with a contemporary radiotherapeutic approach offers safe and effective palliation of symptomatic splenomegaly in myeloproliferative disorders.

  3. Chronic morphine increases Fos-positive neurons after concurrent cornea and tail stimulation.

    PubMed

    Robbins, Ashlee; Schmitt, David; Winterson, Barbara J; Meng, Ian D

    2012-02-01

    The aim of the present study was to examine the effect of chronic morphine exposure on diffuse noxious inhibitory controls in a large population of neurons throughout the medullary dorsal horn, as assessed using immunocytochemistry for c-Fos protein. Overuse of medications, including the opioids, to treat migraine headache can lead to progressively more frequent headaches. In addition, chronic daily headache sufferers and chronic opioid users both lack the inhibition of pain produced by noxious stimulation of a distal body region, often referred to as diffuse noxious inhibitory controls. In urethane anesthetized rats, Fos-positive neurons were quantified in chronic morphine and vehicle-treated animals following 52°C noxious thermal stimulation of the cornea with and without the application of a spatially remote noxious stimulus (placement of the tail in 55°C water). When compared to chronic morphine-treated animals that did not receive the spatially remote noxious stimulus, chronic morphine-treated animals given corneal stimulation along with the spatially remote noxious stimulus demonstrated a 163% increase (P < .05) in the number of Fos-positive neurons in the superficial laminae of the medullary dorsal horn and a 682% increase (P < .01) in deep laminae that was restricted to the side ipsilateral to the applied stimulus. In contrast, no significant difference was found in Fos-like immunoreactivity in vehicle-treated animals given concurrent cornea and tail stimulation or only cornea stimulation in either superficial or deep laminae. It is proposed that an increase in descending facilitation and subsequent loss of diffuse noxious inhibitory controls contributes to the development of medication overuse headache. © 2011 American Headache Society.

  4. Differences among myeloproliferative disorders in the behavior of their restricted progenitor cells in culture.

    PubMed

    Croizat, H; Amato, D; McLeod, D L; Eskinazi, D; Axelrad, A A

    1983-09-01

    We have studied the behavior in culture of circulating restricted hemopoietic progenitor cells from patients with idiopathic myelofibrosis (IMF), polycythemia vera (PV), and essential thrombocytopenia (ET). We have found differences in circulating granulocyte-macrophage, erythroid, and megakaryocytic progenitors that appear to be specific for these chronic myeloproliferative disorders. In IMF, most affected were granulocyte-macrophage progenitor cells (CFU-C), which circulated in increased numbers and were heterogeneous in their sensitivity to the regulatory factor(s) present in phytohemagglutinin (PHA) stimulated T-lymphocyte conditioned medium (CM). Most CFU-C were either highly sensitive to, or independent from, stimulatory factors, while others showed normal sensitivity. In some IMF patients, circulating megakaryocytic progenitors (CFU-M) were present that were capable of giving rise to colonies in the absence of added CM or erythropoietin (EPO). In PV, we confirmed the presence of circulating erythroid progenitor cells that give rise to colonies in culture without the addition of EPO. The number of circulating CFU-C was normal and they responded normally to CM. In ET, failure to detect 7-day circulating restricted progenitor cells was a common observation; the level of other circulating restricted progenitors was in the low normal range. Thus, despite certain common features, including a primary lesion at the level of the pluripotential hemopoietic stem cell, the myeloproliferative disorders differ with respect to the behavior in culture of their circulating restricted progenitor cells. These results have led us to postulate a second regulatory lesion in the pluripotential stem cell that differs in these disorders and is expressed at the level of the respective restricted progenitor cells.

  5. Bosutinib: a review of its use in patients with Philadelphia chromosome-positive chronic myelogenous leukemia.

    PubMed

    Syed, Yahiya Y; McCormack, Paul L; Plosker, Greg L

    2014-02-01

    Bosutinib (Bosulif®) is an orally administered small molecule tyrosine kinase inhibitor (TKI) of BCR-ABL and SRC family kinases. It is indicated for the treatment of adult patients with chronic-, accelerated-, or blast-phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy (imatinib, dasatinib, or nilotinib) [USA] or for a small subpopulation of these patients for whom imatinib, nilotinib, and dasatinib are not considered appropriate treatment options (EU). In a multinational pivotal trial (n = 547), bosutinib treatment resulted in a major cytogenetic response (MCyR) at 24 weeks in one-third of all treated patients with imatinib-resistant chronic-phase CML who had no previous exposure to any TKIs other than imatinib (primary endpoint), with similar results observed in chronic-phase CML patients who were intolerant of imatinib and naïve to all other TKIs. MCyRs were also seen in more than one-quarter of evaluable patients with chronic-phase CML previously treated with multiple TKIs. Most of the patients with chronic-phase CML achieved a complete hematologic response with bosutinib and some patients with advanced phases of CML achieved an overall hematologic response. Responses were seen irrespective of the type of BCR-ABL mutation at baseline, except T315I. Bosutinib had a manageable tolerability profile in the pivotal trial, with ≤21 % of patients with chronic-phase CML discontinuing the treatment because of adverse events. Diarrhea was the most common adverse event but was generally manageable, with only few patients discontinuing the treatment because of diarrhea. Therefore, bosutinib is a useful TKI option for patients with Ph+ CML in second-line or greater settings.

  6. Chronic stress, hippocampus and parvalbumin-positive interneurons: what do we know so far?

    PubMed

    Zaletel, Ivan; Filipović, Dragana; Puškaš, Nela

    2016-06-01

    The hippocampus is a brain structure involved in the regulation of hypothalamic-pituitary-adrenal (HPA) axis and stress response. It plays an important role in the formation of declarative, spatial and contextual memory, as well as in the processing of emotional information. As a part of the limbic system, it is a very susceptible structure towards the effects of various stressors. The molecular mechanisms of structural and functional alternations that occur in the hippocampus under chronic stress imply an increased level of circulating glucocorticoids (GCs), which is an HPA axis response to stress. Certain data show that changes induced by chronic stress may be independent from the GCs levels, opening the possibility of existence of other poorly explored mechanisms and pathways through which stressors act. The hippocampal GABAergic parvalbumin-positive (PV+) interneurons represent an especially vulnerable population of neurons in chronic stress, which may be of key importance in the development of mood disorders. However, cellular and molecular hippocampal changes that arise as a consequence of chronic stress still represent a large and unexplored area. This review discusses the current knowledge about the PV+ interneurons of the hippocampus and the influence of chronic stress on this intriguing population of neurons.

  7. Dysregulation of the intrinsic apoptotic pathway mediates megakaryocytic hyperplasia in myeloproliferative neoplasms

    PubMed Central

    Malherbe, Jacques A J; Fuller, Kathryn A; Mirzai, Bob; Kavanagh, Simon; So, Chi-Chiu; Ip, Ho-Wan; Guo, Belinda B; Forsyth, Cecily; Howman, Rebecca; Erber, Wendy N

    2016-01-01

    Aims Megakaryocyte expansion in myeloproliferative neoplasms (MPNs) is due to uncontrolled proliferation accompanied by dysregulation of proapoptotic and antiapoptotic mechanisms. Here we have investigated the intrinsic and extrinsic apoptotic pathways of megakaryocytes in human MPNs to further define the mechanisms involved. Methods The megakaryocytic expression of proapoptotic caspase-8, caspase-9, Diablo, p53 and antiapoptotic survivin proteins was investigated in bone marrow specimens of the MPNs (n=145) and controls (n=15) using immunohistochemistry. The megakaryocyte percentage positivity was assessed by light microscopy and correlated with the MPN entity, JAK2V617F/CALR mutation status and platelet count. Results The proportion of megakaryocytes in the MPNs expressing caspase-8, caspase-9, Diablo, survivin and p53 was significantly greater than controls. A greater proportion of myeloproliferative megakaryocytes expressed survivin relative to its reciprocal inhibitor, Diablo. Differences were seen between myelofibrosis, polycythaemia vera and essential thrombocythaemia for caspase-9 and p53. CALR-mutated cases had greater megakaryocyte p53 positivity compared to those with the JAK2V617F mutation. Proapoptotic caspase-9 expression showed a positive correlation with platelet count, which was most marked in myelofibrosis and CALR-mutated cases. Conclusions Disruptions targeting the intrinsic apoptotic cascade promote megakaryocyte hyperplasia and thrombocytosis in the MPNs. There is progressive dysfunction of apoptosis as evidenced by the marked reduction in proapoptotic caspase-9 and accumulation of p53 in myelofibrosis. The dysfunction of caspase-9, which is necessary for proplatelet formation, may be the mechanism for the excess thrombocytosis associated with CALR mutations. Survivin seems to be the key protein mediating the megakaryocyte survival signature in the MPNs and is a potential therapeutic target. PMID:27060176

  8. Unilateral nevoid telangiectasia syndrome (UNTS) associated with chronic hepatitis C virus and positive immunoreactivity for VEGF.

    PubMed

    Smith, J A; Kamangar, F; Prakash, N; Fung, M A; Konia, T; Fazel, N

    2014-06-15

    Unilateral Nevoid Telangectasia Syndrome (UNTS) is characterized by superficial telangiectasias in a unilateral distribution. Vascular endothelial growth factor (VEGF) may play a role in the pathogenesis of UNTS in patients with underlying hepatic disease. We report a case of a patient with UNTS accompanied by chronic hepatitis C virus infection, with a normal serum estrogen profile and strong positive immunohistochemical staining of lesional skin with VEGF.

  9. Improved targeting of JAK2 leads to increased therapeutic efficacy in myeloproliferative neoplasms

    PubMed Central

    Bhagwat, Neha; Koppikar, Priya; Keller, Matthew; Marubayashi, Sachie; Shank, Kaitlyn; Rampal, Raajit; Qi, Jun; Kleppe, Maria; Patel, Hardik J.; Shah, Smit K.; Taldone, Tony; Bradner, James E.; Chiosis, Gabriela

    2014-01-01

    The discovery of JAK2/MPL mutations in patients with myeloproliferative neoplasms (MPN) led to clinical development of Janus kinase (JAK) inhibitors for treatment of MPN. These inhibitors improve constitutional symptoms and splenomegaly but do not significantly reduce mutant allele burden in patients. We recently showed that chronic exposure to JAK inhibitors results in inhibitor persistence via JAK2 transactivation and persistent JAK–signal transducer and activator of transcription signaling. We performed genetic and pharmacologic studies to determine whether improved JAK2 inhibition would show increased efficacy in MPN models and primary samples. Jak2 deletion in vivo led to profound reduction in disease burden not seen with JAK inhibitors, and deletion of Jak2 following chronic ruxolitinib therapy markedly reduced mutant allele burden. This demonstrates that JAK2 remains an essential target in MPN cells that survive in the setting of chronic JAK inhibition. Combination therapy with the heat shock protein 90 (HSP90) inhibitor PU-H71 and ruxolitinib reduced total and phospho-JAK2 and achieved more potent inhibition of downstream signaling than ruxolitinib monotherapy. Combination treatment improved blood counts, spleen weights, and reduced bone marrow fibrosis compared with ruxolitinib alone. These data suggest alternate approaches that increase JAK2 targeting, including combination JAK/HSP90 inhibitor therapy, are warranted in the clinical setting. PMID:24470592

  10. 3q26.2/EVI1 rearrangement is associated with poor prognosis in classical Philadelphia chromosome-negative myeloproliferative neoplasms.

    PubMed

    Hu, Zhihong; Medeiros, L Jeffrey; Wang, Wei; Chen, Zi; Tang, Guilin; Hodjat, Parsa; Yang, Su; Fang, Lianghua; Li, Yan; Verstovsek, Srdan; Hu, Shimin

    2017-03-24

    Classical Philadelphia chromosome-negative myeloproliferative neoplasms are a group of closely related myeloid disorders with different histologic features and clinical presentations at an early stage, but all later develop into a similar fibrotic stage with variable risk of acute transformation. The significance of 3q26.2/EVI1 rearrangement has been well recognized in acute myeloid leukemia, myelodysplastic syndrome, and chronic myeloid leukemia. However, the clinical importance of 3q26.2/EVI1 rearrangement in classical Philadelphia chromosome-negative myeloproliferative neoplasms is unknown. Here we reported 15 patients with classical Philadelphia chromosome-negative myeloproliferative neoplasms showing 3q26.2 rearrangement, including inv(3)(q21q26.2) (n=6), t(3;21)(q26.2;q22)(n=4), t(3;3)(q21;q26.2)(n=3), inv(3)(q13.3q26.2)(n=1), and t(3;12)(q26.2;p13)(n=1). In addition to 3q26.2 rearrangement, 9 of 15 cases had other concurrent karyotypical abnormalities, including -7/7q- and -5/5q-. There were 8 men and 7 women with a median age of 59 years (range, 35-79 years) at initial diagnosis of myeloproliferative neoplasms: 8 patients had primary myelofibrosis, 4 had polycythemia vera, and 3 had essential thrombocythemia. JAK2 V617F mutation was detected in 8/14 patients, including 4/4 with polycythemia vera. The median interval from the initial diagnosis of myeloproliferative neoplasms to the detection of 3q26.2 rearrangement was 44 months (range, 1-219 months). At time of emergence of 3q26.2 rearrangement, 11 patients were in blast phase and 2 patients had increased blasts (6-19%). Dyspoiesis, predominantly in megakaryocytes, were detected in all patients with adequate specimens at time of 3q26.2 rearrangement. Following 3q26.2 rearrangement, 12 patients received chemotherapy, but none of them achieved complete remission. Of 14 patients with follow-up information, all died with a median overall survival time of only 3 months (range 0-14 months) after the emergence of

  11. Parathyroid incidentalomas detected during thyroid ultrasonography and effect of chronic thyroiditis on false positive parathyroid lesions.

    PubMed

    Ozdemir, Didem; Arpaci, Dilek; Ucler, Rifki; Cuhaci, Neslihan; Ersoy, Reyhan; Cakir, Bekir

    2012-12-01

    We aimed to determine the prevalence of parathyroid incidentalomas in patients referred for thyroid ultrasonography (US) and investigate the role of chronic thyroiditis on false positive lesions. Patients suspected to have parathyroid lesions during thyroid US were recorded prospectively between August 2009 and January 2010. Patients referred for parathyroid US and patients with known high serum calcium or parathyroid hormone (PTH) levels were excluded. Suspected parathyroid lesions were defined as hypoechoic, homogeneous, solid lesions with regular margins located outside the thyroid lobe, most commonly inferior to the thyroid gland. Thyroid US was performed in 6,528 patients. There were 78 patients (1.19 %) (73 female and 5 male) with suspected parathyroid lesion. The diagnosis of a true parathyroid adenoma was confirmed in 6 (7.69 %) patients. In patients with true adenoma, mean serum calcium, phosphorus, and PTH levels were 10.57 ± 0.48 mg/dl, 3.03 ± 0.52 mg/dl, and 182.91 ± 46.62 pg/ml, respectively. Among 72 patients with false positive parathyroid lesion, antithyroid peroxidase antibody was positive in 50 (69.4 %), antithyroglobulin antibody was positive in 46 (63.9 %), and one of these antibodies were positive in 59 (81.9 %) patients. Also, 46 (63.9 %) of these patients had thyroid dysfunctions (43 hypothyroidism and 3 hyperthyroidism) and 59 (81.9 %) had chronic thyroiditis ultrasonographically. Parathyroid incidentaloma was detected in 0.09 % of patients referred for thyroid US. The presence of clinically or ultrasonographically chronic thyroiditis might cause inadvertent interpretation of a hypoechoic lesion as a parathyroid pathology during thyroid US.

  12. Electromyography of symmetrical trunk movements and trunk position sense in chronic stroke patients

    PubMed Central

    Liao, Chien-Fen; Liaw, Lih-Jiun; Wang, Ray-Yau; Su, Fong-Chin; Hsu, Ar-Tyan

    2015-01-01

    [Purpose] To explore the differences in bilateral trunk muscle activation between chronic stroke patients and healthy controls, this study investigated the symmetry index and cross-correlation of trunk muscles during trunk flexion and extension movements. This study also assessed the differences in trunk reposition error between groups and the association between trunk reposition error and bilateral trunk muscle activation. [Subjects and Methods] Fifteen stroke patients and 15 age- and gender-matched healthy subjects participated. Bilateral trunk muscle activations were collected by electromyography during trunk flexion and extension. Trunk reposition errors in trunk flexion and extension directions were recorded by a Qualisys motion capture system. [Results] Compared with the healthy controls, the stroke patients presented lower symmetrical muscle activation of the bilateral internal oblique and lower cross-correlation of abdominal muscles during trunk flexion, and lower symmetry index and cross-correlation of erector spinae in trunk extension. They also showed a larger trunk extension reposition error. A smaller trunk reposition error was associated with higher cross-correlation of bilateral trunk muscles during trunk movements in all subjects. [Conclusion] Trunk muscle function during symmetrical trunk movements and trunk reposition sense were impaired in the chronic stroke patients, and trunk position sense was associated with trunk muscle functions. Future studies should pay attention to symmetrical trunk movements as well as trunk extension position sense for patients with chronic stroke. PMID:26504267

  13. The myeloproliferative neoplasms, unclassifiable: clinical and pathological considerations.

    PubMed

    Gianelli, Umberto; Cattaneo, Daniele; Bossi, Anna; Cortinovis, Ivan; Boiocchi, Leonardo; Liu, Yen-Chun; Augello, Claudia; Bonometti, Arturo; Fiori, Stefano; Orofino, Nicola; Guidotti, Francesca; Orazi, Attilio; Iurlo, Alessandra

    2017-02-01

    In this study, we investigate in detail the morphological, clinical and molecular features of 71 consecutive patients with a diagnosis of myeloproliferative neoplasms, unclassifiable. We performed a meticulous morphological analysis and found that most of the cases displayed a hypercellular bone marrow (70%) with normal erythropoiesis without left-shifting (59%), increased granulopoiesis with left-shifting (73%) and increased megakaryocytes with loose clustering (96%). Megakaryocytes displayed frequent giant forms with hyperlobulated or bulbous nuclei and/or other maturation defects. Interestingly, more than half of the cases displayed severe bone marrow fibrosis (59%). Median values of hemoglobin level and white blood cells count were all within the normal range; in contrast, median platelets count and lactate dehydrogenase were increased. Little less than half of the patients (44%) showed splenomegaly. JAK2V617F mutation was detected in 72% of all patients. Among the JAK2-negative cases, MPLW515L mutation was found in 17% and CALR mutations in 67% of the investigated cases, respectively. Finally, by multiple correspondence analysis of the morphological profiles, we found that all but four of the cases could be grouped in three morphological clusters with some features similar to those of the classic BCR-ABL1-negative myeloproliferative neoplasms. Analysis of the clinical parameters in these three clusters revealed discrepancies with the morphological profile in about 55% of the patients. In conclusion, we found that the category of myeloproliferative neoplasm, unclassifiable is heterogeneous but identification of different subgroups is possible and should be recommended for a better management of these patients.

  14. NCCN Guidelines Insights: Myeloproliferative Neoplasms, Version 2.2018.

    PubMed

    Mesa, Ruben A; Jamieson, Catriona; Bhatia, Ravi; Deininger, Michael W; Fletcher, Christopher D; Gerds, Aaron T; Gojo, Ivana; Gotlib, Jason; Gundabolu, Krishna; Hobbs, Gabriela; McMahon, Brandon; Mohan, Sanjay R; Oh, Stephen; Padron, Eric; Papadantonakis, Nikolaos; Pancari, Philip; Podoltsev, Nikolai; Rampal, Raajit; Ranheim, Erik; Reddy, Vishnu; Rein, Lindsay A M; Scott, Bart; Snyder, David S; Stein, Brady L; Talpaz, Moshe; Verstovsek, Srdan; Wadleigh, Martha; Wang, Eunice S; Bergman, Mary Anne; Gregory, Kristina M; Sundar, Hema

    2017-10-01

    Myeloproliferative neoplasms (MPNs) are a group of heterogeneous disorders of the hematopoietic system that include myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET). PV and ET are characterized by significant thrombohemorrhagic complications and a high risk of transformation to MF and acute myeloid leukemia. The diagnosis and management of PV and ET has evolved since the identification of mutations implicated in their pathogenesis. These NCCN Guideline Insights discuss the recommendations outlined in the NCCN Guidelines for the risk stratification, treatment, and special considerations for the management of PV and ET. Copyright © 2017 by the National Comprehensive Cancer Network.

  15. Update on the management of Philadelphia chromosome positive chronic myelogenous leukemia: role of nilotinib

    PubMed Central

    Emole, Josephine; Talabi, Taiwo; Pinilla-Ibarz, Javier

    2016-01-01

    Chronic myelogenous leukemia (CML) is a pluripotent stem cell disease characterized by the presence of the Philadelphia chromosome and the bcr-abl gene. The discovery of tyrosine kinase inhibitors (TKIs) revolutionized therapy for CML, such that durable response, increased overall survival, and increased progression-free survival of patients in chronic phase CML is now possible. Due to resistance and intolerance to imatinib, there was need for development of second- and third-generation TKIs for the treatment of CML. This review examines the role of nilotinib, an oral second-generation TKI, in the treatment of Philadelphia positive CML. The pharmacology, efficacy, and safety of nilotinib are critically evaluated. Patient-related issues, including tolerance, drug interactions, and quality of life issues are also examined. PMID:27013862

  16. An evaluation of a positive youth development program for adolescents with chronic illness.

    PubMed

    Maslow, Gary; Adams, Cathleen; Willis, Matthew; Neukirch, Jodie; Herts, Kate; Froehlich, Wendy; Calleson, Diane; Rickerby, Michelle

    2013-02-01

    Youth with chronic illness often struggle transitioning to adulthood and adult medical care. This article examines the outcomes of a group mentoring program called The Adolescent Leadership Council (TALC) that brings together high school participants and college mentors, all with chronic illness. TALC uses a positive youth development (PYD) approach, emphasizing strong relationships between youth and adults in an environment where youth can learn important life skills and take a leadership role. A pre-/postprogram participant survey was conducted for high school participants using a loneliness scale and a transition readiness survey. An alumni survey was conducted with all high school and college mentor graduates to assess educational-, vocational-, and health care-related outcomes. Program records review and the alumni survey indicated that TALC was consistent with the PYD program model. Twenty high school students participated in the pre-/postprogram outcomes evaluation, which demonstrated a decrease in loneliness from 46 to 38.5 (p < .001) and an increase in health care self-advocacy from 3.8 to 4.2 (p < .001). Thirty-four alumni participated in the alumni survey. All high school and college mentor alumni had graduated from high school and college, respectively, and all were either currently in school or working. The majority of alumni were seeing adult providers for medical care. The TALC program applies the principles of PYD to support positive educational, vocational, and health care outcomes for youth with chronic illness. Program development using the PYD perspective is an important new approach for supporting adult development of youth with chronic illness. Copyright © 2013 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

  17. Increased CD4+/CD8+ Double-Positive T Cells in Chronic Chagasic Patients

    PubMed Central

    Giraldo, Nicolas A.; Bolaños, Natalia I.; Cuellar, Adriana; Guzman, Fanny; Uribe, Ana Maria; Bedoya, Astrid; Olaya, Natalia; Cucunubá, Zulma M.; Roa, Nubia; Rosas, Fernando; Velasco, Víctor; Puerta, Concepción J.; González, John M.

    2011-01-01

    Background CD4+/CD8+ double positive (DP) T cells have been described in healthy individuals as well as in patients with autoimmune and chronic infectious diseases. In chronic viral infections, this cell subset has effector memory phenotype and displays antigen specificity. No previous studies of double positive T cells in parasite infections have been carried out. Methodology/Principal Findings Seventeen chronic chagasic patients (7 asymptomatic and 10 symptomatic) and 24 non-infected donors, including 12 healthy and 12 with non-chagasic cardiomyopathy donors were analyzed. Peripheral blood was stained for CD3, CD4, CD8, HLA-DR and CD38, and lymphocytes for intracellular perforin. Antigen specificity was assessed using HLA*A2 tetramers loaded with T. cruzi K1 or influenza virus epitopes. Surface expression of CD107 and intracellular IFN-γ production were determined in K1-specific DP T cells from 11 chagasic donors. Heart tissue from a chronic chagasic patient was stained for both CD8 and CD4 by immunochemistry. Chagasic patients showed higher frequencies of DP T cells (2.1%±0.9) compared with healthy (1.1%±0.5) and non-chagasic cardiomyopathy (1.2%±0.4) donors. DP T cells from Chagasic patients also expressed more HLA-DR, CD38 and perforin and had higher frequencies of T. cruzi K1-specific cells. IFN-γ production in K1-specific cells was higher in asymptomatic patients after polyclonal stimulation, while these cells tended to degranulate more in symptomatic donors. Immunochemistry revealed that double positive T cells infiltrate the cardiac tissue of a chagasic donor. Conclusions Chagasic patients have higher percentages of circulating double positive T cells expressing activation markers, potential effector molecules and greater class I antigenic specificity against T. cruzi. Although K1 tetramer positive DP T cell produced little IFN-γ, they displayed degranulation activity that was increased in symptomatic patients. Moreover, K1-specific DP T cells can

  18. Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms.

    PubMed

    Grand, Francis H; Hidalgo-Curtis, Claire E; Ernst, Thomas; Zoi, Katerina; Zoi, Christine; McGuire, Carolann; Kreil, Sebastian; Jones, Amy; Score, Joannah; Metzgeroth, Georgia; Oscier, David; Hall, Andrew; Brandts, Christian; Serve, Hubert; Reiter, Andreas; Chase, Andrew J; Cross, Nicholas C P

    2009-06-11

    Recent evidence has demonstrated that acquired uniparental disomy (aUPD) is a novel mechanism by which pathogenetic mutations in cancer may be reduced to homozygosity. To help identify novel mutations in myeloproliferative neoplasms (MPNs), we performed a genome-wide single nucleotide polymorphism (SNP) screen to identify aUPD in 58 patients with atypical chronic myeloid leukemia (aCML; n = 30), JAK2 mutation-negative myelofibrosis (MF; n = 18), or JAK2 mutation-negative polycythemia vera (PV; n = 10). Stretches of homozygous, copy neutral SNP calls greater than 20Mb were seen in 10 (33%) aCML and 1 (6%) MF, but were absent in PV. In total, 7 different chromosomes were involved with 7q and 11q each affected in 10% of aCML cases. CBL mutations were identified in all 3 cases with 11q aUPD and analysis of 574 additional MPNs revealed a total of 27 CBL variants in 26 patients with aCML, myelofibrosis or chronic myelomonocytic leukemia. Most variants were missense substitutions in the RING or linker domains that abrogated CBL ubiquitin ligase activity and conferred a proliferative advantage to 32D cells overexpressing FLT3. We conclude that acquired, transforming CBL mutations are a novel and widespread pathogenetic abnormality in morphologically related, clinically aggressive MPNs.

  19. Classification, diagnosis and management of myeloproliferative disorders in the JAK2V617F era.

    PubMed

    Tefferi, Ayalew

    2006-01-01

    JAK2V617F, a somatic gain-of-function mutation involving the JAK2 tyrosine kinase gene, occurs in nearly all patients with polycythemia vera (PV) but also in a variable proportion of patients with other myeloid disorders; mutational frequency is estimated at approximately 50% in both essential thrombocythemia (ET) and myelofibrosis (MF), up to 20% in certain subcategories of atypical myeloproliferative disorder (atypical MPD), less than 3% in de novo myelodysplastic syndrome (MDS) or acute myeloid leukemia, and 0% in chronic myeloid leukemia (CML). Accordingly, there is now molecular justification for grouping PV, ET, and MF together in a distinct MPD category (i.e., classic, BCR-ABL(-) MPD) that is separate from chronic myeloid leukemia (CML), MDS, and atypical MPD. To date, JAK2V617F has not been described in patients with reactive myeloproliferation, lymphoid disorders, or solid tumor. Therefore, the presence of JAK2V617F strongly suggests an underlying MPD and it is therefore reasonable to consider JAK2V617F-based laboratory tests for the evaluation of polycythemia, primary thrombocytosis, unexplained leukocytosis, bone marrow fibrosis, or abdominal vein thrombosis. Current information on disease-specific prognostic relevance of JAK2V617F is inconclusive and confounded by inter-study differences in the performance of mutation screening assays. Regardless, the discovery of JAK2V617F has reinforced the pathogenetic contribution of JAK-STAT signaling in MPD and identifies JAK2 as a valid drug target.

  20. Poly(ADP-Ribose) Polymerase Inhibitor Hypersensitivity in Aggressive Myeloproliferative Neoplasms

    PubMed Central

    Pratz, Keith W.; Koh, Brian; Patel, Anand G.; Flatten, Karen S.; Poh, Weijie; Herman, James G.; Dilley, Robert; Harrell, Maria I.; Smith, B. Douglas; Karp, Judith E.; Swisher, Elizabeth M.; McDevitt, Michael A.; Kaufmann, Scott H.

    2016-01-01

    Purpose DNA repair defects have been previously reported in myeloproliferative neoplasms (MPNs). Inhibitors of poly(ADP-ribose) polymerase (PARP) have shown activity in solid tumors with defects in homologous recombination (HR). The present study was performed to assess MPN sensitivity to PARP inhibitors ex vivo. Experimental Design HR pathway integrity in circulating myeloid cells was evaluated by assessing formation of RAD51 foci after treatment with ionizing radiation or PARP inhibitors. Sensitivity of MPN erythroid and myeloid progenitors to PARP inhibitors was evaluated using colony formation assays. Results Six of 14 MPN primary samples had reduced formation of RAD51 foci after exposure to ionizing radiation, suggesting impaired HR. This phenotype was not associated with a specific MPN subtype, JAK2 mutation status or karyotype. MPN samples showed increased sensitivity to the PARP inhibitors veliparib and olaparib compared to normal myeloid progenitors. This hypersensitivity, which was most pronounced in samples deficient in DNA damage-induced RAD51 foci, was observed predominantly in samples from patients with diagnoses of chronic myelogenous leukemia, chronic myelomonocytic leukemia or unspecified myelodysplastic/MPN overlap syndromes. Conclusions Like other neoplasms with HR defects, MPNs exhibit PARP inhibitor hypersensitivity compared to normal marrow. These results suggest that further preclinical and possibly clinical study of PARP inhibitors in MPNs is warranted. PMID:26979391

  1. Ondansetron in Treating Patients With Advanced Cancer and Chronic Nausea and Vomiting Not Caused by Cancer Treatment

    ClinicalTrials.gov

    2016-07-01

    Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Nausea and Vomiting; Precancerous Condition; Small Intestine Cancer; Unspecified Adult Solid Tumor, Protocol Specific; Unspecified Childhood Solid Tumor, Protocol Specific

  2. Back to Biology: New Insights on Inheritance in Myeloproliferative Disorders

    PubMed Central

    Braunstein, Evan M.

    2015-01-01

    The myeloproliferative disorders (MPDs) are a group of hematologic diseases with significant overlap in both clinical phenotype and genetic etiology. While most often caused by acquired somatic mutations in hematopoietic stem cells, the presence of familial clustering in MPD cases suggests that inheritance is an important factor in the etiology of this disease. Though far less common than sporadic disease, inherited MPDs can be clinically indistinguishable from sporadic disease. Recently, germline mutations in Janus kinase 2 (JAK2) and MPL, two genes frequently mutated in sporadic MPD, have been shown to cause inherited thrombocytosis. Study of the function of these mutant proteins has led to a new understanding of the biological mechanisms that produce myeloproliferative disease. In this review, we summarize the data regarding inherited mutations that cause or predispose to MPDs, with a focus on the biological effects of mutant proteins. We propose that defining inherited MPDs in this manner has the potential to simplify diagnosis in a group of disorders that can be difficult to differentiate clinically. PMID:25195195

  3. Epigenetic therapy in myeloproliferative neoplasms: evidence and perspectives

    PubMed Central

    Vannucchi, Alessandro M; Guglielmelli, Paola; Rambaldi, Alessandro; Bogani, Costanza; Barbui, Tiziano

    2009-01-01

    The classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), which include polycythaemia vera, essential thrombocythaemia and primary myelofibrosis, originate from a stem cell-derived clonal myeloproliferation that manifests itself with variable haematopoietic cell lineage involvement; they are characterized by a high degree of similarities and the chance to transform each to the other and to evolve into acute leukaemia. Their molecular pathogenesis has been associated with recurrent acquired mutations in janus kinase 2 (JAK2) and myeloproliferative leukemia virus oncogene (MPL). These discoveries have simplified the diagnostic approach and provided a number of clues to understanding the phenotypic expression of MPNs; furthermore, they represented a framework for developing and/or testing in clinical trials small molecules acting as tyrosine kinase inhibitors. On the other hand, evidence of abnormal epigenetic gene regulation as a mechanism potentially contributing to the pathogenesis and the phenotypic diversity of MPNs is still scanty; however, study of epigenetics in MPNs represents an active field of research. The first clinical trials with epigenetic drugs have been completed recently, whereas others are still ongoing; results have been variable and at present do not allow any firm conclusion. Novel basic and translational information concerning epigenetic gene regulation in MPNs and the perspectives for therapy will be critically addressed in this review. PMID:19522842

  4. Contemporary Use of Interferon Therapy in the Myeloproliferative Neoplasms.

    PubMed

    Foucar, Charles Elliott; Stein, Brady Lee

    2017-09-25

    The purpose of this article is to review the current evidence behind interferon therapy in patients with myeloproliferative neoplasms. Preliminary analysis suggests that interferon may be non-inferior to hydroxyurea in patients with polycythemia vera and essential thrombocytosis. Responses have been observed regardless of JAK2 mutational status, but the presence of non-JAK2 somatic mutations may negatively influence response rates. Pegylated interferon has proven efficacy for patients with myeloproliferative neoplasms. Both newly diagnosed and previously treated patients with polycythemia vera and essential thrombocytosis exhibit high hematologic response rates, and some of these patients achieve molecular responses as well. Interferon therapy leads to lower rates of hematologic response in MF patients, but patients earlier on in their disease course have a better chance of responding. There are ongoing trials comparing pegylated interferon to hydroxyurea in essential thrombocytosis (ET) and polycythemia vera (PV), and early analysis suggests non-inferiority. However, longer follow-up is needed before drawing any conclusions. Future research is needed to better define characteristics of the best responders and to determine whether novel forms of interferon therapy or combination therapy with interferon can enhance efficacy and tolerability.

  5. Incidence of gastroesophageal reflux disease and positive maxillary antral cultures in children with symptoms of chronic rhinosinusitis.

    PubMed

    Nation, Javan; Kaufman, Michael; Allen, Meredith; Sheyn, Anthony; Coticchia, James

    2014-02-01

    Studies have shown that gastroesophageal reflux disease occurs more frequently than expected in children with chronic rhinosinusitis. The objective of this study is to further understand the relationship of pediatric chronic rhinosinusitis and gastroesophageal reflux disease in children with symptoms of rhinorrhea, nasal congestion, and chronic cough. A retrospective chart review of 63 children, ages 6 months to 10 years old with rhinorrhea, nasal congestion, and chronic cough. The patients underwent maxillary cultures, adenoidectomy, and distal third esophageal biopsies. Children with esophageal biopsies showing esophagitis were classified as positive for gastroesophageal reflux disease, and maxillary antral swabs growing a high density of bacteria were classified as positive for chronic rhinosinusitis. Six months to 5 years old children (n=43), 6 (14%) had simultaneous positive maxillary antral cultures and positive esophageal biopsies, 11 (26%) had positive esophageal biopsies alone, 23 (53%) had positive maxillary antral cultures alone, and 3 (7%) had neither. Six to 10 years old children (n=20), 9 (45%) had simultaneous positive maxillary antral cultures and positive esophageal biopsies, 1 (5%) patient had positive esophageal biopsies alone, 3 (15%) patients had positive maxillary antral cultures alone, and 7 (35%) patients had neither. Twenty-seven (42%) of the patients from the whole study had gastroesophageal reflux positive biopsies. The younger children were statistically likely to have chronic rhinosinusitis and gastroesophageal reflux disease independently of each other (p=0.0002). A direct group comparison found the younger group to have independent chronic rhinosinusitis and gastroesophageal reflux disease and the older group to have simultaneous chronic rhinosinusitis and gastroesophageal reflux disease (p=0.0006). In children with the presenting symptoms of rhinorrhea, nasal congestion, and chronic cough, younger children tend to have either chronic

  6. Chronic ketamine produces altered distribution of parvalbumin-positive cells in the hippocampus of adult rats.

    PubMed

    Sabbagh, Jonathan J; Murtishaw, Andrew S; Bolton, Monica M; Heaney, Chelcie F; Langhardt, Michael; Kinney, Jefferson W

    2013-08-29

    The underlying mechanisms of schizophrenia pathogenesis are not well understood. Increasing evidence supports the glutamatergic hypothesis that posits a hypofunction of the N-methyl D-aspartate (NMDA) receptor on specific gamma amino-butyric acid (GABA)-ergic neurons may be responsible for the disorder. Alterations in the GABAergic system have been observed in schizophrenia, most notably a change in the expression of parvalbumin (PV) in the cortex and hippocampus. Several reports also suggest abnormal neuronal migration may play a role in the etiology of schizophrenia. The current study examined the positioning and distribution of PV-positive cells in the hippocampus following chronic treatment with the NMDA receptor antagonist ketamine. A robust increase was found in the number of PV-positive interneurons located outside the stratum oriens (SO), the layer where most of these cells are normally localized, as well as an overall numerical increase in CA3 PV cells. These results suggest ketamine leads to an abnormal distribution of PV-positive cells, which may be indicative of aberrant migratory activity and possibly related to the Morris water maze deficits observed. These findings may also be relevant to alterations observed in schizophrenia populations.

  7. Nilotinib and Combination Chemotherapy in Treating Patients With Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia or Blastic Phase Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2015-10-29

    B-cell Adult Acute Lymphoblastic Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia

  8. Regular control at the general practitioner is positively correlated with patient satisfaction with chronic care management.

    PubMed

    Bjørnholt Nielsen, Pernille; Witzel, Simone

    2016-03-01

    The aim of the study is to identify how disease management programmes for patients with a chronic disease work. This issue is explored from the patients' perspective. Specifically, we study how transition and coordination are related to the patient's perception of quality of care, with a particular focus on the general practitioner's (GP) role. The study is based on a survey conducted among patients with Type 2 diabetes, chronic obstructive pulmonary disease (COPD) or acute coronary syndrome (ACS) in the Central Denmark Region in 2011 and 2012. Data are analysed using logistic regression models. A total of 4,174 patients answered the questionnaire. The response rate was 43%. Whether the patient attends regular visits with the GP or not has a significant influence on both the patient's overall perception of the healthcare sector and on the patient's perception of the organisation of care. Variation among patient groups was identified and COPD patients had the least positive overall perception of the care received. Patients who visit their GP for regular control both have a better overall perception of the healthcare sector and are more likely to think that their treatment is well organised. Patients with COPD have a less positive score than patients with ACS and diabetes. none. not relevant.

  9. Comparison of intermittent positive pressure breathing and temporary positive expiratory pressure in patients with severe chronic obstructive pulmonary disease.

    PubMed

    Nicolini, Antonello; Mollar, Elena; Grecchi, Bruna; Landucci, Norma

    2014-01-01

    Results supporting the use and the effectiveness of positive expiratory, pressure devices in chronic obstructive pulmonary disease (COPD) patients are still controversial, We have tested the hypothesis that adding TPEP or IPPB to standard pharmacological therapy may provide additional clinical benefit over, pharmacological therapy only in patients with severe COPD. Fourty-five patients were randomized in three groups: a group was treated; with IPPB,a group was treated with TPEP and a group with pharmacological; therapy alone (control group). Primary outcome measures included the measurement of scale or, questionnaire concerning dyspnea (MRC scale),dyspnea,cough, and, sputum (BCSS) and quality of life (COPD assessment test) (CAT). Secondary, outcome measures were respiratory function testing,arterial blood gas,analysis,and hematological examinations. Both patients in the IPPB group and in the TPEP group showed a significant, improvement in two of three tests (MRC,CAT) compared to the control, group.However,in the group comparison analysis for, the same variables between IPPB group and TPEP group we observed a, significant improvement in the IPPB group (P≤.05 for MRC and P≤.01 for, CAT). The difference of action of the two techniques are evident in the results of, pulmonary function testing: IPPB increases FVC, FEV1, and MIP; this reflects, its capacity to increase lung volume. Also TPEP increases FVC and FEV1 (less, than IPPB), but increases MEP, while decreasing total lung capacity and, residual volume. The two techniques (IPPB and TPEP) improves significantly dyspnea; quality of; life tools and lung function in patients with severe COPD. IPPB demonstrated a greater effectiveness to improve dyspnea and quality of life tools (MRC, CAT) than TPEP. Copyright © 2013 SEPAR. Published by Elsevier Espana. All rights reserved.

  10. Influence of chronic neck pain on cervical joint position error (JPE): Comparison between young and elderly subjects.

    PubMed

    Alahmari, Khalid A; Reddy, Ravi Shankar; Silvia, Paul; Ahmad, Irshad; Nagaraj, Venkat; Mahtab, Mohammad

    2017-08-03

    Evaluation of cervical joint position sense in subjects with chronic neck pain has gained importance in recent times. Different authors have established increased joint position error (JPE) in subjects with acute neck pain. However, there is a paucity of studies to establish the influence of chronic neck pain on cervical JPE. The objective of the study was to understand the influence of chronic neck pain on cervical JPE, and to examine the differences in cervical JPE between young and elderly subjects with chronic neck pain. Forty-two chronic neck pain patients (mean age 47.4) were compared for cervical JPE with 42 age-matched healthy subjects (mean age 47.8), using a digital inclinometer. The cervical JPE were measured in flexion, extension, and rotation in right and left movement directions. The comparison of JPE showed significantly larger errors in subjects with chronic neck pain when compared to healthy subjects (p< 0.001). The errors were larger in all of the movement directions tested. Comparison between young and older subjects with chronic neck pain revealed no significant differences (P> 0.05) in cervical JPE. Cervical joint position sense is impaired in subjects with chronic neck pain.

  11. Comparison of Positive Youth Development for Youth With Chronic Conditions With Healthy Peers.

    PubMed

    Maslow, Gary R; Hill, Sherika N; Pollock, McLean D

    2016-12-01

    Adolescents with childhood-onset chronic condition (COCC) are at increased risk for physical and psychological problems. Despite being at greater risk and having to deal with traumatic experiences and uncertainty, most adolescents with COCC do well across many domains. The Positive Youth Development (PYD) perspective provides a framework for examining thriving in youth and has been useful in understanding positive outcomes for general populations of youth as well as at-risk youth. This study aimed to compare levels of PYD assets between youth with COCC and youth without illness. Participants with COCC were recruited from specialty pediatric clinics while healthy participants were recruited from a large pediatric primary care practice. Inclusion criteria for participants included being (1) English speaking, (2) no documented intellectual disability in electronic medical record, and (3) aged between 13 and 18 years during the recruitment period. Univariate and bivariate analyses on key variables were conducted for adolescents with and without COCC. Finally, we performed multivariable linear regressions for PYD and its subdomains. There were no significant differences between overall PYD or any of the subdomains between the two groups. Multivariable linear regression models showed no statistically significant relationship between chronic condition status and PYD or the subdomains. The findings from this study support the application of the PYD perspective to this population of youth. The results of this study suggest that approaches shown to benefit healthy youth, could be used to promote positive outcomes for youth with COCC. Copyright © 2016 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

  12. Progenitor genotyping reveals a complex clonal architecture in a subset of CALR-mutated myeloproliferative neoplasms.

    PubMed

    Martin, Sarah; Wright, Casey M; Scott, Linda M

    2017-04-01

    The identification of acquired CALR mutations in patients with essential thrombocythaemia (ET) or myelofibrosis (MF) has meant that disease-initiating mutations can now be detected in about 90% of all patients with a myeloproliferative neoplasm (MPN). Here, we show that only those CALR mutations that cause a +1 frameshift, thereby altering the carboxy-terminus of calreticulin, promote cytokine independence in vitro; in-frame deletions were not functional, and are unlikely to be the pathogenetic mutation underlying some MPN cases. Expression of the thrombopoietin receptor, MPL, was also necessary for factor-independence. Although the CALR mutations are considered to occur only in JAK2 V617F-negative cases and in a heterozygous state, progenitor genotyping revealed that this is not always true. Notably, CALR mutation-positive MPNs can be polyclonal: in one case, two distinct CALR mutation-positive subpopulations could be identified; in another, separate populations of JAK2 V617F-positive and CALR-mutated cells were present. Mitotic recombination involving chromosome 19 in a third instance resulted in the emergence of a CALR mutation-homozygous subclone. Collectively, our studies demonstrate that occasional patients with CALR mutation-positive ET or MF carry other MPN-initiating genetic mutations (including JAK2 V617F), acquire "secondary mutations" before or after the CALR mutation, or evolve over time to being CALR mutation-homozygous.

  13. Diagnosis of del(5q) MDS, 14 Years after JAK-2 Positive PV Appearance: Complete Remission of both Diseases with Lenalidomide Monotherapy

    PubMed Central

    Vaccarino, Antonella; Dogliotti, Irene; Marletto, Fabio; Demarchi, Andrea; Bazzan, Mario

    2016-01-01

    This is the report of the clinical case of a patient who presents the association of a JAK-2 positive chronic myeloproliferative neoplasia to a subsequent 5q- myelodysplastic syndrome, developed after about 14 years from the first diagnosis. Patient’s symptoms had rapidly worsened, and she became transfusion-dependent. Therapy with low-dose Lenalidomide quickly reduced the splenomegaly and completely brought white cells counts, haemoglobin, and platelets back to normal. After more than one year from the start, blood cell count is still normal. As far as we know, this is the first case of an effective treatment with Lenalidomide reported in this clinical setting. PMID:27872730

  14. Diagnosis of del(5q) MDS, 14 Years after JAK-2 Positive PV Appearance: Complete Remission of both Diseases with Lenalidomide Monotherapy.

    PubMed

    Vaccarino, Antonella; Dogliotti, Irene; Marletto, Fabio; Demarchi, Andrea; Bazzan, Mario

    2016-01-01

    This is the report of the clinical case of a patient who presents the association of a JAK-2 positive chronic myeloproliferative neoplasia to a subsequent 5q- myelodysplastic syndrome, developed after about 14 years from the first diagnosis. Patient's symptoms had rapidly worsened, and she became transfusion-dependent. Therapy with low-dose Lenalidomide quickly reduced the splenomegaly and completely brought white cells counts, haemoglobin, and platelets back to normal. After more than one year from the start, blood cell count is still normal. As far as we know, this is the first case of an effective treatment with Lenalidomide reported in this clinical setting.

  15. Clofarabine, Cytarabine, and Filgrastim in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia, Advanced Myelodysplastic Syndrome, and/or Advanced Myeloproliferative Neoplasm

    ClinicalTrials.gov

    2016-12-27

    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); Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Refractory Anemia With Excess Blasts; Untreated Adult Acute Myeloid Leukemia; Myeloproliferative Neoplasm With 10% Blasts or Higher

  16. Primary myelofibrosis and the myeloproliferative neoplasms: the role of individual variation.

    PubMed

    Stein, Brady L; Moliterno, Alison R

    2010-06-23

    The classic myeloproliferative neoplasms--essential thrombocytosis, polycythemia vera, and primary myelofibrosis--are acquired, clonal hematopoietic stem cell disorders characterized by an overproduction of mature blood cells, bone marrow hypercellularity, extramedullary hematopoiesis, a tendency for thrombosis, and, rarely, leukemic transformation. Despite being classified as neoplastic diseases, the myeloproliferative neoplasms are often characterized by longevity, with survival measured in decades, even in the absence of treatment. Primary myelofibrosis is the rarest of the myeloproliferative neoplasms, is the most obscure with regard to its pathophysiology, and carries the least favorable although highly variable natural history. The identification of molecular lesions specific to the myeloproliferative neoplasms, in particular JAK2 V617F, has broadened understanding of the common features within these disorders and has advanced diagnostic, prognostic, and therapeutic tools. This article highlights the challenges inherent in the management of primary myelofibrosis and presents an opportunity to address the basis of individual variation within a rare and complex disorder.

  17. Suppression of E-protein activity interferes with the development of BCR-ABL-mediated myeloproliferative disease.

    PubMed

    Ko, Jinkyung; Patel, Nihal; Ikawa, Tomokatsu; Kawamoto, Hiroshi; Frank, Oliver; Rivera, Richard R; Van Etten, Richard A; Murre, Cornelis

    2008-09-02

    E-proteins are a class of helix-loop-helix (HLH) proteins, which play multiple roles throughout lymphoid development. The DNA binding activities of the E-proteins are regulated by a distinct class of antagonistic HLH proteins, named Id1-4. Here we demonstrate that Id2 deficient mice in a C57BL/6 genetic background exhibit increased cellularity in the granulocyte/myeloid progenitor compartment and show significantly higher numbers of maturing neutrophils. Within 6 months of age, Id2 deficient mice succumbed from overwhelming granulocytosis. The disease closely mimicked the distinctive features of human chronic myeloid leukemia: leukocytosis with maturing neutrophils, splenomegaly, hepatomegaly, and myeloid infiltration into peripheral tissues, including spleen, liver, and lungs. Strikingly, forced Id2 expression in murine bone marrow cells substantially delayed the onset of myeloproliferative disease (MPD). Collectively, these studies show that suppression of E-protein activity interferes with the development of BCR-ABL-mediated MPD.

  18. Changes in joint position sense after conservatively treated chronic lateral ankle instability.

    PubMed

    Kynsburg, A; Halasi, T; Tállay, A; Berkes, I

    2006-12-01

    Improvement of ankle proprioception through physiotherapy (a.k.a. proprioceptive training) is a widely accepted conservative treatment modality of chronic functional lateral ankle instability. Clinical studies provided controversial data on its proprioceptive effect. Aim of this study was to gain evidence on the efficacy of proprioceptive training on ankle joint position sense. Ten patients (five males and five females, aged 23.3+/-5.4 years) were treated conservatively for chronic lateral ankle instability with a special training programme over 6 weeks. For the assessment of joint position sense we used the slope-box test, first applied and described by Robbins et al. (Br J Sports Med 29:242-247, 1995). The test was performed before the start and after the end of the training programme, measuring joint position sense on 11 different slope amplitudes in four directions (anterior, posterior, lateral and medial) in random order each on both ankles. Comparisons were made between pre- and post-training results as well as versus a control-group of ten healthy athletes. Overall the proprioceptive sensory function of the studied group has improved, but this improvement was not significant in all directions. Only two patients have shown significant improvement of joint position sense in all directions (mean estimate error improvement: 2.47 degrees ), while conservative treatment was partially successful in five others (mean estimate error improvement: 0.73 degrees ). The follow-up results of these seven patients were comparable with the values measured in the control-group. Three patients did not show any improvements (mean estimate error improvement: -0.55 degrees ) (overall difference between improving and non-improving patients: P<0.0001). Mean absolute estimate error profiles of the seven improving patients became similar to the profiles of healthy athletes, while these changes could not be observed in the case of the three non-improving participants. Proprioceptive

  19. A rapid, highly accurate method for quantifying CALR mutant allele burden in persons with myeloproliferative neoplasms.

    PubMed

    Yao, Qiu-Mei; Zhou, Jiao; Gale, Robert Peter; Li, Jin-Lan; Li, Ling-Di; Li, Ning; Chen, Shan-Shan; Ruan, Guo-Rui

    2015-10-01

    Calreticulin (CALR) mutations were recently identified in a substantial proportion of persons with essential thrombocythemia (ET) and with primary myelofibrosis (PMF) without JAK2(V617F). Consequently rapid, sensitive, and specific methods to detect and quantify these mutations are needed. We studied samples from 1088 persons with myeloproliferative neoplasms (MPNs) including 421 JAK2(V617F) negative subjects with ET, PMF, polycythemia vera (PV), chronic myeloid leukemia (CML) and hyper-eosinophilic syndrome (HES). Detection of CALR exon 9 mutations was done by PCR amplification followed by fragment length analysis and direct sequencing. Dilution assays were used to determine CALR mutant allele burden. We detected CALR mutations in blood and bone marrow samples from 152 subjects with ET and with PMF but not in samples from normal or persons with PV, CML, or HES. CALR mutant peaks were distinct from wild-type peaks and dilution experiments indicated a sensitivity level of 0.5-5% for a CALR mutant allele in a wild-type background. Diverse types of mutations were detected including deletions, insertions, and complex indels. All mutations were confirmed by direct sequencing. We also used dilution experiments to quantify mutant allele burden. We were able to reproducibly detect mutant allele levels as low 5% (0.5-5%) in a wild-type background. PCR amplification followed by fragment length analysis is a rapid, sensitive, and specific method for screening persons with MPNs for CALR mutations, especially those with ET and PMF and for estimating mutant allele burden.

  20. JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms

    PubMed Central

    Jones, Amy V; Chase, Andrew; Silver, Richard T; Oscier, David; Zoi, Katerina; Wang, Y Lynn; Cario, Holger; Pahl, Heike L; Collins, Andrew; Reiter, Andreas; Grand, Francis; Cross, Nicholas C P

    2014-01-01

    Chronic myeloproliferative neoplasms (MPNs) are a group of related conditions characterized by the overproduction of cells from one or more myeloid lineages. More than 95% of cases of polycythemia vera, and roughly half of essential thrombocythemia and primary myelofibrosis acquire a unique somatic 1849G>T JAK2 mutation (encoding V617F) that is believed to be a critical driver of excess proliferation1–4. We report here that JAK2V617F-associated disease is strongly associated with a specific constitutional JAK2 haplotype, designated 46/1, in all three disease entities compared to healthy controls (polycythemia vera, n = 192, P = 2.9 × 10−16; essential thrombocythemia, n = 78, P = 8.2 × 10−9 and myelofibrosis, n = 41, P = 8.0 × 10−5). Furthermore, JAK2V617F specifically arises on the 46/1 allele in most cases. The 46/1 JAK2 haplotype thus predisposes to the development of JAK2V617F-associated MPNs (OR = 3.7; 95% CI = 3.1–4.3) and provides a model whereby a constitutional genetic factor is associated with an increased risk of acquiring a specific somatic mutation. PMID:19287382

  1. Physical Activity as a Nonpharmacological Symptom Management Approach in Myeloproliferative Neoplasms: Recommendations for Future Research.

    PubMed

    Eckert, Ryan; Huberty, Jennifer; Gowin, Krisstina; Mesa, Ruben; Marks, Lisa

    2016-07-24

    Essential thrombocythemia, polycythemia vera, and myelofibrosis are rare chronic hematological malignancies known as myeloproliferative neoplasms (MPNs) and are characterized by deregulated myeloid lineage cell production, splenomegaly, and heterogeneous symptom profiles. MPN patients suffer from a significant symptom burden (eg, fatigue, depressive symptoms, early satiety) and an impaired overall quality of life (QoL). Current treatments typically include pharmacological approaches, which may come with additional side effects and may be limited by treatment-associated toxicities (ie, cytopenias). Nonpharmacological approaches such as physical activity may be beneficial for reducing symptom burden and improving QoL. To date, no studies have examined physical activity as a nonpharmacological approach in MPN patients despite preliminary evidence supporting its benefit in other hematological cancers. The purpose of this article is to (1) review the literature related to physical activity and specific hematological cancer subtypes and to (2) make suggestions for future research involving physical activity in MPN patients as a symptom management strategy. A brief review of studies examining physical activity in leukemias, lymphomas, and myelomas (excluding stem-cell transplant patients) was conducted. There is preliminary evidence to suggest that physical activity may be an effective approach to improve patient-reported outcomes (fatigue, depression, anxiety, sleep), physical fitness (cardiovascular fitness, balance, body composition), and overall QoL in other hematological cancers. Based on encouraging findings in other hematological cancers, future research should examine the feasibility and effectiveness of physical activity in MPN patients. © The Author(s) 2016.

  2. Association of Lymphoid Malignancies and Philadelphia-Chromosome Negative Myeloproliferative Neoplasms: Clinical Characteristics, Therapy and Outcome

    PubMed Central

    Masarova, Lucia; Newberry, Kate J.; Pierce, Sherry A.; Estrov, Zeev; Cortes, Jorge E.; Kantarjian, Hagop M.; Verstovsek, Srdan

    2015-01-01

    The co-occurrence of myeloproliferative and lymphoproliferative neoplasms (MPN/LPN) has been reported, mostly in case reports. The aim of this study was to assess the characteristics and clinical course of the coexistent diseases. Among 9866 patients who presented to our institution from 1960 to 2014, 34 (0.3%) were diagnosed with MPN/LPN. LPN was diagnosed first in 16 patients, second in 15, and at the same time in 3. The time to secondary malignancy was longer when LPN was diagnosed first (119 vs 98 months). Myelofibrosis (41%), polycythemia vera (24%), and essential thrombocythemia (18%) were the most common MPNs, and non-Hodgkin lymphoma (50%) and chronic lymphocytic leukemia (32%) were the most common LPNs. Seventy-three percent of patients treated for MPN and 72% of those treated for LPN achieved a complete response. After a median follow-up from MPN diagnosis of 84 months, 16 patients are alive and 18 died (4 related to MPN and 2 LPN). Coexistent MPN/LPN is a rare event that does not appear to predict worse outcomes. Treatment choice is generally oriented towards controlling the prevalent disease; the other malignancy may influence treatment strategies in selected cases. PMID:26012362

  3. Myeloproliferative neoplasms: From JAK2 mutations discovery to JAK2 inhibitor therapies

    PubMed Central

    Passamonti, Francesco; Maffioli, Margherita; Caramazza, Domenica; Cazzola, Mario

    2011-01-01

    Most BCR-ABL1-negative myeloproliferative neoplasms (MPN) carry an activating JAK2 mutation. Approximately 96% of patients with polycythemia vera (PV) harbors the V617F mutation in JAK2 exon 14, whereas the minority of JAK2 (V617F)-negative subjects shows several mutations in exon 12. Other mutation events as MPL, TET2, LNK, EZH2 have been described in chronic phase, while NF1, IDH1, IDH2, ASX1, CBL and Ikaros in blast phase of MPN. The specific pathogenic implication of these mutations is under investigation, but they may have a role in refinement of diagnostic criteria and in development of new prognostic models. Several trials with targeted therapy (JAK inhibitors) are ongoing mostly involving patients with PMF, post-PV MF and post-essential thrombocythemia (ET) MF. Treatment with ruxolitinib and TG101348 has shown clinically significant benefits, particularly in improvement of splenomegaly and constitutional symptoms in MF patients. On the other hand, JAK inhibitors have not thus far shown disease-modifying activity therefore any other deduction on these new drugs seems premature. PMID:21646683

  4. Nutrition Prescription to Achieve Positive Outcomes in Chronic Kidney Disease: A Systematic Review

    PubMed Central

    Ash, Susan; Campbell, Katrina L.; Bogard, Jessica; Millichamp, Anna

    2014-01-01

    In Chronic Kidney Disease (CKD), management of diet is important in prevention of disease progression and symptom management, however evidence on nutrition prescription is limited. Recent international CKD guidelines and literature was reviewed to address the following question “What is the appropriate nutrition prescription to achieve positive outcomes in adult patients with chronic kidney disease?” Databases included in the search were Medline and CINAHL using EBSCOhost search engine, Embase and the Cochrane Database of Systematic Reviews published from 2000 to 2009. International guidelines pertaining to nutrition prescription in CKD were also reviewed from 2000 to 2013. Three hundred and eleven papers and eight guidelines were reviewed by three reviewers. Evidence was graded as per the National Health and Medical Research Council of Australia criteria. The evidence from thirty six papers was tabulated under the following headings: protein, weight loss, enteral support, vitamin D, sodium, fat, fibre, oral nutrition supplements, nutrition counselling, including protein and phosphate, nutrients in peritoneal dialysis solution and intradialytic parenteral nutrition, and was compared to international guidelines. While more evidence based studies are warranted, the customary nutrition prescription remains satisfactory with the exception of Vitamin D and phosphate. In these two areas, additional research is urgently needed given the potential of adverse outcomes for the CKD patient. PMID:24451311

  5. Successful Omalizumab treatment in HIV positive patient with chronic spontaneous urticaria: a case report.

    PubMed

    Iemoli, E; Niero, F; Borgonovo, L; Cossu, M V; Piconi, S

    2017-03-01

    We described a case of a 56 year old homosexual HIV positive man who presented a history of CSU since one year (2012). All the allergologic, immunologic and microbiologic tests to evaluate the pathogenesis of wheals resulted negative. Therefore in June 2015 we decided to start therapy with Omalizumab while the patient kept on effective antiretroviral therapy with 310 cells/mm3 TCD4 counts and undetectable HIV viremia. After two monthly subcutaneuous injection of 150 mg of Omalizumab the patient had no more urticarial symptoms. UAS7 (Urticaria Activity Score over 7 days) and Cu-Q2oL (chronic urticarial quality of life questionnaire) dropped respectively to 14 from 42 and to 0 from 40 with increase of TCD4 counts while viral load remained undetectable. In November 2015, i.e. 4 months after the end of Omalizumab therapy, the patient was still asymptomatic with persistent effective immune-virological response to antiretroviral therapy. This case report confirms the excellent tolerability and efficacy of anti-IgE therapy in the treatment of spontaneous chronic urticarial even in an immunodepressed patient for HIV infection. Omalizumab therapy shows a remarkable clinical success and had no effect on peripheral TCD4 counts and HIV viral load.

  6. Transfer factor in the attempted treatment of patients with HBsAg-positive chronic liver disease.

    PubMed Central

    Jain, S; Thomas, H C; Sherlock, S

    1977-01-01

    Six patients with hepatitis B surface antigen-positive (HBsAg-pos) chronic liver disease have been treated with transfer factor (TF) prepared from leucocytes of normal blood donors with no history of hepatitis, and with TF from subjects recently recovered from type B hepatitis. In three patients there were transient elevations of aspartate transaminase (AsT) after 'specific' TF, representing damage or destruction of hepatocytes, and in two of these patients there was coincidental complement consumption, suggesting that TF had stimulated production of antibody. In one other patient there was an increase in E-rosetting lymphocyte (ERL) concentration representing a change in T-lymphocyte reactivity. One of the two patients who had no measured response to TF had a primary liver cell carcinoma and was receiving prednisolone therapy. TF prepared from subjects who have recently recovered from type B hepatitis may have temporarily altered the immunological status of patients with HBsAg-pos chronic liver disease, but it did not have a beneficial therapeutic effect. PMID:606432

  7. The effect of neck torsion on joint position error in subjects with chronic neck pain.

    PubMed

    Chen, Xiaoqi; Treleaven, Julia

    2013-12-01

    The conventional cervical joint position error (JPE) test has been used as a measure of cervical afferent dysfunction in people with neck pain. However, head movement during the test may also stimulate the vestibular system. This study's objective is to investigate the effect of the modified JPE test with a neck torsion manoeuvre in order to determine if the new test is a more definitive measure of cervical afferent dysfunction. Twenty five volunteers with chronic neck pain and 26 healthy controls aged 18 to 60 were assessed on three tests of JPE: 'JPE conventional', 'JPE torsion' and 'Enbloc' (Control) using Fastrak and laser apparatus. The neck pain group was found to have significantly greater JPE in one conventional JPE test and almost all the torsion tests (p < 0.05). No differences in Enbloc(Control) tests were seen. Moderate to strong significant correlations were also seen between measures of JPE using the Fastrak and laser methodology (p ≤ 0.01). The results of this preliminary study indicate that 'JPE torsion' may be a more suitable test than 'JPE conventional' for cervical afferent dysfunction in people with chronic neck pain although future comparisons with people suffering from vestibulopathy is warranted to support these findings. Additionally, the laser method is comparable to Fastrak and may be useful as a clinical measure of repositioning errors for both conventional and torsion tests. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. Nutrition prescription to achieve positive outcomes in chronic kidney disease: a systematic review.

    PubMed

    Ash, Susan; Campbell, Katrina L; Bogard, Jessica; Millichamp, Anna

    2014-01-22

    In Chronic Kidney Disease (CKD), management of diet is important in prevention of disease progression and symptom management, however evidence on nutrition prescription is limited. Recent international CKD guidelines and literature was reviewed to address the following question "What is the appropriate nutrition prescription to achieve positive outcomes in adult patients with chronic kidney disease?" Databases included in the search were Medline and CINAHL using EBSCOhost search engine, Embase and the Cochrane Database of Systematic Reviews published from 2000 to 2009. International guidelines pertaining to nutrition prescription in CKD were also reviewed from 2000 to 2013. Three hundred and eleven papers and eight guidelines were reviewed by three reviewers. Evidence was graded as per the National Health and Medical Research Council of Australia criteria. The evidence from thirty six papers was tabulated under the following headings: protein, weight loss, enteral support, vitamin D, sodium, fat, fibre, oral nutrition supplements, nutrition counselling, including protein and phosphate, nutrients in peritoneal dialysis solution and intradialytic parenteral nutrition, and was compared to international guidelines. While more evidence based studies are warranted, the customary nutrition prescription remains satisfactory with the exception of Vitamin D and phosphate. In these two areas, additional research is urgently needed given the potential of adverse outcomes for the CKD patient.

  9. Linezolid in late-chronic prosthetic joint infection caused by gram-positive bacteria.

    PubMed

    Cobo, Javier; Lora-Tamayo, Jaime; Euba, Gorane; Jover-Sáenz, Alfredo; Palomino, Julián; del Toro, Ma Dolores; Rodríguez-Pardo, Dolors; Riera, Melchor; Ariza, Javier

    2013-05-01

    Linezolid may be an interesting alternative for prosthetic joint infection (PJI) due to its bioavailability and its antimicrobial spectrum. However, experience in this setting is scarce. The aim of the study was to assess linezolid's clinical and microbiological efficacy, and also its tolerance. This was a prospective, multicenter, open-label, non-comparative study of 25 patients with late-chronic PJI caused by Gram-positive bacteria managed with a two-step exchange procedure plus 6 weeks of linezolid. Twenty-two (88%) patients tolerated linezolid without major adverse effects, although a global decrease in the platelet count was observed. Three patients were withdrawn because of major toxicity, which reversed after linezolid stoppage. Among patients who completed treatment, 19 (86%) demonstrated clinical and microbiological cure. Two patients presented with clinical and microbiological failure, and one showed clinical cure and microbiological failure. In conclusion, linezolid showed good results in chronic PJI managed with a two-step exchange procedure. Tolerance seems acceptable, though close surveillance is required.

  10. JAK2 GGCC haplotype in MPL mutated myeloproliferative neoplasms.

    PubMed

    Pietra, Daniela; Casetti, Ilaria; Da Vià, Matteo C; Elena, Chiara; Milanesi, Chiara; Rumi, Elisa

    2012-07-01

    JAK2 (V617F) is associated with a genetic predisposition to its acquisition,as it is preferentially found in subjects with a common constitutional JAK2 haplotype known as 46/1 or GGCC. A recent study suggests that a genetic predisposition to acquisition of MPL mutation may exist in sporadic patients, since an association was found with the JAK2 46/1 haplotype. We genotyped 509 patients with myeloproliferative neoplasms (MPN), 7% of which carrying a somatic mutation of MPL Exon 10. We found that the JAK2 GGCC haplotype was closely associated with JAK2 (V617F) (OR 1.84, P < 0.001) but not with MPL mutations (OR 0.98), suggesting a different genetic background for these molecular lesions.

  11. Chromosome 7 monosomy and deletions in myeloproliferative diseases.

    PubMed

    Tripputi, P; Cassani, B; Alfano, R; Graziani, D; Cigognini, D; Doi, P; Bignotto, M; Corneo, G; Coggi, G

    2001-09-01

    We studied deletion and monosomy of chromosome 7 in 150 patients with myeloproliferative diseases. We found 8/150 patients with monosomy 7 by cytogenetics and 4/150 with deletions of the long arm of chromosome 7 by restriction fragment length polymorphism (RFLP) analysis performed with Southern and polymerase chain reaction. To overcome limitation of RFLP analysis, we restricted loss of heterozygosity study with microsatellites to 45 patients, observing deletion 7q31.1 in 7/45 patients. In all patients with molecular alterations the deletion was observed only in myeloid cells, while the monosomy was detected in both myeloid precursor and lymphocytes. This finding suggests a CD34-totipotent stem cell origin for the monosomy and a colony forming unit - granulocyte, erythrocyte, monocyte, megakaryocytes (CFU-GEMM) stem cell origin for the deletions.

  12. [Latest Research Advance of Myeloproliferative Diseases Related Genes-Review].

    PubMed

    Xiao, Yu-Hong; Wang, Yi-Hao; Shao, Zong-Hong

    2017-08-01

    JAK2, MPL and CALR gene mutations play an important role in the onset of myeloproliferative disease(MPD). The latest researches show that the difference of ATP binding ability between the wild type JAK2 protein and mutated JAK2 protein can help us understand the pathogenesis of the MPD further, and the clinical manifestation is related to the mutation burden of the JAK2. In some ET and PMF patients, research find the expression of MPL mutation, which can affects the progress of the disease by collaborating with the JAK2 mutation. CALR mutation is a gene related with the MPD that has been found recently. The pathogenesis of the CALR is similar to that of the JAK2, while there are some features in clinical manifestation comparing with the other mutations.

  13. Advances in understanding the pathogenesis of familial myeloproliferative neoplasms.

    PubMed

    Rumi, Elisa; Cazzola, Mario

    2017-09-01

    Myeloproliferative neoplasms (MPNs) are generally acquired as a result of a somatic stem cell mutation leading to clonal expansion of myeloid precursors. In addition to sporadic cases, familial MPN occurs when one or several MPN affect different relatives of the same family. MPN driver mutations (JAK2, CALR, MPL) are somatically acquired also in familial cases, so a genetic predisposition to acquire one of the MPN driver mutations would be inherited, even though the causative germline mutations underlying familial MPN remain largely unknown. Recently some germline variants [ATG2B and GSKIP duplication, RBBP6 mutations, SH2B3 (LNK) mutations], which can cause familial MPN, have been reported but these mutations are rare and do not explain most familial cases. Patients with familial MPN show the same clinical features and suffer the same complications as those with sporadic disease. This review aims to offer up-to-date information regarding the genetics of familial MPN. © 2017 John Wiley & Sons Ltd.

  14. Molecular insights into regulation of JAK2 in myeloproliferative neoplasms

    PubMed Central

    Hubbard, Stevan R.

    2015-01-01

    The critical role of Janus kinase-2 (JAK2) in regulation of myelopoiesis was established 2 decades ago, but identification of mutations in the pseudokinase domain of JAK2 in myeloproliferative neoplasms (MPNs) and in other hematologic malignancies highlighted the role of JAK2 in human disease. These findings have revolutionized the diagnostics of MPNs and led to development of novel JAK2 therapeutics. However, the molecular mechanisms by which mutations in the pseudokinase domain lead to hyperactivation of JAK2 and clinical disease have been unclear. Here, we describe recent advances in the molecular characterization of the JAK2 pseudokinase domain and how pathogenic mutations lead to constitutive activation of JAK2. PMID:25824690

  15. Strength deficit of knee flexors is dependent on hip position in adults with chronic hemiparesis.

    PubMed

    Michaelsen, Stella M; Ovando, Angélica C; Bortolotti, Adriano; Bandini, Bruno

    2013-01-01

    The extent to which muscle length affects force production in paretic lower limb muscles after stroke in comparison to controls has not been established. To investigate knee flexor strength deficits dependent on hip joint position in adults with hemiparesis and compare with healthy controls. a cross-sectional study with ten subjects with chronic (63±40 months) hemiparesis with mild to moderate lower limb paresis (Fugl-Meyer score 26±3) and 10 neurologically healthy controls. Isometric knee flexion strength with the hip positioned at 90° and 0° of flexion was assessed randomly on the paretic and non-paretic side of hemiparetic subjects and healthy controls. Subjects were asked to perform a maximal isometric contraction sustained for four seconds and measured by a dynamometer. The ratio of knee flexor strength between these two hip positions was calculated: Hip 0°/Hip 90°. Also, locomotor capacity was evaluated by the timed up and go test and by walking velocity over 10 meters. In subjects with hemiparesis, absolute knee flexion torque decreased (p<0.001) with the hip in extension (at 0°). The ratio of knee flexor torque Hip 0°/Hip 90° on the paretic side in hemiparetics was lower than in controls (p=0.02). Weakness dependent on joint position is more significant in the paretic lower limb of adults with hemiparesis when compared to controls. More attention should be given to lower limb muscle strengthening exercises in individuals with stroke, with emphasis on the strengthening exercises in positions in which the muscle is shortened.

  16. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms.

    PubMed

    Vainchenker, William; Kralovics, Robert

    2017-02-09

    The genetic landscape of classical myeloproliferative neoplasm (MPN) is in large part elucidated. The MPN-restricted driver mutations, including those in JAK2, calreticulin (CALR), and myeloproliferative leukemia virus (MPL), abnormally activate the cytokine receptor/JAK2 pathway and their downstream effectors, more particularly the STATs. The most frequent mutation, JAK2V617F, activates the 3 main myeloid cytokine receptors (erythropoietin receptor, granulocyte colony-stimulating factor receptor, and MPL) whereas CALR or MPL mutants are restricted to MPL activation. This explains why JAK2V617F is associated with polycythemia vera, essential thrombocythemia (ET), and primary myelofibrosis (PMF) whereas CALR and MPL mutants are found in ET and PMF. Other mutations in genes involved in epigenetic regulation, splicing, and signaling cooperate with the 3 MPN drivers and play a key role in the PMF pathogenesis. Mutations in epigenetic regulators TET2 and DNMT3A are involved in disease initiation and may precede the acquisition of JAK2V617F. Other mutations in epigenetic regulators such as EZH2 and ASXL1 also play a role in disease initiation and disease progression. Mutations in the splicing machinery are predominantly found in PMF and are implicated in the development of anemia or pancytopenia. Both heterogeneity of classical MPNs and prognosis are determined by a specific genomic landscape, that is, type of MPN driver mutations, association with other mutations, and their order of acquisition. However, factors other than somatic mutations play an important role in disease initiation as well as disease progression such as germ line predisposition, inflammation, and aging. Delineation of these environmental factors will be important to better understand the precise pathogenesis of MPN.

  17. Effects of Positive and Negative Reinforcement on Daily Living Skills in Chronic Psychiatric Patients in Community Residences.

    ERIC Educational Resources Information Center

    Lippman, Matthew R.; Motta, Robert W.

    1993-01-01

    Examined contingent positive and negative reinforcement and adaptive behavior and mood among 36 chronic, psychiatric outpatients who received either contingent positive token reinforcement to improve daily living skills, negative reinforcement procedure based on removal of free-tokens, or no treatment. Found significant differences between control…

  18. Clinical-laboratory characteristics of ANA-positive chronic idiopathic urticaria.

    PubMed

    Magen, Eli; Waitman, Dan-Andrei; Dickstein, Yoav; Davidovich, Valentina; Kahan, Natan R

    2015-01-01

    Despite the established association between chronic idiopathic/spontaneous urticaria (CIU) and presence of antinuclear antibodies (ANAs), the prevalence of autoimmune comorbidities in this population has not been analyzed. Here, we aim to identify clinical and laboratory manifestations associated with ANA-positive CIU. ANA-positive patients were identified via electronic data capture from the electronic patient record database of Leumit Health care Services (LHS) of Israel. Patient characteristics, medical histories, and details of diagnostic workup, medical treatment, and follow-up were retrieved by performing a chart review of electronic patient records (EPRs). The prevalence of target diseases among ANA(+) CIU(+), ANA(+) CIU(-), and ANA(-) CIU(+) patients was calculated. A total of 91 ANA(+) CIU(+), 3131 ANA(+) CIU(-), and 478 ANA(-) CIU(+) patients were identified. The ANA(+) CIU(+) group was characterized by higher prevalence of Sjögren's syndrome (SS)-A 52 antibodies (Ab) (7.7% versus 2.4%; p = 0.008), SS-A 60 Ab (11% versus 2.8%; p = < 0.001), and SS-B Ab (14.3% versus 3.2%; p < 0.001), compared with ANA(-) CIU(+) group. Additionally, ANA(+) CIU(+) patients were more likely to be diagnosed with thyroid autoimmune diseases, higher C-reactive protein (6.4 ± 10.3 versus 4.1 ± 8.8 mg/L; p = 0.027), and more profound basopenia (0.04 ± 0.09 versus 0.15 ± 0.11 cell/mm(3); p < 0.001) than ANA(-) CIU patients. More ANA(+) CIU(+) patients were resistant to four-fold standard licensed doses of antihistamines than ANA(-) CIU(+) patients [11 (12.1%) versus 29 (6.1%); p = 0.046]. ANA-positive CIU is characterized by higher prevalence of SS-A 52, SS-A 60, and SS-B antibodies and poorer clinical response to antihistamine medications.

  19. Essential Thrombocythemia

    MedlinePlus

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

  20. Primary Myelofibrosis

    MedlinePlus

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

  1. Bone Marrow and Kidney Transplant for Patients With Chronic Kidney Disease and Blood Disorders

    ClinicalTrials.gov

    2017-03-21

    Chronic Kidney Disease; Acute Myeloid Leukemia (AML); Acute Lymphoblastic Leukemia (ALL); Chronic Myelogenous Leukemia (CML); Chronic Lymphocytic Leukemia (CLL); Non-Hodgkin's Lymphoma (NHL); Hodgkin Disease; Multiple Myeloma; Myelodysplastic Syndrome (MDS); Aplastic Anemia; AL Amyloidosis; Diamond Blackfan Anemia; Myelofibrosis; Myeloproliferative Disease; Sickle Cell Anemia; Autoimmune Diseases; Thalassemia

  2. Genomic analysis of clonal eosinophils by CGH arrays reveals new genetic regions involved in chronic eosinophilia.

    PubMed

    Arefi, Maryam; Robledo, Cristina; Peñarrubia, María J; García de Coca, Alfonso; Cordero, Miguel; Hernández-Rivas, Jesús M; García, Juan Luis

    2014-11-01

    To assess the presence of genetic imbalances in patients with myeloproliferative neoplasms (MPNs), 38 patients with chronic eosinophilia were studied by array comparative genomic hybridization (aCGH): seven had chronic myelogenous leukaemia (CML), BCR-ABL1 positive, nine patients had myeloproliferative neoplasia Ph- (MPN-Ph-), three had a myeloid neoplasm associated with a PDGFRA rearrangement, and the remaining two cases were Lymphoproliferative T neoplasms associated with eosinophilia. In addition, 17 patients had a secondary eosinophilia and were used as controls. Eosinophilic enrichment was carried out in all cases. Genomic imbalances were found in 76% of all MPN patients. Losses on 20q were the most frequent genetic abnormality in MPNs (32%), affected the three types of MPN studied. This study also found losses at 11q13.3 in 26% of patients with MPN-Ph- and in 19p13.11 in two of the three patients with an MPN associated with a PDGFRA rearrangement. In addition, 29% of patients with CML had losses on 8q24. In summary, aCGH revealed clonality in eosinophils in most MPNs, suggesting that it could be a useful technique for defining clonality in these diseases. The presence of genetic losses in new regions could provide new insights into the knowledge of these MPN associated with eosinophilia. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. Identification of genomic aberrations associated with disease transformation by means of high-resolution SNP array analysis in patients with myeloproliferative neoplasm.

    PubMed

    Rumi, Elisa; Harutyunyan, Ashot; Elena, Chiara; Pietra, Daniela; Klampfl, Thorsten; Bagienski, Klaudia; Berg, Tiina; Casetti, Ilaria; Pascutto, Cristiana; Passamonti, Francesco; Kralovics, Robert; Cazzola, Mario

    2011-12-01

    Myeloproliferative neoplasms (MPN) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). These disorders may undergo phenotypic shifts, and may specifically evolve into secondary myelofibrosis (MF) or acute myeloid leukemia (AML). We studied genomic changes associated with these transformations in 29 patients who had serial samples collected in different phases of disease. Genomic DNA from granulocytes, i.e., the myeloproliferative genome, was processed and hybridized to genome-wide human SNP 6.0 arrays. Most patients in chronic phase had chromosomal regions with uniparental disomy (UPD) and/or copy number changes. Disease progression to secondary MF or AML was associated with the acquisition of additional chromosomal aberrations in granulocytes (P = 0.002). A close relationship was observed between aberrations of chromosome 9p (UPD and/or gain) and progression from PV to post-PV MF (P = 0.002). The acquisition of one or more aberrations involving chromosome 5, 7, or 17p was specifically associated with progression to AML (OR 5.9, 95% CI 1.2-27.7, P = 0.006), and significantly affected overall survival (HR 18, 95% CI 1.9-164, P = 0.01). These observations indicate that disease progression from chronic-phase MPN to secondary MF or AML is associated with specific chromosomal aberrations that can be detected by means of high-resolution SNP array analysis of granulocyte DNA.

  4. Functional characterization, localization, and inhibitor sensitivity of the TPR-FGFR1 fusion in 8p11 myeloproliferative syndrome.

    PubMed

    Malli, Theodora; Buxhofer-Ausch, Veronika; Rammer, Melanie; Erdel, Martin; Kranewitter, Wolfgang; Rumpold, Holger; Marschon, Renate; Deutschbauer, Sabine; Simonitsch-Klupp, Ingrid; Valent, Peter; Muellner-Ammer, Kirsten; Sebesta, Christian; Birkner, Thomas; Webersinke, Gerald

    2016-01-01

    Myeloid and lymphoid neoplasms with fibroblast growth factor receptor 1 (FGFR1) abnormalities, also known as 8p11 myeloproliferative syndrome (EMS), represent rare and aggressive disorders, associated with chromosomal aberrations that lead to the fusion of FGFR1 to different partner genes. We report on a third patient with a fusion of the translocated promoter region (TPR) gene, a component of the nuclear pore complex, to FGFR1 due to a novel ins(1;8)(q25;p11p23). The fact that this fusion is a rare but recurrent event in EMS prompted us to examine the localization and transforming potential of the chimeric protein. TPR-FGFR1 localizes in the cytoplasm, although the nuclear pore localization signal of TPR is retained in the fusion protein. Furthermore, TPR-FGFR1 enables cytokine-independent survival, proliferation, and granulocytic differentiation of the interleukin-3 dependent myeloid progenitor cell line 32Dcl3, reflecting the chronic phase of EMS characterized by myeloid hyperplasia. 32Dcl3 cells transformed with the TPR-FGFR1 fusion and treated with increasing concentrations of the tyrosine kinase inhibitors ponatinib (AP24534) and infigratinib (NVP-BGJ398) displayed reduced survival and proliferation with IC50 values of 49.8 and 7.7 nM, respectively. Ponatinib, a multitargeted tyrosine kinase inhibitor, is already shown to be effective against several FGFR1-fusion kinases. Infigratinib, tested only against FGFR1OP2-FGFR1 to date, is also efficient against TPR-FGFR1. Taking its high specificity for FGFRs into account, infigratinib could be beneficial for EMS patients and should be further investigated for the treatment of myeloproliferative neoplasms with FGFR1 abnormalities. © 2015 Wiley Periodicals, Inc.

  5. [A rare case of myeloproliferative disease with t(8;13)(p11;q12) associated with eosinophilia and lymphadenopathy].

    PubMed

    Tsyba, N N; Turkina, A G; Chelysheva, E Yu; Nemchenko, I S; Kovrigina, A M; Obukhova, T N; Urnova, E S; Kuzmina, L A; Savchenko, V G

    Myeloproliferative disease associated with FGFR1 rearrangement (8p11), which is included in the 2008 WHO Classification of Myeloid Neoplasms, is a rare and extremely aggressive abnormality. The paper describes a clinical case of a 39-year-old female patient who was detected to have leukocytosis (as high as 47.2·109/l), absolute eosinophilia (as high as 3.1·109/l), and enlarged peripheral lymph nodes during her visit to a doctor. The bone marrow (BM) showed the changes typically encountered in myeloproliferative disease with eosinophilia. The patient was found to have t(8;13)(p11;q12) translocation associated with the rearrangement of the FGFR1 gene located at the 8p11 locus. Molecular and cytogenetic examinations failed to reveal BCR-ABL chimeric transcript, Jak2 V617F mutation, and deletions and translocations involving PDGFRA (4q12) and PDGFRB (5q32-33). The similar changes in the karyotype were also found in the lymph node cells. The undertaken treatment with hydroxyurea and the tyrosine kinase inhibitor dasatinib turned out to be ineffective. The patient underwent allogeneic BM transplantation from a HLA-identical sibling. Graft rejection occurred 6 months later. Allogeneic BM transplantation from the same donor (100% donor chimerism; FGFR1/8р11 translocation was not detected), which was complicated by the development of chronic graft-versus-host reaction, was performed again in March 2015. The patient is being followed up and continues to receive immunosuppressive therapy.

  6. Clonal evolution in Ph{prime}-positive chronic myelogenous leukemia in blast crisis

    SciTech Connect

    Lin, J.H.; Gebre, W.; Kalavar, M. |

    1994-09-01

    Chronic myelogenous leukemia (CML) usually transforms into accelerated and/or blastic phases (ABP) in 2 to 6 years, and patients with CML often succumb to the disease with cytogenetic evolvement. This 43-year-old man was know for his CML for the last 6 years. He experienced clinical deterioration with massive splenomegaly and granulocytic sarcoma in the enlarged axillary lymph nodes. The white blood cell count was 132.2 x 10{sup 9}/L with 14% basophils and less than 5% myeloblasts in the blood and the marrow. The peripheral blood disclosed 46,XY,t(9;22)(q34;q11)[9]/48,XY,+8,t(9;22)(q34;q11),+22q{sup -}[11]. He was treated accordingly and succumbed to the disease 6 months later. In CML, the Ph{prime}-positive finding is present in about 95% of the patients. The remaining Ph{prime}-negative ones are either bcr-positive or bcr-negative. This group may comprise heterogenous myeloid disorders and shows more often RAS gene mutations than {open_quotes}classic{close_quotes} CML. The common chromosomal abnormalities seen in ABP are an additional Ph{prime} chromosome, trisomy 8, isochrosome 17 and trisomy 19. Some 15-35% of patients in ABP show only Ph{prime} without additional mutation. Although overall survival is grim, patients with CML in ABP with additional chromosomal changes, regardless of the blastic natures, fare worse than those without. The presence of clonal evolution at the onset of ABP denotes clinical and hematologic deterioration and adversely effects patient`s survival.

  7. Chronic Kidney Disease Is Positively and Diabetes Mellitus Is Negatively Associated with Abdominal Aortic Aneurysm

    PubMed Central

    Uchida, Haruhito A.; Kakio, Yuki; Umebayashi, Ryoko; Okuyama, Yuka; Fujii, Yasuhiro; Ozawa, Susumu; Yoshida, Masashi; Oshima, Yu; Sano, Shunji; Wada, Jun

    2016-01-01

    Background and Aims Chronic kidney disease (CKD) and diabetes mellitus (DM) are considered as risk factors for cardiovascular diseases. The purpose of this study was to clarify the relationship of CKD and DM with the presence of abdominal aortic aneurysm (AAA). Methods We enrolled 261 patients with AAA (AAA+) and age-and-sex matched 261 patients without AAA (AAA-) at two hospitals between 2008 and 2014, and examined the association between the risk factors and the presence of AAA. Furthermore, in order to investigate the prevalence of AAA in each group, we enrolled 1126 patients with CKD and 400 patients with DM. Results The presence of CKD in patients with AAA+ was significantly higher than that in patients with AAA- (AAA+; 65%, AAA-; 52%, P = 0.004). The presence of DM in patients with AAA+ was significantly lower than that in patients with AAA- (AAA+; 17%, AAA-; 35%, P < 0.001). A multivariate logistic regression analysis demonstrated that hypertension, ischemic heart disease and CKD were independent determinants, whereas, DM was a negatively independent determinant, for the presence of AAA. The prevalence of AAA in patients with CKD 65 years old and above was 5.1%, whereas, that in patients with DM 65 years old and above was only 0.6%. Conclusion CKD is a positively associated with the presence of AAA. In contrast, DM is a negatively associated with the presence of AAA in Japanese population. PMID:27764090

  8. Antibacterial activity of positive and negative polarity low-voltage pulsed current (LVPC) on six typical Gram-positive and Gram-negative bacterial pathogens of chronic wounds.

    PubMed

    Daeschlein, Georg; Assadian, Ojan; Kloth, Luther C; Meinl, Christina; Ney, Frank; Kramer, Axel

    2007-01-01

    The positive effect of electrical stimulation (ES) on wound healing has been shown in vitro and in vivo. On the basis of increased blood flow, protein denaturation, and stimulation of cellular defense, an antibacterial effect of ES is to be expected. Although the antibacterial effect of ES already has been demonstrated in vitro, little attention has been paid to the direct antibacterial effect of changing polarity of the applied current. The aim of this study was to investigate the antibacterial effect of positive and negative monophasic low-voltage pulsed current on typical Gram-positive and Gram-negative pathogens of chronic wounds. Using the Dermapulse-System, three Gram-negative (Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae) and three Gram-positive (Staphylococcus aureus, Staphylococcus epidermidis, Escherichia faecium) organisms were tested against positive and negative polarity low voltage pulsed current. All tested organisms were significantly reduced by ES. The reduction differed significantly between positive polarity and control and negative polarity and control, with the highest log10 reduction factor (RF) achieved with positive polarity. Using positive polarity, the maximum RF was measured for E. coli (median log10 RF 0.83; 25th percentile 0.59, 75th percentile 0.98) and the lowest for S. epidermidis (median log10 RF 0.20; 25th percentile 0.17, 75th percentile 0.24). Yet, there was no significant difference with positive ES against Gram-positive or Gram-negative organisms.

  9. Management of extreme thrombocytosis in myeloproliferative neoplasms: an international physician survey.

    PubMed

    Koren-Michowitz, Maya; Lavi, Noa; Ellis, Martin H; Vannucchi, Alessandro M; Mesa, Ruben; Harrison, Claire N

    2017-01-01

    Extreme thrombocytosis (ExT) has been associated with an increased bleeding risk in myeloproliferative neoplasm (MPN) patients and is included in the high risk category in treatment guidelines. Treatment of patients with ExT has not been studied in prospective trials. To study physicians' approaches to ExT, we distributed a web based questionnaire with clinical case scenarios to 202 members of MPN working groups. Cases included low thrombotic risk essential thrombocythemia (ET) with either JAK2V617F or CALR mutation, polycythemia vera with ExT either with or without leukocytosis, an ET patient needing urgent orthopedic surgery, and a poorly controlled ET patient with acute cerebral venous sinus thrombosis. Responses were received from 90 physicians (45 %) and were variable in most case scenarios. Country of practice had the most significant influence on physician response. The USA and Israel physicians responded similarly in most cases and differently to the Europe physicians. Treatment of asymptomatic JAK2V617F positive ET and target platelet count on cytoreduction were significantly influenced by physician years of experience. Responses were not influenced by the volume of MPN practice or by whether MPN was considered a major interest by the physician. Our results show a lack of consensus on how to manage MPN patients with ExT. Randomized controlled trials properly designed to address these questions are needed.

  10. A portable microfluidic platform for rapid molecular diagnostic testing of patients with myeloproliferative neoplasms.

    PubMed

    Wang, Hua; Zhang, Xinju; Xu, Xiao; Zhang, Qunfeng; Wang, Hengliang; Li, Dong; Kang, Zhihua; Wu, Zhiyuan; Tang, Yigui; An, Zhenhua; Guan, Ming

    2017-08-17

    The ability to simultaneously detect JAK2 V617F and MPL W515K/L mutations would substantially improve the early diagnosis of myeloproliferative neoplasms (MPNs) and decrease the risk of arterial thrombosis. The goal of this study is to achieve a point of care testing platform for simultaneous analysis of major genetic alterations in MPN. Here, we report a microfluidic platform including a glass capillary containing polypropylene matrix that extracts genomic DNA from a drop of whole blood, a microchip for simultaneous multi-gene mutation screening, and a handheld battery-powered heating device. The µmLchip system was successfully used for point-of-care identification of the JAK2 V617F and MPL W515K/L mutations. The µmLchip assays were then validated by mutation analysis with samples from 100 MPN patients who had previously been analyzed via unlabeled probe melting curve analysis or real-time PCR. The results from the µmLchip were in perfect agreement with those from the other methods, except for one discrepant result that was negative in the unlabeled probe melting curve analysis but positive in the µmLchip. After T-A cloning, sequences of cloned PCR products revealed JAK2 V617F mutation in the sample. The portable microfluidic platform may be very attractive in developing point-of-care diagnostics for MPL W515K/L and JAK2 V617F mutations.

  11. Real world epidemiology of myeloproliferative neoplasms: a population based study in Korea 2004-2013.

    PubMed

    Byun, Ja Min; Kim, Young Jin; Youk, Taemi; Yang, John Jeongseok; Yoo, Jongha; Park, Tae Sung

    2017-03-01

    Myeloproliferative neoplasms (MPNs), with an expected increment in number, impose substantial economic and social burdens. To this end, we conducted a nationwide population-based descriptive epidemiology study. We also investigated medical cost associated with MPNs. Prevalence was the highest for essential thrombocythemia (ET) (range 4.1-9.0 per 100,000), followed by polycythemia vera (PV) (range 2.8-5.4 per 100,000) and primary myelofibrosis (PMF) (range 0.5-0.9 per 100,000). ET incurred the highest cumulative total cost at US$35 million and the most frequent hospital visits, while PMF incurred the highest average cost per person at US$5000. The mean hemoglobin level was 16.9 ± 2.2 g/dL for PV males and 15.5 ± 2.7 g/dL for PV females. Further analyses on hemoglobin levels showed the true positive rate of PV from the significantly elevated hemoglobin group (defined as >18.5 g/dL for men and >16.5 g/dL for women) was 3.01% and that of MPNs was 3.1%. Here, we provide the biggest population-based report on MPN epidemiology that can readily be used as a representative Asian data.

  12. Proinflammatory Cytokine IL-6 and JAK-STAT Signaling Pathway in Myeloproliferative Neoplasms

    PubMed Central

    Čokić, Vladan P.; Mitrović-Ajtić, Olivera; Beleslin-Čokić, Bojana B.; Marković, Dragana; Buač, Marijana; Diklić, Miloš; Kraguljac-Kurtović, Nada; Damjanović, Svetozar; Milenković, Pavle; Gotić, Mirjana; Raj, Puri K.

    2015-01-01

    The recent JAK1/2 inhibitor trial in myeloproliferative neoplasms (MPNs) showed that reducing inflammation can be more beneficial than targeting gene mutants. We evaluated the proinflammatory IL-6 cytokine and JAK-STAT signaling pathway related genes in circulating CD34+ cells of MPNs. Regarding laboratory data, leukocytosis has been observed in polycythemia vera (PV) and JAK2V617F mutation positive versus negative primary myelofibrosis (PMF) patients. Moreover, thrombocytosis was reduced by JAK2V617F allele burden in essential thrombocythemia (ET) and PMF. 261 significantly changed genes have been detected in PV, 82 in ET, and 94 genes in PMF. The following JAK-STAT signaling pathway related genes had augmented expression in CD34+ cells of MPNs: CCND3 and IL23A regardless of JAK2V617F allele burden; CSF3R, IL6ST, and STAT1/2 in ET and PV with JAK2V617F mutation; and AKT2, IFNGR2, PIM1, PTPN11, and STAT3 only in PV. STAT5A gene expression was generally reduced in MPNs. IL-6 cytokine levels were increased in plasma, as well as IL-6 protein levels in bone marrow stroma of MPNs, dependent on JAK2V617F mutation presence in ET and PMF patients. Therefore, the JAK2V617F mutant allele burden participated in inflammation biomarkers induction and related signaling pathways activation in MPNs. PMID:26491227

  13. S100 protein positive dendritic cells in primary biliary cirrhosis and other chronic inflammatory liver diseases. Relevance to pathogenesis?

    PubMed Central

    Demetris, A. J.; Sever, C.; Kakizoe, S.; Oguma, S.; Starzl, T. E.; Jaffe, R.

    1989-01-01

    A study to determine the location of dendritic cells, in chronic inflammatory liver disease was performed. S100 protein positivity and dendritic cytoplasmic morphology were used to identify dendritic cells. S100 protein positive dendritic cells (S100 + DC) were found inside the basement membrane between biliary epithelial cells of septal bile ducts of livers affected by early stage PBC, but were not present at later stages. S100 + DC also were seen in areas of piecemeal necrosis in chronic active hepatitis of various etiologies. In contrast, intra-epithelial S100 + DC were not found with any consistency in sclerosing cholangitis, secondary biliary cirrhosis, extrahepatic biliary atresia, or chronic liver allograft rejection, all of which are characterized by inflammatory bile duct damage. The possible relevance of DC in the pathogenesis of PBC is discussed. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:2705505

  14. Management of chronic hepatitis B in an HIV-positive patient with 3TC-resistant hepatitis B virus.

    PubMed

    Ristig, Maria; Drechsler, Henning; Crippin, Jeffrey; Lisker-Melman, Mauricio; Tebas, Pablo

    2003-09-01

    Chronic viral hepatitis has emerged as one of the leading causes of morbidity and mortality among HIV-positive patients. These individuals are at risk for aggressive chronic active hepatitis, cirrhosis, and hepatocellular carcinoma, and eventually, death. Currently available therapies for hepatitis B are limited and include interferon-alpha, lamivudine (3TC), and adefovir. Tenofovir (TDF), a recently approved drug for the treatment of HIV, is also active against hepatitis B. We report the case of a HIV-positive patient with liver cirrhosis secondary to chronic hepatitis B virus (HBV) with evidence of resistance to 3TC. The patient was initially accepted as a liver transplant candidate. However, when TDF was added to his treatment, a remarkable virologic and histopathologic improvement was achieved. The patient was subsequently removed from the liver transplant program and has not suffered from any further hepatic complications.

  15. Positioning.

    ERIC Educational Resources Information Center

    Conone, Ruth M.

    The key to positioning is the creation of a clear benefit image in the consumer's mind. One positioning strategy is creating in the prospect's mind a position that takes into consideration the company's or agency's strengths and weaknesses as well as those of its competitors. Another strategy is to gain entry into a position ladder owned by…

  16. Runx3 deficiency results in myeloproliferative disorder in aged mice.

    PubMed

    Wang, Chelsia Qiuxia; Motoda, Lena; Satake, Masanobu; Ito, Yoshiaki; Taniuchi, Ichiro; Tergaonkar, Vinay; Osato, Motomi

    2013-07-25

    The RUNX family genes encode transcription factors that are involved in development and human diseases. RUNX1 is one of the most frequently mutated genes in human hematological malignancies and is a critical factor for the generation and maintenance of hematopoietic stem cells. Another Runx family gene, Runx3, is known to be expressed in hematopoietic cells. However, its involvement in hematopoiesis remains unclear. Here we show the hematopoietic phenotypes in Runx3 conditional knockout (KO) mice (Runx3(fl/fl);Mx1-Cre(+)): whereas young Runx3 KO mice did not exhibit any significant hematopoietic defects, aged Runx3 KO mice developed a myeloproliferative disorder characterized by myeloid-dominant leukocytosis, splenomegaly, and an increase of hematopoietic stem/progenitor cells (HSPCs). Notably, Runx3-deficient cells showed hypersensitivity to granulocyte-colony stimulating factor, suggesting enhanced proliferative and mobilization capability of Runx3-deficient HSPCs when stimulated. These results suggest that, besides Runx1, Runx3 also plays a role in hematopoiesis.

  17. Mutations in myeloproliferative neoplasms - their significance and clinical use.

    PubMed

    Schischlik, Fiorella; Kralovics, Robert

    2017-09-25

    Clonal hematologic diseases of the blood such as polycythemia vera, essential thrombocythemia and primary myelofibrosis belong to the BCR-ABL negative Myeloproliferative Neoplasms (MPN). These diseases are characterized by clonal expansion of hematopoietic precursor cells followed by increased production of differentiated cells of the myeloid lineage. Initiation of clonal hematopoiesis, formation of a clinical phenotype as well as disease progression form part of MPN disease evolution. The disease is driven by acquired somatic mutations in critical pathways such as cytokine signaling, epigenetic regulation, RNA splicing, and transcription factor signaling. Areas covered: The following review aims to provide an overview of the mutational landscape of MPN, the impact of these mutations in MPN pathogenesis as well as their prognostic value. Finally, a summary of how these mutations are being used or could potentially be used for the treatment of MPN patients is presented. Expert commentary: The genetic landscape of MPN patients has been successfully dissected within the past years with the advent of new sequencing technologies. Integrating the genetic information within a clinical setting is already benefitting patients in terms of disease monitoring and prognostic information of disease progression but will be further intensified within the next years.

  18. AKT is a therapeutic target in myeloproliferative neoplasms

    PubMed Central

    Khan, Irum; Huang, Zan; Wen, Qiang; Stankiewicz, Monika J.; Gilles, Laure; Goldenson, Benjamin; Schultz, Rachael; Diebold, Lauren; Gurbuxani, Sandeep; Finke, Christy M.; Lasho, Terra L.; Koppikar, Priya; Pardanani, Animesh; Stein, Brady; Altman, Jessica K.; Levine, Ross L.; Tefferi, Ayalew; Crispino, John D.

    2014-01-01

    The majority of patients with BCR-ABL1-negative myeloproliferative neoplasms (MPN) harbor mutations in JAK2 or MPL, which lead to constitutive activation of the JAK/STAT, PI3K, and ERK signaling pathways. JAK inhibitors by themselves are inadequate in producing selective clonal suppression in MPN and are associated with hematopoietic toxicities. MK-2206 is a potent allosteric AKT inhibitor that was well tolerated, including no evidence of myelosuppression, in a phase I study of solid tumors. Herein, we show that inhibition of PI3K/AKT signaling by MK-2206 affected the growth of both JAK2V617F or MPLW515L-expressing cells via reduced phosphorylation of AKT and inhibition of its downstream signaling molecules. Moreover, we demonstrate that MK-2206 synergizes with Ruxolitinib in suppressing the growth of JAK2V617F mutant SET2 cells. Importantly MK-2206 suppressed colony formation from hematopoietic progenitor cells in patients with primary myelofibrosis (PMF) and alleviated hepatosplenomegaly and reduced megakaryocyte burden in the bone marrows, livers and spleens of mice with MPLW515L-induced MPN. Together, these findings establish AKT as a rational therapeutic target in the MPNs. PMID:23748344

  19. Impact of Inflammation on Myeloproliferative Neoplasm Symptom Development.

    PubMed

    Geyer, Holly L; Dueck, Amylou C; Scherber, Robyn M; Mesa, Ruben A

    2015-01-01

    Myeloproliferative neoplasms (essential thrombocythemia, ET; polycythemia vera, PV; myelofibrosis, MF) are monoclonal malignancies associated with genomic instability, dysregulated signaling pathways, and subsequent overproduction of inflammatory markers. Acknowledged for their debilitating symptom profiles, recent investigations have aimed to determine the identity of these markers, the upstream sources stimulating their development, their prevalence within the MPN population, and the role they play in symptom development. Creation of dedicated Patient Reported Outcome (PRO) tools, in combination with expanded access to cytokine analysis technology, has resulted in a surge of investigations evaluating the potential associations between symptoms and inflammation. Emerging data demonstrates clear relationships between individual MPN symptoms (fatigue, abdominal complaints, microvascular symptoms, and constitutional symptoms) and cytokines, particularly IL-1, IL-6, IL-8, and TNF-α. Information is also compiling on the role symptoms paradoxically play in the development of cytokines, as in the case of fatigue-driven sedentary lifestyles. In this paper, we explore the symptoms inherent to the MPN disorders and the potential role inflammation plays in their development.

  20. Genomic diversity in myeloproliferative neoplasms: focus on myelofibrosis

    PubMed Central

    2015-01-01

    The classical myeloproliferative neoplasms (MPNs) are a group of clonal diseases comprising essential thrombocythaemia (ET), polycythaemia vera (PV) and primary myelofibrosis (PMF). PMF is the rarest disease sub type and has been challenging to address due to the lack of a specific genetic marker, inadequate risk identification models and a highly variable clinical course. Continuous efforts have over time, seen the inclusion of cytogenetic information in prognostic scoring models that have resulted in improved risk stratification models providing further rationale for therapeutic management. Technological advances using single nucleotide polymorphism arrays increased the detection of known and novel MPN related changes and variant detection by massively parallel sequencing provided a large scale screening tool for the multitude of somatic gene mutations that have more recently been described in MPN. Some of these mutations show an association with specific cytogenetic changes or phenotypes. While PMF occurs mainly in adults, it has also been described in paediatric cases and shows distinct histopathological, genetic and clinical features in comparison. This review provides an overview of the genomics landscape of PMF and current developments in MPN therapy. PMID:26835366

  1. Therapy with JAK2 inhibitors for Myeloproliferative Neoplasms

    PubMed Central

    Santos, Fabio P. S.; Verstovsek, Srdan

    2015-01-01

    The development of JAK2 inhibitors followed the discovery of activating mutation of JAK2 (JAK2V617F) in patients with classic Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPNs). It is now known that mutations activating the JAK-STAT pathway are ubiquitous in Ph-negative MPNs, and that deregulated JAK-STAT pathway plays a central role in the pathogenesis of these disorders. JAK2 inhibitors thus are effective in both patients with and without the JAK2V617F mutation. Clinical trials conducted in patients with myelofibrosis have demonstrated that these drugs lead to substantial improvements in systemic symptoms, splenomegaly, leukocytosis and thrombocytosis. Results of one randomized clinical trial suggest that JAK2 inhibition may also lead to improved survival. There are still significant challenges to be overcome, as these drugs do not improve bone marrow fibrosis and do not lead to significant reduction in the allele burden of JAK2V617F. In this manuscript we review the rationale for using JAK2 inhibitors in Ph-negative MPNs and results of more recent clinical trials with these drugs. PMID:23009939

  2. Targeting JAK2 in the therapy of myeloproliferative neoplasms

    PubMed Central

    Reddy, Mamatha M.; Deshpande, Anagha; Sattler, Martin

    2014-01-01

    Introduction Myeloproliferative neoplasms (MPNs) are a group of stem cell diseases, including polycythemia vera, essential thrombocythemia and primary myelofibrosis. Currently, there is no curative therapy for these diseases other than bone marrow transplant; therefore there is an apparent need for palliative treatment. MPNs are frequently associated with activating mutations in Janus Kinase 2 (JAK2); small molecule drugs targeting this molecule have entered clinical trials. Areas covered In this review novel JAK2 inhibitors will be discussed and alternative approaches to inhibiting their transforming potential will be highlighted. Expert opinion Current clinical approaches do not only aim at blocking JAK2 activity, but also at reducing its stability and expression. Inhibition of heat shock protein 90 (HSP90) and deacetylase inhibitors (DACi) have the potential to significantly enhance the efficacy of JAK2 inhibitors. Preliminary results from clinical trials indicate the feasibility and efficacy of JAK2 targeted approaches. However, JAK2 inhibitor treatment is limited by dose-dependent toxicity and combination treatment might be required. The discovery of JAK2 mutations that cause secondary resistance in vitro would further highlight the need for the development of next generation JAK2 inhibitors and novel synergistic approaches. PMID:22339244

  3. Molecular and genetic bases of myeloproliferative disorders: questions and perspectives.

    PubMed

    Plo, Isabelle; Vainchenker, William

    2009-01-01

    The discovery of the JAK2V617F mutation followed by the discovery of JAK2 exon 12 and MPLW515 mutations has completely modified the understanding, diagnosis, and management of the classic myeloproliferative disorders (MPDs), which include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Nonetheless, genetic defects have not yet been identified in about 40% of ET and PMF. There is now strong evidence that these mutations are the oncogenic events that drive these disorders and are responsible for most biologic and clinical abnormalities. In addition, there are convincing data indicating that the number of JAK2V617F copies (homozygosity vs. heterozygosity) is important in explaining how a single mutation can be associated with several disorders. However, it is still uncertain whether these mutations are sufficient to explain the full development, heterogeneity, and progression of MPD, or if other genetic or epigenetic events are also necessary. In this review, we discuss different hypothetical models of MPD pathogenesis supported by recent findings. Further characterization of the molecular events operating in these disorders will be essential in fully understanding their pathogenesis and in developing new therapeutic approaches.

  4. How to manage children and young adults with myeloproliferative neoplasms.

    PubMed

    Barbui, T

    2012-07-01

    On the basis of my personal clinical and research experience and validated by the current literature, my approach to the management of pediatric (age <18 years) and young patients (age <40 years) with classic myeloproliferative neoplasms is presented by focusing on diagnosis, patient communication, risk stratification and therapy. The WHO-2008 diagnostic criteria are recommended, even though in children suspected with essential thrombocythemia (ET), a specific set of diagnostic features may be required. Patient communication includes information on natural history, genetic abnormalities and counseling in all women of child-bearing age. The main challenge in children and young adults with ET and polycythemia vera (PV) is to avoid recurrence of major thrombosis by selecting those patients who ultimately can benefit from cytotoxic and antithrombotic therapy without increasing the incidence of drug-induced side effects. In asymptomatic low-risk patients no therapy is prescribed while in high-risk low-dose aspirin, hydroxyurea and interferon-alpha are my first line drugs. My first decision when considering treatment of a young patient with primary myelofibrosis (PMF) or post-PV or post ET-myelofibrosis, is whether he/she qualifies for bone marrow allotransplantation. In the remaining young PMF patients palliative therapy or experimental drugs are considered.

  5. Impact of Inflammation on Myeloproliferative Neoplasm Symptom Development

    PubMed Central

    Geyer, Holly L.; Dueck, Amylou C.; Scherber, Robyn M.; Mesa, Ruben A.

    2015-01-01

    Myeloproliferative neoplasms (essential thrombocythemia, ET; polycythemia vera, PV; myelofibrosis, MF) are monoclonal malignancies associated with genomic instability, dysregulated signaling pathways, and subsequent overproduction of inflammatory markers. Acknowledged for their debilitating symptom profiles, recent investigations have aimed to determine the identity of these markers, the upstream sources stimulating their development, their prevalence within the MPN population, and the role they play in symptom development. Creation of dedicated Patient Reported Outcome (PRO) tools, in combination with expanded access to cytokine analysis technology, has resulted in a surge of investigations evaluating the potential associations between symptoms and inflammation. Emerging data demonstrates clear relationships between individual MPN symptoms (fatigue, abdominal complaints, microvascular symptoms, and constitutional symptoms) and cytokines, particularly IL-1, IL-6, IL-8, and TNF-α. Information is also compiling on the role symptoms paradoxically play in the development of cytokines, as in the case of fatigue-driven sedentary lifestyles. In this paper, we explore the symptoms inherent to the MPN disorders and the potential role inflammation plays in their development. PMID:26538823

  6. Reproducibility of the WHO histological criteria for the diagnosis of Philadelphia chromosome-negative myeloproliferative neoplasms.

    PubMed

    Gianelli, Umberto; Bossi, Anna; Cortinovis, Ivan; Sabattini, Elena; Tripodo, Claudio; Boveri, Emanuela; Moro, Alessia; Valli, Riccardo; Ponzoni, Maurilio; M Florena, Ada; F Orcioni, Giulio; Ascani, Stefano; Bonoldi, Emanuela; Iurlo, Alessandra; Gugliotta, Luigi; Franco, Vito

    2014-06-01

    This study, performed on behalf of the Italian Registry of Thrombocythaemias (Registro Italiano Trombocitemie), aimed to test the inter-observer reproducibility of the histological parameters proposed by the WHO classification for the diagnosis of the Philadelphia chromosome-negative myeloproliferative neoplasms. A series of 103 bone marrow biopsy samples of Philadelphia chromosome-negative myeloproliferative neoplasms consecutively collected in 2004 were classified according to the WHO criteria as follows: essential thrombocythaemia (n=34), primary myelofibrosis (n=44) and polycythaemia vera (n=25). Two independent groups of pathologists reviewed the bone marrow biopsies. The first group was asked to reach a collegial 'consensus' diagnosis. The second group reviewed individually all the cases to recognize the main morphological parameters indicated by the WHO classification and report their results in a database. They were subsequently instructed to individually build a 'personal' diagnosis of myeloproliferative neoplasms subtype just assembling the parameters collected in the database. Our results indicate that high levels of agreement (≥70%) have been reached for about all of the morphological features. Moreover, among the 18 evaluated histological features, 11 resulted statistically more useful for the differential diagnosis among the different Philadelphia chromosome-negative myeloproliferative neoplasms. Finally, we found a high percentage of agreement (76%) between the 'personal' and 'consensus' diagnosis (Cohen's kappa statistic >0.40). In conclusion, our results support the use of the histological criteria proposed by the WHO classification for the Philadelphia chromosome-negative myeloproliferative neoplasms to ensure a more precise and early diagnosis for these patients.

  7. JAK2 Inhibition: Reviewing a New Therapeutical Option in Myeloproliferative Neoplasms

    PubMed Central

    Bellido, Mar; te Boekhorst, Peter A. W.

    2012-01-01

    JAK2 is a tyrosine kinase gene that plays an essential role in the development of normal haematopoiesis. Hyperactivation of JAK2 occurs in myeloproliferative neoplasms by different mechanisms. As a consequence, JAK2 inhibitors have been designed to suppress the cytokine signalling cascade caused by the constitutive activation of JAK2. In clinical trials, JAK2 inhibitors are efficient in decreasing spleen size, controlling clinical symptoms, and improving quality of life in patients with myeloproliferative neoplasms. However, JAK2 inhibitors are unable to target uncommitted hematopoietic progenitors responsible of the initiation of the myeloproliferative disease. It is expected that, in order to cure the myeloproliferative disease, JAK2 inhibitors should be combined with other drugs to target simultaneously different pathways and to target the initiator hematopoietic cell population in myeloproliferative disorders. Taking advantage of the inhibition of the cytokine cascade of JAK2 inhibitors, these compounds are going to be used not only to treat patients with hematological neoplasms but may also be beneficial to treat patients with rheumatoid arthritis or other inflammatory diseases. PMID:22400031

  8. The curative effect of adefovir dipivoxil treating HBeAg negative chronic hepatitis B and treating HBeAg positive chronic hepatitis B combining interferon α-2b.

    PubMed

    Gu, Junsheng; Sun, Ranran; Shen, Shen; Yu, Zujiang

    2015-07-01

    This study aimed to research the efficiency of adefovir dipivoxil in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B treatment and in combination with α-2b interferon in the treatment of HBeAg-positive chronic hepatitis B. A total of 102 cases of adult patients with HBeAg chronic hepatitis B were selected for testing. HBeAg negative chronic hepatitis B patients took 10mg adefovir dipivoxil capsules once daily, while positive chronic hepatitis B patients were randomly divided into either a treatment group or a control group. The treatment group was administrated with 10mg adefovir dipivoxil capsules, 1 time daily, and injected with 5 million U Recombinant Human Interferon α-2b through muscle every other day. The control group was treated with 10mg adefovir dipivoxil capsules, 1 time per day. We examined alanine aminotransferase (ALT) normalization and the Hepatitis B Virus (HBV)-DNA negative rate (undetectable rate), as well as, HBeAg / hepatitis B e antibody (HBeAb) sero-conversion rate to detect treatment effects. The results proved that after 6 months of medication therapy, the ALT normalization rate was 49.9% and the HBV-DNA negative conversion rate was 54.3%. 18 months into the treatment, showed an ALT normalization rate of 73.2%, while the HBV-DNA negative conversion rate grew to 76.8%. The use of adefovir dipivoxil treatment of the negative chronic HBV has a certain extent combined with α-2b Interferon therapy in treatment of HbeAg positive chronic hepatitis B. After a 48-week observation period, ALT normalization and HBV-DNA rate could not be measured, HBeAg/HBeAb sero-conversion rose higher, indicating that the treatment of the combined drugs is more efficient than taking adefovir dipivoxil by itself, and the data were comparable with the control group (P<0.05). Thus adefovir dipivoxil can greatly improve the restrain function to HBV-DNA and improve the immunity and control ability of the body, with obvious short-term effects, in combination

  9. Treatment of gastric varices with partial splenic embolization in a patient with portal vein thrombosis and a myeloproliferative disorder

    PubMed Central

    Gianotti, Robert; Charles, Hearns; Hymes, Kenneth; Chandarana, Hersh; Sigal, Samuel

    2014-01-01

    Therapeutic options for gastric variceal bleeding in the presence of extensive portal vein thrombosis associated with a myeloproliferative disorder are limited. We report a case of a young woman who presented with gastric variceal bleeding secondary to extensive splanchnic venous thrombosis due to a Janus kinase 2 mutation associated myeloproliferative disorder that was managed effectively with partial splenic embolization. PMID:25339837

  10. Treatment of gastric varices with partial splenic embolization in a patient with portal vein thrombosis and a myeloproliferative disorder.

    PubMed

    Gianotti, Robert; Charles, Hearns; Hymes, Kenneth; Chandarana, Hersh; Sigal, Samuel

    2014-10-21

    Therapeutic options for gastric variceal bleeding in the presence of extensive portal vein thrombosis associated with a myeloproliferative disorder are limited. We report a case of a young woman who presented with gastric variceal bleeding secondary to extensive splanchnic venous thrombosis due to a Janus kinase 2 mutation associated myeloproliferative disorder that was managed effectively with partial splenic embolization.

  11. Acute Effects of Continuous Positive Air way Pressure on Pulse Pressure in Chronic Heart Failure

    PubMed Central

    Quintão, Mônica; Chermont, Sérgio; Marchese, Luana; Brandão, Lúcia; Bernardez, Sabrina Pereira; Mesquita, Evandro Tinoco; Rocha, Nazareth de Novaes; Nóbrega, Antônio Claudio L.

    2014-01-01

    Background Patients with heart failure (HF) have left ventricular dysfunction and reduced mean arterial pressure (MAP). Increased adrenergic drive causes vasoconstriction and vessel resistance maintaining MAP, while increasing peripheral vascular resistance and conduit vessel stiffness. Increased pulse pressure (PP) reflects a complex interaction of the heart with the arterial and venous systems. Increased PP is an important risk marker in patients with chronic HF (CHF). Non-invasive ventilation (NIV) has been used for acute decompensated HF, to improve congestion and ventilation through both respiratory and hemodynamic effects. However, none of these studies have reported the effect of NIV on PP. Objective The objective of this study was to determine the acute effects of NIV with CPAP on PP in outpatients with CHF. Methods Following a double-blind, randomized, cross-over, and placebo-controlled protocol, twenty three patients with CHF (17 males; 60 ± 11 years; BMI 29 ± 5 kg/cm2, NYHA class II, III) underwent CPAP via nasal mask for 30 min in a recumbent position. Mask pressure was 6 cmH2O, whereas placebo was fixed at 0-1 cmH2O. PP and other non invasive hemodynamics variables were assessed before, during and after placebo and CPAP mode. Results CPAP decreased resting heart rate (Pre: 72 ± 9; vs. Post 5 min: 67 ± 10 bpm; p < 0.01) and MAP (CPAP: 87 ± 11; vs. control 96 ± 11 mmHg; p < 0.05 post 5 min). CPAP decreased PP (CPAP: 47 ± 20 pre to 38 ± 19 mmHg post; vs. control: 42 ± 12 mmHg, pre to 41 ± 18 post p < 0.05 post 5 min). Conclusion NIV with CPAP decreased pulse pressure in patients with stable CHF. Future clinical trials should investigate whether this effect is associated with improved clinical outcome. PMID:24676373

  12. Hepatitis B virus replication in steroid-treated severe HBsAg-positive chronic active hepatitis.

    PubMed

    Davis, G L; Czaja, A J; Taswell, H F; Ludwig, J; Go, V L

    1985-02-01

    To determine the effect of corticosteroids on the replication of hepatitis B virus and to assess the relationship between virus replication and prognosis, the behavior of serum and tissue HBcAg was evaluated in 16 patients with severe HBsAg-positive chronic active hepatitis who were treated with prednisone and followed for up to 10 years (mean +/- SEM, 66 +/- 9 months). Hepatitis B virus replication was assessed in serum by a solid-phase radioimmunoassay of Dane particle-associated HBcAg and in liver tissue by indirect immunoperoxidase staining for HBcAg. Despite the presence of severe inflammatory activity, only low levels of hepatitis B virus replication were demonstrated. Mean serum HBcAg levels were low at accession and remained essentially unchanged or gradually decreased during corticosteroid therapy. Serum HBcAg appeared in only one patient in whom no virus replication was detected prior to therapy. HBeAg was frequently detected at low titers by radioimmunoassay when serum HBcAg was undetectable. Loss of HBcAg preceded loss of HBeAg by radioimmunoassay, and disappearance of both markers was a prerequisite for sustained histologic remission. In eight patients, inflammation was present despite absence of serum or tissue HBcAg; in three of these, disease activity continued after loss of HBeAg. We conclude that low levels of hepatitis B virus replication may be associated with severe inflammatory activity, and these levels are not increased by long-term corticosteroid therapy. Inflammation can continue despite loss of HBeAg and absence of detectable virus replication.

  13. Survival implications of molecular heterogeneity in variant Philadelphia-positive chronic myeloid leukaemia.

    PubMed

    Reid, Alistair G; Huntly, Brian J P; Grace, Colin; Green, Anthony R; Nacheva, Elisabeth P

    2003-05-01

    The BCR-ABL fusion in chronic myeloid leukaemia (CML) is generated by the Philadelphia (Ph) translocation t(9;22) or, in 10% of patients, variants thereof (vPh). Deletion encompassing the reciprocal product (ABL-BCR) from the derivative chromosome 9 [der(9)] occurs in 15% of all patients, but with greater frequency in vPh patients. Reports of physical separation of ABL-BCR in non-deleted patients, as well as evolution from classical to variant Ph, introduce further heterogeneity to the vPh subgroup and raise the possibility that such translocations may herald disease progression. Survival analyses, however, have thus far yielded contradictory results. We assessed the frequency of der(9) deletions, ABL-BCR abrogation, cytogenetic evolution and cryptic rearrangement in a large cohort of 54 patients with vPh CML. Deletions encompassing ABL-BCR were detected in 37% of patients, consistent with a model in which a greater number of chromosome breaks increases the risk of genomic loss. The components of ABL-BCR were physically separated in a further 52% of patients while fused in the remaining 11%. Evolution from classical to vPh was demonstrated in three patients. The difference in survival, as indicated by Kaplan-Meier analysis, was marked between classical and vPh patients (105 vs 60 months respectively; P = 0.0002). Importantly, this difference disappeared when patients with deletions were removed from the analysis. Our study showed that, despite the existence of several levels of genomic heterogeneity in variant Ph-positive CML, der(9) deletion status is the key prognostic factor.

  14. Positive relationship between p42.3 gene and inflammation in chronic non-atrophic gastritis.

    PubMed

    Chen, Ping; Cui, Yun; Fu, Qing Yan; Lu, You Yong; Fang, Jing Yuan; Chen, Xiao Yu

    2015-10-01

    Gastric cancer (GC) is a typical type of inflammation-related tumor. The p42.3 gene is shown to be highly expressed in GC, but its association with gastritis remains unknown. We aimed to explore the relationship between gastric inflammation and p42.3 gene in vitro and in vivo. Normal gastric epithelial cells (GES-1) were treated with Helicobacter pylori (H. pylori) and tumor necrosis factor (TNF)-α. Total cell mRNA and protein were extracted and collected, and polymerase chain reaction and Western blot were performed to determine the relative expression of p42.3 gene. In total, 291 biopsy samples from patients with chronic non-atrophic gastritis were collected and immunohistochemistry was used to measure the p42.3 protein expression. The association between p42.3 protein expression and the clinicopathological characteristics of these patients were analyzed. Both H. pylori and TNF-α significantly enhanced the p42.3 protein expression in GES-1 cells in a time and dose-dependent manner. In addition, p42.3 gene expression was positively associated with the severity of gastric mucosal inflammation and H. pylori infection (P = 0.000). Its expression was significantly more common in severe gastric inflammation and in H. pylori-infected cases. p42.3 gene expression is associated with gastric mucosal inflammation that can be upregulated by TNF-α and H. pylori infection. © 2015 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

  15. Acute effects of continuous positive air way pressure on pulse pressure in chronic heart failure.

    PubMed

    Quintão, Mônica; Chermont, Sérgio; Marchese, Luana; Brandão, Lúcia; Bernardez, Sabrina Pereira; Mesquita, Evandro Tinoco; Novaes Rocha, Nazareth de; Nóbrega, Antônio Claudio L

    2014-02-01

    Patients with heart failure (HF) have left ventricular dysfunction and reduced mean arterial pressure (MAP). Increased adrenergic drive causes vasoconstriction and vessel resistance maintaining MAP, while increasing peripheral vascular resistance and conduit vessel stiffness. Increased pulse pressure (PP) reflects a complex interaction of the heart with the arterial and venous systems. Increased PP is an important risk marker in patients with chronic HF (CHF). Non-invasive ventilation (NIV) has been used for acute decompensated HF, to improve congestion and ventilation through both respiratory and hemodynamic effects. However, none of these studies have reported the effect of NIV on PP. The objective of this study was to determine the acute effects of NIV with CPAP on PP in outpatients with CHF. Following a double-blind, randomized, cross-over, and placebo-controlled protocol, twenty three patients with CHF (17 males; 60±11 years; BMI 29±5 kg/cm2, NYHA class II, III) underwent CPAP via nasal mask for 30 min in a recumbent position. Mask pressure was 6 cmH2O, whereas placebo was fixed at 0-1 cmH2O. PP and other non invasive hemodynamics variables were assessed before, during and after placebo and CPAP mode. CPAP decreased resting heart rate (Pre: 72±9; vs. Post 5 min: 67±10 bpm; p<0.01) and MAP (CPAP: 87±11; vs. control 96±11 mmHg; p<0.05 post 5 min). CPAP decreased PP (CPAP: 47±20 pre to 38±19 mmHg post; vs. control: 42±12 mmHg, pre to 41±18 post p<0.05 post 5 min). NIV with CPAP decreased pulse pressure in patients with stable CHF. Future clinical trials should investigate whether this effect is associated with improved clinical outcome.

  16. Increased incidence of another cancer in myeloproliferative neoplasms patients at the time of diagnosis.

    PubMed

    Pettersson, Helna; Knutsen, Håvar; Holmberg, Erik; Andréasson, Björn

    2015-02-01

    Several studies have reported an increased incidence of coexistent cancer in patients with myeloproliferative neoplasms (MPN), and myelosuppressive treatment has been speculated to be one of the causes. In this study, we have concentrated on malignancies diagnosed before the MPN diagnosis to eliminate the possible influence of MPN treatment. The patients were recruited from the Swedish and Norwegian cancer registries. One thousand seven hundred and 45 patients from the Swedish MPN Quality Registry and 468 patients from the Norwegian National Cancer Registry were included in this study covering a 3-yr period. The results show that primary concurrent cancer is higher among patients with MPN compared to the general population. When pooled together, the Swedish and the Norwegian cohort showed increased prevalence of all types of cancer in general compared with the general population, standard prevalence ratio (SPR) of 1.20 (95% CI 1.07-1.34). Significantly high SPRs were reached for skin malignant melanoma [1.89 (95% CI 1.33-2.62)], prostate cancer [1.39 (95% CI 1.11-1.71)], and hematologic cancer [1.49 (95% CI 1.00-2.12)]. In the polycythemia vera group, the risk of having prior malignant melanoma of the skin was significant, with an SPR of 2.20 (95% CI 1.17-3.77). For patients with essential thrombocythemia and primary myelofibrosis, no significant risks were found. Coexisting cancers have a high impact on the treatment strategies of MPN, as it narrows down the treatment options. Chronic inflammation, as a common denominator of MPN with other cancers, can catalyze each other's existence and progression. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Myeloproliferative neoplasms and inflammation: whether to target the malignant clone or the inflammatory process or both.

    PubMed

    Koschmieder, S; Mughal, T I; Hasselbalch, H C; Barosi, G; Valent, P; Kiladjian, J-J; Jeryczynski, G; Gisslinger, H; Jutzi, J S; Pahl, H L; Hehlmann, R; Maria Vannucchi, A; Cervantes, F; Silver, R T; Barbui, T

    2016-05-01

    The Philadelphia-negative myeloproliferative neoplasms (MPNs) are clonal disorders involving hematopoietic stem and progenitor cells and are associated with myeloproliferation, splenomegaly and constitutional symptoms. Similar signs and symptoms can also be found in patients with chronic inflammatory diseases, and inflammatory processes have been found to play an important role in the pathogenesis and progression of MPNs. Signal transduction pathways involving JAK1, JAK2, STAT3 and STAT5 are causally involved in driving both the malignant cells and the inflammatory process. Moreover, anti-inflammatory and immune-modulating drugs have been used successfully in the treatment of MPNs. However, to date, many unresoved issues remain. These include the role of somatic mutations that are present in addition to JAK2V617F, CALR and MPL W515 mutations, the interdependency of malignant and nonmalignant cells and the means to eradicate MPN-initiating and -maintaining cells. It is imperative for successful therapeutic approaches to define whether the malignant clone or the inflammatory cells or both should be targeted. The present review will cover three aspects of the role of inflammation in MPNs: inflammatory states as important differential diagnoses in cases of suspected MPN (that is, in the absence of a clonal marker), the role of inflammation in MPN pathogenesis and progression and the use of anti-inflammatory drugs for MPNs. The findings emphasize the need to separate the inflammatory processes from the malignancy in order to improve our understanding of the pathogenesis, diagnosis and treatment of patients with Philadelphia-negative MPNs.

  18. Differential Dynamics of CALR Mutant Allele Burden in Myeloproliferative Neoplasms during Interferon Alfa Treatment

    PubMed Central

    Holmström, Morten O.; Thomassen, Mads; Kruse, Torben A; Pallisgaard, Niels; Larsen, Thomas S.; de Stricker, Karin; Skov, Vibe; Hasselbalch, Hans C.

    2016-01-01

    Discovery of somatic mutations in the calreticulin gene (CALR) has identified a subgroup of Philadelphia-negative chronic myeloproliferative neoplasms (MPN) with separate haematological characteristics and prognosis. CALR mutations serve as novel markers both of diagnostic value and as targets for monitoring molecular responses during therapy. Interferon-α (IFN) selectively targets the malignant clone in a subset of MPN patients and can induce both haematological and molecular remissions in CALR mutated essential thrombocythemia (ET) patients. We investigated the response to IFN in a cohort of 21 CALR mutated MPN patients including ET, prefibrotic primary myelofibrosis (pre-PMF), and primary myelofibrosis (PMF) with a median follow-up of 31 months. For evaluation of a molecular response, we developed highly sensitive quantitative PCR (qPCR) assays for monitoring the mutant allele burden of the two most prevalent CALR mutations (type 1 and type 2). Thirteen patients (62%) experienced a decrease in the mutant allele burden with a median decline of 29% from baseline. However, only four patients, including patients with ET, pre-PMF, and PMF diagnosis, achieved molecular responder (MR) status with >50% reduction in mutant allele burden according to European LeukemiaNet (ELN) guidelines. MR patients displayed significant differences in the dynamics of the CALR mutant load with regard to time to response and dynamics in mutant allele burden after discontinuation of IFN treatment. Furthermore, we highlight the prognostic value of the CALR mutant allele burden by showing a close association with leucocyte- and platelet counts, hemoglobin concentration, in addition to plasma lactate dehydrogenase (LDH) irrespective of molecular response and treatment status. PMID:27764253

  19. Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD)

    PubMed Central

    McCurdy, BR

    2012-01-01

    Executive Summary In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions. After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses. The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at: http://www.hqontario.ca/en/mas/mas_ohtas_mn.html. Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive

  20. Circulating Endothelial Cells in Patients with Venous Thromboembolism and Myeloproliferative Neoplasms

    PubMed Central

    Torres, Cláudia; Fonseca, Ana Mafalda; Leander, Magdalena; Matos, Rui; Morais, Sara; Campos, Manuel; Lima, Margarida

    2013-01-01

    Background Circulating endothelial cells (CEC) may be a biomarker of vascular injury and pro-thrombotic tendency, while circulating endothelial progenitor cells (CEP) may be an indicator for angiogenesis and vascular remodelling. However, there is not a universally accepted standardized protocol to identify and quantify these cells and its clinical relevancy remains to be established. Objectives To quantify CEC and CEP in patients with venous thromboembolism (VTE) and with myeloproliferative neoplasms (MPN), to characterize the CEC for the expression of activation (CD54, CD62E) and procoagulant (CD142) markers and to investigate whether they correlate with other clinical and laboratory data. Patients and Methods Sixteen patients with VTE, 17 patients with MPN and 20 healthy individuals were studied. The CEC and CEP were quantified and characterized in the blood using flow cytometry, and the demographic, clinical and laboratory data were obtained from hospital records. Results We found the CEC counts were higher in both patient groups as compared to controls, whereas increased numbers of CEP were found only in patients with MPN. In addition, all disease groups had higher numbers of CD62E+ CEC as compared to controls, whereas only patients with VTE had increased numbers of CD142+ and CD54+ CEC. Moreover, the numbers of total and CD62+ CEC correlated positively with the white blood cells (WBC) counts in both groups of patients, while the numbers of CEP correlated positively with the WBC counts only in patients with MPN. In addition, in patients with VTE a positive correlation was found between the numbers of CD54+ CEC and the antithrombin levels, as well as between the CD142+ CEC counts and the number of thrombotic events. Conclusions Our study suggests that CEC counts may reveal endothelial injury in patients with VTE and MPN and that CEC may express different activation-related phenotypes depending on the disease status. PMID:24339944

  1. The JAK2 46/1 haplotype predisposes to MPL-mutated myeloproliferative neoplasms

    PubMed Central

    Jones, Amy V.; Campbell, Peter J.; Beer, Philip A.; Schnittger, Susanne; Vannucchi, Alessandro M.; Zoi, Katerina; Percy, Melanie J.; McMullin, Mary Frances; Scott, Linda M.; Tapper, William; Silver, Richard T.; Oscier, David; Harrison, Claire N.; Grallert, Harald; Kisialiou, Aliaksei; Strike, Paul; Chase, Andrew J.; Green, Anthony R.

    2010-01-01

    The 46/1 JAK2 haplotype predisposes to V617F-positive myeloproliferative neoplasms, but the underlying mechanism is obscure. We analyzed essential thrombocythemia patients entered into the PT-1 studies and, as expected, found that 46/1 was overrepresented in V617F-positive cases (n = 404) versus controls (n = 1492, P = 3.9 × 10−11). The 46/1 haplotype was also overrepresented in cases without V617F (n = 347, P = .009), with an excess seen for both MPL exon 10 mutated and V617F, MPL exon 10 nonmutated cases. Analysis of further MPL-positive, V617F-negative cases confirmed an excess of 46/1 (n = 176, P = .002), but no association between MPL mutations and MPL haplotype was seen. An excess of 46/1 was also seen in JAK2 exon 12 mutated cases (n = 69, P = .002), and these mutations preferentially arose on the 46/1 chromosome (P = .029). No association between 46/1 and clinical or laboratory features was seen in the PT-1 cohort either with or without V617F. The excess of 46/1 in JAK2 exon 12 cases is compatible with both the “hypermutability” and “fertile ground” hypotheses, but the excess in MPL-mutated cases argues against the former. No difference in sequence, splicing, or expression of JAK2 was found on 46/1 compared with other haplotypes, suggesting that any functional difference of JAK2 on 46/1, if it exists, must be relatively subtle. PMID:20304805

  2. Coexistence of chronic lymphocytic leukemia and polycythemia vera: a case report and review of the literature.

    PubMed

    Korkmaz, Serdal; Kulakoglu, Sinan; Gorkem, Hasan; Aygun, Bilal; Cetinkaya, Ali

    2016-01-01

    Polycythemia vera is a Philadelphia chromosome-negative myeloproliferative neoplasm. Chronic lymphocytic leukemia is a monoclonal expansion of a CD5+ CD19+ B lymphocytes. Chronic myeloproliferative neoplasms may coexist with indolent B-cell malignant lymphomas of various types. The association of chronic lymphocytic leukemia with polycythemia vera is a rare event with only a few cases of coexistence ever reported. We report a 56-year-old man in whom these two disorders were diagnosed concomitantly. Possible etiopathogenic relationships between both disorders are discussed in this case report. 6.

  3. Comparing airways clearance techniques in chronic obstructive pulmonary disease and bronchiectasis: positive expiratory pressure or temporary positive expiratory pressure? A retrospective study.

    PubMed

    D'Abrosca, Francesco; Garabelli, Barbara; Savio, Gloria; Barison, Agnese; Appendini, Lorenzo; Oliveira, Luis V F; Baiardi, Paola; Balbi, Bruno

    Airway clearance techniques include positive expiratory pressure, commonly used in our clinical practice, and a recently introduced temporary positive expiratory pressure device called UNIKO(®). It is unclear which one provides the best benefit to patients. The aim of this observational 4-year study was to retrospectively compare the efficacy of and specific indications for temporary positive expiratory pressure compared to positive expiratory pressure in a standard rehabilitation program. We retrospectively collected data from 162 subjects (107 males, mean age 70±9 years, 97 with primary diagnosis of chronic obstructive pulmonary disease, 65 with bronchiectasis), 51 treated with temporary positive expiratory pressure and 111 with positive expiratory pressure. Subjects showed significant improvement in ratio of partial pressure arterial oxygen and fraction of inspired oxygen (p<0.001), forced vital capacity, forced expiratory volume in one second, peak expiratory flow, arterial oxygen saturation, and partial pressure arterial oxygen with no significant difference between positive expiratory pressure and temporary positive expiratory pressure groups apart from forced expiratory flow, which increased only in the positive expiratory pressure group. Evaluating specific subgroups, temporary positive expiratory pressure was more effective than positive expiratory pressure in improving gas transfer in subjects with emphysema and in those on oxygen therapy, as the effective supplement oxygen flow decreased significantly (p=0.034 and 0.046 respectively for temporary positive expiratory pressure vs. positive expiratory pressure). In subjects on mechanical ventilation, positive expiratory pressure was superior to temporary positive expiratory pressure in increasing forced expiratory flow (p=0.018). The physiological parameters of both groups improved significantly and similarly. Subgroup analysis suggests that temporary positive expiratory pressure could provide some

  4. Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms.

    PubMed

    Rumi, Elisa; Cazzola, Mario

    2017-02-09

    Philadelphia-negative classical myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The 2016 revision of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues includes new criteria for the diagnosis of these disorders. Somatic mutations in the 3 driver genes, that is, JAK2, CALR, and MPL, represent major diagnostic criteria in combination with hematologic and morphological abnormalities. PV is characterized by erythrocytosis with suppressed endogenous erythropoietin production, bone marrow panmyelosis, and JAK2 mutation. Thrombocytosis, bone marrow megakaryocytic proliferation, and presence of JAK2, CALR, or MPL mutation are the main diagnostic criteria for ET. PMF is characterized by bone marrow megakaryocytic proliferation, reticulin and/or collagen fibrosis, and presence of JAK2, CALR, or MPL mutation. Prefibrotic myelofibrosis represents an early phase of myelofibrosis, and is characterized by granulocytic/megakaryocytic proliferation and lack of reticulin fibrosis in the bone marrow. The genomic landscape of MPNs is more complex than initially thought and involves several mutant genes beyond the 3 drivers. Comutated, myeloid tumor-suppressor genes contribute to phenotypic variability, phenotypic shifts, and progression to more aggressive disorders. Patients with myeloid neoplasms are at variable risk of vascular complications, including arterial or venous thrombosis and bleeding. Current prognostic models are mainly based on clinical and hematologic parameters, but innovative models that include genetic data are being developed for both clinical and trial settings. In perspective, molecular profiling of MPNs might also allow for accurate evaluation and monitoring of response to innovative drugs that target the mutant clone.

  5. Clinical significance of circulating microparticles in Ph− myeloproliferative neoplasms

    PubMed Central

    Zhang, Wenjuan; Qi, Jiaqian; Zhao, Shixiang; Shen, Wenhong; Dai, Lan; Han, Wei; Huang, Man; Wang, Zhaoyue; Ruan, Changgeng; Wu, Depei; Han, Yue

    2017-01-01

    Microparticles (MPs) are small membrane vesicles that are classified into subcategories based on their origin, such as platelet-derived MPs (PMPs), endothelial MPs (EMPs), red blood cell MPs (RMPs) and tissue factor MPs (TF + MPs). Philadelphia chromosome-negative myeloproliferative neoplasms (Ph−MPN) are disorders characterized by abnormal haematopoiesis, thrombosis and the JAK2V617F mutation. MPs are biomarkers for procoagulant state in cancer patients, but their relevance in patients with Ph−MPN was unclear. The present study aimed to measure MP variation in MPN patients and evaluate association with the JAK2V617F mutation and with thrombosis and splenomegaly. In total, 92 patients with MPN were enrolled in the present study, including 60 with essential thrombocythaemia (ET), 20 with polycythaemia vera (PV), and 12 with primary myelofibrosis (PMF). RMPs, PMPs, TF + MPs and EMPs were measured by flow cytometry. The levels of RMPs, PMPs, EMPs and TF + MPs in patients with Ph−MPN were all found to be significantly increased compared with controls (P<0.05). Additionally, the levels of all four types of MPs in the PMF group were significantly increased compared with the PV group (P<0.05), and the level of RMPs in the PMF group was significantly increased compared with the ET group (P<0.05). MP levels were increased in the Ph−MPN patients with thrombosis compared with patients without thrombosis (P<0.05). MP levels were increased in Ph−MPN patients with splenomegaly compared with patients without splenomegaly (P<0.05). The level of PMPs in patients with the JAK2V617F mutation was increased compared with patients without the mutation (P<0.05). In conclusion, the present study showed that MPs are associated with Ph−MPN pathogenesis, and may promote thrombosis. PMID:28789461

  6. Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms

    PubMed Central

    2017-01-01

    Philadelphia-negative classical myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The 2016 revision of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues includes new criteria for the diagnosis of these disorders. Somatic mutations in the 3 driver genes, that is, JAK2, CALR, and MPL, represent major diagnostic criteria in combination with hematologic and morphological abnormalities. PV is characterized by erythrocytosis with suppressed endogenous erythropoietin production, bone marrow panmyelosis, and JAK2 mutation. Thrombocytosis, bone marrow megakaryocytic proliferation, and presence of JAK2, CALR, or MPL mutation are the main diagnostic criteria for ET. PMF is characterized by bone marrow megakaryocytic proliferation, reticulin and/or collagen fibrosis, and presence of JAK2, CALR, or MPL mutation. Prefibrotic myelofibrosis represents an early phase of myelofibrosis, and is characterized by granulocytic/megakaryocytic proliferation and lack of reticulin fibrosis in the bone marrow. The genomic landscape of MPNs is more complex than initially thought and involves several mutant genes beyond the 3 drivers. Comutated, myeloid tumor-suppressor genes contribute to phenotypic variability, phenotypic shifts, and progression to more aggressive disorders. Patients with myeloid neoplasms are at variable risk of vascular complications, including arterial or venous thrombosis and bleeding. Current prognostic models are mainly based on clinical and hematologic parameters, but innovative models that include genetic data are being developed for both clinical and trial settings. In perspective, molecular profiling of MPNs might also allow for accurate evaluation and monitoring of response to innovative drugs that target the mutant clone. PMID:28028026

  7. Overexpression of the VAV proto-oncogene product is associated with B-cell chronic lymphocytic leukaemia displaying loss on 13q

    PubMed Central

    Prieto-Sánchez, Rosario M.; Hernández, José A.; García, Juan L.; Gutiérrez, Norma C.; Miguel, Jesús San; Bustelo, Xosé R.; Hernández, Jesús M.

    2007-01-01

    Summary The expression of the VAV proto-oncogene in 57 patients with chronic myeloproliferative disease (CMD), B-cell acute lymphoblastic leukaemia (BALL) and B-cell non-Hodgkin Lymphoma (B-NHL), and 61 with B-cell chronic lymphocytic leukaemia (B-CLL) was analysed. VAV overexpression was observed in 19.5% of cases and 81% of VAV-positive tumours also displayed VAV phosphorylation. Overexpression was not observed in B-ALL or CMD, but 13% of B-NHL and 34.4% of B-CLL patients (P = 0.002) overexpressed VAV. The overexpression and phosphorylation of VAV was detected more frequently in 13q- chronic lymphocytic leukaemias (71.4%) versus other B-CLLs (23.4%, P = 0.001). Overexpression of VAV protein is a frequent event in patients with B-CLL displaying loss of 13q sequences. PMID:16704440

  8. Position of the Academy of Nutrition and Dietetics: the role of nutrition in health promotion and chronic disease prevention.

    PubMed

    Slawson, Deborah Leachman; Fitzgerald, Nurgul; Morgan, Kathleen T

    2013-07-01

    It is the position of the Academy of Nutrition and Dietetics that primary prevention is the most effective and affordable method to prevent chronic disease, and that dietary intervention positively impacts health outcomes across the life span. Registered dietitians and dietetic technicians, registered are critical members of health care teams and are essential to delivering nutrition-focused preventive services in clinical and community settings, advocating for policy and programmatic initiatives, and leading research in disease prevention and health promotion. Health-promotion and disease-prevention strategies are effective at reducing morbidity and mortality and improving quality of life, and have a significant impact on the leading causes of disease. By applying these principles within a social ecological theoretical framework, positive influence can be applied across the spectrum of engagement: at intrapersonal, interpersonal, institutional, community, and public policy levels. Through the application of efficacious and cost-effective interventions, registered dietitians and dietetic technicians, registered, can positively impact public health as well as health outcomes for the individuals that they counsel. This position paper supports the "Practice Paper of the Academy of Nutrition and Dietetics: The Role of Nutrition in Health Promotion and Chronic Disease Prevention" published on the Academy's website at: www.eatright.org/positions.

  9. 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

  10. Dasatinib in Treating Young Patients With Recurrent or Refractory Solid Tumors or Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia or Chronic Myelogenous Leukemia That Did Not Respond to Imatinib Mesylate

    ClinicalTrials.gov

    2013-02-04

    Accelerated Phase Chronic Myelogenous Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Childhood Chronic Myelogenous Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Meningeal Chronic Myelogenous Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Relapsing Chronic Myelogenous Leukemia; Unspecified Childhood Solid Tumor, Protocol Specific

  11. Role of tyrosine-kinase inhibitors in myeloproliferative neoplasms: comparative lessons learned

    PubMed Central

    Pinilla-Ibarz, Javier; Sweet, Kendra L; Corrales-Yepez, Gabriela M; Komrokji, Rami S

    2016-01-01

    An important pathogenetic distinction in the classification of myeloproliferative neoplasms (MPNs) is the presence or absence of the BCR–ABL fusion gene, which encodes a unique oncogenic tyrosine kinase. The BCR–ABL fusion, caused by the formation of the Philadelphia chromosome (Ph) through translocation, constitutes the disease-initiating event in chronic myeloid leukemia. The development of successive BCR–ABL-targeted tyrosine-kinase inhibitors has led to greatly improved outcomes in patients with chronic myeloid leukemia, including high rates of complete hematologic, cytogenetic, and molecular responses. Such levels of treatment success have long been elusive for patients with Ph-negative MPNs, because of the difficulties in identifying specific driver proteins suitable as drug targets. However, in recent years an improved understanding of the complex pathobiology of classic Ph-negative MPNs, characterized by variable, overlapping multimutation profiles, has prompted the development of better and more broadly targeted (to pathway rather than protein) treatment options, particularly JAK inhibitors. In classic Ph-negative MPNs, overactivation of JAK-dependent signaling pathways is a central pathogenic mechanism, and mutually exclusive mutations in JAK2, MPL, and CALR linked to aberrant JAK activation are now recognized as key drivers of disease progression in myelofibrosis (MF). In clinical trials, the JAK1/JAK2 inhibitor ruxolitinib – the first therapy approved for MF worldwide – improved disease-related splenomegaly and symptoms independent of JAK2V617F mutational status, and prolonged survival compared with placebo or standard therapy in patients with advanced MF. In separate trials, ruxolitinib also provided comprehensive hematologic control in patients with another Ph-negative MPN – polycythemia vera. However, complete cytogenetic or molecular responses with JAK inhibitors alone are normally not observed, underscoring the need for novel

  12. Neuromodulation of chronic headaches: position statement from the European Headache Federation

    PubMed Central

    2013-01-01

    The medical treatment of patients with chronic primary headache syndromes (chronic migraine, chronic tension-type headache, chronic cluster headache, hemicrania continua) is challenging as serious side effects frequently complicate the course of medical treatment and some patients may be even medically intractable. When a definitive lack of responsiveness to conservative treatments is ascertained and medication overuse headache is excluded, neuromodulation options can be considered in selected cases. Here, the various invasive and non-invasive approaches, such as hypothalamic deep brain stimulation, occipital nerve stimulation, stimulation of sphenopalatine ganglion, cervical spinal cord stimulation, vagus nerve stimulation, transcranial direct current stimulation, repetitive transcranial magnetic stimulation, and transcutaneous electrical nerve stimulation are extensively published although proper RCT-based evidence is limited. The European Headache Federation herewith provides a consensus statement on the clinical use of neuromodulation in headache, based on theoretical background, clinical data, and side effect of each method. This international consensus further gives recommendations for future studies on these new approaches. In spite of a growing field of stimulation devices in headaches treatment, further controlled studies to validate, strengthen and disseminate the use of neurostimulation are clearly warranted. Consequently, until these data are available any neurostimulation device should only be used in patients with medically intractable syndromes from tertiary headache centers either as part of a valid study or have shown to be effective in such controlled studies with an acceptable side effect profile. PMID:24144382

  13. Discipline and the Chronically Ill Child: What Are the Management Strategies To Promote Positive Patient Outcomes?

    ERIC Educational Resources Information Center

    Richardson, Rita C.

    This paper reviews various discipline models and applies them to obtaining cooperation and compliance with medical treatment of children with chronic and acute medical conditions, especially End-Stage Renal Disease (ESRD). The definition of Other Health Impairments in the Individuals with Disabilities Education Act is cited and related to the…

  14. Myeloproliferative neoplasms and the JAK/STAT signaling pathway: an overview

    PubMed Central

    de Freitas, Renata Mendes; da Costa Maranduba, Carlos Magno

    2015-01-01

    Myeloproliferative neoplasms are caused by a clonal proliferation of a hematopoietic progenitor. First described in 1951 as ‘Myeloproliferative Diseases’ and reevaluated by the World Health Organization classification system in 2011, myeloproliferative neoplasms include polycythemia vera, essential thrombocythemia and primary myelofibrosis in a subgroup called breakpoint cluster region-Abelson fusion oncogene-negative neoplasms. According to World Health Organization regarding diagnosis criteria for myeloproliferative neoplasms, the presence of the JAK2 V617F mutation is considered the most important criterion in the diagnosis of breakpoint cluster region-Abelson fusion oncogene-negative neoplasms and is thus used as a clonal marker. The V617F mutation in the Janus kinase 2 (JAK2) gene produces an altered protein that constitutively activates the Janus kinase/signal transducers and activators of transcription pathway and other pathways downstream as a result of signal transducers and activators of transcription which are subsequently phosphorylated. This affects the expression of genes involved in the regulation of apoptosis and regulatory proteins and modifies the proliferation rate of hematopoietic stem cells. PMID:26408371

  15. Renal thrombotic microangiopathy and FIP1L1/PDGFRα-associated myeloproliferative variant of hypereosinophilic syndrome

    PubMed Central

    Langlois, Anne Lyse; Shehwaro, Nathalie; Rondet, Claire; Benbrik, Youssef; Maloum, Karim; Gueutin, Victor; Rouvier, Philippe; Izzedine, Hassane

    2013-01-01

    We report a case of renal thrombotic microangiopathy (TMA) in a myeloproliferative variant of hypereosinophilic syndrome (HES) in a 24-year-old man which resolved with imatinib therapy. This is one of a few cases in the literature to date describing TMA in HES, suggesting that the pathogenesis of thrombosis is at least in part related to damage from activated eosinophils. PMID:27293571

  16. Renal thrombotic microangiopathy and FIP1L1/PDGFRα-associated myeloproliferative variant of hypereosinophilic syndrome.

    PubMed

    Langlois, Anne Lyse; Shehwaro, Nathalie; Rondet, Claire; Benbrik, Youssef; Maloum, Karim; Gueutin, Victor; Rouvier, Philippe; Izzedine, Hassane

    2013-08-01

    We report a case of renal thrombotic microangiopathy (TMA) in a myeloproliferative variant of hypereosinophilic syndrome (HES) in a 24-year-old man which resolved with imatinib therapy. This is one of a few cases in the literature to date describing TMA in HES, suggesting that the pathogenesis of thrombosis is at least in part related to damage from activated eosinophils.

  17. Bone marrow microvessel density and plasma angiogenic factors in myeloproliferative neoplasms: clinicopathological and molecular correlations.

    PubMed

    Lekovic, Danijela; Gotic, Mirjana; Skoda, Radek; Beleslin-Cokic, Bojana; Milic, Natasa; Mitrovic-Ajtic, Olivera; Nienhold, Ronny; Sefer, Dijana; Suboticki, Tijana; Buac, Marijana; Markovic, Dragana; Diklic, Milos; Cokic, Vladan P

    2017-03-01

    Increased angiogenesis in BCR-ABL1 negative myeloproliferative neoplasms (MPNs) has been recognized, but its connection with clinical and molecular markers needs to be defined. The aims of study were to (1) assess bone marrow (BM) angiogenesis measured by microvessel density (MVD) using CD34 and CD105 antibodies; (2) analyze correlation of MVD with plasma angiogenic factors including vascular endothelial growth factor, basic fibroblast growth factor, and interleukin-8; (3) examine the association of MVD with clinicopathological and molecular markers. We examined 90 de novo MPN patients (30 polycythemia vera (PV), primary myelofibrosis (PMF), essential thrombocythemia (ET)) and 10 age-matched controls. MVD was analyzed by immunohistochemistry "hot spot" method, angiogenic factors by immunoassay and JAK2V617F, and CALR mutations by DNA sequencing and allelic PCR. MVD was significantly increased in MPNs compared to controls (PMF > PV > ET). Correlation between MVD and plasma angiogenic factors was found in MPNs. MVD was significantly increased in patients with JAK2V617F mutation and correlated with JAK2 mutant allele burden (CD34-MVD: ρ = 0.491, p < 0.001; CD105-MVD: ρ = 0.276, p = 0.02) but not with CALR mutation. MVD correlated with leukocyte count, serum lactate dehydrogenase, hepatomegaly, and splenomegaly. BM fibrosis was significantly associated with CD34-MVD, CD105-MVD, interleukin-8, and JAK2 mutant allele burden. JAK2 homozygote status had positive predictive value (100%) for BM fibrosis. Patients with prefibrotic PMF had significantly higher MVD than patients with ET, and we could recommend MVD to be additional histopathological marker to distinguish these two entities. This study also highlights the strong correlation of MVD with plasma angiogenic factors, JAK2 mutant allele burden, and BM fibrosis in MPNs.

  18. Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms

    PubMed Central

    Malcovati, Luca; Papaemmanuil, Elli; Bowen, David T.; Boultwood, Jacqueline; Della Porta, Matteo G.; Pascutto, Cristiana; Travaglino, Erica; Groves, Michael J.; Godfrey, Anna L.; Ambaglio, Ilaria; Gallì, Anna; Da Vià, Matteo C.; Conte, Simona; Tauro, Sudhir; Keenan, Norene; Hyslop, Ann; Hinton, Jonathan; Mudie, Laura J.; Wainscoat, James S.; Futreal, P. Andrew; Stratton, Michael R.; Campbell, Peter J.; Hellström-Lindberg, Eva

    2011-01-01

    In a previous study, we identified somatic mutations of SF3B1, a gene encoding a core component of RNA splicing machinery, in patients with myelodysplastic syndrome (MDS). Here, we define the clinical significance of these mutations in MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). The coding exons of SF3B1 were screened using massively parallel pyrosequencing in patients with MDS, MDS/MPN, or acute myeloid leukemia (AML) evolving from MDS. Somatic mutations of SF3B1 were found in 150 of 533 (28.1%) patients with MDS, 16 of 83 (19.3%) with MDS/MPN, and 2 of 38 (5.3%) with AML. There was a significant association of SF3B1 mutations with the presence of ring sideroblasts (P < .001) and of mutant allele burden with their proportion (P = .002). The mutant gene had a positive predictive value for ring sideroblasts of 97.7% (95% confidence interval, 93.5%-99.5%). In multivariate analysis including established risk factors, SF3B1 mutations were found to be independently associated with better overall survival (hazard ratio = 0.15, P = .025) and lower risk of evolution into AML (hazard ratio = 0.33, P = .049). The close association between SF3B1 mutations and disease phenotype with ring sideroblasts across MDS and MDS/MPN is consistent with a causal relationship. Furthermore, SF3B1 mutations are independent predictors of favorable clinical outcome, and their incorporation into stratification systems might improve risk assessment in MDS. PMID:21998214

  19. HDAC8 overexpression in mesenchymal stromal cells from JAK2+ myeloproliferative neoplasms: a new therapeutic target?

    PubMed

    Ramos, Teresa L; Sánchez-Abarca, Luis Ignacio; Redondo, Alba; Hernández-Hernández, Ángel; Almeida, Antonio M; Puig, Noemí; Rodríguez, Concepción; Ortega, Rebeca; Preciado, Silvia; Rico, Ana; Muntión, Sandra; González Porras, José Ramón; Del Cañizo, Consuelo; Sánchez-Guijo, Fermín

    2017-03-07

    Histone deacetylases (HDACs) are involved in epigenetic modulation and their aberrant expression has been demonstrated in myeloproliferative neoplasms (MPN). HDAC8 inhibition has been shown to inhibit JAK2/STAT5 signaling in hematopoietic cells from MPN. Nevertheless, the role of HDAC8 expression in bone marrow-mesenchymal stromal cells (BM-MSC) has not been assessed. In the current work we describe that HDAC8 is significantly over-expressed in MSC from in JAK-2 positive MPN compared to those from healthy-donors (HD-MSC). Using a selective HDAC8 inhibitor (PCI34051), we verified that the subsequent decrease in the protein and mRNA expression of HDAC8 is linked with an increased apoptosis of malignant MSC whereas it has no effects on normal MSC. In addition, HDAC8 inhibition in MPN-MSC also decreased their capacity to maintain neoplastic hematopoiesis, by increasing the apoptosis, cell-cycle arrest and colony formation of JAK2+-hematopoietic cells. Mechanistic studies using different MPN cell lines revealed that PCI34051 induced their apoptosis, which is enhanced when were co-cultured with JAK2V617F-MSC, decreased their colony formation and the phosphorylation of STAT3 and STAT5. In summary, we show for the first time that the inhibition of HDAC8 in MSC from JAK2+ MPN patients selectively decreases their hematopoietic-supporting ability, suggesting that HDAC8 may be a potential therapeutic target in this setting by acting not only on hematopoietic cells but also on the malignant microenvironment.

  20. HDAC8 overexpression in mesenchymal stromal cells from JAK2+ myeloproliferative neoplasms: a new therapeutic target?

    PubMed Central

    Ramos, Teresa L.; Sánchez-Abarca, Luis Ignacio; Redondo, Alba; Hernández-Hernández, Ángel; Almeida, Antonio M.; Puig, Noemí; Rodríguez, Concepción; Ortega, Rebeca; Preciado, Silvia; Rico, Ana; Muntión, Sandra; González Porras, José Ramón; Cañizo, Consuelo Del; Sánchez-Guijo, Fermín

    2017-01-01

    Histone deacetylases (HDACs) are involved in epigenetic modulation and their aberrant expression has been demonstrated in myeloproliferative neoplasms (MPN). HDAC8 inhibition has been shown to inhibit JAK2/STAT5 signaling in hematopoietic cells from MPN. Nevertheless, the role of HDAC8 expression in bone marrow-mesenchymal stromal cells (BM-MSC) has not been assessed. In the current work we describe that HDAC8 is significantly over-expressed in MSC from in JAK-2 positive MPN compared to those from healthy-donors (HD-MSC). Using a selective HDAC8 inhibitor (PCI34051), we verified that the subsequent decrease in the protein and mRNA expression of HDAC8 is linked with an increased apoptosis of malignant MSC whereas it has no effects on normal MSC. In addition, HDAC8 inhibition in MPN-MSC also decreased their capacity to maintain neoplastic hematopoiesis, by increasing the apoptosis, cell-cycle arrest and colony formation of JAK2+-hematopoietic cells. Mechanistic studies using different MPN cell lines revealed that PCI34051 induced their apoptosis, which is enhanced when were co-cultured with JAK2V617F-MSC, decreased their colony formation and the phosphorylation of STAT3 and STAT5. In summary, we show for the first time that the inhibition of HDAC8 in MSC from JAK2+ MPN patients selectively decreases their hematopoietic-supporting ability, suggesting that HDAC8 may be a potential therapeutic target in this setting by acting not only on hematopoietic cells but also on the malignant microenvironment. PMID:28390197

  1. Dissecting Genomic Aberrations in Myeloproliferative Neoplasms by Multiplex-PCR and Next Generation Sequencing

    PubMed Central

    Schubert, Claudia; Chatain, Nicolas; Sontag, Stephanie; Isfort, Susanne; Ortiz-Brüchle, Nadina; Schmitt, Karla; Krüger, Luisa; Zerres, Klaus; Zenke, Martin; Brümmendorf, Tim H.; Koschmieder, Steffen

    2015-01-01

    In order to assess the feasibility of amplicon-based parallel next generation sequencing (NGS) for the diagnosis of myeloproliferative neoplasms (MPN), we investigated multiplex-PCR of 212 amplicons covering genomic mutational hotspots in 48 cancer-related genes. Samples from 64 patients with MPN and five controls as well as seven (myeloid) cell lines were analyzed. Healthy donor and reactive erythrocytosis samples showed several frequent single-nucleotide polymorphisms (SNPs) but no known pathogenic mutation. Sequencing of the cell lines confirmed the presence of the known mutations. In the patient samples, JAK2 V617F was present in all PV, 4 of 10 ET, and 16 of 19 MF patients. The JAK2 V617F allele burden was different in the three groups (ET, 33+/-22%; PV 48+/-28% and MF 68+/- 29%). Further analysis detected both previously described and undescribed mutations (i.e., G12V NRAS, IDH1 R132H, E255G ABL, and V125G IDH1 mutations). One patient with lymphoid BC/Ph+ ALL who harbored a T315I ABL mutation and was treated with ponatinib was found to have developed a newly acquired V216M TP53 mutation (12% of transcripts) when becoming resistant to ponatinib. Ponatinib led to a decrease of ABL T315I positive transcripts from 47% before ponatinib treatment to 16% at the time of ponatinib resistance in this patient, suggesting that both TP53 and ABL mutations were present in the same clone and that the newly acquired TP53 mutation might have caused ponatinib resistance in this patient. In conclusion, amplicon-sequencing-based NGS allows simultaneous analysis of multiple MPN associated genes for diagnosis and during treatment and measurement of the mutant allele burden. PMID:25894969

  2. Angiogenic factors are increased in circulating granulocytes and CD34(+) cells of myeloproliferative neoplasms.

    PubMed

    Subotički, Tijana; Mitrović Ajtić, Olivera; Beleslin-Čokić, Bojana B; Nienhold, Ronny; Diklić, Miloš; Djikić, Dragoslava; Leković, Danijela; Bulat, Tanja; Marković, Dragana; Gotić, Mirjana; Noguchi, Constance T; Schechter, Alan N; Skoda, Radek C; Čokić, Vladan P

    2017-02-01

    It has been shown that angiogenesis and inflammation play an important role in development of most hematological malignancies including the myeloproliferative neoplasm (MPN). The aim of this study was to investigate and correlate the levels of key angiogenic molecules such as hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) in peripheral blood and bone marrow cells of MPN patients, along with JAK2V617F mutation allele burden and effects of therapy. HIF-1α and VEGF gene expression were decreased, while eNOS mRNA levels were increased in granulocytes of MPN patients. Furthermore, positively correlated and increased VEGF and eNOS protein levels were in negative correlation with HIF-1α levels in granulocytes of MPN patients. According to immunoblotting, the generally augmented angiogenic factors demonstrated JAK2V617F allele burden dependence only in granulocytes of PMF. The angiogenic factors were largely reduced after hydroxyurea therapy in granulocytes of MPN patients. Levels of eNOS protein expression were stimulated by Calreticulin mutations in granulocytes of essential thrombocythemia. Immunocytochemical analyses of CD34(+) cells showed a more pronounced enhancement of angiogenic factors than in granulocytes. Increased gene expression linked to the proinflammatory TGFβ and MAPK signaling pathways were detected in CD34(+) cells of MPN patients. In conclusion, the angiogenesis is increased in several cell types of MPN patients supported by the transcriptional activation of inflammation-related target genes, and is not limited to bone marrow stroma cells. It also appears that some of the benefit of hydroxyurea therapy of the MPN is mediated by effects on angiogenic factors. © 2016 Wiley Periodicals, Inc.

  3. Association between anti-HBc positivity and hepatocellular carcinoma in HBsAg-negative subjects with chronic liver disease

    PubMed Central

    Coppola, Nicola; Onorato, Lorenzo; Sagnelli, Caterina; Sagnelli, Evangelista; Angelillo, Italo F.

    2016-01-01

    Abstract A meta-analysis was performed to ascertain to what extent hepatitis B surface antigen (HBsAg)-negative/anti-hepatitis B core (anti-HBc)-positive subjects with chronic liver disease are at a higher risk of developing hepatocellular carcinoma (HCC) than the anti-HBc-negative. All studies included had to fulfill the following characteristics and inclusion criteria: they investigated the relationship between HBsAg-negative/anti-HBc-positive serology and the occurrence of HCC, whether a case–control or cohort study, they provided relative risk (RR) or odds ratios (ORs) and 95% confidence intervals (CIs), were available as a full text written in English, and were published and indexed up to April 2015. Twenty-six original studies met the inclusion criteria, allowing a meta-analysis on 44,553 patients. The risk of HCC among the 9986 anti-HBc-positive subjects was 67% higher than in the 34,567 anti-HBc-negative (95% CI = 1.44–1.95, P < 0.0001). The results were similar when groups of patients with a different stage of liver disease (patients with chronic liver disease, patients with cirrhosis), with different ethnicity (Asian and non-Asian) and etiology (HCV and non-HCV) were considered. The risk of HCC was significantly higher in the 651 anti-HBs/anti-HBc-positive patients (RR = 1.36; 95% CI = 1.17–1.58, P = 0.03) and in the 595 anti-HBs-negative/anti-HBc-positive subjects (RR = 2.15; 95% CI = 1.58–2.92, P < 0.0001) than in the 1242 anti-HBs/anti-HBc negative. However, the RR from 8 studies indicated that the risk of HCC was 35% lower among the anti-HBs/anti-HBc-positive subjects compared to the anti-HBs-negative/anti-HBc-positive (RR = 0.65; 95% CI = 0.52–0.8, P < 0.0001). This meta-analysis shows that in HBsAg-negative subjects with chronic liver disease, anti-HBc positivity is strongly associated with the presence of HCC, an association observed in all subgroups according to the stage of the disease

  4. Facet joint pain in chronic spinal pain: an evaluation of prevalence and false-positive rate of diagnostic blocks.

    PubMed

    Manchukonda, Rajeev; Manchikanti, Kavita N; Cash, Kimberly A; Pampati, Vidyasagar; Manchikanti, Laxmaiah

    2007-10-01

    A retrospective review. Evaluation of the prevalence of facet or zygapophysial joint pain in chronic spinal pain of cervical, thoracic, and lumbar origin by using controlled, comparative local anesthetic blocks and evaluation of false-positive rates of single blocks in the diagnosis of chronic spinal pain of facet joint origin. Facet or zygapophysial joints are clinically important sources of chronic cervical, thoracic, and lumbar spine pain. The previous studies have demonstrated the value and validity of controlled, comparative local anesthetic blocks in the diagnosis of facet joint pain, with a prevalence of 15% to 67% variable in lumbar, thoracic, and cervical regions. False-positive rates of single diagnostic blocks also varied from 17% to 63%. Five hundred consecutive patients receiving controlled, comparative local anesthetic blocks of medial branches for the diagnosis of facet or zygapophysial joint pain were included. Patients were investigated with diagnostic blocks using 0.5 mL of 1% lidocaine per nerve. Patients with lidocaine-positive results were further studied using 0.5 mL of 0.25% bupivacaine per nerve on a separate occasion. Medial branch blocks were performed with intermittent fluoroscopic visualization, at 2 levels to block a single joint. A positive response was considered as one with at least 80% pain relief from a block of at least 2 hours duration when lidocaine was used, and at least 3 hours or longer than the duration of relief with lidocaine when bupivacaine was used, and also the ability to perform prior painful movements. A total of 438 patients met inclusion criteria. The prevalence of facet joint pain was 39% in the cervical spine [95% confidence interval (CI), 32%-45%]; 34% (95% CI, 22%-47%) in the thoracic pain; and 27% (95% CI, 22%-33%) in the lumbar spine. The false-positive rate with a single block in the cervical region was 45%, in the thoracic region was 42%, and in the lumbar region 45%. This retrospective review once again

  5. The cognitive impact of chronic low back pain: Positive effect of multidisciplinary pain therapy.

    PubMed

    Schiltenwolf, Marcus; Akbar, Michael; Neubauer, Eva; Gantz, Simone; Flor, Herta; Hug, Andreas; Wang, Haili

    2017-10-06

    Little is known about the affected cognitive problems in chronic low back pain patients. For this patient cohort research mostly focused on memory of pain, rather than cognitive difficulties related to pain. Chronic pain may be associated with specific (yet undefined) cognitive deficits that affect everyday behaviour. We set out to compare the cognitive function of patients with chronic low back pain (cLBP) in the course of multidisciplinary pain treatments before and after therapy. Thirty-three patients with cLBP and 25 healthy controls between 20 and 70 years were recruited into the study. The inclusion criteria for patients were: (1) a history of at least 12 weeks of chronic myofascial low back pain without radicular pain sensation before enrolment; (2) grade II and higher chronicity according to von Korff; (3) no opioid medication. The patients recruited had a mean pain duration of 7.13±7.16 years and reported a mean pain intensity of 6.62±2.04 (visual analogue score, VAS). Their mean back function according to the Funktionsfragebogen Hannover (FFbH, a questionnaire comparable with the Health Assessment Questionnaire) was 52.39±20.23%. At three time points (before therapy, 3 weeks and 6 months after therapy) the study subjects were assessed prospectively with a battery of visual memory tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB). These included choice reaction time (CRT), pattern recognition memory (PRM) and spatial span (SSP). In parallel, the Trail-Making Test (TMT-A, TMT-B) and the Wechsler Adult Intelligence Scale (WAIS-III) were used to evaluate intelligence and cognitive flexibility. At the beginning of MDPT (T1), it took patients with cLBP significantly longer than HC to complete TMT-A (38.29±19.99s vs 30.25±14.19s, p=0.047) and TMT-B (72.10±26.98s vs 55.99±22.14s, p=0.034). There were no significant differences between patients and HC in CRT, PRM and SSP. Three weeks (T2) and 6 months (T3) after MDPT, TMT

  6. Serum vitamin D levels are positively associated with varicella zoster immunity in chronic dialysis patients

    PubMed Central

    Chao, Chia-Ter; Lee, Szu-Ying; Yang, Wei-Shun; Yen, Chung-Jen; Chiang, Chih-Kang; Huang, Jenq-Wen; Hung, Kuan-Yu

    2014-01-01

    Uremia results in a relatively immunocompromised status, and patients under chronic dialysis have an elevated risk of developing herpes zoster (HZ). We sought to investigate the relationship between vitamin D status and immunity to varicella-zoster virus (VZV). A multicenter prevalent hemodialysis cohort was assembled between 2012 and 2013. We assayed the biochemical parameters, 25-hydroxy- (25-OH-D) and 1,25-dihydroxyvitamin D, vitamin D-binding protein levels in the sera. VZV immunity was quantitated using VZV-specific glycoprotein IgG and IgM titers. Eighty-eight patients were enrolled and their sera were analyzed. Chronic hemodialysis patients with 25-OH-D < 30 ng/ml (insufficiency or deficiency) had significantly lower VZV-IgG than those with sufficient 25-OH-D (p = 0.04). This discrepancy became more prominent if active vitamin D users alone were analyzed (p = 0.01). Generalized additive modeling showed that those with 25-OH-D higher than 27.8 ng/ml or bioavailable 25-OH-D higher than 3.88 ng/ml had significantly higher VZV-IgG levels than those with lower values. Linear regression suggested that both total and bioavailable 25-OH-D were significantly associated with higher VZV-IgG levels (p = 0.003 [total] and 0.01 [bioavailable]), whereas patients with cancer had lower VZV-IgG. Vitamin D may therefore be a potentially useful choice for raising VZV immunity in chronic dialysis patients. PMID:25487609

  7. Diagnosis, prevention, and management of bleeding episodes in Philadelphia-negative myeloproliferative neoplasms: recommendations by the Hemostasis Working Party of the German Society of Hematology and Medical Oncology (DGHO) and the Society of Thrombosis and Hemostasis Research (GTH).

    PubMed

    Appelmann, Iris; Kreher, Stephan; Parmentier, Stefani; Wolf, Hans-Heinrich; Bisping, Guido; Kirschner, Martin; Bergmann, Frauke; Schilling, Kristina; Brümmendorf, Tim H; Petrides, Petro E; Tiede, Andreas; Matzdorff, Axel; Griesshammer, Martin; Riess, Hanno; Koschmieder, Steffen

    2016-04-01

    Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPN) comprise a heterogeneous group of chronic hematologic malignancies. The quality of life, morbidity, and mortality of patients with MPN are primarily affected by disease-related symptoms, thromboembolic and hemorrhagic complications, and progression to myelofibrosis and acute leukemia. Major bleeding represents a common and important complication in MPN, and the incidence of such bleeding events will become even more relevant in the future due to the increasing disease prevalence and survival of MPN patients. This review discusses the causes, differential diagnoses, prevention, and management of bleeding episodes in patients with MPN, aiming at defining updated standards of care in these often challenging situations.

  8. Stress-related Clinical Pain and Mood in Women with Chronic Pain: Moderating Effects of Depression and Positive Mood Induction

    PubMed Central

    Davis, Mary C.; Thummala, Kirti; Zautra, Alex J.

    2014-01-01

    Background Chronic pain with co-morbid depression is characterized by poor mood regulation and stress-related pain. Purpose Compare depressed and non-depressed pain patients in mood and pain stress reactivity and recovery, and test whether a post-stress positive mood induction moderates pain recovery. Methods Women with fibromyalgia and/or osteoarthritis (N=110) underwent interpersonal stress and were then randomly assigned by pain condition and depression status, assessed via the Center for Epidemiological Studies-Depression scale, to positive versus neutral mood induction. Results Depression did not predict stress-related reactivity in despondency, joviality, or clinical pain. However, depression X mood condition predicted recovery in joviality and clinical pain; depressed women recovered only in the positive mood condition, whereas non-depressed women recovered in both mood conditions. Conclusions Depression does not alter pain and mood stress reactivity, but does impair recovery. Boosting post-stress jovial mood ameliorates pain recovery deficits in depressed patients, a finding relevant to chronic pain interventions. PMID:24532393

  9. Stress-related clinical pain and mood in women with chronic pain: moderating effects of depression and positive mood induction.

    PubMed

    Davis, Mary C; Thummala, Kirti; Zautra, Alex J

    2014-08-01

    Chronic pain with comorbid depression is characterized by poor mood regulation and stress-related pain. This study aims to compare depressed and non-depressed pain patients in mood and pain stress reactivity and recovery, and test whether a post-stress positive mood induction moderates pain recovery. Women with fibromyalgia and/or osteoarthritis (N = 110) underwent interpersonal stress and were then randomly assigned by pain condition and depression status, assessed via the Center for Epidemiological Studies-Depression scale, to positive versus neutral mood induction. Depression did not predict stress-related reactivity in despondency, joviality, or clinical pain. However, depression × mood condition predicted recovery in joviality and clinical pain; depressed women recovered only in the positive mood condition, whereas non-depressed women recovered in both mood conditions. Depression does not alter pain and mood stress reactivity, but does impair recovery. Boosting post-stress jovial mood ameliorates pain recovery deficits in depressed patients, a finding relevant to chronic pain interventions.

  10. Allogeneic hematopoietic stem cell transplant in adult patients with myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndromes.

    PubMed

    Sharma, Prashant; Shinde, Shivani S; Damlaj, Moussab; Hefazi Rorghabeh, Mehrdad; Hashmi, Shahrukh K; Litzow, Mark R; Hogan, William J; Gangat, Naseema; Elliott, Michelle A; Al-Kali, Aref; Tefferi, Ayalew; Patnaik, Mrinal M

    2017-04-01

    MDS/MPN (myelodysplastic syndrome/myeloproliferative neoplasm) overlap syndromes are myeloid malignancies for which allogeneic hematopoietic stem cell transplant (allo-HSCT) is potentially curative. We describe transplant outcomes of 43 patients - 35 with chronic myelomonocytic leukemia, CMML (of which 17 had blast transformation, BT) and eight with MDS/MPN-unclassifiable (MDS/MPN,U). At median follow-up of 21 months, overall survival (OS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 55%, 29%, and 25% respectively in CMML without BT and 47%, 40%, and 34% respectively in CMML with BT. Higher HSCT-comorbidity index (HSCT-CI >3 versus ≤3; p = 0.015) and splenomegaly (p = 0.006) predicted worse OS in CMML without BT. In CMML with BT, engraftment failure (p = 0.006) and higher HSCT-CI (p = 0.03) were associated with inferior OS, while HSCT within 1-year of diagnosis was associated with improved OS (p = 0.045). In MDS/MPN,U, at median follow-up of 15 months, OS, CIR, and NRM were 62%, 30%, and 14%, respectively.

  11. Molecular drug targets in myeloproliferative neoplasms: mutant ABL1, JAK2, MPL, KIT, PDGFRA, PDGFRB and FGFR1

    PubMed Central

    Tefferi, Ayalew

    2009-01-01

    Abstract Therapeutically validated oncoproteins in myeloproliferative neoplasms (MPN) include BCR-ABL1 and rearranged PDGFR proteins. The latter are products of intra- (e.g. FIP1L1-PDGFRA) or inter-chromosomal (e.g.ETV6-PDGFRB) gene fusions. BCR-ABL1 is associated with chronic myelogenous leukaemia (CML) and mutant PDGFR with an MPN phenotype characterized by eosinophilia and in addition, in case of FIP1L1-PDGFRA, bone marrow mastocytosis. These genotype-phenotype associations have been effectively exploited in the development of highly accurate diagnostic assays and molecular targeted therapy. It is hoped that the same will happen in other MPN with specific genetic alterations: polycythemia vera (JAK2V617F and other JAK2 mutations), essential thrombocythemia (JAK2V617F and MPL515 mutations), primary myelofibrosis (JAK2V617F and MPL515 mutations), systemic mastocytosis (KITD816V and other KIT mutations) and stem cell leukaemia/lymphoma (ZNF198-FGFR1 and other FGFR1 fusion genes). The current review discusses the above-listed mutant molecules in the context of their value as drug targets. PMID:19175693

  12. The mutation profile of JAK2, MPL and CALR in Mexican patients with Philadelphia chromosome-negative myeloproliferative neoplasms.

    PubMed

    Labastida-Mercado, Nancy; Galindo-Becerra, Samantha; Garcés-Eisele, Javier; Colunga-Pedraza, Perla; Guzman-Olvera, Valeria; Reyes-Nuñez, Virginia; Ruiz-Delgado, Guillermo J; Ruiz-Argüelles, Guillermo J

    2015-03-01

    By using molecular markers, it is possible to gain information on both the classification and etiopathogenesis of chronic myeloproliferative neoplasias (MPN). In a group of 27 Mexican mestizo patients with MPNs, we studied seven molecular markers: the BCR/ABL1 fusion gene, the JAK2 V617F mutation, the JAK2 exon 12 mutations, the MPL W515L mutation, the MPL W515K mutation, and the calreticulin (CALR) exon 9 deletion or insertion. Patients with the BCR/ABL1 fusion gene were excluded. We studied 14 patients with essential thrombocythemia (ET), eight with polycythemia vera (PV), four with primary myelofibrosis (MF), and one with undifferentiated MPN. We found twelve individuals with the JAK2 V617F mutation; five of them had been clinically classified as PV, five as ET, and one as MF. One patient with the MPL W515L was identified with a clinical picture of ET. Five patients with the CALR mutation were identified, four ET and one MF. No individuals with either the MPL W515K mutation or the JAK2 exon 12 mutations were identified. The most consistent relationship was that between PV and the JAK2 V617F mutation (p=.01). Despite its small size, the study shows much less prevalence of JAK2 mutation in PV, ET and MF, which does not match international data. Copyright © 2015 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.

  13. The Polymorphisms in LNK Gene Correlated to the Clinical Type of Myeloproliferative Neoplasms

    PubMed Central

    Hu, Yang; Liu, Qian; Bu, Dingfang; Tan, Mei; Wu, Liusong; Zhu, Ping

    2016-01-01

    Objective LNK is an adapter protein negatively regulating the JAK/STAT cell signaling pathway. In this study, we observed the correlation between variation in LNK gene and the clinical type of myeloproliferative neoplasms (MPN). Methods A total of 285 MPN cases were recruited, including essential thrombocythemia (ET) 154 cases, polycythemia vera (PV) 76 cases, primary myelofibrosis (PMF) 19 cases, and chronic myeloid leukemia (CML) 36 cases. Ninety-three healthy individuals were used as normal controls. V617F mutation in JAK2 was identified by allele-specific PCR method, RT-PCR was used for the detection of BCR/ABL1 fusion gene, and mutations and variations in coding exons and their flanking sequences of LNK gene were examined by PCR-sequencing. Results Missense mutations of A300V, V402M, and R415H in LNK were found in 8 patients including ET (4 cases, all combined with JAK2-V617F mutation), PV (2 cases, one combined with JAK2-V617F mutation), PMF (one case, combined with JAK2-V617F mutation) and CML (one case, combined with BCR/ABL1 fusion gene). The genotype and allele frequencies of the three SNPs (rs3184504, rs111340708 and rs78894077) in LNK were significantly different between MPN patients and controls. For rs3184504 (T/C, in exon2), the T allele (p.262W) and TT genotype were frequently seen in ET, PV and PMF (P<0.01), and C allele (p.262R) and CC genotype were frequently seen in CML (P<0.01). For rs78894077 (T/C, in exon1), the T allele (p.242S) was frequently found in ET (P<0.05). For rs111340708 (TGGGGx5/TGGGGx4, in intron 5), the TGGGG x4 allele was infrequently found in ET, PMF and CML(P<0.01). Conclusion Mutations in LNK could be found in some of MPN patients in the presence or absence of JAK2-V617F mutation. Several polymorphisms in LNK gene may affect the clinical type or the genetic predisposition of MPN. PMID:27111338

  14. Positive expiratory pressure via mask does not improve ventilation inhomogeneity more than huffing and coughing in individuals with stable chronic obstructive pulmonary disease and chronic sputum expectoration.

    PubMed

    Osadnik, Christian; Stuart-Andrews, Christopher; Ellis, Samantha; Thompson, Bruce; McDonald, Christine F; Holland, Anne E

    2014-01-01

    Positive expiratory pressure (PEP) has been used to promote airway clearance in individuals with chronic obstructive pulmonary disease (COPD) for many years; however, its mechanism of action and benefits are unclear. Previous authors have suggested that PEP improves collateral ventilation via changes in lung volumes. It was the aim of this study to determine whether PEP improves ventilation inhomogeneity more than controlled huffing and coughing in individuals with stable COPD. Twelve participants with COPD (mean forced expiratory volume in 1 s 45% predicted) and chronic sputum expectoration performed PEP therapy (10-20 cm H2O) or controlled huffing and coughing in random order on alternate study days with a 48-hour washout. Measures of acinar and conductive airway ventilation (S(acin), S(cond)), lung volumes, spirometry and sputum wet weight were recorded before, immediately after and 90 min following treatment. Ease of expectoration [visual analogue scale (VAS)] and oxyhaemoglobin saturation were assessed immediately following treatment. There were no significant differences between the effect of either test condition at any time point for any test parameter. Mean Sacin immediately following PEP and control conditions was 0.465 and 0.438 litre(-1), respectively (p = 0.45 for comparison between conditions) and mean S(cond) was 0.042 and 0.039 litre(-1) (p = 0.55). PEP therapy did not significantly enhance total mean sputum expectoration compared to controlled huffing and coughing (7.06 vs. 6.15 g; p = 0.51) and did not improve ease of expectoration (VAS PEP 4.8 cm vs. control 4.1 cm; p = 0.53). Any therapeutic benefits of PEP in individuals with COPD and chronic sputum expectoration are unlikely to be mediated by improvements in ventilation or lung volumes. Copyright © 2013 S. Karger AG, Basel.

  15. Distinct quasispecies characteristics and positive selection within the core gene in chronic hepatitis B virus infected child and adult patients.

    PubMed

    Haijun, Deng; Yong, Huang; Ailong, Huang; Quanxin, Long

    2015-05-01

    There are significant differences in clinical characteristics between chronic hepatitis B virus infected (CHB) child and adult patients. Viral quasispecies characteristics are associated with its pathogenic properties. For hepatitis B virus (HBV), its core region is the main immune recognition region for its enriched epitopes. In our study, we discuss the quasispecies characteristics and positive selection within core gene within chronic HBV infected child and adult patients. By analyzing 170 core gene sequences from child CHB patients and 121 core genes sequences from adult CHB patients, quasispecies characteristics were described by sequence complexity, diversity, non-synonymous substitution ratio (dN) and synonymous substitution ratios (dS). In addition, positive selection sites were also determined by bioinformatics tools. Then, all these parameters were compared between child and adult CHB patient groups. Compared with child patients, adult patients with CHB showed distinct quasispecies characteristics within the core region, had a higher sequence complexity and diversity and more positive selection sites, suggesting that the adult CHB patients had a higher immune selection pressure on the HBV core gene. Reduced selection pressure on the HBV core gene in hepatitis B e antigen (HBeAg)-positive CHB patients than HBeAg negative CHB patients were observed in both adult and child patient groups. The majority of the screened positive selection sites lay within human leukocyte antigens (HLA)-restricted epitopes. In conclusion, this study analyzed the quasispecies characteristics discrepancy between child and adult patients with CHB, and revealed the possible reason for the distinct clinical characteristics in the perspective of population genetics.

  16. On-treatment HBV DNA dynamics predict virological breakthrough in entecavir-treated HBeAg-positive chronic hepatitis B

    PubMed Central

    Huang, Yi-Jie; Chang, Chi-Sen; Yeh, Hong-Zen; Yang, Sheng-Shun

    2017-01-01

    Background & aims Virological breakthrough (VBT) could be a manifestation of chronic hepatitis B (CHB) in patients treated with long-term nucleot(s)ide analogues. We aimed to determine the association of on-treatment serum hepatitis B virus (HBV) DNA with VBT in HBeAg-positive CHB patients receiving entecavir (ETV) treatment. Methods A retrospective cohort study, including 162 consecutive patients (95 men and 67 women; mean age, 43.1±13.4 years) with HBeAg-positive CHB treated with ETV for at least 48 weeks between August 2008 and May 2015, was conducted. Univariate and multivariate cox regression analysis were used to identify associations with VBT and clinical factors, including HBV DNA and HBeAg serum status. Results Among the 162 ETV-treated HBeAg-positive CHB patients, eighteen patients (11.1%) experienced VBT (VBT group), whereas the other 144 patients were without VBT (non-VBT group). The cumulative rate of HBV DNA < 100 IU/mL in the VBT group and the non-VBT group at week 48 were 44.44% and 70.14%, and at week 96 were 58.33% and 92.56%, respectively (p = 0.015). The cumulative rate of HBeAg seroclearance in the VBT group and non-VBT group at week 48 and week 96 were statistically significant (p = 0.014). Multivariate analysis disclosed that failure to achieve HBeAg seroclearance were the factors significantly associated with VBT. Conclusions Our results demonstrated that on-treatment HBV DNA could probably predict VBT in ETV-treated HBeAg-positive chronic hepatitis B patients. Failure to achieve HBeAg seroclearance was associated with VBT in ETV-treated HBeAg-positive CHB patients. HBV DNA >100IU/mL at 48 weeks is potentially a predictor for VBT. PMID:28350873

  17. Thinking positively about chronic illness: An exploration of optimism, illness perceptions and well-being in patients with Parkinson's disease.

    PubMed

    Hurt, Catherine S; Burn, David J; Hindle, John; Samuel, Mike; Wilson, Ken; Brown, Richard G

    2014-05-01

    Holding positive beliefs about illness and having an optimistic outlook have been associated with increased well-being across a range of health conditions. However, research has indicated that being very optimistic may not actually be beneficial, and holding a realistic attitude is more adaptive in some forms of chronic illness, for example, Parkinson's disease (PD). This study aimed to explore the nature of relationships between illness perceptions, optimism and well-being: specifically, whether a linear or non-linear relationship best described the data. Additionally, the proposed moderating effect of optimism on the relationship between illness perceptions and well-being was tested. A total of 109 participants with idiopathic PD completed questionnaire measures of illness perception, optimism, mood and health-related quality of life (HRQoL). Multiple regression analyses were used to explore relationships between illness perceptions, optimism, mood and HRQoL. The potential curvilinear effects of illness perceptions and optimism were modelled using squared variables and linear and quadratic curve estimation. Holding positive illness perceptions predicted better well-being. Some evidence for a non-linear relationship between optimism and mood was found. Optimism had a significant moderating effect on the relationship between specific illness perceptions and outcome. Optimism appears to provide protection against some negative perceptions of illness and was associated with better mood and HRQoL. The findings indicate that specific illness perceptions may be beneficial targets for therapy. Therapeutic interventions should focus on enhancing positive perceptions of PD but potentially more importantly general optimistic attitude to maximize well-being. What is already known on this subject? Positive illness perceptions and high optimism are associated with better well-being in a range of conditions, both chronic and acute. Preliminary studies suggest that in chronic

  18. [Part I. End-stage chronic organ failures: a position paper on shared care planning. The Integrated Care Pathway].

    PubMed

    Gristina, Giuseppe R; Orsi, Luciano; Carlucci, Annalisa; Causarano, Ignazio R; Formica, Marco; Romanò, Massimo

    2014-01-01

    In Italy the birth rate decrease together with the continuous improvement of living conditions on one hand, and the health care progress on the other hand, led in recent years to an increasing number of patients with chronic mono- or multi-organ failures and in an extension of their life expectancy. However, the natural history of chronic failures has not changed and the inescapable disease's worsening at the end makes more rare remissions, increasing hospital admissions rate and length of stay. Thus, when the "end-stage" get close clinicians have to engage the patient and his relatives in an advance care planning aimed to share a decision making process regarding all future treatments and related ethical choices such as patient's best interests, rights, values, and priorities. A right approach to the chronic organ failures end-stage patients consists therefore of a careful balance between the new powers of intervention provided by the biotechnology and pharmacology (intensive care), both with the quality of remaining life supplied by physicians to these patients (proportionality and beneficence) and the effective resources rationing and allocation (distributive justice). However, uncertainty still marks the criteria used by doctors to assess prognosis of these patients in order to make decisions concerning intensive or palliative care. The integrated care pathway suggested in this position paper shared by nine Italian medical societies, has to be intended as a guide focused to identify end-stage patients and choosing for them the best care option between intensive treatments and palliative care.

  19. Mechanisms of Disease Persistence in Chronic Myelogenous Leukemia (CML)

    DTIC Science & Technology

    2006-10-01

    neoplasms . Am J Clin Pathol. 2002;118:560-566. Annual Report – CM050037 Brian J. Druker, MD Page 13 of 39 19. Florian S, Sonneck K, Hauswirth AW, et al...Murine JAK2V617F-Positive Myeloproliferative Disease. Cancer Res 66:11156-11165. 204. Annual Report – CM050037 Brian J. Druker, MD Page 33 of 39...Characterization of murine JAK2V617F-positive myeloproliferative disease. Cancer Res. 66(23):11156-65 2006. Annual Report – CM050037 Brian J. Druker, MD Page 39 of 39

  20. The Positive Impact of Integrative Medicine in the Treatment of Recalcitrant Chronic daily Headache: A Series of Case Reports

    PubMed Central

    Amoils, Sandi; Lester, Tiffany; Woolford, Liz; Gallagher, Lisa

    2014-01-01

    People who suffer from recalcitrant chronic daily headache (CDH)—a primary, episodic headache occurring at least 15 days per month, and lasting four or more hours per day for at least three consecutive months1—have generally tried many pain relief medications with few positive results. These patients often continue to add more and more medications and travel from clinician to clinician seeking help, without relief. Patients with recalcitrant CDH are often caught in a vicious cycle of increasing pain which results in a substantial impact from their disease on productivity and quality of life. Studies in the United States and Europe indicate that four to five percent of the general population has recalcitrant CDH,2 which encompasses transformed migraine and chronic tension-type headache.3 The disability associated with recalcitrant CDH is substantial, as patients have a significantly diminished quality of life and mental health, as well as impaired physical, social, and occupational functioning.4,5 Research shows that CDH may not be treated effectively with conventional medicine (CM). Integrative medicine (IM) offers a complex, personalized intervention necessary to treat CDH. Many integrative therapies have shown benefit, effectiveness, cost effectiveness and low side effect profile in patients with both chronic headache and chronic pain.6-17 Yet even within the IM community, clinicians often struggle with the balance between providing evidence-based therapy and patient-centered, complex, personalized integrative approaches, which may use popular but unproven therapies. In this article, we present a series of cases comprising patients with CDH who had previously been recalcitrant to CM approaches. In each case, employing a five-pronged treatment algorithm resulted in the successful IM treatment of CDH. By using this five-pronged approach, clinicians can offer the standardized protocols and scientific rationale they are accustomed to when employing CM options

  1. Positive Affect as a Source of Resilience for Women in Chronic Pain.

    ERIC Educational Resources Information Center

    Zautra, Alex J.; Johnson, Lisa M.; Davis, Mary C.

    2005-01-01

    A sample of 124 women with osteoarthritis or fibromyalgia, or both, completed initial assessments for demographic data, health status, and personality traits and 10-12 weekly interviews regarding pain, stress, negative affect, and positive affect. Multilevel modeling analyses indicated that weekly elevations of pain and stress predicted increases…

  2. Positive Affect as a Source of Resilience for Women in Chronic Pain.

    ERIC Educational Resources Information Center

    Zautra, Alex J.; Johnson, Lisa M.; Davis, Mary C.

    2005-01-01

    A sample of 124 women with osteoarthritis or fibromyalgia, or both, completed initial assessments for demographic data, health status, and personality traits and 10-12 weekly interviews regarding pain, stress, negative affect, and positive affect. Multilevel modeling analyses indicated that weekly elevations of pain and stress predicted increases…

  3. Chronic variable stress prevents amphetamine-elicited 50-kHz calls in rats with low positive affectivity.

    PubMed

    Kõiv, Kadri; Metelitsa, Mait; Vares, Marten; Tiitsaar, Kai; Raudkivi, Karita; Jaako, Külli; Vulla, Kaspar; Shimmo, Ruth; Harro, Jaanus

    2016-04-01

    The relationship between stress response and positive affective states is thought to be bidirectional: whilst stress can lead to a blunted hedonic response, positive affect reduces the negative effects of stress. We have previously shown that persistently high positive affectivity as measured by 50-kHz ultrasonic vocalizations (USVs) is protective against chronic variable stress (CVS). The present study examined the effect of CVS on 50-kHz USVs elicited by amphetamine administration, simultaneously considering the stable inter-individual differences in positive affectivity. Forty juvenile male Wistar rats were categorised as of high (HC) or low (LC) positive affectivity based on their 50-kHz USV response to imitation of rough-and-tumble play ('tickling'). As adults, the rats were subjected to four weeks of CVS, after which D-amphetamine was administered in five daily doses followed by a challenge dose (all 1mg/kg IP) nine days later. CVS reduced sucrose preference in LC-rats only. After CVS, amphetamine-elicited 50-kHz USVs were significantly reduced in LC-rats, the effect of stress in HC-rats being smaller and less consistent. In previously stressed and amphetamine-treated LC-rats, locomotor response to amphetamine was attenuated. In stressed LC-rats, DOPAC levels and dopamine turnover were increased in striatum after amphetamine treatment, and dopamine D1 receptor levels were upregulated in nucleus accumbens. LC-rats had lower isoleucine levels in frontal cortex. These results show that stress-related changes in response to amphetamine are dependent on inter-individual differences in positive affectivity both at neurochemical and behavioural levels, and further support the notion of higher vulnerability of animals with low positive affect. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

  4. Opioids for chronic noncancer pain: a position paper of the American Academy of Neurology.

    PubMed

    Franklin, Gary M

    2014-09-30

    The Patient Safety Subcommittee requested a review of the science and policy issues regarding the rapidly emerging public health epidemic of prescription opioid-related morbidity and mortality in the United States. Over 100,000 persons have died, directly or indirectly, from prescribed opioids in the United States since policies changed in the late 1990s. In the highest-risk group (age 35-54 years), these deaths have exceeded mortality from both firearms and motor vehicle accidents. Whereas there is evidence for significant short-term pain relief, there is no substantial evidence for maintenance of pain relief or improved function over long periods of time without incurring serious risk of overdose, dependence, or addiction. The objectives of the article are to review the following: (1) the key initiating causes of the epidemic; (2) the evidence for safety and effectiveness of opioids for chronic pain; (3) federal and state policy responses; and (4) recommendations for neurologists in practice to increase use of best practices/universal precautions most likely to improve effective and safe use of opioids and to reduce the likelihood of severe adverse and overdose events. © 2014 American Academy of Neurology.

  5. Exercise & Sports Science Australia Position Statement on exercise training and chronic heart failure.

    PubMed

    Selig, Steve E; Levinger, Itamar; Williams, Andrew D; Smart, Neil; Holland, David J; Maiorana, Andrew; Green, Daniel J; Hare, David L

    2010-05-01

    Chronic heart failure (CHF) is a complex syndrome characterised by progressive decline in left ventricular function, low exercise tolerance and raised mortality and morbidity. Regular exercise participation has been shown to be a safe and effective treatment modality in the majority of CHF patients, partially reversing some of the maladaptations evident in myocardial and skeletal muscle function, and resulting in improvements in physical fitness and quality of life, and perhaps reduced mortality. The volume and intensity of exercise that is recommended depends on the syndrome severity, however in most patients it should consist of a combination of low-to-moderate intensity aerobic (endurance) exercise on most days of the week and individually prescribed low-to-moderate intensity resistance (strength) training at least twice per week. Additionally, all patients should be closely monitored prior to and during exercise for contraindications by an appropriately trained health professional. The purpose of this statement is to inform and guide exercise practitioners and health professionals in the safe and effective prescription and supervision of exercise for patients with CHF.

  6. JAK-STAT signaling in the therapeutic landscape of myeloproliferative neoplasms.

    PubMed

    O'Sullivan, Jennifer M; Harrison, Claire N

    2017-08-15

    Myeloproliferative neoplasms (MPN) are a group of disorders defined by clonal proliferation of mature myeloid cells with overlapping clinical features. The driver mutations of these disorders, namely JAK2 (Janus Kinase), MPL (Myeloproliferative Leukaemia Virus) and CALR (Calreticulin) upregulate JAK-STAT signaling with increase in downstream transcription and gene expression. Epigenetic mutations are prevalent in MPNs but their interplay with aberrant JAK-STAT signaling is not known. This understanding lead to development of first targeted treatment in MPN; ruxolitinib for primary myelofibrosis. This has shown clinical benefit in overall survival and symptoms improvement but has yet to show significant disease modifying effects. This review will focus on contemporaneous understanding of altered JAK-STAT signaling in MPN and targeted treatments in clinical practice. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Molecular monitoring of 8p11 myeloproliferative syndrome in an infant.

    PubMed

    Zhang, Wenyong W; Habeebu, Sultan; Sheehan, Andrea M; Naeem, Rizwan; Hernandez, Vivian S; Dreyer, Zoann E; López-Terrada, Dolores

    2009-11-01

    The 8p11 myeloproliferative syndrome is a rare hematologic malignancy derived from a pluripotent hematopoietic stem cell associated with rearrangements involving the fibroblast growth factor receptor 1 (FGFR1) gene located on chromosome 8p11. The most common translocation, t(8;13) (p11;q13), results in a ZNF198-FGFR1 fusion gene and constitutively active FGFR1 tyrosine kinase activity. Typical pathologic findings include myeloid hyperplasia, lymphadenopathy, precursor T-lymphoblastic lymphoma, and eosinophilia. The disease is usually associated with an aggressive course and progression to acute myeloid leukemia is frequent. We report here the first case of 8p11 myeloproliferative syndrome in an infant and demonstrate the value of molecular testing in the diagnosis and minimal disease monitoring of this rare disease.

  8. Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms

    PubMed Central

    Tapper, William; Jones, Amy V.; Kralovics, Robert; Harutyunyan, Ashot S.; Zoi, Katerina; Leung, William; Godfrey, Anna L.; Guglielmelli, Paola; Callaway, Alison; Ward, Daniel; Aranaz, Paula; White, Helen E.; Waghorn, Katherine; Lin, Feng; Chase, Andrew; Joanna Baxter, E.; Maclean, Cathy; Nangalia, Jyoti; Chen, Edwin; Evans, Paul; Short, Michael; Jack, Andrew; Wallis, Louise; Oscier, David; Duncombe, Andrew S.; Schuh, Anna; Mead, Adam J.; Griffiths, Michael; Ewing, Joanne; Gale, Rosemary E.; Schnittger, Susanne; Haferlach, Torsten; Stegelmann, Frank; Döhner, Konstanze; Grallert, Harald; Strauch, Konstantin; Tanaka, Toshiko; Bandinelli, Stefania; Giannopoulos, Andreas; Pieri, Lisa; Mannarelli, Carmela; Gisslinger, Heinz; Barosi, Giovanni; Cazzola, Mario; Reiter, Andreas; Harrison, Claire; Campbell, Peter; Green, Anthony R.; Vannucchi, Alessandro; Cross, Nicholas C.P.

    2015-01-01

    Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2V617F-negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10−10) and rs2201862 (MECOM; meta-analysis P=1.96 × 10−9). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2V617F-positive cases. rs9376092 has a stronger effect in JAK2V617F-negative cases with CALR and/or MPL mutations (Breslow–Day P=4.5 × 10−7), whereas in JAK2V617F-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ2 P=7.3 × 10−7). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype. PMID:25849990

  9. Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms

    PubMed Central

    2015-01-01

    JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile. PMID:26288683

  10. Effect of methotrexate on JAK/STAT pathway activation in myeloproliferative neoplasms.

    PubMed

    Thomas, Sally; Fisher, Katherine; Snowden, John; Danson, Sarah; Brown, Stephen; Zeidler, Martin

    2015-02-26

    The myeloproliferative neoplasms are a group of haematological malignancies characterised by pathological activation of the JAK/STAT (Janus kinase and signal transducer and activator of transcription) intracellular signalling pathway. 50-95% of patients have an acquired mutation (JAK2V617F) causing constitutive activation of JAK2. Our aim was to find new treatments for myeloproliferative neoplasms by identifying compounds that suppress JAK/STAT pathway activation. We used a luciferase-based transcriptional assay in the low complexity Drosophila model system to screen a library of 2000 small molecules for modulators of JAK/STAT pathway activation. Screen hits were validated with western blotting in the HDLM-2 Hodgkin's lymphoma cell line. The HEL cell line, in which constitutive JAK/STAT pathway activation is caused by JAK2V617F, was used to determine the relevance of screen hits for treatment of myeloproliferative neoplasms. Methotrexate and the chemically similar drug aminopterin were independently identified as strong inhibitors of the Drosophila JAK/STAT pathway, an effect conserved to human cells. Methotrexate did not affect protein phosphorylation in other intracellular signalling pathways. Methotrexate caused significant suppression of JAK/STAT activation in HEL cells at a concentration equivalent to that seen in patients taking low-dose oral methotrexate (p≤0·001). Our results suggest that methotrexate is a promising treatment for myeloproliferative neoplasms that could be translated into clinical trials after assessment in primary cells. These results are particularly relevant in myelofibrosis. Inhibitors of JAK1/2 improve symptoms and prolong life in myelofibrosis, but their use is limited by cost. Other existing therapies for myelofibrosis appear no more effective than placebo. Methotrexate might bring the benefits of JAK/STAT pathway inhibition at a lower cost. Cancer Research UK, Yorkshire Cancer Research, UK Medical Research Council, Wellcome Trust

  11. Changes in Depressive Symptoms among Older Adults with Multiple Chronic Conditions: Role of Positive and Negative Social Support.

    PubMed

    Ahn, SangNam; Kim, Seonghoon; Zhang, Hongmei

    2016-12-26

    Depression severely affects older adults in the United States. As part of the social environment, significant social support was suggested to ameliorate depression among older adults. We investigate how varying forms of social support moderate depressive symptomatology among older adults with multiple chronic conditions (MCC). Data were analyzed using a sample of 11,400 adults, aged 65 years or older, from the 2006-2012 Health and Retirement Study. The current study investigated the moderating effects of positive or negative social support from spouse, children, other family, and friends on the association between MCC and depression. A linear mixed model with repeated measures was used to estimate the effect of MCC on depression and its interactions with positive and negative social support in explaining depression among older adults. Varying forms of social support played different moderating roles in depressive symptomatology among older adults with MCC. Positive spousal support significantly weakened the deleterious effect of MCC on depression. Conversely, all negative social support from spouse, children, other family, and friends significantly strengthened the deleterious effect of MCC on depression. Minimizing negative social support and maximizing positive spousal support can reduce depression caused by MCC and lead to successful aging among older adults.

  12. Changes in Depressive Symptoms among Older Adults with Multiple Chronic Conditions: Role of Positive and Negative Social Support

    PubMed Central

    Ahn, SangNam; Kim, Seonghoon; Zhang, Hongmei

    2016-01-01

    Depression severely affects older adults in the United States. As part of the social environment, significant social support was suggested to ameliorate depression among older adults. We investigate how varying forms of social support moderate depressive symptomatology among older adults with multiple chronic conditions (MCC). Data were analyzed using a sample of 11,400 adults, aged 65 years or older, from the 2006–2012 Health and Retirement Study. The current study investigated the moderating effects of positive or negative social support from spouse, children, other family, and friends on the association between MCC and depression. A linear mixed model with repeated measures was used to estimate the effect of MCC on depression and its interactions with positive and negative social support in explaining depression among older adults. Varying forms of social support played different moderating roles in depressive symptomatology among older adults with MCC. Positive spousal support significantly weakened the deleterious effect of MCC on depression. Conversely, all negative social support from spouse, children, other family, and friends significantly strengthened the deleterious effect of MCC on depression. Minimizing negative social support and maximizing positive spousal support can reduce depression caused by MCC and lead to successful aging among older adults. PMID:28035968

  13. Positive Psychological Wellbeing Is Required for Online Self-Help Acceptance and Commitment Therapy for Chronic Pain to be Effective

    PubMed Central

    Trompetter, Hester R.; Bohlmeijer, Ernst T.; Lamers, Sanne M. A.; Schreurs, Karlein M. G.

    2016-01-01

    The web-based delivery of psychosocial interventions is a promising treatment modality for people suffering from chronic pain, and other forms of physical and mental illness. Despite the promising findings of first studies, patients may vary in the benefits they draw from self-managing a full-blown web-based psychosocial treatment. We lack knowledge on moderators and predictors of change during web-based interventions that explain for whom web-based interventions are especially (in)effective. In this study, we primarily explored for which chronic pain patients web-based Acceptance and Commitment Therapy (ACT) was (in)effective during a large three-armed randomized controlled trial. Besides standard demographic, physical and psychosocial factors we focused on positive mental health. Data from 238 heterogeneously diagnosed chronic pain sufferers from the general Dutch population following either web-based ACT (n = 82), or one of two control conditions [web-based Expressive Writing (EW; n = 79) and Waiting List (WL; n = 77)] were analysed. ACT and EW both consisted of nine modules and lasted nine to 12 weeks. Exploratory linear regression analyses were performed using the PROCESS macro in SPSS. Pain interference at 3-month follow-up was predicted from baseline moderator (characteristics that influence the outcome of specific treatments in comparison to other treatments) and predictor (characteristics that influence outcome regardless of treatment) variables. The results showed that none of the demographic or physical characteristics moderated ACT treatment changes compared to both control conditions. The only significant moderator of change compared to both EW and WL was baseline psychological wellbeing, and pain intensity was a moderator of change compared to EW. Furthermore, higher pain interference, depression and anxiety, and also lower levels of emotional well-being predicted higher pain interference in daily life 6 months later. These results suggest that web

  14. Positive Psychological Wellbeing Is Required for Online Self-Help Acceptance and Commitment Therapy for Chronic Pain to be Effective.

    PubMed

    Trompetter, Hester R; Bohlmeijer, Ernst T; Lamers, Sanne M A; Schreurs, Karlein M G

    2016-01-01

    The web-based delivery of psychosocial interventions is a promising treatment modality for people suffering from chronic pain, and other forms of physical and mental illness. Despite the promising findings of first studies, patients may vary in the benefits they draw from self-managing a full-blown web-based psychosocial treatment. We lack knowledge on moderators and predictors of change during web-based interventions that explain for whom web-based interventions are especially (in)effective. In this study, we primarily explored for which chronic pain patients web-based Acceptance and Commitment Therapy (ACT) was (in)effective during a large three-armed randomized controlled trial. Besides standard demographic, physical and psychosocial factors we focused on positive mental health. Data from 238 heterogeneously diagnosed chronic pain sufferers from the general Dutch population following either web-based ACT (n = 82), or one of two control conditions [web-based Expressive Writing (EW; n = 79) and Waiting List (WL; n = 77)] were analysed. ACT and EW both consisted of nine modules and lasted nine to 12 weeks. Exploratory linear regression analyses were performed using the PROCESS macro in SPSS. Pain interference at 3-month follow-up was predicted from baseline moderator (characteristics that influence the outcome of specific treatments in comparison to other treatments) and predictor (characteristics that influence outcome regardless of treatment) variables. The results showed that none of the demographic or physical characteristics moderated ACT treatment changes compared to both control conditions. The only significant moderator of change compared to both EW and WL was baseline psychological wellbeing, and pain intensity was a moderator of change compared to EW. Furthermore, higher pain interference, depression and anxiety, and also lower levels of emotional well-being predicted higher pain interference in daily life 6 months later. These results suggest that web

  15. De novo combination therapy adefovir plus lamivudine as a treatment for women of child-bearing age with HBeAg-positive chronic hepatitis B before pregnancy.

    PubMed

    Ma, Li-Na; Ding, Xiang-Chun; Liu, Xiao-Yan; Xu, Chun-Qiong; Liu, Shuai-Wei; Yan, Xie

    2014-03-01

    Substantial progress has been achieved in antiviral therapy for chronic hepatitis B; however, options for women of child-bearing age with HBeAg-positive chronic hepatitis B remain a challenge. In this study, we sought to determine whether de novo combination therapy of Adefovir plus Lamivudine was a super treatment for women of child-bearing age with HBeAg-positive chronic hepatitis B prior to conception. A total of 122 women patients of child-bearing age with HBeAg-positive chronic hepatitis B were randomly assigned to receive (i) 10 mg Adefovir plus 100 mg Lamivudine (64 patients) or (ii) 10 mg Adefovir monotherapy (58 patients), administrated orally once daily for 96 weeks. The therapeutic efficacy within each group was compared at weeks 48 and 96. The results showed that de novo combination therapy of Adefovir plus Lamivudine significantly reduced HBV-DNA detectability, and enhanced ALT normalization and HBeAg seroconversion in women of child-bearing age with HBeAg-positive chronic hepatitis B. No virological breakthrough and genotypic resistance were observed in the combination therapy group. Additionally, the combination therapy with Adefovir plus Lamivudine was well tolerated. This study suggests that de novo combination therapy of Adefovir plus Lamivudine offers a therapeutic advantage for women of child-bearing age with HBeAg-positive chronic hepatitis B when taken before conception.

  16. The Burden of JAK2V617F Mutated Allele in Turkish Patients With Myeloproliferative Neoplasms

    PubMed Central

    Yonal-Hindilerden, Ipek; Daglar-Aday, Aynur; Akadam-Teker, Basak; Yilmaz, Ceylan; Nalcaci, Meliha; Yavuz, Akif Selim; Sargin, Deniz

    2015-01-01

    Background Studies regarding the impact of JAK2V617F allele burden on phenotypic properties and clinical course in Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPNs) have reported variable results. We aimed to analyze the association of mutated JAK2V617F allele burden with laboratory characteristics and clinical phenotype in Turkish patients (107 essential thrombocythemia (ET) and 77 primary myelofibrosis (PMF)). Methods Peripheral blood samples of 184 patients with Ph-negative MPNs were analyzed for JAK2V617F allele status and burden. JAK2 MutaScreen assay (Ipsogen, Luminy Biotech, Marseille, France) was used to detect the JAK2V617F status and quantitative JAK2V617F allele burdens in genomic DNA using TaqMan allelic discrimination. Results Frequency of JAK2V617F-positive patients with high mutation load (allele burden > 50%) was higher in PMF compared to ET (23.4% and 4.7%, respectively; P = 0.001). We found significant association between ET patients with high JAK2V617F allele burden and lower hemoglobin (Hgb) and hematocrit (Hct), higher LDH levels and more prevalent massive splenomegaly (P = 0.001, P = 0.001, P = 0.012 and P = 0.015, respectively). ET patients with high mutation load displayed higher prevalence of bleeding compared to low mutation load and wild-type mutational status (P = 0.003). Rate of DVT was significantly higher in ET patients with mutant allele burden in upper half compared to lower half and wild-type (P = 0.029). We observed significant association between PMF patients with high JAK2V617F allele burden and higher Hgb, Hct levels and leukocyte counts (P = 0.003, P = 0.021 and P = 0.001, respectively). Conclusions Our study demonstrated JAK2V617F allele burden correlates with clinical features in ET and PMF. We conclude quantification of JAK2V617F mutation contributes to the workup of Ph-negative MPNs. PMID:25584101

  17. Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms

    PubMed Central

    Hinds, David A.; Barnholt, Kimberly E.; Mesa, Ruben A.; Kiefer, Amy K.; Do, Chuong B.; Eriksson, Nicholas; Mountain, Joanna L.; Francke, Uta; Tung, Joyce Y.; Nguyen, Huong (Marie); Zhang, Haiyu; Gojenola, Linda; Zehnder, James L.

    2016-01-01

    We conducted a genome-wide association study (GWAS) to identify novel predisposition alleles associated with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) and JAK2 V617F clonal hematopoiesis in the general population. We recruited a web-based cohort of 726 individuals with polycythemia vera, essential thrombocythemia, and myelofibrosis and 252 637 population controls unselected for hematologic phenotypes. Using a single-nucleotide polymorphism (SNP) array platform with custom probes for the JAK2 V617F mutation (V617F), we identified 497 individuals (0.2%) among the population controls who were V617F carriers. We performed a combined GWAS of the MPN cases plus V617F carriers in the control population (n = 1223) vs the remaining controls who were noncarriers for V617F (n = 252 140). For these MPN cases plus V617F carriers, we replicated the germ line JAK2 46/1 haplotype (rs59384377: odds ratio [OR] = 2.4, P = 6.6 × 10−89), previously associated with V617F-positive MPN. We also identified genome-wide significant associations in the TERT gene (rs7705526: OR = 1.8, P = 1.1 × 10−32), in SH2B3 (rs7310615: OR = 1.4, P = 3.1 × 10−14), and upstream of TET2 (rs1548483: OR = 2.0, P = 2.0 × 10−9). These associations were confirmed in a separate replication cohort of 446 V617F carriers vs 169 021 noncarriers. In a joint analysis of the combined GWAS and replication results, we identified additional genome-wide significant predisposition alleles associated with CHEK2, ATM, PINT, and GFI1B. All SNP ORs were similar for MPN patients and controls who were V617F carriers. These data indicate that the same germ line variants endow individuals with a predisposition not only to MPN, but also to JAK2 V617F clonal hematopoiesis, a more common phenomenon that may foreshadow the development of an overt neoplasm. PMID:27365426

  18. Changes in joint position sense after surgically treated chronic lateral ankle instability

    PubMed Central

    Halasi, T; Kynsburg, A; Tallay, A; Berkes, I

    2005-01-01

    Background: A search of the literature shows that the effect of surgery on ankle proprioception has been hardly investigated. Objective: To examine the effect of anatomical reconstruction of the anterolateral capsuloligamentous complex on ankle joint position sense. Methods: A prospective study using the "slope box" test. Ten consecutive patients were included in the study, and 10 healthy athletes represented the control group. Results: Similar test-retest reliability rates (overall reliability 0.92; p = 0.0013) were obtained to those of the original designers of the method. There were no significant differences with respect to side dominance (p = 0.9216). Investigation of the characteristics of mean absolute estimate errors showed that the controls tested became error prone in the range of slope altitudes 7.5–25° in every direction, compared with the range 0–5° (range of p values 0.00003–0.00072). The results of the intervention group showed that, for the two main directions of interest (anterior and lateral), preoperative differences in mean absolute estimate errors between injured (anterior 3.91 (2.81)°; lateral 4.06 (2.85)°) and healthy (anterior 2.94 (2.21)°, lateral 3.19 (2.64)°) sides (anterior, p = 0.0124; lateral, p = 0.0250) had disappeared (postoperative differences: anterior, p = 0.6906; lateral, p = 0.4491). The afflicted ankle had improved significantly after surgery in both important directions (anterior, p<0.0001; lateral, p = 0.0023). Conclusions: The study shows that differences in joint position sense between healthy and injured ankles disappeared as the result of surgery. Preoperative data show that proprioceptive malfunction is a cause of functional instability. If treatment is by means of surgery, the retensioning of the original anterolateral structures is inevitable, even if other grafting or surgical techniques are used. PMID:16244190

  19. A phase 1/2 study of bosutinib in Japanese adults with Philadelphia chromosome-positive chronic myeloid leukemia.

    PubMed

    Nakaseko, Chiaki; Takahashi, Naoto; Ishizawa, Kenichi; Kobayashi, Yukio; Ohashi, Kazuteru; Nakagawa, Yasunori; Yamamoto, Kazuhito; Miyamura, Koichi; Taniwaki, Masafumi; Okada, Masaya; Kawaguchi, Tatsuya; Shibata, Atsushi; Fujii, Yosuke; Ono, Chiho; Ohnishi, Kazunori

    2015-02-01

    This phase 1/2 study evaluated the safety and pharmacokinetics (part 1) and efficacy and safety (part 2) of bosutinib in Japanese Philadelphia chromosome-positive (Ph+) chronic-phase (CP) or advanced-phase chronic myeloid leukemia (CML) patients resistant/intolerant to previous imatinib (2L) or imatinib+dasatinib/nilotinib (3L). Based on dose-limiting toxicities and previous studies, the part 2 bosutinib starting dose was 500 mg/day (n = 63). For CP CML 2L (n = 28), the cumulative major cytogenetic response (MCyR) rate by week 24 was 36 % (primary endpoint); the cumulative major molecular response (MMR) rate through the study was 43 %. Transformation to accelerated/blast phase (AP/BP) was observed in one patient. Progression-free survival (PFS) and overall survival (OS) rates at 96 weeks were 94 and 96 %, respectively. Of seven advanced-phase 2L patients, one had confirmed complete hematologic response at week 84, and one had AP/BP transformation. PFS and OS rates at week 96 were 21 and 43 %. For 3L (n = 11), cumulative MCyR rate by week 24 was 18 %; cumulative MMR rate was 18 %; no transformations occurred. Common non-hematologic adverse events (AEs) were diarrhea (95 %), rash (57 %), and nasopharyngitis (51 %). Sixteen patients discontinued due to adverse events; no deaths occurred within 30 days of the last dose. Bosutinib 500 mg/day demonstrated efficacy and manageable toxicity in Japanese Ph+ CML patients resistant/intolerant to imatinib.

  20. Non-invasive Positive Airway Pressure in Obesity Hypoventilation Syndrome and Chronic Obstructive Pulmonary Disease: Present and Future Perspectives.

    PubMed

    Ramírez-Molina, Victor R; Gómez-de-Terreros, Francisco J; Barca-Durán, Javier; Masa, Juan F

    2017-08-01

    Obesity hypoventilation syndrome (OHS) is a sleep disorder that has acquired great importance worldwide because of its prevalence and association with obesity leading to increased morbidity and mortality with reduced quality of life. The primary feature is insufficient sleep-related ventilation, resulting in abnormally elevated arterial carbon dioxide pressure (PaCO2) during sleep and demonstration of daytime hypoventilation. There are three main mechanisms that can generate diurnal hypoventilation in obese patients: alteration of the respiratory mechanics secondary to obesity; central hypoventilation secondary to leptin resistance and sleep disorder with sleep hypoventilation and obstructive apnoeas, which can be potentially solved with the use of positive airway pressure: non-invasive ventilation (NIV) and continuous positive airway pressure (CPAP). There are no established guidelines for the treatment of OHS, and only a few randomised controlled trials have been published. In this review, we have gone over the role of positive airway pressure, in particular the mechanisms that produce improvement, ventilatory modes available, clinical applications, technical considerations and future research. In addition, we added a review on NIV efficacy in chronic obstructive pulmonary disease (COPD), both in acute respiratory failure due to exacerbation and mainly in stable setting where more controversy and scientific contributions are coming.

  1. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1

    PubMed Central

    Tefferi, A

    2010-01-01

    Myeloproliferative neoplasms (MPNs) originate from genetically transformed hematopoietic stem cells that retain the capacity for multilineage differentiation and effective myelopoiesis. Beginning in early 2005, a number of novel mutations involving Janus kinase 2 (JAK2), Myeloproliferative Leukemia Virus (MPL), TET oncogene family member 2 (TET2), Additional Sex Combs-Like 1 (ASXL1), Casitas B-lineage lymphoma proto-oncogene (CBL), Isocitrate dehydrogenase (IDH) and IKAROS family zinc finger 1 (IKZF1) have been described in BCR-ABL1-negative MPNs. However, none of these mutations were MPN specific, displayed mutual exclusivity or could be traced back to a common ancestral clone. JAK2 and MPL mutations appear to exert a phenotype-modifying effect and are distinctly associated with polycythemia vera, essential thrombocythemia and primary myelofibrosis; the corresponding mutational frequencies are ∼99, 55 and 65% for JAK2 and 0, 3 and 10% for MPL mutations. The incidence of TET2, ASXL1, CBL, IDH or IKZF1 mutations in these disorders ranges from 0 to 17% these latter mutations are more common in chronic (TET2, ASXL1, CBL) or juvenile (CBL) myelomonocytic leukemias, mastocytosis (TET2), myelodysplastic syndromes (TET2, ASXL1) and secondary acute myeloid leukemia, including blast-phase MPN (IDH, ASXL1, IKZF1). The functional consequences of MPN-associated mutations include unregulated JAK-STAT (Janus kinase/signal transducer and activator of transcription) signaling, epigenetic modulation of transcription and abnormal accumulation of oncoproteins. However, it is not clear as to whether and how these abnormalities contribute to disease initiation, clonal evolution or blastic transformation. PMID:20428194

  2. Selection Criteria for Patients With Chronic Ankle Instability in Controlled Research: A Position Statement of the International Ankle Consortium

    PubMed Central

    Gribble, Phillip A.; Delahunt, Eamonn; Bleakley, Christopher M.; Caulfield, Brian; Docherty, Carrie L.; Fong, Daniel Tik-Pui; Fourchet, François; Hertel, Jay; Hiller, Claire E.; Kaminski, Thomas W.; McKeon, Patrick O.; Refshauge, Kathryn M.; van der Wees, Philip; Vicenzino, William; Wikstrom, Erik A.

    2014-01-01

    ABSTRACT While research on chronic ankle instability (CAI) and awareness of its impact on society and health care systems has grown substantially in the last 2 decades, the inconsistency in participant or patient selection criteria across studies presents a potential obstacle to addressing the problem properly. This major gap within the literature limits the ability to generalize this evidence to the target patient population. Therefore, there is a need to provide standards for patient or participant selection criteria in research focused on CAI with justifications using the best available evidence. The International Ankle Consortium provides this position paper to present and discuss an endorsed set of selection criteria for patients with CAI based on the best available evidence to be used in future research and study designs. These recommendations will enhance the validity of research conducted in this clinical population with the end goal of bringing the research evidence to the clinician and patient. PMID:24377963

  3. Surfactant and continuous positive airway pressure for the prevention of chronic lung disease: History, reality, and new challenges.

    PubMed

    Aly, Hany; Mohamed, Mohamed A; Wung, Jen-Tien

    2017-10-01

    The discovery of surfactant was one of the most significant research events to occur in the history of neonatology. Certainly, surfactant saved lives for premature infants who were otherwise considered non-viable. However, the prevention of chronic lung disease did not progress and it became clear that a significant portion of the help surfactant provides to the premature lung is counteracted by mechanical ventilation. A dilemma exists over the priorities in premature management to intubate and administer surfactant or not to intubate and support these infants non-invasively with the use of continuous positive airway pressure. A new hydrophilic surfactant preparation has been developed with the hope to enable the introduction of surfactant therapy without the need for tracheal intubation. Clinical trials on this product are currently in progress. This article provides the history and prospect of respiratory distress management in premature infants and evaluates the current evidence for non-invasive practices. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. The overwhelmingly positive response to Dasatinib of a patient with multiple blast crisis of chronic myeloid leukemia

    PubMed Central

    Xu, Zhengli; Zheng, Miao; Wu, Chaonan; Ma, Yujia; Meng, Li; Zhou, Jianfeng; Wang, Ying

    2015-01-01

    Blastic phase (BP), the terminal phase of chronic myeloid leukemia (CML), can occur in any of the hematopoietic lineages. Extramedullary blastic crisis (EBC) is a rare form of blastic crisis, which has an extremely poor prognosis. As the tyrosine kinase inhibitor (TKI), Dasatinib is a more effective treatment drug than Imatinib and Nilotinib for this type of CML, because it has greater potency and penetrates through the blood-brain barrier to reach the cerebrospinal fluid (CSF). This report examines the case of a 22-year-old woman with CML, who successively suffered from monocytic blast crisis, lymphoid blast crisis, and central nervous system EBC. She had an overwhelmingly positive response to taking Dasatinib and eventually achieved lasting complete remission. PMID:25785155

  5. Reliability and validity of cervical position measurements in individuals with and without chronic neck pain

    PubMed Central

    Neil, Joseph; Tallon, Allison; Adamo, Diane E.

    2015-01-01

    Objectives The cervical range of motion device (CROM) has been shown to provide reliable forward head position (FHP) measurement when the upper cervical angle (UCA) is controlled. However, measurement without UCA standardization is reflective of habitual patterns. Criterion validity has not been reported. The purposes of this study were to establish: (1) criterion validity of CROM FHP and UCA compared to Optotrak data, (2) relative reliability and minimal detectable change (MDC95) in patients with and without cervical pain, and (3) to compare UCA and FHP in patients with and without pain in habitual postures. Methods (1) Within-subjects single session concurrent criterion validity design. Simultaneous CROM and OP measurement was conducted in habitual sitting posture in 16 healthy young adults. (2) Reliability and MDC95 of UCA and FHP were calculated from three trials. (3) Values for adults over 35 years with cervical pain and age-matched healthy controls were compared. Results (1) Forward head position distances were moderately correlated and UCA angles were highly correlated. The mean (standard deviation) differences can be expected to vary between 1·48 cm (1·74) for FHP and −1·7 (2·46)° for UCA. (2) Reliability for CROM FHP measurements were good to excellent (no pain) and moderate (pain). Cervical range of motion FHP MDC95 was moderately low (no pain), and moderate (pain). Reliability for CROM UCA measurements was excellent and MDC95 low for both groups. There was no difference in FHP distances between the pain and no pain groups, UCA was significantly more extended in the pain group (P<0·05). Discussion Cervical range of motion FHP measurements were only moderately correlated with Optotrak data, and limits of agreement (LOA) and MDC95 were relatively large. There was also no difference in CROM FHP distance between older symptomatic and asymptomatic individuals. Cervical range of motion FHP measurement is therefore not recommended as a clinical outcome

  6. Reliability and validity of cervical position measurements in individuals with and without chronic neck pain.

    PubMed

    Dunleavy, Kim; Neil, Joseph; Tallon, Allison; Adamo, Diane E

    2015-09-01

    The cervical range of motion device (CROM) has been shown to provide reliable forward head position (FHP) measurement when the upper cervical angle (UCA) is controlled. However, measurement without UCA standardization is reflective of habitual patterns. Criterion validity has not been reported. The purposes of this study were to establish: (1) criterion validity of CROM FHP and UCA compared to Optotrak data, (2) relative reliability and minimal detectable change (MDC95) in patients with and without cervical pain, and (3) to compare UCA and FHP in patients with and without pain in habitual postures. (1) Within-subjects single session concurrent criterion validity design. Simultaneous CROM and OP measurement was conducted in habitual sitting posture in 16 healthy young adults. (2) Reliability and MDC95 of UCA and FHP were calculated from three trials. (3) Values for adults over 35 years with cervical pain and age-matched healthy controls were compared. (1) Forward head position distances were moderately correlated and UCA angles were highly correlated. The mean (standard deviation) differences can be expected to vary between 1·48 cm (1·74) for FHP and -1·7 (2·46)° for UCA. (2) Reliability for CROM FHP measurements were good to excellent (no pain) and moderate (pain). Cervical range of motion FHP MDC95 was moderately low (no pain), and moderate (pain). Reliability for CROM UCA measurements was excellent and MDC95 low for both groups. There was no difference in FHP distances between the pain and no pain groups, UCA was significantly more extended in the pain group (P<0·05). Cervical range of motion FHP measurements were only moderately correlated with Optotrak data, and limits of agreement (LOA) and MDC95 were relatively large. There was also no difference in CROM FHP distance between older symptomatic and asymptomatic individuals. Cervical range of motion FHP measurement is therefore not recommended as a clinical outcome measure. Cervical range of motion UCA

  7. Temporal response of positive and negative regulators in response to acute and chronic exercise training in mice

    PubMed Central

    Olenich, Sara A; Gutierrez-Reed, Navarre; Audet, Gerald N; Olfert, I Mark

    2013-01-01

    Angiogenesis is controlled by a balance between positive and negative angiogenic factors, but temporal protein expression of many key angiogenic regulators in response to exercise are still poorly defined. In C57BL/6 mice, we evaluated the temporal protein expression of several pro-angiogenic and anti-angiogenic factors in response to (1) a single acute bout of exercise and (2) chronic exercise training resulting from 3, 5, 7, 14 and 28 days of voluntary wheel running. Following acute exercise, protein levels of vascular endothelial growth factor-A (VEGF), endostatin and nucleolin were increased at 2–4 h (P < 0.05), whereas matrix metalloproteinase (MMP)-2 was elevated within a 12–24 h window (P < 0.05). Training increased muscle capillarity 11%, 15% and 22% starting with 7, 14 and 28 days of training, respectively (P < 0.01). Basal VEGF and MMP-2 were increased by 31% and 22%, respectively, compared to controls (P < 0.05) after 7 days (7d) training, but decreased to back to baseline after 14d training. After 28d training VEGF fell 49% below baseline control (P < 0.01). Basal muscle expression of thrombospondin 1 (TSP-1) was ∼900% greater in 14d- and 28d-trained mice compared to either 5d- and 7d-trained mice (P < 0.05), and tended to increase by ∼180–258% compared to basal control levels (P < 0.10). The acute responsiveness of VEGF to exercise in untrained mice (i.e. 161% increase, P < 0.001) was lost with capillary adaptation occurring after 7, 14 and 28d training. Taken together, these data support the notion that skeletal muscle angiogenesis is controlled by a balance between positive and negative mitogens, and reveals a complex, highly-coordinated, temporal scheme whereby these factors can differentially influence capillary growth in response to acute versus chronic exercise. PMID:23878369

  8. An Outbreak of Heinz Body Positive Hemolytic Anemia in Chronic Hemodialysis Patients1

    PubMed Central

    Pyo, Heui-Jung; Kwon, Young Joo; Wee, Kyoung So; Kwon, So Young; Lee, Chang Hong; Kim, Suhnggwon; Lee, Jung Sang; Cho, Soo-Hun; Cha, Chul Whan

    1993-01-01

    During the four month period, from December 1988 to March 1989, there was an outbreak of Heinz body positive hemolytic anemia in 34 patients undergoing hemodialysis in a 500-bed hospital, Seoul, Korea. The episodes of hemolysis were not reduced by changing the charcoal column and reverse osmosis system, or by adding ascorbic acid to the dialysate. The concentrations of nitrate, copper, aluminum and zinc in the treated water were all within the standards for hemodialysis. The chloramine concentration of the treated water was over 0.6 mg/L, markedly exceeding the allowable level of 0.1 mg/L. This high level of chloramine was proved to be due to the contamination of the water source by raw sewage. After we changed the source of water supply to another, no more episodes of hemolytic anemia occurred. It is concluded that chloramine is one of the major contaminants causing dialysis-induced hemolytic anemia and regular determinations are necessary, especially during winter and dry seasons. PMID:8031729

  9. MBP-positive and CD11c-positive cells are associated with different phenotypes of Korean patients with non-asthmatic chronic rhinosinusitis.

    PubMed

    Kim, Dong-Kyu; Park, Min-Hyun; Chang, Dong-Yeop; Eun, Kyung Mi; Shin, Hyun-Woo; Mo, Ji-Hun; Shin, Eui-Cheol; Jin, Hong Ryul; Shin, Sue; Roh, Eun Youn; Han, Doo Hee; Kim, Dae Woo

    2014-01-01

    Asthmatic nasal polyps primarily exhibit eosinophilic infiltration. However, the identities of the immune cells that infiltrate non-asthmatic nasal polyps remain unclear. Thus, we thought to investigate the distribution of innate immune cells and its clinical relevance in non-asthmatic chronic rhinosinusitis (CRS) in Korea. Tissues from uncinate process (UP) were obtained from controls (n = 18) and CRS without nasal polyps (CRSsNP, n = 45). Nasal polyps (NP) and UP were obtained from CRS with nasal polyps (CRSwNP, n = 56). The innate immune cells was evaluated by immunohistochemistry such as, eosinophil major basic protein (MBP), tryptase, CD68, CD163, CD11c, 2D7, human neutrophil elastase (HNE) and its distribution was analyzed according to clinical parameters. In comparisons between UP from each group, CRSwNP had a higher number of MPB(+), CD68(+), and CD11c(+) cells relative to CRSsNP. Comparisons between UP and NP from CRSwNP indicated that NP have a higher infiltrate of MBP(+), CD163(+), CD11c(+), 2D7(+) and HNE(+) cells, whereas fewer CD68(+) cells were found in NP. In addition, MBP(+) and CD11c(+) cells were increased from UP of CRSsNP, to UP of CRSwNP, and to NP of CRSwNP. Moreover, in UP from CRSwNP, the number of MBP(+) and CD11c(+) cells positively correlated with CT scores. In the analysis of CRSwNP phenotype, allergic eosinophilic polyps had a higher number of MBP(+), tryptase(+), CD11c(+), 2D7(+) cells than others, whereas allergic non-eosinophilic polyps showed mainly infiltration of HNE(+) and 2D7(+) cells. The infiltration of MBP(+) and CD11c(+) innate immune cells show a significant association with phenotype and disease extent of CRS and allergic status also may influences cellular phenotype in non-asthmatic CRSwNP in Korea.

  10. MBP-Positive and CD11c-Positive Cells Are Associated with Different Phenotypes of Korean Patients with Non-Asthmatic Chronic Rhinosinusitis

    PubMed Central

    Chang, Dong-Yeop; Eun, Kyung Mi; Shin, Hyun-Woo; Mo, Ji-Hun; Shin, Eui-Cheol; Jin, Hong Ryul; Shin, Sue; Roh, Eun Youn; Han, Doo Hee; Kim, Dae Woo

    2014-01-01

    Background Asthmatic nasal polyps primarily exhibit eosinophilic infiltration. However, the identities of the immune cells that infiltrate non-asthmatic nasal polyps remain unclear. Thus, we thought to investigate the distribution of innate immune cells and its clinical relevance in non-asthmatic chronic rhinosinusitis (CRS) in Korea. Methods Tissues from uncinate process (UP) were obtained from controls (n = 18) and CRS without nasal polyps (CRSsNP, n = 45). Nasal polyps (NP) and UP were obtained from CRS with nasal polyps (CRSwNP, n = 56). The innate immune cells was evaluated by immunohistochemistry such as, eosinophil major basic protein (MBP), tryptase, CD68, CD163, CD11c, 2D7, human neutrophil elastase (HNE) and its distribution was analyzed according to clinical parameters. Results In comparisons between UP from each group, CRSwNP had a higher number of MPB+, CD68+, and CD11c+ cells relative to CRSsNP. Comparisons between UP and NP from CRSwNP indicated that NP have a higher infiltrate of MBP+, CD163+, CD11c+, 2D7+ and HNE+ cells, whereas fewer CD68+ cells were found in NP. In addition, MBP+ and CD11c+ cells were increased from UP of CRSsNP, to UP of CRSwNP, and to NP of CRSwNP. Moreover, in UP from CRSwNP, the number of MBP+ and CD11c+ cells positively correlated with CT scores. In the analysis of CRSwNP phenotype, allergic eosinophilic polyps had a higher number of MBP+, tryptase+, CD11c+, 2D7+ cells than others, whereas allergic non-eosinophilic polyps showed mainly infiltration of HNE+ and 2D7+ cells. Conclusions The infiltration of MBP+ and CD11c+ innate immune cells show a significant association with phenotype and disease extent of CRS and allergic status also may influences cellular phenotype in non-asthmatic CRSwNP in Korea. PMID:25361058

  11. Heliox and noninvasive positive-pressure ventilation: a role for heliox in exacerbations of chronic obstructive pulmonary disease?

    PubMed

    Hess, Dean R

    2006-06-01

    Evidence-based respiratory therapy for exacerbations of chronic obstructive pulmonary disease (COPD) includes oxygen, inhaled bronchodilators, and noninvasive positive-pressure ventilation. Examining the physics of gas flow, a case can be made either for or against the use of helium-oxygen mixture (heliox) in the care of patients with COPD. The evidence for the use of heliox in patients with COPD exacerbation is not strong at present. Most of the peer-reviewed literature consists of case reports, case series, and physiologic studies in small samples of carefully selected patients. Some patients with COPD exacerbation have a favorable physiologic response to heliox therapy, but predicting who will be a responder is difficult. Moreover, the use of heliox is hampered by the lack of widespread availability of an approved heliox delivery system. Appropriately designed randomized controlled trials with patient-important outcomes, such as avoidance of intubation, decreased intensive-care-unit and hospital days, and decreased cost of therapy, are sorely needed to establish the role of heliox in patients with COPD exacerbation, including those receiving noninvasive positive-pressure ventilation. Lacking such evidence, the use of heliox in patients with COPD exacerbation cannot be considered standard therapy.

  12. Does life course socio-economic position influence chronic disabling pain in older adults? A general population study.

    PubMed

    Lacey, Rosie J; Belcher, John; Croft, Peter R

    2013-08-01

    Chronic pain is the leading cause of disability in developed countries. Prevalence is linked with socio-economic position (SEP), but little is known about the influence of SEP on disabling pain over the life course. We have investigated the influence of different life course trajectories of SEP on disabling pain ('pain interference') in postal surveys of adults aged ≥50 years sampled from the general population of adults registered with three UK general practices. Current pain interference was measured using the dichotomized 36-item Short-Form (SF-36) health survey. Three recalled SEP measures (age left school, longest job and current/most recent job) were dichotomized into low SEP (left school at or before minimum school leaving age; reported routine or manual occupations) and high SEP, from which eight life course SEP trajectories were constructed. Associations of (i) eight SEP trajectories and (ii) three individual SEP measures adjusted for each other, with pain interference, adjusted for potential confounders, were calculated using logistic regression. A total of 2533 individuals provided data on all three SEP measures. A consistently low life course SEP trajectory was significantly associated with current pain interference compared with a high trajectory [odds ratio (OR) = 2.76, 95% confidence interval (CI): 2.19-3.47], even after adjustment for age and gender. Further adjustment reduced the association but it remained significant (OR = 2.04; 95% CI: 1.55-2.68). In the model with individual measures, low age left school (OR = 1.45; 95% CI: 1.15-1.82) and manual longest job (OR = 1.47; 95% CI: 1.13-1.91) were independently associated with pain interference. Our results highlight the potential for reducing chronic disabling pain in later life by addressing inequalities in both childhood education and adult occupational opportunities.

  13. Results of therapy with interferon alpha and cyclic combination chemotherapy in patients with philadelphia chromosome positive chronic myelogenous leukemia in early chronic phase.

    PubMed

    Giles, F J; Kantarjian, H; O'Brien, S; Rios, M B; Cortes, J; Beran, M; Koller, C; Keating, M; Talpaz, M

    2001-04-01

    The objective of the study was to investigate the toxicity and efficacy of cyclic combination therapy offered to patients with Ph-positive CML having a sub-optimal response to IFN-alpha. Patients in early chronic phase CML were treated with IFN-alpha at 5MU/m(2) daily. Patients who did not achieve cytogenetic response after 6 months of IFN-alpha therapy, or Ph-suppression to less than 35% Ph-positive cells (partial cytogenetic response) after 12 months of therapy were offered cyclic intensive chemotherapy every 6 months, with IFN-alpha maintenance between cycles. The initial 3 cycles included daunorubicin, vincristine, cytosine arabinoside (ara-C) and prednisone (DOAP). Later cycles were given with cyclophosphamide replacing daunorubicin (COAP). Of 74 patients treated, 61 (82%) achieved complete hematologic response (CHR): 51 (69%) had a cytogenetic response, which was major (Ph < 35%) in 31 (42%), and complete in 23 (31%). Fifty-five patients (74%) achieved CHR by 6 months of therapy, 38 (69%; 51% of total) with a cytogenetic response - 13 (24%) had a major cytogenetic response. Seventeen patients received at least 1 course of DOAP therapy. Median survival of the overall cohort of patients was 120 months. With a median follow-up of 145 months (103+ to 155+ months), 40 patients (54%) have died. The median duration of cytogenetic response was 35 months (range 3 to 149+ months) and the estimated 10-year cytogenetic response rate was 37%. A durable complete cytogenetic response was observed in 16 patients (20%) with a median duration of 139+ months (range 12+ to 149+ months), 11 of them (15%) are now off IFN-alpha therapy for a median of 57+ months (range 12+ to 128+ months). The projected 10-year survival was 50% for the study group versus 35% for 208 patients who received other IFN-alpha based regimens at the MD Anderson Cancer Center (p<.01). In conclusion, the addition of intensive chemotherapy may improve survival in patients with CML who have not obtained an

  14. 20 alpha-hydroxysteroid dehydrogenase expression in a murine virus-induced myeloproliferative syndrome.

    PubMed

    Marcovistz, R; Le Bousse-Kerdiles, M C; Maillere, B; Smadja-Joffe, F; Poirrier, V; Jasmin, C

    1991-11-01

    The myeloproliferative sarcoma virus (MPSV) infection in DBA/2 mice leads to important quantitative and qualitative changes in their hemopoiesis. These findings suggest a disturbance in the production and action of a certain hemopoietic factor similar to IL3. Here, we show that the level of the 20 alpha-hydroxysteroid dehydrogenase (20 alpha-SDH) expression, which can be induced by IL3, is dramatically increased in spleen and thymus of MPSV-infected mice. Our results suggest that quantification of 20 alpha-SDH activity can be used to indicate abnormal production of a growth factor similar to IL3 in hemopoietic system diseases.

  15. Evolving Therapeutic Strategies for the Classic Philadelphia-Negative Myeloproliferative Neoplasms

    PubMed Central

    Kaplan, Jason B.; Stein, Brady L.; McMahon, Brandon; Giles, Francis J.; Platanias, Leonidas C.

    2016-01-01

    Despite the emergence of JAK inhibitors, there is a need for disease-modifying treatments for Philadelphia-negative myeloproliferative neoplasms (MPNs). JAK inhibitors ameliorate symptoms and address splenomegaly, but because of the heterogeneous contributors to the disease process, JAK inhibitor monotherapy incompletely addresses the burden of disease. The ever-growing understanding of MPN pathogenesis has provided the rationale for testing novel and targeted therapeutic agents, as monotherapies or in combination, in preclinical and clinical settings. A number of intriguing options have emerged, and it is hoped that further progress will lead to significant changes in the natural history of MPNs. PMID:26870834

  16. Myeloproliferative Neoplasms, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology.

    PubMed

    Mesa, Ruben; Jamieson, Catriona; Bhatia, Ravi; Deininger, Michael W; Gerds, Aaron T; Gojo, Ivana; Gotlib, Jason; Gundabolu, Krishna; Hobbs, Gabriela; Klisovic, Rebecca B; Kropf, Patricia; Mohan, Sanjay R; Oh, Stephen; Padron, Eric; Podoltsev, Nikolai; Pollyea, Daniel A; Rampal, Raajit; Rein, Lindsay A M; Scott, Bart; Snyder, David S; Stein, Brady L; Verstovsek, Srdan; Wadleigh, Martha; Wang, Eunice S; Bergman, Mary Anne; Gregory, Kristina M; Sundar, Hema

    2016-12-01

    Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are a group of heterogeneous disorders of the hematopoietic system collectively known as Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). The diagnosis and the management of patients with MPNs have evolved since the identification of mutations that activate the JAK pathway (JAK2, CALR, and MPL mutations) and the development of targeted therapies has resulted in significant improvements in disease-related symptoms and quality of life. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnostic workup of MPN (MF, PV, and ET), risk stratification, treatment, and supportive care strategies for the management of MF.

  17. Cost-effectiveness analysis of antiviral therapies for hepatitis B e antigen-positive chronic hepatitis B patients in China.

    PubMed

    Zhang, Chi; Ke, Weixia; Gao, Yanhui; Zhou, Shudong; Liu, Li; Ye, Xiaohua; Yao, Zhenjiang; Yang, Yi

    2015-03-01

    Several antiviral therapies are now available for patients with chronic hepatitis B (CHB), but the most cost-effective strategy for Chinese patients is unclear. The aim of this study was to estimate the long-term cost effectiveness of the antiviral treatments (lamivudine, adefovir, telbivudine and entecavir) for hepatitis B e antigen (HBeAg)-positive CHB patients in China. A Markov model was used to simulate the life-time (41-year time span) costs and effectiveness associated with antiviral treatments from the perspective of Chinese healthcare. Relative model parameters were derived from Chinese population studies. Costs and effectiveness were discounted at 5 %. The highest retail prices for generic and branded drug prices were also considered. Probabilistic sensitivity analysis and one-way sensitivity analysis were used to explore model uncertainties. In the base-case analysis, the least quality-adjusted life years (QALYs) were obtained with adefovir as the reference strategy. Lamivudine generated the highest incremental cost-effectiveness ratio (ICER), with an additional US$35,000 needed to gain one additional QALY for generic drugs and US$36,000 for branded drugs. Entecavir had the lowest ICER of US$7,600 and US$9,100, respectively. The projected 10-year cumulative incidences of compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma (HCC) and mortality for entecavir were lower than the other strategies. In probabilistic sensitivity analyses, entecavir was the preferred option at a threshold of US$18,924 per QALY. In patients with HBeAg-positive CHB in China, entecavir is a cost-effective option compared with other therapies for CHB.

  18. Oscillating Positive Expiratory Pressure on Respiratory Resistance in Chronic Obstructive Pulmonary Disease With a Small Amount of Secretion

    PubMed Central

    Gastaldi, Ada Clarice; Paredi, Paolo; Talwar, Anjana; Meah, Sally; Barnes, Peter J.; Usmani, Omar S.

    2015-01-01

    Abstract This study aims to evaluate the acute effects of an oscillating positive expiratory pressure device (flutter) on airways resistance in patients with chronic obstructive pulmonary disease (COPD). Randomized crossover study: 15 COPD outpatients from Asthma Lab–Royal Brompton Hospital underwent spirometry, impulse oscillometry (IOS) for respiratory resistance (R) and reactance (X), and fraction exhaled nitric oxide (FeNO) measures. Thirty minutes of flutter exercises: a “flutter-sham” procedure was used as a control, and airway responses after a short-acting bronchodilator were also assessed. Respiratory system resistance (R): in COPD patients an increase in X5insp (−0.21 to −0.33 kPa/L/s) and Fres (24.95 to 26.16 Hz) occurred immediately after flutter exercises without bronchodilator. Following 20 min of rest, a decrease in the R5, ΔR5, R20, X5, and Ax was observed, with R5, R20, and X5 values lower than baseline, with a moderate effect size; there were no changes in FeNO levels or spirometry. The use of flutter can decrease the respiratory system resistance and reactance and expiratory flow limitation in stable COPD patients with small amounts of secretions. PMID:26496331

  19. Intrahepatic HBV DNA as a predictor of antivirus treatment efficacy in HBeAg-positive chronic hepatitis B patients

    PubMed Central

    Lu, Hai-Ying; Zhuang, Li-Wei; Yu, Yan-Yan; Ivan, Hadad; Si, Chong-Wen; Zeng, Zheng; Li, Jun; Hou, Dong-Ming; Chen, Xin-Yue; Han, Zhong-Hou; Chen, Yong

    2007-01-01

    AIM: To evaluate the effect of antiviral agents on intrahepatic HBV DNA in HBeAg-positive chronic hepatitis B patients. METHODS: Seventy-one patients received treatment with lamivudine, interferon alpha (IFN-α2b) or sequential therapy with lamivudine-IFN-α2b for 48 wk. All subjects were followed up for 24 wk. Serum and intrahepatic HBV DNA were measured quantitatively by PCR. HBV genotypes were analyzed by PCR-RFLP. RESULTS: At the end of treatment, the intrahepatic HBV DNA level in 71 patients decreased from a mean of (6.1 ± 1.0) log10 to (4.9 ± 1.4) log10. Further, a larger decrease was seen in the intrahepatic HBV DNA level in patients with HBeAg seroconversion. Intrahepatic HBV DNA level (before and after treatment) was not significantly affected by the patients’ HBV genotype, or by the probability of virological flare after treatment. CONCLUSION: Intrahepatic HBV DNA can be effectively lowered by antiviral agents and is a significant marker for monitoring antivirus treatment. Low intrahepatic HBV DNA level may achieve better efficacy of antivirus treatment. PMID:17569128

  20. Relationship between JAK2V617F mutation, allele burden and coagulation function in Ph-negative myeloproliferative neoplasms.

    PubMed

    Hu, Linhui; Pu, Lianfang; Ding, Yangyang; Li, Manman; Cabanero, Michael; Xie, Jingxin; Zhou, Dejun; Yang, Dongdong; Zhang, Cui; Wang, Huiping; Zhai, Zhimin; Ru, Xiang; Li, Jingrong; Xiong, Shudao

    2017-07-01

    Our aim was to explore the relationship between JAK2V617F mutation allele burden and hematological parameters especially in coagulation function in Chinese population. This study included 133 Ph-negative myeloproliferative neoplasms (MPNs) patients between 2013 and 2016. All the clinical and experimental data of patients were collected at the time of the diagnosis without any prior treatment, including blood parameters, coagulation function, splenomegaly, vascular events and chromosome karyotype. PCR and qPCR were used to detect JAK2V617F mutation and JAK2V617F mutation allele burden. In polycythemia vera patients, a positive correlation between the allele burden of JAK2V617F mutation and PLT counts was found; in essential thrombocythemia (ET) patients, WBC counts, RBC counts, HB, and HCT were higher in mutated patients than in wild-type patients. Furthermore, PT-INR was higher in ET and PMF mutated patients. In addition, a positive correlation between the allele burden of JAK2V617F mutation and activated partial thromboplastin time (APTT) was observed in JAK2V617F mutated ET patients. Higher hematologic parameters including counts of WBC, RBC, and PLT are closely associated with JAK2V617F mutation and its burden in Ph-negative MPNs; importantly, PT-INR, APTT are also related to JAK2V617F mutation and allele burden. Thus, our data indicate that JAK2V617F mutation allele burden might not only represent the burden of MPN but also alter the coagulation function.

  1. Elastic Tape Improved Shoulder Joint Position Sense in Chronic Hemiparetic Subjects: A Randomized Sham-Controlled Crossover Study

    PubMed Central

    Souza, Matheus Bragança; Desloovere, Kaat; Russo, Thiago Luiz

    2017-01-01

    Background Elastic tape has been widely used in clinical practice in order to improve upper limb (UL) sensibility. However, there is little evidence that supports this type of intervention in stroke patients. Objective To verify the effect of elastic tape, applied to the paretic shoulder, on joint position sense (JPS) during abduction and flexion in subjects with chronic hemiparesis compared to sham tape (non-elastic tape). Furthermore, to verify if this potential effect is correlated to shoulder subluxation measurements and sensorimotor impairment. Methods A crossover and sham-controlled study was conducted with post-stroke patients who were randomly allocated into two groups: 1) those who received Sham Tape (ST) first and after one month they received Elastic Tape (ET); 2) those who received Elastic Tape (ET) first and after one month they received Sham Tape (ST). The JPS was evaluated using a dynamometer. The absolute error for shoulder abduction and flexion at 30° and 60° was calculated. Sensorimotor impairment was determined by Fugl-Meyer, and shoulder subluxation was measured using a caliper. Results Thirteen hemiparetic subjects (average time since stroke 75.23 months) participated in the study. At baseline (before interventions), the groups were not different for abduction at 30° (p = 0.805; p = 0.951), and 60° (p = 0.509; p = 0.799), or flexion at 30° (p = 0.872; p = 0.897) and 60° (p = 0.853; p = 0.970). For the ET group, differences between pre and post-elastic tape for abduction at 30° (p<0.010) and 60° (p<0.010), and flexion at 30° p<0.010) and 60° (p<0.010) were observed. For the ST group, differences were also observed between pre and post-elastic tape for abduction at 30° (p<0.010) and 60° (p<0.010), and flexion at 30° (p<0.010,) and 60° (p<0.010). Potential effects were only correlated with shoulder subluxation during abduction at 30° (p = 0.001, r = -0.92) and 60° (p = 0.020, r = -0.75). Conclusion Elastic tape improved shoulder

  2. Elastic Tape Improved Shoulder Joint Position Sense in Chronic Hemiparetic Subjects: A Randomized Sham-Controlled Crossover Study.

    PubMed

    Santos, Gabriela Lopes Dos; Souza, Matheus Bragança; Desloovere, Kaat; Russo, Thiago Luiz

    2017-01-01

    Elastic tape has been widely used in clinical practice in order to improve upper limb (UL) sensibility. However, there is little evidence that supports this type of intervention in stroke patients. To verify the effect of elastic tape, applied to the paretic shoulder, on joint position sense (JPS) during abduction and flexion in subjects with chronic hemiparesis compared to sham tape (non-elastic tape). Furthermore, to verify if this potential effect is correlated to shoulder subluxation measurements and sensorimotor impairment. A crossover and sham-controlled study was conducted with post-stroke patients who were randomly allocated into two groups: 1) those who received Sham Tape (ST) first and after one month they received Elastic Tape (ET); 2) those who received Elastic Tape (ET) first and after one month they received Sham Tape (ST). The JPS was evaluated using a dynamometer. The absolute error for shoulder abduction and flexion at 30° and 60° was calculated. Sensorimotor impairment was determined by Fugl-Meyer, and shoulder subluxation was measured using a caliper. Thirteen hemiparetic subjects (average time since stroke 75.23 months) participated in the study. At baseline (before interventions), the groups were not different for abduction at 30° (p = 0.805; p = 0.951), and 60° (p = 0.509; p = 0.799), or flexion at 30° (p = 0.872; p = 0.897) and 60° (p = 0.853; p = 0.970). For the ET group, differences between pre and post-elastic tape for abduction at 30° (p<0.010) and 60° (p<0.010), and flexion at 30° p<0.010) and 60° (p<0.010) were observed. For the ST group, differences were also observed between pre and post-elastic tape for abduction at 30° (p<0.010) and 60° (p<0.010), and flexion at 30° (p<0.010,) and 60° (p<0.010). Potential effects were only correlated with shoulder subluxation during abduction at 30° (p = 0.001, r = -0.92) and 60° (p = 0.020, r = -0.75). Elastic tape improved shoulder JPS of subjects with chronic hemiparesis

  3. A cost-utility analysis of drug treatments in patients with HBeAg-positive chronic hepatitis B in Thailand

    PubMed Central

    2014-01-01

    Background Only lamivudine has been included for patients with chronic hepatitis B (CHB) in the National List of Essential Drugs (NLED), a pharmaceutical reimbursement list in Thailand. There have also been no economic evaluation studies of CHB drug treatments conducted in Thailand yet. In order to fill this gap in policy research, the objective of this study was to compare the cost-utility of each drug therapy (Figure 1) with palliative care in patients with HBeAg-positive CHB. Methods A cost-utility analysis using an economic evaluation model was performed to compare each drug treatment for HBeAg-positive CHB patients. A Markov model was used to estimate the relevant costs and health outcomes during a lifetime horizon based on a societal perspective. Direct medical costs, direct non-medical costs, and indirect costs were included, and health outcomes were denoted in life years (LYs) and quality-adjusted life years (QALYs). The results were presented as an incremental cost effectiveness ratio (ICER) in Thai baht (THB) per LY or QALY gained. One-way sensitivity and probabilistic sensitivity analyses were applied to investigate the effects of model parameter uncertainties. Results The ICER values of providing generic lamivudine with the addition of tenofovir when drug resistance occurred, generic lamivudine with the addition of tenofovir based on the road map guideline, and tenofovir monotherapy were -14,000 (USD -467), -8,000 (USD -267) , and -5,000 (USD -167) THB per QALY gained, respectively. However, when taking into account all parameter uncertainties in the model, providing generic lamivudine with the addition of tenofovir when drug resistance occurred (78% and 75%) and tenofovir monotherapy (18% and 24%) would yield higher probabilities of being cost-effective at the societal willingness to pay thresholds of 100,000 (USD 3,333) and 300,000 (USD 10,000) THB per QALY gained in Thailand, respectively. Conclusions Based on the policy recommendations from this

  4. A cost-utility analysis of drug treatments in patients with HBeAg-positive chronic hepatitis B in Thailand.

    PubMed

    Tantai, Narisa; Chaikledkaew, Usa; Tanwandee, Tawesak; Werayingyong, Pitsaphun; Teerawattananon, Yot

    2014-04-14

    Only lamivudine has been included for patients with chronic hepatitis B (CHB) in the National List of Essential Drugs (NLED), a pharmaceutical reimbursement list in Thailand. There have also been no economic evaluation studies of CHB drug treatments conducted in Thailand yet. In order to fill this gap in policy research, the objective of this study was to compare the cost-utility of each drug therapy (Figure 1) with palliative care in patients with HBeAg-positive CHB. A cost-utility analysis using an economic evaluation model was performed to compare each drug treatment for HBeAg-positive CHB patients. A Markov model was used to estimate the relevant costs and health outcomes during a lifetime horizon based on a societal perspective. Direct medical costs, direct non-medical costs, and indirect costs were included, and health outcomes were denoted in life years (LYs) and quality-adjusted life years (QALYs). The results were presented as an incremental cost effectiveness ratio (ICER) in Thai baht (THB) per LY or QALY gained. One-way sensitivity and probabilistic sensitivity analyses were applied to investigate the effects of model parameter uncertainties. The ICER values of providing generic lamivudine with the addition of tenofovir when drug resistance occurred, generic lamivudine with the addition of tenofovir based on the road map guideline, and tenofovir monotherapy were -14,000 (USD -467), -8,000 (USD -267) , and -5,000 (USD -167) THB per QALY gained, respectively. However, when taking into account all parameter uncertainties in the model, providing generic lamivudine with the addition of tenofovir when drug resistance occurred (78% and 75%) and tenofovir monotherapy (18% and 24%) would yield higher probabilities of being cost-effective at the societal willingness to pay thresholds of 100,000 (USD 3,333) and 300,000 (USD 10,000) THB per QALY gained in Thailand, respectively. Based on the policy recommendations from this study, the Thai government decided to

  5. False-positive PCR detection of Tropheryma whipplei in cerebrospinal fluid and biopsy samples from a child with chronic lymphocytic meningitis.

    PubMed

    Goyo, Daniel; Camacho, Ana; Gómez, Carmen; de Las Heras, Rogelio Simón; Otero, Joaquín R; Chaves, Fernando

    2009-11-01

    We report the case of a teenager with chronic lymphocytic meningitis for whom Tropheryma whipplei 16S rRNA PCR results were positive in two cerebrospinal fluid samples and one duodenal biopsy specimen. PCR targeting another specific sequence of Tropheryma whipplei and sequencing of the initially amplified 16S rRNA fragment did not confirm the results.

  6. Activation of the thrombopoietin receptor by mutant calreticulin in CALR-mutant myeloproliferative neoplasms.

    PubMed

    Araki, Marito; Yang, Yinjie; Masubuchi, Nami; Hironaka, Yumi; Takei, Hiraku; Morishita, Soji; Mizukami, Yoshihisa; Kan, Shin; Shirane, Shuichi; Edahiro, Yoko; Sunami, Yoshitaka; Ohsaka, Akimichi; Komatsu, Norio

    2016-03-10

    Recurrent somatic mutations of calreticulin (CALR) have been identified in patients harboring myeloproliferative neoplasms; however, their role in tumorigenesis remains elusive. Here, we found that the expression of mutant but not wild-type CALR induces the thrombopoietin (TPO)-independent growth of UT-7/TPO cells. We demonstrated that c-MPL, the TPO receptor, is required for this cytokine-independent growth of UT-7/TPO cells. Mutant CALR preferentially associates with c-MPL that is bound to Janus kinase 2 (JAK2) over the wild-type protein. Furthermore, we demonstrated that the mutant-specific carboxyl terminus portion of CALR interferes with the P-domain of CALR to allow the N-domain to interact with c-MPL, providing an explanation for the gain-of-function property of mutant CALR. We showed that mutant CALR induces the phosphorylation of JAK2 and its downstream signaling molecules in UT-7/TPO cells and that this induction was blocked by JAK2 inhibitor treatment. Finally, we demonstrated that c-MPL is required for TPO-independent megakaryopoiesis in induced pluripotent stem cell-derived hematopoietic stem cells harboring the CALR mutation. These findings imply that mutant CALR activates the JAK2 downstream pathway via its association with c-MPL. Considering these results, we propose that mutant CALR promotes myeloproliferative neoplasm development by activating c-MPL and its downstream pathway.

  7. Cerebral venous thrombosis and myeloproliferative neoplasms: results from two large databases.

    PubMed

    Dentali, Francesco; Ageno, Walter; Rumi, Elisa; Casetti, Ilaria; Poli, Daniela; Scoditti, Umberto; Maffioli, Margherita; di Minno, Matteo Nicola Dario; Caramazza, Domenica; Pietra, Daniela; De Stefano, Valerio; Passamonti, Francesco

    2014-07-01

    Myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Patients with MPNs are prone to develop arterial and venous thrombosis either at diagnosis or during follow-up; in particular splancnic vein is strongly associated with MPN. Conversely, presence of MPN is uncommon in patients with deep vein thrombosis of the lower extremities and with pulmonary embolism. Only few studies with conflicting results have evaluated the prevalence of an underlying MPN in patients with cerebral venous thrombosis (CVT), and limited evidence exists on the incidence of CVT in patients with established MPN. We assessed the frequency of MPNs in a series of 706 patients with cerebral vein thrombosis (CVT) and the frequency of CVT in a cohort of 2,143 MPNs patients. Twenty-seven CVT patients (3.8%) were diagnosed with MPN: 9 before CVT (1.3%), 4 concomitantly (0.6%), and 14 after CVT (2.0%). Nine CVT cases (0.4%) were diagnosed in the MPN cohort, with a slightly higher frequency in PV (five of 735, 0.7%) than in ET (three of 964, 0.3%) and in PMF (one of 444, 0.2%). Considering the analyses of these databases jointly, the results obtained suggest a weak association between CVT and MPNs and ultimately suggest that a thorough investigation looking for an underlying MPN may not be warranted in all the patients with CVT without overt myeloproliferative features. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. Novel molecular mechanism of cellular transformation by a mutant molecular chaperone in myeloproliferative neoplasms.

    PubMed

    Araki, Marito; Komatsu, Norio

    2017-10-01

    Deregulation of the cytokine-receptor signaling pathway plays a significant role in tumorigenesis. Such deregulation is frequently caused by alterations in the genes involved in the signaling pathway. At the end of 2013, recurrent somatic mutations in the calreticulin (CALR) gene that encodes a molecular chaperone were identified in a subset of patients with Philadelphia-chromosome negative myeloproliferative neoplasms (MPN). The present review focuses on the role of CALR mutations in the oncogenic transformations observed in MPN. All the CALR mutations were found to generate a + 1 frameshift in the reading frame on exon 9, which encodes the carboxy (C)-terminus end of CALR, and thus conferred a common mutant-specific sequence in all the CALR mutants. The mutant CALR (but not the wild-type) constitutively activates the thrombopoietin (TPO) receptor, myeloproliferative leukemia protein (MPL), even in the absence of TPO to induce cellular transformation. Preferential interaction between the mutant CALR and MPL is achieved by a presumptive conformational change induced by the mutant-specific C-terminus domain, which allows N-domain binding to MPL. Even though mutant CALR is expressed on the cell surface and is secreted out of cells, it only presents autocrine capacity for MPL activation. These findings define a novel molecular mechanism by which the mutant molecular chaperone constitutively activates the cytokine receptor to induce cellular transformation. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  9. Whole-exome sequencing reveals potential molecular predictors of relapse after discontinuation of the targeted therapy in chronic myeloid leukemia patients.

    PubMed

    Smirnikhina, Svetlana A; Lavrov, Alexander V; Chelysheva, Ekaterina Yu; Adilgereeva, Elmira P; Shukhov, Oleg A; Turkina, Anna; Kutsev, Sergey I

    2016-07-01

    Chronic myeloid leukemia (CML) is a myeloproliferative disease well treated by tyrosine kinase inhibitors (TKIs). The aim was to identify genes with a predictive value for relapse-free survival after TKI cessation in CML patients. We performed whole-exome sequencing of DNA from six CML patients in long-lasting deep molecular remission. Patients were divided into two groups with relapse (n = 3) and without relapse (n = 3) after TKI discontinuation. We found variants in genes CYP1B1, ALPK2, and IRF1 in group of patients with relapse and one variant in gene PARP9 in group of patients without relapse. We verified prognostic value of the found markers in a small group of patients with TKI discontinuation and demonstrated their high sensitivity (77%), specificity (86%), positive (85%), and negative (79%) predictive values. Thus we revealed genetic variants, which are potential markers of outcome prediction in CML patients after TKI discontinuation.

  10. Painful ANA-positive scleroderma-like disease with acral ulcerations: a case of chronic gangrenous ergotism.

    PubMed

    Wollina, Uwe; Hansel, Gesine; Gruner, Monika; Schönlebe, Jaqueline; Heinig, Birgit; Köstler, Erich

    2007-09-01

    Chronic ergotism is a rare cause of limb ischemia. In this case report, the authors present a 62-year-old woman with history of long-term use of ergotamine alkaloids for the treatment of menstrual pain, who developed a severe painful disease initially misdiagnosed as systemic sclerosis (scleroderma) for 3 decades. She presented with a combination of acral gangrene, foot ulcer, renal obstruction, mild pulmonary fibrosis, and reduced esophageal motility. Right-sided renal obstruction was evident. The condition was extremely painful and had led to muscular contractions and immobility, drug abuse, and anemia. After establishing the diagnosis of chronic gangrenous ergotism, changing drug therapy, mobilization, and treatment of chronic wounds, she showed a remarkable recovery. Eventually the foot ulcer was closed successfully using a mesh graft transplantation, and the patient was able to walk alone. Chronic ergotism is rare but has to be taken into account when presented with painful chronic digital and foot ulcers.

  11. Prevalence of chronic headache with and without medication overuse: associations with socioeconomic position and physical and mental health status.

    PubMed

    Westergaard, Maria Lurenda; Glümer, Charlotte; Hansen, Ebba Holme; Jensen, Rigmor Højland

    2014-10-01

    Near-daily intake of acute symptomatic medication for frequent headache increases the risk for medication-overuse headache (MOH). Chronic headache (CH) and MOH prevalences are inversely related to socioeconomic position (SEP). It is not known how SEP influences the health status of people with these headaches. This cross-sectional study examined the prevalence of CH in Denmark; possible associations between CH and education, work status, and income; and the health status of people with CH across socioeconomic strata. A total of 129,150 individuals aged ⩾ 16 years were invited to the 2010 Danish National Health Survey. Data on SEP indicators and purchases of prescription drugs in 2009 were retrieved from national registers. Respondents with headache ⩾ 15 days per month over 3 months were classified as having CH. Those with concurrent over-the-counter analgesic intake of ⩾ 15 days per month or prescription medication overuse (⩾ 20 or ⩾ 30 defined daily doses per month depending on the drug or drugs) were classified as having MOH. Associations between headache and SEP were analyzed by logistic regression, and associations between headache and health status scores, by linear regression. Physical and mental health composite scores (SF-12) were summarized per headache group, stratified by SEP, and compared to the sample mean. Analyses were adjusted for stratified sampling and nonresponse. The response rate was 53.1%. CH prevalence was 3.3% with 53.0% of cases having concurrent medication overuse (MOH prevalence 1.8%). CH was more prevalent among those individuals with low SEP. Health status scores were significantly lower among persons with CH in all SEP categories. The burden of CH can be reduced by preventing and treating MOH.

  12. Microarray and Proteomic Analyses of Myeloproliferative Neoplasms with a Highlight on the mTOR Signaling Pathway

    PubMed Central

    Čokić, Vladan P.; Mossuz, Pascal; Han, Jing; Socoro, Nuria; Beleslin-Čokić, Bojana B.; Mitrović, Olivera; Subotički, Tijana; Diklić, Miloš; Leković, Danijela; Gotić, Mirjana; Puri, Raj K.; Noguchi, Constance Tom; Schechter, Alan N.

    2015-01-01

    The gene and protein expression profiles in myeloproliferative neoplasms (MPNs) may reveal gene and protein markers of a potential clinical relevance in diagnosis, treatment and prediction of response to therapy. Using cDNA microarray analysis of 25,100 unique genes, we studied the gene expression profile of CD34+ cells and granulocytes obtained from peripheral blood of subjects with essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). The microarray analyses of the CD34+ cells and granulocytes were performed from 20 de novo MPN subjects: JAK2 positive ET, PV, PMF subjects, and JAK2 negative ET/PMF subjects. The granulocytes for proteomic studies were pooled in 4 groups: PV with JAK2 mutant allele burden above 80%, ET with JAK2 mutation, PMF with JAK2 mutation and ET/PMF with no JAK2 mutation. The number of differentially regulated genes was about two fold larger in CD34+ cells compared to granulocytes. Thirty-six genes (including RUNX1, TNFRSF19) were persistently highly expressed, while 42 genes (including FOXD4, PDE4A) were underexpressed both in CD34+ cells and granulocytes. Using proteomic studies, significant up-regulation was observed for MAPK and PI3K/AKT signaling regulators that control myeloid cell apoptosis and proliferation: RAC2, MNDA, S100A8/9, CORO1A, and GNAI2. When the status of the mTOR signaling pathway related genes was analyzed, PI3K/AKT regulators were preferentially up-regulated in CD34+ cells of MPNs, with down-regulated major components of the protein complex EIF4F. Molecular profiling of CD34+ cells and granulocytes of MPN determined gene expression patterns beyond their recognized function in disease pathogenesis that included dominant up-regulation of PI3K/AKT signaling. PMID:26275051

  13. Updated and Expanded Study of Polycythemia Vera and Other Myeloproliferative Neoplasms in the Tri-County Area

    PubMed Central

    Buchanich, J. M.; Mertz, K. J.; Washington, T. L.; Logue, J. N.; Marchetto, D.; Roda, P. I.; Irvin-Barnwell, E.

    2016-01-01

    Introduction The results of a 2001–2005 polycythemia vera (PV) investigation in Eastern Pennsylvania revealed a disease cluster plus underreporting and false reporting to the Pennsylvania Cancer Registry (PCR). Purpose The objectives of this study were 1) to assess PV reporting to the PCR in 2006–2009, 2) to determine whether a cancer cluster persisted, and 3) to determine whether other myeloproliferative neoplasms (MPNs), including essential thrombocytopenia (ET), were subject to similar reporting problems. Methods Cases were identified from: 1) PCR records from the Tri-County, 2) reviewing billing records at Tri-County hematologist/oncologist offices, and 3) self-identification. An expert panel of physicians reviewed medical records and determined “true,” “false,” or “indeterminate” cases reported to the PCR. The analyses were conducted to determine sensitivity and positive predictive value (PPV) of case reporting to the PCR, estimate cancer incidence rates, and evaluate the presence of cancer clusters. Results Of 290 cases identified, 90% were from the original PCR, 9% from billing records, and 1% from self-report. Fifty-five cases consented to participate, and medical records were obtained for 44. The expert panel determined that 45% were true cases, 32% were false cases, and 23% were indeterminate. PV had 100% (95% CI, 59–100) sensitivity, but only 47% PPV (95% CI, 20–70): ET had 78% (95% CI, 47–99) sensitivity and 100% PPV (95% CI, 59–100). Low participation and chart review rates led to rates with wide confidence intervals. We did not identify any PV cancer clusters, but we did identify a cluster of 9 ET cases in the Wilkes-Barre, Pennsylvania area. Conclusion The current study was limited by the low response rate (22%) from MPN patients in the Tri-County area. This study identified 47% PPV for PV reporting and 100% PPV for ET. PMID:25803630

  14. Aberrant let7a/HMGA2 signaling activity with unique clinical phenotype in JAK2-mutated myeloproliferative neoplasms.

    PubMed

    Chen, Chih-Cheng; You, Jie-Yu; Lung, Jrhau; Huang, Cih-En; Chen, Yi-Yang; Leu, Yu-Wei; Ho, Hsing-Ying; Li, Chian-Pei; Lu, Chang-Hsien; Lee, Kuan-Der; Hsu, Chia-Chen; Gau, Jyh-Pyng

    2017-03-01

    High mobility group AT-hook 2 (HMGA2) is an architectural transcription factor that is negatively regulated by let-7 microRNA through binding to it's 3'-untranslated region. Transgenic mice expressing Hmga2 with a truncation of its 3'-untranslated region has been shown to exhibit a myeloproliferative phenotype. To decipher the let-7-HMGA2 axis in myeloproliferative neoplasms, we employed an in vitro model supplemented with clinical correlation. Ba/F3 cells with inducible JAK2V617F expression (Ton.JAK2.V617F cells) showed upregulation of HMGA2 with concurrent let-7a repression. Ton.JAK2.V617F cells treated with a let-7a inhibitor exhibited further escalation of Hmga2 expression, while a let-7a mimic diminished the Hmga2 transcript level. Hmga2 overexpression conferred JAK2-mutated cells with a survival advantage through inhibited apoptosis. A pan-JAK inhibitor, INC424, increased the expression of let-7a, downregulated the level of Hmga2, and led to increased apoptosis in Ton.JAK2.V617F cells in a dose-dependent manner. In samples from 151 patients with myeloproliferative neoplasms, there was a modest inverse correlation between the expression levels of let-7a and HMGA2 Overexpression of HMGA2 was detected in 29 (19.2%) of the cases, and it was more commonly seen in patients with essential thrombocythemia than in those with polycythemia vera (26.9% vs 12.7%, P=0.044). Patients with upregulated HMGA2 showed an increased propensity for developing major thrombotic events, and they were more likely to harbor one of the 3 driver myeloproliferative neoplasm mutations in JAK2, MPL and CALR Our findings suggest that, in a subset of myeloproliferative neoplasm patients, the let-7-HMGA2 axis plays a prominent role in the pathogenesis of the disease that leads to unique clinical phenotypes.

  15. Bosutinib in the treatment of patients with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia: an overview.

    PubMed

    Shen, Ann Q; Wilson, Nicole M; Gleason, Shannon L; Khoury, Hanna Jean

    2014-02-01

    Bosutinib is an orally bioavailable SRC/ABL tyrosine kinase inhibitor with activity against all phases of resistant chronic myeloid leukemia that do not express the T315I or V299L ABL kinase domain mutations. Bosutinib has a unique toxicity profile that is manageable. This paper provides an overview of bosutinib, covering pharmacodynamics and pharmacokinetic properties, results of treatment in newly diagnosed and previously treated chronic myeloid leukemia patients, as well as common side effects.

  16. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome–positive chronic myeloid leukemia patients with resistance or intolerance to imatinib

    PubMed Central

    Kantarjian, Hagop M.; Brümmendorf, Tim H.; Kim, Dong-Wook; Turkina, Anna G.; Shen, Zhi-Xiang; Pasquini, Ricardo; Khoury, H. Jean; Arkin, Steven; Volkert, Angela; Besson, Nadine; Abbas, Richat; Wang, Junyuan; Leip, Eric; Gambacorti-Passerini, Carlo

    2011-01-01

    Bosutinib, a dual Src/Abl kinase inhibitor, has shown potent activity against chronic myeloid leukemia (CML). In this phase 1/2 study we evaluated bosutinib in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. Part 1 was a dose-escalation study to determine the recommended starting dose for part 2; part 2 evaluated the efficacy and safety of bosutinib 500 mg once-daily dosing. The study enrolled 288 patients with imatinib-resistant (n = 200) or imatinibintolerant (n = 88) CML and no other previous kinase inhibitor exposure. At 24 weeks, 31% of patients achieved major cytogenetic response (primary end point). After a median follow-up of 24.2 months, 86% of patients achieved complete hematologic remission, 53% had a major cytogenetic response (41% had a complete cytogenetic response), and 64% of those achieving complete cytogenetic response had a major molecular response. At 2 years, progression-free survival was 79%; overall survival at 2 years was 92%. Responses were seen across Bcr-Abl mutants, except T315I. Bosutinib exhibited an acceptable safety profile; the most common treatment-emergent adverse event was mild/moderate, typically self-limiting diarrhea. Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (9%), rash (9%), and vomiting (3%). These data suggest bosutinib is effective and tolerable in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. This trial was registered at http://www.clinicaltrials.gov as NCT00261846. PMID:21865346

  17. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib.

    PubMed

    Cortes, Jorge E; Kantarjian, Hagop M; Brümmendorf, Tim H; Kim, Dong-Wook; Turkina, Anna G; Shen, Zhi-Xiang; Pasquini, Ricardo; Khoury, H Jean; Arkin, Steven; Volkert, Angela; Besson, Nadine; Abbas, Richat; Wang, Junyuan; Leip, Eric; Gambacorti-Passerini, Carlo

    2011-10-27

    Bosutinib, a dual Src/Abl kinase inhibitor, has shown potent activity against chronic myeloid leukemia (CML). In this phase 1/2 study we evaluated bosutinib in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. Part 1 was a dose-escalation study to determine the recommended starting dose for part 2; part 2 evaluated the efficacy and safety of bosutinib 500 mg once-daily dosing. The study enrolled 288 patients with imatinib-resistant (n = 200) or imatinib-intolerant (n = 88) CML and no other previous kinase inhibitor exposure. At 24 weeks, 31% of patients achieved major cytogenetic response (primary end point). After a median follow-up of 24.2 months, 86% of patients achieved complete hematologic remission, 53% had a major cytogenetic response (41% had a complete cytogenetic response), and 64% of those achieving complete cytogenetic response had a major molecular response. At 2 years, progression-free survival was 79%; overall survival at 2 years was 92%. Responses were seen across Bcr-Abl mutants, except T315I. Bosutinib exhibited an acceptable safety profile; the most common treatment-emergent adverse event was mild/moderate, typically self-limiting diarrhea. Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (9%), rash (9%), and vomiting (3%). These data suggest bosutinib is effective and tolerable in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. This trial was registered at http://www.clinicaltrials.gov as NCT00261846.

  18. A best practice position statement on pregnancy in chronic kidney disease: the Italian Study Group on Kidney and Pregnancy.

    PubMed

    Cabiddu, Gianfranca; Castellino, Santina; Gernone, Giuseppe; Santoro, Domenico; Moroni, Gabriella; Giannattasio, Michele; Gregorini, Gina; Giacchino, Franca; Attini, Rossella; Loi, Valentina; Limardo, Monica; Gammaro, Linda; Todros, Tullia; Piccoli, Giorgina Barbara

    2016-06-01

    Pregnancy is increasingly undertaken in patients with chronic kidney disease (CKD) and, conversely, CKD is increasingly diagnosed in pregnancy: up to 3 % of pregnancies are estimated to be complicated by CKD. The heterogeneity of CKD (accounting for stage, hypertension and proteinuria) and the rarity of several kidney diseases make risk assessment difficult and therapeutic strategies are often based upon scattered experiences and small series. In this setting, the aim of this position statement of the Kidney and Pregnancy Study Group of the Italian Society of Nephrology is to review the literature, and discuss the experience in the clinical management of CKD in pregnancy. CKD is associated with an increased risk for adverse pregnancy-related outcomes since its early stage, also in the absence of hypertension and proteinuria, thus supporting the need for a multidisciplinary follow-up in all CKD patients. CKD stage, hypertension and proteinuria are interrelated, but they are also independent risk factors for adverse pregnancy-related outcomes. Among the different kidney diseases, patients with glomerulonephritis and immunologic diseases are at higher risk of developing or increasing proteinuria and hypertension, a picture often difficult to differentiate from preeclampsia. The risk is higher in active immunologic diseases, and in those cases that are detected or flare up during pregnancy. Referral to tertiary care centres for multidisciplinary follow-up and tailored approaches are warranted. The risk of maternal death is, almost exclusively, reported in systemic lupus erythematosus and vasculitis, which share with diabetic nephropathy an increased risk for perinatal death of the babies. Conversely, patients with kidney malformation, autosomal-dominant polycystic kidney disease, stone disease, and previous upper urinary tract infections are at higher risk for urinary tract infections, in turn associated with prematurity. No risk for malformations other than those

  19. Initial fluconazole prophylaxis may not be required in adults with acute leukemia or myelodysplastic/myeloproliferative disorders after reduced intensity conditioning peripheral blood stem cell allogeneic transplantation.

    PubMed

    Brissot, Eolia; Cahu, Xavier; Guillaume, Thierry; Delaunay, Jacques; Ayari, Sameh; Peterlin, Pierre; Le Bourgeois, Amandine; Harousseau, Jean-Luc; Milpied, Noel; Bene, Marie-Christine; Moreau, Philippe; Mohty, Mohamad; Chevallier, Patrice

    2015-04-01

    In the myeloablative transplant setting, the early use of fluconazole prophylaxis provides a benefit in overall survival. Recent changes in transplantation practices, including the use of peripheral blood stem cells (PBSC) and/or reduced intensity conditioning (RIC) regimen may have favorably impacted the epidemiology of invasive fungal infections (IFI) after allogeneic stem cell transplantation (allo-SCT). Yet, the impact of removing fluconazole prophylaxis after RIC PBSC allotransplant is ill known. Here, a retrospective analysis was performed comparing patients who received fluconazole as antifungal prophylaxis (n = 53) or not (n = 56) after allo-SCT for acute leukemia or myelodysplastic/myeloproliferative syndrome. Sixteen IFI were documented (14 %) at a median time of 103 days after transplantation, including eight before day +100, at a similar rate, whether the patients received fluconazole prophylaxis (13 %) or not (16 %). IFI were due mainly to Aspergillus species (87 %), and only two Candida-related IFI (13 %) were documented in the non-fluconazole group before day +100. The incidences of IFI (overall, before or after day +100) as well as 3-year overall and disease-free survival, non-relapse mortality, or acute and chronic graft-versus-host disease (GVHD) were similar between both groups. In conclusion, this study suggests that fluconazole may not be required at the initial phase of RIC allo-SCT using PBSC. This result has to be confirmed prospectively while Aspergillus prophylaxis should be discussed in this particular setting.

  20. Use of the Draeger Apollo to Deliver Bilevel Positive Pressure Ventilation During Awake Frontal Craniotomy for a Patient with Severe Chronic Obstructive Pulmonary Disease.

    PubMed

    Lee, Susie So-Hyun; Berman, Mitchell F

    2015-12-01

    In this case report, we describe the use of the Draeger Apollo anesthesia machine to deliver bilevel positive airway pressure (BiPAP) to a patient with severe chronic obstructive pulmonary disease and a history of lung resection undergoing frontal craniotomy for the removal of a brain tumor under moderate to deep sedation. BiPAP in the perioperative period has been described for purposes of preoxygenation and postextubation recruitment. Although its utility as a mode of ventilation during moderate to deep sedation has been demonstrated, it has not come into widespread use. We describe the intraoperative use of pressure support mode on the anesthesia machine to deliver noninvasive positive pressure ventilation through a standard anesthesia mask. Given its ease of access and effectiveness, it is our belief that intraoperative BiPAP may reduce hypoxemia and/or hypercarbia in patients with chronic obstructive pulmonary disease and obstructive sleep apnea undergoing moderate to deep sedation.

  1. mTOR Inhibitors Alone and in Combination with JAK2 Inhibitors Effectively Inhibit Cells of Myeloproliferative Neoplasms

    PubMed Central

    Martinelli, Serena; Tozzi, Lorenzo; Guglielmelli, Paola; Bosi, Alberto; Vannucchi, Alessandro M.

    2013-01-01

    Background Dysregulated signaling of the JAK/STAT pathway is a common feature of chronic myeloproliferative neoplasms (MPN), usually associated with JAK2V617F mutation. Recent clinical trials with JAK2 inhibitors showed significant improvements in splenomegaly and constitutional symptoms in patients with myelofibrosis but meaningful molecular responses were not documented. Accordingly, there remains a need for exploring new treatment strategies of MPN. A potential additional target for treatment is represented by the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway that has been found constitutively activated in MPN cells; proof-of-evidence of efficacy of the mTOR inhibitor RAD001 has been obtained recently in a Phase I/II trial in patients with myelofibrosis. The aim of the study was to characterize the effects in vitro of mTOR inhibitors, used alone and in combination with JAK2 inhibitors, against MPN cells. Findings Mouse and human JAK2V617F mutated cell lines and primary hematopoietic progenitors from MPN patients were challenged with an allosteric (RAD001) and an ATP-competitive (PP242) mTOR inhibitor and two JAK2 inhibitors (AZD1480 and ruxolitinib). mTOR inhibitors effectively reduced proliferation and colony formation of cell lines through a slowed cell division mediated by changes in cell cycle transition to the S-phase. mTOR inhibitors also impaired the proliferation and prevented colony formation from MPN hematopoietic progenitors at doses significantly lower than healthy controls. JAK2 inhibitors produced similar antiproliferative effects in MPN cell lines and primary cells but were more potent inducers of apoptosis, as also supported by differential effects on cyclinD1, PIM1 and BcLxL expression levels. Co-treatment of mTOR inhibitor with JAK2 inhibitor resulted in synergistic activity against the proliferation of JAK2V617F mutated cell lines and significantly reduced erythropoietin-independent colony growth in patients with polycythemia vera

  2. Health resource utilization and cost associated with myeloproliferative neoplasms in a large United States health plan.

    PubMed

    Mehta, Jyotsna; Wang, Hongwei; Fryzek, Jon P; Iqbal, Sheikh Usman; Mesa, Ruben

    2014-10-01

    Myelofibrosis (MF), polycythemia vera (PV) and essential thrombocythemia (ET) may lead to bone marrow fibrosis. Because the disease course of ET and PV are long and the disease course of MF may be fatal, healthcare resource utilization (HRU) associated costs of these neoplasms are especially important to understand. We used a large US health insurance claim database to describe the costs of these diseases. Compared to age-gender matched comparisons without myeloproliferative neoplasms (MPN), all aspects of HRU that we examined, including inpatient, outpatient and emergency room visits and pharmacy, as well as overall healthcare expenditures, were significantly higher in patients with MF, PV and ET (e.g. MF total costs = $54 168 vs. $10 203; PV = $14 903 vs. $7913; ET = $29 553 vs. $8026) than in matched comparisons. In order to reduce the burden of illness associated with these diseases, continued efforts in the development of more efficacious treatments for these disorders are needed.

  3. Splanchnic vein thrombosis in myeloproliferative neoplasms: pathophysiology and molecular mechanisms of disease.

    PubMed

    How, Joan; Zhou, Amy; Oh, Stephen T

    2017-03-01

    Myeloproliferative neoplasms (MPNs) are the most common underlying prothrombotic disorder found in patients with splanchnic vein thrombosis (SVT). Clinical risk factors for MPN-associated SVTs include younger age, female sex, concomitant hypercoagulable disorders, and the JAK2 V617F mutation. These risk factors are distinct from those associated with arterial or deep venous thrombosis (DVT) in MPN patients, suggesting disparate disease mechanisms. The pathophysiology of SVT is thought to derive from local interactions between activated blood cells and the unique splanchnic endothelial environment. Other mutations commonly found in MPNs, including CALR and MPL, are rare in MPN-associated SVT. The purpose of this article is to review the clinical and molecular risk factors for MPN-associated SVT, with particular focus on the possible mechanisms of SVT formation in MPN patients.

  4. Chasing down the triple-negative myeloproliferative neoplasms: Implications for molecular diagnostics.

    PubMed

    Langabeer, Stephen E

    2016-01-01

    The majority of patients with classical myeloproliferative neoplasms (MPN) of polycythemia vera, essential thrombocythemia, and primary myelofibrosis harbor distinct disease-driving mutations within the JAK2, CALR, or MPL genes. The term triple-negative has been recently applied to those MPN without evidence of these consistent mutations, prompting whole or targeted exome sequencing approaches to determine the driver mutational status of this subgroup. These strategies have identified numerous novel mutations that occur in alternative exons of both JAK2 and MPL, the majority of which result in functional activation. Current molecular diagnostic approaches may possess insufficient coverage to detect these alternative mutations, prompting further consideration of targeted exon sequencing into routine diagnostic practice. How to incorporate these illuminating findings into the expanding molecular diagnostic algorithm for MPN requires continual attention.

  5. Splanchnic vein thrombosis in myeloproliferative neoplasms: pathophysiology and molecular mechanisms of disease

    PubMed Central

    How, Joan; Zhou, Amy; Oh, Stephen T.

    2016-01-01

    Myeloproliferative neoplasms (MPNs) are the most common underlying prothrombotic disorder found in patients with splanchnic vein thrombosis (SVT). Clinical risk factors for MPN-associated SVTs include younger age, female sex, concomitant hypercoagulable disorders, and the JAK2 V617F mutation. These risk factors are distinct from those associated with arterial or deep venous thrombosis (DVT) in MPN patients, suggesting disparate disease mechanisms. The pathophysiology of SVT is thought to derive from local interactions between activated blood cells and the unique splanchnic endothelial environment. Other mutations commonly found in MPNs, including CALR and MPL, are rare in MPN-associated SVT. The purpose of this article is to review the clinical and molecular risk factors for MPN-associated SVT, with particular focus on the possible mechanisms of SVT formation in MPN patients. PMID:28246554

  6. Myeloproliferative Disease: An Unusual Cause of Raynaud's Phenomenon and Digital Ischaemia

    PubMed Central

    Huws, Gwenan; Lawson, Tom

    2016-01-01

    We describe a 59-year-old female who presented with ischaemic digits, preceded by a 6-month history of Raynaud's phenomenon affecting her fingers and toes. There were no clinical or laboratory features of primary vasculitis or connective tissue disease, Doppler imaging was normal, and bloods were unremarkable aside from a platelet count of 786 × 109/L (150–400) and white cells of 16 × 109/L (4–11). In view of the thrombocytosis a JAK2 mutation assay was requested which confirmed a JAK2 V617F mutation, suggesting essential thrombocytosis (ET) as the cause. She received treatment with hydroxycarbamide which normalised her platelet count and led to a complete resolution of her Raynaud's symptoms. Raynaud's phenomenon is a rare manifestation of ET. Myeloproliferative disorders such as ET should be considered in the differential diagnosis of Raynaud's phenomenon and vasculitis. PMID:27895669

  7. Novel germline mutations in the calreticulin gene: implications for the diagnosis of myeloproliferative neoplasms.

    PubMed

    Szuber, Natasha; Lamontagne, Bruno; Busque, Lambert

    2016-07-27

    Mutations in the calreticulin (CALR) gene are found in the majority of Janus kinase 2-negative myeloproliferative neoplasms MPN and, thus far, have exclusively been reported as acquired, somatic mutations. We assessed the mutational status of exon 9 of the CALR gene in 2000 blood samples submitted to our centre and identified 12 subjects (0.6%) harbouring distinctive CALR mutations, all with an allelic frequency of 50% and all involving indels occurring as multiples of 3 bp. Buccal cell samples obtained from these patients confirmed the germline nature of the mutations. Importantly, these germline mutations were not diagnostic of MPN. We thus report for the first time the identification and confirmation of germline mutations in CALR distinct from those somatic mutations that define classical MPN. The finding of a non-standard CALR mutation with an allelic frequency of 50% should raise suspicion of the possibility of a germline CALR mutation and these cases investigated further.

  8. Monitoring Minimal Residual Disease in the Myeloproliferative Neoplasms: Current Applications and Emerging Approaches

    PubMed Central

    2016-01-01

    The presence of acquired mutations within the JAK2, CALR, and MPL genes in the majority of patients with myeloproliferative neoplasms (MPN) affords the opportunity to utilise these mutations as markers of minimal residual disease (MRD). Reduction of the mutated allele burden has been reported in response to a number of therapeutic modalities including interferon, JAK inhibitors, and allogeneic stem cell transplantation; novel therapies in development will also require assessment of efficacy. Real-time quantitative PCR has been widely adopted for recurrent point mutations with assays demonstrating the specificity, sensitivity, and reproducibility required for clinical utility. More recently, approaches such as digital PCR have demonstrated comparable, if not improved, assay characteristics and are likely to play an increasing role in MRD monitoring. While next-generation sequencing is increasingly valuable as a tool for diagnosis of MPN, its role in the assessment of MRD requires further evaluation. PMID:27840830

  9. Pharmacobiological Approach for the Clinical Development of Ruxolitinib in Myeloproliferative Neoplasms

    PubMed Central

    Eliaçık, Eylem; Işık, Ayşe; Aksu, Salih; Üner, Ayşegül; Büyükaşık, Yahya; Sayınalp, Nilgün; Göker, Hakan; Özcebe, Osman İ.; Haznedaroğlu, İbrahim C.

    2015-01-01

    Ruxolitinib, a JAK1 and JAK2 inhibitor drug, has recently been approved for the treatment of patients with high- or intermediate-risk myelofibrosis with symptomatic splenomegaly. Ruxolitinib is the first clinically useful targeted therapy in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). The aim of this paper is to indicate pharmacobiological aspects of ruxolitinib within the potential context of MPNs. Pharmacobiological assessments, in addition to knowledge of the risk profile for ruxolitinib in MPNs, are required. We propose hypotheses based on our experience in a splenectomized MPN patient with hyperproliferative bone marrow and moderate fibrosis receiving ruxolitinib. We believe that a true clinical development approach for this drug should include pharmacobiological assessments for ruxolitinib in addition to the disease risk profile of MPNs. PMID:26316485

  10. Circulating Cytokine Levels as Markers of Inflammation in Philadelphia Negative Myeloproliferative Neoplasms: Diagnostic and Prognostic Interest

    PubMed Central

    Mondet, Julie; Hussein, Kais; Mossuz, Pascal

    2015-01-01

    Cytokines are well known mediators of numerous physiological and pathological processes. They contribute to the regulation of normal hematopoiesis but increasing data suggest that they also have a clinical impact in some hematopoietic malignancies. In particular, there is evidence that cytokines are implicated in the functional symptoms of Philadelphia negative myeloproliferative neoplasms (Ph− MPNs), suggesting that evaluation of circulating levels of cytokines could be of clinical interest for the characterization of patients at the time of diagnosis and for disease prognosis. In this review, we present the current knowledge on alteration of circulating cytokine profiles in MPNs and their role in myelofibrosis pathogenesis. Phenotypic correlation, prognostic value of cytokines, and impact of JAK inhibitors are also discussed. PMID:26525644

  11. Transient myeloproliferative disorder in neonates without Down syndrome: case report and review.

    PubMed

    Schifferli, Alexandra; Hitzler, Johann; Bartholdi, Deborah; Heinimann, Karl; Hoeller, Sylvia; Diesch, Tamara; Kühne, Thomas

    2015-05-01

    Transient myeloproliferative disorder (TMD) is a clonal proliferation of megakaryoblasts, typically occurring in newborns with Down syndrome. It is believed that TMD occurs in the presence of GATA1 mutation together with trisomy 21. However, a limited number of patients with TMD but without Down syndrome have been reported, all with a blast population with numeric or rarely structural chromosome 21 abnormalities. We present the first case of a newborn boy with a TMD without trisomy 21 and without any of the mentioned molecular or cytogenetic abnormalities. This case report suggests that unknown disease mechanisms may provoke or mimic TMD. This case report is followed by a concise review of the literature discussing the different entities and pathomechanisms of TMD and acute megakaryocytic leukaemia in patients with or without Down syndrome. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. Clonality in myeloproliferative disorders: Analysis by means of polymerase chain reaction

    SciTech Connect

    Gilliland, D.G.; Blanchard, K.L.; Levy, J.; Perrin, S.; Bunn, H.F. )

    1991-08-01

    The myeloproliferative syndromes are acquired disorders of hematopoiesis that provide insights into the transition from somatic cell mutation to neoplasia. The clonal origin of specific blood cells can be assessed in patients with X chromosome-linked polymorphisms, taking advantage of random inactivation of the X chromosome. The authors have adapted the PCR for determination of clonality on as few as 100 cells, including individual colonies grown in culture. Amplifying a polymorphic portion of the X chromosome-linked phosphoglycerate kinase (PGK) gene after selective digestion of the active X chromosome with a methylation-sensitive restriction enzyme gave results fully concordant with standard Southern blotting of DNA samples form normal (polyclonal) polymorphonuclear cells (PMN) as well as clonal PMN from patients with myelodysplastic syndrome and polycythemia vera (PCV). They have used this technique to demonstrate heterogeneity of lineage involvement in patients with PCV. The same clinical phenotype may arise from clonal proliferation of different hematopoietic progenitors.

  13. JAK Inhibitors and other Novel Agents in Myeloproliferative Neoplasms: Are We Hitting the Target?

    PubMed

    Kucine, Nicole; Levine, Ross L

    2011-08-01

    The discovery of somatic mutations in the JAK-STAT signaling pathway was a major breakthrough in our understanding of the molecular pathogenesis of the myeloproliferative neoplasms (MPNs) polycythemia vera, essential thrombocytosis, and primary myelofibrosis. This finding led to the development of small molecule inhibitors targeting Janus kinase (JAK) 2 and other JAK family members. Currently, there are a number of research and clinical trials ongoing with JAK inhibitors. While the appeal of inhibiting JAK2 is clear, studies to date suggest that JAK2 inhibitor monotherapy might not be sufficient to cause reductions in disease allele burden in MPN patients. There is compelling evidence that JAK inhibitors are improving symptoms and therefore quality of life for patients. It will be important to investigate the efficacy of JAK inhibitors in preclinical and clinical studies to better understand their effects, while at the same time pursuing alternative therapies which might offer benefit to MPN patients alone and in combination with JAK inhibitors.

  14. Post-therapeutic acute malignant myeloproliferative syndrome and acute nonlymphocytic leukemia in non-Hodgkin's lymphoma

    SciTech Connect

    Gomez, G.A.; Aggarwal, K.K.; Han, T.

    1982-12-01

    In a prospective randomized study of treatment with radiation therapy (RT) or RT + chemotherapy (CT) for patients with non-Hodgkin's lymphoma Stages I-III, one patient developed an acute malignant myeloproliferative syndrome (AMMS) and four others acute nonlymphocytic leukemia (ANLL). There was correlation between the intensity of treatment and development of this complication: Among patients treated with local radiation with or without chemotherapy no cases of AMMS or ANLL were observed. However, patients treated with total lymphoid irradiation alone (TLI) had an observed to expected ratio of 162. Among patients treated with TLI plus CT this ratio increased to over 1000. The cytogenetic, clinical, and hematologic abnormalities of these patients are discussed.

  15. Myeloproliferative Disease: An Unusual Cause of Raynaud's Phenomenon and Digital Ischaemia.

    PubMed

    Beynon, Celia; Huws, Gwenan; Lawson, Tom

    2016-01-01

    We describe a 59-year-old female who presented with ischaemic digits, preceded by a 6-month history of Raynaud's phenomenon affecting her fingers and toes. There were no clinical or laboratory features of primary vasculitis or connective tissue disease, Doppler imaging was normal, and bloods were unremarkable aside from a platelet count of 786 × 109/L (150-400) and white cells of 16 × 109/L (4-11). In view of the thrombocytosis a JAK2 mutation assay was requested which confirmed a JAK2 V617F mutation, suggesting essential thrombocytosis (ET) as the cause. She received treatment with hydroxycarbamide which normalised her platelet count and led to a complete resolution of her Raynaud's symptoms. Raynaud's phenomenon is a rare manifestation of ET. Myeloproliferative disorders such as ET should be considered in the differential diagnosis of Raynaud's phenomenon and vasculitis.

  16. Serum Levels of Soluble IL-2R, CD4 and CD8 in Chronic Active HCV Positive Hepatitis

    PubMed Central

    Candore, G.; Cigna, D.; Tripi, S.; Di Gaetano, G.; Migneco, G.; Montalto, G.; Ruggieri, I.; Notarbartolo, A.

    1994-01-01

    The aim of the present study was to compare serum levels of soluble forms of interleukin-2 receptor, CD4 and CD8, released by lymphocytes during activation ofthe immune system, in patients with histologically verified chronic active hepatitis associated to hepatitis C virus infection, with those in healthy subjects. Significantly higher levels of soluble IL-2R and soluble CD8 were found in patients with chronic active hepatitis compared with controls. In contrast no difference was found for soluble CD4 values in the two groups. No correlations were found for both sIL-2R and sCD8 and these two molecules with other parameters of liver function. These results indicate that in these patients there is a general activation of the immune system, but the lack of correlation with parameters of liver function strengthens the suggestion that this activation does not play a role in the pathogenesis of chronic type C hepatitis. PMID:18472940

  17. Best Clinical Practices for the Sleep Center Adjustment of Noninvasive Positive Pressure Ventilation (NPPV) in Stable Chronic Alveolar Hypoventilation Syndromes

    PubMed Central

    2010-01-01

    Summary: Noninvasive positive pressure ventilation (NPPV) devices are used during sleep to treat patients with diurnal chronic alveolar hypoventilation (CAH). Bilevel positive airway pressure (BPAP) using a mask interface is the most commonly used method to provide ventilatory support in these patients. BPAP devices deliver separately adjustable inspiratory positive airway pressure (IPAP) and expiratory positive airway pressure (EPAP). The IPAP and EPAP levels are adjusted to maintain upper airway patency, and the pressure support (PS = IPAP-EPAP) augments ventilation. NPPV devices can be used in the spontaneous mode (the patient cycles the device from EPAP to IPAP), the spontaneous timed (ST) mode (a backup rate is available to deliver IPAP for the set inspiratory time if the patient does not trigger an IPAP/EPAP cycle within a set time window), and the timed (T) mode (inspiratory time and respiratory rate are fixed). During NPPV titration with polysomnography (PSG), the pressure settings, backup rate, and inspiratory time (if applicable) are adjusted to maintain upper airway patency and support ventilation. However, there are no widely available guidelines for the titration of NPPV in the sleep center. A NPPV Titration Task Force of the American Academy of Sleep Medicine reviewed the available literature and developed recommendations based on consensus and published evidence when available. The major recommendations derived by this consensus process are as follows: General Recommendations:The indications, goals of treatment, and side effects of NPPV treatment should be discussed in detail with the patient prior to the NPPV titration study.Careful mask fitting and a period of acclimatization to low pressure prior to the titration should be included as part of the NPPV protocol.NPPV titration with PSG is the recommended method to determine an effective level of nocturnal ventilatory support in patients with CAH. In circumstances in which NPPV treatment is initiated

  18. Myelodysplastic and myeloproliferative disorders of childhood: a study of 167 patients.

    PubMed

    Luna-Fineman, S; Shannon, K M; Atwater, S K; Davis, J; Masterson, M; Ortega, J; Sanders, J; Steinherz, P; Weinberg, V; Lange, B J

    1999-01-15

    Myelodysplastic syndromes (MDS) and myeloproliferative syndromes (MPS) of childhood are a heterogeneous group of clonal disorders of hematopoiesis with overlapping clinical features and inconsistent nomenclature. Although a number of genetic conditions have been associated with MDS and MPS, the overall contribution of inherited predispositions is uncertain. We report a retrospective study examining clinical features, genetic associations, and outcomes in 167 children with MDS and MPS. Of these patients, 48 had an associated constitutional disorder. One hundred one patients had adult-type myelodysplastic syndrome (A-MDS), 60 had juvenile myelomonocytic leukemia (JMML), and 6 infants with Down syndrome had a transient myeloproliferative syndrome (TMS). JMML was characterized by young age at onset and prominent hepatosplenomegaly, whereas patients with A-MDS were older and had little or no organomegaly. The most common cytogenetic abnormalities were monosomy 7 or del(7q) (53 cases); this was common both in patients with JMML and those with A-MDS. Leukemic transformation was observed in 32% of patients, usually within 2 years of diagnosis. Survival was 25% at 16 years. Favorable prognostic features at diagnosis included age less than 2 years and a hemoglobin F level of less than 10%. Older patients tended to present with an adult-type MDS that is accommodated within the French-American-British system. In contrast, infants and young children typically developed unique disorders with overlapping features of MDS and MPS. Although the type and intensity of therapy varied markedly in this study, the overall outcome was poor except in patients with TMS.

  19. Leukaemic transformation of Philadelphia chromosome-negative myeloproliferative neoplasms: are Asian patients different?

    PubMed

    Cherian, R; Wong, G C

    2012-05-01

    Leukaemic transformation (LT) is rare in the natural history of Philadelphia(Ph) chromosome-negative myeloproliferative disorders (MPD), and has a dismal prognosis. Little literature is available on Asian patients. The aim of this study is to report a single institution experience of Asian patients who developed acute leukaemia after being diagnosed and treated for Ph chromosome-negative MPDs, and to compare the findings of this series with similar studies from the literature. Patients were recruited from the MPD registry of Singapore General Hospital, Department of Hematology. Clinical data including treatment modalities and duration of use in myeloproliferative phase, latency to LT, characteristics of leukaemia, chemotherapy administered and survival after LT were examined. Over a 29-year period from 1980 to 2009, there were 22 Asian patients with LT of Ph chromosome-negative MPD of which four had polycythaemia vera (PV), nine had essential thrombocythaemia (ET), seven had myelofibrosis (MF) and two had unspecified MPD at diagnosis. Primary treatment modality was Hydroxyurea (HU) during MPD phase. Median latency to LT was 14 years for PV, 10 years for ET and 1 year for MF. Median age at LT diagnosis was 67.5 years. Nine patients had complex cytogenetics, with abnormalities of chromosomes 5 and 7 being common. Overall, median survival was 2 months after LT. Eight patients who received induction chemotherapy had a median survival of 2.5 months. Survival was independent of MPD type and treatment administered. None received stem cell transplantation. LT of Ph chromosome-negative MPD is rare and uniformly fatal. Despite chemotherapy, survival was poor, and patients succumbed to refractory disease and infections. Asian patients did not have a more favourable outcome. It remains to be investigated whether upfront stem cell transplant may be a treatment option. © 2011 The Authors. Internal Medicine Journal © 2011 Royal Australasian College of Physicians.

  20. Impact of bone marrow pathology on the clinical management of Philadelphia chromosome-negative myeloproliferative neoplasms.

    PubMed

    Pozdnyakova, Olga; Hasserjian, Robert P; Verstovsek, Srdan; Orazi, Attilio

    2015-05-01

    Philadelphia chromosome-negative myeloproliferative neoplasms include primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET). Although these 3 entities share many pathogenic characteristics, such as dysregulated Janus kinase (JAK)/signal transducer and activator of transcription signaling, they differ substantially regarding prognosis, progression to myelofibrosis (MF), risk of leukemic transformation, and specific medical needs. Accurate diagnosis and classification of myeloproliferative neoplasms are prerequisites for appropriate risk-based therapy and should be based on an integrated approach following the World Health Organization guidelines that, in addition to clinical, molecular, and cytogenetic evaluation, includes the examination of bone marrow morphology. Reticulin fibrosis at presentation in ET and PV is associated with increased risk of myelofibrotic transformation, and higher fibrosis grade in patients with MF is associated with worse prognosis. Additional assessment of collagen deposition and osteosclerosis may further increase diagnostic and prognostic precision. Moreover, the evaluation of bone marrow pathology has become very important in the new era of disease-modifying agents. In randomized controlled phase 3 studies, the JAK1/JAK2 inhibitor ruxolitinib provided rapid and lasting improvement in MF-related splenomegaly and symptom burden as well as a survival advantage compared with placebo or best available therapy. Follow-up for up to 5 years of patients who participated in a phase 1/2 study of ruxolitinib, revealed stabilization or reversal of bone marrow fibrosis in a proportion of patients with MF. Combinations of JAK inhibitors with other therapies, including agents with antifibrotic and/or anti-inflammatory properties, may possibly decrease bone marrow fibrosis further and favorably influence clinical outcomes. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  1. Regional Differences in Chronic Stress-induced Alterations in Mast Cell and Protease-activated Receptor-2-positive Cell Numbers in the Colon of Ws/Ws Rats.

    PubMed

    Kim, Yong Sung; Lee, Moon Young; Ryu, Han Seung; Choi, Eul-Sig; Oh, Jung Taek; Yun, Ki Jung; Choi, Suck Chei

    2014-01-01

    There have been no reports on the effect of chronic psychological stress on colonic immune cells or the regional differences. We aimed to investigate the effect of chronic psychological stress on the number of mast cells and protease-activated receptor (PAR)-2-positive cells in the rat colonic mucosa. Six-week-old and 14-week-old Ws/Ws rats, which lack mast cells after 10 weeks, were used as control and mast cell-deficient groups, respectively. The rats were divided into stress and sham-treated groups. Rats in the stressed group were exposed to water avoidance stress (WAS, 1 hour/day) for 13 days. Fecal pellet output and the number of mast cells and PAR-2-positive cells in colonic mucosa were compared between the WAS and sham groups. In 6-week-old rats, the WAS group showed a significantly higher number of mast cells compared to the sham group. In 14-week-old rats, mast cells were nearly absent in the colonic mucosa. WAS significantly increased PAR-2-positive cells in 14-week-old rats, but not in 6-week-old rats. Indirect estimation of PAR-2-positive mast cells in 6-week-old rats suggested that the majority of increased mast cells following WAS did not express PAR-2. WAS increased mast cells and PAR-2-positive cells mainly in the proximal colon. Fecal pellet output was continuously higher in the WAS group than in the sham group, and the difference was significant for both 6-week-old and 14-week-old rats. Chronic psychological stress increased the number of mast cells and PAR-2-positive cells in rat colonic mucosa, and these increases were more prominent in the proximal colon.

  2. Effects of a Tailored Positive Psychology Intervention on Well-Being and Pain in Individuals With Chronic Pain and a Physical Disability: A Feasibility Trial.

    PubMed

    Müller, Rachel; Gertz, Kevin J; Molton, Ivan R; Terrill, Alexandra L; Bombardier, Charles H; Ehde, Dawn M; Jensen, Mark P

    2016-01-01

    To determine the feasibility, acceptability, and efficacy of a computer-based positive psychology intervention in individuals with a physical disability and chronic pain. Individuals with spinal cord injury, multiple sclerosis, neuromuscular disease, or postpolio syndrome and chronic pain were randomly assigned to a positive psychology or a control condition. Participants in the intervention group were instructed to practice 4 personalized positive psychology exercises. Participants in the control group were instructed to write about life details for 8 weeks. Participants completed online well-being and pain-related questionnaires at baseline, posttreatment, and at the 2.5-month follow-up, and rated treatment satisfaction at posttreatment. Ninety-six participants were randomized and 68 (70%) completed follow-up assessments. Participants in the positive psychology intervention group reported significant pretreatment to posttreatment improvements in pain intensity, pain control, pain catastrophizing, pain interference, life satisfaction, positive affect, and depression. Improvements in life satisfaction, depression, pain intensity, pain interference, and pain control were maintained to the 2.5-month follow-up. Participants in the control group reported significant pretreatment to posttreatment improvements in life satisfaction, and pretreatment to follow-up improvements in pain intensity and pain control. Significant between-group differences, favoring the treatment group, emerged for pretreatment to posttreatment improvements in pain intensity and pain control. Participants were similarly satisfied with both treatments. The results support the feasibility, acceptability, and potential efficacy of a computer-based positive psychology intervention for improving well-being and pain-related outcomes in individuals with physical disabilities and chronic pain, and indicate that a full trial of the intervention is warranted.

  3. Evaluation of the cost-effectiveness of entecavir versus lamivudine in hepatitis BeAg-positive chronic hepatitis B patients.

    PubMed

    Yuan, Yong; Iloeje, Uchenna H; Hay, Joel; Saab, Sammy

    2008-01-01

    As new treatment options for chronic hepatitis B virus (HBV) become available, evaluations of cost-effectiveness become important. Entecavir is a deoxyguanine nucleoside analogue approved by the U.S. Food and Drug Administration in March 2005 for HBV infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (alanine aminotransferase or aspartate aminotransferase) or histologically active disease. Entecavir has demonstrated greater suppression of viral replication compared with lamivudine, but also has a relatively higher drug acquisition cost in the United States. To estimate the long-term health and economic impact of treating HBV with entecavir versus lamivudine in patients who are positive for hepatitis B e antigen (HBeAg) based on the efficacy and safety results of the Phase 3, double-blind, randomized controlled trial, Benefits of Entecavir for Hepatitis B Liver Disease (BEHoLD). A decision tree model was developed to evaluate the cost-effectiveness of entecavir compared with lamuvidine in suppressing HBV DNA to an undetectable level. Risks for compensated cirrhosis (CC), decompensated cirrhosis (DC), and hepatocellular carcinoma (HCC) were derived from the published Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV, 2006) study, a longitudinal (mean follow-up: 11.4 years) cohort study of community residents who were seropositive for the hepatitis B surface antigen; 85% of REVEAL-HBV participants were HBeAg-negative. To estimate future risks of CC, DC, and HCC, the REVEAL-HBV study's multivariate-adjusted relative risks of CC, DC, and HCC for 5 HBV DNA (viral load level) categories were applied to posttreatment HBV DNA levels obtained from the BEHoLD trial of 709 HBeAg-positive HBV patients treated with entecavir (n = 354) or lamivudine (n = 355). Entecavir and lamivudine were assigned annual costs of $7,365 and $2

  4. (Bad) Feelings about Meeting Them? Episodic and Chronic Intergroup Emotions Associated with Positive and Negative Intergroup Contact As Predictors of Intergroup Behavior.

    PubMed

    Kauff, Mathias; Asbrock, Frank; Wagner, Ulrich; Pettigrew, Thomas F; Hewstone, Miles; Schäfer, Sarina J; Christ, Oliver

    2017-01-01

    Based on two cross-sectional probability samples (Study 1: N = 1,382, Study 2: N = 1,587), we studied the interplay between positive and negative intergroup contact, different types of intergroup emotions (i.e., episodic intergroup emotions encountered during contact and more general chronic intergroup emotions), and outgroup behavior in the context of intergroup relations between non-immigrant Germans and foreigners living in Germany. In Study 1, we showed that positive and negative contact are related to specific episodic intergroup emotions (i.e., anger, fear and happiness). Results of Study 2 indicate an indirect effect of episodic intergroup emotions encountered during contact experiences on specific behavioral tendencies directed at outgroup members via more chronic situation-independent intergroup emotions. As expected, anger predicted approaching (discriminatory) behavioral tendencies (i.e., aggression) while fear predicted avoidance. The results extend the existing literature on intergroup contact and emotions by addressing positive and negative contact simultaneously and differentiating between situation-specific episodic and chronic intergroup emotions in predicting discriminatory behavioral tendencies.

  5. Chronic kidney disease as a global public health problem: approaches and initiatives - a position statement from Kidney Disease Improving Global Outcomes.

    PubMed

    Levey, A S; Atkins, R; Coresh, J; Cohen, E P; Collins, A J; Eckardt, K-U; Nahas, M E; Jaber, B L; Jadoul, M; Levin, A; Powe, N R; Rossert, J; Wheeler, D C; Lameire, N; Eknoyan, G

    2007-08-01

    Chronic kidney disease (CKD) is increasingly recognized as a global public health problem. There is now convincing evidence that CKD can be detected using simple laboratory tests, and that treatment can prevent or delay complications of decreased kidney function, slow the progression of kidney disease, and reduce the risk of cardiovascular disease (CVD). Translating these advances to simple and applicable public health measures must be adopted as a goal worldwide. Understanding the relationship between CKD and other chronic diseases is important to developing a public health policy to improve outcomes. The 2004 Kidney Disease Improving Global Outcomes (KDIGO) Controversies Conference on 'Definition and Classification of Chronic Kidney Disease' represented an important endorsement of the Kidney Disease Outcome Quality Initiative definition and classification of CKD by the international community. The 2006 KDIGO Controversies Conference on CKD was convened to consider six major topics: (1) CKD classification, (2) CKD screening and surveillance, (3) public policy for CKD, (4) CVD and CVD risk factors as risk factors for development and progression of CKD, (5) association of CKD with chronic infections, and (6) association of CKD with cancer. This report contains the recommendations from the meeting. It has been reviewed by the conference participants and approved as position statement by the KDIGO Board of Directors. KDIGO will work in collaboration with international and national public health organizations to facilitate implementation of these recommendations.

  6. An international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults.

    PubMed

    Savona, Michael R; Malcovati, Luca; Komrokji, Rami; Tiu, Ramon V; Mughal, Tariq I; Orazi, Attilio; Kiladjian, Jean-Jacques; Padron, Eric; Solary, Eric; Tibes, Raoul; Itzykson, Raphael; Cazzola, Mario; Mesa, Ruben; Maciejewski, Jaroslaw; Fenaux, Pierre; Garcia-Manero, Guillermo; Gerds, Aaron; Sanz, Guillermo; Niemeyer, Charlotte M; Cervantes, Francisco; Germing, Ulrich; Cross, Nicholas C P; List, Alan F

    2015-03-19

    Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) are hematologically diverse stem cell malignancies sharing phenotypic features of both myelodysplastic syndromes and myeloproliferative neoplasms. There are currently no standard treatment recommendations for most adult patients with MDS/MPN. To optimize efforts to improve the management and disease outcomes, it is essential to identify meaningful clinical and biologic end points and standardized response criteria for clinical trials. The dual dysplastic and proliferative features in these stem cell malignancies define their uniqueness and challenges. We propose response assessment guidelines to harmonize future clinical trials with the principal objective of establishing suitable treatment algorithms. An international panel comprising laboratory and clinical experts in MDS/MPN was established involving 3 independent academic MDS/MPN workshops (March 2013, December 2013, and June 2014). These recommendations are the result of this collaborative project sponsored by the MDS Foundation. © 2015 by The American Society of Hematology.

  7. SOCS3 tyrosine phosphorylation as a potential bio-marker for myeloproliferative neoplasms associated with mutant JAK2 kinases

    PubMed Central

    Elliott, Joanne; Suessmuth, Yvonne; Scott, Linda M.; Nahlik, Krystyna; McMullin, Mary Frances; Constantinescu, Stefan N.; Green, Anthony R.; Johnston, James A.

    2009-01-01

    JAK2 V617F, identified in the majority of patients with myeloproliferative neoplasms, tyrosine phosphorylates SOCS3 and escapes its inhibition. Here, we demonstrate that the JAK2 exon 12 mutants described in a subset of V617F-negative MPN cases, also stabilize tyrosine phosphorylated SOCS3. SOCS3 tyrosine phosphorylation was also observed in peripheral blood mononuclear cells and granulocytes isolated from patients with JAK2 H538QK539L or JAK2 F537-K539delinsL mutations. JAK kinase inhibitors, which effectively inhibited the proliferation of cells expressing V617F or K539L, also caused a dose-dependent reduction in both mutant JAK2 and SOCS3 tyrosine phosphorylation. We propose, therefore, that SOCS3 tyrosine phosphorylation may be a novel bio-marker of myeloproliferative neoplasms resulting from a JAK2 mutation and a potential reporter of effective JAK2 inhibitor therapy currently in clinical development. PMID:19229050

  8. An international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults

    PubMed Central

    Malcovati, Luca; Komrokji, Rami; Tiu, Ramon V.; Mughal, Tariq I.; Orazi, Attilio; Kiladjian, Jean-Jacques; Padron, Eric; Solary, Eric; Tibes, Raoul; Itzykson, Raphael; Cazzola, Mario; Mesa, Ruben; Maciejewski, Jaroslaw; Fenaux, Pierre; Garcia-Manero, Guillermo; Gerds, Aaron; Sanz, Guillermo; Niemeyer, Charlotte M.; Cervantes, Francisco; Germing, Ulrich; Cross, Nicholas C. P.; List, Alan F.

    2015-01-01

    Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) are hematologically diverse stem cell malignancies sharing phenotypic features of both myelodysplastic syndromes and myeloproliferative neoplasms. There are currently no standard treatment recommendations for most adult patients with MDS/MPN. To optimize efforts to improve the management and disease outcomes, it is essential to identify meaningful clinical and biologic end points and standardized response criteria for clinical trials. The dual dysplastic and proliferative features in these stem cell malignancies define their uniqueness and challenges. We propose response assessment guidelines to harmonize future clinical trials with the principal objective of establishing suitable treatment algorithms. An international panel comprising laboratory and clinical experts in MDS/MPN was established involving 3 independent academic MDS/MPN workshops (March 2013, December 2013, and June 2014). These recommendations are the result of this collaborative project sponsored by the MDS Foundation. PMID:25624319

  9. JAK2 mutants (e.g., JAK2V617F) and their importance as drug targets in myeloproliferative neoplasms

    PubMed Central

    Gäbler, Karoline; Behrmann, Iris; Haan, Claude

    2013-01-01

    The Janus kinase 2 (JAK2) mutant V617F and other JAK mutants are found in patients with myeloproliferative neoplasms and leukemias. Due to their involvement in neoplasia and inflammatory disorders, Janus kinases are promising targets for kinase inhibitor therapy. Several small-molecule compounds are evaluated in clinical trials for myelofibrosis, and ruxolitinib (INCB018424, Jakafi®) was the first Janus kinase inhibitor to receive clinical approval. In this review we provide an overview of JAK2V617F signaling and its inhibition by small-molecule kinase inhibitors. In addition, myeloproliferative neoplasms are discussed regarding the role of JAK2V617F and other mutant proteins of possible relevance. We further give an overview about treatment options with special emphasis on possible combination therapies. PMID:24069563

  10. Best clinical practices for the sleep center adjustment of noninvasive positive pressure ventilation (NPPV) in stable chronic alveolar hypoventilation syndromes.

    PubMed

    Berry, Richard B; Chediak, Alejandro; Brown, Lee K; Finder, Jonathan; Gozal, David; Iber, Conrad; Kushida, Clete A; Morgenthaler, Timothy; Rowley, James A; Davidson-Ward, Sally L

    2010-10-15

    Noninvasive positive pressure ventilation (NPPV) devices are used during sleep to treat patients with diurnal chronic alveolar hypoventilation (CAH). Bilevel positive airway pressure (BPAP) using a mask interface is the most commonly used method to provide ventilatory support in these patients. BPAP devices deliver separately adjustable inspiratory positive airway pressure (IPAP) and expiratory positive airway pressure (EPAP). The IPAP and EPAP levels are adjusted to maintain upper airway patency, and the pressure support (PS = IPAP-EPAP) augments ventilation. NPPV devices can be used in the spontaneous mode (the patient cycles the device from EPAP to IPAP), the spontaneous timed (ST) mode (a backup rate is available to deliver IPAP for the set inspiratory time if the patient does not trigger an IPAP/EPAP cycle within a set time window), and the timed (T) mode (inspiratory time and respiratory rate are fxed). During NPPV titration with polysomnography (PSG), the pressure settings, backup rate, and inspiratory time (if applicable) are adjusted to maintain upper airway patency and support ventilation. However, there are no widely available guidelines for the titration of NPPV in the sleep center. A NPPV Titration Task Force of the American Academy of Sleep Medicine reviewed the available literature and developed recommendations based on consensus and published evidence when available. The major recommendations derived by this consensus process are as follows: General Recommendations: 1. The indications, goals of treatment, and side effects of NPPV treatment should be discussed in detail with the patient prior to the NPPV titration study. 2. Careful mask fitting and a period of acclimatization to low pressure prior to the titration should be included as part of the NPPV protocol. 3. NPPV titration with PSG is the recommended method to determine an effective level of nocturnal ventilatory support in patients with CAH. In circumstances in which NPPV treatment is

  11. Insulin resistance, selfish brain, and selfish immune system: an evolutionarily positively selected program used in chronic inflammatory diseases

    PubMed Central

    2014-01-01

    Insulin resistance (IR) is a general phenomenon of many physiological states, disease states, and diseases. IR has been described in diabetes mellitus, obesity, infection, sepsis, trauma, painful states such as postoperative pain and migraine, schizophrenia, major depression, chronic mental stress, and others. In arthritis, abnormalities of glucose homeostasis were described in 1920; and in 1950 combined glucose and insulin tests unmistakably demonstrated IR. The phenomenon is now described in rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, polymyalgia rheumatica, and others. In chronic inflammatory diseases, cytokine-neutralizing strategies normalize insulin sensitivity. This paper delineates that IR is either based on inflammatory factors (activation of the immune/ repair system) or on the brain (mental activation via stress axes). Due to the selfishness of the immune system and the selfishness of the brain, both can induce IR independent of each other. Consequently, the immune system can block the brain (for example, by sickness behavior) and the brain can block the immune system (for example, stress-induced immune system alterations). Based on considerations of evolutionary medicine, it is discussed that obesity per se is not a disease. Obesity-related IR depends on provoking factors from either the immune system or the brain. Chronic inflammation and/or stress axis activation are thus needed for obesity-related IR. Due to redundant pathways in stimulating IR, a simple one factor-neutralizing strategy might help in chronic inflammatory diseases (inflammation is the key), but not in obesity-related IR. The new considerations towards IR are interrelated to the published theories of IR (thrifty genotype, thrifty phenotype, and others). PMID:25608958

  12. JAK2 p.V617F allele burden in myeloproliferative neoplasms one month after allogeneic stem cell transplantation significantly predicts outcome and risk of relapse

    PubMed Central

    Lange, Thoralf; Edelmann, Anja; Siebolts, Udo; Krahl, Rainer; Nehring, Claudia; Jäkel, Nadja; Cross, Michael; Maier, Jacqueline; Niederwieser, Dietger; Wickenhauser, Claudia

    2013-01-01

    The risk profile and prognosis of patients with myelofibrosis is well described by the Dynamic International Prognostic Scoring System risk categorization. Allogeneic stem cell transplantation is considered for intermediate-2/high risk disease. However, indicators of prognosis after transplantation are still lacking. Seventy simultaneously collected pairs of trephine and blood samples were quantified for JAK2 p.V617F allele burden to compare test sensitivity. The course of 30 patients with JAK2 p.V617F-positive myeloproliferative neoplasia was correlated with allele burden after transplantation. Monitoring can be performed on full blood samples as well as trephine biopsies, provided that techniques with ample sensitivity (0.01% to 0.001%) are available. Measurement of allele burden on day 28 after transplantation discriminates two prognostic groups: patients with a JAK2 p.V617F allele burden >1% have a significantly higher risk of relapse of JAK2 p.V617F positive neoplasia (P=0.04) and a poorer overall survival (P<0.01). In conclusion, measurement of JAK2 p.V617F allele burden early after transplantation is an important predictive parameter in monitoring patients following this treatment. As this might provide an important tool in early management of imminent early relapse it will be important to define consensus guidelines for optimal monitoring. PMID:23300178

  13. Positive associations between infections of Toxoplasma gondii and seropositivity with Anisakis simplex in human patients suffering from chronic urticaria.

    PubMed

    Fernández-Fígares, V; Rodero, M; Valls, A; De Frutos, C; Daschner, A; Cuéllar, C

    2015-11-01

    Toxoplasma gondii is a food-borne and orofecal microorganism which produces chronic infection, and attempts have been made to prove its negative association with atopy in the context of the hygiene hypothesis. Anisakis simplex is a fish parasite associated with chronic urticaria (CU) in endemic regions. We analysed the relationship between both infectious agents in CU. We included 42 patients with chronic urticaria (18 patients with CU associated with A. simplex sensitization and 24 not sensitized CU patients). Patients were assessed for atopy by a skin prick test (SPT) against common aeroallergens and for respiratory symptoms. Anisakis simplex sensitization was assessed by SPT and specific IgE by CAP fluoro-enzyme immunoassay (CAP-FEIA). Anti-T. gondii IgG levels were measured by enzyme-linked immunosorbent assay (ELISA). CU patients were analysed with respect to T. gondii seropositivity, A. simplex sensitization, atopy and immigrant status. The seroprevalence of T. gondii was 40.5% in CU patients and 42.1% in the control group. Immigrants were more frequently infected by T. gondii (41.2% versus 12%; P =0.036). Anti-T. gondii IgG antibodies were associated with past A. simplex parasitism (odds ratio 6.73; P =0.03) and independently with atopic sensitization (odds ratio 5.85; P =0.04). In CU patients, T. gondii has no protective effect on atopic sensitization or A. simplex sensitization.

  14. Assessing positive mental health in people with chronic physical health problems: correlations with socio-demographic variables and physical health status.

    PubMed

    Lluch-Canut, Teresa; Puig-Llobet, Montserrat; Sánchez-Ortega, Aurelia; Roldán-Merino, Juan; Ferré-Grau, Carmen

    2013-10-05

    A holistic perspective on health implies giving careful consideration to the relationship between physical and mental health. In this regard the present study sought to determine the level of Positive Mental Health (PMH) among people with chronic physical health problems, and to examine the relationship between the observed levels of PMH and both physical health status and socio-demographic variables. The study was based on the Multifactor Model of Positive Mental Health (Lluch, 1999), which comprises six factors: Personal Satisfaction (F1), Prosocial Attitude (F2), Self-control (F3), Autonomy (F4), Problem-solving and Self-actualization (F5), and Interpersonal Relationship Skills (F6). The sample comprised 259 adults with chronic physical health problems who were recruited through a primary care center in the province of Barcelona (Spain). Positive mental health was assessed by means of the Positive Mental Health Questionnaire (Lluch, 1999). Levels of PMH differed, either on the global scale or on specific factors, in relation to the following variables: age: global PMH scores decreased with age (r=-0.129; p=0.038); b) gender: men scored higher on F1 (t=2.203; p=0.028) and F4 (t=3.182; p=0.002), while women scored higher on F2 (t -3.086; p=0.002) and F6 (t=-2.744; p=0.007); c) number of health conditions: the fewer the number of health problems the higher the PMH score on F5 (r=-0.146; p=0.019); d) daily medication: polymedication patients had lower PMH scores, both globally and on various factors; e) use of analgesics: occasional use of painkillers was associated with higher PMH scores on F1 (t=-2.811; p=0.006). There were no significant differences in global PMH scores according to the type of chronic health condition. The only significant difference in the analysis by factors was that patients with hypertension obtained lower PMH scores on the factor Autonomy (t=2.165; p=0.032). Most people with chronic physical health problems have medium or high levels of PMH

  15. Assessing positive mental health in people with chronic physical health problems: correlations with socio-demographic variables and physical health status

    PubMed Central

    2013-01-01

    Background A holistic perspective on health implies giving careful consideration to the relationship between physical and mental health. In this regard the present study sought to determine the level of Positive Mental Health (PMH) among people with chronic physical health problems, and to examine the relationship between the observed levels of PMH and both physical health status and socio-demographic variables. Methods The study was based on the Multifactor Model of Positive Mental Health (Lluch, 1999), which comprises six factors: Personal Satisfaction (F1), Prosocial Attitude (F2), Self-control (F3), Autonomy (F4), Problem-solving and Self-actualization (F5), and Interpersonal Relationship Skills (F6). The sample comprised 259 adults with chronic physical health problems who were recruited through a primary care center in the province of Barcelona (Spain). Positive mental health was assessed by means of the Positive Mental Health Questionnaire (Lluch, 1999). Results Levels of PMH differed, either on the global scale or on specific factors, in relation to the following variables: age: global PMH scores decreased with age (r=-0.129; p=0.038); b) gender: men scored higher on F1 (t=2.203; p=0.028) and F4 (t=3.182; p=0.002), while women scored higher on F2 (t -3.086; p=0.002) and F6 (t=-2.744; p=0.007); c) number of health conditions: the fewer the number of health problems the higher the PMH score on F5 (r=-0.146; p=0.019); d) daily medication: polymedication patients had lower PMH scores, both globally and on various factors; e) use of analgesics: occasional use of painkillers was associated with higher PMH scores on F1 (t=-2.811; p=0.006). There were no significant differences in global PMH scores according to the type of chronic health condition. The only significant difference in the analysis by factors was that patients with hypertension obtained lower PMH scores on the factor Autonomy (t=2.165; p=0.032). Conclusions Most people with chronic physical health

  16. Stat5 is critical for the development and maintenance of myeloproliferative neoplasm initiated by Nf1 deficiency.

    PubMed

    Sachs, Zohar; Been, Raha A; DeCoursin, Krista J; Nguyen, Hanh T; Mohd Hassan, Nurul A; Noble-Orcutt, Klara E; Eckfeldt, Craig E; Pomeroy, Emily J; Diaz-Flores, Ernesto; Geurts, Jennifer L; Diers, Miechaleen D; Hasz, Diane E; Morgan, Kelly J; MacMillan, Margaret L; Shannon, Kevin M; Largaespada, David A; Wiesner, Stephen M

    2016-10-01

    Juvenile myelomonocytic leukemia is a rare myeloproliferative neoplasm characterized by hyperactive RAS signaling. Neurofibromin1 (encoded by the NF1 gene) is a negative regulator of RAS activation. Patients with neurofibromatosis type 1 harbor loss-of-function mutations in NF1 and have a 200- to 500-fold increased risk of juvenile myelomonocytic leukemia. Leukemia cells from patients with juvenile myelomonocytic leukemia display hypersensitivity to certain cytokines, such as granulocyte-macrophage colony-stimulating factor. The granulocyte-macrophage colony-stimulating factor receptor utilizes pre-associated JAK2 to initiate signals after ligand binding. JAK2 subsequently activates STAT5, among other downstream effectors. Although STAT5 is gaining recognition as an important mediator of growth factor signaling in myeloid leukemias, the contribution of STAT5 to the development of hyperactive RAS-initiated myeloproliferative disease has not been well described. In this study, we investigated the consequence of STAT5 attenuation via genetic and pharmacological approaches in Nf1-deficient murine models of juvenile myelomonocytic leukemia. We found that homozygous Stat5 deficiency extended the lifespan of Nf1-deficient mice and eliminated the development of myeloproliferative neoplasm associated with Nf1 gene loss. Likewise, we found that JAK inhibition with ruxolitinib attenuated myeloproliferative neoplasm in Nf1-deficient mice. Finally, we found that primary cells from a patient with KRAS-mutant juvenile myelomonocytic leukemia displayed reduced colony formation in response to JAK2 inhibition. Our findings establish a central role for STAT5 activation in the pathogenesis of juvenile myelomonocytic leukemia and suggest that targeting this pathway may be of clinical utility in these patients.

  17. Increased intrahepatic quasispecies heterogeneity correlates with off-treatment sustained response to nucleos(t)ide analogues in e antigen-positive chronic hepatitis B patients.

    PubMed

    Chen, L; Gan, Q R; Zhang, D Q; Yao, L F; Lin, R S; Li, Q; Lin, M H; Yu, D M; Zhang, X X; Pan, C

    2016-02-01

    Finite treatment with nucleos(t)ide analogues (NAs) remains a great challenge for chronic hepatitis B in the clinic. This study aimed to investigate the relationship between intrahepatic quasispecies heterogeneity and the NAs off-treatment outcomes in a prospective cohort. Eighteen HBeAg-positive patients with chronic hepatitis B who achieved the cessation criteria underwent liver biopsy, and stopped treatment thereafter. Patients were followed up prospectively for 1 year. The reverse transcriptase (RT) gene of intrahepatic hepatitis B virus (HBV) was cloned and sequenced. Intrahepatic quasispecies heterogeneity and specific gene mutations were analysed using bioinformatic methods. Ten patients achieved sustained response, and eight patients developed viral relapse. The intrahepatic quasispecies Shannon entropy and nucleotide diversity within either RT or the surface (S) region of patients with sustained response were significantly higher (p < 0.05) than those of patients who had a viral relapse. Intrahepatic quasispecies Shannon entropy at the nucleotide level predicted the sustained off-treatment response (area under receiver operating characteristics curve 0.925; 95% CI 0.807-1.000; p 0.003). More positive selection sites and N-glycosylation mutations within the S region were found in patients with sustained response than in the patients with viral relapse (p < 0.01). Most of the positive selection sites in patients with sustained response were located in reported HLA-I-restricted or HLA-II-restricted epitopes. Intrahepatic quasispecies heterogeneity at the end of treatment was correlated with off-treatment outcomes in HBeAg-positive patients with chronic hepatitis B. More immune escape mutations were found within the S region in patients with sustained response. The higher intrahepatic quasispecies heterogeneity indicated a more robust immune control over HBV, which in turn maintained a sustained response after withdrawal of NAs.

  18. Cueing, demand fading, and positive reinforcement to establish self-feeding and oral consumption in a child with chronic food refusal.

    PubMed

    Luiselli, J K

    2000-07-01

    A 3-year-old child with multiple medical disorders and chronic food refusal was treated successfully using a program that incorporated antecedent control procedures combined with positive reinforcement. The antecedent manipulations included visual cueing of a criterion number of self-feeding responses that were required during meals to receive reinforcement and a gradual increase in the imposed criterion (demand fading) that was based on improved frequency of oral consumption. As evaluated in a changing criterion design, the child learned to feed himself as an outcome of treatment. One year following intervention, he was consuming a variety of foods and had gained weight. Advantages of antecedent control methods for the treatment of chronic food refusal are discussed.

  19. Positive patch- and photopatch-test reactions to methylene bis-benzotriazolyl tetramethylbutylphenol in patients with both atopic dermatitis and chronic actinic dermatitis.

    PubMed

    Gonzalez, Mercedes E; Soter, Nicholas A; Cohen, David E

    2011-01-01

    Ultraviolet filters are the most common topical photoallergens. Although currently not available on the US market, methylene bis-benzotriazolyl tetramethylbutylphenol (referred to as bisoctrizole on product labels) represents a new class of UV filters that have both organic and inorganic properties and are widely available in different preparations in Europe, South America, and Asia. We report two patients with atopic dermatitis and chronic actinic dermatitis who had positive patch- and photopatch-test reactions, which suggested both an allergic contact and a photoallergic contact dermatitis from bisoctrizole. Neither patient could identify previous or current contact with the chemical; nonetheless, it is possible that either the allergic contact or photoallergic contact dermatitis from bisoctrizole led to their chronic actinic dermatitis.

  20. ADIPOSITY-BASED CHRONIC DISEASE AS A NEW DIAGNOSTIC TERM: THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT.

    PubMed

    Mechanick, Jeffrey I; Hurley, Daniel L; Garvey, W Timothy

    2017-03-01

    The American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) have created a chronic care model, advanced diagnostic framework, clinical practice guidelines, and clinical practice algorithm for the comprehensive management of obesity. This coordinated effort is not solely based on body mass index as in previous models, but emphasizes a complications-centric approach that primarily determines therapeutic decisions and desired outcomes. Adiposity-Based Chronic Disease (ABCD) is a new diagnostic term for obesity that explicitly identifies a chronic disease, alludes to a precise pathophysiologic basis, and avoids the stigmata and confusion related to the differential use and multiple meanings of the term "obesity." Key elements to further the care of patients using this new ABCD term are: (1) positioning lifestyle medicine in the promotion of overall health, not only as the first algorithmic step, but as the central, pervasive action; (2) standardizing protocols that comprehensively and durably address weight loss and management of adiposity-based complications; (3) approaching patient care through contextualization (e.g., primordial prevention to decrease obesogenic environmental risk factors and transculturalization to adapt evidence-based recommendations for different ethnicities, cultures, and socio-economics); and lastly, (4) developing evidence-based strategies for successful implementation, monitoring, and optimization of patient care over time. This AACE/ACE blueprint extends current work and aspires to meaningfully improve both individual and population health by presenting a new ABCD term for medical diagnostic purposes, use in a complications-centric management and staging strategy, and precise reference to the obesity chronic disease state, divested from counterproductive stigmata and ambiguities found in the general public sphere. AACE = American Association of Clinical Endocrinologists ABCD = Adiposity

  1. The effect of a cellulose dressing and topical vancomycin on methicillin-resistant Staphylococcus aureus (MRSA) and Gram-positive organisms in chronic wounds: a case series.

    PubMed

    Albaugh, Karen W; Biely, Scott A; Cavorsi, Joseph P

    2013-05-01

    High levels of persistent bacteria may contribute to wound chronicity and delayed healing. A prospective study was conducted to: 1) evaluate the effect of applying vancomycin topically on appropriately cultured chronic lower leg wounds, specifically methicillin-resistant Staphylococcus aureus (MRSA) and Gram-positive bacteria, and 2) evaluate its effect in combination with a cellulose dressing on healing. Twenty-three (23) outpatients (11 men, 12 women, average age 65 years [range 39-89 years]) with lower extremity wounds (15 venous ulcers, six chronic open wounds with a history of diabetes, and two chronic open trauma wounds) averaging 43.58 weeks' (range 5-121 weeks) duration and swab-cultured positive for MRSA or Gram-positive bacteria were provided 1 g vancomycin delivered by a cellulose dressing and changed every 72 hours. Patients served as their own control, and all wounds were debrided once a week. Wound surface area and bacterial and exudate levels were recorded weekly during the 3-week pretreatment period and compared to 3-week treatment period levels. Patients were followed until healed. Mean change in wound surface area was +14.5% (SD 71.91) per week before and -24.6% (SD 13.59) during the vancomycin treatment period (P = 0.014), average exudate levels decreased from 2.75 (range 1-4) to 1.81 (range 0-3) (P = 0.016), and the number of patients with positive wound cultures for MRSA or Gram-positive bacteria decreased from 23 to four after the 3-week study period. All wounds healed after an average of 8.18 weeks (SD 4.76, range 2-17 weeks). The results of this study suggest topical vancomycin applied using a dressing that retains moisture reduces wound bacterial load and may facilitate healing. Randomized, controlled clinical studies to evaluate the effectiveness and efficacy of this treatment modality and explore the relationship between wound culture results and healing are warranted.

  2. Acute myelomonocytic leukemia with inv(16)(p13q22) complicating Philadelphia chromosome positive chronic myeloid leukemia.

    PubMed

    Heim, S; Christensen, B E; Fioretos, T; Sørensen, A G; Pedersen, N T

    1992-03-01

    The reciprocal translocation (9;22)(q34;q11) is highly characteristic of chronic myeloid leukemia (CML) and the pericentric inversion inv(16)(p13q22) is almost only found in acute nonlymphocytic leukemia of the myelomonocytic subtype (ANLL M4). Only twice before have an inv(16) and a t(9;22) been found in the same cells, and both times the patients seemed to have de novo ANLL M4. We describe the case of a 21-year-old man who in July 1986 presented with a clinically and hematologically classic chronic phase CML. Treatment with busulfan led to no improvement; instead in September 1986 he developed blast crisis with ANLL M4Eo morphology. He was now cytogenetically examined and the karyotype 45,X,-Y,t(9;22)(q34;q11),inv(16)(p13q22) was found. Southern blot analysis of the bone marrow DNA sampled at this time revealed a standard rearrangement in the 3' end of the M-bcr. Intensive cytostatic treatment caused cytopenia followed by complete hematologic, clinical, and cytogenetic reversal to chronic phase CML, so that in January 1987 the bone marrow karyotype was 46,XY,t(9;22)(q34;q11). Persistent splenomegaly was treated with splenectomy, and a chloroma of the skin was removed by irradiation. In March 1987 he received an allogeneic bone marrow transplant. Since then his only medical problem has been mild graft-versus-host disease; he is well and is working full time as a blacksmith.

  3. Philadelphia-positive T-cell acute lymphoblastic leukemia with polymyositis, migratory polyarthritis and hypercalcemia following a chronic myeloid leukemia.

    PubMed

    Lima, M; Coutinho, J; Bernardo, L; dos Anjos Teixeira, M; Casais, C; Canelhas, A; Queirós, L; Orfão, A; Justiça, B

    2002-03-01

    Transformation of chronic myeloid leukemia (CML) often results in acute myeloblastic or, less frequently, in precursor B-cell acute lymphoblastic leukemia (ALL). T-cell blast crisis is rare. Hypercalcemia has also been described as a rare complication of CML, but this usually occurs as a terminal event. Here we report a case of a 35-year-old woman who developed a CD4(+)/CD8(+) T-cell ALL 2 years after the diagnosis of a typical Ph(+) CML. Polymyositis and polyarthritis preceded by 4 months, and symptomatic hypercalcemia occurred just before blastic transformation, probably representing paraneoplastic manifestations of the disease.

  4. [Postoperative bed header position after burr-hole drainage of chronic subdural haematoma: systematic review and meta-analysis of randomised controlled trials].

    PubMed

    Alcalá-Cerra, Gabriel; Moscote-Salazar, Luis Rafael; Paternina-Caicedo, Ángel; Gutiérrez-Paternina, Juan José; Niño-Hernández, Lucía M; Sabogal-Barrios, Rubén

    2014-01-01

    Several studies have suggested the possible influence of postoperative bed header position on the risk of symptomatic recurrences and medical complications in patients who have been intervened due chronic subdural haematomas. Nevertheless, this hypothesis has not been assessed by a meta-analysis. All randomised controlled trials analysing symptomatic recurrence rates in patients who underwent burr-hole drainage of chronic subdural haematomas, describing postoperative bed header positioning, were included. The primary outcome was risk of recurrence and the secondary outcome were the risks of reoperation and medical complications. Results were presented as pooled relative risks, with 95% confidence intervals. A total of 4 controlled studies were included. Pooled relative risks were: symptomatic recurrences 0.51 ([95% CI: 0.22-1.16]; P=.11), reoperations, 1.07 ([95% CI: 0.42-2.69]; P=.89) and medical complications, 1.15 ([95% CI: 0.7-1.91]; P=.58). No statistically significant heterogeneity was found in any of the analyses. There were no differences regarding frequency of symptomatic recurrences, reoperations or medical complications in patients who were maintained in a flat position compared with those whose bed header was elevated during the postoperative course. Despite there being consistency between the results, there is a potential risk of bias; thus proscribing definitive recommendations until studies with higher methodological quality are available. Copyright © 2013 Sociedad Española de Neurocirugía. Published by Elsevier España. All rights reserved.

  5. Correlation of motor control in the supine position and assistive device used for ambulation in chronic incomplete spinal cord-injured persons.

    PubMed

    Tang, S F; Tuel, S M; McKay, W B; Dimitrijevic, M R

    1994-01-01

    Neurocontrol of movement after spinal cord injury (SCI) is often spared, but few studies have investigated the chronic incomplete SCI patient. Multichannel surface electromyography (SEMG) can describe characteristics of neurocontrol during a series of volitional and reflex events. The relationship of these neurocontrol characteristics to clinical function is incompletely described. This study, retrospectively, evaluated the relationship between neurocontrol patterns evoked by lower limb movement in the supine position and the assistive device used for ambulation in chronic, incomplete SCI persons. The records of 15 neurologically healthy (9 male, 6 female) and 36 incomplete SCI persons (27 male, 9 female) (C2-T10) were used. SEMG was recorded from both quadriceps, adductors, hamstrings, anterior tibialis and triceps surae muscles and displayed on a stripchart for analysis. SEMG patterns of activity recorded in the supine position during volitional, unilateral, multijoint (hip and knee flexion and extension) movement attempts were characterized, divided into seven groups and compared with the subjects' self-selected ambulation device (independent, cane, crutches, walker or nonambulatory). The neurocontrol patterns recorded in the supine position correlated well with the SCI subjects ambulatory assistive device. Marked decreases in motor unit output and/or loss of motor organization were found in the nonambulatory group. Coactivation of proximal muscles, poor timing of muscle activity and radiation of activity into contralateral muscles were also noted in subjects who required a walker or crutches. To a lesser degree, abnormal motor patterns were also noted in subjects who ambulated with a cane or independently.

  6. Self-Management and Quality of Life in Chronic Obstructive Pulmonary Disease (COPD): The Mediating Effects of Positive Affect

    PubMed Central

    Benzo, Roberto P.; Abascal-Bolado, Beatriz; Dulohery, Megan M.

    2015-01-01

    Objective This study aimed to increase our understanding of general self-management (SM) abilities in COPD by determining if SM can predict disease specific quality of life (QoL), by investigating whether specific SM domains are significant in COPD and by exploring the mediating effect of the positive/negative affect in the association between SM and QoL. Methods Cross-sectional study based on 292 patients with COPD. Measures included demographics, lung function, gait speed, health care utilization, positive/negative affect, SM abilities, breathlessness and disease specific QoL. We performed, correlation, multiple regression models and mediation analysis (positive/negative affect being mediator between SM and QoL association). Results After controlling for breathlessness, living alone, marital status, hospitalization history, age and lung function, SM related to QoL (p< 0.0001). Investment in behaviors (hobbies and social relationships) and self-efficacy are SM domains independently related to QoL in COPD. Positivity measured by the positive/negative affect ratio completely mediates the relationship of SM with QoL. Conclusion SM is independently associated with disease specific QoL in COPD after adjustment significant covariates but positive/negative affect ratio completely mediates the relationship of SM with QoL. Practice implications Measuring positive/negative affect and addressing investment behavior and self-efficacy are important in implementing COPD-SM programs. PMID:26632024

  7. Self-management and quality of life in chronic obstructive pulmonary disease (COPD): The mediating effects of positive affect.

    PubMed

    Benzo, Roberto P; Abascal-Bolado, Beatriz; Dulohery, Megan M

    2016-04-01

    This study aimed to increase our understanding of general self-management (SM) abilities in COPD by determining if SM can predict disease specific quality of life (QoL), by investigating whether specific SM domains are significant in COPD and by exploring the mediating effect of the positive/negative affect in the association between SM and QoL. Cross-sectional study based on 292 patients with COPD. Measures included demographics, lung function, gait speed, health care utilization, positive/negative affect, SM abilities, breathlessness and disease specific QoL. We performed, correlation, multiple regression models and mediation analysis (positive/negative affect being mediator between SM and QoL association). After controlling for breathlessness, living alone, marital status, hospitalization history, age and lung function, SM related to QoL (p<0.0001). Investment in behaviors (hobbies and social relationships) and self-efficacy are SM domains independently related to QoL in COPD. Positivity measured by the positive/negative affect ratio completely mediates the relationship of SM with QoL. SM is independently associated with disease specific QoL in COPD after adjustment significant covariates but positive/negative affect ratio completely mediates the relationship of SM with QoL. Measuring positive/negative affect and addressing investment behavior and self-efficacy are important in implementing COPD-SM programs. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  8. Temsirolimus and Imatinib Mesylate in Treating Patients With Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2013-01-11

    Accelerated Phase Chronic Myelogenous Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Chronic Phase Chronic Myelogenous Leukemia; Relapsing Chronic Myelogenous Leukemia

  9. Nilotinib first-line therapy in patients with Philadelphia chromosome-negative/BCR-ABL-positive chronic myeloid leukemia in chronic phase: ENEST1st sub-analysis.

    PubMed

    Hochhaus, Andreas; Mahon, Franҫois-Xavier; le Coutre, Philipp; Petrov, Ljubomir; Janssen, Jeroen J W M; Cross, Nicholas C P; Rea, Delphine; Castagnetti, Fausto; Hellmann, Andrzej; Rosti, Gianantonio; Gattermann, Norbert; Coronel, Maria Liz Paciello; Gutierrez, Maria Asuncion Echeveste; Garcia-Gutierrez, Valentin; Vincenzi, Beatrice; Dezzani, Luca; Giles, Francis J

    2017-07-01

    The ENEST1st sub-analysis presents data based on Philadelphia chromosome (Ph) status, i.e., Ph+ and Ph-/BCR-ABL1 + chronic myeloid leukemia. Patients received nilotinib 300 mg twice daily, up to 24 months. At screening, 983 patients were identified as Ph+ and 30 patients as Ph-/BCR-ABL + based on cytogenetic and RT-PCR assessment; 76 patients had unknown karyotype (excluded from this sub-analysis). In the Ph-/BCR-ABL1 + subgroup, no additional chromosomal aberrations were reported. In the Ph+ subgroup, 952 patients had safety and molecular assessments. In the Ph-/BCR-ABL1 + subgroup, 30 patients had safety assessments and 28 were followed up for molecular assessments. At 18 months, the molecular response (MR) 4 rate [MR(4); BCR-ABL1 ≤0.01% on International Scale (IS)] was similar in the Ph-/BCR-ABL1+ (39.3%) and Ph+ subgroups (38.1%). By 24 months, the cumulative rates of major molecular response (BCR-ABL1(IS) ≤0.1%;), MR(4), and MR(4.5) (BCR-ABL1(IS) ≤0.0032%) were 85.7, 60.7, and 50.0%, respectively, in the Ph-/BCR-ABL1 + subgroup, and 80.3, 54.7, and 38.3%, respectively, in the Ph+ subgroup. In both Ph-/BCR-ABL1 + and Ph+ subgroups, rash (20 and 22%), pruritus (16.7 and 16.7%), nasopharyngitis (13.3 and 10.4%), fatigue (10 and 14.2%), headache (10 and 15.8%), and nausea (6.7 vs 11.4%) were frequent non-hematologic adverse events, whereas hypophosphatemia (23.3 and 6.8%), anemia (10 and 6.5%), and thrombocytopenia (3.3 and 10.2%) were the common hematologic/biochemical laboratory events. Based on similar molecular response and safety results in both subgroups, we conclude that Ph-/BCR-ABL1 + patients benefit from nilotinib in the same way as Ph+ patients.

  10. [Differential diagnosis of chronic myeloic leucemia in infancy (author's transl)].

    PubMed

    Binder, C; Pichler, E; Radaskiewicz, T; Scheibenreiter, S

    1976-01-01

    A 3 months old girl presented with significant enlargement of liver, spleen and lymphnodes, with moderate anemia, thrombopenia and leucocytosis. In the differential count there was a shift to the left and an increase of monocyte-like cells (35%). Differential diagnosis included leucemoid reaction, infectious mononucleosis, myelo-proliferative disorder with a missing C chromosome and chronic myeloid leucemia. Clinical symptoms, cytochemistry and caryotype of bone marrow cells suggested infantile chronic myeloic leucemia and normal ALP index and possibly normal HbF. Treatment with 6-mercaptopurine was followed by partial remission. The therapeutic consequences of exact differential diagnosis are discussed.

  11. Hypercalcemia as the presenting feature of t-cell lymphoid blast crisis of ph-positive chronic myeloid leukemia.

    PubMed

    Nadal, E; Cervantes, F; Rosiñol, L; Talarn, C; Montserrat, E

    2001-03-01

    Hypercalcemia is a rare complication of chronic myeloid leukemia (CML), usually seen in the accelerated or blastic phases of the disease and associated with a poor prognosis. T-cell lymphoid phenotype is also an infrequent finding in the blast crisis (BC) of CML. A CML patient who had hypercalcemia as the presenting feature of a T-cell BC is reported. She was a 78 year-old woman who, at four months of CML diagnosis, developed weakness, bone pain, and mental confusion, with hypercalcemia being subsequently found. Although the peripheral blood and bone marrow were consistent with the chronic phase of CML, mediastinal enlargement, a soft tissue mass adjacent to the iliac bone, and multiple osteolytic lesions were seen. Serum levels of parathyroid hormone (PTH) and PTH-related peptide were normal, whereas the search for a second neoplasm was negative. The hypercalcemia initially responded to conventional treatment, but it reappeared two weeks later. Coincidentally, a high proportion of blast cells of T-cell origin at the cortical thymocyte stage were observed in the patient's peripheral blood and bone marrow, and she died shortly afterwards.

  12. Differences and similarities in the trajectories of self-esteem and positive and negative affect in persons with chronic illness: an explorative longitudinal study.

    PubMed

    Bonsaksen, Tore; Lerdal, Anners; Småstuen, Milada Cvancarova; Fagermoen, May Solveig

    2016-01-01

    Chronic illness is a risk factor for low self-esteem, and the research literature needs to include more studies of self-esteem and its development in chronic illness groups using longitudinal and comparative designs. The aim of this study was to explore the trajectories of self-esteem and of positive and negative affect in persons with morbid obesity and in persons with chronic obstructive pulmonary disease (COPD). Patient education course attendants in Norway having morbid obesity (n=139) or COPD (n=97) participated in the study. Data concerning self-esteem, positive and negative affect, and sociodemographic background were collected at the start and at the end of the patient education, with subsequent follow-ups at 3, 6, and 12 months. Data were analyzed using linear mixed models for repeated measures. Taking all measurements into account, our data revealed a statistically significant increase in self-esteem for participants with morbid obesity but not for those with COPD. There were no significant differences in levels of negative and positive affect between the two groups, and the time-trajectories were also similar. However, participants in both groups achieved lower levels of negative affect for all the successive measurement points. An increase in self-esteem during the first year after the patient education course was observed for persons with morbid obesity, but not for persons with COPD. Initial higher levels of self-esteem in the participants with COPD may indicate that they are less troubled with low self-esteem than people with morbid obesity are. The pattern of reduced negative affect for both groups during follow-up is promising.

  13. Differences and similarities in the trajectories of self-esteem and positive and negative affect in persons with chronic illness: an explorative longitudinal study

    PubMed Central

    Bonsaksen, Tore; Lerdal, Anners; Småstuen, Milada Cvancarova; Fagermoen, May Solveig

    2016-01-01

    Background Chronic illness is a risk factor for low self-esteem, and the research literature needs to include more studies of self-esteem and its development in chronic illness groups using longitudinal and comparative designs. The aim of this study was to explore the trajectories of self-esteem and of positive and negative affect in persons with morbid obesity and in persons with chronic obstructive pulmonary disease (COPD). Methods Patient education course attendants in Norway having morbid obesity (n=139) or COPD (n=97) participated in the study. Data concerning self-esteem, positive and negative affect, and sociodemographic background were collected at the start and at the end of the patient education, with subsequent follow-ups at 3, 6, and 12 months. Data were analyzed using linear mixed models for repeated measures. Results Taking all measurements into account, our data revealed a statistically significant increase in self-esteem for participants with morbid obesity but not for those with COPD. There were no significant differences in levels of negative and positive affect between the two groups, and the time-trajectories were also similar. However, participants in both groups achieved lower levels of negative affect for all the successive measurement points. Conclusion An increase in self-esteem during the first year after the patient education course was observed for persons with morbid obesity, but not for persons with COPD. Initial higher levels of self-esteem in the participants with COPD may indicate that they are less troubled with low self-esteem than people with morbid obesity are. The pattern of reduced negative affect for both groups during follow-up is promising. PMID:27574438

  14. Aberrant let7a/HMGA2 signaling activity with unique clinical phenotype in JAK2-mutated myeloproliferative neoplasms

    PubMed Central

    Chen, Chih-Cheng; You, Jie-Yu; Lung, Jrhau; Huang, Cih-En; Chen, Yi-Yang; Leu, Yu-Wei; Ho, Hsing-Ying; Li, Chian-Pei; Lu, Chang-Hsien; Lee, Kuan-Der; Hsu, Chia-Chen; Gau, Jyh-Pyng

    2017-01-01

    High mobility group AT-hook 2 (HMGA2) is an architectural transcription factor that is negatively regulated by let-7 microRNA through binding to it’s 3′-untranslated region. Transgenic mice expressing Hmga2 with a truncation of its 3′-untranslated region has been shown to exhibit a myeloproliferative phenotype. To decipher the let-7-HMGA2 axis in myeloproliferative neoplasms, we employed an in vitro model supplemented with clinical correlation. Ba/F3 cells with inducible JAK2V617F expression (Ton.JAK2.V617F cells) showed upregulation of HMGA2 with concurrent let-7a repression. Ton.JAK2.V617F cells treated with a let-7a inhibitor exhibited further escalation of Hmga2 expression, while a let-7a mimic diminished the Hmga2 transcript level. Hmga2 overexpression conferred JAK2-mutated cells with a survival advantage through inhibited apoptosis. A pan-JAK inhibitor, INC424, increased the expression of let-7a, downregulated the level of Hmga2, and led to increased apoptosis in Ton.JAK2.V617F cells in a dose-dependent manner. In samples from 151 patients with myeloproliferative neoplasms, there was a modest inverse correlation between the expression levels of let-7a and HMGA2. Overexpression of HMGA2 was detected in 29 (19.2%) of the cases, and it was more commonly seen in patients with essential thrombocythemia than in those with polycythemia vera (26.9% vs. 12.7%, P=0.044). Patients with upregulated HMGA2 showed an increased propensity for developing major thrombotic events, and they were more likely to harbor one of the 3 driver myeloproliferative neoplasm mutations in JAK2, MPL and CALR. Our findings suggest that, in a subset of myeloproliferative neoplasm patients, the let-7-HMGA2 axis plays a prominent role in the pathogenesis of the disease that leads to unique clinical phenotypes. PMID:28057739

  15. Diversity of breakpoints of variant Philadelphia chromosomes in chronic myeloid leukemia in Brazilian patients

    PubMed Central

    Chauffaille, Maria de Lourdes Lopes Ferrari; Bandeira, Ana Carolina de Almeida; da Silva, Aline Schiavoni Guarnieri

    2014-01-01

    Background Chronic myeloid leukemia is a myeloproliferative disorder characterized by the Philadelphia chromosome or t(9;22)(q34.1;q11.2), resulting in the break-point cluster region-Abelson tyrosine kinase fusion gene, which encodes a constitutively active tyrosine kinase protein. The Philadelphia chromosome is detected by karyotyping in around 90% of chronic myeloid leukemia patients, but 5–10% may have variant types. Variant Philadelphia chromosomes are characterized by the involvement of another chromosome in addition to chromosome 9 or 22. It can be a simple type of variant when one other chromosome is involved, or complex, in which two or more chromosomes take part in the translocation. Few studies have reported the incidence of variant Philadelphia chromosomes or the breakpoints involved among Brazilian chronic myeloid leukemia patients. Objective The aim of this report is to describe the diversity of the variant Philadelphia chromosomes found and highlight some interesting breakpoint candidates for further studies. Methods the Cytogenetics Section Database was searched for all cases with diagnoses of chronic myeloid leukemia during a 12-year period and all the variant Philadelphia chromosomes were listed. Results Fifty (5.17%) cases out of 1071 Philadelphia-positive chronic myeloid leukemia were variants. The most frequently involved chromosome was 17, followed by chromosomes: 1, 20, 6, 11, 2, 10, 12 and 15. Conclusion Among all the breakpoints seen in this survey, six had previously been described: 11p15, 14q32, 15q11.2, 16p13.1, 17p13 and 17q21. The fact that some regions get more frequently involved in such rare rearrangements calls attention to possible predisposition that should be further studied. Nevertheless, the pathological implication of these variants remains unclear. PMID:25638762

  16. Vimentin-positive astrocytes in canine distemper: a target for canine distemper virus especially in chronic demyelinating lesions?

    PubMed

    Seehusen, Frauke; Orlando, Enzo A; Wewetzer, Konstantin; Baumgärtner, Wolfgang

    2007-12-01

    In canine distemper demyelinating leukoencephalitis (DL), caused by canine distemper virus (CDV), astrocytes represent the main virus target. In these cells, glial fibrillary acidic protein (GFAP) is the main intermediate filament, whereas vimentin occurs early in the astrocytic lineage and is replaced gradually by GFAP. To further characterize the role of astrocytic infection in dogs with DL, an animal model for multiple sclerosis, formalin-fixed paraffin-embedded cerebella were investigated immunohistochemically and by immunofluorescence. The expression and morphological alterations of these intermediate filaments were also determined by immunofluorescence studies of CDV-infected canine mixed brain cell cultures. In acute distemper lesions, the astrocytic response was mainly composed of GFAP- and CDV-positive cells. In contrast, vimentin-positive astrocyte-like cells were present in advanced lesions, which represented the main cell type harboring the pathogen, indicating a change in cell tropism and/or susceptibility of glial cells during lesion progression in CDV encephalomyelitis. Canine cell cultures were composed of GFAP-positive astrocytes, vimentin-positive cells and other glial cells. Following infection with the CDV-R252 strain, GFAP-positive astrocytes, especially multinucleated syncytial giant cells, displayed a disrupted cytoskeleton, whereas vimentin-positive cells though more frequently infected did not show any alteration in the filament network. This indicates increased vulnerability of mature GFAP-positive astrocytes compared to immature, vimentin-positive astrocytes. The latter, however, exhibited increased susceptibility to CDV. To conclude, the present findings indicate a change in cell tropism of CDV and/or the occurrence of less differentiated astrocytes representing a permanent source for virus infection and spread in advanced lesions of DL.

  17. Happy Despite Pain: A Randomized Controlled Trial of an 8-Week Internet-delivered Positive Psychology Intervention for Enhancing Well-being in Patients With Chronic Pain.

    PubMed

    Peters, Madelon L; Smeets, Elke; Feijge, Marion; van Breukelen, Gerard; Andersson, Gerhard; Buhrman, Monica; Linton, Steven J

    2017-11-01

    There is preliminary evidence for the efficacy of positive psychology interventions for pain management. The current study examined the effects of an internet-based positive psychology self-help program for patients with chronic musculoskeletal pain and compared it with an internet-based cognitive-behavioral program. A randomized controlled trial was carried out with 3 conditions: an internet-delivered positive psychology program, an internet-delivered cognitive-behavioral program and waitlist control. A total of 276 patients were randomized to 1 of the 3 conditions and posttreatment data were obtained from 206 patients. Primary outcomes were happiness, depression, and physical impairments at posttreatment and at 6-month follow-up. Intention-to-treat analyses were carried out using mixed regression analyses. Both treatments led to significant increases in happiness and decreases in depression. Physical impairments did not significantly decrease compared with waitlist. Improvements in happiness and depression were maintained until 6-month follow-up. There were no overall differences in the efficacy of the 2 active interventions but effects seemed to be moderated by education. Patients with a higher level of education profited slightly more from the positive psychology intervention than from the cognitive-behavioral program. The results suggest that an internet-based positive psychology and cognitive-behavioral self-help interventions for the management of chronic pain are clinically useful. Because the self-help exercises as used in the current program do not require therapist involvement, dissemination potential is large. Further studies should examine whether it can best be used as stand-alone or add-on treatment combined with established pain treatment programs.

  18. DNA repair genes polymorphisms and genetic susceptibility to Philadelphia-negative myeloproliferative neoplasms in a Portuguese population: The role of base excision repair genes polymorphisms.

    PubMed

    Azevedo, Ana P; Silva, Susana N; De Lima, João P; Reichert, Alice; Lima, Fernando; Júnior, Esmeraldina; Rueff, José

    2017-06-01

    The role of base excision repair (BER) genes in Philadelphia-negative (PN)-myeloproliferative neoplasms (MPNs) susceptibility was evaluated by genotyping eight polymorphisms [apurinic/apyrimidinic endodeoxyribonuclease 1, mutY DNA glycosylase, earlier mutY homolog (E. coli) (MUTYH), 8-oxoguanine DNA glycosylase 1, poly (ADP-ribose) polymerase (PARP) 1, PARP4 and X-ray repair cross-complementing 1 (XRCC1)] in a case-control study involving 133 Caucasian Portuguese patients. The results did not reveal a correlation between individual BER polymorphisms and PN-MPNs when considered as a whole. However, stratification for essential thrombocythaemia revealed i) borderline effect/tendency to increased risk when carrying at least one variant allele for XRCC1_399 single-nucleotide polymorphism (SNP); ii) decreased risk for Janus kinase 2-positive patients carrying at least one variant allele for XRCC1_399 SNP; and iii) decreased risk in females carrying at least one variant allele for MUTYH SNP. Combination of alleles demonstrated an increased risk to PN-MPNs for one specific haplogroup. These findings may provide evidence for gene variants in susceptibility to MPNs. Indeed, common variants in DNA repair genes may hamper the capacity to repair DNA, thus increasing cancer susceptibility.

  19. DNA repair genes polymorphisms and genetic susceptibility to Philadelphia-negative myeloproliferative neoplasms in a Portuguese population: The role of base excision repair genes polymorphisms

    PubMed Central

    Azevedo, Ana P.; Silva, Susana N.; De Lima, João P.; Reichert, Alice; Lima, Fernando; Júnior, Esmeraldina; Rueff, José

    2017-01-01

    The role of base excision repair (BER) genes in Philadelphia-negative (PN)-myeloproliferative neoplasms (MPNs) susceptibility was evaluated by genotyping eight polymorphisms [apurinic/apyrimidinic endodeoxyribonuclease 1, mutY DNA glycosylase, earlier mutY homolog (E. coli) (MUTYH), 8-oxoguanine DNA glycosylase 1, poly (ADP-ribose) polymerase (PARP) 1, PARP4 and X-ray repair cross-complementing 1 (XRCC1)] in a case-control study involving 133 Caucasian Portuguese patients. The results did not reveal a correlation between individual BER polymorphisms and PN-MPNs when considered as a whole. However, stratification for essential thrombocythaemia revealed i) borderline effect/tendency to increased risk when carrying at least one variant allele for XRCC1_399 single-nucleotide polymorphism (SNP); ii) decreased risk for Janus kinase 2-positive patients carrying at least one variant allele for XRCC1_399 SNP; and iii) decreased risk in females carrying at least one variant allele for MUTYH SNP. Combination of alleles demonstrated an increased risk to PN-MPNs for one specific haplogroup. These findings may provide evidence for gene variants in susceptibility to MPNs. Indeed, common variants in DNA repair genes may hamper the capacity to repair DNA, thus increasing cancer susceptibility. PMID:28599464

  20. Signal Transduction in the Chronic Leukemias: Implications for Targeted Therapies

    PubMed Central

    Ahmed, Wesam; Van Etten, Richard A.

    2013-01-01

    The chronic leukemias, including chronic myeloid leukemia (CML), the Philadelphia-negative myeloproliferative neoplasms (MPNs), and chronic lymphocytic leukemia (CLL), have been characterized extensively for abnormalities of cellular signaling pathways. This effort has led to the elucidation of the central role of dysregulated tyrosine kinase signaling in the chronic myeloid neoplasms and of constitutive B-cell receptor signaling in CLL. This, in turn, has stimulated the development of small molecule inhibitors of these signaling pathways for therapy of chronic leukemia. Although the field is still in its infancy, the clinical results with these agents have ranged from encouraging (CLL) to spectacular (CML). In this review, we summarize recent studies that have helped to define the signaling pathways critical to the pathogenesis of the chronic leukemias. We also discuss correlative studies emerging from clinical trials of drugs targeting these pathways. PMID:23307472

  1. Deficits in the extinction of ethanol-seeking behavior following chronic intermittent ethanol exposure are attenuated with positive allosteric modulation of mGlu5.

    PubMed

    Gass, J T; McGonigal, J T; Chandler, L J

    2017-02-01

    Alcoholism is a chronic relapsing disorder characterized by periods of heavy alcohol consumption and unsuccessful attempts at abstinence. Relapse is one of the most problematic aspects in the treatment of alcoholism and is triggered by ethanol-associated cues. Extinction-based cue exposure therapies have proven ineffective in the treatment of alcoholism. However, positive allosteric modulation of mGlu5 with CDPPB enhances the extinction learning of alcohol-seeking behavior. The current study investigated the impact of chronic alcohol exposure on the extinction of ethanol-seeking behavior. Adult Wistar rats were trained to self-administer alcohol with a light/tone stimulus serving as the alcohol cue. After training, one group of rats was exposed to chronic intermittent ethanol (CIE) daily for a period of 2 weeks to induce ethanol dependence. Control rats were exposed to air for the same period of time. Both groups were then retrained to self-administer ethanol and subsequently tested for changes in extinction learning. CIE exposed rats consumed more ethanol compared to their pre-CIE levels and to control rats. During extinction training, CIE rats responded significantly more on the previously active lever and required more sessions to reach extinction criteria compared to control rats. Treatment with CDPPB facilitated extinction in control rats and attenuated the increased resistance to extinction in CIE-exposed rats. These results demonstrate that chronic ethanol exposure not only alters ethanol intake, but also the extinction of ethanol-seeking behaviors. The ability to attenuate deficits through modulation of mGlu5 provides a potential target for pharmacological manipulation that could ultimately reduce relapse in alcoholics. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Ultrasound measurement of deep abdominal muscle activity in sitting positions with different stability levels in subjects with and without chronic low back pain.

    PubMed

    Rasouli, Omid; Arab, Amir Massoud; Amiri, Mohsen; Jaberzadeh, Shapour

    2011-08-01

    The purpose of this study was to investigate the changes in the thickness of the transversus abdominis (TrA) and internal oblique (IO) muscles in three sitting postures with different levels of stability. The technique of ultrasound imaging was used for individuals with and without chronic low back pain (LBP). A sample of 40 people participated in this study. Subjects were categorised into two groups: with LBP (N = 20) and without LBP (N = 20). Changes in the thickness of tested muscles were normalized under three different sitting postures to actual muscle thickness at rest in the supine lying position and were expressed as a percentage of thickness change. The percentage of thickness change in TrA and IO increased as the stability of the sitting position decreased in both groups. However, the percentages of thickness change in all positions were less in subjects with LBP. There was a significant difference in thickness change in TrA when sitting on a gym ball between subjects with and without LBP but no difference was found when sitting on a chair. There was no significant difference in thickness change in IO in all positions between the two groups. Our findings indicate that difference in the percentage of thickness change in TrA between subjects with and without LBP increases as the stability of sitting position decreases.

  3. Myeloproliferative disorders in patients with rheumatoid arthritis treated with total body irradiation

    SciTech Connect

    Urowitz, M.B.; Rider, W.D.

    1985-01-21

    Four patients with refractory rheumatoid arthritis were treated with total body irradiation administered in two sittings, 300 to 400 rads to each half of the body. All four patients had taken antimetabolites prior to receiving total body irradiation, and two continued to use them after total body irradiation. Two patients had taken alkylating agents before, and one had used them after total body irradiation. All patients showed clinical improvement. However, in two patients myeloproliferative disorders developed: a myelodysplastic preleukemia at 40 months after total body irradiation in one and acute myelogenous leukemia at 25 months in the other. Total body irradiation differs from total nodal irradiation in the total dose of irradiation (300 to 400 rads versus 2,000 to 3,000), and in the duration of the therapy (two sittings versus treatment over several weeks to months). Furthermore, the patients in the total body irradiation study frequently used cytotoxic drugs before and/or after irradiation, whereas in one total nodal irradiation study, azathioprine (2 mg/kg per day or less) was permitted, but no other cytotoxic agents were allowed. Rheumatologists may therefore face a binding decision when deciding to treat a patient with rheumatoid arthritis with either a cytotoxic drug or irradiation.

  4. The Mutation Profile of Calreticulin in Patients with Myeloproliferative Neoplasms and Acute Leukemia

    PubMed Central

    Wang, Jingyi; Hao, Jianguo; He, Na; Ji, Chunyan; Ma, Daoxin

    2016-01-01

    Objective: Calreticulin (CALR) plays important roles in cell proliferation, apoptosis, and immune responses. CALR mutations were described recently in Janus kinase 2 gene (JAK2)-negative or MPL-negative primary myelofibrosis (PMF) and essential thrombocythemia (ET) patients. CALR trails JAK2 as the second most mutated gene in myeloproliferative neoplasms (MPNs). However, little is known about CALR mutation in Chinese patients with leukemia. In the present study, a cohort of 305 Chinese patients with hematopoietic neoplasms was screened for CALR mutations, with the aim of uncovering the frequency of CALR mutations in leukemia and MPNs. Materials and Methods: Polymerase chain reaction and direct sequencing were performed to analyze mutations of CALR in 305 patients with hematopoietic malignancies, including 135 acute myeloid leukemia patients, 57 acute lymphoblastic leukemia patients, and 113 MPN patients. Results: CALR mutations were found in 10.6% (12 of 113) of samples from patients with MPNs. CALR mutations were determined in 11.3% (6 of 53), 21.7% (5 of 23), and 9.1% (1/11) of patients with ET, PMF, and unclassifiable MPN, respectively. Conclusion: We showed that MPN patients carrying CALR mutations presented with higher platelet counts and lower hemoglobin levels compared to those with mutated JAK2. However, all of the leukemia patients had negative results for CALR mutations. PMID:26377485

  5. Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms

    PubMed Central

    Jankowska, Anna M.; Szpurka, Hadrian; Tiu, Ramon V.; Makishima, Hideki; Afable, Manuel; Huh, Jungwon; O'Keefe, Christine L.; Ganetzky, Rebecca; McDevitt, Michael A.

    2009-01-01

    Chromosomal abnormalities are frequent in myeloid malignancies, but in most cases of myelodysplasia (MDS) and myeloproliferative neoplasms (MPN), underlying pathogenic molecular lesions are unknown. We identified recurrent areas of somatic copy number–neutral loss of heterozygosity (LOH) and deletions of chromosome 4q24 in a large cohort of patients with myeloid malignancies including MDS and related mixed MDS/MPN syndromes using single nucleotide polymorphism arrays. We then investigated genes in the commonly affected area for mutations. When we sequenced TET2, we found homozygous and hemizygous mutations. Heterozygous and compound heterozygous mutations were found in patients with similar clinical phenotypes without LOH4q24. Clinical analysis showed most TET2 mutations were present in patients with MDS/MPN (58%), including CMML (6/17) or sAML (32%) evolved from MDS/MPN and typical MDS (10%), suggesting they may play a ubiquitous role in malignant evolution. TET2 mutations affected conserved domains and the N terminus. TET2 is widely expressed in hematopoietic cells but its function is unknown, and it lacks homology to other known genes. The frequency of mutations in this candidate myeloid regulatory gene suggests an important role in the pathogenesis of poor prognosis MDS/MPN and sAML and may act as a disease gene marker for these often cytogenetically normal disorders. PMID:19372255

  6. Splanchnic vein thrombosis in myeloproliferative neoplasms: risk factors for recurrences in a cohort of 181 patients

    PubMed Central

    De Stefano, V; Vannucchi, A M; Ruggeri, M; Cervantes, F; Alvarez-Larrán, A; Iurlo, A; Randi, M L; Pieri, L; Rossi, E; Guglielmelli, P; Betti, S; Elli, E; Finazzi, M C; Finazzi, G; Zetterberg, E; Vianelli, N; Gaidano, G; Nichele, I; Cattaneo, D; Palova, M; Ellis, M H; Cacciola, E; Tieghi, A; Hernandez-Boluda, J C; Pungolino, E; Specchia, G; Rapezzi, D; Forcina, A; Musolino, C; Carobbio, A; Griesshammer, M; Barbui, T

    2016-01-01

    We retrospectively studied 181 patients with polycythaemia vera (n=67), essential thrombocythaemia (n=67) or primary myelofibrosis (n=47), who presented a first episode of splanchnic vein thrombosis (SVT). Budd–Chiari syndrome (BCS) and portal vein thrombosis were diagnosed in 31 (17.1%) and 109 (60.3%) patients, respectively; isolated thrombosis of the mesenteric or splenic veins was detected in 18 and 23 cases, respectively. After this index event, the patients were followed for 735 patient years (pt-years) and experienced 31 recurrences corresponding to an incidence rate of 4.2 per 100 pt-years. Factors associated with a significantly higher risk of recurrence were BCS (hazard ratio (HR): 3.03), history of previous thrombosis (HR: 3.62), splenomegaly (HR: 2.66) and leukocytosis (HR: 2.8). Vitamin K-antagonists (VKA) were prescribed in 85% of patients and the recurrence rate was 3.9 per 100 pt-years, whereas in the small fraction (15%) not receiving VKA more recurrences (7.2 per 100 pt-years) were reported. Intracranial and extracranial major bleeding was recorded mainly in patients on VKA and the corresponding rate was 2.0 per 100 pt-years. In conclusion, despite anticoagulation treatment, the recurrence rate after SVT in myeloproliferative neoplasms is high and suggests the exploration of new avenues of secondary prophylaxis with new antithrombotic drugs and JAK-2 inhibitors. PMID:27813534

  7. Cytogenetic correlates of TET2 mutations in 199 patients with myeloproliferative neoplasms

    PubMed Central

    Hussein, Kebede; Abdel-Wahab, Omar; Lasho, Terra L.; Van Dyke, Daniel L.; Levine, Ross L.; Hanson, Curtis A.; Pardanani, Animesh; Tefferi, Ayalew

    2015-01-01

    TET2 is a putative tumor suppressor gene located at chromosome 4q24. TET2 mutations were recently described in several myeloid neoplasms but correlations with cytogenetic findings have not been studied. Among a recently described cohort of patients with myeloproliferative neoplasms (MPN) who underwent TET2 mutation analysis, 199 had information on karyotype at diagnosis or time of TET2 testing: 71 polycythemia vera (PV), 55 primary myelofibrosis (PMF), 43 essential thrombocythemia (ET), 13 post-PV MF, 7 post-ET MF, and 10 blast phase MPN. Forty eight patients (24%) exhibited abnormal karyotype: 15 favorable (sole 20q-, 13q-, or +9), 8 unfavorable (complex karyotype or sole +8), and 25 “other” cytogenetic abnormalities. We found no significant difference either in the incidence or type of cytogenetic abnormalities between TET2 mutated (n = 25) and unmutated (n = 174) cases. Seventy nine patients, including 14 with TET2 mutations, underwent follow-up cytogenetic testing and the findings were again not affected by TET2 mutational status. We conclude that TET2 mutated MPN patients are not cytogenetically different than their TET2 unmutated counterparts. PMID:19957346

  8. PML-RARA can increase hematopoietic self-renewal without causing a myeloproliferative disease in mice

    PubMed Central

    Welch, John S.; Yuan, Wenlin; Ley, Timothy J.

    2011-01-01

    Acute promyelocytic leukemia (APL) is characterized by the t(15;17) translocation that generates the fusion protein promyelocytic leukemia–retinoic acid receptor α (PML-RARA) in nearly all cases. Multiple prior mouse models of APL constitutively express PML-RARA from a variety of non-Pml loci. Typically, all animals develop a myeloproliferative disease, followed by leukemia in a subset of animals after a long latent period. In contrast, human APL is not associated with an antecedent stage of myeloproliferation. To address this discrepancy, we have generated a system whereby PML-RARA expression is somatically acquired from the mouse Pml locus in the context of Pml haploinsufficiency. We found that physiologic PML-RARA expression was sufficient to direct a hematopoietic progenitor self-renewal program in vitro and in vivo. However, this expansion was not associated with evidence of myeloproliferation, more accurately reflecting the clinical presentation of human APL. Thus, at physiologic doses, PML-RARA primarily acts to increase hematopoietic progenitor self-renewal, expanding a population of cells that are susceptible to acquiring secondary mutations that cause progression to leukemia. This mouse model provides a platform for more accurately dissecting the early events in APL pathogenesis. PMID:21364283

  9. Common germline variation at the TERT locus contributes to familial clustering of myeloproliferative neoplasms

    PubMed Central

    Jäger, Roland; Harutyunyan, Ashot S; Rumi, Elisa; Pietra, Daniela; Berg, Tiina; Olcaydu, Damla; Houlston, Richard S; Cazzola, Mario; Kralovics, Robert

    2014-01-01

    The C allele of the rs2736100 single nucleotide polymorphism located in the second intron of the TERT gene has recently been identified as a susceptibility factor for myeloproliferative neoplasms (MPN) in the Icelandic population. Here, we evaluate the role of TERT rs2736100_C in sporadic and familial MPN in the context of the previously identified JAK2 GGCC predisposition haplotype. We have confirmed the TERT rs2736100_C association in a large cohort of Italian sporadic MPN patients. The risk conferred by TERT rs2736100_C is present in all molecular and diagnostic MPN subtypes. TERT rs2736100_C and JAK2 GGCC are independently predisposing to MPN and have an additive effect on disease risk, together explaining a large fraction of the population attributable fraction (PAF = 73.06%). We found TERT rs2736100_C significantly enriched (P = 0.0090) in familial MPN compared to sporadic MPN, suggesting that low-penetrance variants may be responsible for a substantial part of familial clustering in MPN. Am. J. Hematol. 89:1107–1110, 2014. © 2014 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc. PMID:25196853

  10. Targeted next-generation sequencing identified novel mutations in triple-negative myeloproliferative neoplasms.

    PubMed

    Chang, Yu-Cheng; Lin, Huan-Chau; Chiang, Yi-Hao; Chen, Caleb Gon-Shen; Huang, Ling; Wang, Wei-Ting; Cheng, Chun-Chia; Lin, Johnson; Chang, Yi-Fang; Chang, Ming-Chih; Hsieh, Ruey-Kuen; Chen, Shu-Jen; Lim, Ken-Hong; Kuo, Yuan-Yeh

    2017-05-01

    Mutations in JAK2, MPL and CALR genes have been identified in the majority of myeloproliferative neoplasm (MPN) patients, and patients negative for these three mutations are the so-called triple-negative (TN) MPN. In this study, we examined the mutational profiles of 16 triple-negative MPN patients including 7 essential thrombocythemia (ET), 1 primary myelofibrosis and 8 polycythemia vera (PV). Targeted next-generation sequencing was performed using the ACTOnco Comprehensive Cancer Panel (Ion AmpliSeq Comprehensive Cancer Panel, Life Technologies) to target all coding exons of 409 cancer-related genes. Overall, 30 nonsynonymous somatic mutations were detected in 12 (75%) patients with a range of 1-5 mutations per sample. Notably, one ET patient was found to have JAK2V617F and KITP551L mutations at very low allele frequency. One MPLP70L and 1 MPLM602T mutations were identified each in 1 ET and 1 PV, respectively. Other recurrent mutations were also identified including KMT2C, KMT2D, IRS2, SYNE1, PDE4DIP, SETD2, ATM, TNFAIP3 and CCND2. In addition, germline mutations were also found in some cancer-related genes. Copy number changes were rare in this cohort of TN MPNs. In conclusion, both somatic and germline mutations can be detected in TN MPN patients.

  11. Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms

    PubMed Central

    Mullenders, Jasper; Aranda-Orgilles, Beatriz; Lhoumaud, Priscillia; Keller, Matthew; Pae, Juhee; Wang, Kun; Kayembe, Clarisse; Rocha, Pedro P.; Raviram, Ramya; Gong, Yixiao; Premsrirut, Prem K.; Tsirigos, Aristotelis; Bonneau, Richard; Skok, Jane A.; Cimmino, Luisa; Hoehn, Daniela

    2015-01-01

    The cohesin complex (consisting of Rad21, Smc1a, Smc3, and Stag2 proteins) is critically important for proper sister chromatid separation during mitosis. Mutations in the cohesin complex were recently identified in a variety of human malignancies including acute myeloid leukemia (AML). To address the potential tumor-suppressive function of cohesin in vivo, we generated a series of shRNA mouse models in which endogenous cohesin can be silenced inducibly. Notably, silencing of cohesin complex members did not have a deleterious effect on cell viability. Furthermore, knockdown of cohesin led to gain of replating capacity of mouse hematopoietic progenitor cells. However, cohesin silencing in vivo rapidly altered stem cells homeostasis and myelopoiesis. Likewise, we found widespread changes in chromatin accessibility and expression of genes involved in myelomonocytic maturation and differentiation. Finally, aged cohesin knockdown mice developed a clinical picture closely resembling myeloproliferative disorders/neoplasms (MPNs), including varying degrees of extramedullary hematopoiesis (myeloid metaplasia) and splenomegaly. Our results represent the first successful demonstration of a tumor suppressor function for the cohesin complex, while also confirming that cohesin mutations occur as an early event in leukemogenesis, facilitating the potential development of a myeloid malignancy. PMID:26438359

  12. HSP90 and HSP70: Implication in Inflammation Processes and Therapeutic Approaches for Myeloproliferative Neoplasms

    PubMed Central

    Sevin, Margaux; Girodon, François; Garrido, Carmen; de Thonel, Aurélie

    2015-01-01

    Myeloproliferative neoplasms (MPN) are clonal stem cell disorders that lead to the excessive production of one or more blood cell lineages. It has been reported that, in most MPN, inflammatory cytokines are frequently increased, indicating that inflammation plays a crucial role in these disorders. Heat shock proteins (HSP) are induced in response to many stressful conditions from heat shock to hypoxia and inflammation. Besides their chaperone and cytoprotective functions, HSPs are key players during inflammation, hence the term “chaperokine.” Through their chaperone activity, HSP90, a stabilizer of many oncogenes (e.g., JAK2), and HSP70, a powerful antiapoptotic chaperone, tightly regulate Nuclear Factor-kappa B signalling, a critical pathway in mediating inflammatory responses. In light of this potential, several HSP90 inhibitors have been generated as anticancer agents able to degrade oncogenes. As it turns out, however, these drugs are also potent inhibitors of the inflammatory response in various diseases. Given the chaperone potential of HSP70 and the fact that HSP90 inhibitors induce HSP70, interest in HSP70 inhibitors is also increasing. Here, we focus on the implication of HSP90 and HSP70 in inflammatory responses and on the emergence of new therapeutic approaches in MPN based on HSP inhibitors. PMID:26549943

  13. Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms

    PubMed Central

    Pietra, D; Rumi, E; Ferretti, V V; Buduo, C A Di; Milanesi, C; Cavalloni, C; Sant'Antonio, E; Abbonante, V; Moccia, F; Casetti, I C; Bellini, M; Renna, M C; Roncoroni, E; Fugazza, E; Astori, C; Boveri, E; Rosti, V; Barosi, G; Balduini, A; Cazzola, M

    2016-01-01

    A quarter of patients with essential thrombocythemia or primary myelofibrosis carry a driver mutation of CALR, the calreticulin gene. A 52-bp deletion (type 1) and a 5-bp insertion (type 2 mutation) are the most frequent variants. These indels might differentially impair the calcium binding activity of mutant calreticulin. We studied the relationship between mutation subtype and biological/clinical features of the disease. Thirty-two different types of CALR variants were identified in 311 patients. Based on their predicted effect on calreticulin C-terminal, mutations were classified as: (i) type 1-like (65%); (ii) type 2-like (32%); and (iii) other types (3%). Corresponding CALR mutants had significantly different estimated isoelectric points. Patients with type 1 mutation, but not those with type 2, showed abnormal cytosolic calcium signals in cultured megakaryocytes. Type 1-like mutations were mainly associated with a myelofibrosis phenotype and a significantly higher risk of myelofibrotic transformation in essential thrombocythemia. Type 2-like CALR mutations were preferentially associated with an essential thrombocythemia phenotype, low risk of thrombosis despite very-high platelet counts and indolent clinical course. Thus, mutation subtype contributes to determining clinical phenotype and outcomes in CALR-mutant myeloproliferative neoplasms. CALR variants that markedly impair the calcium binding activity of mutant calreticulin are mainly associated with a myelofibrosis phenotype. PMID:26449662

  14. HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans

    PubMed Central

    Marubayashi, Sachie; Koppikar, Priya; Taldone, Tony; Abdel-Wahab, Omar; West, Nathan; Bhagwat, Neha; Caldas-Lopes, Eloisi; Ross, Kenneth N.; Gönen, Mithat; Gozman, Alex; Ahn, James H.; Rodina, Anna; Ouerfelli, Ouathek; Yang, Guangbin; Hedvat, Cyrus; Bradner, James E.; Chiosis, Gabriela; Levine, Ross L.

    2010-01-01

    JAK2 kinase inhibitors were developed for the treatment of myeloproliferative neoplasms (MPNs), following the discovery of activating JAK2 mutations in the majority of patients with MPN. However, to date JAK2 inhibitor treatment has shown limited efficacy and apparent toxicities in clinical trials. We report here that an HSP90 inhibitor, PU-H71, demonstrated efficacy in cell line and mouse models of the MPN polycythemia vera (PV) and essential thrombocytosis (ET) by disrupting JAK2 protein stability. JAK2 physically associated with both HSP90 and PU-H71 and was degraded by PU-H71 treatment in vitro and in vivo, demonstrating that JAK2 is an HSP90 chaperone client. PU-H71 treatment caused potent, dose-dependent inhibition of cell growth and signaling in JAK2 mutant cell lines and in primary MPN patient samples. PU-H71 treatment of mice resulted in JAK2 degradation, inhibition of JAK-STAT signaling, normalization of peripheral blood counts, and improved survival in MPN models at doses that did not degrade JAK2 in normal tissues or cause substantial toxicity. Importantly, PU-H71 treatment also reduced the mutant allele burden in mice. These data establish what we believe to be a novel therapeutic rationale for HSP90 inhibition in the treatment of JAK2-dependent MPN. PMID:20852385

  15. Uses and Abuses of JAK2 and MPL Mutation Tests in Myeloproliferative Neoplasms

    PubMed Central

    Tefferi, Ayalew; Noel, Pierre; Hanson, Curtis A.

    2011-01-01

    JAK2V617F is sufficiently prevalent in BCR-ABL1-negative myeloproliferative neoplasms (MPNs) to be useful as a clonal marker. JAK2V617F mutation screening is indicated for the evaluation of erythrocytosis, thrombocytosis, splanchnic vein thrombosis, and otherwise unexplained BCR-ABL1-negative granulocytosis. However, the mutation does not provide additional value in the presence of unequivocal morphologic diagnosis, and its presence does not necessarily distinguish one MPN from another or provide useful prognostic information. In general, quantitative cell-based JAK2V617F mutation assays are preferred because the additional information obtained on mutant allele burden enhances diagnostic certainty and facilitates monitoring of response to treatment. JAK2 exon 12 mutation screening is indicated only in the presence of JAK2V617F-negative erythrocytosis that is associated with a subnormal serum erythropoietin level. MPL mutations are neither frequent nor specific enough to warrant their routine use for MPN diagnosis, but they may be useful in resolving specific diagnostic problems. The practice of en bloc screening for JAK2V617F, JAK2 exon 12, and MPL mutations is scientifically irrational and economically irresponsible. PMID:21723416

  16. Incidence, Survival and Prevalence Statistics of Classical Myeloproliferative Neoplasm in Korea

    PubMed Central

    2016-01-01

    The nationwide statistical analysis of each disease of classical myeloproliferative neoplasm (MPN) in Korea has not been reported yet. To this end, we have analyzed incidence rates, survival rates and treatment pattern of polycythemia vera (PV), primary myelofibrosis (MF) and essential thrombocythemia (ET) using Korea National Cancer Incidence Database (KNCIDB) and Health Insurance Review and Assessment Service (HIRA) database. Between 2003 and 2011, a total of 4,342 new cases of MPN were reported to the KNCIDB. ET was the most common, followed by MF and PV. The crude incidence rates for PV, MF, and ET have increased during the period, reaching 0.40, 0.15, and 0.84 per 100,000, respectively. Five-year relative survival rate of all MPN patients was 89.3%, with lowest relative survival rate with MF (53.1%). The prevalence of each disease estimated from HIRA data also increased during the study period. Notably, ET was found to be most prevalent. The prescription rate of hydroxyurea and phlebotomy to PV, MF and ET patients remained constant over the period, and the prescription rate of hydroxyurea was higher in patients with age over 60 years. This is the first Korean nationwide statistics of MPN, using central registry data. This set of data can be utilized to compare the Korean MPN status to international data and guidelines. PMID:27550486

  17. Incidence, Survival and Prevalence Statistics of Classical Myeloproliferative Neoplasm in Korea.

    PubMed

    Lim, Yoojoo; Lee, Jeong Ok; Bang, Soo Mee

    2016-10-01

    The nationwide statistical analysis of each disease of classical myeloproliferative neoplasm (MPN) in Korea has not been reported yet. To this end, we have analyzed incidence rates, survival rates and treatment pattern of polycythemia vera (PV), primary myelofibrosis (MF) and essential thrombocythemia (ET) using Korea National Cancer Incidence Database (KNCIDB) and Health Insurance Review and Assessment Service (HIRA) database. Between 2003 and 2011, a total of 4,342 new cases of MPN were reported to the KNCIDB. ET was the most common, followed by MF and PV. The crude incidence rates for PV, MF, and ET have increased during the period, reaching 0.40, 0.15, and 0.84 per 100,000, respectively. Five-year relative survival rate of all MPN patients was 89.3%, with lowest relative survival rate with MF (53.1%). The prevalence of each disease estimated from HIRA data also increased during the study period. Notably, ET was found to be most prevalent. The prescription rate of hydroxyurea and phlebotomy to PV, MF and ET patients remained constant over the period, and the prescription rate of hydroxyurea was higher in patients with age over 60 years. This is the first Korean nationwide statistics of MPN, using central registry data. This set of data can be utilized to compare the Korean MPN status to international data and guidelines.

  18. Role of TET2 and ASXL1 mutations in the pathogenesis of myeloproliferative neoplasms

    PubMed Central

    Abdel-Wahab, Omar; Tefferi, Ayalew; Levine, Ross L.

    2012-01-01

    Synopsis Since the discovery of activating mutations in JAK2 in patients with myeloproliferative neoplasms (MPNs) in 2005, gene discovery efforts have identified additional disease alleles which can predate or occur subsequent to acquisition of JAK2/MPL mutations. In 2009, single nucleotide polymorphism (SNP) arrays and comparative genomic hybridization array (aCGH) based profiling led to the identification of somatic copy-number loss and mutations in the genes TET2 and ASXL1 in MPN patients. Biochemical and biological characterization of the TET and ASXL family of proteins have provided valuable insights into new modes of epigenetic regulation of gene transcription. Mutations in TET2 and ASXL1 are also important biomarkers for disease outcome amongst patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Despite these important insights, the relevance of these mutations to outcome and to therapeutic response in MPN patients is not yet clear. Genetic analysis of MPN patient cohorts with adequate sample size and clear clinical annotation are needed to understand the importance of these mutations on MPN phenotype, risk of transformation to leukemia, response to therapy, and influence on overall survival. PMID:23009937

  19. Loss of Runx1 perturbs adult hematopoiesis and is associated with a myeloproliferative phenotype

    PubMed Central

    Growney, Joseph D.; Shigematsu, Hirokazu; Li, Zhe; Lee, Benjamin H.; Adelsperger, Jennifer; Rowan, Rebecca; Curley, David P.; Kutok, Jeffery L.; Akashi, Koichi; Williams, Ifor R.; Speck, Nancy A.; Gilliland, D. Gary

    2005-01-01

    Homozygous loss of function of Runx1 (Runt-related transcription factor 1 gene) during murine development results in an embryonic lethal phenotype characterized by a complete lack of definitive hematopoiesis. In light of recent reports of disparate requirements for hematopoietic transcription factors during development as opposed to adult hematopoiesis, we used a conditional gene-targeting strategy to effect the loss of Runx1 function in adult mice. In contrast with the critical role of Runx1 during development, Runx1 was not essential for hematopoiesis in the adult hematopoietic compartment, though a number of significant hematopoietic abnormalities were observed. Runx1 excision had lineage-specific effects on B- and T-cell maturation and pronounced inhibition of common lymphocyte progenitor production. Runx1 excision also resulted in inefficient platelet production. Of note, Runx1-deficient mice developed a mild myeloproliferative phenotype characterized by an increase in peripheral blood neutrophils, an increase in myeloid progenitor populations, and extramedullary hematopoiesis composed of maturing myeloid and erythroid elements. These findings indicate that Runx1 deficiency has markedly different consequences during development compared with adult hematopoiesis, and they provide insight into the phenotypic manifestations of Runx1 deficiency in hematopoietic malignancies. PMID:15784726

  20. Molecular characterization of EZH2 mutant patients with myelodysplastic/myeloproliferative neoplasms.

    PubMed

    Rinke, J; Müller, J P; Blaess, M F; Chase, A; Meggendorfer, M; Schäfer, V; Winkelmann, N; Haferlach, C; Cross, N C P; Hochhaus, A; Ernst, T

    2017-09-01

    Mutations in the epigenetic regulator gene EZH2 are frequently observed in patients with myelodysplastic/myeloproliferative neoplasms (MDS/MPN; 10-13%) and are associated with a poor outcome. To gain more insight into EZH2 pathology, we sought to genetically characterize a cohort of 41 EZH2-mutated MDS/MPN patients using targeted deep next-generation sequencing (NGS), colony-forming progenitor assays and transcriptome analysis. Stable short hairpin RNA (shRNA)-mediated downregulation of EZH2 was performed in MDS-derived F-36P, MOLM-13 and OCI-M2 cells to study EZH2-specific changes. Targeted NGS revealed a complex pattern of mutations with a total of 190 individual mutations. EZH2 mutations frequently co-occur with TET2 (58%), RUNX1 (40%) and ASXL1 (34%) mutations. Colony assays indicated EZH2 mutations to be mostly early events in leukemogenesis and showed a complex mutational hierarchy. Gene expression data revealed a number of differently expressed genes between EZH2 wild-type and mutant patients including known EZH2 targets. Comparison of patient transcriptome to EZH2-downregulated cell line data revealed several genes as novel EZH2 targets, showing opposite as well as unidirectional regulation between cell lines and patients. Some genes, such as CXXC5, ETS1 and VAV3 have previously been implied to have a role in leukemogenesis. Their precise role in MDS/MPN needs to be further investigated.

  1. Mutational analysis in BCR-ABL-negative classic myeloproliferative neoplasms: impact on prognosis and therapeutic choices.

    PubMed

    Tefferi, Ayalew

    2010-04-01

    The diagnostic value of JAK2 mutational analysis in myeloproliferative neoplasms (MPN) is now well established and endorsed by the World Health Organization classification system for hematologic malignancies. The current review is focused on the prognostic impact and therapeutic relevance of JAK2 and other MPN-associated mutations in polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Mutations involving JAK2, MPL, TET2, and ASXL1 are discussed. In general, within a specific disease category, the mere presence or absence of any one of these mutations does not appear to correlate with survival or development of blast phase disease, myelofibrosis, or thrombosis. In contrast, interesting associations between JAK2V617F allele burden and clinical outcome (e.g. lower quartile range allele burden and shorter survival in PMF and higher allele burden and fibrotic transformation in PV) have been made, but require further validation, and their impact on treatment choices is not clear. Similarly, although detection of JAK2V617F status post allogeneic hematopoietic cell transplant indicates minimal residual disease, the general use of mutant allele burden for monitoring treatment response has not been systematically studied. Current information on mutational status and response to JAK2 inhibitor drug therapy is too preliminary to draw any conclusions.

  2. New Strategies in Myeloproliferative Neoplasms: The Evolving Genetic and Therapeutic Landscape

    PubMed Central

    Patel, Ami B.; Vellore, Nadeem A.; Deininger, Michael W.

    2015-01-01

    The classical BCR-ABL1-negative myeloproliferative neoplasms (MPNs) include essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF). While these clonal disorders share certain clinical and genetic features, MF in particular is distinct for its complex mutational landscape, severe disease phenotype and poor prognosis. The genetic complexity inherent to MF has made this disease extremely challenging to treat. Pharmacologic JAK inhibition has proven to be a transformative therapy in MPNs, alleviating symptom burden and improving survival, but has been hampered by off-target toxicities and, as monotherapy, has shown limited effects on mutant allele burden. In this review, we discuss the genetic heterogeneity contributing to the pathogenesis of MPNs, focusing on novel driver and epigenetic mutations and how they relate to combination therapeutic strategies. We discuss results from ongoing studies of new JAK inhibitors and report on new drugs and drug combinations that have demonstrated success in early preclinical and clinical trials, including Type II JAK inhibitors, anti-fibrotic agents and telomerase inhibitors. PMID:26933174

  3. Positioning the principles of precision medicine in care pathways for allergic rhinitis and chronic rhinosinusitis - A EUFOREA-ARIA-EPOS-AIRWAYS ICP statement.

    PubMed

    Hellings, P W; Fokkens, W J; Bachert, C; Akdis, C A; Bieber, T; Agache, I; Bernal-Sprekelsen, M; Canonica, G W; Gevaert, P; Joos, G; Lund, V; Muraro, A; Onerci, M; Zuberbier, T; Pugin, B; Seys, S F; Bousquet, J

    2017-09-01

    Precision medicine (PM) is increasingly recognized as the way forward for optimizing patient care. Introduced in the field of oncology, it is now considered of major interest in other medical domains like allergy and chronic airway diseases, which face an urgent need to improve the level of disease control, enhance patient satisfaction and increase effectiveness of preventive interventions. The combination of personalized care, prediction of treatment success, prevention of disease and patient participation in the elaboration of the treatment plan is expected to substantially improve the therapeutic approach for individuals suffering from chronic disabling conditions. Given the emerging data on the impact of patient stratification on treatment outcomes, European and American regulatory bodies support the principles of PM and its potential advantage over current treatment strategies. The aim of the current document was to propose a consensus on the position and gradual implementation of the principles of PM within existing adult treatment algorithms for allergic rhinitis (AR) and chronic rhinosinusitis (CRS). At the time of diagnosis, prediction of success of the initiated treatment and patient participation in the decision of the treatment plan can be implemented. The second-level approach ideally involves strategies to prevent progression of disease, in addition to prediction of success of therapy, and patient participation in the long-term therapeutic strategy. Endotype-driven treatment is part of a personalized approach and should be positioned at the tertiary level of care, given the efforts needed for its implementation and the high cost of molecular diagnosis and biological treatment. © 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

  4. The meaning of life and health experience for the Chinese elderly with chronic illness: a qualitative study from positive health philosophy.

    PubMed

    Zhang, Heng; Shan, WeiYing; Jiang, AnLi

    2014-10-01

    Ageing and the concurrent prevalence of chronic disease in older adults produce a great burden and challenge for family, society and individuals. There is a definite need to build the science about caring for older Chinese adults from their perspective to inform health-care professionals. The aim of the study was to investigate the meaning of life and health experience of Chinese elderly with chronic illness and identify health potential from a positive perspective. A qualitative descriptive study was undertaken to interview 11 older adults ages 64-92 in a day centre. In 2011, the data were collected and analysed by thematic analysis. Four interrelated themes indicated a rich meaning of life and health experience from the older adults: (i) happiness lies in contentment; (ii) sense of responsibility; (iii) letting nature take its course; (iv) and proactive self-balance. These interrelated themes with partial conflict presented a dialectic meaning of life and were interpreted from traditional Chinese culture and compared with positive health philosophy. The significance of finding will encourage nursing practice work with clients and identify the potential and self-help strength of the elderly. © 2013 Wiley Publishing Asia Pty Ltd.

  5. Myeloperoxidase-Related Chlorination Activity Is Positively Associated with Circulating Ceruloplasmin in Chronic Heart Failure Patients: Relationship with Neurohormonal, Inflammatory, and Nutritional Parameters

    PubMed Central

    Cabassi, Aderville; Binno, Simone Maurizio; Tedeschi, Stefano; Graiani, Gallia; Galizia, Cinzia; Bianconcini, Michele; Coghi, Pietro; Fellini, Federica; Ruffini, Livia; Govoni, Paolo; Piepoli, Massimo; Perlini, Stefano; Regolisti, Giuseppe; Fiaccadori, Enrico

    2015-01-01

    Rationale. Heart failure (HF) is accompanied by the development of an imbalance between oxygen- and nitric oxide-derived free radical production leading to protein nitration. Both chlorinating and peroxidase cycle of Myeloperoxidase (MPO) contribute to oxidative and nitrosative stress and are involved in tyrosine nitration of protein. Ceruloplasmin (Cp) has antioxidant function through its ferroxidase I (FeOxI) activity and has recently been proposed as a physiological defense mechanism against MPO inappropriate actions. Objective. We investigated the relationship between plasma MPO-related chlorinating activity, Cp and FeOxI, and nitrosative stress, inflammatory, neurohormonal, and nutritional biomarkers in HF patients. Methods and Results. In chronic HF patients (n = 81, 76 ± 9 years, NYHA Class II (26); Class III (29); Class IV (26)) and age-matched controls (n = 17, 75 ± 11 years, CTR), plasma MPO chlorinating activity, Cp, FeOxI, nitrated protein, free Malondialdehyde, BNP, norepinephrine, hsCRP, albumin, and prealbumin were measured. Plasma MPO chlorinating activity, Cp, BNP, norepinephrine, and hsCRP were increased in HF versus CTR. FeOxI, albumin, and prealbumin were decreased in HF. MPO-related chlorinating activity was positively related to Cp (r = 0.363, P < 0.001), nitrated protein, hsCRP, and BNP and inversely to albumin. Conclusions. Plasma MPO chlorinated activity is increased in elderly chronic HF patients and positively associated with Cp, inflammatory, neurohormonal, and nitrosative parameters suggesting a role in HF progression. PMID:26539521

  6. Review of Positive Psychology Outcome Measures for Chronic Illness, Traumatic Brain Injury and Older Adults: Adaptability in Dementia?

    PubMed

    Stoner, Charlotte R; Orrell, Martin; Spector, Aimee

    2015-01-01

    Despite positive psychology being increasingly recognised as an important agent in well-being, there is a lack of standardised outcome measures for psychosocial dementia research. This review assessed positive psychology outcome measures using standardised criterion in populations that were identified as having shared characteristics. It aimed to identify robust measures that were suitable for potential adaption or use within a dementia population. The review identified 16 positive psychology outcome measures (and 8 further psychometric assessments of these) within the constructs of resilience, self-efficacy, religiousness/spirituality, life valuation, sense of coherence, autonomy, resourcefulness and a combined measure (CASP-19). Scale development studies were subject to a quality assessment, and most were found to be lacking information on reproducibility and responsiveness. A wide range of measures within the constructs of positive psychology was identified as having potential utility for psychosocial research within a dementia population. Examples included the CD-RISC, GSWB, SWLS, MPAQ, RSOA and CASP-19. It is recommended that such scales are further adapted or validated for people with dementia. Underreporting of appropriate psychometric analyses hampered this review, and it is recommended that future authors endeavour to report such analyses. © 2015 S. Karger AG, Basel.

  7. Circadian variation of cardiac autonomic nervous activity is well preserved in patients with mild to moderate chronic heart failure: effect of patient position.

    PubMed

    Miyamoto, Shoichi; Fujita, Masatoshi; Tambara, Keiichi; Sekiguchi, Hiroyuki; Eiho, Shigeru; Hasegawa, Koji; Tamaki, Shun-ichi

    2004-02-01

    It remains unclear whether circadian variation (CV) of cardiac autonomic nervous activity (CANA) is preserved in patients with chronic heart failure (CHF) as in healthy subjects. We have demonstrated that CANA in CHF patients is largely affected by patient recumbent position. We studied eight mild to moderate CHF patients and eight age, sex-matched healthy subjects. Each subject underwent 24-h ambulatory ECG monitoring. One channel was used to record the CM5 lead, and another to record the signal of patient position from a newly developed, small-sized detector. By using spectral analysis of heart rate variability, frequency-domain measures were calculated. Normalized high-frequency (HF: 0.15-0.40 Hz) power was used as an index of vagal activity and the low frequency (LF: 0.04-0.15 Hz)/HF power ratio was used as an index of sympathovagal balance. These indexes in the same recumbent position were compared between night (2:00-4:00 a.m.) and morning (6:00-8:00 a.m.). In healthy subjects, a definite CV of CANA was observed in each recumbent position. In patients with CHF, in each position, normalized HF power was lower in the morning than at night, whereas LF/HF was higher in the morning than at night. Thus, CANA in CHF patients is influenced not only by patient position but also by the time of day. CV of CANA in mild to moderate CHF patients is well preserved when taking patient position into consideration.

  8. Prognostic and predictive implications of Sokal, Euro and EUTOS scores in chronic myeloid leukaemia in the imatinib era-experience from a tertiary oncology centre in Southern India.

    PubMed

    Kuntegowdanahalli, Lakshmaiah Chinnagiriyappa; Kanakasetty, Govind Babu; Thanky, Aditi Harsh; Dasappa, Lokanatha; Jacob, Linu Abraham; Mallekavu, Suresh Babu; Lakkavalli, Rajeev Krishnappa; Kadabur, Lokesh N; Haleshappa, Rudresha Antapura

    2016-01-01

    Chronic myeloid leukaemia (CML) is a myeloproliferative disorder. Over the years many prognostic models have been developed to better risk stratify this disease at baseline. Sokal, Euro, and EUTOS scores were developed in varied populations initially receiving various therapies. Here we try to identify their predictive and prognostic implication in a larger population of Indian patients with CML-CP (chronic phase) in the imatinib era.

  9. Increased risks of polycythemia vera, essential thrombocythemia, and myelofibrosis among 24 577 first-degree relatives of 11 039 patients with myeloproliferative neoplasms in Sweden

    PubMed Central

    Goldin, Lynn R.; Kristinsson, Sigurdur Y.; Helgadottir, Elin A.; Samuelsson, Jan; Björkholm, Magnus

    2008-01-01

    Previous small studies have reported familial clustering of myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). We identified 6217 PV, 2838 ET, 1172 MF, and 812 MPN unclassifiable (NOS) patients diagnosed in Sweden, 43 550 controls, and first-degree relatives of cases (n = 24 577) and controls (n = 99 542). Using a marginal survival model, we calculated relative risks (RRs) and 95% confidence intervals as measures of familial aggregation. Relatives of MPN patients had significantly increased risks of PV (RR = 5.7; 3.5-9.1), ET (RR = 7.4; 3.7-14.8), and MPN NOS (RR = 7.5; 2.7-20.8). Analyses stratified by type of first-degree relative revealed consistently higher risks for siblings, compatible with a model of recessive genetic inheritance, which can be confirmed only by identifying the susceptibility gene(s). Mean age at MPN diagnosis was not different (P = .20) for affected relatives of cases (57.5 years) versus controls (60.6 years), and risk of MPN by age was not different for parents versus offspring of MPN cases (P = .10), providing no support for anticipation. Relatives of MPN patients had a borderline increased risk of chronic myeloid leukemia (CML; RR = 1.9; 0.9-3.8; P = .09). Our findings of 5- to 7-fold elevated risk of MPNs among first-degree relatives of MPN patients support the hypothesis that common, strong, shared susceptibility genes predispose to PV, ET, MF, and possibly CML. PMID:18451307

  10. Hepatitis B Reactivation in a HBsAg-Negative, HBcAb-Positive Patient Receiving Fludarabine for the Treatment of Chronic Lymphocytic Leukaemia.

    PubMed

    Toscanini, Federica; De Leo, Pasqualina; Calcagno, Giuseppe; Malfatti, Federica; Grasso, Alessandro; Anselmo, Marco

    2011-01-01

    Hepatitis B virus (HBV) reactivation is an increasingly recognized cause of morbidity and mortality in patients undergoing chemotherapy. In haematology, the risk of reactivation of B hepatitis among HBsAg-positive patients has been documented; therefore, use of lamivudine prophylaxis is recommended before starting chemotherapy. Differently, for HBsAg-negative patients with markers of previous HBV infection (i.e., presence of isolated anti-HBc positivity) (anticore patients) management strategies are not univocal. We describe a rare case of HBV reactivation in an anticore patient after fludarabine therapy for chronic lymphocytic leukaemia. The patient fully recovered after a 6-month course of lamivudine with persistent HBV-DNA clearance and loss of HBsAg. The most important feature of this case is that fludarabine alone infrequently determines HBV reactivation, especially in anticore patients. Therefore, we suggest that patients candidates to receive fludarabine therapy should be considered for lamivudine prophylaxis, not only if HBsAg-positive, but even if anticore-positive only.

  11. 52-Week Efficacy and Safety of Telbivudine with Conditional Tenofovir Intensification at Week 24 in HBeAg-Positive Chronic Hepatitis B

    PubMed Central

    Piratvisuth, Teerha; Komolmit, Piyawat; Tanwandee, Tawesak; Sukeepaisarnjaroen, Wattana; Chan, Henry L. Y.; Pessôa, Mário G.; Fassio, Eduardo; Ono, Suzane K.; Bessone, Fernando; Daruich, Jorge; Zeuzem, Stefan; Cheinquer, Hugo; Pathan, Rashidkhan; Dong, Yuhong; Trylesinski, Aldo

    2013-01-01

    Background and Aims The Roadmap concept is a therapeutic framework in chronic hepatitis B for the intensification of nucleoside analogue monotherapy based on early virologic response. The efficacy and safety of this approach applied to telbivudine treatment has not been investigated. Methods A multinational, phase IV, single-arm open-label study (ClinicalTrials.gov ID NCT00651209) was undertaken in HBeAg-positive, nucleoside-naive adult patients with chronic hepatitis B. Patients received telbivudine (600 mg once-daily) for 24 weeks, after which those with undetectable serum HBV DNA (<300 copies/mL) continued to receive telbivudine alone while those with detectable DNA received telbivudine plus tenofovir (300 mg once-daily). Outcomes were assessed at Week 52. Results 105 patients commenced telbivudine monotherapy, of whom 100 were included in the efficacy analysis. Fifty-five (55%) had undetectable HBV DNA at Week 24 and continued telbivudine monotherapy; 45 (45%) received tenofovir intensification. At Week 52, the overall proportion of undetectable HBV DNA was 93% (93/100) by last-observation-carried-forward analysis (100% monotherapy group, 84% intensification group) and no virologic breakthroughs had occurred. ALT normalization occurred in 77% (87% monotherapy, 64% intensification), HBeAg clearance in 43% (65% monotherapy, 16% intensification), and HBeAg seroconversion in 39% (62% monotherapy, 11% intensification). Six patients had HBsAg clearance. Myalgia was more common in the monotherapy group (19% versus 7%). No decrease in the mean glomerular filtration rate occurred in either treatment group at Week 52. Conclusions Telbivudine therapy with tenofovir intensification at Week 24, where indicated by the Roadmap strategy, appears effective and well tolerated for the treatment of chronic hepatitis B. Trial Registration ClinicalTrials.gov NCT00651209 PMID:23390496

  12. JAK2 and genomic instability in the myeloproliferative neoplasms: a case of the chicken or the egg?

    PubMed Central

    Scott, Linda M.; Rebel, Vivienne I.

    2012-01-01

    The myeloproliferative neoplasms (MPNs) are a particularly useful model for studying mutation accumulation in neoplastic and the mechanisms of the molecular cells, understanding underlying defects our current This review summarizes acquisition. present their in patients with an MPN, and the effects of mutations targeting Janus kinase 2 (JAK2)-mediated intracellular signaling on DNA damage, and on the elimination of mutation-bearing cells by programmed cell death. Moreover, we discuss findings that suggest that the acquisition of disease-initiating mutations in hematopoietic stem cells of some MPN patients may be the consequence of an inherent genomic instability that was not previously appreciated. PMID:22641564

  13. Kidney Disease: Improving Global Outcomes guidelines on anaemia management in chronic kidney disease: a European Renal Best Practice position statement.

    PubMed

    Locatelli, Francesco; Bárány, Peter; Covic, Adrian; De Francisco, Angel; Del Vecchio, Lucia; Goldsmith, David; Hörl, Walter; London, Gerard; Vanholder, Raymond; Van Biesen, Wim

    2013-06-01

    Recently, the Kidney Disease: Improving Global Outcomes (KDIGO) group has produced comprehensive clinical practice guidelines for the management of anaemia in CKD patients. These guidelines addressed all of the important points related to anaemia management in CKD patients, including therapy with erythropoieis stimulating agents (ESA), iron therapy, ESA resistance and blood transfusion use. Because most guidelines were 'soft' rather than 'strong', and because global guidelines need to be adapted and implemented into the regional context where they are used, on behalf of the European Renal Best Practice Advisory Board some of its members, and other external experts in this field, who were not participants in the KDIGO guidelines group, were invited to participate in this anaemia working group to examine and comment on the KDIGO documents in this position paper. In this article, the group concentrated only on those guidelines which we considered worth amending or adapting. All guidelines not specifically mentioned are fully endorsed.

  14. Routine blood examinations combined with morphological analysis for the diagnosis of myelodysplastic/myeloproliferative neoplasms

    PubMed Central

    Wu, Huanling; Sun, Hui; Zhang, Zhifen; Li, Xiangli; Li, Yuantang; Li, Li; Xu, Rui; Wang, Zie; Tian, Wenjun

    2016-01-01

    In 2008, the World Health Organization (WHO) introduced a new hematological neoplasm category; myelodysplastic/myeloproliferative neoplasms (MDS/MPN), which included four main subcategories. This disease is often misdiagnosed, which delays effective therapy. The present study evaluated the role of routine blood examinations and morphological analysis of peripheral blood cells in the reliable diagnosis of MDS/MPN. In total, 236 adult MDS/MPN patients were analyzed. The analysis included 10 routine blood parameters measured using a Sysmex XE-2100™, 3 differential percentage parameters and 7 morphological features of peripheral blood cells which were analyzed by optical microscopy, and 3 differential absolute count numbers obtained based on the corresponding differential percentages and absolute count of blood cells. The parameters were compared among the subcategories and a value of P<0.05 was considered to indicate a statistically significant difference. The median white blood cell and hemoglobin counts of the patients were 18.0×109/l and 88 g/l, respectively. The proportion of monocytes increased to 8% (1.82×109/l), the proportion of blast cells increased to 1% (0.5×109/l) and that of neutrophil precursors increased to 10% (1.98×109/l). A total of 87% of all patients presented with hypogranulation and 71% presented with abnormal condensed nuclear chromatin in granulocytes. Atypical monocytes were observed in 73% of all patients and Pseudo-Pelger cells were observed in 60%. Significant differences were detected among the subcategories. The present study demonstrated that combining blood routine parameters and the morphological analysis of peripheral blood cells have an essential role in the reliable diagnosis of MDS/MPN based on WHO categories. PMID:27895799

  15. Critical appraisal of the role of ruxolitinib in myeloproliferative neoplasm-associated myelofibrosis

    PubMed Central

    Barosi, Giovanni; Rosti, Vittorio; Gale, Robert Peter

    2015-01-01

    The recent approval of molecular-targeted therapies for myeloproliferative neoplasm-associated myelofibrosis (MPN-MF) has dramatically changed its therapeutic landscape. Ruxolitinib, a JAK1/JAK2 tyrosine kinase inhibitor, is now widely used for first- and second-line therapy in persons with MPN-MF, especially those with disease-related splenomegaly, intermediate- or high-risk disease, and constitutional symptoms. The goal of this work is to critically analyze data supporting use of ruxolitinib in the clinical settings approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). We systematically reviewed the literature and analyzed the risk of biases in the two randomized studies (COMFORT I and COMFORT II) on which FDA and EMA approval was based. Our strategy was to apply the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) approach by evaluating five dimensions of evidence: (1) overall risk of bias, (2) imprecision, (3) inconsistency, (4) indirectness, and (5) publication bias. Based on these criteria, we downgraded the evidence from the COMFORT I and COMFORT II trials for performance, attrition, and publication bias. In the disease-associated splenomegaly sphere, we upgraded the quality of evidence because of large effect size but downgraded it because of comparator choice and outcome indirectness (quality of evidence, low). In the sphere of treating persons with intermediate- or high-risk disease, we downgraded the evidence because of imprecision in effect size measurement and population indirectness. In the sphere of disease-associated symptoms, we upgraded the evidence because of the large effect size, but downgraded it because of comparator indirectness (quality of evidence, moderate). In conclusion, using the GRADE technique, we identified factors affecting the quality of evidence that were otherwise unstated. Identifying and evaluating these factors should influence the confidence with which physicians

  16. Analysis of genomic aberrations and gene expression profiling identifies novel lesions and pathways in myeloproliferative neoplasms

    PubMed Central

    Rice, K L; Lin, X; Wolniak, K; Ebert, B L; Berkofsky-Fessler, W; Buzzai, M; Sun, Y; Xi, C; Elkin, P; Levine, R; Golub, T; Gilliland, D G; Crispino, J D; Licht, J D; Zhang, W

    2011-01-01

    Polycythemia vera (PV), essential thrombocythemia and primary myelofibrosis, are myeloproliferative neoplasms (MPNs) with distinct clinical features and are associated with the JAK2V617F mutation. To identify genomic anomalies involved in the pathogenesis of these disorders, we profiled 87 MPN patients using Affymetrix 250K single-nucleotide polymorphism (SNP) arrays. Aberrations affecting chr9 were the most frequently observed and included 9pLOH (n=16), trisomy 9 (n=6) and amplifications of 9p13.3–23.3 (n=1), 9q33.1–34.13 (n=1) and 9q34.13 (n=6). Patients with trisomy 9 were associated with elevated JAK2V617F mutant allele burden, suggesting that gain of chr9 represents an alternative mechanism for increasing JAK2V617F dosage. Gene expression profiling of patients with and without chr9 abnormalities (+9, 9pLOH), identified genes potentially involved in disease pathogenesis including JAK2, STAT5B and MAPK14. We also observed recurrent gains of 1p36.31–36.33 (n=6), 17q21.2–q21.31 (n=5) and 17q25.1–25.3 (n=5) and deletions affecting 18p11.31–11.32 (n=8). Combined SNP and gene expression analysis identified aberrations affecting components of a non-canonical PRC2 complex (EZH1, SUZ12 and JARID2) and genes comprising a ‘HSC signature' (MLLT3, SMARCA2 and PBX1). We show that NFIB, which is amplified in 7/87 MPN patients and upregulated in PV CD34+ cells, protects cells from apoptosis induced by cytokine withdrawal. PMID:22829077

  17. γ-Glutamyl Transferase Is an Independent Biomarker of Splanchnic Thrombosis in Patients With Myeloproliferative Neoplasm

    PubMed Central

    Görtzen, Jan; Hunka, Lena M.; Vonnahme, Maria; Praktiknjo, Michael; Kaifie, Andrea; Fimmers, Rolf; Jansen, Christian; Heine, Annkristin; Lehmann, Jennifer; Goethert, Joachim R.; Gattermann, Norbert; Goekkurt, Eray; Platzbecker, Uwe; Brossart, Peter; Strassburg, Christian P.; Brummendorf, Tim H.; Koschmieder, Steffen; Wolf, Dominik; Trebicka, Jonel

    2016-01-01

    Abstract Myeloproliferative neoplasms (MPNs) are associated with an increased risk of thrombotic events and constitute the major risk factor of splanchnic venous thrombosis (SVT) in Western countries. Although timely anticoagulation resolves SVT, unrecognized SVT frequently leads to portal hypertension and, potentially, variceal bleeding, which may render anticoagulation difficult. Thus, early identification of SVT development is clinically relevant in MPN patients. In this retrospective analysis, we included 126 patients with MPN and/or SVT referred to our hospital between 2009 and 2014. A total of 86 patients diagnosed with MPN formed the first cohort (PV n = 18, ET n = 16, and MF n = 40), whereas 40 patients who had SVT without adjunct MPN formed a control cohort. Median follow-up period was 960 days. Clinical and laboratory data were collected and analyzed for the identification of potential biomarkers applying descriptive statistics, nonparametric testing, Kaplan–Meier, and logistic regression analysis. The relevance of the identified biomarkers was evaluated in an independent 2nd cohort of 181 patients from the MPN registry of the Study Alliance of Leukemia (SAL-MPN). Thirty-three MPN patients (38%) in the 1st cohort had SVT. Elevated levels of aspartate aminotransferase, alanine aminotransferase, serum bilirubin, or γ-GT were significantly correlated to the presence of SVT. In multivariate testing, CRP and aspartate aminotransferase were predictors for survival and γ-GT remained the only significant variable associated with SVT in MPN patients (P < 0.05). These findings were confirmed in the 2nd cohort comprising 42% of patients with MPN suffering from SVT. Elevated γ-GT levels indicate SVT in MPN patients, whereas CRP levels are independent predictors of patient survival. PMID:27196445

  18. Prognostication in Philadelphia Chromosome Negative Myeloproliferative Neoplasms: a Review of the Recent Literature.

    PubMed

    Zhou, Amy; Afzal, Amber; Oh, Stephen T

    2017-09-25

    The prognosis for patients with Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) is highly variable. All Ph-negative MPNs carry an increased risk for thrombotic complications, bleeding, and leukemic transformation. Several clinical, biological, and molecular prognostic factors have been identified in recent years, which provide important information in guiding management of patients with Ph-negative MPNs. In this review, we critically evaluate the recent published literature and discuss important new developments in clinical and molecular factors that impact survival, disease transformation, and thrombosis in patients with polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Recent studies have identified several clinical factors and non-driver mutations to have prognostic impact on Ph-negative MPNs independent of conventional risk stratification and prognostic models. In polycythemia vera (PV), leukocytosis, abnormal karyotype, phlebotomy requirement on hydroxyurea, increased bone marrow fibrosis, and mutations in ASXL1, SRSF2, and IDH2 were identified as additional adverse prognostic factors. In essential thrombocythemia (ET), JAK2 V617F mutation, splenomegaly, and mutations in SH2B3, SF3B1, U2AF1, TP53, IDH2, and EZH2 were found to be additional negative prognostic factors. Bone marrow fibrosis and mutations in ASXL1, SRSF2, EZH2, and IDH1/2 have been found to be additional prognostic factors in primary myelofibrosis (PMF). CALR mutations appear to be a favorable prognostic factor in PMF, which has not been clearly demonstrated in ET. The prognosis for patients with PV, ET, and PMF is dependent upon the presence or absence of several clinical, biological, and molecular risk factors. The significance of additional risk factors identified in these recent studies will need further validation in prospective studies to determine how they may be best utilized in the management of these disorders.

  19. Detection of JAK2 V617F mutation increases the diagnosis of myeloproliferative neoplasms

    PubMed Central

    ZHANG, SHU-PENG; LI, HUI; LAI, REN-SHENG

    2015-01-01

    The Janus kinase (JAK)2 gene, which is located on chromosome 9p24, is involved in the signaling transduction pathways of the hematopoietic and immune system. Mutations in the JAK2 gene have served as disease markers for myeloproliferative neoplasms (MPNs). The aim of the present study was to investigate the occurrence of the JAK2 gene mutation in 140 clinical samples, and to evaluate its clinical significance in MPNs and other hematological diseases. Genomic DNA was extracted from the peripheral blood leukocytes or bone marrow karyocytes of 140 clinical samples, which included 130 patients with various types of hematological disease and 10 control patients. In addition, exons 12 and 14 of the JAK2 gene were analyzed by direct sequencing and the mutation rates of various MPN subtypes were evaluated. Of the 140 samples, exons 12 and 14 were tested in 74 samples, however, exon 14 only was tested in 66 samples. No mutations were identified in exon 12. The V617F mutation rate in polycythemia vera was 82.1% (23/28), and the mutation rates in essential thrombocythemia histiocytosis, primary myelofibrosis and other MPNs were 53.1% (17/32), 40.0% (4/10) and 60.0% (6/10), respectively. Therefore, the total mutation rate of the JAK2 gene in MPN was 62.5% (50/80). For non-MPN hematological diseases, four V617F mutations were detected in samples of leukocytosis of unknown origin (4/12), however, no JAK2 V617F mutations were identified in the 10 controls. Therefore, JAK2 V617F mutations may present a novel marker for diagnosis of MPNs. Furthermore, the direct sequencing method appeared to be satisfactory for the clinical gene testing of hematological samples. PMID:25624900

  20. Hormonal and Reproductive Factors and Risk of Myeloproliferative Neoplasms in Postmenopausal Women

    PubMed Central

    Leal, Alexis D.; Thompson, Carrie A.; Wang, Alice H.; Vierkant, Robert A.; Habermann, Thomas M.; Ross, Julie A.; Mesa, Ruben A.; Virnig, Beth A.; Cerhan, James R.

    2015-01-01

    Background Hormonal and reproductive history has been associated with risk of some hematologic malignancies, but their role in myeloproliferative neoplasms (MPN) is largely unknown. Methods Using a population-based cohort study, we evaluated the association of these factors with risk of MPN overall, and for essential thrombocythemia (ET) and polycythemia vera (PV) specifically. Incident MPN cases from 1993–2004 were identified via linkage to Medicare. Relative risks (RR) and 95% confidence intervals (CI) were estimated utilizing Cox proportional hazard regression. Results After >250,000 person-years of follow-up, 257 cases of MPN were identified (172 ET, 64 PV). Ever use of hormone therapy (HT) was associated with an increased risk of ET (RR=1.63; 95%CI 1.19–2.23) but a decreased risk of PV (RR=0.58; 95%CI 0.34–0.98). There were no statistically significant associations of oral contraceptives or reproductive factors with MPN risk overall, or by MPN subtype. Bilateral oophorectomy was associated with increased risk of ET (RR=1.58; 95%CI 1.11–2.25) and decreased risk of PV (RR=0.32; 95%CI 0.12–0.88). There was no association of ovulatory years with ET risk, however there was increased risk of PV (RR=1.68 for >36.8 compared to ≤27.6 years; p-trend=0.045). Adjustment for potential confounding factors did not alter these associations. Conclusions HT use and bilateral oophorectomy had opposite associations for ET and PV. Except for ovulatory years and PV risk, reproductive history did not appear to play a role in the etiology of MPN. PMID:26564251

  1. Frequencies, Laboratory Features, and Granulocyte Activation in Chinese Patients with CALR-Mutated Myeloproliferative Neoplasms

    PubMed Central

    Tian, Ruiyuan; Chang, Jianmei; Li, Jianlan; Tan, Yanhong; Xu, Zhifang; Ren, Fanggang; Zhao, Junxia; Pan, Jie; Zhang, Na; Wang, Xiaojuan; He, Jianxia; Yang, Wanfang; Wang, Hongwei

    2015-01-01

    Somatic mutations in the CALR gene have been recently identified as acquired alterations in myeloproliferative neoplasms (MPNs). In this study, we evaluated mutation frequencies, laboratory features, and granulocyte activation in Chinese patients with MPNs. A combination of qualitative allele-specific polymerase chain reaction and Sanger sequencing was used to detect three driver mutations (i.e., CALR, JAK2V617F, and MPL). CALR mutations were identified in 8.4% of cases with essential thrombocythemia (ET) and 5.3% of cases with primary myelofibrosis (PMF). Moreover, 25% of polycythemia vera, 29.5% of ET, and 48.1% of PMF were negative for all three mutations (JAK2V617F, MPL, and CALR). Compared with those patients with JAK2V617F mutation, CALR-mutated ET patients displayed unique hematological phenotypes, including higher platelet counts, and lower leukocyte counts and hemoglobin levels. Significant differences were not found between Chinese PMF patients with mutants CALR and JAK2V617F in terms of laboratory features. Interestingly, patients with CALR mutations showed markedly decreased levels of leukocyte alkaline phosphatase (LAP) expression, whereas those with JAK2V617F mutation presented with elevated levels. Overall, a lower mutant rate of CALR gene and a higher triple-negative rate were identified in the cohort of Chinese patients with MPNs. This result indicates that an undiscovered mutant gene may have a significant role in these patients. Moreover, these pathological features further imply that the disease biology varies considerably between mutants CALR and JAK2V617F. PMID:26375990

  2. Tissue microarray technique is applicable to bone marrow biopsies of myeloproliferative neoplasms.

    PubMed

    Limberger, Kathrin A; Bogatyreva, Lioudmila; Todorova, Rumyana; Herde, Bettina; Hauschke, Dieter; Pahl, Heike L; Werner, Martin; Aumann, Konrad

    2017-01-01

    Tissue microarray (TMA) technique is an established high-throughput method to analyze multiple tissue specimens in parallel. However, in order to obtain reliable results from immunohistochemical analyses of TMA blocks, cell composition of TMA spots must correspond to whole tissue sections (WTS) particularly in tissues with a heterogeneous cell composition as it is the case in myeloproliferative neoplasms (MPN). The aim of this study was to validate TMA of bone marrow biopsies from MPN patients. TMAs of MPN bone marrow biopsies (ET: n = 26, PV: n = 26, and PMF: n = 29) were compiled in triplicates and MPN-specific histological parameters were assessed. Results of TMA spots were compared with WTS' results using the intra-class correlation coefficient (ICC). Immunohistochemical NFE2 and calreticulin stainings of the TMA with quantitative evaluation were per