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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. 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 ...

  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. 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 ...

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

    ClinicalTrials.gov

    2016-07-20

    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. 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

  7. 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

  8. Hematopoietic Growth Factors, Signaling and the Chronic Myeloproliferative Disorders

    PubMed Central

    Kaushansky, Kenneth

    2006-01-01

    The chronic myeloproliferative diseases (CMDs) are a group of conditions characterized by unregulated blood cell production, that due either to excessive numbers of erythrocytes, leukocytes or platelets, or their defective function cause symptoms and signs of fatigue, headache, ruddy cyanosis, hemorrhage, abdominal distension, and the complications of vascular thrombosis. In the late 19th century Vaquez provided the first description of polycythemia vera (PV) and Hueck defined idiopathic myelofibrosis (IMF). In 1920, di Guglielmo established criteria for patients with essential thrombocythemia (ET). In 1951 Dameshek argued that these disorders, along with chronic myelogenous leukemia (CML) display many similar clinical and laboratory features (1), and grouped them. In 2002 the World Health Organization expanded the definition of CMDs to also include chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia/hypereosinophilic syndrome (CEL/HES) and systemic mast cell disorder (SMCD; 2). While the molecular pathogenesis of CML is well known (3), and the causes of CEL/HES and SMCD have been identified in about half of all cases (4,5), until very recently the etiologies of the three classically defined CMDs, PV, IMF and ET, were poorly understood. Each of these disorders is characterized by excessive hematopoiesis, a process usually dependent on one or more hematopoietic growth factors (HGFs). This review will focus on how our knowledge of the molecular mechanisms by which HGFs are produced, bind cell surface receptors and transduce survival and proliferative signals have provided the platform on which the multiple origins of CMDs can be understood and novel therapeutic interventions designed. PMID:17055768

  9. The spectrum of JAK2-positive myeloproliferative neoplasms.

    PubMed

    Kiladjian, Jean-Jacques

    2012-01-01

    The discovery of the JAK2V617F mutation triggered an unexpected flowering of basic and clinical studies in the field of myeloproliferative neoplasms (MPNs), resulting after just a few years in an exceptional amount of new information. One important consequence of those new findings was the modification of the World Health Organization classification and diagnostic algorithms for these diseases, which is still based on the original concept developed by William Dameshek in 1951 and keeps distinct entities under the umbrella of classical Philadelphia-negative MPNs. These MPNs are essential thrombocythemia, polycythemia vera, and primary myelofibrosis. Could a new molecular classification be a better tool to manage MPN patients? Several studies have shown that essential thrombocythemia and primary myelofibrosis can be divided into distinct subtypes based on the presence of the JAK2V617F mutation. Can we now define JAK2-positive diseases to depict a distinct entity from JAK2-negative MPNs? This chapter reviews the significance of JAK2 mutation positivity in the diagnosis, prognosis, and therapy of MPNs.

  10. 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

  11. Composition of immune complexes and their relation to plasma fibronectin in chronic myeloproliferative disorders.

    PubMed Central

    Baglin, T P; Simpson, A W; Price, S M; Boughton, B J

    1987-01-01

    High concentrations of circulating immune complexes were detected by polyethylene glycol precipitation in 11 of 20 patients with myelofibrosis secondary to chronic myeloproliferative disease. Circulating immune complexes showed a positive correlation with plasma IgG concentrations both in patients and controls. Covariance analysis of the two groups showed significantly increased polyethylene glycol precipitable IgG in patients when adjusted for plasma IgG concentrations, indicating that the patients had significantly increased concentrations of complexed IgG. The immune complexes contained IgG, C3, and fibronectin and were inversely correlated with plasma fibronectin concentrations, suggesting that this major non-specific opsonin is important for the normal clearance of immune complexes. Therapeutic plasmapheresis efficiently removed circulating complexes and produced an increase in plasma fibronectin. This suggests that plasmapheresis may be useful for controlling immune complex mediated complications of these disorders. PMID:3429676

  12. Is JAK2V617F Mutation the Only Factor for Thrombosis in Philadelphia-Negative Chronic Myeloproliferative Neoplasms?

    PubMed

    Uyanik, Mehmet Sevki; Baysal, Mehmet; Pamuk, Gulsum Emel; Maden, Muhammet; Akker, Mustafa; Umit, Elif Gulsum; Demir, Muzaffer; Aydogdu, Erkan

    2016-09-01

    The most common genetic disorder in Philadelphia negative chronic myeloproliferative neoplasms is the JAK2-V617F mutation. In the present study, we aimed to determine risk factors for thrombosis in patients with essential thrombocytosis and polycythemia vera. We screened the medical records of 101 patients. Risk factors which may predict thrombosis were recorded. Venous thrombosis (VT) before diagnosis was significantly higher in JAK2 positive patients. VT after diagnosis was similar in JAK2 positive and negative groups, and was significantly higher in elderly patients. Treatment places importance on the JAK2 mutation under unmodifiable cardiovascular risk factors such as advanced age after diagnosis. PMID:27429517

  13. Centrosomal targeting of tyrosine kinase activity does not enhance oncogenicity in chronic myeloproliferative disorders.

    PubMed

    Bochtler, T; Kirsch, M; Maier, B; Bachmann, J; Klingmüller, U; Anderhub, S; Ho, A D; Krämer, A

    2012-04-01

    Constitutive tyrosine kinase activation by reciprocal chromosomal translocation is a common pathogenetic mechanism in chronic myeloproliferative disorders. Since centrosomal proteins have been recurrently identified as translocation partners of tyrosine kinases FGFR1, JAK2, PDGFRα and PDGFRβ in these diseases, a role for the centrosome in oncogenic transformation has been hypothesized. In this study, we addressed the functional role of centrosomally targeted tyrosine kinase activity. First, centrosomal localization was not routinely found for all chimeric fusion proteins tested. Second, targeting of tyrosine kinases to the centrosome by creating artificial chimeric fusion kinases with the centrosomal targeting domain of AKAP450 failed to enhance the oncogenic transforming potential in both Ba/F3 and U2OS cells, although phospho-tyrosine-mediated signal transduction pathways were initiated at the centrosome. We conclude that the centrosomal localization of constitutively activated tyrosine kinases does not contribute to disease pathogenesis in chronic myeloproliferative disorders. PMID:22015771

  14. The chronic myeloproliferative disorders and mutation of JAK2: Dameshek's 54 year old speculation comes of age.

    PubMed

    Kaushansky, Kenneth

    2007-03-01

    In 1951, William Dameshek speculated on the common origin of the chronic myeloproliferative disorders--polycythemia vera (PV), essential thrombocythemia (ET), chronic idiopathic myelofibrosis (IMF), and chronic myelogenous leukemia (CML). Subsequent work suggested that all arose from the hematopoietic stem cell. About 20 years ago the oncogene responsible for CML, bcr-abl, was identified, and more recently the mutant genes that cause hypereosinophilic syndrome and systemic mast cell disorder have been discovered. However, until very recently, the origin of PV, ET, and IMF have defied molecular explanation. In 2005, four separate groups working on tyrosine kinase signal transduction reported a gain-of-function, valine-to-phenyalanine, mutation at position 617 in the JH2 domain of the Janus kinase (JAK) 2 cytoplasmic tyrosine kinase. This mutation requires the presence of the erythropoietin, thrombopoietin, or granulocyte-colony stimulating factor receptor/s for function, the mutation leads to functional hyperactivity and appears responsible for hematopoietic growth factor hypersensitivity, the most characteristic finding in these disorders. Virtually all patients with PV and substantial proportions of those with ET and IMF have now been shown to harbor this mutation. The mutant kinase appears to be a useful diagnostic test for myeloproliferative disorders and may have prognostic value. Future research will undoubtedly focus on the development of specific inhibitors as therapeutic agents as well as answering a number of questions that remain regarding the role of signal intensity, genotypic and phenotypic expression and the possible involvement of additional as yet unidentified mutations in these disorders.

  15. HFE C282Y mutation as a genetic modifier influencing disease susceptibility for chronic myeloproliferative disease.

    PubMed

    Andrikovics, Hajnalka; Meggyesi, Nora; Szilvasi, Aniko; Tamaska, Julia; Halm, Gabriella; Lueff, Sandor; Nahajevszky, Sarolta; Egyed, Miklos; Varkonyi, Judit; Mikala, Gabor; Sipos, Andrea; Kalasz, Laszlo; Masszi, Tamas; Tordai, Attila

    2009-03-01

    Iron metabolism has been implicated in carcinogenesis and several studies assessed the potential role of genetic variants of proteins involved in iron metabolism (HFE C282Y, TFR S142G) in different malignancies. Few reports addressed this issue with relation to chronic myeloproliferative disorders (CMPD). The aims of our study were (a) to examine the potential associations of CMPD development with genetic modifiers of iron metabolism in a large cohort of CMPD patients; (b) to examine associations of genetic variants of proteins involved in iron metabolism; and acquired JAK2 V617F mutation with clinical characteristics of CMPD. HFE C282Y was genotyped in 328 CMPD patients and 996 blood donors as controls, HFE H63D, and TFR S142G were tested in CMPD patients and 171 first time blood donors. JAK2 V617F mutation was tested in CMPD patients and in 122 repeated blood donors. Decreased C282Y allele frequency (allele frequency+/-95% confidence interval) was found in the CMPD group (1.8%+/-1.0%) compared with controls (3.4%+/-0.8%; P=0.048). TFR S142G allele frequency was reduced among V617F-negative CMPD patients (34.8%+/-7.6%) compared with controls (47.8%+/-5.4%; P=0.02). The frequency of JAK2 V617F was 75.9% (249 of 328) in the CMPD group. At presentation, elevated hemoglobin levels were found in V617F-positive patients compared with V617F-negative counterparts (P<0.000). Vascular complications (26.6% versus 15.2%; P=0.039) as well as female gender (57.4% versus 41.8%; P=0.019) were more common in V617F-positive patients. We found that HFE C282Y might be associated with a protective role against CMPD. Because chronic iron deficiency or latent anemia may trigger disease susceptibility for CMPD, HFE C282Y positivity may be a genetic factor influencing this effect.

  16. 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

  17. 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.

  18. 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. PMID:27468853

  19. [Experience in treating portal thromboses in patients with chronic myeloproliferative diseases].

    PubMed

    Melikyan, A L; Sukhanova, G A; Vakhrusheva, M V; Subortseva, I N; Orel, E B

    2016-01-01

    Patients with myeloproliferative diseases (MPD) are noted to be at high risk for portal thromboses. This problem gives rise to disability if it is untimely treated or resistant to therapy. The paper gives the experience of the Outpatient Department of the Hematology Research Center, Ministry of Health of the Russian Federation, in using antithrombin III in MPD patients (3 patients with primary myelofibrosis, 3 with essential thrombocythemia) and acute and subacute portal vein thromboses resistant to therapy with direct anticoagulants. In all 5 cases, the use of antithrombin III in combination with low-molecular-weight heparin showed a positive clinical effect as rapid relief of pain syndrome and comparatively early (3-week to 1.5-2-month) recanalization of thrombosed vessels. Three clinical cases are described in detail.

  20. [Experience in treating portal thromboses in patients with chronic myeloproliferative diseases].

    PubMed

    Melikyan, A L; Sukhanova, G A; Vakhrusheva, M V; Subortseva, I N; Orel, E B

    2016-01-01

    Patients with myeloproliferative diseases (MPD) are noted to be at high risk for portal thromboses. This problem gives rise to disability if it is untimely treated or resistant to therapy. The paper gives the experience of the Outpatient Department of the Hematology Research Center, Ministry of Health of the Russian Federation, in using antithrombin III in MPD patients (3 patients with primary myelofibrosis, 3 with essential thrombocythemia) and acute and subacute portal vein thromboses resistant to therapy with direct anticoagulants. In all 5 cases, the use of antithrombin III in combination with low-molecular-weight heparin showed a positive clinical effect as rapid relief of pain syndrome and comparatively early (3-week to 1.5-2-month) recanalization of thrombosed vessels. Three clinical cases are described in detail. PMID:26978616

  1. 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

  2. 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

  3. Myelodysplastic/ Myeloproliferative Neoplasms Treatment

    MedlinePlus

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

  4. 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.

  5. 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

  6. 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

    2016-10-07

    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

  7. 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

  8. Atypical chronic myeloid leukemia is clinically distinct from unclassifiable myelodysplastic/myeloproliferative neoplasms

    PubMed Central

    Hasserjian, Robert P.; Fox, Patricia S.; Rogers, Heesun J.; Geyer, Julia T.; Chabot-Richards, Devon; Weinzierl, Elizabeth; Hatem, Joseph; Jaso, Jesse; Kanagal-Shamanna, Rashmi; Stingo, Francesco C.; Patel, Keyur P.; Mehrotra, Meenakshi; Bueso-Ramos, Carlos; Young, Ken H.; Dinardo, Courtney D.; Verstovsek, Srdan; Tiu, Ramon V.; Bagg, Adam; Hsi, Eric D.; Arber, Daniel A.; Foucar, Kathryn; Luthra, Raja; Orazi, Attilio

    2014-01-01

    Atypical chronic myeloid leukemia (aCML) is a rare subtype of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) largely defined morphologically. It is, unclear, however, whether aCML-associated features are distinctive enough to allow its separation from unclassifiable MDS/MPN (MDS/MPN-U). To study these 2 rare entities, 134 patient archives were collected from 7 large medical centers, of which 65 (49%) cases were further classified as aCML and the remaining 69 (51%) as MDS/MPN-U. Distinctively, aCML was associated with many adverse features and an inferior overall survival (12.4 vs 21.8 months, P = .004) and AML-free survival (11.2 vs 18.9 months, P = .003). The aCML defining features of leukocytosis and circulating myeloid precursors, but not dysgranulopoiesis, were independent negative predictors. Other factors, such as lactate dehydrogenase, circulating myeloblasts, platelets, and cytogenetics could further stratify MDS/MPN-U but not aCML patient risks. aCML appeared to have more mutated RAS (7/20 [35%] vs 4/29 [14%]) and less JAK2p.V617F (3/42 [7%] vs 10/52 [19%]), but was not statistically significant. Somatic CSF3R T618I (0/54) and CALR (0/30) mutations were not detected either in aCML or MDS/MPN-U. In conclusion, within MDS/MPN, the World Health Organization 2008 criteria for aCML identify a subgroup of patients with features clearly distinct from MDS/MPN-U. The MDS/MPN-U category is heterogeneous, and patient risk can be further stratified by a number of clinicopathological parameters. PMID:24627528

  9. 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

  10. Acute promyelocytic leukemia co-existing with JAK2 V617F positive myeloproliferative neoplasm: a case report

    PubMed Central

    Mamorska-Dyga, Aleksandra; Wu, Jingjing; Khattar, Pallavi; Ronny, Faisal M. H.; Islam, Humayun; Seiter, Karen

    2016-01-01

    The V617F mutation of Janus-associated kinase 2 (JAK2) is commonly seen in myeloproliferative neoplasms (MPN). Transformation of JAK2 positive MPNs to acute leukemia has been reported. We here report a case of acute promyelocytic leukemia which was later confirmed to have a co-existing JAK2 V617F positive MPN. In addition, the patient was found to have FLT3-TKD mutation, which, together with PML/RARa, could play a role in the MPN transformation to APL. PMID:27358900

  11. 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.

  12. Management of side effects of BCR/ABL-negative chronic myeloproliferative neoplasm therapies. Focus on anagrelide.

    PubMed

    Antelo, María Luisa; de Las Heras, Natalia; Gonzalez Porras, Jose Ramón; Kerguelen, Ana; Raya, Jose María

    2015-12-01

    Although hydroxyurea is considered the first-line cytoreductive therapy in high-risk patients with polycythemia vera or essential thrombocythemia, approximately 20-25% of patients develop resistance or intolerance and they need an alternative therapy. Anagrelide is the treatment of choice in patients with essential thrombocythemia intolerant or with resistance to hydroxyurea. Anagrelide is usually well tolerated. Although there is concern about the increased risk of cardiac side effects, in most cases these are mild, and easily manageable. In this paper, the available evidence about the management of patients with myeloproliferative neoplasms, with a special focus on the side effects of drug therapies is reviewed.

  13. Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable

    MedlinePlus

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

  14. 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

  15. [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.

  16. 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

  17. JAK2V617F-positive endothelial cells contribute to clotting abnormalities in myeloproliferative neoplasms

    PubMed Central

    Etheridge, S. Leah; Roh, Michelle E.; Cosgrove, Megan E.; Sangkhae, Veena; Fox, Norma E.; Chen, Junmei; López, José A.; Kaushansky, Kenneth; Hitchcock, Ian S.

    2014-01-01

    The Janus kinase 2 (JAK2) V617F mutation is the primary pathogenic mutation in patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). Although thrombohemorrhagic incidents are the most common causes of morbidity and mortality in patients with MPNs, the events causing these clotting abnormalities remain unclear. To identify the cells responsible for the dysfunctional hemostasis, we used transgenic mice expressing JAK2V617F in specific lineages involved in thrombosis and hemostasis. When JAK2V617F was expressed in both hematopoietic and endothelial cells (ECs), the mice developed a significant MPN, characterized by thrombocytosis, neutrophilia, and splenomegaly. However, despite having significantly higher platelet counts than controls, these mice showed severely attenuated thrombosis following injury. Interestingly, platelet activation and aggregation in response to agonists was unaltered by JAK2V617F expression. Subsequent bone marrow transplants revealed the contribution of both endothelial and hematopoietic compartments to the attenuated thrombosis. Furthermore, we identified a potential mechanism for this phenotype through JAK2V617F-regulated inhibition of von Willebrand factor (VWF) function and/or secretion. JAK2V617F+ mice display a condition similar to acquired von Willebrand syndrome, exhibiting significantly less high molecular weight VWF and reduced agglutination to ristocetin. These findings greatly advance our understanding of thrombohemorrhagic events in MPNs and highlight the critical role of ECs in the pathology of hematopoietic malignancies. PMID:24469804

  18. 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

  19. Unbiased pro-thrombotic features at diagnosis in 977 thrombocythemic patients with Philadelphia-negative chronic myeloproliferative neoplasms.

    PubMed

    Gugliotta, Luigi; Iurlo, Alessandra; Gugliotta, Gabriele; Tieghi, Alessia; Specchia, Giorgina; Gaidano, Gianluca; Scalzulli, Potito R; Rumi, Elisa; Dragani, Alfredo; Martinelli, Vincenzo; Santoro, Cristina; Randi, Maria Luigia; Tagariello, Giuseppe; Candoni, Anna; Cattaneo, Daniele; Ricco, Alessandra; Palmieri, Raffaele; Liberati, Marina A; Langella, Maria; Rago, Angela; Bergamaschi, Micaela; Monari, Paola; Miglio, Rossella; Santoro, Umberto; Cacciola, Rossella; Rupoli, Serena; Mastrullo, Lucia; Musto, Pellegrino; Mazzucconi, Maria Gabriella; Vignetti, Marco; Cortelezzi, Agostino; Vianelli, Nicola; Martino, Bruno; De Stefano, Valerio; Passamonti, Francesco; Vannucchi, Alessandro M

    2016-07-01

    In patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPNs), the anti-thrombotic and/or cytoreductive treatment in the follow-up may affect the evaluation of the pro-thrombotic weight of the clinical and biological characteristics at diagnosis. In order to avoid this potential confounding effect, we investigated the relationship between prior thrombosis (PrTh: thrombosis occurred before diagnosis and before treatment) and the characteristics at diagnosis in 977 thrombocythemic patients with MPN, reclassified according to the WHO 2008 criteria. PrTh occurred in 194 (19.9%) patients, with similar rates in the different MPNs. In multivariate analysis, PrTh rate was significantly related to minor thrombocytosis (platelets ≤700×10(9)/L), leukocytosis (leukocytes >10×10(9)/L), higher hematocrit (HCT >45%), JAK2 V617F mutation, older age, and cardiovascular risk factors (CVRFs). The highest PrTh rate (33.9%) was associated with the coexistence of minor thrombocytosis and leukocytosis. Of note, the inverse relationship between PrTh rate and platelet count is consistent with the hemostatic paradox of thrombocytosis. In conclusion, this analysis in MPN patients disclosed the unbiased characteristics at diagnosis with a pro-thrombotic effect. Moreover, it suggests that the optimal control of blood cells counts, and CVRFs might be of utmost importance in the prevention of thrombosis during the follow-up. PMID:27107744

  20. Detection of the activating JAK2 V617F mutation in paraffin-embedded trephine bone marrow biopsies of patients with chronic myeloproliferative diseases.

    PubMed

    Horn, Thomas; Kremer, Marcus; Dechow, Tobias; Pfeifer, Walther M; Geist, Birgit; Perker, Michael; Duyster, Justus; Quintanilla-Martinez, Leticia; Fend, Falko

    2006-07-01

    The discovery of the activating V617F mutation in the JAK2 tyrosine kinase in a high proportion of patients with Ph- chronic myeloproliferative diseases (CMPD) represents a diagnostic breakthrough for these disorders. Trephine bone marrow biopsy is an essential part of the diagnostic workup of CMPD and represents a valuable archival source of DNA. Therefore, we studied 152 paraffin-embedded trephines with CMPD and related disorders for the presence of the V617F mutation, using both allele-specific polymerase chain reaction (PCR) and nested PCR with subsequent digestion with BsaXI. Only 6 of 152 (4%) samples were not evaluable because of poor DNA quality. The V617F mutation was detected in 27 of 28 (96%) cases of polycythemia vera, 17 of 23 (74%) cases of essential thrombocythemia, 28 of 45 (62%) cases of chronic idiopathic myelofibrosis, six of eight (75%) cases of CMPD unclassified, and two of four (50%) cases of myelodysplastic/myeloproliferative syndrome. Ph+ chronic myelogenous leukemia (four cases), reactive (secondary) erythrocytosis (14 cases), and thrombocytosis (one case) as well as normal controls (19 cases) all lacked the V617F mutation. Based on results of BsaXI digestion and sequencing, 24 of 54 (44%) evaluable V617F+ cases were considered homozygously mutated. Thus, detection of the V617F JAK2 mutation is feasible in paraffin-embedded trephine biopsies and represents a major advance in the diagnostic evaluation of CMPD.

  1. 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.

  2. 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/ ...

  3. 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/ ...

  4. 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/ ...

  5. 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

  6. 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

  7. 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.

  8. 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.

  9. 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

  10. 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

  11. Drugs Approved for Myeloproliferative Disorders

    MedlinePlus

    ... Ask about Your Treatment Research Drugs Approved for Myeloproliferative Neoplasms This page lists cancer drugs approved by the ... that are not listed here. Drugs Approved for Myeloproliferative Neoplasms Adriamycin PFS (Doxorubicin Hydrochloride) Adriamycin RDF (Doxorubicin Hydrochloride) ...

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

    PubMed

    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; Olalla Saad, Sara T; Traina, Fabiola

    2016-02-01

    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

  13. 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

  14. Immune complexes in myeloproliferative disorders.

    PubMed

    Lewis, C M; Pegrum, G D

    1977-12-01

    A fluorescein-labelled anti-human immunoglobulin was used to demonstrate that peripheral blood from patients with myelofibrosis had a high proportion of phagocytic cells containing fluorescent immune complexes. Cells from patients with other myeloproliferative diseases (either chronic myeloid leukaemia or polycythaemia rubra vera) did not show similar intracellular immune complexes. Serum from patients with myelofibrosis incubated with polymorphs from healthy subjects caused the appearance of inclusions similar to those found when the patients' own cells were used, the healthy phagocytes apparently engulfing complexes from the patients' sera. The presence of platelets or complement did not alter the incidence of intracellular fluorescence. These tests may help in the diagnosis of myelofibrosis and may also be valuable in recognising the onset of this condition in patients with polycythaemia rubra vera.

  15. 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.

  16. What Is Chronic Myelomonocytic Leukemia?

    MedlinePlus

    ... In this way CMML is more like a myeloproliferative disease ( myelo -- bone marrow, proliferative -- excessive growth). Chronic myeloid leukemia is an example of a myeloproliferative disease where there is an overproduction of white ...

  17. Thrombocytosis associated with a myeloproliferative disorder in a dog.

    PubMed

    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. PMID:2722642

  18. 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.

  19. 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)

  20. Familial myeloproliferative disease.

    PubMed

    Gilbert, H S

    1998-12-01

    The occurrence of one or more myeloproliferative disease (MPD) syndromes in 42 families is described. MPD appeared in a single generation in 10 families, two generations in 30 families and three generations in two families. In contrast to sparse case reports of familial polycythaemia vera, familial essential thrombocythaemia, or familial agnogenic myeloid metaplasia, in which all the involved members presented with the same MPD, 21 of the 42 families in the present series had members who presented with different MPD variants. The occurrence of multiple disease phenotypes in 'MPD families' is entirely consistent with the accepted theory of MPD as a disease arising from clonal expansion of a pluripotential haematopoietic precursor cell (PHPC) that retains its pluripotentiality and produces an array of inter-related syndromes, each named for the predominant haematic cell type involved in the proliferation. Changes in disease phenotype during the course of MPD and 'hybrid' phenotypes at the time of diagnosis are common. This report challenges the previously accepted belief that PV and other MPD variants are sporadic and randomly-occurring, and that familial occurrence of MPD is rare. The ability to identify 'MPD families' by surveying a large population of patients with MPD through the Internet, as was done in this study, and heightened awareness of familial occurrence and its phenotypic heterogeneity, should facilitate further characterization of the mode of inheritance in familial MPD and the nature of the gene mutations responsible for the dysregulation of haematopoiesis.

  1. 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

  2. [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.

  3. 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…

  4. 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

  5. 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.

  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. 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

  8. Chronic Endometritis and Positive Mycoplasma Cultures: Is There a Correlation?

    PubMed Central

    Nyirjesy, Paul; Amin-Hanjani, Soheil

    1995-01-01

    Objective: This study was undertaken to assess the impact of mycoplasma strains (Mycoplasma hominis or Ureaplasma urealyticum) on the development of chronic endometritis. Methods: Fifty-eight patients with acute pelvic infection were enrolled in this prospective cohort study. Endometrial cultures and biopsies were obtained on admission and 5–7 and 21–28 days after completion of treatment. Results: Of 148 samples, 40 were positive for mycoplasma strains (group A) and 58 were positive for mycoplasma with other pathogens (group B). Twenty-seven samples were positive for other pathogens only (group C). Chronic endometritis was seen in 7 (17.5%), 30 (51.7%), and 10 (37%) in group A, B, and C patients, respectively. Conclusions: The presence of mycoplasma strains in the endometrial cavity was not found to be associated with an increased incidence of chronic endometritis. PMID:18475413

  9. Distinct clinical characteristics of myeloproliferative neoplasms with calreticulin mutations

    PubMed Central

    Andrikovics, Hajnalka; Krahling, Tunde; Balassa, Katalin; Halm, Gabriella; Bors, Andras; Koszarska, Magdalena; Batai, Arpad; Dolgos, Janos; Csomor, Judit; Egyed, Miklos; Sipos, Andrea; Remenyi, Peter; Tordai, Attila; Masszi, Tamas

    2014-01-01

    Somatic insertions/deletions in the calreticulin gene have recently been discovered to be causative alterations in myeloproliferative neoplasms. A combination of qualitative and quantitative allele-specific polymerase chain reaction, fragment-sizing, high resolution melting and Sanger-sequencing was applied for the detection of three driver mutations (in Janus kinase 2, calreticulin and myeloproliferative leukemia virus oncogene genes) in 289 cases of essential thrombocythemia and 99 cases of primary myelofibrosis. In essential thrombocythemia, 154 (53%) Janus kinase 2 V617F, 96 (33%) calreticulin, 9 (3%) myeloproliferative leukemia virus oncogene gene mutation-positive and 30 triple-negative (11%) cases were identified, while in primary myelofibrosis 56 (57%) Janus kinase 2 V617F, 25 (25%) calreticulin, 7 (7%) myeloproliferative leukemia virus oncogene gene mutation-positive and 11 (11%) triple-negative cases were identified. Patients positive for the calreticulin mutation were younger and had higher platelet counts compared to Janus kinase 2 mutation-positive counterparts. Calreticulin mutation-positive patients with essential thrombocythemia showed a lower risk of developing venous thrombosis, but no difference in overall survival. Calreticulin mutation-positive patients with primary myelofibrosis had a better overall survival compared to that of the Janus kinase 2 mutation-positive (P=0.04) or triple-negative cases (P=0.01). Type 2 calreticulin mutation occurred more frequently in essential thrombocythemia than in primary myelofibrosis (P=0.049). In essential thrombocythemia, the calreticulin mutational load was higher than the Janus kinase 2 mutational load (P<0.001), and increased gradually in advanced stages. Calreticulin mutational load influenced blood counts even at the time point of diagnosis in essential thrombocythemia. We confirm that calreticulin mutation is associated with distinct clinical characteristics and explored relationships between mutation

  10. [Role of the activating mutation Val617Phe of Janus kinase 2 gene in myeloproliferative diseases and significance of its detection].

    PubMed

    Andrikovics, Hajnalka; Szilvási, Anikó; Meggyesi, Nóra; Király, Viktória; Halm, Gabriella; Lueff, Sándor; Nahajevszky, Sarolta; Mikala, Gábor; Sipos, Andrea; Lovas, Nóra; Csukly, Zoltán; Mátrai, Zoltán; Tamáska, Júlia; Tordai, Attila; Masszi, Tamás

    2007-02-01

    The Val617Phe point mutation of Janus kinase 2 gene is believed to participate in the pathogenesis of myeloproliferative syndrome characterised by the clonal alteration of hematopoietic stem cells. According to current results, the frequency of Val617Phe activating mutation is around 80% in polycythaemia vera, 35% in essential thrombocythemia, and 50% in chronic idiopathic myelofibrosis. The diagnoses of polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis were so far based on the exclusion of secondary factors as well as bone marrow biopsy histology. The goal of the present work was to establish simple molecular genetic techniques for the routine testing of Janus kinase 2 gene Val617Phe mutation, and to compare the clinical phenotypes of Val617Phe mutation positive and negative myeloproliferative syndromes. We employed the allele specific polymerase chain technique for detection of Val617Phe mutation in 252 patients with myeloproliferative syndrome. We measured Val617Phe frequency as 85,4% (117/137) in polycythemia vera, 56,6% (56/99) in essential thrombocythemia, and 87,5% (14/16) in idiopathic myelofibrosis. We found significantly elevated hemoglobin levels and white blood cell counts (measured at the time of diagnosis) in Val617Phe-positive polycythemia vera and essential thrombocythemia patient groups compared to Val617Phe-negative patients. However, the frequencies of splenomegaly and other complications (thrombosis, bleeding, transformation to acute leukemia) were not significantly different between the mutation-positive and negative groups. In conclusion, the non-invasive mutation analysis of the Janus kinase 2 Val617Phe is suitable for routine laboratory application and helps the differential diagnosis of myeloproliferative syndrome. Although the exact role of Val617Phe mutation testing has not yet been identified on the basis of a broad professional consensus, the testing is suggested in cases of erythrocytoses and thrombocytoses of

  11. The Role of MicroRNAs in Myeloproliferative Neoplasia.

    PubMed

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

    2016-07-01

    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

  12. 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

  13. 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. PMID:25844656

  14. Myeloproliferative Neoplasms: A Contemporary Review.

    PubMed

    Tefferi, Ayalew; Pardanani, Animesh

    2015-04-01

    Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) constitute the BCR-ABL1-negative myeloproliferative neoplasms and are characterized by mutually exclusive Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL) mutations; respective frequencies of these mutations are approximately 95%, 0%, and 0% in PV, 60%, 20%, and 3% in ET, and 60%, 25%, and 7% in PMF. These mutations might be accompanied by other mutations that are less specific to myeloproliferative neoplasms but are prognostically relevant, such as additional sex combs-like 1 (ASXL1). Characteristic bone marrow morphology is required for World Health Organization-compliant diagnosis, especially in distinguishing ET from prefibrotic PMF and masked PV. Survival is the longest in ET, although still inferior to that of the age- and sex-matched control population; median survivals for patients younger than 60 years are approximately 33 years for ET, 24 for PV, and 15 for PMF. Major disease complications include thrombosis and leukemic or fibrotic transformation. In PV and ET, risk factors for survival include older age, leukocytosis, and thrombosis, whereas JAK2 mutation in ET is associated with increased risk of thrombosis. In PMF, type 1 or type 1-like CALR mutations are associated with superior and ASXL1 with inferior survival. Prevention of thrombosis in PV is secured by phlebotomy (hematocrit target <45%) and in both PV and ET by low-dose aspirin therapy; high-risk patients derive additional antithrombotic benefit from cytoreductive therapy with hydroxyurea as first-line and interferon-alfa and busulfan as second-line drugs of choice. Although the JAK inhibitor ruxolitinib was recently approved for use in hydroxyurea-resistant PV, its role in routine clinical practice remains debatable. In myelofibrosis, stem cell transplant is the current treatment of choice for genetically or clinically high-risk disease; for all other patients

  15. Treatment for Chronic Pain in Patients With Advanced Cancer

    ClinicalTrials.gov

    2010-11-07

    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

  16. 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

  17. Positive end expiratory pressure in acute and chronic respiratory distress.

    PubMed

    Greenough, A; Chan, V; Hird, M F

    1992-03-01

    The optimum level of positive end expiratory pressure (PEEP) was determined in 16 infants with respiratory distress syndrome (median gestational age 29 weeks, median postnatal age 1 day) and in 16 infants with chronic respiratory distress (median gestational age 25 weeks, median postnatal age 15 days). All infants were studied at a PEEP sequence of 3, 0, 3, 6, and 3 cm H2O, all other ventilator parameters being kept constant. Each PEEP level was maintained for 20 minutes and at the end of each period arterial blood gas was checked. During acute respiratory distress syndrome there were no significant changes in oxygenation but arterial carbon dioxide tension (PaCO2) significantly decreased from a mean of 4.93 kPa at 3 cm H2O to 4.40 kPa at 0 cm H2O and increased to a mean of 5.87 kPa at 6 cm H2O. In the infants with chronic respiratory distress, oxygenation fell from a mean of 8.66 kPa at 3 cm H2O to 6.40 kPa at 0 cm H2O and improved at 6 cm H2O to a mean of 10.50 kPa. There were no significant changes in PaCO2. We conclude that addition of PEEP, up to 6 cm H2O, may be useful even after the first week of life. High levels of PEEP, however, have previously been reported, in certain infants, to result in circulatory disturbance. It is therefore important to assess the use of 6 cm H2O PEEP in a controlled study of longer term clinical outcome.

  18. Positive end expiratory pressure in acute and chronic respiratory distress.

    PubMed Central

    Greenough, A; Chan, V; Hird, M F

    1992-01-01

    The optimum level of positive end expiratory pressure (PEEP) was determined in 16 infants with respiratory distress syndrome (median gestational age 29 weeks, median postnatal age 1 day) and in 16 infants with chronic respiratory distress (median gestational age 25 weeks, median postnatal age 15 days). All infants were studied at a PEEP sequence of 3, 0, 3, 6, and 3 cm H2O, all other ventilator parameters being kept constant. Each PEEP level was maintained for 20 minutes and at the end of each period arterial blood gas was checked. During acute respiratory distress syndrome there were no significant changes in oxygenation but arterial carbon dioxide tension (PaCO2) significantly decreased from a mean of 4.93 kPa at 3 cm H2O to 4.40 kPa at 0 cm H2O and increased to a mean of 5.87 kPa at 6 cm H2O. In the infants with chronic respiratory distress, oxygenation fell from a mean of 8.66 kPa at 3 cm H2O to 6.40 kPa at 0 cm H2O and improved at 6 cm H2O to a mean of 10.50 kPa. There were no significant changes in PaCO2. We conclude that addition of PEEP, up to 6 cm H2O, may be useful even after the first week of life. High levels of PEEP, however, have previously been reported, in certain infants, to result in circulatory disturbance. It is therefore important to assess the use of 6 cm H2O PEEP in a controlled study of longer term clinical outcome. PMID:1575557

  19. Molecular analyses of 15,542 patients with suspected BCR-ABL1-negative myeloproliferative disorders allow to develop a stepwise diagnostic workflow

    PubMed Central

    Schnittger, Susanne; Bacher, Ulrike; Eder, Christiane; Dicker, Frank; Alpermann, Tamara; Grossmann, Vera; Kohlmann, Alexander; Kern, Wolfgang; Haferlach, Claudia; Haferlach, Torsten

    2012-01-01

    We investigated 15,542 patients with suspected BCR-ABL1- negative myeloproliferative or myelodysplastic/myeloproliferative neoplasm (including 359 chronic myelomonocytic leukemia) by a molecular marker set. JAK2V617F was detected in the suspected categories as follows: polycythemia vera 88.3%, primary myelofibrosis 53.8%, essential thrombocythemia 50.2%, and not further classifiable myeloproliferative neoplasms 38.0%. JAK2 exon 12 mutations were detected in 40.0% JAK2V617F-negative suspected polycythemia vera, MPLW515 mutations in 13.2%JAK2V617F-negative primary myelofibrosis and 7.1% JAK2V617F-negative essential thrombocythemia. TET2 mutations were distributed across all entities but were most frequent in suspected chronic myelomonocytic leukemia (77.8%). CBL mutations were identified in suspected chronic myelomonocytic leukemia (13.9%), primary myelofibrosis (8.0%), and not further classifiable myeloproliferative neoplasm (7.0%). This leads to a stepwise workflow for suspected myeloproliferative neoplasms starting with JAK2V617F and investigating JAK2V617F-negative patients for JAK2 exon 12 or MPL mutations, respectively. In cases in which a myeloproliferative neoplasm cannot be established, analysis for TET2, CBL and EZH2 mutations may be indicated. PMID:22511494

  20. 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

  1. The kinetics of clonal dominance in myeloproliferative disorders.

    PubMed

    Catlin, Sandra N; Guttorp, Peter; Abkowitz, Janis L

    2005-10-15

    To study clonal evolution in myeloproliferative disorders, we used stochastic models of hematopoiesis for mouse and cat, species for which the in vivo kinetics of hematopoietic stem cells (HSCs) have been experimentally defined. We determined the consequence if 1 HSC became able to survive without the support of a microenvironmental niche while the rest of its behavior did not change. Neoplastic cells persisted and dominated hematopoiesis in 14% of mice and 17% of cats, requiring mean times of 2.5 +/- 0.5 and 7.0 +/- 1.2 years, respectively (n=1000 simulations/species). In both species, when the number of neoplastic HSCs exceeded 0.5% of all HSCs, clonal dominance was inevitable. Our results can explain the absence of clonal myeloproliferative disorders in mice (lifetime, 2 years), are consistent with clinical observations in cats, and provide insight into the progression of chronic myelogenous leukemia (CML) in humans. They also demonstrate that competition for microenvironmental support can lead to the suppression of normal hematopoiesis as neoplasia evolves. Toxic or immunologic suppression of normal HSCs is not required.

  2. 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

  3. Ptch2 loss drives myeloproliferation and myeloproliferative neoplasm progression.

    PubMed

    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; Dierks, Christine

    2016-02-01

    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.

  4. 32P in the treatment of myeloproliferative disorders

    PubMed Central

    McMullin, Mary Frances; Cuthbert, Robert; Houston, Russell

    2016-01-01

    32P has been available for the treatment of myeloproliferative neoplasms (MPNs) for over seventy years. It was first used in 1938 by John H Lawrence in the treatment of polycythaemia and chronic leukaemias. With the introduction of agents such as hydroxycarbamide, interferon and anagrelide the role of 32P has been diminished. Today, Polycythaemia Rubra Vera (PRV) and Essential Thrombocythaemia (ET) remain the only myeloproliferative conditions in which 32P is indicated. Materials and Methods We carried out a retrospective review of all patients who had received 32P in Northern Ireland over a 24 year period. The time to successful response, duration of response, and associated complications were reviewed. Results 32P was successful in inducing remission in 90% of patients. This remission was sustained following one dose without the need for further therapy in 37% of cases. 47% required repeated doses. 26% required recommencement of alternative therapies. No cases of thrombosis, myelofibrosis or acute leukaemia were observed. Discussion We conclude that 32P is a well-tolerated and efficacious treatment option in the elderly. We discuss our results compared with previous work in this area. 32P will continue to be offered to elderly patients in our practice. PMID:27601760

  5. 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

  6. Comparison of mutated JAK2 and ABL1 as oncogenes and drug targets in myeloproliferative disorders

    PubMed Central

    Walz, Christoph; Cross, Nicholas C. P.; Van Etten, Richard A.; Reiter, Andreas

    2012-01-01

    Constitutively activated mutants of the non-receptor tyrosine kinases (TK) ABL1 and JAK2 play a central role in the pathogenesis of clinically and morphologically distinct chronic myeloproliferative disorders but are also found in some cases of de novo acute leukemia and lymphoma. Ligand-independent activation occurs as a consequence of point mutations or insertions/deletions within functionally relevant regulatory domains (JAK2), or the creation of TK fusion proteins by balanced reciprocal translocations, insertions or episomal amplification (ABL1 and JAK2). Specific abnormalities are correlated with clinical phenotype, although some are broad and encompass several WHO-defined entities. TKs are excellent drug targets as exemplified by the activity of imatinib in BCR-ABL1-positive disease, particularly chronic myeloid leukemia. Resistance to imatinib is seen in a minority of cases and is often associated with the appearance of secondary point mutations within the TK domain of BCR-ABL1. These mutations are highly variable in their sensitivity to increased doses of imatinib or alternative TK-inhibitors such as nilotinib or dasatinib. Selective and non-selective inhibitors of JAK2 are currently being developed and encouraging data from pre-clinical experiments and initial phase-I-studies regarding efficacy and potential toxicity of these compounds have already been reported. PMID:18528425

  7. 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

  8. Atypical Chronic Myelogenous Leukemia

    MedlinePlus

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

  9. 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

  10. A pilot study of the Histone-Deacetylase inhibitor Givinostat in patients with JAK2V617F positive chronic myeloproliferative neoplasms.

    PubMed

    Rambaldi, Alessandro; Dellacasa, Chiara Maria; Finazzi, Guido; Carobbio, Alessandra; Ferrari, Maria Luisa; Guglielmelli, Paola; Gattoni, Elisabetta; Salmoiraghi, Silvia; Finazzi, Maria Chiara; Di Tollo, Silvia; D'Urzo, Carmine; Vannucchi, Alessandro M; Barosi, Giovanni; Barbui, Tiziano

    2010-08-01

    A phase II A study was conducted to evaluate the safety and efficacy of Givinostat, a novel Histone-Deacetylases inhibitor, in patients with Polycythaemia Vera (PV, n = 12), Essential Thrombocythaemia (ET, n = 1) and Myelofibrosis (n = 16), bearing the JAK2V617F mutation. The study was approved by the local ethics committees and all human participants gave written informed consent. Givinostat was given orally for 24 weeks at a starting dose of 50 mg twice daily. The median treatment duration was 20 weeks. Reasons for treatment discontinuation were disease progression (n = 6), grade 2 thrombocytopenia (n = 1), psychiatric symptoms (n = 1) and withdrawn consent (n = 2). A dose reduction was applied in 10 patients while a temporary interruption occurred in 15. Among 13 PV/ET patients, 1 complete, 6 partial and 4 no responses were documented at study end while 2 patients went off-study, prematurely. Three major responses were registered among 16 MF patients. Pruritus disappeared in most patients and reduction of splenomegaly was observed in 75% of PV/ET and 38% of MF patients. Reverse transcription polymerase chain reaction identified a trend to reduction of the JAK2V617F allele burden. Givinostat was well tolerated and could induce haematological response in most PV and some MF patients. PMID:20560970

  11. [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

  12. 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:…

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

    ClinicalTrials.gov

    2016-05-19

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

  14. 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

  15. 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

  16. Combined MEK and JAK inhibition abrogates murine myeloproliferative neoplasm

    PubMed Central

    Kong, Guangyao; Wunderlich, Mark; Yang, David; Ranheim, Erik A.; Young, Ken H.; Wang, Jinyong; Chang, Yuan-I; Du, Juan; Liu, Yangang; Tey, Sin Ruow; Zhang, Xinmin; Juckett, Mark; Mattison, Ryan; Damnernsawad, Alisa; Zhang, Jingfang; Mulloy, James C.; Zhang, Jing

    2014-01-01

    Overactive RAS signaling is prevalent in juvenile myelomonocytic leukemia (JMML) and the myeloproliferative variant of chronic myelomonocytic leukemia (MP-CMML) in humans, and both are refractory to conventional chemotherapy. Conditional activation of a constitutively active oncogenic Nras (NrasG12D/G12D) in murine hematopoietic cells promotes an acute myeloproliferative neoplasm (MPN) that recapitulates many features of JMML and MP-CMML. We found that NrasG12D/G12D-expressing HSCs, which serve as JMML/MP-CMML–initiating cells, show strong hyperactivation of ERK1/2, promoting hyperproliferation and depletion of HSCs and expansion of downstream progenitors. Inhibition of the MEK pathway alone prolonged the presence of NrasG12D/G12D-expressing HSCs but failed to restore their proper function. Consequently, approximately 60% of NrasG12D/G12D mice treated with MEK inhibitor alone died within 20 weeks, and the remaining animals continued to display JMML/MP-CMML–like phenotypes. In contrast, combined inhibition of MEK and JAK/STAT signaling, which is commonly hyperactivated in human and mouse CMML, potently inhibited human and mouse CMML cell growth in vitro, rescued mutant NrasG12D/G12D-expressing HSC function in vivo, and promoted long-term survival without evident disease manifestation in NrasG12D/G12D animals. These results provide a strong rationale for further exploration of combined targeting of MEK/ERK and JAK/STAT in treating patients with JMML and MP-CMML. PMID:24812670

  17. 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.

  18. Impaired Right Ventricular-Pulmonary Vascular Function in Myeloproliferative Neoplasms

    PubMed Central

    Roach, Emir C.; Park, Margaret M.; Tang, W.H. Wilson; Thomas, James D.; Asosingh, Kewal; Kalaycio, Matt; Erzurum, Serpil C.; Farha, Samar

    2014-01-01

    Background Increased bone marrow hemangioblast numbers, alterations in erythroid/myeloid lineages, increased reticulin, and greater circulating bone marrow progenitor cells are present in patients with pulmonary arterial hypertension (PAH). The data suggest that myeloid progenitors contribute to the pathogenesis of PAH, but there is little data on prevalence of pulmonary vascular disease among different forms of myeloid diseases. We hypothesized that there would be a higher prevalence of pulmonary vascular disease in myeloproliferative neoplasms that have high circulating progenitor cells, such as myelofibrosis and chronic myelogenous leukemia (CML), as compared to those with low circulating progenitors, as in aplastic anemia. Methods Patients with myelofibrosis, CML and aplastic anemia who underwent echocardiographic evaluation of cardiac function in preparation for bone marrow transplantation at the Cleveland Clinic between 1997–2012 were identified using electronic medical records for demographic data, blood cell counts, and pulmonary function tests. All echocardiograms were uniformly analyzed in a blinded fashion by an advanced sonographer and cardiologist for measures of right and left ventricular function and estimation of pulmonary vascular disease. Results Gender and race distribution between disease groups were similar. Myelofibrosis [N=19] and aplastic anemia [N=30] had increased right ventricle (RV) wall thickness compared to CML [N=82] [RV Thickness (cm): aplastic anemia 0.7 ± 0.1, CML 0.5 ± 0.1 and myelofibrosis 0.7 ± 0.1; p = 0.02]. Patients with myelofibrosis had higher levels of estimated RV systolic pressure as compared to the other groups [RVSP (mmHg): aplastic anemia 29.9 ± 1.5, CML 26.2 ± 1.1 and myelofibrosis 36.7 ± 3.7; p < 0.01]. Conclusion The findings suggest an important role for myeloid progenitors in maintenance of pulmonary-vascular health, in which abnormal myeloproliferative progenitors are associated with right ventricle

  19. JAK2 V617F mutation, mesenteric vein thrombosis, and myeloproliferative disorders.

    PubMed

    Owens, Christopher D

    2010-07-01

    Mesenteric vein thrombosis is a rare disorder that is often the first manifestation of a systemic condition such as a hypercoagulable state or cancer. In particular, myeloproliferative disorders can present as mesenteric vein thrombosis even in the setting of relatively normal peripheral blood counts. A recent novel mutation in the Janus activated kinase 2 gene involving a gain-of-function substitute of valine to phenylalanine at position 617 (JAK2 V617F) has been discovered to be prevalent in patients with mesenteric vein thrombosis and myeloproliferative disorders. This article reports a patient who presented with mesenteric vein thrombosis and relatively normal peripheral blood counts. He was diagnosed with essential thrombocythemia after he tested positive for the JAK2 V617F mutation.

  20. 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

  1. Future therapies for the myeloproliferative neoplasms.

    PubMed

    Scherber, Robyn; Mesa, Ruben A

    2011-03-01

    Ever since their description as "myeloproliferative syndromes" by William Dameshek in 1951, the myeloproliferative neoplasms (MPNs) have been managed by the selective use of rather mundane, nonspecific therapies that rely on either antiplatelet effects or myelosuppression. The year 2005 ushered in a new era of drug development and discovery for the MPNs after the description of the JAK2 V617F mutation and the role this constitutively active tyrosine kinase has in MPN pathogenesis. Subsequently, multiple pharmacologic agents have begun (or are about to begin) testing for the inhibition of JAK2 in an attempt to improve the treatment of MPNs. Both primary myelofibrosis and myelofibrosis following essential thrombocythemia or polycythemia vera have been the targets of the most extensive testing of these agents to date. Responses to these oral JAK2 inhibitors have been primarily intended to reduce splenomegaly and meaningfully improve symptoms; effects on the JAK2 V617F allele burden or marrow histology are limited. Toxicities have ranged from myelosuppression to significant diarrhea. Additional agents with other mechanisms of action are also targeting JAK2, including histone deacetylase inhibitors and mTOR inhibitors. The results of preliminary trials of JAK2 inhibitors in polycythemia vera and essential thrombocythemia have been mixed but are premature. Many questions remain as to the optimal JAK2 inhibitory strategy and the full extent of the benefit of single-agent JAK2 inhibition.

  2. The Calreticulin gene and myeloproliferative neoplasms.

    PubMed

    Clinton, Aoibhinn; McMullin, Mary Frances

    2016-10-01

    The Philadelphia negative myeloproliferative neoplasms include polycythaemia vera (PV), essential thrombocytopenia (ET) and primary myelofibrosis (PMF). Patients with these conditions were mainly thought to harbour JAK2V617F mutations or an Myeloproliferative leukaemia (MPL) substitution. In 2013, two revolutionary studies identified recurrent mutations in a gene that encodes the protein calreticulin (CALR). This mutation was detected in patients with PMF and ET with non-mutated JAK2 or MPL but was absent in patients with PV. The CALR gene encodes the calreticulin protein, which is a multifactorial protein, mainly located in the endoplasmic reticulum in chromosome 19 and regulates calcium homeostasis, chaperones and has also been implicated in multiple cellular processes including cell signalling, regulation of gene expression, cell adhesion, autoimmunity and apoptosis. Somatic 52 bp deletions and recurrent 52 bp insertion mutations in CALR were detected and all resulted in frameshift and clusters in exon 9 of the gene. This review will summarise the current knowledge on the CALR gene and mutation of the gene in pathological conditions and patient phenotypes.

  3. The Calreticulin gene and myeloproliferative neoplasms.

    PubMed

    Clinton, Aoibhinn; McMullin, Mary Frances

    2016-10-01

    The Philadelphia negative myeloproliferative neoplasms include polycythaemia vera (PV), essential thrombocytopenia (ET) and primary myelofibrosis (PMF). Patients with these conditions were mainly thought to harbour JAK2V617F mutations or an Myeloproliferative leukaemia (MPL) substitution. In 2013, two revolutionary studies identified recurrent mutations in a gene that encodes the protein calreticulin (CALR). This mutation was detected in patients with PMF and ET with non-mutated JAK2 or MPL but was absent in patients with PV. The CALR gene encodes the calreticulin protein, which is a multifactorial protein, mainly located in the endoplasmic reticulum in chromosome 19 and regulates calcium homeostasis, chaperones and has also been implicated in multiple cellular processes including cell signalling, regulation of gene expression, cell adhesion, autoimmunity and apoptosis. Somatic 52 bp deletions and recurrent 52 bp insertion mutations in CALR were detected and all resulted in frameshift and clusters in exon 9 of the gene. This review will summarise the current knowledge on the CALR gene and mutation of the gene in pathological conditions and patient phenotypes. PMID:27354406

  4. [Immunosuppressive therapy in patients with HBeAg-positive chronic active hepatitis B?].

    PubMed

    Maier, K P; Lepiorz, H; Berthold, H; Gerok, W

    1982-08-01

    The course of HBsAg-positive chronic active hepatitis was followed in 36 patients who were treated by immunosuppression and in 45 controls by means of serial determinations of HBeAg titers and by repeated biopsies of the liver. In the treated group remission occurred in 52% (HBeAg negative) resp. 48% (HBeAg positive); in the control group these percentages were almost identical, that is to say 61% resp. 41%. During therapy 5 out of 9 HBeAg positive patients and 7 out of 12 HBeAg negative patients developed cirrhosis of the liver as compared to 5 resp. 10, and 2 resp. 12 patients in the control group. Judging from these results it seems unlikely, that the course of HBsAg positive, chronic-active hepatitis in patients, whose serum shows a positive HBeAg titer by immunodiffusion, might be influenced in a positive way by immunosuppressive therapy.

  5. Changing concepts of diagnostic criteria of myeloproliferative disorders and the molecular etiology and classification of myeloproliferative neoplasms: from Dameshek 1950 to Vainchenker 2005 and beyond.

    PubMed

    Michiels, Jan Jacques; Berneman, Zwi; Schroyens, Wilfried; De Raeve, Hendrik

    2015-01-01

    The Polycythemia Vera Study Group (PVSG) and WHO classifications distinguished the Philadelphia (Ph(1)) chromosome-positive chronic myeloid leukemia from the Ph(1)-negative myeloproliferative neoplasms (MPN) essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (MF) or primary megakaryocytic granulocytic myeloproliferation (PMGM). Half of PVSG/WHO-defined ET patients show low serum erythropoietin levels and carry the JAK2(V617F) mutation, indicating prodromal PV. The positive predictive value of a JAK2(V617F) PCR test is 95% for the diagnosis of PV, and about 50% for ET and MF. The WHO-defined JAK2(V617F)-positive ET comprises three ET phenotypes at clinical and bone marrow level when the integrated WHO and European Clinical, Molecular and Pathological (ECMP) criteria are applied: normocellular ET (WHO-ET), hypercellular ET due to increased erythropoiesis (prodromal PV) and hypercellular ET associated with megakaryocytic granulocytic myeloproliferation (EMGM). Four main molecular types of clonal MPN can be distinguished: JAK2(V617F)-positive ET and PV; JAK2 wild-type ET carrying the MPL(515); mutations in the calreticulin (CALR) gene in JAK2/MPL wild-type ET and MF, and a small proportion of JAK2/MPL/CALR wild-type ET and MF patients. The JAK2(V617F) mutation load is low in heterozygous normocellular WHO-ET. The JAK2(V617F) mutation load in hetero-/homozygous PV and EMGM is clearly related to MPN disease burden in terms of splenomegaly, constitutional symptoms and fibrosis. The JAK2 wild-type ET carrying the MPL(515) mutation is featured by clustered small and giant megakaryocytes with hyperlobulated stag-horn-like nuclei, in a normocellular bone marrow (WHO-ET), and lacks features of PV. JAK2/MPL wild-type, CALR mutated hypercellular ET associated with PMGM is featured by dense clustered large immature dysmorphic megakaryocytes and bulky (cloud-like) hyperchromatic nuclei, which are never seen in WHO-ECMP-defined JAK2(V617F) mutated ET

  6. The history of myeloproliferative disorders: before and after Dameshek.

    PubMed

    Tefferi, A

    2008-01-01

    In 1951, William Dameshek described the concept of 'myeloproliferative disorders (MPDs)' by grouping together chronic myelogenous leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) and erythroleukemia; he reasoned that a self-perpetuating trilineage myeloproliferation underlined their pathogenesis. Pre-Dameshek luminaries who laid the foundation for this unifying concept include Bennett, Virchow, Heuck, Vaquez, Osler, Di Guglielmo and Epstein. In 1960, Nowell and Hungerford discovered the Philadelphia (Ph) chromosome in CML. In 1967, Fialkow and colleagues used X-linked polymorphisms to establish CML as a clonal stem cell disease. Also in 1967, the PV Study Group was summoned by Louis Wasserman to study the natural history of PV and conduct large-scale clinical trials. In 1972, Janet Rowley deciphered the Ph chromosome as a reciprocal translocation between chromosomes 9 and 22, thus paving the way for its subsequent characterization as an oncogenic BCR-ABL mutation. In 1996, Brian Druker discovered imatinib-a small molecule ABL inhibitor with exceptional therapeutic activity in CML. In 2005, a gain-of-function JAK2 mutation (JAK2V617F) was described in BCR-ABL-negative MPDs, raising the prospect of a CML-like treatment strategy in PV, ET and PMF. The current review considers these and other landmark events in the history of MPDs.

  7. 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

  8. 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

  9. 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

  10. [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. PMID:24709317

  11. Transient myeloproliferative disorder with partial trisomy 21.

    PubMed

    Takahashi, Takahide; Inoue, Akira; Yoshimoto, Junko; Kanamitsu, Kiichiro; Taki, Tomohiko; Imada, Masahide; Yamada, Mutsuko; Ninomiya, Shinsuke; Toki, Tsutomu; Terui, Kiminori; Ito, Etsuro; Shimada, Akira

    2015-11-01

    Myeloid malignancy with Down syndrome (ML-DS) is estimated to have a step-wise leukemogenesis including GATA1 mutation. Trisomy 21 is essential for ML-DS; however, we do not know exactly which gene or genes located on chromosome 21 are necessary for the ML-DS. We report a female infant with transient myeloproliferative disorder (TMD) and partial trisomy 21. SNP array analysis showed 10 Mb amplification of 21q22.12-21q22.3, which included DYRK1A, ERG, and ETS but not the RUNX1 gene. With two other reported TMD cases having partial trisomy 21, DYRK1A, ERG, and ETS were the most likely genes involved in collaboration with the GATA1 mutation. PMID:26138905

  12. Factors Contributing to Chronic Ankle Instability: Kinesthesia and Joint Position Sense

    PubMed Central

    Konradsen, Lars

    2002-01-01

    Objective: To present a comprehensive review of the influence of altered kinesthesia and joint position sense on chronic ankle instability and to present a model connecting deficits in ankle position sense with the increased risk of sustaining lateral ankle sprains. Data Sources: I searched MEDLINE for the years 1966–2001 using the key words ankle and kinesthesia or position sense and books on proprioception. Data Synthesis: Study findings suggest a risk for unprovoked lateral ankle sprains when the lateral border of the foot accidentally catches the ground surface during the late swing phase of normal locomotion. In normal situations, the lateral border of the foot clears the ground by only 5 mm, and a small increase in ankle-position error may substantially increase the risk of a collision. Findings of affected kinesthesia and joint position sense in subjects with chronically unstable ankles dominate over studies showing nonsignificant results, but the answer is far from clear. Conclusions/Recommendations: Changes in joint position sense and kinesthesia of a magnitude found in subjects with chronically unstable ankles can lead to an increased risk of sustaining lateral ankle sprains. Results from a small number of studies suggest that balance and coordination training can restore the increased uncertainty of joint positioning to normal levels. PMID:12937559

  13. Characterization of CD34+ hematopoietic progenitor cells in JAK2V617F and CALR-mutated myeloproliferative neoplasms.

    PubMed

    Angona, Anna; Alvarez-Larrán, Alberto; Bellosillo, Beatriz; Longarón, Raquel; Camacho, Laura; Fernández-Rodríguez, M Concepción; Pairet, Silvia; Besses, Carles

    2016-09-01

    Mutations in JAK2 or CALR are observed in patients with myeloproliferative neoplasms (MPN). To get further insight in the dynamics of the mutant clone, we assessed the mutant allele burden in hematopoietic stem cells (HSCs), hematopoietic progenitor cells (HPCs) and granulocytes from 138 patients [51 polycythemia vera (PV), 58 essential thrombocythemia (ET) and 29 myelofibrosis (MF)]. CALR-mutated ET patients harbored a higher mutant load at progenitor level than JAK2V617F-positive ET (HSCs: 39.9% vs 7.5% p<0.001, HPCs: 32.7% vs 7.7% p<0.001). Moreover, HSCs of CALR-mutated ET patients showed a similar mutational load than patients with CALR-mutated MF (39.9% vs 48.2%, p=0.17). Regarding JAK2V617F MPN, PV and ET patients showed a low mutational burden at progenitor level whereas in the myelofibrotic phase the dominance of the mutated clone was a constant finding. In conclusion, the size of the mutated clone in chronic phase MPN is different according to genotype with CALR-mutated ET showing a pattern similar to that observed in MF. PMID:27427771

  14. 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

  15. [Meglumine acridonacetate in combined antiviral treatment of HBeAg-positive chronic hepatitis B].

    PubMed

    Stel'makh, V V; Okovityĭ, S V; Romantsov, M G; Tuan, N Kh; Oiungerel, M

    2013-06-01

    647 patients with HBeAg positive chronic hepatitis B who have not previously received antiviral therapy were participated in randomized, post-marketing, double-blinded, placebo-controlled clinical trial. Interferon inducer cycloferon was presented as study drug. 323 patients with chronic hepatitis B (HBV) with "wild" HBeAg(+) strain of HBV were treated with cycloferon and Lamivudin for 48 weeks. Control group included 324 patients with similar pathology, treated with Lamivudin and placebo for 48 weeks. The study has shown the benefit of cycloferon+lamivudin treatment in comparison with lamivudin monotherapy. Improving of liver histology in 48 weeks of the therapy was observed in 71% of patients in Study group in comparison with 57% in control group (p<0.01). Combined therapy has resulted in decrease of relapse by 24 week of the follow-up period (13% vs. 86%, p<0.001). The higher efficacy of cycloferon+lamivudin in patients with HBeAg positive chronic hepatitis B has proven the role of own antiviral effect of interferon inducer cycloferon, interferon effect of cycloferon in the elimination of virus-infected hepatocytes, as well as the presence of an immunomodulatory effect of the preparation, aimed at the elimination of HBeAg and HBsAg with the following seroconversion. 48-week course of combined antiviral therapy of HBeAg-positive patients with chronic hepatitis B is recommended as first-line therapy for patients with HBeAg-positive chronic hepatitis B, who have not previously received nucleoside analogues, as well as alternative therapy of Lamivudin-refractory patients. PMID:23863208

  16. Positional effects on distribution of ventilation in chronic obstructive pulmonary disease

    SciTech Connect

    Shim, C.; Chun, K.J.; Williams, M.H. Jr.; Blaufox, M.D.

    1986-09-01

    Ventilation is distributed predominantly to the dependent lung in normal persons in the decubitus position. We evaluated the distribution of ventilation in four patients with mild-to-moderate chronic obstructive pulmonary disease using 81mKr gas. Patients were tested in the sitting and right and left decubitus positions with and without the application of positive end expiratory pressure (PEEP). In contrast to findings in controls, ventilation was predominantly distributed to the nondependent lung in patients in the decubitus position. Mean ventilation in the right lung decreased from 51% of the total in the sitting position to 31% in the right decubitus position; it increased with the application of 10 cm PEEP. Reduced ventilation in the dependent lung most likely is caused by closure of the airways after a decrease in volume. Application of PEEP resulted in increased lung volume and preferential distribution of ventilation to the dependent lung.

  17. 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

  18. Determination of whether screening tests for chronic atrophic gastritis really has a positive predictive value.

    PubMed

    Di Paola, Flaviano; D'Angelo, Valentina; Tatangelo, Fabiana; Barchiesi, Vittoria; Rizzo, Marianna; Cantile, Monica; Botti, Gerardo; Cavalcanti, Ernesta

    2015-09-01

    Intestinal‑type gastric adenocarcinomas are preceded by precancerous lesions, which begin with chronic atrophic gastritis. Over the last few years, multiple serological screening techniques have been performed and commercialized for the diagnosis of chronic atrophic gastritis. In the present study, 123 patients were recruited at the International Cancer Institute 'G. Pascale' Foundation (Naples, Italy) to test commercial kits for the serological determination of chronic atrophic gastritis, supported by histological analysis, according to the International Group of Gastroenterologists 'Operative Link for Gastritis Assessment Staging System'. The results revealed a significant discrepancy between serological screening and histological evaluation in 10.6% of patients, which highlighted the dubious positive predictive value of commercial serological screening kits.

  19. 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.

  20. The genetic basis of myeloproliferative disorders.

    PubMed

    Skoda, Radek

    2007-01-01

    For many decades, myeloproliferative disorders (MPD) were largely neglected orphan diseases. The conceptual work of William Dameshek in 1951 provided the basis for understanding MPD as a continuum of related syndromes, possibly with a common pathogenetic cause. Recognition of the clonal origin of peripheral blood cells in MPD in 1976 and the ability to grow erythroid colonies in vitro in the absence of added growth factors in 1974 initiated the search for genetic alterations that might be responsible for myeloproliferation. Mutations in the genes for the erythropoietin receptor, thrombopoietin and the von Hippel-Lindau protein were found to cause familial syndromes resembling MPD, but despite their phenotypic similarities, none of these mutations were later found in patients with the sporadic form of MPD. The discovery of activating mutations in the Janus kinase 2 (JAK2) in most patients with MPD has fully transformed and energized the MPD field. Sensitive assays for detecting the JAK2-V617F mutation have become an essential part of the diagnostic work-up, and JAK2 now constitutes a prime target for developing specific inhibitors for the treatment of patients with MPD. Despite this progress, many questions remain unsolved, including how a single JAK2 mutation causes three different MPD phenotypes, what other genes might be involved in the pathogenesis, and what are the factors determining the progression to acute leukemia.

  1. 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

  2. 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

  3. Inactivation of polycomb repressive complex 2 components in myeloproliferative and myelodysplastic/myeloproliferative neoplasms.

    PubMed

    Score, Joannah; Hidalgo-Curtis, Claire; Jones, Amy V; Winkelmann, Nils; Skinner, Alison; Ward, Daniel; Zoi, Katerina; Ernst, Thomas; Stegelmann, Frank; Döhner, Konstanze; Chase, Andrew; Cross, Nicholas C P

    2012-02-01

    The polycomb repressive complex 2 (PRC2) is a highly conserved histone H3 lysine 27 methyltransferase that regulates the expression of developmental genes. Inactivating mutations of the catalytic component of PRC2, EZH2, are seen in myeloid disorders. We reasoned that the other 2 core PRC2 components, SUZ12 and EED, may also be mutational targets in these diseases, as well as associated factors such as JARID2. SUZ12 mutations were identified in 1 of 2 patients with myelodysplastic syndrome/myeloproliferative neoplasms with 17q acquired uniparental disomy and in 2 of 2 myelofibrosis cases with focal 17q11 deletions. All 3 were missense mutations affecting the highly conserved VEFS domain. Analysis of a further 146 myelodysplastic syndrome/myeloproliferative neoplasm patients revealed an additional VEFS domain mutant, yielding a total mutation frequency of 1.4% (2 of 148). We did not find mutations of JARID2 or EED in association with acquired uniparental disomy for chromosome 6p or 11q, respectively; however, screening unselected cases identified missense mutations in EED (1 of 148; 1%) and JARID2 (3 of 148; 2%). All 3 SUZ12 mutations tested and the EED mutation reduced PRC2 histone methyltransferase activity in vitro, demonstrating that PRC2 function may be compromised in myeloid disorders by mutation of distinct genes.

  4. 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

  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. 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

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

    PubMed

    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.

  8. Genetics Home Reference: 8p11 myeloproliferative syndrome

    MedlinePlus

    ... resources address the diagnosis or management of 8p11 myeloproliferative syndrome: Cancer.Net from the American Society of Clinical Oncology: ... Hodgkin's Lymphoma KidsHealth from Nemours: Leukemia MalaCards: 8p11 ... associated with FGFR1 rearrangement Patient Support and Advocacy ...

  9. 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

  10. 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

  11. Frequency of Latent and Smear Positive Tuberculosis in Chronic Psychotic Disorders

    PubMed Central

    Ebrahimi, Hannan; Mohammadi, Alieh; Jahromi, Sina Khajeh; Naghdipour, Misa; Ebrahimi, Hossein

    2013-01-01

    Objective Screening is one of the ways to combat Tuberculosis (TB) and should be mostly concentrated on groups showing some symptoms of the disease. Tuberculosis can be transferred from person to person in laboratories, prisons and psychiatry hospitals. The purpose of this study was to survey pulmonary TB in patients with schizophrenia in Rasht. Methods In this descriptive-cross sectional, Two hundred fifty seven consecutive patients with chronic psychotic disorder hospitalized in psychotic hospitals underwent purified protein derivative (PPD) test. PPD test was done with the unit 5T which was injected subcutaneously on anterior surface and at the top of left forearm. The results of the test were interpreted by the pen technique method and based on transverse diameter of induration of about 48-72 hrs. Induration size due to hypersensitivity to PPD more than 10mm was considered positive. Patients with positive PPD test underwent complementary sputum smear. Data were analyzed using chi- square and T test. Results The mean age of patients was 45±10 years; 75.5% were male, 74.7% were single, 10.5% married, 7.8% divorced, and 68.1% were smokers. These patients suffered from chronic psychotic disorder at the mean time of 15±7.9 years. In 74 patients (28%) positive PPD test were recorded, but active pulmonary TB was not found in complementary experiments of PPD sample. Based on data analysis, only age and gender showed a significant relationship with the results of the PPD test (P < 0.05). Conclusions This study showed that patients with positive PPD test are much more than the normal population, but active pulmonary TB was not observed in our samples. Since these patients are in clinical and closed places, more programs for screening are required. PMID:23682252

  12. 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

  13. 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.

  14. 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…

  15. 8p11 myeloproliferative syndrome: diagnostic challenges and pitfalls.

    PubMed

    Antic, Darko A; Vukovic, Vojin M; Milosevic Feenstra, Jelena D; Kralovics, Robert; Bogdanovic, Andrija D; Dencic Fekete, Marija S; Mihaljevic, Biljana S

    2016-01-01

    8p11 myeloproliferative syndrome (EMS) is a very rare clinicopathological entity which is characterized by the appearance of a myeloproliferative neoplasm in the bone marrow, peripheral lymphadenopathy, usually caused by T or B lymphoblastic lymphoma/leukemia, and a reciprocal translocation involving chromosome 8p11. Herein we describe a 22-year-old male patient with unusual clinical presentation of EMS. Namely, he initially presented with prolonged epistaxis. Complete blood count showed elevated hemoglobin (17.7g/dl), thrombocytopenia (98x109/l) and leukocytosis (57x109/l). Bone marrow aspirate and biopsy findings corresponded with the presence of a myeloproliferative neoplasm while cytogenetic analysis revealed t(8;13)(p11q12). After that ZMYM2-FGFR1 in-frame fusion was confirmed at the molecular level. Immediately after establishing the diagnosis of a myeloproliferative neoplasm (MPN) generalized lymphadenopathy was developed. Histopathologic examination of lymph node sample confirmed the diagnosis of a T cell lymphoblastic lymphoma without bone marrow involvement. Four cycles of Hyper CVAD chemotherapy were administered with complete morphological and cytogenetic remission. Four weeks after evaluation, patient developed peripheral blood monocytosis and eosinophilia without bone marrow criteria for acute leukemia. Cytogenetic analysis showed t(8;13) accompanied by complex numerical and structural aberrations. The patient underwent allogeneic stem cell transplantation (allo-SCT) from HLA matched sister and he subsequently achieved complete remission. In conclusion, patients with MPN and translocations involving chromosome 8 need to be carefully evaluated for EMS. However, having in mind the very aggressive clinical course of EMS allo-SCT is the only potential curative option. PMID:27569099

  16. 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

  17. 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

  18. Detection Of Rankl Positive Cells in Gingival Tissue in Healthy & Chronic Periodontal Disease Patients-A Comparative Study

    PubMed Central

    Gita, Bagavad; Chandrasekaran, S. C.

    2014-01-01

    Aim & Objective: The receptor activator of NF-kappa B ligand (RANKL) and its decoy receptor, osteoprotegerin (OPG), are the important proteins implicated in osteoclastogenesis. This study aimed to identify & quantify RANKL positive cells in gingival tissues in healthy & diseased patients & the study looks for immunohistochemical evidence of the expression of the protein in gingival tissue samples. Materials and Methods: Patients were randomly selected. Thirty subject each for (test & control). Age range of 25-55y, either sex was selected. Tissue samples were collected from Control – Healthy Gingiva & Test-Chronic Periodontitis Patients. Tissue sections were prepared. An Immunohistochemical analysis was done & cell counting was done for RANKL positive cells. Results: Immunohistochemical staining showed that RANKL-positive cells were significantly distributed in the inflammatory epithelium & connective tissue zone of diseased & non-diseased gingiva. RANKL, positive cells was increased significantly in patients with chronic periodontitis (p < 0.05). Conclusion: These findings imply that in this comparative study of gingival tissue for, RANKL positive cells, these cells were present in both healthy & chronic periodontitis samples, but number of positive cells present is significantly increased in chronic periodontitis. PMID:25584312

  19. Foot Placement and Arm Position Affect the Five Times Sit-to-Stand Test Time of Individuals with Chronic Stroke

    PubMed Central

    Kwong, Patrick W. H.; Ng, Shamay S. M.; Chung, Raymond C. K.; Ng, Gabriel Y. F.

    2014-01-01

    Objectives. To investigate the effect of two foot placements (normal or posterior placement) and three arm positions (hands on the thighs, arms crossed over chest, and augmented arm position with elbow extended) on the five times sit-to-stand (FTSTS) test times of individuals with chronic stroke. Design. Cross-sectional study. Setting. University-based rehabilitation clinic. Participants. A convenience sample of community-dwelling individuals with chronic stroke (N = 45). Methods. The times in completing the FTSTS with two foot placements and the three arm positions were recorded by stopwatch. Results. Posterior foot placement led to significantly shorter FTSTS times when compared with normal foot placement in all the 3 arm positions (P ≤ 0.001). In addition, hands on thigh position led to significantly longer FTSTS times than the augmented arm position (P = 0.014). Conclusion. Our results showed that foot placement and arm position could influence the FTSTS times of individuals with chronic stroke. Standardizing the foot placement and arm position in the test procedure is essential, if FTSTS test is intended to be used repeatedly on the same subject. PMID:25032220

  20. Chronic Kidney Disease and Antiretroviral Therapy in HIV-Positive Individuals: Recent Developments.

    PubMed

    Achhra, Amit C; Nugent, Melinda; Mocroft, Amanda; Ryom, Lene; Wyatt, Christina M

    2016-06-01

    Chronic kidney disease (CKD) has emerged as an important health concern in HIV-positive individuals. Preventing long-term kidney toxicity from an antiretroviral therapy is therefore critical. Selected antiretroviral agents, especially tenofovir disoproxil fumarate (TDF) and some ritonavir-boosted protease inhibitors (PI/rs), have been associated with increased risk of CKD. However, the CKD risk attributable to these agents is overall small, especially in those with low baseline risk of CKD and normal renal function. CKD risk in HIV-positive individuals can be further minimized by timely identification of those with worsening renal function and discontinuation of potentially nephrotoxic agents. Clinicians can use several monitoring tools, including the D:A:D risk score and routine measurements of estimated glomerular filtration (eGFR) and proteinuria, to identify high-risk individuals who may require an intervention. Tenofovir alafenamide (TAF), a TDF alternative, promises to be safer in terms of TDF-associated kidney and bone toxicity. While the short-term data on TAF does indicate lower eGFR decline and lower risk of proteinuria (vs. TDF), long-term data on renal safety of TAF are still awaited. Promising results have also emerged from recent trials on alternative dual-therapy antiretroviral regimens which exclude the nucleoside(tide) reverse transcriptase class as well as possibly the PI/rs, thereby reducing the drug burden, and possibly the toxicity. However, long-term safety or benefits of these dual-therapy regimens are still unclear and will need to be studied in future prospective studies. Finally, addressing risk factors such as hypertension and diabetes will continue to be important in this population. PMID:27130284

  1. 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

  2. Positive Interventions for Children with Chronic Illness: Parents' and Teachers' Concerns and Recommendations

    ERIC Educational Resources Information Center

    Shiu, Shiona

    2004-01-01

    Schools today are faced with increasing numbers of students with chronic illness. Medical advances, which improve health and prolong life, and increased incidence levels among some illnesses have led to this increase. Children with a chronic illness are more likely to encounter academic, social and emotional difficulties. The challenge facing…

  3. Opposing effects of acute versus chronic blockade of frontal cortex somatostatin-positive inhibitory neurons on behavioral emotionality in mice.

    PubMed

    Soumier, Amelie; Sibille, Etienne

    2014-08-01

    Reduced expression of somatostatin (SST) is reported across chronic brain conditions including major depression and normal aging. SST is a signaling neuropeptide and marker of gamma-amino butyric acid (GABA) neurons, which specifically inhibit pyramidal neuron dendrites. Studies in auditory cortex suggest that chronic reduction in dendritic inhibition induces compensatory homeostatic adaptations that oppose the effects of acute inhibition. Whether such mechanisms occur in frontal cortex (FC) and affect behavioral outcome is not known. Here, we used two complementary viral vector strategies to examine the effects of acute vs chronic inhibition of SST-positive neurons on behavioral emotionality in adult mice. SST-IRES-Cre mice were injected in FC (prelimbic/precingulate) with CRE-dependent adeno-associated viral (AAV) vector encoding the engineered Gi/o-coupled human muscarinic M4 designer receptor exclusively activated by a designer drug (DREADD-hM4Di) or a control reporter (AAV-DIO-mCherry) for acute or chronic cellular inhibition. A separate cohort was injected with CRE-dependent AAV vectors expressing diphtheria toxin (DTA) to selectively ablate FC SST neurons. Mice were assessed for anxiety- and depressive-like behaviors (defined as emotionality). Results indicate that acute inhibition of FC SST neurons increased behavioral emotionality, whereas chronic inhibition decreased behavioral emotionality. Furthermore, ablation of FC SST neurons also decreased behavioral emotionality under baseline condition and after chronic stress. Together, our results reveal opposite effects of acute and chronic inhibition of FC SST neurons on behavioral emotionality and suggest the recruitment of homeostatic plasticity mechanisms that have implications for understanding the neurobiology of chronic brain conditions affecting dendritic-targeting inhibitory neurons.

  4. 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

  5. Improvement in exercise endurance in patients with chronic airflow limitation using continuous positive airway pressure.

    PubMed

    O'Donnell, D E; Sanii, R; Younes, M

    1988-12-01

    To cope with the increased ventilatory demands of exercise, patients with severe expiratory flow limitation adopt strategies that ultimately place greater demands on their inspiratory muscles. Increased inspiratory muscle work may contribute to dyspnea causation and exercise limitation in such patients even before their ventilatory ceiling is attained. In this setting, continuous positive airway pressure (CPAP) should, by favorably affecting inspiratory muscle function and respiratory sensation, improve exercise performance. Six patients with chronic airflow limitation (CAL) (FEV1 +/- SD = 35 +/- 12% predicted) undertook constant-load, submaximal, cycle exercise at 50% of their predetermined maximal oxygen consumption: CPAP of 4 to 5 cm H2O was delivered during one exercise session and bracketed by one or two unassisted control sessions. In four patients, CPAP-assisted (4 to 5 cm H2O) exercise was bracketed by two unassisted control exercise sessions; two remaining patients undertook CPAP-assisted exercise and one unassisted control session. CPAP resulted in a significant increase in exercise endurance time (TLIM) (by 48%: CPAP TLIM (mean +/- SE) = 8.82 +/- 1.90 min; averaged control TLIM = 5.98 +/- 1.23 min (p less than 0.01). CPAP effectively ameliorated exertional dyspnea in the majority of patients; selected dyspnea ratings (Borg scale) during control (final minute) and CPAP at isotime, at comparable levels of ventilation, were (mean +/- SD) 7.83 +/- 2.25 and 5.5 +/- 2.2, respectively (p less than 0.025). Breathing frequency fell significantly during CPAP application (at isotime) by 17% (p less than 0.02); other steady-state ventilatory variables and end-expiratory lung volumes were not significantly different during CPAP and control.(ABSTRACT TRUNCATED AT 250 WORDS)

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

    ClinicalTrials.gov

    2016-10-03

    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

  7. 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

  8. 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

  9. 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

  10. Hematopoietic stem cells, progenitor cells and leukemic stem cells in adult myeloproliferative neoplasms.

    PubMed

    Ng, Ashley P

    2013-05-01

    The understanding of myeloproliferative neoplasms has changed dramatically since Dameshek proposed his classification over 50 years ago. Our knowledge of the types of cells which constitute the hematopoietic system and of how they are regulated has also appreciated significantly over this time. This review relates what is currently known about the acquired genetic mutations associated with adult myeloproliferative neoplasms to how they lead to the hematopoietic perturbations of myeloproliferative disease. There is a particular focus on how stem and progenitor cell compartments are affected by BCR-ABL1 and JAK2V617F mutations, and the particular issue of resistance of leukemic stem cells to conventional and targeted therapies. PMID:23013358

  11. Are occupational, hobby, or lifestyle exposures associated with Philadelphia chromosome positive chronic myeloid leukaemia?

    PubMed Central

    Bjork, J; Albin, M; Welinder, H; Tinnerberg, H; Mauritzson, N; Kauppinen, T; Stromberg, U; Johansson, B; Billstrom, R; Mikoczy, Z; Ahlgren, T; Nilsson, P; Mitelman, F; Hagmar, L

    2001-01-01

    OBJECTIVES—To investigate a broad range of occupational, hobby, and lifestyle exposures, suggested as risk factors for Philadelphia chromosome positive (Ph+) chronic myeloid leukaemia (CML).
METHODS—A case-control study, comprising 255 Ph+CML patients from southern Sweden and matched controls, was conducted. Individual data on work tasks, hobbies, and lifestyle exposures were obtained by telephone interviews. Occupational hygienists assessed occupational and hobby exposures for each subject individually. Also, occupational titles were obtained from national registries, and group level exposure—that is, the exposure proportion for each occupational title—was assessed with a job exposure matrix. The effects of 11 exposures using individual data and two exposures using group data (organic solvents and animal dust) were estimated.
RESULTS—For the individual data on organic solvents, an effect was found for moderate or high intensity of exposure (odds ratio (OR) 3.4, 95% confidence interval (95% CI) 1.1 to 11) and for long duration (15-20 years) of exposure (OR 2.1, 95% CI 1.1 to 4.0). By contrast, the group data showed no association (OR 0.69, 95% CI 0.27 to 1.8; moderate or high intensity versus no exposure). For extremely low frequency electromagnetic fields (EMFs), only individual data were available. An association with long occupational exposure to EMFs was found (OR 2.3, 95% CI 1.2 to 4.5). However, no effect of EMF intensity was indicated. No significant effects of benzene, gasoline or diesel, or tobacco smoking were found. OR estimates below unity were suggested for personal use of hair dye and for agricultural exposures.
CONCLUSIONS—Associations between exposure to organic solvents and EMFs, and Ph+CML were indicated but were not entirely consistent.


Keywords: risk factors; epidemiology; case-control study PMID:11600728

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

    ClinicalTrials.gov

    2015-12-28

    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

  13. 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

    2008-09-01

    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.

  14. A Concise Update on Risk Factors, Therapy, and Outcome of Leukemic Transformation of Myeloproliferative Neoplasms.

    PubMed

    Mascarenhas, John

    2016-08-01

    Myeloproliferative neoplasms (MPN) in chronic phase that evolve into blast phase (BP) hold a dismal prognosis and represent an urgent unmet clinical need. The mutational landscape of MPN-BP is distinct from de novo acute myeloid leukemia and offers insight into molecular mechanisms contributing to clonal evolution providing potential novel drug targets. A number of retrospective studies have identified patient- and disease-specific variables associated with increased risk of leukemic transformation (LT) of an underlying MPN. Several prognostic models have been developed to identify those MPN patients at highest risk for LT that may warrant early aggressive therapeutic intervention. Acute myeloid leukemia-type induction chemotherapy does not offer a significant survival benefit for MPN-BP unless followed by hematopoietic stem-cell transplantation. Unfortunately, most patients with MPN-BP are not candidates for hematopoietic stem-cell transplantation as a result of advanced age, competing comorbid conditions, or lack of an acceptable donor graft option. JAK2 inhibitor monotherapy is effective in reducing splenomegaly and symptom burden in the majority of treated patients with myelofibrosis, but LT can still occur. High-dose JAK2 inhibitor monotherapy appears tolerable but only modestly active in the treatment of MPN-BP. Current JAK2 inhibitor-based combination therapy approaches are supported by preclinical investigation and are currently being tested in multicenter clinical trials. PMID:27521308

  15. 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

  16. 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

  17. 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

  18. Complement fixing hepatitis B core antigen immune complexes in the liver of patients with HBs antigen positive chronic disease.

    PubMed Central

    Rizzetto, M; Bonino, F; Crivelli, O; Canese, M G; Verme, G

    1976-01-01

    One hundred and fifty-two biopsies from serologically HBsAg positive and negative patients with liver disease were studied in immunofluorescence: for the presence of the surface (HBs) and the core (HBc) antigenic determinants foeterminants of the hepatitis B virus, of immunoglobulins and complement (C) deposits, and for the capacity to fix human C. Circumstantial evidence is presented suggesting that HBc immune-complexes are a relevant feature in the establishment and progression of chronic HBSAg liver disease. C fixation by liver cells was shown in all HBC positive patients with chronic hepatitis; an active form was present in every case, except two with a persistent hepatitis, an inverse ratio of HBc to C binding fluorescence being noted between active chronic hepatitis and cirrhotic patients. HBc without C fixation was observed in only three patients in the incubation phase of infectious hepatitis. IgG deposits were often found in HBc containing, C fixing nuclei. No C binding or IgG deposits were observed in acute self-limited type B hepatitis, in serologically positive patients with normal liver or minimal histological lesions, with and without HBs cytoplasmic fluorescence in their biopsy, or in serologically negative individuals. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:1001973

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

    PubMed

    Martelletti, Paolo; Jensen, Rigmor H; Antal, Andrea; Arcioni, Roberto; Brighina, Filippo; de Tommaso, Marina; Franzini, Angelo; Fontaine, Denys; Heiland, Max; Jürgens, Tim P; Leone, Massimo; Magis, Delphine; Paemeleire, Koen; Palmisani, Stefano; Paulus, Walter; May, Arne

    2013-10-21

    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.

  20. 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

  1. 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…

  2. Essential Thrombocythemia

    MedlinePlus

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

  3. Primary Myelofibrosis

    MedlinePlus

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

  4. 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

  5. Association of Chronic Hepatitis C Infection with T-Cell Phenotypes in HIV-Negative and HIV-Positive Women

    PubMed Central

    Kuniholm, Mark H.; Xie, Xianhong; Anastos, Kathryn; Kaplan, Robert C.; Xue, Xiaonan; Kovacs, Andrea; Peters, Marion G.; Seaberg, Eric C.; French, Audrey L.; Young, Mary A.; Augenbraun, Michael; Martinson, Jeffrey A.; Bush, Kristin A.; Landay, Alan L.; Strickler, Howard D.

    2014-01-01

    Background Hepatitis C virus (HCV) viremia is thought to have broad, systemic effects on the cellular immune system that go beyond its impact on just those T-cells that are HCV-specific. However, prior studies of chronic HCV and circulating T-cell subsets (activation and differentiation phenotypes) in HIV-negatives used general population controls, rather than a risk-appropriate comparison group. Studies in HIV-positives did not address overall immune status (total CD4+ count). Methods We used fresh blood from HIV-positive and at-risk HIV-negative women, with and without chronic HCV, to measure percentages of activated CD4+ and CD8+ T-cells, Tregs, and T-cell differentiation phenotypes (naïve, central memory (CM), effector memory (EM), and terminally differentiated effector). This included 158 HIV-negatives and 464 HIV-positives, of whom 18 and 63, respectively, were HCV viremic. Results In multivariate models of HIV-negatives, HCV viremia was associated with 25% fewer naïve CD4+ (P=0.03), 33% more EM CD4+ (P=0.0002) and 37% fewer CM CD8+ (P=0.02) T-cells. Among HIV-positives we observed only one of these three relationships: higher percentage of EM CD4+ among HCV viremic women. Further, the association with EM CD4+ among HIV-positives was limited to individuals with diminished immune status (total CD4+ count ≤500 cells/μL), as were associations of HCV viremia with higher percentages of activated CD4+ and Tregs. Among HIV-positives with high CD4+ count, no significant associations were observed. Conclusions These data suggest that HCV viremia in HIV-negatives is associated with accelerated T-cell differentiation, but among HIV-positives the impact of HCV viremia is less straightforward and varies by total CD4+ count. PMID:25314250

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

    PubMed

    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 JAK2 (V617F) 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 combination

  7. Tocilizumab Efficacy in a Patient with Positive Anti-CCP Chronic Lyme Arthritis

    PubMed Central

    Hirsch, Julianna; Rosner, Itzhak; Rimar, Doron; Kaly, Lisa; Rozenbaum, Michael; Boulman, Nina; Slobodin, Gleb

    2016-01-01

    Context: Lyme arthritis, a manifestation of tick-borne Lyme disease, can prove to be refractory to classic treatment. Case Report: We present a case of a 48-year-old male, diagnosed with chronic Lyme arthritis, refractory to recurrent and prolonged courses of doxycycline, ceftriaxone, as well as hydroxychloroquine and methotrexate. The patient responded partially to tumor necrosis factor (TNF)-alpha blockade by etanercept and, finally, entered long-term remission after his treatment was switched to tocilizumab. Conclusion: Off label treatment by biologic disease modifying antirheumatic drugs can be considered in selected patients with severe antibiotic-resistant Lyme arthritis.C. PMID:27213145

  8. The Metabonomic Studies of Tongue Coating in H. pylori Positive Chronic Gastritis Patients

    PubMed Central

    Liu, Xuan; Sun, Zhu-Mei; Liu, Yan-Na; Ji, Qing; Sui, Hua; Zhou, Li-Hong; Li, Fu-Feng; Li, Qi

    2015-01-01

    In Traditional Chinese Medicine (TCM), tongue diagnosis (TD) has been an important diagnostic method for the last 3000 years. Tongue coating can be used as a very sensitive marker to determine the progress of chronic gastritis. Therefore, the scientific, qualitative, and quantitative study for the pathophysiologic basis of tongue coating (TC) emerged as a major direction for the objective research of TD. In our current report, we used GC/MS technology to determine the potential changes of metabolites and identify special metabolic biomarkers in the TC of H. pylori infected chronic gastritis patients. Four discriminative metabolites were identified by GC/MS between the TC of H. pylori infection (G + H) and without H. pylori infection (G − H) patients: ethylene, cephaloridine, γ-aminobutyric acid, and 5-pyroglutamic acid, indicating that changes in amino acid metabolism are possibly involved in the formation of TC, and the amino acid metabolites are part of the material components of TC in G + H patients. PMID:26557866

  9. [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; Kuz'mina, L A; Savchenko, V G

    2016-01-01

    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. PMID:27459622

  10. 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.

  11. [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. PMID:24553592

  12. Prevalence of normal head CT and positive CT findings in a large cohort of patients with chronic headaches

    PubMed Central

    Khandelwal, N; Prabhakar, Anuj; Satish Kumar, A; Ahuja, Chirag K; Singh, Paramjeet

    2015-01-01

    This study was carried out to ascertain the frequency of normal head computed tomography (CT) scans and positive CT scan findings in patients having chronic headache as chief complaint. Head CT scans done over a period of two years were retrospectively evaluated. On the basis of CT reports, the patients were divided into two groups: Group A, having headache as the only complaint, and Group B, having headache and additional neurological signs or symptoms. A total of 2498 patient reports were evaluated. There were 1772 patients in Group A and 726 patients in Group B. In Group A, 82% (n = 1453) patients had normal head CT, whereas in Group B 74.5% (n = 541) patients had a normal CT scan. There were 13.22% head CT scans showing significant findings in Group B, as compared to 6.2% in Group A. Both these differences were found to be statistically significant. CT findings such as infections, neoplasm, hydrocephalus, and extra-axial collections were higher in Group B when compared to Group A. CT examination in patients with isolated chronic headache is normal in high percentage of patients. The frequency and distribution of various CT findings over different age groups in a large cohort of patients presenting with chronic headache are discussed. PMID:26342061

  13. 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

  14. 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

  15. Effect of chronic stress on behavior and cerebral oxidative metabolism in rats with high or low positive affect.

    PubMed

    Mällo, T; Matrov, D; Kõiv, K; Harro, J

    2009-12-15

    The 50 kHz ultrasonic vocalizations (USVs) in rats have been associated with positive affect and rewarding experience. We have previously reported that stable inter-individual differences exist in the expression of these USVs (chirps). We have examined the effect of four weeks of chronic variable stress on cerebral oxidative metabolism, and depression and anxiety related behavior in male and female high (HC) and low (LC) chirping rats. Significant differences in regional oxidative metabolic activity as measured by cytochrome c oxidase (COX) histochemistry were found between male and female rats: Females had lower oxidative metabolism in several brainstem areas such as dorsal and median raphe and pontine nucleus, some cortical areas, and reward-related forebrain regions such as striatum and nucleus accumbens, but higher oxidative metabolism in amygdala and related limbic regions. Chronic stress increased oxidative metabolism in several depression-related brain regions in male but not female LC-rats such as amygdala, hippocampus and anterior thalamus. No systematic behavioral effect of stress was evident in females. In LC males, stress elicited increased levels of 22-kHz USVs, earlier and more stable reduction of weight gain, persistently lower sucrose intake and preference, and higher levels of immobility in the forced swimming test. These behavioral changes, accompanied by increased oxidative metabolism in limbic brain regions, indicate greater vulnerability to stress of male LC-rats, and suggest that in males low inherent positive affectivity predisposes to anxiety and affective disorders.

  16. 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…

  17. 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.

  18. 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.

  19. 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

  20. 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

  1. 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

  2. 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

  3. CALR mutation profile in Irish patients with myeloproliferative neoplasms.

    PubMed

    Haslam, Karl; Conneally, Eibhlin; Flynn, Catherine M; Cahill, Mary R; Gilligan, Oonagh; O'Shea, Derville; Langabeer, Stephen E

    2016-09-01

    Insertion and/or deletion mutations of the CALR gene have recently been demonstrated to be the second most common driver mutations in the myeloproliferative neoplasms (MPNs) of essential thrombocythemia (ET) and primary myelofibrosis (PMF). Given the diagnostic and emerging prognostic significance of these mutations, in addition to the geographical heterogeneity reported, the incidence of CALR mutations was determined in an Irish cohort of patients with MPNs with a view to incorporate this analysis into a prospective screening program. A series of 202 patients with known or suspected ET and PMF were screened for the presence of CALR mutations. CALR mutations were detected in 58 patients. Type 1 and Type 1-like deletion mutations were the most common (n=40) followed by Type 2 and Type 2-like insertion mutations (n=17). The CALR mutation profile in Irish ET and PMF patients appears similar to that in other European populations. Establishment of this mutational profile allows the introduction of a rational, molecular diagnostic algorithm in cases of suspected ET and PMF that will improve clinical management. PMID:27352261

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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. PMID:26854026

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. 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

  14. Cytogenetic profile of 1,863 Ph/BCR-ABL-positive chronic myelogenous leukemia patients from the Chinese population.

    PubMed

    Mu, Qitian; Ma, Qiuling; Wang, Yungui; Chen, Zhimei; Tong, Xiangmin; Chen, Fei-Fei; Lu, Ying; Jin, Jie

    2012-07-01

    Cytogenetic analyses of chronic myelogenous leukemia (CML) have been performed previously in a large number of reports, but systematical research based on large sample sizes from the Chinese population is seldom available. In this study, we analyzed the cytogenetic profiles of 1,863 Philadelphia (Ph)/BCR-ABL-positive CML patients from a research center in China. Of 1,266 newly diagnosed CML patients, the median age was 41 years, which is younger than the median age of diagnosis in western populations. The incidence of additional chromosome abnormalities (ACA) was 3.1% in newly diagnosed chronic phase (CP), 9.1% in CP after therapy, 35.4% in accelerated phase, and 52.9% in blast crisis (BC), reflecting cytogenetic evolution with CML progression. A higher prevalence of ACA was observed in variant Ph translocations than in standard t(9;22) in the disease progression, especially in BC (88.2% vs. 50%, P = 0.002). Moreover, a hyperdiploid karyotype and trisomy 8 were closely correlated with myeloid BC, while a hypodiploid karyotype and monosomy 7 were associated with lymphoid-BC. Among subsets of myeloid-BC, myeloid-BC with minimal differentiation had a higher ACA rate than myeloid-BC with granulocytic differentiation (80% vs. 46.8%, P = 0.009) and myeloid-BC with monocytic differentiation (80% vs. 42.9%, P = 0.006). These data provide novel insights into cytogenetics of CML within the Chinese population.

  15. 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

  16. Pregnancy outcomes in myeloproliferative neoplasms: UK prospective cohort study.

    PubMed

    Alimam, Samah; Bewley, Susan; Chappell, Lucy C; Knight, Marian; Seed, Paul; Gray, Gabriella; Harrison, Claire; Robinson, Susan

    2016-10-01

    The reported higher risk of maternal and fetal complications in women with myeloproliferative neoplasms (MPN) poses challenge during pregnancy. A national prospective study of maternal and fetal outcomes of pregnant women with a diagnosis of MPN was undertaken via the United Kingdom Obstetric Surveillance System between January 2010 and December 2012. Fifty-eight women with a diagnosis of MPN were identified; 47 (81%) essential thrombocythaemia, five (9%) polycythaemia vera, five (9%) myelofibrosis and one (2%) MPN-unclassified. There were 58 live births. The incidence of miscarriage was 1·7/100 (95% confidence interval [CI]: 0·04-9·24) and the perinatal mortality rate was 17/1000 (95% CI: 0·44-92·36) live and stillbirths. Incidence of maternal complications was 9% (5/57) pre-eclampsia, 9% (5/57) post-partum haemorrhage and 3·5% (2/57) post-partum haematoma. There were no maternal deaths or thrombotic events. Delivery was induced in 45% (24/53) of women and the Caesarean section rate was 45% (24/53). The majority (85%, 45/53) delivered at term (>37 weeks gestation). Twenty-two percent (12/54) of neonates were below the 10% centile for growth and 13% (7/54) required admission to a neonatal care-unit; there were no neonatal deaths. The findings of this large, UK prospective study suggests women with MPN appear to have successful pregnancies with better outcomes than would be anticipated from the literature.

  17. Pregnancy outcomes in myeloproliferative neoplasms: UK prospective cohort study.

    PubMed

    Alimam, Samah; Bewley, Susan; Chappell, Lucy C; Knight, Marian; Seed, Paul; Gray, Gabriella; Harrison, Claire; Robinson, Susan

    2016-10-01

    The reported higher risk of maternal and fetal complications in women with myeloproliferative neoplasms (MPN) poses challenge during pregnancy. A national prospective study of maternal and fetal outcomes of pregnant women with a diagnosis of MPN was undertaken via the United Kingdom Obstetric Surveillance System between January 2010 and December 2012. Fifty-eight women with a diagnosis of MPN were identified; 47 (81%) essential thrombocythaemia, five (9%) polycythaemia vera, five (9%) myelofibrosis and one (2%) MPN-unclassified. There were 58 live births. The incidence of miscarriage was 1·7/100 (95% confidence interval [CI]: 0·04-9·24) and the perinatal mortality rate was 17/1000 (95% CI: 0·44-92·36) live and stillbirths. Incidence of maternal complications was 9% (5/57) pre-eclampsia, 9% (5/57) post-partum haemorrhage and 3·5% (2/57) post-partum haematoma. There were no maternal deaths or thrombotic events. Delivery was induced in 45% (24/53) of women and the Caesarean section rate was 45% (24/53). The majority (85%, 45/53) delivered at term (>37 weeks gestation). Twenty-two percent (12/54) of neonates were below the 10% centile for growth and 13% (7/54) required admission to a neonatal care-unit; there were no neonatal deaths. The findings of this large, UK prospective study suggests women with MPN appear to have successful pregnancies with better outcomes than would be anticipated from the literature. PMID:27612319

  18. Efficacy of PEGylated Interferon in Treatment-Experienced Chinese Patients With HBeAg Positive Chronic Hepatitis B

    PubMed Central

    Xiong, Yue-Li; Li, Hu; Liu, Fen; Zhang, Dazhi; Ren, Hong; Hu, Peng

    2016-01-01

    Background After treatment cessation, a high prevalence of relapse was reported in chronic hepatitis B (CHB) patients in China, especially in nucleot(s)ide analogues (NUCs)-experienced patients. Re-treatment for these patients remains unsolved. Objectives This study aims to evaluate the efficacy of PEGylated interferon in HBeAg positive patients with exposure to antiviral therapy. Patients and Methods A total of 55 treatment-experienced, HBeAg positive Chinese patients were enrolled in this study. Of these patients, 33 were NUCs-experienced and 22 were interferon-experienced. PEGylated interferon was administered to 34 patients; and 21 patients were retreated with conventional interferon. Results Of the 34 treatment-experienced patients who received PEGylated interferon, 52.9% achieved virologic response, and 41.2% achieved HBeAg loss and seroconversion. Patients who were treated with PEGylated interferon for 48 weeks achieved higher virologic response (80%); HBeAg loss (60%); HBeAg seroconversion (60%); and HBsAg loss (5%) than patients treated for 24 weeks with PEGylated interferon. Their responses were also higher than those who were treated with conventional interferon. HBeAg seroconversion in treatment-experienced patients was independently associated with 48-week PEGylated interferon therapy duration. Conclusions PEGylated interferon was effective in treatment-experienced patients with HBeAg positive CHB, and showed higher rates of virological response, HBeAg loss, and seroconversion. The results provide important information regarding the role of re-treatment with PEGylated interferon in treatment-experienced HBeAg positive patients. PMID:27257427

  19. 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

  20. Secondary chromosomal changes in 34 Philadelphia-chromosome-positive chronic myelocytic leukemia patients from the Mexican West.

    PubMed

    Meza Espinoza, Juan Pablo; Judith Picos Cárdenas, Verónica; Gutiérrez-Angulo, Melva; González García, Juan Ramón

    2004-01-15

    The clonal evolution in t(9;22)-positive chronic myelocytic leukemia (CML) is well established. Four major changes occur in more than 70% of patients: +8, i(17q), +19, and an extra Philadelphia chromosome. The frequencies of secondary chromosomal changes in 34 patients from the states of Jalisco, Nayarit, Michoacán, and Colima (the Mexican West) with Philadelphia-chromosome-positive CML were assessed. The most frequent abnormalities were tetraploidy (12 cases); +8, inv(3)(q21q26), and octoploidy (3 cases each); and +der(22)(2 cases). Some translocations not previously associated with CML were observed, such as t(2;7)(p12;q36), t(3;6)(q26;p25), t(3;17)(q26;p13), and t(6;17)(q21;q23 approximately q25). Significant differences were found for +8 with respect to population results from Japan and from southern, eastern, and western Europe; for i(17)(q10) from eastern Europe; for +19 from Japan and western Europe; and for +der(22) from Japan, southern Europe, and western Europe. Although polyploidy could result from endomitosis, there is no direct evidence that the BCR/ABL protein influences such a process; however, protein kinases such as MAPK, which are involved in endomitosis, are activated by the BCR/ABL protein, and so the BCR/ABL protein could promote endomitosis through the MAPK pathway.

  1. 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

  2. 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

  3. 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

  4. 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.

  5. Acquisition of genomic events leading to lymphoblastic transformation in a rare case of myeloproliferative neoplasm with BCR-JAK2 fusion transcript.

    PubMed

    Duployez, Nicolas; Nibourel, Olivier; Ducourneau, Benoît; Grardel, Nathalie; Boyer, Thomas; Bories, Claire; Darre, Stéphane; Coiteux, Valérie; Berthon, Céline; Preudhomme, Claude; Roche-Lestienne, Catherine

    2016-10-01

    We report a case of myeloproliferative neoplasm (MPN) with an atypical t(9;22;15)(p24;q11;q21) translocation, leading to a BCR-JAK2 fusion, associated with a trisomy of chromosome 8 in clonal evolution at karyotype. Patient's evolution was marked by an aggressive clinical course with rapid progression to blast phase within the first year after diagnosis. Examination of matched chronic phase and blast crisis samples by SNP-array karyotyping identified secondary acquired cryptic genetic events at the time of lymphoblastic transformation, including biallelic IKZF1 alteration and EBF1 and CDKN2A/B codeletions. This case is the first report describing acquisition of secondary genetic events leading to acute lymphoblastic progression in a rare MPN with BCR-JAK2 fusion. PMID:26935241

  6. Deficiency of β Common Receptor Moderately Attenuates the Progression of Myeloproliferative Neoplasm in NrasG12D/+ Mice*

    PubMed Central

    Zhang, Jingfang; Ranheim, Erik A.; Du, Juan; Liu, Yangang; Wang, Jinyong; Kong, Guangyao; Zhang, Jing

    2015-01-01

    Activating Ras signaling is a major driver in juvenile and the myeloproliferative variant of chronic myelomonocytic leukemia (JMML/MP-CMML). Numerous studies suggest that GM-CSF signaling plays a central role in establishing and maintaining JMML/MP-CMML phenotypes in human and mouse. However, it remains elusive how GM-CSF signaling impacts on JMML/MP-CMML initiation and progression. Here, we investigate this issue in a well characterized MP-CMML model induced by endogenous NrasG12D/+ mutation. In this model, NrasG12D/+ hematopoietic stem cells (HSCs) are required to initiate and maintain CMML phenotypes and serve as CMML-initiating cells. We show that the common β chain of the GM-CSF receptor (βc) is dispensable for NrasG12D/+ HSC function; loss of βc does not affect the expansion, increased self-renewal, or myeloid differentiation bias in NrasG12D/+ HSCs. Therefore, βc−/− does not abrogate CMML in NrasG12D/+ mice. However, βc deficiency indeed significantly reduces NrasG12D/+-induced splenomegaly and spontaneous colony formation and prolongs the survival of CMML-bearing mice, suggesting that GM-CSF signaling plays an important role in promoting CMML progression. Together, our results suggest that inhibiting GM-CSF signaling in JMML/MP-CMML patients might alleviate disease symptoms but would not eradicate the disease. PMID:26082490

  7. 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

  8. Total Lymphoid Irradiatione—Antithymocyte Globulin Conditioning and Allogeneic Transplantation for Patients with Myelodysplastic Syndromes and Myeloproliferative Neoplasms

    PubMed Central

    Benjamin, Jonathan; Chhabra, Saurabh; Kohrt, Holbrook E.; Lavori, Philip; Laport, Ginna G.; Arai, Sally; Johnston, Laura; Miklos, David B.; Shizuru, Judith A.; Weng, Wen-Kai; Negrin, Robert S.; Lowsky, Robert

    2015-01-01

    Allogeneic hematopoietic cell transplantation (allo HCT) is the only curative therapy for the myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), but treatment toxicity has been a barrier to its more widespread use. The nonmyeloablative regimen of total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) permits the establishment of donor hematopoiesis necessary for the graft-versus-malignancy effect and is protective against acute graft-versus-host disease (aGVHD), but it has minimal direct cytotoxicity against myeloid diseases. We explored the use of TLI-ATG conditioning to treat 61 patients with allo HCT for MDS (n = 32), therapy-related myeloid neoplasms (n = 15), MPN (n = 9), and chronic myelomonocytic leukemia (n = 5). The median age of all patients was 63 years (range, 50 to 73). The cumulative incidence of aGVHD grades II to IV was 14% (95% confidence interval [CI], 4% to 23%) and for grades III to IV, 4% (95% CI, 0 to 9%), and it did not differ between patients who received allografts from related or unrelated donors. The cumulative incidence of nonrelapse mortality (NRM) at 100 days, 12 months, and 36 months was 0%, 7%, and 11%. Overall survival and progression-free survival were 41% (95% CI, 29% to 53%) and 35% (95% CI, 23% to 48%), respectively. The safety and tolerability of TLI-ATG, as exemplified by its low NRM, provides a foundation for further risk-adapted or prophylactic interventions to prevent disease progression. PMID:24607552

  9. 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

  10. A point mutation of zebrafish c-cbl gene in the ring finger domain produces a phenotype mimicking human myeloproliferative disease.

    PubMed

    Peng, X; Dong, M; Ma, L; Jia, X-E; Mao, J; Jin, C; Chen, Y; Gao, L; Liu, X; Ma, K; Wang, L; Du, T; Jin, Y; Huang, Q; Li, K; Zon, L I; Liu, T; Deng, M; Zhou, Y; Xi, X; Zhou, Y; Chen, S

    2015-12-01

    Controlled self-renewal and differentiation of hematopoietic stem/progenitor cells (HSPCs) are critical for vertebrate development and survival. These processes are tightly regulated by the transcription factors, signaling molecules and epigenetic factors. Impaired regulations of their function could result in hematological malignancies. Using a large-scale zebrafish N-ethyl-N-nitrosourea mutagenesis screening, we identified a line named LDD731, which presented significantly increased HSPCs in hematopoietic organs. Further analysis revealed that the cells of erythroid/myeloid lineages in definitive hematopoiesis were increased while the primitive hematopoiesis was not affected. The homozygous mutation was lethal with a median survival time around 14-15 days post fertilization. The causal mutation was located by positional cloning in the c-cbl gene, the human ortholog of which, c-CBL, is found frequently mutated in myeloproliferative neoplasms (MPN) or acute leukemia. Sequence analysis showed the mutation in LDD731 caused a histidine-to-tyrosine substitution of the amino acid codon 382 within the RING finger domain of c-Cbl. Moreover, the myeloproliferative phenotype in zebrafish seemed dependent on the Flt3 (fms-like tyrosine kinase 3) signaling, consistent with that observed in both mice and humans. Our study may shed new light on the pathogenesis of MPN and provide a useful in vivo vertebrate model of this syndrome for screening drugs.

  11. A point mutation of zebrafish c-cbl gene in the ring finger domain produces a phenotype mimicking human myeloproliferative disease.

    PubMed

    Peng, X; Dong, M; Ma, L; Jia, X-E; Mao, J; Jin, C; Chen, Y; Gao, L; Liu, X; Ma, K; Wang, L; Du, T; Jin, Y; Huang, Q; Li, K; Zon, L I; Liu, T; Deng, M; Zhou, Y; Xi, X; Zhou, Y; Chen, S

    2015-12-01

    Controlled self-renewal and differentiation of hematopoietic stem/progenitor cells (HSPCs) are critical for vertebrate development and survival. These processes are tightly regulated by the transcription factors, signaling molecules and epigenetic factors. Impaired regulations of their function could result in hematological malignancies. Using a large-scale zebrafish N-ethyl-N-nitrosourea mutagenesis screening, we identified a line named LDD731, which presented significantly increased HSPCs in hematopoietic organs. Further analysis revealed that the cells of erythroid/myeloid lineages in definitive hematopoiesis were increased while the primitive hematopoiesis was not affected. The homozygous mutation was lethal with a median survival time around 14-15 days post fertilization. The causal mutation was located by positional cloning in the c-cbl gene, the human ortholog of which, c-CBL, is found frequently mutated in myeloproliferative neoplasms (MPN) or acute leukemia. Sequence analysis showed the mutation in LDD731 caused a histidine-to-tyrosine substitution of the amino acid codon 382 within the RING finger domain of c-Cbl. Moreover, the myeloproliferative phenotype in zebrafish seemed dependent on the Flt3 (fms-like tyrosine kinase 3) signaling, consistent with that observed in both mice and humans. Our study may shed new light on the pathogenesis of MPN and provide a useful in vivo vertebrate model of this syndrome for screening drugs. PMID:26104663

  12. 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

  13. Positive shift of Nav1.8 current inactivation curve in injured neurons causes neuropathic pain following chronic constriction injury.

    PubMed

    Li, Guixia; Liu, Xifang; Du, Jingnan; Chen, Jianzhao; She, Fenglin; Wu, Chunfu; Li, Chunli

    2015-09-01

    Neuropathic pain is a global medical concern, characterized by spontaneous pain, heat hyperalgesia and mechanical allodynia. The condition has been associated with alterations in the voltage‑gated sodium channels, Nav1.8 and Nav1.9, in nociceptive neurons termed nociceptors. However, an explanation for the contribution of these channels to the phenotype observed in neuropathic pain remains to be elucidated. The changes induced by chronic constriction injury (CCI) to Nav1.8 and Nav1.9 mRNA and protein levels, as well as electrical currents in injured and contralateral non‑injured dorsal root ganglion (DRG) neurons are described in the present study. A marked downregulation was observed for each Nav isoform transcript and protein expressed in injured neurons with the exception of the Nav1.9 protein, which exhibited no change, while in contralateral non‑injured neurons, the levels of protein and mRNA remained unchanged. Nav isoform functional analysis was then performed in L(4‑6) DRG neurons 14 days after CCI. The Nav1.8 current density was markedly decreased in injured DRG neurons following CCI. The voltage‑dependent activation of the Nav1.8 channel in these neurons was shifted to depolarized potentials by 5.3 mV, while it was shifted to hyperpolarized potentials by 10 mV for inactivation. The electrophysiological function of Nav1.9 was not affected by CCI. The present study demonstrated that ectopic discharge following CCI, which was likely induced by a positive shift in the Nav1.8 current inactivation curve in injured neurons, enhanced the excitability of the neurons by facilitating tetrodotoxin‑resistant sodium channels into the fast inactivation state and did not occur as a result of a compensatory redistribution in the contralateral uninjured neurons. PMID:26005195

  14. [Continuous positive airway pressure and high-frequency independent lung ventilation in patients with chronic obstructive lung diseases].

    PubMed

    Fedorova, E A; Vyzhigina, M A; Gal'perin, Iu S; Zhukova, S G; Titov, V A; Godin, A V

    2004-01-01

    The original hypoxemia, hypercapnia, high pulmonary hypertension, high resistance of microcirculation vessels, right volumetric ventricular overload, persistent sub-edema of pulmonary intersticium as well as disparity of ventilation and perfusion between both lungs are the main problems in patients with chronic obstructive disease of the lungs (CODL). Such patients are, as a rule, intolerant to the independent lung collaboration or artificial single-stage ventilation (ASV). Patients with respiratory insufficiency, stages 2 and 3, and with a pronounced impaired type of ventilation have originally a deranged blood gas composition, like hypoxemia or hypercapnia. The application of volume-controllable bi-pulmonary ASV in such patients maintains an adequate gas exchange hemodynamics. However, ASV is accompanied by a significantly reduced gas-exchange function of the single ventilated lung and by essentially worsened intrapulmonary hemodynamics. Therefore, what is needed is to use alternative methods of independent lung ventilation in order to eliminate the gas-exchange impairments and to enable surgical interventions at thoracic organs in such patients (who are intolerant to ASV). A choice of a method and means of oxygen supply to the independent lung is of great importance. The possibility to avoid a high pressure in the airways, while maintaining, simultaneously, an adequate gas exchange, makes the method related with maintaining a constant positive pressure in the airways (CPPA) a priority one in case of CODL patients. The use of constant high-frequency ventilation in the independent lung in patients with obstructive pulmonary lesions does not improve the gas exchange or hemodynamics. Simultaneously, a growing total pulmonary resistance and an increasing pressure in the pulmonary artery are observed. Consequently, the discussed method must not be used for the ventilation support of the independent lung in patients with the obstructive type of the impaired external

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

    PubMed

    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; Baxter, E Joanna; 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 JAK2(V617F)-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 JAK2(V617F)-positive cases. rs9376092 has a stronger effect in JAK2(V617F)-negative cases with CALR and/or MPL mutations (Breslow-Day P=4.5 × 10(-7)), whereas in JAK2(V617F)-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ(2) 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

  16. 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

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

    PubMed

    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; Baxter, E Joanna; 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

    2015-04-07

    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 JAK2(V617F)-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 JAK2(V617F)-positive cases. rs9376092 has a stronger effect in JAK2(V617F)-negative cases with CALR and/or MPL mutations (Breslow-Day P=4.5 × 10(-7)), whereas in JAK2(V617F)-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ(2) 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.

  18. Bosutinib in the treatment of patients with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia: an overview

    PubMed Central

    Shen, Ann Q.; Wilson, Nicole M.; Gleason, Shannon L.

    2014-01-01

    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. PMID:24490020

  19. Characterization of mpl cytoplasmic domain sequences required for myeloproliferative leukemia virus pathogenicity.

    PubMed Central

    Bénit, L; Courtois, G; Charon, M; Varlet, P; Dusanter-Fourt, I; Gisselbrecht, S

    1994-01-01

    v-mpl is a truncated form of a receptor-like chain which belongs to the cytokine receptor superfamily. This sequence has been transduced in the myeloproliferative leukemia virus as an env-mpl fusion gene responsible for an acute myeloproliferative disorder in mice. We constructed a series of viral mutants in the mpl sequence. Analysis of their oncogenic potential in vivo indicated that a critical 69-amino-acid-long cytoplasmic domain of v-Mpl is required for myoproliferative leukemia virus pathogenicity. We also developed an in vitro assay and showed that expression of the env-mpl gene confers growth factor independence to murine as well as to human hematopoietic growth factor-dependent cell lines. These findings strongly suggest that v-Mpl delivers a constitutive proliferative signal through a limited region of its cytoplasmic domain. Images PMID:8035524

  20. Circulating high molecular weight IgG fibronectin complexes in myeloproliferative disorders.

    PubMed Central

    Baglin, T P; Price, S M; Boughton, B J

    1990-01-01

    The plasma of patients with myeloproliferative diseases was examined by polyethylene glycol (PEG) precipitation, analytical ultracentrifugation, and immunoaffinity chromatography for the presence of high molecular weight complexes of IgG and fibronectin. Abnormal circulating high molecular weight material was identified by ultracentrifugation in all patients. This was precipitated by PEG and was shown by exclusion chromatography to contain IgG in a high molecular weight form. Examination of plasma by immunoaffinity chromatography supported previous evidence for complex formation between IgG and fibronectin. These findings are further evidence that abnormal high molecular weight IgG complexes are a prominent feature of myeloproliferative disorders and implicate IgG fibronectin complex formation. PMID:2318985

  1. 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

  2. HDL and Glut1 inhibition reverse a hypermetabolic state in mouse models of myeloproliferative disorders.

    PubMed

    Gautier, Emmanuel L; Westerterp, Marit; Bhagwat, Neha; Cremers, Serge; Shih, Alan; Abdel-Wahab, Omar; Lütjohann, Dieter; Randolph, Gwendalyn J; Levine, Ross L; Tall, Alan R; Yvan-Charvet, Laurent

    2013-02-11

    A high metabolic rate in myeloproliferative disorders is a common complication of neoplasms, but the underlying mechanisms are incompletely understood. Using three different mouse models of myeloproliferative disorders, including mice with defective cholesterol efflux pathways and two models based on expression of human leukemia disease alleles, we uncovered a mechanism by which proliferating and inflammatory myeloid cells take up and oxidize glucose during the feeding period, contributing to energy dissipation and subsequent loss of adipose mass. In vivo, lentiviral inhibition of Glut1 by shRNA prevented myeloproliferation and adipose tissue loss in mice with defective cholesterol efflux pathway in leukocytes. Thus, Glut1 was necessary to sustain proliferation and potentially divert glucose from fat storage. We also showed that overexpression of the human ApoA-I transgene to raise high-density lipoprotein (HDL) levels decreased Glut1 expression, dampened myeloproliferation, and prevented fat loss. These experiments suggest that inhibition of Glut-1 and HDL cholesterol-raising therapies could provide novel therapeutic approaches to treat the energy imbalance observed in myeloproliferative disorders.

  3. 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

  4. 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

  5. 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

  6. 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

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

    PubMed

    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; Gotlib, Jason

    2016-08-25

    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

  8. Failure of acute and chronic administration of delta 9-tetrahydrocannabinol to affect the repeated acquisition of serial position response in pigeons.

    PubMed

    McMillan, D E

    1988-01-01

    Pigeons were trained to acquire a new four-response position sequence each day by pecking three response keys in a predetermined order. The key color varied after each correct response prior to food delivery. Acute administration of delta 9-tetrahydrocannabinol (delta 9-THC) up to a dose that completely eliminated responding, had no effect on total acquisition errors, or on within session patterns of error elimination. Chronic administration of delta 9-THC (3-10 mg/kg/day), either before or after the session for 4-7 weeks, also did not affect these error measures, although rates of responding were markedly suppressed and at times no responding occurred. Discontinuation of delta 9-THC administration for periods of 4-6 weeks also was without effect on errors. These experiments suggest that neither acute nor chronic delta 9-THC produce specific effects on the repeated acquisition of serial position responses in pigeons.

  9. 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.

  10. 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. PMID:26588034

  11. MPL W515L/K Mutations in Chronic Myeloproliferative Neoplasms

    PubMed Central

    Akpınar, Timur Selçuk; Hançer, Veysel Sabri; Nalçacı, Meliha; Diz-Küçükkaya, Reyhan

    2013-01-01

    Objective: The MPL gene encodes the thrombopoietin receptor. Recently MPL mutations (MPL W515L or MPL W515K) were described in patients with essential thrombocythemia (ET) and primary (idiopathic) myelofibrosis (PMF). The prevalence and the clinical importance of these mutations are not clear. In the present study, we aimed to investigate the frequency and clinical significance of MPL W515L/K mutations in our patients with ET and PMF. Materials and Methods: A total of 77 patients (66 were diagnosed with ET and 11 with PMF) and 42 healthy controls were included in the study. Using peripheral blood samples, the presence of MPL W515L/K mutations and JAK-2 V617F mutation were analyzed by real-time polymerase chain reaction. Results: In our study, MPL W515L/K or JAK-2 V617F mutations were not observed in healthy controls. JAK-2 V617F mutation was present in 35 patients, of whom 29 had ET (43.9%, 29/66) and 6 had PMF (54.5%, 6/11). In the patient group, MPL W515L/K mutations were found in only 2 PMF cases, and these cases were negative for JAK-2 V617F mutation. The prevalence of MPL W515L/K mutations in the patient group was 2.6%, and the prevalence of MPL W515L/K mutations among the cases negative for the JAK-2 V617F mutation was found to be 4.8%. The 2 cases with MPL W515L/K mutations had long follow-up times (124 months and 71 months, respectively), had no thrombotic or hemorrhagic complications, and had no additional cytogenetic anomalies. Conclusion: MPL W515L/K mutations may be helpful for identifying clonal disease in MPN patients with no established Ph chromosome or JAK-2 V617F mutation. Conflict of interest:None declared. PMID:24385746

  12. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up.

    PubMed

    Larson, R A; Hochhaus, A; Hughes, T P; Clark, R E; Etienne, G; Kim, D-W; Flinn, I W; Kurokawa, M; Moiraghi, B; Yu, R; Blakesley, R E; Gallagher, N J; Saglio, G; Kantarjian, H M

    2012-10-01

    Evaluating Nilotinib Efficacy and Safety in Clinical Trials Newly Diagnosed Patients compares nilotinib and imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). With a minimum follow-up of 3 years, major molecular response, molecular response of BCR-ABL≤ 0.01% expressed on the international scale (BCR-ABL(IS); MR(4)) and BCR-ABL(IS)≤ 0.0032% (MR(4.5)) rates were significantly higher with nilotinib compared with imatinib, and differences in the depth of molecular response between nilotinib and imatinib have increased over time. No new progressions occurred on treatment since the 2-year analysis. Nilotinib was associated with a significantly lower probability of progression to accelerated phase/blast crisis vs imatinib (two (0.7%) progressions on nilotinib 300 mg twice daily, three (1.1%) on nilotinib 400 mg twice daily and 12 (4.2%) on imatinib). When considering progressions occurring after study treatment discontinuation, the advantage of nilotinib over imatinib in preventing progression remained significant (nine (3.2%) progressions on nilotinib 300 mg twice daily, six (2.1%) on nilotinib 400 mg twice daily and 19 (6.7%) on imatinib). Both nilotinib and imatinib were well tolerated, with minimal changes in safety over time. Nilotinib continues to demonstrate superior efficacy in all key response and outcome parameters compared with imatinib for the treatment of patients with newly diagnosed CML-CP.

  13. Effects of doxazosin as the third agent on morning hypertension and position-related blood pressure changes in diabetic patients with chronic kidney disease.

    PubMed

    Yasuda, Gen; Saka, Sanae; Ando, Daisaku; Hirawa, Nobuhito

    2015-01-01

    We conducted a prospective study to assess the effects of doxazosin, as the third agent, on morning and position-related blood pressure (BP) in 77 diabetic patients with chronic kidney disease, who were allocated randomly to doxazosin and diuretics groups. Doxazosin decreased morning BP but diuretics could not decrease pre-awakening diastolic BP. Only doxazosin improved sympathovagal balance. Doxazosin and diuretics decreased standing and sitting BP but only doxazosin improved sympathovagal balance regardless of body positions. Doxazosin did not decrease absolute BP changes shortly after standing. In diabetic patients, doxazosin decreased morning BP through improving sympathovagal balance without causing significant orthostatic hypotension (ClinicalTrials.gov number, NCT00295555).

  14. 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

  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. Determinants of Overall and Progression-Free Survival of Nigerian Patients with Philadelphia-Positive Chronic Myeloid Leukemia

    PubMed Central

    Oyekunle, Anthony A.; Bolarinwa, Rahman A.; Oyelese, Adesola T.; Salawu, Lateef; Durosinmi, Muheez A.

    2015-01-01

    Objective. The tyrosine kinase inhibitors have markedly changed the disease course for patients with Ph+ and/or BCR-ABL1+ chronic myeloid leukemia (CML). This study was embarked upon to assess the long-term effects of imatinib therapy on survival in adult Nigerian patients with CML. Methods. All adult patients on imatinib (400–600 mg) seen from July 2003 to December 2010 were assessed. Male/female distribution was 171/101, with a median age of 38 (range, 20–75) years. Overall survival (OS) and progression-free survival (PFS) were determined using the Kaplan-Meier techniques. Results. Of all the 272 patients, 205 were in chronic phase, 54 in accelerated phase, and five in blastic phase, at commencement of imatinib. As at December 2010, 222 were alive. OS at 1 and 5 years was 94% and 63%, while PFS was 89% and 54%, respectively. Similarly, amongst the 205 patients in chronic phase, OS at 1 and 5 years was 97% and 68%, while PFS was 92% and 57%. Conclusion. Imatinib's place as first-line therapy in the treatment of CML has further been reinforced in our patients, with improved survival and reduced morbidity, comparable with outcomes in other populations. PMID:26435715

  17. 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.

  18. 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

  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. 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.

  1. 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

  2. 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

  3. Transient neonatal myeloproliferative disorder without Down syndrome and detection of GATA1 mutation.

    PubMed

    Magalhães, Isis Quezado; Splendore, Alessandra; Emerenciano, Mariana; Córdoba, Mara Santos; Córdoba, Jose Carlos; Allemand, Paula Azevedo; Ferrari, Iris; Pombo-de-Oliveira, Maria S

    2005-01-01

    Transient myeloproliferative disorder is a form of self-limited leukemia that occurs almost exclusively in neonates with Down syndrome. The authors report an unusual case of a newborn without constitutional trisomy 21 who developed undifferentiated leukemia and subsequently achieved clinical and molecular remission without chemotherapy. Cytogenetics and molecular analysis have shown trisomy 21 and GATA1 mutation restricted to leukemic cells. G-to-T transversion was detected, which is predicted to result in a premature stop codon (c.119G>T; pGlu67X) in diagnosis samples. These findings emphasize that there must be a powerful interaction between GATA1 and trisomy 21 in leukemogenesis process.

  4. “Preleukemic or smoldering” chronic myelogenous leukemia (CML):BCR-ABL1 positive: A brief case report

    PubMed Central

    Bennett, John M.; Dsouza, Kevin G.; Patel, Mehul; O’Dwyer, Kristen

    2014-01-01

    Chronic myelogenous leukemia (CML), in the Chronic Phase (CP), is often suspected as a result of a complete blood count (CBC), which shows increased granulocytes, mostly mature including a peak in myelocytes, increased basophils, and rarely blasts and/or promyelocytes. Morphologic dysplasia is not present. CML is confirmed by detecting the characteristic Philadelphia chromosome (Ph)[t(9;22)(q34;q11.2)] by routine cytogenetics or fluorescent in situ hybridization (FISH) or molecular studies (RT-PCR) for the bcr-abl fusion gene. The most common feature of CML is an elevated WBC count, usually above 25×103/µL, and frequently above 100×103/µL. We report a case of confirmed Ph+CML with a normal CBC detected because of the presence of rare myelocytes and 2% basophils [Fig. 1]. Previous leukocyte counts for the preceding eight years were normal with the exception of one done four months prior to his presentation that showed an abnormal differential with 1% basophils, 2% metamyelocytes and 2% myelocytes. PMID:25709891

  5. Effect of chronic continuous positive airway pressure (CPAP) therapy on upper airway size in patients with sleep apnoea/hypopnoea syndrome.

    PubMed Central

    Mortimore, I. L.; Kochhar, P.; Douglas, N. J.

    1996-01-01

    BACKGROUND: There is evidence to suggest that chronic continuous positive airway pressure (CPAP) therapy may produce reversible changes in upper airway morphology and function in patients with sleep apnoea/hypopnoea. This study was designed to examine the effect of chronic CPAP therapy on upper airway calibre. METHODS: Twenty four men with the sleep apnoea/hypopnoea syndrome (mean (SE) apnoea/hypopnoea index 37 (5)) underwent lateral cephalometry with measurement of posterior airway space performed before and at least three months after initiation of CPAP therapy. RESULTS: There was no weight change between the two assessments and mean CPAP use was 4.8 (0.4) hours per night. Posterior airway space (PAS) was measured in erect and supine postures. PAS supine increased with CPAP therapy from a mean (SE) of 11.8 (0.8) mm to 13.4 (0.8) mm, but PAS erect did not. Correlation of the change in PAS (dPAS) before and after CPAP therapy showed an increase with increasing CPAP compliance measured as machine run time both for dPAS supine (r = 0.68) and dPAS erect (r = 0.47). CONCLUSIONS: Patients with the sleep apnoea/hypopnoea syndrome regularly using CPAP for more than four hours per night all showed an increase in dPAS supine. The use of chronic CPAP increases PAS supine probably by a reduction in upper airway oedema, and the change in size is dependent on CPAP use. PMID:8711654

  6. 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

  7. 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.

  8. BCR-JAK2 fusion in a myeloproliferative neoplasm with associated eosinophilia.

    PubMed

    He, Rong; Greipp, Patricia T; Rangan, Aruna; Mai, Ming; Chen, Dong; Reichard, Kaaren K; Nelsen, Laura L; Pardanani, Animesh; Hanson, Curtis A; Viswanatha, David S

    2016-05-01

    Janus kinase 2 (JAK2) is located on chromosome 9 at band p24 and JAK2V617F is the most common mutation in Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-MPN). However, rearrangement of JAK2 is a rare event. We report a case of myeloproliferative neoplasm, unclassifiable (MPN-U) with BCR-JAK2 fusion confirmed by molecular studies. Conventional chromosome analysis (CC) revealed t(9;22)(p24;q11.2) and fluorescence in situ hybridization (FISH) showed a JAK2 gene rearrangement in 88% of interphase nuclei. The BCR-JAK2 fusion was confirmed by multiplex reverse transcriptase polymerase chain reaction (RT-PCR) and demonstrated two in-frame 5'BCR/3'JAK2 transcripts with BCR exon 1 juxtaposed to JAK2 exon 15 and exon 17, respectively. Our results, together with literature review, reveal BCR-JAK2 fusions as oncogenic genetic alterations that are associated with myeloid or lymphoid neoplasms and are frequently characterized by eosinophilia. Further, patients with BCR-JAK2 are candidates for JAK2 inhibitor therapy. Given the distinct clinical and pathological characteristics, we believe that hematological neoplasms harboring BCR-JAK2 should be included as an additional distinct entity to the current WHO category of "myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR", and testing for a JAK2 fusion should be pursued in neoplasms with a karyotypic 9p24 abnormality. PMID:27134074

  9. A new myeloproliferative disorder associated with chromosomal translocations involving 8p11: a review.

    PubMed

    Macdonald, D; Aguiar, R C; Mason, P J; Goldman, J M; Cross, N C

    1995-10-01

    Chromosomal breakpoints associated with malignancy are known to cluster at particular regions of the karyotype. Based on a review of the literature we have identified a novel leukaemia syndrome associated with translocations involving 8p11. This syndrome is distinct from the previously described translocation t(8;16)(p11;p13) associated with acute monoblastic leukaemia. We have summarized the clinical and cytogenetic features of 13 case reports which describe a myeloproliferative syndrome with eosinophilia, lymphadenopathy and a high incidence of T cell non-Hodgkin's lymphoma with progression to acute myeloid leukaemia. The translocations involving 8p11 were: either t(8;13)(p11-12;q11-12), t(8;9) (p11;q32-34) or t(6;8)(q27;p12). In two cases of t(8;13) molecular studies have mapped the chromosome 13 breakpoint to a 1.5 Mbp region, but a full molecular characterization of these translocations is required. In view of the striking clinicopathological and karyotypic similarities between these cases we propose that they be considered a single nosological entity and termed '8p11 myeloproliferative syndrome'. PMID:7564500

  10. 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

  11. Targeting Hedgehog signaling pathway and autophagy overcomes drug resistance of BCR-ABL-positive chronic myeloid leukemia.

    PubMed

    Zeng, Xian; Zhao, Hui; Li, Yubin; Fan, Jiajun; Sun, Yun; Wang, Shaofei; Wang, Ziyu; Song, Ping; Ju, Dianwen

    2015-01-01

    The frontline tyrosine kinase inhibitor (TKI) imatinib has revolutionized the treatment of patients with chronic myeloid leukemia (CML). However, drug resistance is the major clinical challenge in the treatment of CML. The Hedgehog (Hh) signaling pathway and autophagy are both related to tumorigenesis, cancer therapy, and drug resistance. This study was conducted to explore whether the Hh pathway could regulate autophagy in CML cells and whether simultaneously regulating the Hh pathway and autophagy could induce cell death of drug-sensitive or -resistant BCR-ABL(+) CML cells. Our results indicated that pharmacological or genetic inhibition of Hh pathway could markedly induce autophagy in BCR-ABL(+) CML cells. Autophagic inhibitors or ATG5 and ATG7 silencing could significantly enhance CML cell death induced by Hh pathway suppression. Based on the above findings, our study demonstrated that simultaneously inhibiting the Hh pathway and autophagy could markedly reduce cell viability and induce apoptosis of imatinib-sensitive or -resistant BCR-ABL(+) cells. Moreover, this combination had little cytotoxicity in human peripheral blood mononuclear cells (PBMCs). Furthermore, this combined strategy was related to PARP cleavage, CASP3 and CASP9 cleavage, and inhibition of the BCR-ABL oncoprotein. In conclusion, this study indicated that simultaneously inhibiting the Hh pathway and autophagy could potently kill imatinib-sensitive or -resistant BCR-ABL(+) cells, providing a novel concept that simultaneously inhibiting the Hh pathway and autophagy might be a potent new strategy to overcome CML drug resistance.

  12. Position statement for the use of omalizumab in the management of chronic spontaneous urticaria in Indian patients

    PubMed Central

    Godse, Kiran; Rajagopalan, Murlidhar; Girdhar, Mukesh; Kandhari, Sanjiv; Shah, Bela; Chhajed, Prashant N.; Tahiliani, Sushil; Shankar, D. S. Krupa; Somani, Vijay; Zawar, Vijay

    2016-01-01

    Chronic spontaneous urticaria (CSU) affects 1% of the world population and also their quality of life, and 50% of these patients are refractory to H1-antihistamines. Omalizumab is a humanized monoclonal anti-IgE antibody that binds with free IgE antibodies and reduces the circulating levels of free IgE. This reduction in free IgE prevents mast-cell degranulation. The EAACI/GA2LEN/EDF/WAO guidelines recommend omalizumab as the third-line of therapy as an add-on to antihistamines. The recommended dose of omalizumab is 300 mg, 4 weekly in the management of CSU refractory to standard of care with H1-antihistamines in adults and adolescents ≥12 years of age. In some patients, a dose of 150 mg may be acceptable. Omalizumab has a good safety profile. However, due to the biologic nature of the drug, all patients administered omalizumab must be observed for 2 h after administration for anaphylactoid reactions. There have been no studies on the effect of impaired renal or hepatic function on the pharmacokinetics of omalizumab. While no particular dose adjustment is recommended, omalizumab should be administered with caution in these patients. PMID:26955580

  13. BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: a review.

    PubMed

    An, Xin; Tiwari, Amit K; Sun, Yibo; Ding, Pei-Rong; Ashby, Charles R; Chen, Zhe-Sheng

    2010-10-01

    Chronic Myeloid Leukemia (CML) is a clonal disease characterized by the presence of the Philadelphia (Ph+) chromosome and its oncogenic product, BCR-ABL, a constitutively active tyrosine kinase, that is present in >90% of the patients. Epidemiologic data indicates that almost 5000 new cases are reported every year and 10% of these patients eventually succumb to the disease. The treatment of CML was revolutionized by the introduction of imatinib mesylate (IM, Gleevec), a BCR-ABL tyrosine kinase inhibitor (TKI). The clinical use of specific BCR-ABL inhibitors has resulted in a significantly improved prognosis, response rate, overall survival, and patient outcome in CML patients compared to previous therapeutic regimens. However, the complete eradication of CML in patients receiving imatinib was limited by the emergence of resistance mostly due to mutations in the ABL kinase domain and to a lesser extent by molecular residual disease after treatment. The second-generation BCR-ABL TKIs nilotinib (Tasigna) and dasatinib (Sprycel), showed significant activity in clinical trials in patients intolerant or resistant to imatinib therapy, except in those patients with the T315I BCR-ABL mutation. Identifying key components involved in the CML pathogenesis may lead to the exploration of new approaches that might eventually overcome resistance mediated to the BCR-ABL TKIs. Here, we present an overview about the current treatment of Ph+ CML patients with the TKIs and the obstacles to successful treatment with these drugs.

  14. 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

  15. 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

  16. Leucapheresis for management of retinopathy in chronic myeloid leukaemia.

    PubMed

    Mohamed, Muhajir; Oakley, Carmen; McEwen, Fiona; Connelley, Georgina

    2015-01-01

    Chronic myeloid leukaemia is a myeloproliferative neoplasm characterised by granulocytic hyperplasia in the bone marrow and the presence of a specific cytogenetic abnormality known as Philadelphia chromosome with fusion of breakpoint cluster region (BCR) and ableson (ABL) genes. Retinopathy is a rare sight-threatening complication of chronic myeloid leukaemia, which occurs due to leucostasis in retinal blood vessels. We report a case of a patient who presented with visual impairment due to leucostasis, who was successfully managed by leucapheresis along with BCR-ABL tyrosine kinase inhibitor. PMID:26628310

  17. [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.

  18. Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO).

    PubMed

    Levey, Andrew S; Eckardt, Kai-Uwe; Tsukamoto, Yusuke; Levin, Adeera; Coresh, Josef; Rossert, Jerome; De Zeeuw, Dick; Hostetter, Thomas H; Lameire, Norbert; Eknoyan, Garabed

    2005-06-01

    Chronic kidney disease (CKD) is a worldwide public health problem, with adverse outcomes of kidney failure, cardiovascular disease (CVD), and premature death. A simple definition and classification of kidney disease is necessary for international development and implementation of clinical practice guidelines. Kidney Disease: Improving Global Outcomes (KDIGO) conducted a survey and sponsored a controversies conference to (1) provide a clear understanding to both the nephrology and nonnephrology communities of the evidence base for the definition and classification recommended by Kidney Disease Quality Outcome Initiative (K/DOQI), (2) develop global consensus for the adoption of a simple definition and classification system, and (3) identify a collaborative research agenda and plan that would improve the evidence base and facilitate implementation of the definition and classification of CKD. The K/DOQI definition and classification were accepted, with clarifications. CKD is defined as kidney damage or glomerular filtration rate (GFR) <60 mL/min/1.73 m(2) for 3 months or more, irrespective of cause. Kidney damage in many kidney diseases can be ascertained by the presence of albuminuria, defined as albumin-to-creatinine ratio >30 mg/g in two of three spot urine specimens. GFR can be estimated from calibrated serum creatinine and estimating equations, such as the Modification of Diet in Renal Disease (MDRD) Study equation or the Cockcroft-Gault formula. Kidney disease severity is classified into five stages according to the level of GFR. Kidney disease treatment by dialysis and transplantation should be noted. Simple, uniform classifications of CKD by cause and by risks for kidney disease progression and CVD should be developed. PMID:15882252

  19. 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. PMID:26916570

  20. 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.

  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. 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.

  3. Nocturnal nasal continuous positive airway pressure in patients with chronic obstructive pulmonary disease. Influence on waking respiratory muscle function.

    PubMed

    Mezzanotte, W S; Tangel, D J; Fox, A M; Ballard, R D; White, D P

    1994-10-01

    Patients with COPD often have reduced inspiratory muscle strength and endurance as well as poor exercise tolerance. Increased inspiratory work during sleep (probably due to increased upper airway resistance) may further strain these compromised respiratory muscles in COPD patients. We hypothesized that nasal continuous positive airway pressure (CPAP) might reduce respiratory work during sleep in COPD patients and thereby improve waking inspiratory muscle function. To test this hypothesis, eight male COPD patients were treated with sustained nocturnal nasal CPAP. Inspiratory muscle strength (maximum inspiratory pressure) and endurance (sustained inspiratory pressure) as well as clinical performance (12-min walk) were assessed before and after therapy. We observed that compared with matched controls, COPD patients treated with nocturnal nasal CPAP had significant and substantial improvement in inspiratory muscle strength and endurance as well as functional ability as assessed by the 12-min walk. In addition, CPAP did not significantly alter sleep quality or oxygenation in the patients studied. We conclude that nocturnal nasal CPAP improves inspiratory muscle performance during wakefulness in COPD patients, which is very likely a product of the reduced work of breathing during sleep while these individuals received CPAP.

  4. 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.

  5. 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.

  6. 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

  7. 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

  8. Azathioprine in autologous serum skin test positive chronic urticaria: A case–control study in a tertiary care hospital of eastern India

    PubMed Central

    Bhanja, Dulal Chandra; Ghoshal, Loknath; Das, Sudip; Das, Suchibrata; Roy, Alok Kumar

    2015-01-01

    Context: Urticaria, also referred to as hives or wheals is a common and distinctive reaction pattern characterized by spontaneous eruption of wheals. About 30–50% of patients categorized as idiopathic urticaria have autoimmune urticaria, needing immunosuppressive agents. Immunosuppressive agents are either too costly or have serious side effects. Azathioprine seems to address both these issues, being less costly. Aims: The aim was to evaluate the role of azathioprine in autologous serum skin test (ASST) positive chronic urticaria (CU). Settings and Design: A single-blind randomized control trial of ASST positive patients of CU. Materials and Methods: Patients with positive ASST were allotted into two treatment groups, named group A and group B. Patients in group A were administered azathioprine (50 mg/day) for a period of 8 weeks and followed up till 36 weeks, while patients in group B were given placebo pills. All patients were directed to take levocetirizine (5 mg) on as and when basis, in addition. Urticaria was assessed by total severity score. Statistical Analysis Used: MedCalc statistical software (v 12.5 for Windows) to calculate P values in independent samples by t-test, Mann–Whitney test, Friedmann test, and ANOVA. Results: Administration of azathioprine in group A resulted in a significant diminution of the intensity of the disease as well as in the requirement of rescue antihistamine (positive primary and secondary outcome). Conclusion: Azathioprine not only had immunomodulatory properties during the treatment period, but also had lasting therapeutic effect as well. There were some gastrointestinal side effects in the initial stages but no incidence of hematological or biochemical disturbances. PMID:26009713

  9. HLA-C and KIR combined genotype as new response marker for HBeAg-positive chronic hepatitis B patients treated with interferon-based combination therapy.

    PubMed

    Stelma, F; Jansen, L; Sinnige, M J; van Dort, K A; Takkenberg, R B; Janssen, H L A; Reesink, H W; Kootstra, N A

    2016-08-01

    Current treatment for chronic hepatitis B infection (CHB) consists of interferon-based therapy. However, for unknown reasons, a large proportion of patients with CHB do not respond to this treatment. Hence, there is a pressing need to establish response markers to select patients who will benefit from therapy and to spare potential nonresponders from unnecessary side effects of antiviral therapy. Here, we assessed whether HLA-C and KIR genotypes were associated with treatment outcome for CHB. Twelve SNPs in or near the HLA-C gene were genotyped in 86 CHB patients (41 HBeAg positive; 45 HBeAg negative) treated with peginterferon alfa-2a + adefovir. Genotyping of killer immunoglobin-like receptors (KIRs) was performed by SSP-PCR. One SNP in HLA-C (rs2308557) was significantly associated with combined response in HBeAg-positive CHB patients (P = 0.003). This SNP is linked to the HLA-C group C1 or C2 classification, which controls KIR binding. The combination of KIR2DL1 with its ligand HLA-C2 was observed significantly more often in HBeAg-positive patients with a combined response (13/14) than in nonresponders (11/27, P = 0.001). Patients with the KIR2DL1/C2 genotype had significantly higher baseline ALT levels (136 vs 50 U/L, P = 0.002) than patients without this combination. Furthermore, KIR2DL1-C2 predicted response independent of HBV genotype and ALT at baseline. HLA-C and KIR genotype is strongly associated with response in HBeAg-positive CHB patients treated with interferon-based therapy. In combination with other known response markers, HLA-C/KIR genotype could enable the selection of patients more likely to respond to interferon-based therapy. PMID:26945896

  10. A case of a 17-year-old male with neurofascin-155 antibody-positive chronic inflammatory demyelinating polyradiculoneuropathy presenting with tremor and ataxia.

    PubMed

    Itaya, Kazuhiro; Inoue, Manabu; Iizuka, Natsuko; Shimizu, Yuki; Yuki, Nobuhiro; Ichikawa, Hiroo

    2016-09-29

    A 17-year-old male with no medical history noticed weakness of his limbs with imbalance and subsequent finger tremors. Physical examination revealed features of polyneuropathy, including diffuse weakness, distal symmetrical numbness with impaired deep sensation and areflexia in all limbs. Postural tremor was present in fingers. Ataxia was apparent in both lower limbs, causing a wide-based gait with a positive Romberg sign. Cerebrospinal fluid contained elevated total protein without pleocytosis. A nerve conduction study disclosed demyelinating features with prolonged terminal latencies, slow velocities with delayed F-wave latencies, and prominent temporal dispersion. These findings led to diagnosis of typical chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with notable feature of postural finger tremor and ataxia of unknown cause. These atypical features prompted us to examine neurofascin-155 (NF155) antibodies, which were positive. No significant improvement occurred after initial administration of intravenous immunoglobulin and subsequent plasma exchange. However, corticosteroids with intravenous pulse therapy followed by oral prednisolone significantly improved the symptoms. Patients with CIDP with anti-NF155 antibodies may have similar clinical features and constitute a CIDP subgroup. In such patients, corticosteroids may be more effective than intravenous immunoglobulin. Further studies are needed to define the features of this subgroup and determine effective therapy for CIDP.

  11. Vitamin D in patients with chronic kidney disease: a position statement of the Working Group "Trace Elements and Mineral Metabolism" of the Italian Society of Nephrology.

    PubMed

    Morrone, Luigi Francesco; Bolasco, Pergiorgio; Camerini, Corrado; Cianciolo, Giuseppe; Cupisti, Adamasco; Galassi, Andrea; Mazzaferro, Sandro; Russo, Domenico; Russo, Luigi; Cozzolino, Mario

    2016-06-01

    In the late 1970s, calcitriol was introduced into clinical practice for the management of secondary renal hyperparathyroidism in chronic kidney disease (CKD). Since then, the use of calcifediol or other native forms of vitamin D was largely ignored until the publication of the 2009 Kidney Disease Improving Global Outcomes (KDIGO) recommendations. The guidelines suggested that measurement of circulating levels of 25(OH)D (calcifediol) and its supplementation were to be performed on the same basis as for the general population. This indication was based on the fact that the precursors of active vitamin D had provided to CKD patients considerable benefits in survival, mainly due to their pleiotropic effects on the cardiovascular system. However, despite the long-term use of various classes of vitamin D in CKD, a clear definition is still lacking concerning the most appropriate time for initiation of therapy, the best compound to prescribe (active metabolites or analogs), the proper dosage, and the most suitable duration of therapy. The aim of this position statement is to provide and critically appraise the current plentiful evidence on vitamin D in different clinical settings related to CKD, particularly focusing on outcomes, monitoring and treatment-associated risks. However, it should be taken in account that position statements are meant to provide guidance; therefore, they are not to be considered prescriptive for all patients and, importantly, they cannot replace the judgment of clinicians. PMID:27062486

  12. [Treatment of anemia in chronic kidney disease--position statement of the Croatian Society for Nephrology, Dialysis and Transplantation and review of the KDIGO and ERPB guidelines].

    PubMed

    Rački, Sanjin; Bašić-Jukić, Nikolina; Kes, Petar; Ljutić, Dragan; Lovčić, Vesna; Prkačin, Ingrid; Radić, Josipa; Vujičić, Božidar; Bubić, Ivan; Jakić, Marko; Belavić, Žarko; Sefer, Siniša; Pehai, Mario; Klarić, Dragan; Gulin, Marijana

    2014-04-01

    Renal anemia is the result of chronic kidney disease (CKD) and deteriorates with disease progression. Anemia may be the first sign of kidney disease. In all patients with anemia and CKD, diagnostic evaluation is required. Prior to diagnosing renal anemia, it is necessary to eliminate the other possible causes. Direct correlation between the concentration of hemoglobin and the stage of renal failure is well known. Early development of anemia is common in diabetic patients. Correction of anemia may slow the progression of CKD. Anemia is an independent risk factor for developing cardiovascular disease in patients with CKD. Treatment of anemia in patients with CKD is based on current guidelines. Recently, the Kidney Disease: Improving Global Outcomes (KDIGO) group has produced comprehensive clinical practice guidelines for the management of anemia in CKD patients and ERBP (European Renal Best Practice) group its position statement and comments on the KDIGO guidelines. The Croatian Society of Nephrology, Dialysis and Transplantation (HDNDT) has already published its own guidelines based on the recommendations and positive experience of European and international professional societies, as well as on own experience. The latest version of Croatian guidelines was published in 2008. Since then, on the basis of research and clinical practice, there have been numerous changes in the modern understanding of the treatment of anemia in CKD. Consequently, HDNDT hereby publishes a review of the recent recommendations of international professional societies, expressing the attitude about treating anemia in CKD as a basis for new guidelines tailored to the present time.

  13. 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

  14. Phase II trial of hyper CVAD and dasatinib in patients with relapsed Philadelphia chromosome positive acute lymphoblastic leukemia or blast phase chronic myeloid leukemia.

    PubMed

    Benjamini, Ohad; Dumlao, Theresa Liu; Kantarjian, Hagop; O'Brien, Susan; Garcia-Manero, Guillermo; Faderl, Stefan; Jorgensen, Jeffrey; Luthra, Rajyalakshmi; Garris, Rebecca; Thomas, Deborah; Kebriaei, Partow; Champlin, Richard; Jabbour, Elias; Burger, Jan; Cortes, Jorge; Ravandi, Farhad

    2014-03-01

    Dasatinib is a second generation tyrosine kinase inhibitor, with activity in imatinib resistant Ph-positive ALL.We have treated 34 patients with relapsed Philadelphia chromosome positive acute lymphoblastic leukemia(ALL) (n519) or lymphoid blast phase of chronic myelogenous leukemia (CML-LB) (n515) with the combination of dasatinib and the hyper CVAD regimen. Prior regimens included hyper CVAD plus imatinib(n511, 4 had transplant in first CR), other combination chemotherapy (n512), monotherapy with kinase inhibitors other than dasatinib (n59), and investigational agents (n52). Pretreatment ABL mutations were noted in 10 patients. The overall response rate was 91%, with 24 patients (71%) achieving complete response(CR), and 7(21%) CR with incomplete platelet recovery (CRp). Two patients died during induction and one had progressive disease. Twenty-six patients (84%) achieved complete cytogenetic remission after one cycle of therapy. Overall, 13 patients (42%) achieved complete molecular response, and 11 patients (35%) had major molecular response (BCR-ABL/ABL<0.1%). Nine patients proceeded to allogeneic transplantation.Grades 3 and 4 toxicities included hemorrhage, pleural and pericardial effusions and infections. The median follow-up for patients with CML-LB is 37.5 months (range, 7–70 months) with a 3-year overall survival of 70%;68% remained in CR at 3 years. For ALL patients, the median follow-up is 52 months (range, 45–59 months)with a 3-year survival of 26%; 30% remain in CR at 3 years. The combination of Hyper CVAD regimen with dasatinib is effective in patients with relapsed Ph-positive ALL and CML-LB. PMID:24779033

  15. Vitamin E and C supplementation reduces oxidative stress, improves antioxidant enzymes and positive muscle work in chronically loaded muscles of aged rats.

    PubMed

    Ryan, Michael J; Dudash, Holly J; Docherty, Megan; Geronilla, Kenneth B; Baker, Brent A; Haff, G Gregory; Cutlip, Robert G; Alway, Stephen E

    2010-11-01

    Aging is associated with increased oxidative stress. Muscle levels of oxidative stress are further elevated with exercise. The purpose of this study was to determine if dietary antioxidant supplementation would improve muscle function and cellular markers of oxidative stress in response to chronic repetitive loading in aging. The dorsiflexors of the left limb of aged and young adult Fischer 344 Brown×Norway rats were loaded 3 times weekly for 4.5 weeks using 80 maximal stretch-shortening contractions per session. The contra-lateral limb served as the intra-animal control. The rats were randomly assigned to a diet supplemented with Vitamin E and Vitamin C or normal non-supplemented rat chow. Biomarkers of oxidative stress were measured in the tibialis anterior muscle. Repetitive loading exercise increased maximal isometric force, negative work and positive work in the dorsiflexors of young adult rats. Only positive work increased in the aged animals that were supplemented with Vitamin E and C. Markers of oxidative stress (H(2)O(2), total GSH, GSH/GSSG ratio, malondialdehyde and 8-OHdG) increased in the tibialis anterior muscles from aged and young adult animals with repetitive loading, but Vitamin E and C supplements attenuated this increase. MnSOD activity increased with supplementation in the young adult animals. CuZnSOD and catalase activity increased with supplementation in young adult and aged animals and GPx activity increased with exercise in the non-supplemented young adult and aged animals. The increased levels of endogenous antioxidant enzymes after Vitamin E and C supplementation appear to be regulated by post-transcriptional modifications that are affected differently by age, exercise, and supplementation. These data suggest that antioxidant supplementation improves indices of oxidative stress associated with repetitive loading exercise and aging and improves the positive work output of muscles in aged rodents.

  16. Transient elastography and APRI score: looking at false positives and false negatives. Diagnostic performance and association to fibrosis staging in chronic hepatitis C

    PubMed Central

    Mendes, L.C.; Ferreira, P.A.; Miotto, N.; Zanaga, L.; Gonçales, E.; Lazarini, M.S.; Gonçales, F.L.; Stucchi, R.S.B.; Vigani, A.G.

    2016-01-01

    Although long regarded as the gold standard for liver fibrosis staging in chronic hepatitis C (CHC), liver biopsy (LB) implies both the risk of an invasive procedure and significant variability. The aim of this study was to evaluate the diagnostic performance for transient elastography (TE) and aspartate aminotransferase to platelet index (APRI) used alone and in combination compared to liver biopsy and to analyze false positive/negative results. Patients with CHC, and no previous clinical diagnosis of cirrhosis were enrolled to undergo liver biopsy, TE and APRI. A total of 182 adult patients with a median age of 55 years and median body mass index of 26.71 kg/m2 were analyzed. On LB, 56% of patients had significant levels of fibrosis (METAVIR F≥2) and 28% had advanced fibrosis (F3/F4). The strongest performance for both tests was observed for exclusion of advanced fibrosis with good negative predictive values (89 and 86%, respectively). Low necroinflammatory activity on LB was associated with false negative TE. False positives were associated with NASH and smaller LB fragments. Correlation between APRI and Fibroscan for F≥2 was 100% and 84% for F≥3 and remained high in both false negative and false positive instances, correctly identifying F<2 in 71% of cases and F<3 in 78% (and potentially foregoing up to 84% of LB). We concluded that low individual performance indicators could be attributable to limitations of LB. Poorer differentiation of lower levels of fibrosis is a known issue for LB and remains so for noninvasive tests. Good predictability is possible, however, for advanced fibrosis. PMID:27533769

  17. 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

  18. 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

  19. 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

  20. Phase II study of dasatinib in Philadelphia chromosome-negative acute and chronic myeloid diseases, including systemic mastocytosis

    PubMed Central

    Verstovsek, Srdan; Tefferi, Ayalew; Cortes, Jorge; O’Brien, Susan; Garcia-Manero, Guillermo; Pardanani, Animesh; Akin, Cem; Faderl, Stefan; Manshouri, Taghi; Thomas, Deborah; Kantarjian, Hagop

    2016-01-01

    Molecular characterization of Philadelphia chromosome-negative (Ph−) chronic myeloproliferative disorders, such as systemic mastocytosis (SM), has provided a clear rationale for investigating novel targeted therapies. The tyrosine kinase (TK) inhibitor dasatinib is 325-fold more potent against Bcr-Abl TK than imatinib in vitro, significantly inhibiting wild-type KIT and PDGFR-B TKs, and is active against cells carrying the mutant KIT-D816V gene. In this phase 2, open-label study, the efficacy of dasatinib (140 mg/day) was investigated in 67 patients with various Ph− myeloid disorders, including SM (N=33; 28 KIT-D816V positive). The overall response rate to dasatinib in patients with SM was 33%. Only two patients, one with SM-myelofibrosis and one with SM-chronic eosinophilic leukemia, achieved complete response (elimination of mastocytosis) lasting for 5 and 16 months, respectively. Both patients were negative for KIT-D816V mutation, had low tryptase levels, abnormal WBC counts, and anemia, and had failed prior therapy with erythropoietin. Additional 9 SM patients had symptomatic response, lasting 3 to 18+ months. Complete responses were achieved in two other patients (acute myeloid leukemia, hypereosinophilic syndrome). No responses were observed among patients with myelodysplastic syndromes and primary myelofibrosis. The majority of adverse events were grade 1/2. These data show that dasatinib may benefit a selected group of SM patients, primarily by improving their symptoms. PMID:18559612

  1. Stat5 is critical for the development and maintenance of myeloproliferative neoplasm initiated by Nf1 deficiency

    PubMed Central

    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.

    2016-01-01

    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. PMID:27418650

  2. [Chronic myelogenous leukemia: diagnosis and treatment].

    PubMed

    Demeter, Judit; Poros, Anna; Bödör, Csaba; Horváth, Laura; Masszi, Tamás

    2016-09-01

    Chronic myelogenous leukemia is a clonal myeloproliferative neoplasm caused by reciprocal translocation involving chromosomes 9 and 22 resulting in the expression of a constitutively activated BCR-ABL1 tyrosine kinase that leads to the malignant transformation of the hematopoietic stem cells. The condition was previously known as a relentlessly progressive disease, but the treatment was revolutionalized by the efficacy of tyrosine kinase inhibitors. Therapeutic success is thus currently determined by the depth of molecular response achieved on therapy. Multiple tyrosine kinase agents are available even for the first line treatment. This guideline summarizes current focal points of the treatment of chronic myelogenous leukemia specific to Hungary and provides definitions for optimal molecular responses in this condition. Orv. Hetil., 2016, 157(37), 1459-1468. PMID:27615196

  3. Occurrence of yeasts, enterococci and other enteric bacteria in subgingival biofilm of HIV-positive patients with chronic gingivitis and necrotizing periodontitis

    PubMed Central

    Gaetti-Jardim Júnior, Elerson; Nakano, Viviane; Wahasugui, Thais C.; Cabral, Fátima C.; Gamba, Rosa; Avila-Campos, Mario Julio

    2008-01-01

    The purpose of this study was to determine the prevalence of enteric bacteria and yeasts in biofilm of 80 HIV-positive patients with plaque-associated gingivitis or necrotizing periodontitis. Patients were subjected to extra, intra oral and radiographic examinations. The oral hygiene, bleeding on probing, gingival conditions, and attachment loss were evaluated. Clinical specimens were collected from gingival crevices or periodontal pockets, transferred to VMGA III, diluted and transferred to Sabouraud Dextrose agar with 100 μg/ml of chloramphenicol, peptone water, EVA broth, EMB agar, SS agar, Bile esculin agar and Brilliant green agar. Isolation of yeasts was carried out at room temperature, for 3-7 days; and for the isolation of enteric microorganisms plates were incubated at 37°C, for 24-48 h. The yeasts identification was performed according to the carbon and nitrogen assimilation, fermentation of carbohydrates and germ tube formation. Bacteria were identified according to their colonial and cellular morphologies and biochemical tests. Yeasts were identified as Candida albicans and its occurrence was more common in patients with CD4+ below 200/mm3 and was affected by the extension of periodontal involvement (P = 0.0345). Enteric bacteria recovered from clinical specimens were identified as Enterobacter sakazakii, Enterobacter cloacae, Serratia liquefaciens, Klebsiella oxytoca and Enterococcus sp. Enterobacteriaceae and enterococci were detected in 32.5% of clinical samples from patients with necrotizing periodontitis. In conclusion, non-oral pathogenic bacteria and C. albicans were more prevalent in periodontal sites of HIV-positive patients with necrotizing periodontitis and chronic gingivitis. PMID:24031212

  4. High rates of viral suppression after long-term entecavir treatment of Asian patients with hepatitis B e antigen-positive chronic hepatitis B.

    PubMed

    Pan, Calvin Q; Tong, Myron; Kowdley, Kris V; Hu, Ke-Qin; Chang, Ting-Tsung; Lai, Ching-Lung; Yoon, Seung Kew; Lee, Samuel S; Cohen, David; Tang, Hong; Tsai, Naoky

    2012-09-01

    There are limited data on the effects of long-term entecavir therapy in Asian patients with chronic hepatitis B (CHB). We performed a post hoc analysis of 94 Asian hepatitis B e antigen-positive (HBeAg+), nucleos(t)ide analogue-naive patients who received 5 years of therapy with entecavir (up to 2 years in study ETV-022 and the remainder in study ETV-901). Among patients completing week 240, 95% (63 of 66) had levels of hepatitis B virus DNA <300 copies/mL, and 76% (50 of 66) had normalized levels of alanine aminotransferase. In addition to patients who achieved a serologic response during ETV-022, a further 40% (26 of 65) achieved HBeAg loss, and 18% (12 of 65) underwent HBeAg seroconversion through year 5 of entecavir therapy. No resistance to entecavir was detected, and the safety profile was consistent with previous reports. The long-term efficacy and safety of entecavir are therefore comparable between Asians and the overall population of HBeAg+ patients with CHB.

  5. Spontaneous Soft Tissue Haematomas- A Rare Presentation of Chronic Myeloid Leukemic (CML)

    PubMed Central

    Lakhotia, Manoj; Prajapati, Gopal Raj; Choudhary, Akanksha; Gandhi, Ronak

    2015-01-01

    Spontaneous soft tissue haematomas are rarely found in haematological malignancies. Chronic myeloid leukemia (CML) is a myeloproliferative disorder which rarely present with thrombo-haemorrhagic phenomenon. It is a malignant clonal disorder of pleuripotent stem cells that results in increase in myeloid, erythroid and platelets cells in peripheral blood and marked myeloid hyperplasia in bone marrow. It is characterized by the presence of Philadelphia chromosome (Ph) with BCR – ABL 1 fusion gene. This gene is responsible for the formation of 210 KDa chimeric proteins with enhanced tyrosine kinase activity which leads to the abnormal bone marrow cell proliferation and to the clinical and morphologic manifestations of leukemia. Cutaneous and mucous membrane bleeding is common in CML whereas bleeding in deep soft tissue is rarely found because of qualitative and quantitative platelet abnormalities. Here, we report a case of CML (BCR-ABL rearrangement positive) who presented with large haematoma in the anterior as well as posterior compartment of left thigh and treated successfully with hydroxyurea and imatinib. PMID:26417552

  6. Chronic myelomonocytic leukemia: Forefront of the field in 2015

    PubMed Central

    Benton, Christopher B; Nazha, Aziz; Pemmaraju, Naveen; Garcia-Manero, Guillermo

    2016-01-01

    Chronic myelomonocytic leukemia (CMML) includes components of both myelodysplastic syndrome and myeloproliferative neoplasms and is associated with a characteristic peripheral monocytosis. CMML is caused by the proliferation of an abnormal hematopoietic stem cell clone and may be influenced by microenvironmental changes. The disease is rare and has undergone revisions in its classification. We review the recent classification strategies as well as diagnostic criteria, focusing on CMML’s genetic alterations and unique pathophysiology. We also discuss the latest molecular characterization of the disease, including how molecular factors affect current prognostic models. Finally, we focus on available treatment strategies, with a special emphasis on experimental and forthcoming therapies. PMID:25869097

  7. Improved Efficacy of a pegylated interferon-α-2a stepwise optimization treatment strategy in the treatment of hepatitis B e antigen-positive chronic hepatitis B patients.

    PubMed

    Zhou, Pu; Yang, Feifei; Wang, Jinyu; Mao, Richeng; Qi, Xun; Huang, Yuxian; Zhang, Jiming

    2015-05-01

    Current pegylated interferon-α (PEG-IFN) treatment for chronic hepatitis B (CHB) e-antigen (HBeAg)-positive patients are suboptimal, and effective ways of improving PEG-IFN treatment efficacy are needed.This retrospective cohort study compared the efficacy of a PEG-IFN stepwise optimization treatment (PEG-IFN SOT) strategy with that of a 48-week PEG-IFN standard therapy (PEG-IFN ST) in HBeAg-positive CHB patients.A total of 110 patients were included in our study. Of these, 70 received the PEG-IFN SOT and 40 received the PEG-IFN ST (control group). We based the decision whether to add adefovir and/or extend the PEG-IFN-based treatment to 96 weeks on the patients' 12-week or 24-week early virological response (12W EVR, at least a 2 log10 reduction in HBV DNA copies/mL at week 12; 24W EVR, at least 1 log10 reduction in HBsAg IU/mL or HBsAg <1500 IU/mL at week 24) and their 48-week partial response (48W PR, 1.0 ≤HBeAg ≤10.0 S/CO or HBeAg >10.0 S/CO but HBsAg <1000 IU/mL).The HBeAg seroconversion rate 24 weeks post-PEG-IFN treatment was significantly higher in the PEG-IFN SOT than the PEG-IFN ST group (50% vs 22.5%, P = 0.005). The HBsAg clearance rates in the PEG-IFN SOT and ST groups were 10% and 0% (P = 0.04), respectively. Receiving PEG-IFN SOT (OR = 0.26, P = 0.01), ALT × ULN at baseline (OR = 0.74, P = 0.003), and achieving 12 and 24W EVR (OR = 0.29, P = 0.03) were independent factors associated with HBeAg seroconversion.PEG-IFN SOT is a promising strategy for achieving high rates of serological response in HBeAg-positive CHB patients.

  8. Chronic pancreatitis

    MedlinePlus

    Chronic pancreatitis - chronic; Pancreatitis - chronic - discharge; Pancreatic insufficiency - chronic; Acute pancreatitis - chronic ... abuse over many years. Repeated episodes of acute pancreatitis can lead to chronic pancreatitis. Genetics may be ...

  9. Chelation efficacy and erythroid response during deferasirox treatment in patients with myeloproliferative neoplasms in fibrotic phase.

    PubMed

    Latagliata, Roberto; Montagna, Chiara; Porrini, Raffaele; Di Veroli, Ambra; Leonetti, Sabrina Crescenzi; Niscola, Pasquale; Ciccone, Fabrizio; Spadea, Antonio; Breccia, Massimo; Maurillo, Luca; Rago, Angela; Spirito, Francesca; Cedrone, Michele; De Muro, Marianna; Montanaro, Marco; Andriani, Alessandro; Bagnato, Antonino; Montefusco, Enrico; Alimena, Giuliana

    2016-06-01

    At present, very few data are available on deferasirox (DFX) in the treatment of patients with Philadelphia-negative myeloproliferative neoplasms in fibrotic phase (FP-MPN) and transfusion dependence. To address this issue, a retrospective analysis of 28 patients (22 male and 6 female) with FP-MPN and iron overload secondary to transfusion dependence was performed, based on patients enrolled in the database of our regional cooperative group who received treatment with DFX. DFX was started after a median interval from diagnosis of 12.8 months (IR 7.1-43.1) with median ferritin values of 1415 ng/mL (IR 1168-1768). Extra-hematological toxicity was reported in 16 of 28 patients (57.1%), but only two patients discontinued treatment due to toxicity. Among 26 patients evaluable for response (≥6 months of treatment), after a median treatment period of 15.4 months (IR 8.1-22.3), 11 patients (42.3%) achieved a stable and consistent reduction in ferritin levels <1000 ng/mL. As for hematological improvement, 6 of 26 patients (23%) showed a persistent (>3 months) rise of Hb levels >1.5 g/dL, with disappearance of transfusion dependence in four cases. Treatment with DFX is feasible and effective in FP-MPN with iron overload. Moreover, in this setting, an erythroid response can occur in a significant proportion of patients.

  10. 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

  11. 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.

  12. Hemostatic disorders in a JAK2V617F-driven mouse model of myeloproliferative neoplasm

    PubMed Central

    Lamrani, Lamia; Lacout, Catherine; Ollivier, Véronique; Denis, Cécile V.; Gardiner, Elizabeth; Ho Tin Noe, Benoit; Vainchenker, William; Villeval, Jean-Luc

    2014-01-01

    Thrombosis is common in patients suffering from myeloproliferative neoplasm (MPN), whereas bleeding is less frequent. JAK2V617F, the main mutation involved in MPN, is considered as a risk factor for thrombosis, although the direct link between the mutation and hemostatic disorders is not strictly established. We investigated this question using conditional JAK2V617F knock-in mice with constitutive and inducible expression of JAK2V617F in hematopoietic cells, which develop a polycythemia vera (PV)-like disorder evolving into myelofibrosis. In vitro, thrombosis was markedly impaired with an 80% decrease in platelet-covered surface, when JAK2V617F blood was perfused at arterial shear over collagen. JAK2V617F platelets presented only a moderate glycoprotein (GP) VI deficiency not responsible for the defective platelet accumulation. In contrast, a decreased proportion of high-molecular-weight von Willebrand factor multimers could reduce platelet adhesion. Accordingly, the tail bleeding time was prolonged. In the FeCl3-induced thrombosis model, platelet aggregates formed rapidly but were highly unstable. Interestingly, vessels were considerably dilated. Thus, mice developing PV secondary to constitutive JAK2V617F expression exhibit a bleeding tendency combined with the accelerated formation of unstable clots, reminiscent of observations made in patients. Hemostatic defects were not concomitant with the induction of JAK2V617F expression, suggesting they were not directly caused by the mutation but were rather the consequence of perturbations in blood and vessel homeostasis. PMID:24951423

  13. Interferon-alpha for the therapy of myeloproliferative neoplasms: targeting the malignant clone.

    PubMed

    Kiladjian, J-J; Giraudier, S; Cassinat, B

    2016-04-01

    Interferon alpha (IFN-α) has been used for over 30 years to treat myeloproliferative neoplasms (MPNs). IFN-α was shown to induce clinical, hematological, molecular and histopathological responses in small clinical studies. Such combined efficacy has never been achieved with any other drug to date in such a significant proportion of patients. However, toxicity remains a limitation to its broader use despite the development of pegylated forms with better tolerance. Several on going phase 3 studies of peg- IFN-α versus hydroxyurea will help to define its exact place in MPN management. IFN-α efficacy is likely the consequence of a broad range of biological properties, including enhancement of immune response, direct effects on malignant cells and ability to cycle dormant malignant stem cells. However, comprehensive elucidation of its mechanism of action is still lacking. Sustained clinical, molecular and morphological responses after IFN-α discontinuation raised the hope that this drug could eradicate MPN. There is now consistent evidence showing that IFN-α is able to eliminate malignant clones harboring JAK2V617F or Calreticulin mutations. However, the molecular complexity of these diseases could hamper IFN-α efficacy, as the presence of additional non-driver mutations, like in the TET2 gene, could be associated with resistance to IFN-α. Therefore, combined therapy with another targeted agent could be required to eradicate MPN, and the best IFN-α companion for achieving this challenge remains to be determined.

  14. The Use of Anagrelide in Myeloproliferative Neoplasms, with Focus on Essential Thrombocythemia.

    PubMed

    Birgegård, Gunnar

    2016-10-01

    Anagrelide (ANA) is a drug with specific platelet-lowering activity, used primarily in ET, registered as a second-line drug in essential thrombocythemia (ET) in Europe and in some countries as first-line therapy, in USA licensed by FDA for thrombocythemia in myeloproliferative neoplasms (MPN). The platelet-lowering efficacy is similar to that of hydroxycarbamide (HC), around 70 % complete response and 90 % partial response. Side effects are common, especially headache and tachycardia, but usually subside or disappear within a few weeks. Around 20 % of patients stop ANA therapy due to side effects or insufficient response. Studies of treatment patterns in Europe show that ANA is preferentially given to younger patients, probably because of the concern for a possible leukemogenic effect of the common first-line drug, HC. Only two randomized studies have compared the efficacy of ANA and HC in preventing thrombosis and haemorrhage, the larger of them showing a slightly better efficacy of HC, the other showing non-inferiority of ANA to HC. A recent observational 5-year study of 3600 patients shows a low and basically similar efficacy of ANA and other cytoreductive therapies in ET. ANA does not appear to inhibit fibrosis development, and probably due to its anticoagulation properties, the combination of ASA and ANA produces an increased rate of haemorrhage. Combination of ANA with HC or interferon (IFN) is feasible and effective in patients with insufficient platelet response to mono-therapy.

  15. JAK2 inhibition has different therapeutic effects according to myeloproliferative neoplasm development in mice

    PubMed Central

    Debeurme, Franck; Lacout, Catherine; Moratal, Claudine; Bagley, Rebecca G; Vainchenker, William; Adrian, Francisco; Villeval, Jean-Luc

    2015-01-01

    JAK2 inhibition therapy is used to treat patients suffering from myeloproliferative neoplasms (MPN). Conflicting data on this therapy are reported possibly linked to the types of inhibitors or disease type. Therefore, we decided to compare in mice the effect of a JAK2 inhibitor, Fedratinib, in MPN models of increasing severity: polycythemia vera (PV), post-PV myelofibrosis (PPMF) and rapid post-essential thrombocythemia MF (PTMF). The models were generated through JAK2 activation by the JAK2V617F mutation or MPL constant stimulation. JAK2 inhibition induced a correction of splenomegaly, leucocytosis and microcytosis in all three MPN models. However, the effects on fibrosis, osteosclerosis, granulocytosis, erythropoiesis or platelet counts varied according to the disease severity stage. Strikingly, complete blockade of fibrosis and osteosclerosis was observed in the PPMF model, linked to correction of MK hyper/dysplasia, but not in the PTMF model, suggesting that MF development may also become JAK2-independent. Interestingly, we originally found a decreased in the JAK2V617F allele burden in progenitor cells from the spleen but not in other cell types. Overall, this study shows that JAK2 inhibition has different effects according to disease phenotypes and can (i) normalize platelet counts, (ii) prevent the development of marrow fibrosis/osteosclerosis at an early stage and (iii) reduce splenomegaly through blockage of stem cell mobilization in the spleen. PMID:26176817

  16. Centrosome-Kinase Fusions Promote Oncogenic Signaling and Disrupt Centrosome Function in Myeloproliferative Neoplasms

    PubMed Central

    Lee, Joanna Y.; Hong, Wan-Jen; Majeti, Ravindra; Stearns, Tim

    2014-01-01

    Chromosomal translocations observed in myeloproliferative neoplasms (MPNs) frequently fuse genes that encode centrosome proteins and tyrosine kinases. This causes constitutive activation of the kinase resulting in aberrant, proliferative signaling. The function of centrosome proteins in these fusions is not well understood. Among others, kinase centrosome localization and constitutive kinase dimerization are possible consequences of centrosome protein-kinase fusions. To test the relative contributions of localization and dimerization on kinase signaling, we targeted inducibly dimerizable FGFR1 to the centrosome and other subcellular locations and generated a mutant of the FOP-FGFR1 MPN fusion defective in centrosome localization. Expression in mammalian cells followed by western blot analysis revealed a significant decrease in kinase signaling upon loss of FOP-FGFR1 centrosome localization. Kinase dimerization alone resulted in phosphorylation of the FGFR1 signaling target PLCγ, however levels comparable to FOP-FGFR1 required subcellular targeting in addition to kinase dimerization. Expression of MPN fusion proteins also resulted in centrosome disruption in epithelial cells and transformed patient cells. Primary human MPN cells showed masses of modified tubulin that colocalized with centrin, Smoothened (Smo), IFT88, and Arl13b. This is distinct from acute myeloid leukemia (AML) cells, which are not associated with centrosome-kinase fusions and had normal centrosomes. Our results suggest that effective proliferative MPN signaling requires both subcellular localization and dimerization of MPN kinases, both of which may be provided by centrosome protein fusion partners. Furthermore, centrosome disruption may contribute to the MPN transformation phenotype. PMID:24658090

  17. 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

  18. 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

  19. Clinical features of patients with Philadelphia-negative myeloproliferative neoplasms complicated by portal hypertension

    PubMed Central

    Yan, Matthew; Geyer, Holly; Mesa, Ruben; Atallah, Ehab; Callum, Jeannie; Bartoszko, Justyna; Yee, Karen; Maganti, Manjula; Wong, Florence; Gupta, Vikas

    2015-01-01

    Backgroud Portal hypertension (PHTN) has been reported to afflict 7-18% of patients with Philadelphia-negative myeloproliferative neoplasms (MPNs), with complications of variceal bleeding and ascites. The clinical features and outcomes of these patients are unclear. Patients and Methods In this multi-centre retrospective study, we evaluated the clinical features of 51 patients with MPNs complicated by PHTN. Results The diagnosis of underlying MPN was most frequently polycythemia vera (PV) (39%) and primary myelofibrosis (MF) (35%), followed by post-PV myelofibrosis (18%), essential thrombocythemia (ET) (4%) and post-ET myelofibrosis (4%). Frequency of JAK2 V617F mutation appears as expected in the underlying MPN. Thrombosis within the splanchnic circulation was prevalent in patients with polycythemia compared to other MPNs (76% vs. 26%, p=0.0007). Conclusions PV and MF patients have a higher incidence of PHTN in our population, with thrombosis contributing to PHTN development in PV patients. Patients with splanchnic circulation thrombosis are potential candidates for screening for portal hypertension. These data may be useful for developing screening strategies for early detection of PHTN in patients with MPN. PMID:25027569

  20. 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

  1. 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

  2. Cardiac hypertrophy associated with myeloproliferative neoplasms in JAK2V617F transgenic mice

    PubMed Central

    2014-01-01

    Background Myeloproliferative neoplasms (MPNs) are blood malignancies manifested in increased production of red blood cells, white blood cells, and/or platelets. A major molecular lesion associated with the diseases is JAK2V617F, an activation mutation form of tyrosine kinase JAK2. Cardiovascular events represent the leading cause of morbidity and mortality associated MPNs, but the underlying mechanism is not well understood. Methods Previously, we generated JAK2V617F transgenic mice which displayed MPN-like phenotypes. In the present study, we further characterized these mice by analyzing the time course of MPN phenotype development and associated cardiac abnormalities. We performed detailed histochemical staining of cardiac sections. Results JAK2V617F transgenic mice developed cardiomegaly as a subsequent event of increased blood cell production during the course of MPN phenotype development. The cardiomegaly is manifested in increased ventricular wall thickness and enlarged cardiomyocytes. Trichrome and reticulin staining revealed extensive collagen fibrosis in the heart of JAK2V617F transgenic mice. Thrombosis in the coronary artery and inflammatory cell infiltration into cardiac muscle were also observed in JAK2V617F transgenic mice, and the latter event was accompanied by fibrosis. Conclusion JAK2V617F-induced blood disorders have a major impact on heart function and lead to cardiac hypertrophy. JAK2V617F transgenic mice represent an excellent model system to study both hematological malignancies and cardiovascular diseases. PMID:24646493

  3. 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

  4. 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

  5. Chelation efficacy and erythroid response during deferasirox treatment in patients with myeloproliferative neoplasms in fibrotic phase.

    PubMed

    Latagliata, Roberto; Montagna, Chiara; Porrini, Raffaele; Di Veroli, Ambra; Leonetti, Sabrina Crescenzi; Niscola, Pasquale; Ciccone, Fabrizio; Spadea, Antonio; Breccia, Massimo; Maurillo, Luca; Rago, Angela; Spirito, Francesca; Cedrone, Michele; De Muro, Marianna; Montanaro, Marco; Andriani, Alessandro; Bagnato, Antonino; Montefusco, Enrico; Alimena, Giuliana

    2016-06-01

    At present, very few data are available on deferasirox (DFX) in the treatment of patients with Philadelphia-negative myeloproliferative neoplasms in fibrotic phase (FP-MPN) and transfusion dependence. To address this issue, a retrospective analysis of 28 patients (22 male and 6 female) with FP-MPN and iron overload secondary to transfusion dependence was performed, based on patients enrolled in the database of our regional cooperative group who received treatment with DFX. DFX was started after a median interval from diagnosis of 12.8 months (IR 7.1-43.1) with median ferritin values of 1415 ng/mL (IR 1168-1768). Extra-hematological toxicity was reported in 16 of 28 patients (57.1%), but only two patients discontinued treatment due to toxicity. Among 26 patients evaluable for response (≥6 months of treatment), after a median treatment period of 15.4 months (IR 8.1-22.3), 11 patients (42.3%) achieved a stable and consistent reduction in ferritin levels <1000 ng/mL. As for hematological improvement, 6 of 26 patients (23%) showed a persistent (>3 months) rise of Hb levels >1.5 g/dL, with disappearance of transfusion dependence in four cases. Treatment with DFX is feasible and effective in FP-MPN with iron overload. Moreover, in this setting, an erythroid response can occur in a significant proportion of patients. PMID:26277477

  6. The Use of Anagrelide in Myeloproliferative Neoplasms, with Focus on Essential Thrombocythemia.

    PubMed

    Birgegård, Gunnar

    2016-10-01

    Anagrelide (ANA) is a drug with specific platelet-lowering activity, used primarily in ET, registered as a second-line drug in essential thrombocythemia (ET) in Europe and in some countries as first-line therapy, in USA licensed by FDA for thrombocythemia in myeloproliferative neoplasms (MPN). The platelet-lowering efficacy is similar to that of hydroxycarbamide (HC), around 70 % complete response and 90 % partial response. Side effects are common, especially headache and tachycardia, but usually subside or disappear within a few weeks. Around 20 % of patients stop ANA therapy due to side effects or insufficient response. Studies of treatment patterns in Europe show that ANA is preferentially given to younger patients, probably because of the concern for a possible leukemogenic effect of the common first-line drug, HC. Only two randomized studies have compared the efficacy of ANA and HC in preventing thrombosis and haemorrhage, the larger of them showing a slightly better efficacy of HC, the other showing non-inferiority of ANA to HC. A recent observational 5-year study of 3600 patients shows a low and basically similar efficacy of ANA and other cytoreductive therapies in ET. ANA does not appear to inhibit fibrosis development, and probably due to its anticoagulation properties, the combination of ASA and ANA produces an increased rate of haemorrhage. Combination of ANA with HC or interferon (IFN) is feasible and effective in patients with insufficient platelet response to mono-therapy. PMID:27497846

  7. Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms.

    PubMed

    Pietra, D; Rumi, E; Ferretti, V V; Di Buduo, C A; 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

    2016-02-01

    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

  8. The effects of the insulin resistance index on the virologic response to entecavir in patients with HBeAg-positive chronic hepatitis B and nonalcoholic fatty liver disease

    PubMed Central

    Zhu, Li-Yao; Wang, Yu-Gang; Wei, Li-Qing; Zhou, Jian; Dai, Wei-Jie; Zhang, Xiao-Yu

    2016-01-01

    Purpose To further observe and verify the effect of nonalcoholic fatty liver disease (NAFLD) on the response to antiviral therapy in patients with chronic hepatitis B (CHB) and investigate the relationship between the virologic response and insulin resistance. Patients and methods A retrospective study was adopted and 61 NAFLD patients with HBeAg-positive CHB were included as the observation group (group A), and 64 patients with simple CHB were included as the control group (group B). Results After 12 weeks of treatment with entecavir, the total virologic response rate in group A was statistically significantly lower than that in group B (P<0.05). During weeks 24–96, the difference was not statistically significant (P>0.05). In weeks 48 and 96, there was no significant difference in the HBeAg seroconversion rates between the two groups (P>0.05). In weeks 12 and 24, there was also no significant difference in the alanine transaminase (ALT) normalization rate between the two groups (P>0.05). Then, in weeks 48 and 96, the ALT normalization rate of group A was obviously lower than that of group B (P<0.05). Group A patients were divided into group A1 (≤M) and group A2 (>M) according to the median value (M=2.79) of the baseline homeostatic model assessment method insulin resistance levels. In weeks 48 and 96, the ALT normalization rate of group A1 was significantly higher than that of group A2 (P<0.05). The correlation coefficient (r) of the baseline homeostatic model assessment method insulin resistance level and the severity of fatty liver in group A was 0.426 (P=0.001). Conclusion NAFLD cannot affect the long-term total virologic response rate and HBeAg seroconversion rate in CHB patients treated with entecavir but can reduce the long-term biochemical response rate, which has a positive correlation with the severity of fatty liver and the insulin resistance index. PMID:27621595

  9. The effects of the insulin resistance index on the virologic response to entecavir in patients with HBeAg-positive chronic hepatitis B and nonalcoholic fatty liver disease

    PubMed Central

    Zhu, Li-Yao; Wang, Yu-Gang; Wei, Li-Qing; Zhou, Jian; Dai, Wei-Jie; Zhang, Xiao-Yu

    2016-01-01

    Purpose To further observe and verify the effect of nonalcoholic fatty liver disease (NAFLD) on the response to antiviral therapy in patients with chronic hepatitis B (CHB) and investigate the relationship between the virologic response and insulin resistance. Patients and methods A retrospective study was adopted and 61 NAFLD patients with HBeAg-positive CHB were included as the observation group (group A), and 64 patients with simple CHB were included as the control group (group B). Results After 12 weeks of treatment with entecavir, the total virologic response rate in group A was statistically significantly lower than that in group B (P<0.05). During weeks 24–96, the difference was not statistically significant (P>0.05). In weeks 48 and 96, there was no significant difference in the HBeAg seroconversion rates between the two groups (P>0.05). In weeks 12 and 24, there was also no significant difference in the alanine transaminase (ALT) normalization rate between the two groups (P>0.05). Then, in weeks 48 and 96, the ALT normalization rate of group A was obviously lower than that of group B (P<0.05). Group A patients were divided into group A1 (≤M) and group A2 (>M) according to the median value (M=2.79) of the baseline homeostatic model assessment method insulin resistance levels. In weeks 48 and 96, the ALT normalization rate of group A1 was significantly higher than that of group A2 (P<0.05). The correlation coefficient (r) of the baseline homeostatic model assessment method insulin resistance level and the severity of fatty liver in group A was 0.426 (P=0.001). Conclusion NAFLD cannot affect the long-term total virologic response rate and HBeAg seroconversion rate in CHB patients treated with entecavir but can reduce the long-term biochemical response rate, which has a positive correlation with the severity of fatty liver and the insulin resistance index.

  10. [One of the Mechanisms in Blastic Transformation of Chronic Myeloid Leukemia: Epigenetics Abnormality--Review].

    PubMed

    Meng, Zhen; Li, Ying-Hua

    2016-02-01

    Chronic myeloid leukemia is a myeloproliferative disorder characterized by excessive cloning of bone marrow multipotent stem cells. According to the disease course, the CML may be divided into chronic phase (CP), accelerated phase (AP) and blastic phase (BP). At present, the molecular mechanisms of acute transformation of CML has not been fully understood. The recent studies have shown that the epigenetics is one of mechanisms in blastic transformation of CML, including three molecular mechanisms such as DNA modification, histone modifications and RNA-related dysregulation. The molecular mechanisms for epigenetics leading to the transformation of CML are discussed in this review. PMID:26913431

  11. The new genetics of chronic neutrophilic leukemia and atypical CML: implications for diagnosis and treatment

    PubMed Central

    Maxson, Julia E.; George, Tracy I.; Tyner, Jeffrey W.

    2013-01-01

    Although activation of tyrosine kinase pathways is a shared theme among myeloproliferative neoplasms, the pathogenetic basis of chronic neutrophilic leukemia (CNL) has remained elusive. Recently, we identified high-frequency oncogenic mutations in the granulocyte-colony stimulating factor receptor (CSF3R) in CNL and in some patients with atypical chronic myeloid leukemia. Inhibition of Janus kinase 2 or SRC kinase signaling downstream of mutated CSF3R is feasible and should be explored therapeutically. Herein, we discuss the potential impact of these findings for the classification and treatment of these disorders. PMID:23896413

  12. Vatalanib decrease the positive interaction of VEGF receptor-2 and P2X2/3 receptor in chronic constriction injury rats.

    PubMed

    Liu, Shuangmei; Xu, Changshui; Li, Guilin; Liu, Han; Xie, Jinyan; Tu, Guihua; Peng, Haiying; Qiu, Shuyi; Liang, Shangdong

    2012-05-01

    M, an inhibitor of VEGF receptors). The stain values of VEGFR-2, P2X(2) and P2X(3) protein expression in L4/5 DRG of CCI treated with Vatalanib group were significantly decreased compared with those in CCI group (p<0.01). Vatalanib can alleviate chronic neuropathic pain by decreasing the activation of VEGF on VEGFR-2 and the positive interaction between the up-regulated VEGFR-2 and P2X(2/3) receptors in the neuropathic pain signaling. PMID:22361062

  13. 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

  14. Philadelphia-Negative Classical Myeloproliferative Neoplasms: Critical Concepts and Management Recommendations From European LeukemiaNet

    PubMed Central

    Barbui, Tiziano; Barosi, Giovanni; Birgegard, Gunnar; Cervantes, Francisco; Finazzi, Guido; Griesshammer, Martin; Harrison, Claire; Hasselbalch, Hans Carl; Hehlmann, Rudiger; Hoffman, Ronald; Kiladjian, Jean-Jacques; Kröger, Nicolaus; Mesa, Ruben; McMullin, Mary F.; Pardanani, Animesh; Passamonti, Francesco; Vannucchi, Alessandro M.; Reiter, Andreas; Silver, Richard T.; Verstovsek, Srdan; Tefferi, Ayalew

    2011-01-01

    We present a review of critical concepts and produce recommendations on the management of Philadelphia-negative classical myeloproliferative neoplasms, including monitoring, response definition, first- and second-line therapy, and therapy for special issues. Key questions were selected according the criterion of clinical relevance. Statements were produced using a Delphi process, and two consensus conferences involving a panel of 21 experts appointed by the European LeukemiaNet (ELN) were convened. Patients with polycythemia vera (PV) and essential thrombocythemia (ET) should be defined as high risk if age is greater than 60 years or there is a history of previous thrombosis. Risk stratification in primary myelofibrosis (PMF) should start with the International Prognostic Scoring System (IPSS) for newly diagnosed patients and dynamic IPSS for patients being seen during their disease course, with the addition of cytogenetics evaluation and transfusion status. High-risk patients with PV should be managed with phlebotomy, low-dose aspirin, and cytoreduction, with either hydroxyurea or interferon at any age. High-risk patients with ET should be managed with cytoreduction, using hydroxyurea at any age. Monitoring response in PV and ET should use the ELN clinicohematologic criteria. Corticosteroids, androgens, erythropoiesis-stimulating agents, and immunomodulators are recommended to treat anemia of PMF, whereas hydroxyurea is the first-line treatment of PMF-associated splenomegaly. Indications for splenectomy include symptomatic portal hypertension, drug-refractory painful splenomegaly, and frequent RBC transfusions. The risk of allogeneic stem-cell transplantation–related complications is justified in transplantation-eligible patients whose median survival time is expected to be less than 5 years. PMID:21205761

  15. 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

  16. v-mos proteins encoded by myeloproliferative sarcoma virus and its ts159 mutant.

    PubMed Central

    Singh, B; Stocking, C; Walker, R; Yang, Y D; Ostertag, W; Arlinghaus, R B

    1992-01-01

    The myeloproliferative sarcoma virus (MPSV) v-mos protein was predicted to be identical in size to p39c-mos because of an observed one-base deletion in the seventh codon of the env-mos open reading frame, which would allow translation to initiate at the methionine equivalent to codon 32 of the env-mos gene. On the basis of published results, p39c-mos is known to have greatly reduced in vitro protein kinase activity compared with p37env-mos encoded by Moloney murine sarcoma virus. Unexpectedly, the relative activity of the MPSV v-mos protein kinase was comparable to that of p37env-mos. Consistent with this finding, the size of MPSV v-mos protein was found to be similar to the size of p37env-mos. Moreover, the pattern and sizes of phosphorylated bands produced by autophosphorylation of the MPSV v-mos protein were similar to those of p37env-mos. These results were confirmed by in vitro transcription-translation of the MPSV v-mos gene. Resequencing portions of the MPSV mos gene failed to show the deletion within codon 7. Except for the codon 262 deletion, other mutations characteristic of MPSV and temperature-sensitive MPSV v-mos genes were confirmed. A glycine-to-arginine mutation at residue 338 of the MPSV env-mos sequence, previously shown to cause thermosensitivity of the mutant virus (termed ts159) transforming function, yielded a v-mos protein that had significantly reduced protein kinase activity in vitro. These findings indicate that MPSV, like other Moloney murine sarcoma virus strains, also encodes a functional env-mos protein. Images PMID:1309903

  17. Survival Patterns in United States (US) Medicare Enrollees with Non-CML Myeloproliferative Neoplasms (MPN)

    PubMed Central

    Price, Gregory L.; Davis, Keith L.; Karve, Sudeep; Pohl, Gerhardt; Walgren, Richard A.

    2014-01-01

    Purpose Non-CML myeloproliferative neoplasms (MPN) include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). Reported median overall survival (OS) ranges from a few to several years for MF, a decade or more for ET and PV. The study objective was to compare US survival rates of ET, PV, and MF patients with matched non-MPN/non-cancer controls in a nationally representative database. Patients and Methods Data were taken retrospectively from the Survey, Epidemiology, and End Results (SEER)-Medicare linked database. Medicare enrollees with a new SEER MPN diagnosis between Jan 1, 2001 and Dec 31, 2007 were eligible. First MPN diagnosis was required at or after Medicare enrollment to allow for continuous follow-up. Non-MPN/non-cancer control groups were selected from Medicare separately for each MPN subtype and demographically matched to cases at a ratio of 5∶1. Survival was determined starting from the case diagnosis date using the Kaplan-Meier method. Results A total of 3,364 MPN patients (n = 1,217 ET; 1,625 PV; 522 MF) met the inclusion criteria and were matched to controls. Mean age was 78.4, 76.1, and 77.4 years for ET, PV, and MF, respectively, and percent female was 63, 50, and 41. Median OS was significantly (p<0.05) lower for MPN cases vs. controls (ET: 68 vs. 101 months; PV: 65 vs. 104; MF: 24 vs. 106). Conclusions In the US Medicare population, survival in MF patients was worse than that of patients with ET or PV and significantly worse than matched controls. Survival of patients with ET or PV was substantially inferior to matched controls. These findings have implications for the clinical management of MPN patients and underscore the need for effective therapies in all MPN subtypes. PMID:24618579

  18. 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

  19. 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

  20. 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

  1. Association between thromboembolic events and the JAK2 V617F mutation in myeloproliferative neoplasms.

    PubMed

    Takata, Yuka; Seki, Ritsuko; Kanajii, Taisuke; Nohara, Masayuki; Koteda, Satoko; Kawaguchi, Kuniki; Nomura, Kei; Nakamura, Takayuki; Morishige, Satoshi; Oku, Eijirou; Osaki, Koichi; Hashiguchi, Emichitoshi; Mouri, Fumihiko; Yoshimoto, Koji; Nagafuji, Koji; Okamura, Takashi

    2014-01-01

    Thrombotic complications are a major cause of death in patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), which are closely associated with the JAK2 V617F activating mutation. However, whether the presence of the JAK2 V617F mutation affects thrombotic risk is currently unknown, although some reports have suggested a variable association with thrombosis. Therefore, we investigated the association between JAK2 V617F and various complications, including thrombosis, in Japanese patients with MPNs. We assessed the JAK2 V617F status in 140 patients who were diagnosed or doubted as having some type of MPN by utilizing a JAK2 V617F-specific guanine-quenching probe. JAK2 V617F was detected in 31 of 51 patients (60.8%) with essential thrombocythemia, all 16 patients (100%) with polycythemia vera, 4 of 11 patients (36.4%) with primary myelofibrosis, 2 of 18 patients (11.1%) with other types of MPNs, and none of the 44 patients with doubted MPN. In the 78 patients with classical MPN, JAK2 V617F correlated with a leukocyte count ≥10,000/μl (p=0.046). Complications of thrombosis, hemorrhage, and leukemic transformation occurred in 21 (41.2%), 4 (25.0%), and 3 (27.3%) patients with classical MPN, respectively, and thrombotic events (TE) occurred more frequently in patients with JAK2 V617F than without (p=0.047). Based on these findings, initial screening for the JAK2 mutation and careful monitoring for thrombotic events should be performed in patients with MPN. PMID:24858412

  2. Analysis of genomic aberrations and gene expression profiling identifies novel lesions and pathways in myeloproliferative neoplasms.

    PubMed

    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

    2011-11-01

    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.

  3. Analysis of the Ten-Eleven Translocation 2 (TET2) gene mutation in myeloproliferative neoplasms.

    PubMed

    Ha, Jung-Sook; Jeon, Dong-Seok; Kim, Jae-Ryong; Ryoo, Nam-Hee; Suh, Jang-Soo

    2014-01-01

    Loss-of-function mutations in the putative tumor suppressor gene, Ten-Eleven Ttranslocation 2(TET2), have been identified recently in myeloproliferative neoplasms (MPNs). The present study analyzed the TET2 gene in 99 MPNs patients. The overall TET2 mutational frequency was 12.1% (22.2% in polycythemia vera (PV), 9.7% in essential thrombocythemia (ET), 18.2% in primary myelofibrosis (PMF,) and 0% in unclassified MPNs), and 11 mutations (p.Lys95Asnfs*18, p.Gln967Asnfs*40, p.Lys1022Glufs*4, p.Asp1314Metfs*49, p.Gln1534Alafs*43, p.Tyr1618Leufs*4, p.Leu1609Glufs*45, p.Gly1735*, Q599R, c.3409+1G>T, c.4044+2insT) were identified. All the patients with TET2 mutation were accompanied by the JAK2 V617F mutation. The existence of the TET2 mutation was not related to the patient's age, hematologic indices, JAK2 V617F allele burden, frequencies of organomegaly, marrow fibrosis, or thrombotic/hemorrhagic complications in entire MPN patients. However, tendencies toward higher JAK2 V617F allele burdens (88.0±4.3% vs. 19.1±28.7%, P=0.034) and higher Hct (47.4±5.4% vs. 25.5±6.2%, P=0.037) were detected in PMF patients harboring TET2 mutations. Moreover, a significantly higher frequency of organomegaly was identified in ET patients harboring the TET2 mutation (50% vs. 19.6%, P=0.018). The TET2 mutation most likely contributes to clinical phenotypes and shows a high accompanying rate with JAK2 V617F; larger scale studies involving more MPN patients are needed. PMID:24795056

  4. Pentostatin and Lymphocyte Infusion in Preventing Graft Rejection in Patients Who Have Undergone Donor Stem Cell Transplant

    ClinicalTrials.gov

    2016-02-29

    Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Graft Versus Host Disease; Hodgkin Lymphoma; Myelodysplastic/Myeloproliferative Neoplasm; Non-Hodgkin Lymphoma; Plasma Cell Myeloma; Waldenstrom Macroglobulinemia

  5. Increased risk of lymphoid neoplasm in patients with myeloproliferative neoplasm: a study of 1,915 patients

    PubMed Central

    Rumi, Elisa; Passamonti, Francesco; Elena, Chiara; Pietra, Daniela; Arcaini, Luca; Astori, Cesare; Zibellini, Silvia; Boveri, Emanuela; Pascutto, Cristiana; Lazzarino, Mario

    2011-01-01

    Within a cohort of 1,915 consecutive patients with myeloproliferative neoplasm followed for a median time of 5.2 years (range 0–33.3), we investigated the occurrence of lymphoid neoplasm with the aim of defining this risk and to investigate the role of genetic predisposing factors. We identified 22 patients with myeloproliferative neoplasm who developed lymphoid neoplasm over their lifetime. We found that the risk of developing lymphoid neoplasm was 2.79-fold higher (95% CI, 1.80–4.33; P<0.001) than that of the general Italian population. A tag SNP surrogate for JAK2 GGCC haplotype was used to clarify a potential correlation between lymphoid-myeloid neoplasm occurrence and this genetic predisposing factor. As we did not find any difference in GGCC haplotype frequency between patients with both myeloid and lymphoid neoplasm and patients with myeloid neoplasm, JAK2 GGCC haplotype should not be considered a genetic predisposing factor. No difference in familial clustering was observed between the two groups. PMID:21109692

  6. Identification of a novel partner gene, TPR, fused to FGFR1 in 8p11 myeloproliferative syndrome.

    PubMed

    Li, Feng; Zhai, Yong-Ping; Tang, Yu-Mei; Wang, Li-Ping; Wan, Pin-Jun

    2012-09-01

    The 8p11 myeloproliferative syndrome (EMS) is an aggressive neoplasm caused by the fusion of various partner genes to fibroblast growth factor receptor 1 (FGFR1). Various FGFR1 fusions are associated with subtly distinct disease phenotypes. Here, we report a new translocation at the FGFR1 locus in a patient who carried t(1;8)(q25;p11.2) and presented with myeloproliferative neoplasm-like symptoms. The patient was characterized by myeloid hyperplasia of bone marrow, markedly elevated numbers of monocytes, and normal to mildly elevated eosinophils. Initial fluorescent in situ hybridization analysis confirmed that FGFR1 in this patient was disrupted. Subsequent analysis led to the identification of a novel translocation, in which exon 23 of the translocated promoter region (TPR) gene at chromosome band 1q25 was fused to exon 13 of FGFR1 (RefSeq NM_0231102.2). The TPR portion of the fusion protein contains putative functional motifs including an N-terminal TprMet domain, nuclear pore complexes associating domain, and multiple coiled-coil domains. It is likely that one or more of the motifs from TPR contribute to dimerization, resulting in constitutive activation of the FGFR1 kinase domain. Our results further support a critical role of FGFR1 in the pathogenesis of EMS and may lead to more accurate diagnosis and potential targeted therapy.

  7. Circulating Cd34+ cell count differentiates primary myelofibrosis from other Philadelphia-negative myeloproliferative neoplasms: a pragmatic study.

    PubMed

    Orvain, C; Luque Paz, D; Dobo, I; Cottin, L; Le Calvez, G; Chauveau, A; Mercier, M; Farhi, J; Boyer, F; Ianotto, J C; Guibourg, B; Rousselet, M C; Zandecki, M; Ifrah, N; Hunault-Berger, M; Ugo, V; Genevieve, F

    2016-10-01

    A high number of circulating CD34+ cells has been advocated to distinguish primary myelofibrosis from other Philadelphia-negative myeloproliferative neoplasms. We re-evaluated the diagnostic interest of measuring circulating CD34+ cells in 26 healthy volunteers and 256 consecutive patients at diagnosis for whom a myeloproliferative neoplasm was suspected. The ROC curve analysis showed that a number of CD34+ <10/μl excludes the diagnosis of primary myelofibrosis with a sensitivity of 97 % and a specificity of 90 % (area under the curve: 0.93 [0.89-0.98]; p < 0.001). Patients with PMF harboring a CALR mutation had more circulating CD34+ cells than patients with either a JAK 2 or MPL mutation (p = 0.02 and p < 0.01, respectively). These results suggest that this fast, simple, non-invasive, and standardized test is of particular interest to exclude the diagnosis of primary myelofibrosis.

  8. Circulating Cd34+ cell count differentiates primary myelofibrosis from other Philadelphia-negative myeloproliferative neoplasms: a pragmatic study.

    PubMed

    Orvain, C; Luque Paz, D; Dobo, I; Cottin, L; Le Calvez, G; Chauveau, A; Mercier, M; Farhi, J; Boyer, F; Ianotto, J C; Guibourg, B; Rousselet, M C; Zandecki, M; Ifrah, N; Hunault-Berger, M; Ugo, V; Genevieve, F

    2016-10-01

    A high number of circulating CD34+ cells has been advocated to distinguish primary myelofibrosis from other Philadelphia-negative myeloproliferative neoplasms. We re-evaluated the diagnostic interest of measuring circulating CD34+ cells in 26 healthy volunteers and 256 consecutive patients at diagnosis for whom a myeloproliferative neoplasm was suspected. The ROC curve analysis showed that a number of CD34+ <10/μl excludes the diagnosis of primary myelofibrosis with a sensitivity of 97 % and a specificity of 90 % (area under the curve: 0.93 [0.89-0.98]; p < 0.001). Patients with PMF harboring a CALR mutation had more circulating CD34+ cells than patients with either a JAK 2 or MPL mutation (p = 0.02 and p < 0.01, respectively). These results suggest that this fast, simple, non-invasive, and standardized test is of particular interest to exclude the diagnosis of primary myelofibrosis. PMID:27582015

  9. [THE EFFECTIVENESS OF A 10-DAY DRUG THERAPY IN CHILDREN WITH CHRONIC GASTRODUODENAL PATHOLOGY ASSOCIATED WITH CAGA-POSITIVE STRAINS OF HELICOBACTER PYLORI].

    PubMed

    Dudnyk, V M; Rudenko, G M

    2015-01-01

    The results of triple Helicobacter-therapy (omeprazole, amoxicillin, nifuratel) in the treatment of chronic gastroduodenal pathology in children depending on the duration of it's use. The effectiveness of drug therapy was evaluated in terms of eradication of Helicobacter pylori and dynamics of pain, dyspeptic syndrome and astenovegetative syndrome.

  10. Genetics Home Reference: PDGFRA-associated chronic eosinophilic leukemia

    MedlinePlus

    ... area? Other Names for This Condition PDGFRA-associated myeloproliferative neoplasm Related Information How are genetic conditions and genes ... Disorders Hanns A. Pielenz Clinical Research Center for Myeloproliferative Neoplasia, MD Anderson Cancer ... Genetic Testing Registry (1 link) Idiopathic hypereosinophilic ...

  11. Up-regulation of MicroRNA 146b is Associated with Myelofibrosis in Myeloproliferative Neoplasms.

    PubMed

    Ha, Jung-Sook; Jung, Hye-Ra

    2015-01-01

    In this study, our goal was to evaluate whether the expressions of microRNA (miR)-150, miR-146b, miR-31 and miR-95 demonstrate primary myelofibrosis (PMF) specificity, associations with fibrosis grade, hematologic phenotypes, or myeloproliferative neoplasm (MPN)-associated mutations. A total of 51 formalin-fixed and paraffin-embedded bone marrow MPN samples, including 15 polycythemia vera (PV), 26 essential thrombocythemia (ET), and 10 PMF, and 24 normal controls were included. The expression of microRNA (miRNA) was detected by quantitative real-time polymerase chain reaction using miRNA specific primers. RNU6-2 was analyzed for all samples as endogenous control for relative quantification. Information for fibrosis, hematologic parameters, Janus kinase 2 (JAK2) V617F, and calreticulin (CALR) mutations was obtained from medical records. Significant increment of miR-146b was detected in PMF compared to normal controls (P=0.008). Moreover, expression of miR-146b tended to increase according to increment of fibrosis grade, and patients with myelofibrosis (MF) grade 3 showed significantly higher expression than patients with MF 0 to 2 (P=0.022, 0.001 and 0.013, respectively) or normal controls (P<0.001). The expression of miR-31 also showed tendency to increase following fibrosis and miR-150 showed up-regulated expression in ET (P=0.015) compared to normal control. There was no relationship between miRNA expression and hematologic indices except miR-95 showed negative correlation with platelet count (P=0.024). There was no significant correlation between miRNA expression and JAK2 V617F or CALR mutation. Up-regulation of miR-146b could be used as a fibrosis-indicating marker and might be helpful in the study of fibrotic mechanism in MPN, as well as other fibrotic diseases. PMID:26116595

  12. Influence of the JAK2 V617F Mutation and Inherited Thrombophilia on the Thrombotic Risk among Patients with Myeloproliferative Disorders

    PubMed Central

    TEVET, Mihaela; IONESCU, Razvan; DRAGAN, Cornel; LUPU, Anca Roxana

    2015-01-01

    Background: A number of studies showed that the JAK2 V617F mutation increases the thrombotic risk in patients with myeloproliferative disorders (MPN) while others did not reveal this correlation, and it is unknown whether inherited thrombophilia is an additive risk factor in mutated subjects. Our aim was to clarify the contribution of JAK2 V617F to a hypercoagulable state, as well as its interaction with other thrombophilic factors in patients with thrombosis and myeloproliferative disorders. Method: We studied 192 patients with myeloproliferative disorders, 90 with Essential thrombocytemia (ET), 42 with Polycythemia vera (PV) and 60 with Primary or idiopathic myelofibrosis (PMI). From these patients a subgroup of only 62 patients underwent laboratory screening for thrombophilia. Results: The JAK2 V617F mutation was present in 62.8% patients with myeloproliferative disorders, 97.6% with PV, 54.5 % with ET and 53.44% patients with PMI. The mutated patients had a relative risk (RR) for thrombosis at any time of 2.94 in comparison with "wild-type" patients which was 0.93; in those patients having both the mutation and thrombophilia the RR was 3.56 (95% CI 2.41-7.34) compared to patients with neither the mutation nor thrombophilia, suggesting an additive interaction between the two risk factors. Conclusion: In patients with myeloproliferatives neoplasias, the thrombotic risk is higher in the JAK2 V617F-mutated subgroup and it is further increased by the presence of inherited thrombophilia (especially by the presence of mutated F V Leiden and lupus anticoagulant). PMID:26225146

  13. Severe chronic allergic (and related) diseases: a uniform approach--a MeDALL--GA2LEN--ARIA position paper.

    PubMed

    Bousquet, J; Anto, J M; Demoly, P; Schünemann, H J; Togias, A; Akdis, M; Auffray, C; Bachert, C; Bieber, T; Bousquet, P J; Carlsen, K H; Casale, T B; Cruz, A A; Keil, T; Lodrup Carlsen, K C; Maurer, M; Ohta, K; Papadopoulos, N G; Roman Rodriguez, M; Samolinski, B; Agache, I; Andrianarisoa, A; Ang, C S; Annesi-Maesano, I; Ballester, F; Baena-Cagnani, C E; Basagaña, X; Bateman, E D; Bel, E H; Bedbrook, A; Beghé, B; Beji, M; Ben Kheder, A; Benet, M; Bennoor, K S; Bergmann, K C; Berrissoul, F; Bindslev Jensen, C; Bleecker, E R; Bonini, S; Boner, A L; Boulet, L P; Brightling, C E; Brozek, J L; Bush, A; Busse, W W; Camargos, P A M; Canonica, G W; Carr, W; Cesario, A; Chen, Y Z; Chiriac, A M; Costa, D J; Cox, L; Custovic, A; Dahl, R; Darsow, U; Didi, T; Dolen, W K; Douagui, H; Dubakiene, R; El-Meziane, A; Fonseca, J A; Fokkens, W J; Fthenou, E; Gamkrelidze, A; Garcia-Aymerich, J; Gerth van Wijk, R; Gimeno-Santos, E; Guerra, S; Haahtela, T; Haddad, H; Hellings, P W; Hellquist-Dahl, B; Hohmann, C; Howarth, P; Hourihane, J O; Humbert, M; Jacquemin, B; Just, J; Kalayci, O; Kaliner, M A; Kauffmann, F; Kerkhof, M; Khayat, G; Koffi N'Goran, B; Kogevinas, M; Koppelman, G H; Kowalski, M L; Kull, I; Kuna, P; Larenas, D; Lavi, I; Le, L T; Lieberman, P; Lipworth, B; Mahboub, B; Makela, M J; Martin, F; Martinez, F D; Marshall, G D; Mazon, A; Melen, E; Meltzer, E O; Mihaltan, F; Mohammad, Y; Mohammadi, A; Momas, I; Morais-Almeida, M; Mullol, J; Muraro, A; Naclerio, R; Nafti, S; Namazova-Baranova, L; Nawijn, M C; Nyembue, T D; Oddie, S; O'Hehir, R E; Okamoto, Y; Orru, M P; Ozdemir, C; Ouedraogo, G S; Palkonen, S; Panzner, P; Passalacqua, G; Pawankar, R; Pigearias, B; Pin, I; Pinart, M; Pison, C; Popov, T A; Porta, D; Postma, D S; Price, D; Rabe, K F; Ratomaharo, J; Reitamo, S; Rezagui, D; Ring, J; Roberts, R; Roca, J; Rogala, B; Romano, A; Rosado-Pinto, J; Ryan, D; Sanchez-Borges, M; Scadding, G K; Sheikh, A; Simons, F E R; Siroux, V; Schmid-Grendelmeier, P D; Smit, H A; Sooronbaev, T; Stein, R T; Sterk, P J; Sunyer, J; Terreehorst, I; Toskala, E; Tremblay, Y; Valenta, R; Valeyre, D; Vandenplas, O; van Weel, C; Vassilaki, M; Varraso, R; Viegi, G; Wang, D Y; Wickman, M; Williams, D; Wöhrl, S; Wright, J; Yorgancioglu, A; Yusuf, O M; Zar, H J; Zernotti, M E; Zidarn, M; Zhong, N; Zuberbier, T

    2012-01-01

    Concepts of disease severity, activity, control and responsiveness to treatment are linked but different. Severity refers to the loss of function of the organs induced by the disease process or to the occurrence of severe acute exacerbations. Severity may vary over time and needs regular follow-up. Control is the degree to which therapy goals are currently met. These concepts have evolved over time for asthma in guidelines, task forces or consensus meetings. The aim of this paper is to generalize the approach of the uniform definition of severe asthma presented to WHO for chronic allergic and associated diseases (rhinitis, chronic rhinosinusitis, chronic urticaria and atopic dermatitis) in order to have a uniform definition of severity, control and risk, usable in most situations. It is based on the appropriate diagnosis, availability and accessibility of treatments, treatment responsiveness and associated factors such as comorbidities and risk factors. This uniform definition will allow a better definition of the phenotypes of severe allergic (and related) diseases for clinical practice, research (including epidemiology), public health purposes, education and the discovery of novel therapies.

  14. Gene expression profiling of loss of TET2 and/or JAK2V617F mutant hematopoietic stem cells from mouse models of myeloproliferative neoplasms

    PubMed Central

    Kameda, Takuro; Shide, Kotaro; Yamaji, Takumi; Kamiunten, Ayako; Sekine, Masaaki; Hidaka, Tomonori; Kubuki, Yoko; Sashida, Goro; Aoyama, Kazumasa; Yoshimitsu, Makoto; Abe, Hiroo; Miike, Tadashi; Iwakiri, Hisayoshi; Tahara, Yoshihiro; Yamamoto, Shojiro; Hasuike, Satoru; Nagata, Kenji; Iwama, Atsushi; Kitanaka, Akira; Shimoda, Kazuya

    2015-01-01

    Myeloproliferative neoplasms (MPNs) are clinically characterized by the chronic overproduction of differentiated peripheral blood cells and the gradual expansion of malignant intramedullary/extramedullary hematopoiesis. In MPNs mutations in JAK2 MPL or CALR are detected mutually exclusive in more than 90% of cases [1], [2]. Mutations in them lead to the abnormal activation of JAK/STAT signaling and the autonomous growth of differentiated cells therefore they are considered as “driver” gene mutations. In addition to the above driver gene mutations mutations in epigenetic regulators such as TET2 DNMT3A ASXL1 EZH2 or IDH1/2 are detected in about 5%–30% of cases respectively [3]. Mutations in TET2 DNMT3A EZH2 or IDH1/2 commonly confer the increased self-renewal capacity on normal hematopoietic stem cells (HSCs) but they do not lead to the autonomous growth of differentiated cells and only exhibit subtle clinical phenotypes [[4], [6], [7], [8],5]. It was unclear how mutations in such epigenetic regulators influenced abnormal HSCs with driver gene mutations how they influenced the disease phenotype or whether a single driver gene mutation was sufficient for the initiation of human MPNs. Therefore we focused on JAK2V617F and loss of TET2—the former as a representative of driver gene mutations and the latter as a representative of mutations in epigenetic regulators—and examined the influence of single or double mutations on HSCs (Lineage−Sca-1+c-Kit+ cells (LSKs)) by functional analyses and microarray whole-genome expression analyses [9]. Gene expression profiling showed that the HSC fingerprint genes [10] was statistically equally enriched in TET2-knockdown-LSKs but negatively enriched in JAK2V617F–LSKs compared to that in wild-type-LSKs. Double-mutant-LSKs showed the same tendency as JAK2V617F–LSKs in terms of their HSC fingerprint genes but the expression of individual genes differed between the two groups. Among 245 HSC fingerprint genes 100 were more

  15. Chronic Internal Exposure to Low Dose 137Cs Induces Positive Impact on the Stability of Atherosclerotic Plaques by Reducing Inflammation in ApoE-/- Mice.

    PubMed

    Le Gallic, Clélia; Phalente, Yohann; Manens, Line; Dublineau, Isabelle; Benderitter, Marc; Gueguen, Yann; Lehoux, Stephanie; Ebrahimian, Teni G

    2015-01-01

    After Chernobyl and Fukushima Daï Chi, two major nuclear accidents, large amounts of radionuclides were released in the environment, mostly caesium 137 (137Cs). Populations living in contaminated territories are chronically exposed to radionuclides by ingestion of contaminated food. However, questions still remain regarding the effects of low dose ionizing radiation exposure on the development and progression of cardiovascular diseases. We therefore investigated the effects of a chronic internal exposure to 137Cs on atherosclerosis in predisposed ApoE-/- mice. Mice were exposed daily to 0, 4, 20 or 100 kBq/l 137Cs in drinking water, corresponding to range of concentrations found in contaminated territories, for 6 or 9 months. We evaluated plaque size and phenotype, inflammatory profile, and oxidative stress status in different experimental groups. Results did not show any differences in atherosclerosis progression between mice exposed to 137Cs and unexposed controls. However, 137Cs exposed mice developed more stable plaques with decreased macrophage content, associated with reduced aortic expression of pro-inflammatory factors (CRP, TNFα, MCP-1, IFNγ) and adhesion molecules (ICAM-1, VCAM-1 and E-selectin). Lesions of mice exposed to 137Cs were also characterized by enhanced collagen and smooth muscle cell content, concurrent with reduced matrix metalloproteinase MMP8 and MMP13 expression. These results suggest that low dose chronic exposure of 137Cs in ApoE-/- mice enhances atherosclerotic lesion stability by inhibiting pro-inflammatory cytokine and MMP production, resulting in collagen-rich plaques with greater smooth muscle cell and less macrophage content. PMID:26046630

  16. Chronic Internal Exposure to Low Dose 137Cs Induces Positive Impact on the Stability of Atherosclerotic Plaques by Reducing Inflammation in ApoE-/- Mice

    PubMed Central

    Le Gallic, Clélia; Phalente, Yohann; Manens, Line; Dublineau, Isabelle; Benderitter, Marc; Gueguen, Yann; Lehoux, Stephanie; Ebrahimian, Teni G.

    2015-01-01

    After Chernobyl and Fukushima Daï Chi, two major nuclear accidents, large amounts of radionuclides were released in the environment, mostly caesium 137 (137Cs). Populations living in contaminated territories are chronically exposed to radionuclides by ingestion of contaminated food. However, questions still remain regarding the effects of low dose ionizing radiation exposure on the development and progression of cardiovascular diseases. We therefore investigated the effects of a chronic internal exposure to 137Cs on atherosclerosis in predisposed ApoE-/- mice. Mice were exposed daily to 0, 4, 20 or 100 kBq/l 137Cs in drinking water, corresponding to range of concentrations found in contaminated territories, for 6 or 9 months. We evaluated plaque size and phenotype, inflammatory profile, and oxidative stress status in different experimental groups. Results did not show any differences in atherosclerosis progression between mice exposed to 137Cs and unexposed controls. However, 137Cs exposed mice developed more stable plaques with decreased macrophage content, associated with reduced aortic expression of pro-inflammatory factors (CRP, TNFα, MCP-1, IFNγ) and adhesion molecules (ICAM-1, VCAM-1 and E-selectin). Lesions of mice exposed to 137Cs were also characterized by enhanced collagen and smooth muscle cell content, concurrent with reduced matrix metalloproteinase MMP8 and MMP13 expression. These results suggest that low dose chronic exposure of 137Cs in ApoE-/- mice enhances atherosclerotic lesion stability by inhibiting pro-inflammatory cytokine and MMP production, resulting in collagen-rich plaques with greater smooth muscle cell and less macrophage content. PMID:26046630

  17. Short-term Curcuminoid Supplementation for Chronic Pulmonary Complications due to Sulfur Mustard Intoxication: Positive Results of a Randomized Double-blind Placebo-controlled Trial.

    PubMed

    Panahi, Y; Ghanei, M; Bashiri, S; Hajihashemi, A; Sahebkar, A

    2015-11-01

    Pulmonary problems are among the most frequent chronic complications of sulfur mustard (SM) intoxication and are often accompanied by deregulated production of pro-inflammatory cytokines. Curcuminoids, comprising curcumin, demethoxycurcumin and bisdemethoxycurcumin, are phytochemicals with remarkable anti-inflammatory properties that are derived from dried rhizomes of the plant Curcuma longa L. (turmeric). The present pilot study aimed to investigate the clinical effects of supplementation with curcuminoids on markers of pulmonary function and systemic inflammation in SM-intoxicated subjects. In a randomized double-blind placebo-controlled trial, 89 male subjects who were suffering from chronic SM-induced pulmonary complications were recruited and assigned to either curcuminoids (500 mg TID per oral; n=45) or placebo (n=44) for a period of 4 weeks. Efficacy measures were changes in the spirometric parameters (FVC, FEV1, FEV1/FVC) and serum levels of inflammatory mediators including interleukins 6 (IL-6) and 8 (IL-8), tumor necrosis factor-α (TNFα), transforming growth factor-β (TGFβ), high-sensitivity C-reactive protein (hs-CRP), calcitonin gene related peptide (CGRP), substance P and monocyte chemotactic protein-1 (MCP-1). 78 subjects completed the trial. Although FEV1 and FVC remained comparable between the groups, there was a greater effect of curcuminoids vs. placebo in improving FEV1/FVC (p=0.002). Curcuminoids were also significantly more efficacious compared to placebo in modulating all assessed inflammatory mediators: IL-6 (p<0.001), IL-8 (p=0.035), TNFα (p<0.001), TGFβ (p<0.001), substance P (p=0.016), hs-CRP (p<0.001), CGRP (p<0.001) and MCP-1 (p<0.001). Curcuminoids were safe and well-tolerated throughout the trial. Short-term adjunctive therapy with curcuminoids can suppress systemic inflammation in patients suffering from SM-induced chronic pulmonary complications. PMID:25268878

  18. The C allele of JAK2 rs4495487 is an additional candidate locus that contributes to myeloproliferative neoplasm predisposition in the Japanese population

    PubMed Central

    2012-01-01

    Background Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are myeloproliferative neoplasms (MPNs) characterized in most cases by a unique somatic mutation, JAK2 V617F. Recent studies revealed that JAK2 V617F occurs more frequently in a specific JAK2 haplotype, named JAK2 46/1 or GGCC haplotype, which is tagged by rs10974944 (C/G) and/or rs12343867 (T/C). This study examined the impact of single nucleotide polymorphisms (SNPs) of the JAK2 locus on MPNs in a Japanese population. Methods We sequenced 24 JAK2 SNPs in Japanese patients with PV. We then genotyped 138 MPN patients (33 PV, 96 ET, and 9 PMF) with known JAK2 mutational status and 107 controls for a novel SNP, in addition to two SNPs known to be part of the 46/1 haplotype (rs10974944 and rs12343867). Associations with risk of MPN were estimated by odds ratios and their 95% confidence intervals using logistic regression. Results A novel locus, rs4495487 (T/C), with a mutated T allele was significantly associated with PV. Similar to rs10974944 and rs12343867, rs4495487 in the JAK2 locus is significantly associated with JAK2-positive MPN. Based on the results of SNP analysis of the three JAK2 locus, we defined the "GCC genotype" as having at least one minor allele in each SNP (G allele in rs10974944, C allele in rs4495487, and C allele in rs12343867). The GCC genotype was associated with increased risk of both JAK2 V617F-positive and JAK2 V617F-negative MPN. In ET patients, leukocyte count and hemoglobin were significantly associated with JAK2 V617F, rather than the GCC genotype. In contrast, none of the JAK2 V617F-negative ET patients without the GCC genotype had thrombosis, and splenomegaly was frequently seen in this subset of ET patients. PV patients without the GCC genotype were significantly associated with high platelet count. Conclusions Our results indicate that the C allele of JAK2 rs4495487, in addition to the 46/1 haplotype, contributes significantly to the

  19. CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms

    PubMed Central

    Meyer, Sara C.; Keller, Matthew D.; Chiu, Sophia; Koppikar, Priya; Guryanova, Olga A.; Rapaport, Franck; Xu, Ke; Manova, Katia; Pankov, Dmitry; O’Reilly, Richard J.; Kleppe, Maria; McKenney, Anna Sophia; Shih, Alan H.; Shank, Kaitlyn; Ahn, Jihae; Papalexi, Eftymia; Spitzer, Barbara; Socci, Nick; Viale, Agnes; Mandon, Emeline; Ebel, Nicolas; Andraos, Rita; Rubert, Joëlle; Dammassa, Ernesta; Romanet, Vincent; Dölemeyer, Arno; Zender, Michael; Heinlein, Melanie; Rampal, Rajit; Weinberg, Rona Singer; Hoffman, Ron; Sellers, William R.; Hofmann, Francesco; Murakami, Masato; Baffert, Fabienne; Gaul, Christoph; Radimerski, Thomas; Levine, Ross L.

    2015-01-01

    Summary Although clinically tested JAK inhibitors reduce splenomegaly and systemic symptoms, molecular responses are not observed in most myeloproliferative neoplasms (MPN) patients. We previously demonstrated that MPN cells become persistent to type I JAK inhibitors that bind the active conformation of JAK2. We investigated if CHZ868, a type II JAK inhibitor, would demonstrate activity in JAK inhibitor persistent cells, murine MPN models, and MPN patient samples. JAK2- and MPL-mutant cell lines were sensitive to CHZ868, including type I JAK inhibitor persistent cells. CHZ868 showed significant activity in murine MPN models and induced reductions in mutant allele burden not observed with type I JAK inhibitors. These data demonstrate that type II JAK inhibition is a viable therapeutic approach for MPN patients. PMID:26175413

  20. A phase 2 study of MK-0457 in patients with BCR-ABL T315I mutant chronic myelogenous leukemia and philadelphia chromosome-positive acute lymphoblastic leukemia

    PubMed Central

    Seymour, J F; Kim, D W; Rubin, E; Haregewoin, A; Clark, J; Watson, P; Hughes, T; Dufva, I; Jimenez, J L; Mahon, F-X; Rousselot, P; Cortes, J; Martinelli, G; Papayannidis, C; Nagler, A; Giles, F J

    2014-01-01

    Aurora kinase overexpression has been observed in patients with hematologic malignancies. MK-0457, a pan-aurora kinase inhibitor that also inhibits the ABL T315I mutant, was evaluated to treat patients with chronic myelogenous leukemia (CML) or Philadelphia chromosome (Ph+) acute lymphoblastic leukemia (ALL) with the T315I mutation. Adults with Ph+ chronic phase (CP)-, accelerated phase (AP)- or blast phase (BP)-CML, or ALL and documented BCR-ABL T315I mutation were treated with a 5-day continuous infusion of MK-0457 administered every 14 days at 40 mg/m2/h, 32 mg/m2/h or 24 mg/m2/h. Fifty-two patients (CP, n=15; AP, n=14; BP, n=11; Ph+ ALL, n=12) were treated. Overall, 8% of patients achieved major cytogenetic response; 6% achieved unconfirmed complete or partial response; 39% had no response. Two patients (CP CML) achieved complete hematologic response. No patients with advanced CML or Ph+ ALL achieved major hematologic response. The most common adverse event (AE) was neutropenia (50%). The most common grade 3/4 AEs were neutropenia (46%) and febrile neutropenia (35%). MK-0457 demonstrated minimal efficacy and only at higher, intolerable doses; lower doses were tolerated and no unexpected toxicities were observed. These data will assist in the development of future aurora kinase inhibitors and in the selection of appropriate target patient populations. PMID:25127392

  1. Myeloproliferative defects following targeting of the Drf1 gene encoding the mammalian diaphanous related formin mDia1.

    PubMed

    Peng, Jun; Kitchen, Susan M; West, Richard A; Sigler, Robert; Eisenmann, Kathryn M; Alberts, Arthur S

    2007-08-15

    Rho GTPase-effector mammalian diaphanous (mDia)-related formins assemble nonbranched actin filaments as part of cellular processes, including cell division, filopodia assembly, and intracellular trafficking. Whereas recent efforts have led to thorough characterization of formins in cytoskeletal remodeling and actin assembly in vitro, little is known about the role of mDia proteins in vivo. To fill this knowledge gap, the Drf1 gene, which encodes the canonical formin mDia1, was targeted by homologous recombination. Upon birth, Drf1+/- and Drf1-/- mice were developmentally and morphologically indistinguishable from their wild-type littermates. However, both Drf1+/- and Drf1-/- developed age-dependent myeloproliferative defects. The phenotype included splenomegaly, fibrotic and hypercellular bone marrow, extramedullary hematopoiesis in both spleen and liver, and the presence of immature myeloid progenitor cells with high nucleus-to-cytoplasm ratios. Analysis of cell surface markers showed an age-dependent increase in the percentage of CD11b+-activated and CD14+-activated monocytes/macrophages in both spleen and bone marrow in Drf1+/- and Drf1-/- animals. Analysis of the erythroid compartment showed a significant increase in the proportion of splenic cells in S phase and an expansion of erythroid precursors (TER-119+ and CD71+) in Drf1-targeted mice. Overall, knocking out mDia1 expression in mice leads to a phenotype similar to human myeloproliferative syndrome (MPS) and myelodysplastic syndromes (MDS). These observations suggest that defective DRF1 expression or mDia1 function may contribute to myeloid malignancies and point to mDia1 as an attractive therapeutic target in MDS and MPS.

  2. Initial Molecular Response at 3 Months May Predict Both Response and Event-Free Survival at 24 Months in Imatinib-Resistant or -Intolerant Patients With Philadelphia Chromosome–Positive Chronic Myeloid Leukemia in Chronic Phase Treated With Nilotinib

    PubMed Central

    Branford, Susan; Kim, Dong-Wook; Soverini, Simona; Haque, Ariful; Shou, Yaping; Woodman, Richard C.; Kantarjian, Hagop M.; Martinelli, Giovanni; Radich, Jerald P.; Saglio, Giuseppe; Hochhaus, Andreas; Hughes, Timothy P.; Müller, Martin C.

    2012-01-01

    Purpose The association between initial molecular response and longer-term outcomes with nilotinib was examined. Patients and Methods Patients with imatinib-resistant or -intolerant chronic myeloid leukemia in chronic phase from the phase II nilotinib registration study with available postbaseline BCR-ABL1 transcript assessments were included (N = 237). Results BCR-ABL1 transcript levels (International Scale [IS]) at 3 months correlated with complete cytogenetic response (CCyR) by 24 months. Patients with BCR-ABL1 (IS) of > 1% to ≤ 10% at 3 months with nilotinib had higher cumulative incidence of CCyR by 24 months than patients with BCR-ABL1 (IS) of > 10% (53% v 16%). BCR-ABL1 (IS) at 3 months predicted major molecular response (MMR) by 24 months. Cumulative incidence of MMR by 24 months for patients with BCR-ABL1 (IS) of > 0.1% to ≤ 1%, > 1% to ≤ 10%, and > 10% was 65%, 27%, and 9%, respectively. These differences were observed for patients with or without baseline BCR–ABL1 mutations and for those with imatinib resistance or intolerance. Estimated event-free survival (EFS) rates at 24 months decreased with higher transcript levels at 3 months; patients with BCR-ABL1 (IS) of ≤ 1% had an estimated 24-month EFS rate of 82%, compared with 70% for patients with BCR-ABL1 (IS) of > 1% to ≤ 10% and 48% for patients with BCR-ABL1 (IS) of > 10%. Conclusion Patients with BCR-ABL1 (IS) of > 10% at 3 months had a lower cumulative incidence of CCyR and MMR and lower rates of EFS versus patients with BCR-ABL1 (IS) of ≤ 10%. Prospective studies may determine whether close monitoring or alternative therapies are warranted for patients with minimal initial molecular response. PMID:23109697

  3. DETECTION OF HELICOBACTER ANTIGEN IN STOOL SAMPLES AND ITS RELATION TO H. PYLORI POSITIVE CHOLECYSTITIS IN EGYPTIAN PATIENTS WITH CHRONIC CALCULAR CHOLECYSTITIS.

    PubMed

    Hassan, Ehsan H; Gerges, Shawkat S; Ahmed, Rehab; Mostafa, Zeinab M; Al-Hamid, Hager Abd; Abd El-Galil, Heba; Thabet, Suzan

    2015-12-01

    Evidences supporting the association between H. pylori infection and chronic cholecystitis could be found by using direct culture or staining of H. pylori in gallbladder tissues as well as indirect techniques. Stool antigen test has been widely used due to its noninvasive nature. Various stool antigen tests were developed to detect H. pylori using an enzyme immunoassay (EIA) based on monoclonal or polyclonal antibodies This study evaluated the frequency of H. pylori antigen in stool samples of patients with chronic calcular cholecystitis as regard gall bladder histopathological changes. Fifty patients were included presented with symptomatic qholecystolithiasis recruited from the outpatient clinic of National Hepatology and Tropical Medicine Research Institute during 2014-2015. Full history and clinical examination and abdominal ultrasonography were performed. Stool samples were collected, prepared and examined for detection of H. pylori antigen. Cholecystectomy was done for all patients; 45 patients (90%) by laparoscopic Cholecystectomy and 5 patients (10%) by open surgery and removed gallbladders were submitted to pathology department for detection of H. pylori in tissue under microscope using Giemsa stain. The results showed that (82%) were females with mean age (42.6 +/- 1 years). The mean BMI was (29 + 7.2) H. pylori-specific antigen in stool samples was detected in 40% of patients and 38% were detected in patients; tissue, with significant correlation between H. pylori-specific antigen in stool and in tissue. Histopathological pictures infection in tissue were 68.4% mucosal erosions, 63.2% mucosal atrophy, 57.9% mucosal hyperplasia, 26.3% metaplasia, 42.1% musculosa hypertrophy, 26.3% fibrosis, but lymphoid aggregates were in 42.1% of cases. PMID:26939235

  4. Clonal architecture of chronic myelomonocytic leukemias.

    PubMed

    Itzykson, Raphaël; Kosmider, Olivier; Renneville, Aline; Morabito, Margot; Preudhomme, Claude; Berthon, Céline; Adès, Lionel; Fenaux, Pierre; Platzbecker, Uwe; Gagey, Olivier; Rameau, Philippe; Meurice, Guillaume; Oréar, Cédric; Delhommeau, François; Bernard, Olivier A; Fontenay, Michaela; Vainchenker, William; Droin, Nathalie; Solary, Eric

    2013-03-21

    Genomic studies in chronic myeloid malignancies, including myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), and MPN/MDS, have identified common mutations in genes encoding signaling, epigenetic, transcription, and splicing factors. In the present study, we interrogated the clonal architecture by mutation-specific discrimination analysis of single-cell-derived colonies in 28 patients with chronic myelomonocytic leukemias (CMML), the most frequent MPN/MDS. This analysis reveals a linear acquisition of the studied mutations with limited branching through loss of heterozygosity. Serial analysis of untreated and treated samples demonstrates a dynamic architecture on which most current therapeutic approaches have limited effects. The main disease characteristics are early clonal dominance, arising at the CD34(+)/CD38(-) stage of hematopoiesis, and granulomonocytic differentiation skewing of multipotent and common myeloid progenitors. Comparison of clonal expansions of TET2 mutations in MDS, MPN, and CMML, together with functional invalidation of TET2 in sorted progenitors, suggests a causative link between early clonal dominance and skewed granulomonocytic differentiation. Altogether, early clonal dominance may distinguish CMML from other chronic myeloid neoplasms with similar gene mutations.

  5. [Parte III. Ethical and juridical aspects in end-stage chronic organ failures. A position paper on a shared care planning].

    PubMed

    Barbisan, Camillo; Casonato, Carlo; Palermo Fabris, Elisabetta; Piccinni, Mariassunta; Zatti, Paolo

    2014-01-01

    The specific target of an experts panel was to assess in terms of law and ethics the compliance of a new specific decision making algorithm described in the position paper proposed by the Gruppo di Lavoro Insufficienze Croniche d'Organo, with the main goal of the position paper consisting in the shared care planning process. The following specific aspects were assessed by the experts: a) the impact on case law and statute law of a new clinical pathway shared by scientific societies in light of good clinical practice and scientific evidence; b) the relevance of all tools useful to identify the appropriateness of care pathways, recognizing responsibilities and decision-making skills related to the end of life choices made by all stakeholders involved (healthcare professionals, patients and their beloved ones); c) the consistency of the healthcare professionals duties proposed in the position paper with the Italian legal order; d) the opportunity to take into account the role of all healthcare providers involved in care relationship; e) the consistency of the definition of patient rights at the end of life as proposed in the position paper with the Italian legal order and the relevance in this context of simultaneous palliative care; f) the relevance of shared care planning and its consistency with the proposed operative tools; g) the relevance of the conscientious objection issue and the compliance of management tools proposed in the position paper with the results of ethical and legal considerations; h) considerations about available resources allocation.

  6. Mutation Analysis of JAK2V617F, FLT3-ITD, NPM1, and DNMT3A in Chinese Patients with Myeloproliferative Neoplasms

    PubMed Central

    Wang, Min; He, Na; Tian, Tian; Liu, Lu; Yu, Shuang; Ma, Daoxin

    2014-01-01

    Since the discovery of JAK2V617F tyrosine kinase-activating mutation, several genes have been found mutated in myeloproliferative neoplasms (MPNs). FLT3-ITD, NPM1, and DNMT3A mutations frequently occurred in AML patients and have been found conferred with myeloproliferative neoplasms in mouse model. Therefore, we sought to search for mutations in JAK2V617F, FLT3-ITD, NPM1, and DNMT3A in 129 cases including 120 classic MPN cases and 9 MDS/MPN cases. JAK2V617F mutation was found in 60% of the 120 classic MPNs. However, none of the patients displayed FLT3-ITD and NPM1 mutations; only 2 patients harbored DNMT3A R882 mutation. Further studies including whole-genome sequence will be conducted to investigate the possible involvement of these genes in MPN. PMID:24895580

  7. SH2B3 (LNK) mutations from Myeloproliferative Neoplasms patients have mild loss of function against wild type JAK2 and JAK2 V617F

    PubMed Central

    Koren-Michowitz, Maya; Gery, Sigal; Tabayashi, Takayuki; Lin, Dechen; Alvarez, Rocio; Nagler, Arnon; Koeffler, H. Phillip

    2013-01-01

    Summary Somatic point mutations in the PH domain of SH2B3 (LNK), an adaptor protein that is highly expressed in haematopoietic cells, were recently described in patients with myeloproliferative neoplasms. We studied the effect of these mutations on the JAK2 signalling pathway in cells expressing either wild type JAK2 or the JAK2 V617F mutation. Compared to wild type SH2B3, PH domain mutants have mild loss of function, with no evidence for a dominant-negative effect. Mutants retain binding capacity for JAK2, an established SH2B3 target, as well as for the adaptor proteins 14-3-3 and CBL. Our data suggest that the loss of SH2B3 inhibitory function conferred by the PH domain mutations is mild and may collaborate with JAK2 V617F and CBL mutations in order to promote either the development or the progression of myeloproliferative neoplasms. PMID:23590807

  8. The Jak2 Inhibitor, G6, Alleviates Jak2-V617F-Mediated Myeloproliferative Neoplasia by Providing Significant Therapeutic Efficacy to the Bone Marrow1

    PubMed Central

    Kirabo, Annet; Park, Sung O; Majumder, Anurima; Gali, Meghanath; Reinhard, Mary K; Wamsley, Heather L; Zhao, Zhizhuang Joe; Cogle, Christopher R; Bisht, Kirpal S; Keserü, György M; Sayeski, Peter P

    2011-01-01

    We recently developed a Janus kinase 2 (Jak2) small-molecule inhibitor called G6 and found that it inhibits Jak2-V617F-mediated pathologic cell growth in vitro, ex vivo, and in vivo. However, its ability to inhibit Jak2-V617F-mediated myeloproliferative neoplasia, with particular emphasis in the bone marrow, has not previously been examined. Here, we investigated the efficacy of G6 in a transgenic mouse model of Jak2-V617F-mediated myeloproliferative neoplasia. We found that G6 provided therapeutic benefit to the peripheral blood as determined by elimination of leukocytosis, thrombocytosis, and erythrocytosis. G6 normalized the pathologically high plasma concentrations of interleukin 6 (IL-6). In the liver, G6 eliminated Jak2-V617F-driven extramedullary hematopoiesis. With respect to the spleen, G6 significantly reduced both the splenomegaly and megakaryocytic hyperplasia. In the critically important bone marrow, G6 normalized the pathologically high levels of phospho-Jak2 and phospho-signal transducer and activator of transcription 5 (STAT5). It significantly reduced the megakaryocytic hyperplasia in the marrow and completely normalized the M/E ratio. Most importantly, G6 selectively reduced the mutant Jak2 burden by 67%on average, with virtual elimination of mutant Jak2 cells in one third of all treated mice. Lastly, clonogenic assays using marrow stem cells from the myeloproliferative neoplasm mice revealed a time-dependent elimination of the clonogenic growth potential of these cells by G6. Collectively, these data indicate that G6 exhibits exceptional efficacy in the peripheral blood, liver, spleen, and, most importantly, in the bone marrow, thereby raising the possibility that this compound may alter the natural history of Jak2-V617F-mediated myeloproliferative neoplasia. PMID:22131881

  9. Integrative genomic analysis in K562 chronic myelogenous leukemia cells reveals that proximal NCOR1 binding positively regulates genes that govern erythroid differentiation and Imatinib sensitivity

    PubMed Central

    Long, Mark D.; van den Berg, Patrick R.; Russell, James L.; Singh, Prashant K.; Battaglia, Sebastiano; Campbell, Moray J.

    2015-01-01

    To define the functions of NCOR1 we developed an integrative analysis that combined ENCODE and NCI-60 data, followed by in vitro validation. NCOR1 and H3K9me3 ChIP-Seq, FAIRE-seq and DNA CpG methylation interactions were related to gene expression using bootstrapping approaches. Most NCOR1 combinations (24/44) were associated with significantly elevated level expression of protein coding genes and only very few combinations related to gene repression. DAVID's biological process annotation revealed that elevated gene expression was uniquely associated with acetylation and ETS binding. A matrix of gene and drug interactions built on NCI-60 data identified that Imatinib significantly targeted the NCOR1 governed transcriptome. Stable knockdown of NCOR1 in K562 cells slowed growth and significantly repressed genes associated with NCOR1 cistrome, again, with the GO terms acetylation and ETS binding, and significantly dampened sensitivity to Imatinib-induced erythroid differentiation. Mining public microarray data revealed that NCOR1-targeted genes were significantly enriched in Imatinib response gene signatures in cell lines and chronic myelogenous leukemia (CML) patients. These approaches integrated cistrome, transcriptome and drug sensitivity relationships to reveal that NCOR1 function is surprisingly most associated with elevated gene expression, and that these targets, both in CML cell lines and patients, associate with sensitivity to Imatinib. PMID:26117541

  10. Integrative genomic analysis in K562 chronic myelogenous leukemia cells reveals that proximal NCOR1 binding positively regulates genes that govern erythroid differentiation and Imatinib sensitivity.

    PubMed

    Long, Mark D; van den Berg, Patrick R; Russell, James L; Singh, Prashant K; Battaglia, Sebastiano; Campbell, Moray J

    2015-09-01

    To define the functions of NCOR1 we developed an integrative analysis that combined ENCODE and NCI-60 data, followed by in vitro validation. NCOR1 and H3K9me3 ChIP-Seq, FAIRE-seq and DNA CpG methylation interactions were related to gene expression using bootstrapping approaches. Most NCOR1 combinations (24/44) were associated with significantly elevated level expression of protein coding genes and only very few combinations related to gene repression. DAVID's biological process annotation revealed that elevated gene expression was uniquely associated with acetylation and ETS binding. A matrix of gene and drug interactions built on NCI-60 data identified that Imatinib significantly targeted the NCOR1 governed transcriptome. Stable knockdown of NCOR1 in K562 cells slowed growth and significantly repressed genes associated with NCOR1 cistrome, again, with the GO terms acetylation and ETS binding, and significantly dampened sensitivity to Imatinib-induced erythroid differentiation. Mining public microarray data revealed that NCOR1-targeted genes were significantly enriched in Imatinib response gene signatures in cell lines and chronic myelogenous leukemia (CML) patients. These approaches integrated cistrome, transcriptome and drug sensitivity relationships to reveal that NCOR1 function is surprisingly most associated with elevated gene expression, and that these targets, both in CML cell lines and patients, associate with sensitivity to Imatinib.

  11. The number of genes changing expression after chronic exposure to code division multiple access or frequency DMA radiofrequency radiation does not exceed the false-positive rate.

    PubMed

    Whitehead, Timothy D; Moros, Eduardo G; Brownstein, Bernard H; Roti Roti, Joseph L

    2006-09-01

    Experiments with cultured C3H 10T 1/2 cells were performed to determine if exposure to cell phone radiofrequency (RF) radiations induce changes in gene expression. Following a 24 h exposure of 5 W/kg specific adsorption rate, RNA was extracted from the exposed and sham control cells for microarray analysis on Affymetrix U74Av2 Genechips. Cells exposed to 0.68 Gy of X-rays with a 4-h recovery were used as positive controls. The number of gene expression changes induced by RF radiation was not greater than the number of false positives expected based on a sham versus sham comparison. In contrast, the X-irradiated samples showed higher numbers of probe sets changing expression level than in the sham versus sham comparison.

  12. Pegylated interferon in HBeAg-positive and -negative chronic hepatitis B patients: post-treatment 1-year results of three Turkish centres.

    PubMed

    Yamazhan, Tansu; Kurtaran, Behice; Pullukçu, Hüsnü; Yüksel, Esma; Özkaya, Deniz; Taşbakan, Meltem Işıkgöz; Sipahi, Oğuz Reşat; Durusoy, Raika; Aksu, Hasan Salih Zeki

    2014-12-01

    In this study, we aimed to evaluate the 1-year post-treatment follow-up results of 112 patients who received pegylated interferon (PEG-IFN) for 52 weeks. HBeAg negativity/seroconversion and/or negative HBV-DNA at the end of the treatment were considered as response. Patients who had response at the end of treatment but had HBV-DNA breakthrough during 1-year follow-up were considered as relapse. The study group comprised 112 cases (34 HBeAg-positive, 78 HBeAg-negative). In HBeAg-positive and -negative cases, end-of-treatment response rates were 2·9% and 60·2%, whereas 1-year sustained virological response rates were 0 and 33·3%, respectively. When we compared relapse cases versus cases with response at the end of 1-year follow-up, being female and having low viral load were the two parameters associated with higher response rates (Chi-square, P  =  0·028; Mann-Whitney U test, P  =  0·023). Overall non-response rates to PEG-IFN were high (57·1%). Results in HBeAg-positive cases were disappointing.

  13. Single Nucleotide Polymorphism (SNP)-Based Loss of Heterozygosity (LOH) Testing by Real Time PCR in Patients Suspect of Myeloproliferative Disease

    PubMed Central

    Huijsmans, Cornelis J. J.; Poodt, Jeroen; Damen, Jan; van der Linden, Johannes C.; Savelkoul, Paul H. M.; Pruijt, Johannes F. M.; Hilbink, Mirrian; Hermans, Mirjam H. A.

    2012-01-01

    During tumor development, loss of heterozygosity (LOH) often occurs. When LOH is preceded by an oncogene activating mutation, the mutant allele may be further potentiated if the wild-type allele is lost or inactivated. In myeloproliferative neoplasms (MPN) somatic acquisition of JAK2V617F may be followed by LOH resulting in loss of the wild type allele. The occurrence of LOH in MPN and other proliferative diseases may lead to a further potentiating the mutant allele and thereby increasing morbidity. A real time PCR based SNP profiling assay was developed and validated for LOH detection of the JAK2 region (JAK2LOH). Blood of a cohort of 12 JAK2V617F-positive patients (n = 6 25–50% and n = 6>50% JAK2V617F) and a cohort of 81 patients suspected of MPN was stored with EDTA and subsequently used for validation. To generate germ-line profiles, non-neoplastic formalin-fixed paraffin-embedded tissue from each patient was analyzed. Results of the SNP assay were compared to those of an established Short Tandem Repeat (STR) assay. Both assays revealed JAK2LOH in 1/6 patients with 25–50% JAK2V617F. In patients with >50% JAK2V617F, JAK2LOH was detected in 6/6 by the SNP assay and 5/6 patients by the STR assay. Of the 81 patients suspected of MPN, 18 patients carried JAK2V617F. Both the SNP and STR assay demonstrated the occurrence of JAK2LOH in 5 of them. In the 63 JAK2V617F-negative patients, no JAK2LOH was observed by SNP and STR analyses. The presented SNP assay reliably detects JAK2LOH and is a fast and easy to perform alternative for STR analyses. We therefore anticipate the SNP approach as a proof of principle for the development of LOH SNP-assays for other clinically relevant LOH loci. PMID:22768290

  14. Chronic Inflammation in Prostate Biopsy Cores is an Independent Factor that Lowers the Risk of Prostate Cancer Detection and is Inversely Associated with the Number of Positive Cores in Patients Elected to a First Biopsy

    PubMed Central

    Porcaro, Antonio B.; Novella, Giovanni; Mattevi, Daniele; Bizzotto, Leonardo; Cacciamani, Giovanni; Luyk, Nicolò De; Tamanini, Irene; Cerruto, Maria A.; Brunelli, Matteo; Artibani, Walter

    2016-01-01

    Objectives To investigate associations of chronic inflammatory infiltrate (CII) with prostate cancer (PCa) risk and the number of positive cores in patients elected to a first set of biopsies. Materials and Methods Excluding criteria were as follows: active surveillance, prostate specific antigen (PSA) ≥ 30 ng/l, re-biopsies, incidental PCa, less than 14 cores, metastases, or 5-alpha reductase inhibitors. The cohort study was classified as negative (control group) and positive cores between 1 and 2 or > 2. Results The cohort included 421 cases who did not meet the exclusion criteria. PCa was detected in 192 cases (45.6%) of which the number of positive cores was between 1 and 2 in 77 (40.1%) cases. The median PSA was 6.05 ng/ml (range 0.3-29 ng/ml). Linear regression models showed that CII was an independent predictor inversely associated with the risk of PCa. Multinomial logistic regression models showed that CII was an independent factor that was inversely associated with PCa risk in cases with positive cores between 1 and 2 (OR = 0.338; p = 0.004) or more than 2 (OR = 0.076; p < 0.0001) when compared to the control group. Conclusion In a cohort of men undergoing the first biopsy set after prostate assessment, the presence of CII in the biopsy core was an independent factor inversely associated with PCa risk as well as with the number of positive biopsy cores (tumor extension). Clinically, the detection of CII in negative biopsy cores might reduce the risk of PCa in repeat biopsies as well as the probability of detecting multiple positive cores. PMID:27390581

  15. Overcoming the problem of pseudohypoxemia in myeloproliferative disorders: Another trick in the bag.

    PubMed

    Prasad, K N; Manjunath, Prabhu; Priya, L; Sasikumar, Sanjay

    2012-10-01

    Pseudohypoxaemia or spurious hypoxaemia is a recurrent problem faced on arterial blood gas analysis in patients with hyperleucocytosis leading to management dilemmas and unnecessary respiratory interventions. Various methods have been suggested to reduce the magnitude of this problem. We report a case of pseudohypoxaemia due to blast crisis in a patient of chronic myeloid leukaemia where arterial blood gas analysed from precooled syringe helped us resolve the problem and hastened our weaning from oxygen therapy.

  16. A rare case of a three way complex variant positive Philadelphia translocation involving chromosome (9;11;22)(q34;p15;q11) in chronic myeloid leukemia: A case report

    PubMed Central

    Asif, Muhammad; Hussain, Abrar; Rasool, Mahmood

    2016-01-01

    The t(9;22)(q34;q11) translocation is present in 90–95% of patients with chronic myeloid leukemia (CML). Variant complex translocations have been observed in 5–8% of CML patients, in which a third chromosome other than (9;22) is involved. Imatinib mesylate is the first line breakpoint cluster region-Abelson gene (BCR/ABL)-targeted oral therapy for CML, and may produce a complete response in 70–80% of CML patients in the chronic phase. In the present study, a bone marrow sample was used for conventional cytogenetic analysis, and the fluorescence in situ hybridization (FISH) test was used for BCR/ABL gene detection. A hematological analysis was also performed to determine the white blood cell (WBC) count, red blood cell count, hemoglobin levels, packed and mean cell volumes, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration and platelet values of the patient. The hematological analysis of the patient indicated the increased WBC of 186.5×103 cells/µl, and decreased hemoglobin levels of 11.1 g/dl. The FISH test revealed that 67% cells demonstrated BCR/ABL gene translocation. The patient was treated with 400 mg imatinib mesylate daily, and was monitored at various intervals over a 6-month period. The present study reports the rare case of a patient that demonstrates a three-way Philadelphia chromosome-positive translocation involving 46XY,t(9;11;22)(q34;p15;q11)[10], alongside CML in the chronic phase. The translocation was analyzed using cytogenetic and FISH tests.

  17. A rare case of a three way complex variant positive Philadelphia translocation involving chromosome (9;11;22)(q34;p15;q11) in chronic myeloid leukemia: A case report

    PubMed Central

    Asif, Muhammad; Hussain, Abrar; Rasool, Mahmood

    2016-01-01

    The t(9;22)(q34;q11) translocation is present in 90–95% of patients with chronic myeloid leukemia (CML). Variant complex translocations have been observed in 5–8% of CML patients, in which a third chromosome other than (9;22) is involved. Imatinib mesylate is the first line breakpoint cluster region-Abelson gene (BCR/ABL)-targeted oral therapy for CML, and may produce a complete response in 70–80% of CML patients in the chronic phase. In the present study, a bone marrow sample was used for conventional cytogenetic analysis, and the fluorescence in situ hybridization (FISH) test was used for BCR/ABL gene detection. A hematological analysis was also performed to determine the white blood cell (WBC) count, red blood cell count, hemoglobin levels, packed and mean cell volumes, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration and platelet values of the patient. The hematological analysis of the patient indicated the increased WBC of 186.5×103 cells/µl, and decreased hemoglobin levels of 11.1 g/dl. The FISH test revealed that 67% cells demonstrated BCR/ABL gene translocation. The patient was treated with 400 mg imatinib mesylate daily, and was monitored at various intervals over a 6-month period. The present study reports the rare case of a patient that demonstrates a three-way Philadelphia chromosome-positive translocation involving 46XY,t(9;11;22)(q34;p15;q11)[10], alongside CML in the chronic phase. The translocation was analyzed using cytogenetic and FISH tests. PMID:27602125

  18. Molecular genetic tests for JAK2V617F, Exon12_JAK2 and MPLW515K/L are highly informative in the evaluation of patients suspected to have BCR-ABL1-negative myeloproliferative neoplasms

    PubMed Central

    dos Santos, Marcos Tadeu; Mitne-Neto, Miguel; Miyashiro, Kozue; Chauffaille, Maria de Lourdes L Ferrari; Rizzatti, Edgar Gil

    2014-01-01

    Polycythaemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (MF), are the most common myeloproliferative neoplasms (MPN) in patients without the BCR-ABL1 gene rearrangement. They are caused by clonal expansion of haematopoietic stem cells and share, as a diagnostic criterion, the identification of JAK2V617F mutation. Classically, when other clinical criteria are present, a JAK2V617F negative case requires the analysis of Exon12_JAK2 for the diagnosis of PV, and of MPL515K/L mutations for the diagnosis of ET and MF. Here, we evaluated 78 samples from Brazilian patients suspected to have MPN, without stratification for PV, ET or MF. We found that 28 (35.9%) are JAK2V617F carriers; from the 50 remaining samples, one (2%) showed an Exon12_JAK2 mutation, and another (2%) was positive for MPLW515L mutation. In summary, the investigation of JAK2V617F, Exon12_JAK2 and MPLW515K/L was relevant for the diagnosis of 38.4% of patients suspected to have BCR-ABL1-negative MPN, suggesting that molecular genetic tests are useful for a quick and unequivocal diagnosis of MPN. PMID:23986553

  19. Molecular basis of adult-onset and chronic G sub M2 gangliosidoses in patients of Ashkenazi Jewish origin: Substitution of serine for glycine at position 269 of the. alpha. -subunit of. beta. -hexosaminidase

    SciTech Connect

    Paw, B.H.; Kaback, M.M.; Neufeld, E.F. )

    1989-04-01

    Chronic and adult-onset G{sub M2} gangliosidoses are neurological disorders caused by marked deficiency of the A isoenzyme of {beta}-hexosaminidase; they occur in the Ashkenazi Jewish population, though less frequently than classic (infantile) Tay-Sachs disease. Earlier biosynthetic studies had identified a defective {alpha}-subunit that failed to associate with the {beta}-subunit. The authors have now found a guanosine to adenosine transition at the 3{prime} end of exon 7, which causes substitution of serine for glycine at position 269 of the {alpha}-subunit. An RNase protection assay was used to localize the mutation to a segment of mRNA from fibroblasts of a patient with the adult-onset disorder. That segment of mRNA (after reverse transcription) and a corresponding segment of genomic DNA were amplified by the polymerase chain reaction and sequenced by the dideoxy method. The sequence analysis, together with an assay based on the loss of a ScrFI restriction site, showed that the patient was a compound heterozygote who had inherited the 269 (Gly {yields} Ser) mutation from his father and an allelic null mutation from his mother. The 269 (Gly {yields} Ser) mutation, in compound heterozygosity with a presumed null allele, was also found in fetal fibroblasts with an association-defective phenotype and in cells from five patients with chronic G{sub M2} gangliosidosis.

  20. Chronic Bronchitis

    MedlinePlus

    ... chronic. Chronic bronchitis is one type of COPD (chronic obstructive pulmonary disease). The inflamed bronchial tubes produce a lot of mucus. This leads to coughing and difficulty breathing. Cigarette smoking is the most ... diagnose chronic bronchitis, your doctor will look at your signs ...

  1. Effect of administration of caffeine or green tea on the mutation profile in the p53 gene in early mutant p53-positive patches of epidermal cells induced by chronic UVB-irradiation of hairless SKH-1 mice.

    PubMed

    Kramata, Pavel; Lu, Yao-Ping; Lou, You-Rong; Cohen, Julie L; Olcha, Meir; Liu, Sandy; Conney, Allan H

    2005-11-01

    Irradiation of SKH-1 mice with UVB light for 20 weeks resulted in a large number of patches of epidermal cells, which was visualized with an antibody that recognizes mutated p53 protein. Oral treatment of mice with caffeine (0.4 mg/ml) or green tea (6 mg tea solids/ml) as the drinking fluid during UVB irradiation decreased the number of patches by approximately 40%. Sequencing analysis of the p53 gene (exons 3 to 9) detected 88, 82 or 39 point mutations in 67, 70 or 29 patches from water, caffeine or tea treated mice, respectively. A major hotspot at codon 270 (Arg-->Cys) accounted for 47.7% (water), 70.7% (caffeine) or 46.2% (tea) of all mutations. Patches from caffeine treated mice had fewer types of mutations than patches from mice treated with water or tea. Administration of caffeine or tea during 20 weeks of UVB irradiation eliminated mutations at codons 149 (Pro-->Ser) and 210 (Arg-->Cys) but increased the frequency of mutations at codon 238 (Ser-->Phe). Topical applications of caffeine (1.2 mg in 100 microl acetone) once a day, five times a week for 6 weeks after stopping UVB decreased the number of patches by 63% when compared with mice treated with acetone. DNA sequencing analysis detected 63 and 68 mutations in 48 and 57 patches from acetone or caffeine treated mice, respectively. Although no differences in the frequency, position or types of mutations were observed, the caffeine group harbored less homozygous mutations (12.3% of the total) than the acetone group (31.3% of the total, P = 0.029). In summary, oral treatment of mice with caffeine or green tea during chronic UVB irradiation changed the mutation profile of the p53 gene in early mutant p53 positive epidermal patches, and topical applications of caffeine after discontinuation of chronic UVB irradiation specifically eliminated patches harboring homozygous p53 mutations.

  2. Bleeding complications in BCR-ABL negative myeloproliferative neoplasms: prevalence, type, and risk factors in a single-center cohort.

    PubMed

    Kander, Elizabeth M; Raza, Sania; Zhou, Zheng; Gao, Juehua; Zakarija, Anaadriana; McMahon, Brandon J; Stein, Brady L

    2015-11-01

    The BCR-ABL1-negative myeloproliferative neoplasms (MPN) share an increased risk of thrombotic and hemorrhagic complications. Risk factors for hemorrhage are less well defined than those for thrombosis. Because patients with CALR mutations have higher platelet counts compared to JAK2 V617F-mutated patients, bleeding rates may be increased in this group. Our aim was to retrospectively evaluate whether acquired von Willebrand disease (AvWD), thrombocytosis, mutational status, or treatment history are associated with bleeding in a cohort of MPN patients. Using an electronic database, MPN patients seen between 2005 and 2013 were retrospectively identified using ICD-9 codes and billing records. A bleeding event was defined as one that was identified in the medical record and graded based on the Common Terminology Criteria for Adverse Event (CTCAE) version 4.0. Among 351 MPN patients, 15.6 % experienced 64 bleeding event types. There was no association of bleeding with mutational status, gender, MPN subtype, aspirin use, prior thrombosis, or platelet count at presentation. There was an association between bleeding and older age at diagnosis. aVWD was identified in six patients. In this single-center retrospective study, bleeding events were identified in 15 % of patients, and associated with older age at diagnosis. aVWD was rarely tested for in this cohort.

  3. Individualizing Care for Patients With Myeloproliferative Neoplasms: Integrating Genetics, Evolving Therapies, and Patient-Specific Disease Burden.

    PubMed

    Mesa, Ruben A; Passamonti, Francesco

    2016-01-01

    Individualized medicine is important for patients with myeloproliferative neoplasms (MPNs), including essential thrombocythemia, polycythemia vera, and myelofibrosis, which are heterogeneous in terms of genetic mutation profile, prognosis, disease burden, and symptoms. Status of MPN driver mutations in JAK2, CALR, and MPL (or lack of one of these mutations) and other myeloid mutations (ASXL1, SRSF2, CBL, and IDH1/2, among others) affects diagnosis and prognosis. Management begins with estimating the prognosis, disease burden including MPN symptoms, and prevention of vascular events. Allogeneic stem cell transplantation is the definitive therapy in a subset of patients with myelofibrosis, the majority of whom receive JAK inhibition with ruxolitinib to relieve splenomegaly and symptoms and to prolong survival. Ruxolitinib is now a second-line therapy in polycythemia vera, with pegylated interferon being evaluated as a potential front-line therapy compared with hydroxyurea. The therapeutic landscape is evolving to include new JAK inhibitors, which may affect cytopenias (pacritinib and momelotinib), combination therapies including ruxolitinib, and novel targets such as pentraxin and telomerase. Assessing the therapeutic efficacy (including symptom impact) and toxicity of these new approaches is necessary to determine longitudinal management of MPNs in clinical practice and is a key component of "individualizing" care for patients with MPNs. PMID:27249739

  4. Transgenic mice overexpressing arginase 1 in monocytic cell lineage are affected by lympho-myeloproliferative disorders and disseminated intravascular coagulation.

    PubMed

    Astigiano, Simonetta; Morini, Monica; Damonte, Patrizia; Fraternali Orcioni, Giulio; Cassanello, Michela; Puglisi, Andrea; Noonan, Douglas M; Bronte, Vincenzo; Barbieri, Ottavia

    2015-11-01

    Arginase (ARG) is a metabolic enzyme present in two isoforms that hydrolyze l-arginine to urea and ornithine. In humans, ARG isoform 1 is also expressed in cells of the myeloid lineage. ARG activity promotes tumour growth and inhibits T lymphocyte activation. However, the two ARG transgenic mouse lines produced so far failed to show such effects. We have generated, in two different genetic backgrounds, transgenic mice constitutively expressing ARG1 under the control of the CD68 promoter in macrophages and monocytes. Both heterozygous and homozygous transgenic mice showed a relevant increase in mortality at early age, compared with wild-type siblings (67/267 and 48/181 versus 8/149, respectively, both P < 0.005). This increase was due to high incidence of haematologic malignancies, in particular myeloid leukaemia, myeloid dysplasia, lymphomas and disseminated intravascular coagulation (DIC), diseases that were absent in wild-type mice. Atrophy of lymphoid organs due to reduction in T-cell compartment was also detected. Our results indicate that ARG activity may participate in the pathogenesis of lymphoproliferative and myeloproliferative disorders, suggest the involvement of alterations of L-arginine metabolism in the onset of DIC and confirm a role for the enzyme in regulating T-cell homeostasis.

  5. STAT3 supports experimental K-RasG12D–induced murine myeloproliferative neoplasms dependent on serine phosphorylation

    PubMed Central

    Gough, Daniel J.; Marié, Isabelle J.; Lobry, Camille; Aifantis, Iannis

    2014-01-01

    Juvenile myelomonocytic leukemia, acute myeloid leukemia (AML), and other myeloproliferative neoplasms (MPNs) are genetically heterogeneous but frequently display activating mutations in Ras GTPases and activation of signal transducer and activator of transcription 3 (STAT3). Altered STAT3 activity is observed in up to 50% of AML correlating with poor prognosis. Activated STAT proteins, classically associated with tyrosine phosphorylation, support tumor development as transcription factors, but alternative STAT functions independent of tyrosine phosphorylation have been documented, including roles for serine-phosphorylated STAT3 in mitochondria supporting transformation by oncogenic Ras. We examined requirements for STAT3 in experimental murine K-Ras–dependent hematopoietic neoplasia. We show that STAT3 is phosphorylated on S727 but not Y705 in diseased animals. Moreover, a mouse with a point mutation abrogating STAT3 S727 phosphorylation displayed delayed onset and decreased disease severity with significantly extended survival. Activated K-Ras required STAT3 for cytokine-independent growth of myeloid progenitors in vitro, and mitochondrially restricted STAT3 and STAT3-Y705F, both transcriptionally inert mutants, supported factor-independent growth. STAT3 was dispensable for growth of normal or K-Ras–mutant myeloid progenitors in response to cytokines. However, abrogation of STAT3-S727 phosphorylation impaired factor-independent malignant growth. These data document that serine-phosphorylated mitochondrial STAT3 supports neoplastic hematopoietic cell growth induced by K-Ras. PMID:25150294

  6. The Role of Genotypes That Modify the Toxicity of Chemical Mutagens in the Risk for Myeloproliferative Neoplasms

    PubMed Central

    Gross-Davis, Carol Ann; Heavner, Karyn; Frank, Arthur L.; Newschaffer, Craig; Klotz, Judith; Santella, Regina M.; Burstyn, Igor

    2015-01-01

    Background: The etiology of myeloproliferative neoplasms (MPN) (polycythemia vera; essential thrombocythemia; primary myelofibrosis) is unknown, however they are associated with a somatic mutation—JAK2 V617F—suggesting a potential role for environmental mutagens. Methods: We conducted a population-based case-control study in three rural Pennsylvania counties of persons born 1921–1968 and residing in the area between 2000–2008. Twenty seven MPN cases and 292 controls were recruited through random digit dialing. Subjects were genotyped and odds ratios estimated for a select set of polymorphisms in environmentally sensitive genes that might implicate specific environmental mutagens if found to be associated with a disease. Results: The presence of NAT2 slow acetylator genotype, and CYP1A2, GSTA1, and GSTM3 variants were associated with an average 3–5 fold increased risk. Conclusions: Exposures, such as to aromatic compounds, whose toxicity is modified by genotypes associated with outcome in our analysis may play a role in the environmental etiology of MPNs. PMID:25719551

  7. Myeloproliferative neoplasms can be initiated from a single hematopoietic stem cell expressing JAK2-V617F

    PubMed Central

    Lundberg, Pontus; Takizawa, Hitoshi; Kubovcakova, Lucia; Guo, Guoji; Hao-Shen, Hui; Dirnhofer, Stephan; Orkin, Stuart H.; Manz, Markus G.

    2014-01-01

    The majority of patients with myeloproliferative neoplasms (MPNs) carry a somatic JAK2-V617F mutation. Because additional mutations can precede JAK2-V617F, it is questioned whether JAK2-V617F alone can initiate MPN. Several mouse models have demonstrated that JAK2-V617F can cause MPN; however, in all these models disease was polyclonal. Conversely, cancer initiates at the single cell level, but attempts to recapitulate single-cell disease initiation in mice have thus far failed. We demonstrate by limiting dilution and single-cell transplantations that MPN disease, manifesting either as erythrocytosis or thrombocytosis, can be initiated clonally from a single cell carrying JAK2-V617F. However, only a subset of mice reconstituted from single hematopoietic stem cells (HSCs) displayed MPN phenotype. Expression of JAK2-V617F in HSCs promoted cell division and increased DNA damage. Higher JAK2-V617F expression correlated with a short-term HSC signature and increased myeloid bias in single-cell gene expression analyses. Lower JAK2-V617F expression in progenitor and stem cells was associated with the capacity to stably engraft in secondary recipients. Furthermore, long-term repopulating capacity was also present in a compartment with intermediate expression levels of lineage markers. Our studies demonstrate that MPN can be initiated from a single HSC and illustrate that JAK2-V617F has complex effects on HSC biology. PMID:25288396

  8. A mos oncogene-containing retrovirus, myeloproliferative sarcoma virus, transforms rat thyroid epithelial cells and irreversibly blocks their differentiation pattern.

    PubMed Central

    Fusco, A; Portella, G; Di Fiore, P P; Berlingieri, M T; Di Lauro, R; Schneider, A B; Vecchio, G

    1985-01-01

    Differentiated, cloned rat thyroid epithelial cells (424 cells) were infected with a wild-type and a temperature-sensitive strain of the myeloproliferative variant of the Moloney murine sarcoma virus. The thyroid cells were productively infected and transformed by both virus strains and displayed some of the typical properties of malignant cells, such as morphological changes, growth in soft agar, and in vivo tumorigenicity. The acquisition of the transformed phenotype by the virus-infected cells was accompanied by a loss of the typical differentiated features of the thyroid epithelium, such as thyroglobulin (TG) secretion, iodide uptake, and dependence for growth on six factors including thyrotropin, the physiological thyroid stimulator. TG mRNA could not be demonstrated in cells transformed by both viral strains, suggesting a block at the level of the TG gene transcription. While the transformed state of the cell clones infected with the temperature-sensitive strain could be reverted by shifting the cultures to the temperature nonpermissive for transformation (39 degrees C), no reversion of the differentiated functions took place after such a shift, showing that the v-mos oncogene irreversibly shuts off the differentiation of thyroid epithelial cells in vitro. These results demonstrate, for the first time, an oncogenic potential of the v-mos oncogene family towards differentiated epithelial cells in vitro. Images PMID:2993656

  9. Allelic Expression Imbalance of JAK2 V617F Mutation in BCR-ABL Negative Myeloproliferative Neoplasms

    PubMed Central

    Kim, Yeo-Kyeoung; Kim, Hyeoung-Joon; Shin, Jong-Hee; Suh, Soon-Pal; Ryang, Dong-Wook; Shin, Myung-Geun

    2013-01-01

    The discovery of a single point mutation in the JAK2 gene in patients with BCR/ABL-negative myeloproliferative neoplasms (MPNs) has not only brought new insights and pathogenesis, but also has made the diagnosis of MPNs much easier. Although, to date, several mechanisms for the contribution of single JAK2V617F point mutation to phenotypic diversity of MPNs have been suggested in multiple studies, but it is not clear how a unique mutation can cause the phenotypic diversity of MPNs. In this study, our results show that allelic expression imbalance of JAK2 V617F mutant frequently occurs and contributes to phenotypic diversity of BCR-ABL-negative MPNs. The proportion of JAK2 V617F mutant allele was significantly augmented in RNA levels as compared with genomic DNA differently by distinct MPNs subtypes. In detail, preferential expression of JAK2 mutant allele showed threefold increase from the cDNA compared with the genomic DNA from patients with essential thrombocythemia and twofold increase in polycythemia vera. In conclusion, allelic expression imbalance of JAK2 V617F mutant proposes another plausible mechanism for the contribution of single JAK2 point mutation to phenotypic diversity of MPNs. PMID:23349688

  10. CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms

    PubMed Central

    Tyner, Jeffrey W.; Bumm, Thomas G.; Deininger, Jutta; Wood, Lisa; Aichberger, Karl J.; Loriaux, Marc M.; Druker, Brian J.; Burns, Christopher J.; Fantino, Emmanuelle

    2010-01-01

    Activating alleles of Janus kinase 2 (JAK2) such as JAK2V617F are central to the pathogenesis of myeloproliferative neoplasms (MPN), suggesting that small molecule inhibitors targeting JAK2 may be therapeutically useful. We have identified an aminopyrimidine derivative (CYT387), which inhibits JAK1, JAK2, and tyrosine kinase 2 (TYK2) at low nanomolar concentrations, with few additional targets. Between 0.5 and 1.5μM CYT387 caused growth suppression and apoptosis in JAK2-dependent hematopoietic cell lines, while nonhematopoietic cell lines were unaffected. In a murine MPN model, CYT387 normalized white cell counts, hematocrit, spleen size, and restored physiologic levels of inflammatory cytokines. Despite the hematologic responses and reduction of the JAK2V617F allele burden, JAK2V617F cells persisted and MPN recurred upon cessation of treatment, suggesting that JAK2 inhibitors may be unable to eliminate JAK2V617F cells, consistent with preliminary results from clinical trials of JAK2 inhibitors in myelofibrosis. While the clinical benefit of JAK2 inhibitors may be substantial, not the least due to reduction of inflammatory cytokines and symptomatic improvement, our data add to increasing evidence that kinase inhibitor monotherapy of malignant disease is not curative, suggesting a need for drug combinations to optimally target the malignant cells. PMID:20385788

  11. The SKI proto-oncogene enhances the in vivo repopulation of hematopoietic stem cells and causes myeloproliferative disease.

    PubMed

    Singbrant, Sofie; Wall, Meaghan; Moody, Jennifer; Karlsson, Göran; Chalk, Alistair M; Liddicoat, Brian; Russell, Megan R; Walkley, Carl R; Karlsson, Stefan

    2014-04-01

    The proto-oncogene SKI is highly expressed in human myeloid leukemia and also in murine hematopoietic stem cells. However, its operative relevance in these cells remains elusive. We have over-expressed SKI to define its intrinsic role in hematopoiesis and myeloid neoplasms, which resulted in a robust competitive advantage upon transplantation, a complete dominance of the stem and progenitor compartments, and a marked enhancement of myeloid differentiation at the expense of other lineages. Accordingly, enforced expression of SKI induced a gene signature associated with hematopoietic stem cells and myeloid differentiation, as well as hepatocyte growth factor signaling. Here we demonstrate that, in contrast to what has generally been assumed, the significant impact of SKI on hematopoiesis is independent of its ability to inhibit TGF-beta signaling. Instead, myeloid progenitors expressing SKI are partially dependent on functional hepatocyte growth factor signaling. Collectively our results demonstrate that SKI is an important regulator of hematopoietic stem cell activity and its overexpression leads to myeloproliferative disease.

  12. Health care setting and severity, symptom burden, and complications in patients with Philadelphia-negative myeloproliferative neoplasms (MPN): a comparison between university hospitals, community hospitals, and office-based physicians.

    PubMed

    Kaifie, A; Isfort, S; Gattermann, N; Hollburg, W; Klausmann, M; Wolf, D; Maintz, C; Hänel, M; Goekkurt, E; Göthert, J R; Platzbecker, U; Geer, T; Parmentier, S; Jost, E; Serve, H; Ehninger, G; Berdel, W E; Brümmendorf, T H; Koschmieder, Steffen

    2016-09-01

    Philadelphia-negative myeloproliferative neoplasms (MPN) comprise a heterogeneous group of chronic hematological malignancies with significant variations in clinical characteristics. Due to the long survival and the feasibility of oral or subcutaneous therapy, these patients are frequently treated outside of larger academic centers. This analysis was performed to elucidate differences in MPN patients in three different health care settings: university hospitals (UH), community hospitals (CH), and office-based physicians (OBP). The MPN registry of the Study Alliance Leukemia is a non-interventional prospective study including adult patients with an MPN according to WHO criteria (2008). For statistical analysis, descriptive methods and tests for significant differences were used. Besides a different distribution of MPN subtypes between the settings, patients contributed by UH showed an impaired medical condition, a higher comorbidity burden, and more vascular complications. In the risk group analyses, the majority of polycythemia vera (PV) and essential thrombocythemia (ET) patients from UH were classified into the high-risk category due to previous vascular events, while for PV and ET patients in the CH and OBP settings, age was the major parameter for a high-risk categorization. Regarding MPN-directed therapy, PV patients from the UH setting were more likely to receive ruxolitinib within the framework of a clinical trial. In summary, the characteristics and management of patients differed significantly between the three health care settings with a higher burden of vascular events and comorbidities in patients contributed by UH. These differences need to be taken into account for further analyses and design of clinical trials. PMID:27334946

  13. A 90-day study of sub-chronic oral toxicity of 20 nm positively charged zinc oxide nanoparticles in Sprague Dawley rats

    PubMed Central

    Park, Hark-Soo; Kim, Seon-Ju; Lee, Taek-Jin; Kim, Geon-Yong; Meang, EunHo; Hong, Jeong-Sup; Kim, Su-Hyon; Koh, Sang-Bum; Hong, Seung-Guk; Sun, Yle-Shik; Kang, Jin Seok; Kim, Yu-Ri; Kim, Meyoung-Kon; Jeong, Jayoung; Lee, Jong-Kwon; Son, Woo-Chan; Park, Jae-Hak

    2014-01-01

    Purpose The study reported here was conducted to determine the systemic oral toxicity and to find the no-observed-adverse-effect level of 20 nm positively charged zinc oxide (ZnOSM20(+)) nanoparticles in Sprague Dawley rats for 90 days. Methods For the 90-day toxicity study, the high dose was set as 500 mg per kg of body weight (mg/kg) and the middle and low dose were set to 250 mg/kg and 125 mg/kg, respectively. The rats were held for a 14-day recovery period after the last administration, to observe for the persistence or reduction of any toxic effects. A distributional study was also carried out for the systemic distribution of ZnOSM20(+) NPs. Results No rats died during the test period. There were no significant clinical changes due to the test article during the experimental period in functional assessment, body weight, food and water consumption, ophthalmological testing, urine analysis, necropsy findings, or organ weights, but salivation was observed immediately after administration in both sexes. The total red blood cell count was increased, and hematocrit, albumin, mean cell volume, mean cell hemoglobin, and mean cell hemoglobin concentration were decreased significantly compared with control in both 500 mg/kg groups. Total protein and albumin levels were decreased significantly in both sexes in the 250 and 500 mg/kg groups. Histopathological studies revealed acinar cell apoptosis in the pancreas, inflammation and edema in stomach mucosa, and retinal atrophy of the eye in the 500 mg/kg group. Conclusion There were significant parameter changes in terms of anemia in the hematological and blood chemical analyses in the 250 and 500 mg/kg groups. The significant toxic change was observed to be below 125 mg/kg, so the no-observed-adverse-effect level was not determined, but the lowest-observed-adverse-effect level was considered to be 125 mg/kg in both sexes and the target organs were found to be the pancreas, eye, and stomach. PMID:25565829

  14. A Study of Haemostatic Parameters in Patients of Chronic Myeloid Leukaemia

    PubMed Central

    Gupta, Naresh; Singh, Tejinder; Agarwal, Sunita

    2016-01-01

    Introduction Chronic Myeloid Leukaemia (CML) is characterized by derangement of various components of the haemostatic system resulting in thrombo-haemorrhagic complications. Although less common than other myeloproliferative neoplasms, derangement of various components of the haemostatic system is observed in CML. Haemostatic abnormalities have been described in relation to hyperleucostasis and drugs used to treat CML. However, the correlation between haemostatic derangements and phase of CML is unclear in the literature. Aim The purpose of this cross-sectional study was to assay various haemostatic parameters in patients of CML receiving Imatinib and to determine any correlation between them and phases of disease as well as the status of remission. Materials and Methods The study included 30 patients with CML (17 males, 13 females, mean age of 35.53 ± 8.92 years) receiving imatinib mesylate. Haemostatic parameters including platelet counts, Prothrombin Time (PT), activated Partial Thromboplastin Time (APTT), fibrinogen, D-dimers and Factor VIII levels were assayed for all patients using standard methods. Bcr-abl gene product (quantitative) was determined on the peripheral blood by reverse transcriptase polymerase chain reaction (RT-PCR). Patients were grouped into phases of disease (chronic, accelerated and blast) and their response to imatinib was determined in the form of remission (clinical, haematological and molecular). Correlations were drawn between them using spearman’s coefficient. Results A significant positive correlation was found between PT (p=0.002), fibrinogen (p=0.011), D-dimers (p=0.050), Factor VIII levels (p=0.006) with the phase of CML and a significant negative correlation was observed between PT (p=0.003, 0.006), fibrinogen (p=0.010, 0.005), D-dimers (p=0.035, 0.017), Factor VIII levels (p=0.005, 0.001) and clinical and haematological remission respectively. No significant correlation of platelet counts and APTT was seen with the phase of

  15. A Study of Haemostatic Parameters in Patients of Chronic Myeloid Leukaemia

    PubMed Central

    Gupta, Naresh; Singh, Tejinder; Agarwal, Sunita

    2016-01-01

    Introduction Chronic Myeloid Leukaemia (CML) is characterized by derangement of various components of the haemostatic system resulting in thrombo-haemorrhagic complications. Although less common than other myeloproliferative neoplasms, derangement of various components of the haemostatic system is observed in CML. Haemostatic abnormalities have been described in relation to hyperleucostasis and drugs used to treat CML. However, the correlation between haemostatic derangements and phase of CML is unclear in the literature. Aim The purpose of this cross-sectional study was to assay various haemostatic parameters in patients of CML receiving Imatinib and to determine any correlation between them and phases of disease as well as the status of remission. Materials and Methods The study included 30 patients with CML (17 males, 13 females, mean age of 35.53 ± 8.92 years) receiving imatinib mesylate. Haemostatic parameters including platelet counts, Prothrombin Time (PT), activated Partial Thromboplastin Time (APTT), fibrinogen, D-dimers and Factor VIII levels were assayed for all patients using standard methods. Bcr-abl gene product (quantitative) was determined on the peripheral blood by reverse transcriptase polymerase chain reaction (RT-PCR). Patients were grouped into phases of disease (chronic, accelerated and blast) and their response to imatinib was determined in the form of remission (clinical, haematological and molecular). Correlations were drawn between them using spearman’s coefficient. Results A significant positive correlation was found between PT (p=0.002), fibrinogen (p=0.011), D-dimers (p=0.050), Factor VIII levels (p=0.006) with the phase of CML and a significant negative correlation was observed between PT (p=0.003, 0.006), fibrinogen (p=0.010, 0.005), D-dimers (p=0.035, 0.017), Factor VIII levels (p=0.005, 0.001) and clinical and haematological remission respectively. No significant correlation of platelet counts and APTT was seen with the phase of

  16. Genomic quantitative real-time PCR proves residual disease positivity in more than 30% samples with negative mRNA-based qRT-PCR in Chronic Myeloid Leukemia

    PubMed Central

    Pagani, Ilaria S.; Spinelli, Orietta; Mattarucchi, Elia; Pirrone, Cristina; Pigni, Diana; Amelotti, Elisabetta; Lilliu, Silvia; Boroni, Chiara; Intermesoli, Tamara; Giussani, Ursula; Caimi, Luigi; Bolda, Federica; Baffelli, Renata; Candi, Eleonora; Pasquali, Francesco; Lo Curto, Francesco; Lanfranchi, Arnalda; Porta, Fulvio; Rambaldi, Alessandro; Porta, Giovanni

    2014-01-01

    Imatinib mesylate (IM) is the first line therapy against Chronic Myeloid Leukemia, effectively prolonging overall survival. Because discontinuation of treatment is associated with relapse, IM is required indefinitely to maintain operational cure. To assess minimal residual disease, cytogenetic analysis is insensitive in a high background of normal lymphocytes. The qRT-PCR provides highly sensitive detection of BCR-ABL1 transcripts, but mRNA levels are not directly related to the number of leukemic cells, and undetectable results are difficult to interpret. We developed a sensitive approach to detect the number of leukemic cells by a genomic DNA (gDNA) Q-PCR assay based on the break-point sequence, with a formula to calculate the number of Ph-positive cells. We monitored 8 CML patients treated with IM for more than 8 years. We tested each samples by patient specific gDNA Q-PCR in parallel by the conventional techniques. In all samples positive for chimeric transcripts we showed corresponding chimeric gDNA by Q-PCR, and in 32.8% (42/128) of samples with undetectable levels of mRNA we detected the persistence of leukemic cells. The gDNA Q-PCR assay could be a new diagnostic tool used in parallel to conventional techniques to support the clinician's decision to vary or to STOP IM therapy. PMID:25594053

  17. Possible correlation of b3-a2-type bcr-abl messenger RNA defined by semiquantitative RT-PCR to platelet and megakaryocyte counts in Philadelphia-positive chronic myelogenous leukemia.

    PubMed

    Inokuchi, K; Futaki, M; Dan, K; Nomura, T

    1994-04-01

    Thirty-five patients with Philadelphia chromosome (Ph1)-positive chronic myelogenous leukemia (CML) were classified on the basis of the fusion pattern of bcr-abl mRNA determined by the reverse-transcriptase-polymerase chain reaction (RT-PCR) method. Semiquantitative assay of the bcr exon 2/abl exon 2 fused mRNA (b2-a2) and bcr exon 3/abl exon 2 fused mRNA (b3-a2) resulted in 21 patients showing b3-a2 type mRNA, seven showing b2-a2 type and seven showing coexpression. Quantification of the autoradiographic signals of amplified products was estimated using an MCID image analysis system. The relative intensity was defined as the ratio of bcr-abl signal to that of beta-actin. The relationship between the semiquantified bcr-abl mRNA and the platelet/megakaryocyte counts was analyzed. A possible correlation was found between the semiquantified b3-a2 type mRNA and the platelet (p < .05, N = 28) and megakaryocyte (p < .05, N = 13) counts of these patients. This finding suggests the possibility that b3-a2 mRNA may affect the thrombopoietic activity in Ph1-positive CML in a dose-response manner. PMID:7520786

  18. Multi-antigen CMV-MVA Triplex Vaccine in Reducing CMV Complications in Patients Previously Infected With CMV and Undergoing Donor Hematopoietic Cell Transplant

    ClinicalTrials.gov

    2016-08-03

    Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Acute Lymphoblastic Leukemia in Remission; Acute Myeloid Leukemia in Remission; Chronic Lymphocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Cytomegaloviral Infection; Hodgkin Lymphoma; Lymphadenopathy; Lymphoblastic Lymphoma; Myelodysplastic Syndrome; Myelofibrosis; Myeloproliferative Neoplasm; Non-Hodgkin Lymphoma

  19. Molecular identification of a TPR-FGFR1 fusion transcript in an adult with myeloproliferative neoplasm, T-lymphoblastic lymphoma, and a t(1;8)(q25;p11.2).

    PubMed

    Kim, Seon Young; Kim, Ji-Eun; Park, Seonyang; Kim, Hyun Kyung

    2014-06-01

    The 8p11 myeloproliferative syndrome is an aggressive neoplasm associated with chromosomal abnormalities involving rearrangement of the fibroblast growth factor receptor 1 (FGFR1) gene. We report herein a rare case of a t(1;8)(q25;p11.2) with a TPR-FGFR1 rearrangement, in which the patient presented with myeloproliferative neoplasm-like symptoms and T-lymphoblastic lymphoma. Sequence analysis revealed a fusion transcript with exon 22 of the TPR gene joined to exon 13 of the FGFR1 gene, which is a novel breakpoint for the TPR gene in the TPR-FGFR1 rearrangement.

  20. Therapy related myelodysplasia/myeloproliferative neoplasia-unclassified with acute leukemic transformation following Paclitaxel and Carboplatin based chemotherapy in an ovarian cancer patient.

    PubMed

    Vanajakshi, S; Prasad, S V S S; Amina, S S; Kavitha, E; Iravathy Goud, K; Kshitija, K

    2014-09-01

    Alkylating agents used in chemotherapy are mutagenic and have strong leukemogenic potential. The most serious long term complication of chemotherapy is the development of secondary disease, particularly hematological malignancy; they have rarely been reported in the context of ovarian cancer treatment. We describe quite a rare occurrence of a myelodyplastic/myeloproliferative neoplasm, unclassified (MDS/MPN-U) with acute leukemic transformation and multiple cytogenetic abnormalities not usually found together as JAK2 V617F mutation, 5q- and 7q-deletion, after exposure to paclitaxel and carboplatin based chemotherapy in a patient treated for ovarian cancer. We should be aware of such complication whose prognosis is really poor. PMID:25332593

  1. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms

    PubMed Central

    Quintás-Cardama, Alfonso; Vaddi, Kris; Liu, Phillip; Manshouri, Taghi; Li, Jun; Scherle, Peggy A.; Caulder, Eian; Wen, Xiaoming; Li, Yanlong; Waeltz, Paul; Rupar, Mark; Burn, Timothy; Lo, Yvonne; Kelley, Jennifer; Covington, Maryanne; Shepard, Stacey; Rodgers, James D.; Haley, Patrick; Kantarjian, Hagop

    2010-01-01

    Constitutive JAK2 activation in hematopoietic cells by the JAK2V617F mutation recapitulates myeloproliferative neoplasm (MPN) phenotypes in mice, establishing JAK2 inhibition as a potential therapeutic strategy. Although most polycythemia vera patients carry the JAK2V617F mutation, half of those with essential thrombocythemia or primary myelofibrosis do not, suggesting alternative mechanisms for constitutive JAK-STAT signaling in MPNs. Most patients with primary myelofibrosis have elevated levels of JAK-dependent proinflammatory cytokines (eg, interleukin-6) consistent with our observation of JAK1 hyperactivation. Accordingly, we evaluated the effectiveness of selective JAK1/2 inhibition in experimental models relevant to MPNs and report on the effects of INCB018424, the first potent, selective, oral JAK1/JAK2 inhibitor to enter the clinic. INCB018424 inhibited interleukin-6 signaling (50% inhibitory concentration [IC50] = 281nM), and proliferation of JAK2V617F+ Ba/F3 cells (IC50 = 127nM). In primary cultures, INCB018424 preferentially suppressed erythroid progenitor colony formation from JAK2V617F+ polycythemia vera patients (IC50 = 67nM) versus healthy donors (IC50 > 400nM). In a mouse model of JAK2V617F+ MPN, oral INCB018424 markedly reduced splenomegaly and circulating levels of inflammatory cytokines, and preferentially eliminated neoplastic cells, resulting in significantly prolonged survival without myelosuppressive or immunosuppressive effects. Preliminary clinical results support these preclinical data and establish INCB018424 as a promising oral agent for the treatment of MPNs. PMID:20130243

  2. Analysis of Jak2 signaling reveals resistance of mouse embryonic hematopoietic stem cells to myeloproliferative disease mutation

    PubMed Central

    Mascarenhas, Maria I.; Bacon, Wendi A.; Kapeni, Chrysa; Fitch, Simon R.; Kimber, Gillian; Cheng, S. W. Priscilla; Li, Juan; Green, Anthony R.

    2016-01-01

    The regulation of hematopoietic stem cell (HSC) emergence during development provides important information about the basic mechanisms of blood stem cell generation, expansion, and migration. We set out to investigate the role that cytokine signaling pathways play in these early processes and show here that the 2 cytokines interleukin 3 and thrombopoietin have the ability to expand hematopoietic stem and progenitor numbers by regulating their survival and proliferation. For this, they differentially use the Janus kinase (Jak2) and phosphatidylinositol 3-kinase (Pi3k) signaling pathways, with Jak2 mainly relaying the proproliferation signaling, whereas Pi3k mediates the survival signal. Furthermore, using Jak2-deficient embryos, we demonstrate that Jak2 is crucially required for the function of the first HSCs, whereas progenitors are less dependent on Jak2. The JAK2V617F mutation, which renders JAK2 constitutively active and has been linked to myeloproliferative neoplasms, was recently shown to compromise adult HSC function, negatively affecting their repopulation and self-renewal ability, partly through the accumulation of JAK2V617F-induced DNA damage. We report here that nascent HSCs are resistant to the JAK2V617F mutation and show no decrease in repopulation or self-renewal and no increase in DNA damage, even in the presence of 2 mutant copies. More importantly, this unique property of embryonic HSCs is stably maintained through ≥1 round of successive transplantations. In summary, our dissection of cytokine signaling in embryonic HSCs has uncovered unique properties of these cells that are of clinical importance. PMID:26864339

  3. TERT rs2736100 genotypes are associated with differential risk of myeloproliferative neoplasms in Swedish and Chinese male patient populations.

    PubMed

    Dahlström, Jenny; Liu, Tiantian; Yuan, Xiaotian; Saft, Leonie; Ghaderi, Mehran; Wei, Ya Bin; Lavebratt, Catharina; Li, Ping; Zheng, Chengyun; Björkholm, Magnus; Xu, Dawei

    2016-10-01

    The telomerase reverse transcriptase (TERT) gene rs2736100_C allele has recently been shown to be associated with an increased risk for myeloproliferative neoplasms (MPNs) among Caucasians. However, it is unknown if this association is present in other ethnical populations and whether rs2736100 allele frequencies mirror the incidence of MPNs in a population. Here we genotyped TERT rs2736100 variants in 126 Swedish and 101 Chinese MPN patients and their age-, sex-, and ethnically-matched healthy controls. Healthy Chinese adults had a higher frequency of the A allele and lower frequencies of the C allele compared to Swedish counterparts (57.4 vs 47.0 % for A, 42.6 vs 53.0 % for C, P = 0.006). Both Swedish and Chinese patients harbored significantly higher C allele frequency than their controls (62.7 vs 53.0 % and 57.4 vs 42.6 % for Swedish and Chinese, respectively, P = 0.004). Swedes and Chinese bearing the CC genotype had a significantly increased risk of MPN compared to AA carriers (OR = 2.47; 95 % CI: 1.33-4.57, P = 0.003, for Swedes, and OR = 3.45; 95 % CI: 1.52-7.85, P = 0.005, for Chinese). Further analyses showed that rs2736100_CC was associated with robustly enhanced risk in males only (CC vs AA, OR = 5.11; 95 % CI: 2.19-11.92, P < 0.0001). The CC-carrying MPN patients exhibited significantly higher TERT expression than patients with the AC genotype. Collectively, the rs2736100_C is a risk allele for MPNs in Swedish and Chinese males, and the lower incidence of MPNs in the Chinese population is correlated with a lower rs2736100_C risk allele frequency.

  4. Combination of PIM and JAK2 inhibitors synergistically suppresses cell proliferation and overcomes drug resistance of myeloproliferative neoplasms

    PubMed Central

    Greco, Rita; Li, Zhifang; Sun, Fangxian; Barberis, Claude; Tabart, Michel; Patel, Vinod; Schio, Laurent; Hurley, Raelene; Chen, Bo; Cheng, Hong; Lengauer, Christoph; Pollard, Jack; Watters, James; Garcia-Echeverria, Carlos; Wiederschain, Dmitri; Adrian, Francisco; Zhang, JingXin

    2014-01-01

    Inhibitors of JAK2 kinase are emerging as an important treatment modality for myeloproliferative neoplasms (MPN). However, similar to other kinase inhibitors, resistance to JAK2 inhibitors may eventually emerge through a variety of mechanisms. Effective drug combination is one way to enhance therapeutic efficacy and combat resistance against JAK2 inhibitors. To identify potential combination partners for JAK2 compounds in MPN cell lines, we performed pooled shRNA screen targeting 5,000 genes in the presence or absence of JAK2 blockade. One of the top hits identified was MYC, an oncogenic transcription factor that is difficult to inhibit directly, but could be targeted by modulation of upstream regulatory elements such as kinases. We demonstrate herein that PIM kinase inhibitors efficiently suppress MYC protein levels in MPN cell lines. Overexpression of MYC restores the viability of PIM inhibitor-treated cells, revealing causal relationship between MYC down-regulation and cell growth inhibition by PIM compounds. Combination of various PIM inhibitors with a JAK2 inhibitor results in significant synergistic growth inhibition of multiple MPN cancer cell lines and induction of apoptosis. Mechanistic studies revealed strong downregulation of phosphorylated forms of S6 and 4EBP1 by JAK2/PIM inhibitor combination treatment. Finally, such combination was effective in eradicating in vitro JAK2 inhibitor-resistant MPN clones, where MYC is consistently up-regulated. These findings demonstrate that simultaneous suppression of JAK2 and PIM kinase activity by small molecule inhibitors is more effective than either agent alone in suppressing MPN cell growth. Our data suggest that JAK2 and PIM combination might warrant further investigation for the treatment of JAK2-driven hematologic malignancies. PMID:24830942

  5. TERT rs2736100 genotypes are associated with differential risk of myeloproliferative neoplasms in Swedish and Chinese male patient populations.

    PubMed

    Dahlström, Jenny; Liu, Tiantian; Yuan, Xiaotian; Saft, Leonie; Ghaderi, Mehran; Wei, Ya Bin; Lavebratt, Catharina; Li, Ping; Zheng, Chengyun; Björkholm, Magnus; Xu, Dawei

    2016-10-01

    The telomerase reverse transcriptase (TERT) gene rs2736100_C allele has recently been shown to be associated with an increased risk for myeloproliferative neoplasms (MPNs) among Caucasians. However, it is unknown if this association is present in other ethnical populations and whether rs2736100 allele frequencies mirror the incidence of MPNs in a population. Here we genotyped TERT rs2736100 variants in 126 Swedish and 101 Chinese MPN patients and their age-, sex-, and ethnically-matched healthy controls. Healthy Chinese adults had a higher frequency of the A allele and lower frequencies of the C allele compared to Swedish counterparts (57.4 vs 47.0 % for A, 42.6 vs 53.0 % for C, P = 0.006). Both Swedish and Chinese patients harbored significantly higher C allele frequency than their controls (62.7 vs 53.0 % and 57.4 vs 42.6 % for Swedish and Chinese, respectively, P = 0.004). Swedes and Chinese bearing the CC genotype had a significantly increased risk of MPN compared to AA carriers (OR = 2.47; 95 % CI: 1.33-4.57, P = 0.003, for Swedes, and OR = 3.45; 95 % CI: 1.52-7.85, P = 0.005, for Chinese). Further analyses showed that rs2736100_CC was associated with robustly enhanced risk in males only (CC vs AA, OR = 5.11; 95 % CI: 2.19-11.92, P < 0.0001). The CC-carrying MPN patients exhibited significantly higher TERT expression than patients with the AC genotype. Collectively, the rs2736100_C is a risk allele for MPNs in Swedish and Chinese males, and the lower incidence of MPNs in the Chinese population is correlated with a lower rs2736100_C risk allele frequency. PMID:27561898

  6. A TET2 rs3733609 C/T genotype is associated with predisposition to the myeloproliferative neoplasms harboring JAK2V617F and confers a proliferative potential on erythroid lineages

    PubMed Central

    Shen, Xiao-hui; Sun, Nan-nan; Yin, Ya-fei; Liu, Su-fang; Liu, Xiao-liu; Peng, Hong-ling; Dai, Chong-wen; Xu, Yun-xiao; Deng, Ming-yang; Luo, Yun-ya; Zheng, Wen-li; Zhang, Guang-sen

    2016-01-01

    Common germline single-nucleotide polymorphisms (SNPs) at JAK2 locus have been associated with Myeloproliferative neoplasms (MPN). And, the germline sequence variant rs2736100 C in TERT is related to risk of MPN, suggesting a complex association between SNPs and the pathogenesis of MPN. Our previous study (unpublished data) showed that there was a high frequency distribution in rs3733609 C/T genotype at Ten-Eleven Translocation 2 (TET2) locus in one Chinese familial primary myelofibrosis. In the present study, we evaluate the role and clinical significance of rs3733609 C/T genotype in JAK2V617F-positive sporadic MPN (n = 181). TET2 rs3733609 C/T genotype had a higher incidence (13.81%; 25/181) in JAK2V617F-positive sporadic MPN patients than that in normal controls (n = 236) (6.35%; 15/236), which was predisposing to MPN (odds ratio(OR) = 2.361; P = 0.01). MPN patients with rs3733609 C/T genotype had increased leukocyte and platelets counts, elevated hemoglobin concentration in comparison with T/T genotype. Thrombotic events were more common in MPN patients with rs3733609 C/T than those with T/T genotype (P < 0.01). We confirmed that rs3733609 C/T genotype downregulated TET2 mRNA transcription, and the mechanism may be involved in a disruption of the interaction between CCAAT/enhancer binding protein alpha (C/EBPA) and TET2 rs3733609 C/T locus.TET2 rs3733609 C/T genotype stimulated the erythroid hematopoiesis in MPN patients. Altogether, we found a novel hereditary susceptible factor-TET2 rs3733609 C/T variant for the development of MPN, suggesting the variant may be partially responsible for the pathogenesis and accumulation of MPN. PMID:26843622

  7. Physical activity prescription: a critical opportunity to address a modifiable risk factor for the prevention and management of chronic disease: a position statement by the Canadian Academy of Sport and Exercise Medicine.

    PubMed

    Thornton, Jane S; Frémont, Pierre; Khan, Karim; Poirier, Paul; Fowles, Jonathon; Wells, Greg D; Frankovich, Renata J

    2016-09-01

    Non-communicable disease is a leading threat to global health. Physical inactivity is a large contributor to this problem; in fact, the WHO ranks it as the fourth leading risk factor for overall morbidity and mortality worldwide. In Canada, at least 4 of 5 adults do not meet the Canadian Physical Activity Guidelines of 150 min of moderate-to-vigorous physical activity per week. Physicians play an important role in the dissemination of physical activity (PA) recommendations to a broad segment of the population, as over 80% of Canadians visit their doctors every year and prefer to get health information directly from them. Unfortunately, most physicians do not regularly assess or prescribe PA as part of routine care, and even when discussed, few provide specific recommendations. PA prescription has the potential to be an important therapeutic agent for all ages in primary, secondary and tertiary prevention of chronic disease. Sport and exercise medicine (SEM) physicians are particularly well suited for this role and should collaborate with their primary care colleagues for optimal patient care. The purpose of this Canadian Academy and Sport and Exercise Medicine position statement is to provide an evidence-based, best practices summary to better equip SEM and primary care physicians to prescribe PA and exercise, specifically for the prevention and management of non-communicable disease. This will be achieved by addressing common questions and perceived barriers in the field.Author note This position statement has been endorsed by the following nine sport medicine societies: Australasian College of Sports and Exercise Physicians (ACSEP), American Medical Society for Sports Medicine (AMSSM), British Association of Sports and Exercise Medicine (BASEM), European College of Sport & Exercise Physicians (ECOSEP), Norsk forening for idrettsmedisin og fysisk aktivite (NIMF), South African Sports Medicine Association (SASMA), Schweizerische Gesellschaft für Sportmedizin

  8. Physical activity prescription: a critical opportunity to address a modifiable risk factor for the prevention and management of chronic disease: a position statement by the Canadian Academy of Sport and Exercise Medicine.

    PubMed

    Thornton, Jane S; Frémont, Pierre; Khan, Karim; Poirier, Paul; Fowles, Jonathon; Wells, Greg D; Frankovich, Renata J

    2016-09-01

    Non-communicable disease is a leading threat to global health. Physical inactivity is a large contributor to this problem; in fact, the WHO ranks it as the fourth leading risk factor for overall morbidity and mortality worldwide. In Canada, at least 4 of 5 adults do not meet the Canadian Physical Activity Guidelines of 150 min of moderate-to-vigorous physical activity per week. Physicians play an important role in the dissemination of physical activity (PA) recommendations to a broad segment of the population, as over 80% of Canadians visit their doctors every year and prefer to get health information directly from them. Unfortunately, most physicians do not regularly assess or prescribe PA as part of routine care, and even when discussed, few provide specific recommendations. PA prescription has the potential to be an important therapeutic agent for all ages in primary, secondary and tertiary prevention of chronic disease. Sport and exercise medicine (SEM) physicians are particularly well suited for this role and should collaborate with their primary care colleagues for optimal patient care. The purpose of this Canadian Academy and Sport and Exercise Medicine position statement is to provide an evidence-based, best practices summary to better equip SEM and primary care physicians to prescribe PA and exercise, specifically for the prevention and management of non-communicable disease. This will be achieved by addressing common questions and perceived barriers in the field.Author note This position statement has been endorsed by the following nine sport medicine societies: Australasian College of Sports and Exercise Physicians (ACSEP), American Medical Society for Sports Medicine (AMSSM), British Association of Sports and Exercise Medicine (BASEM), European College of Sport & Exercise Physicians (ECOSEP), Norsk forening for idrettsmedisin og fysisk aktivite (NIMF), South African Sports Medicine Association (SASMA), Schweizerische Gesellschaft für Sportmedizin

  9. Hepatitis B core-related antigen levels are associated with response to entecavir and peginterferon add-on therapy in hepatitis B e antigen-positive chronic hepatitis B patients.

    PubMed

    van Campenhout, M J H; Brouwer, W P; van Oord, G W; Xie, Q; Zhang, Q; Zhang, N; Guo, S; Tabak, F; Streinu-Cercel, A; Wang, J; Pas, S D; Sonneveld, M J; de Knegt, R J; Boonstra, A; Hansen, B E; Janssen, H L A

    2016-06-01

    Hepatitis B core-related antigen (HBcrAg), a new serum marker, may be useful in monitoring chronic hepatitis B infection. HBcrAg was measured in 175 hepatitis B e antigen-positive patients treated with entecavir (ETV) with or without peginterferon (PEG-IFN) add-on therapy. Decline in HBcrAg was stronger in patients with vs. without combined response (ETV: -3.22 vs. -1.71 log U/mL, p <0.001; PEG-IFN add-on: -3.16 vs. -1.83 IU/mL, p <0.001) and in patients with vs. without hepatitis B surface antigen (HBsAg) response (ETV: -2.60 vs. -1.74 log U/mL, p <0.001; PEG-IFN add-on: -2.38 vs. -2.15 log U/mL, p = 0.31). HBcrAg was associated with combined response (adjusted odds ratio 0.3, 95% confidence interval 0.2-0.5, p <0.001), but was not superior to quantitative HBsAg (qHBsAg).

  10. Characterization of the CDR3 structure of the Vβ21 T cell clone in patients with P210(BCR-ABL)-positive chronic myeloid leukemia and B-cell acute lymphoblastic leukemia.

    PubMed

    Zha, Xianfeng; Chen, Shaohua; Yang, Lijian; Li, Bo; Chen, Yu; Yan, Xiaojuan; Li, Yangqiu

    2011-10-01

    The clonally expanded T cells identified in most cancer patients that respond to tumor-associated antigen such as P210(BCR-ABL) protein have definite, specific antitumor cytotoxicity. T cell receptor (TCR) Vβ CDR3 repertoire diversity was analyzed in patients with chronic myeloid leukemia (CML) and BCR-ABL(+) B-cell acute lymphoblastic leukemia (B-ALL) by GeneScan. A high frequency of oligoclonal expansion of the TCR Vβ21 subfamily was observed in the peripheral blood of CML and B-ALL patients. These clonally expanded Vβ21 T cells were correlated with the pathophysiologic process of CML. A conserved amino acid motif (SLxxV) was observed within the CDR3 region in only 3 patients with CML. Preferential usage of the Jβ segments was also observed in a minority of patients. The 3-dimensional structures of the CDR3 region containing the same motif or using the same Jβ segment displayed low similarity; on the contrary, the conformation of the CDR3 region containing no conserved motif in some T cell clones was highly similar. In conclusion, our findings indicate a high frequency of TCR Vβ21 subfamily expansion in p210(BCR-ABL)-positive CML and B-ALL patients. The characterization of the CDR3 structure was complex. Regrettably, at this time it was not possible to confirm that the Vβ21 T cell clones were derived from the stimulation of p210(BCR-ABL) protein.

  11. Establishment and characterization of A novel Philadelphia-chromosome positive chronic myeloid leukemia cell line, TCC-S, expressing P210 and P190 BCR/ABL transcripts but missing normal ABL gene.

    PubMed

    Van, Phan Nguyen Thanh; Xinh, Phan Thi; Kano, Yasuhiko; Tokunaga, Katsushi; Sato, Yuko

    2005-03-01

    A novel Philadelphia-chromosome positive (Ph+) cell line, TCC-S, has been established from a patient with Ph+ chronic myeloid leukemia (CML) in the blastic crisis. TCC-S cells were shown to express both P210 and P190 BCR/ABL transcripts by reverse transcriptase-polymerase chain reaction (PCR), although quantitative-PCR revealed that TCC-S cells mainly expressed P210 BCR/ABL transcript. Karyotype analysis revealed several triploid clones which constantly harbored two der(9)del(9) (p12)t(9;22) (q34;qll)s and two del(9) (q21)s. The der(9)del(9) (p12)t(9;22) (q34;q11) is rarely found in other CML cell lines. Moreover, to the best of our knowledge, del(9) (q21) resulting in missing of a restrict region including normal ABL gene has not been found among CML cell lines previously described. Thus, TCC-S cells with only BCR/ABL gene and no normal ABL gene may be a useful tool for functional study of ABL in Ph+ CML.

  12. A case of 8p11 myeloproliferative syndrome with BCR-FGFR1 gene fusion presenting with trilineage acute leukemia/lymphoma, successfully treated by cord blood transplantation.

    PubMed

    Morishige, Satoshi; Oku, Eijiro; Takata, Yuka; Kimura, Yoshizo; Arakawa, Fumiko; Seki, Ritsuko; Imamura, Rie; Osaki, Koichi; Hashiguchi, Michitoshi; Yakushiji, Kazuaki; Mizuno, Shinichi; Yoshimoto, Koji; Nagafuji, Koji; Ohshima, Koichi; Okamura, Takashi

    2013-01-01

    The 8p11 myeloproliferative syndrome is a rare neoplasm associated with chromosomal translocations involving the fibroblast growth factor receptor 1 (FGFR1) gene located at chromosome 8p11-12. FGFR1 encodes a transmembrane receptor tyrosine kinase. The resultant fusion proteins are constitutively active tyrosine kinases that drive the proliferation of hematopoietic cells, whose uncontrolled growth can present as a myeloproliferative neoplasm. We report here the case of a 50-year-old man harboring the t(8;22)(p12;q11) chromosomal translocation in cells from both bone marrow and lymph nodes. He presented with acute leukemia and lymphoma with trilineage features. A novel mRNA in-frame fusion between exon 4 of the breakpoint cluster region (BCR) gene at chromosome 22q11 and exon 9 of FGFR1 gene on chromosome 8p11-12 was identified by reverse transcription polymerase chain reaction analysis and was confirmed by DNA sequencing. Because the patient was refractory to chemotherapy, cord blood transplantation was performed in progressive disease. It resulted in a successful outcome in which cytogenetic complete remission has been maintained for 2 years till date. PMID:23171834

  13. Molecular predictors of response to decitabine in advanced chronic myelomonocytic leukemia: a phase 2 trial.

    PubMed

    Braun, Thorsten; Itzykson, Raphael; Renneville, Aline; de Renzis, Benoit; Dreyfus, François; Laribi, Kamel; Bouabdallah, Krimo; Vey, Norbert; Toma, Andrea; Recher, Christian; Royer, Bruno; Joly, Bertrand; Vekhoff, Anne; Lafon, Ingrid; Sanhes, Laurence; Meurice, Guillaume; Oréar, Cédric; Preudhomme, Claude; Gardin, Claude; Ades, Lionel; Fontenay, Michaela; Fenaux, Pierre; Droin, Nathalie; Solary, Eric

    2011-10-01

    Hydroxyurea is the standard therapy of chronic myelomonocytic leukemia (CMML) presenting with advanced myeloproliferative and/or myelodysplastic features. Response to hypomethylating agents has been reported in heterogeneous series of CMML. We conducted a phase 2 trial of decitabine (DAC) in 39 patients with advanced CMML defined according to a previous trial. Median number of DAC cycles was 10 (range, 1-24). Overall response rate was 38% with 4 complete responses (10%), 8 marrow responses (21%), and 3 stable diseases with hematologic improvement (8%). Eighteen patients (46%) demonstrated stable disease without hematologic improvement, and 6 (15%) progressed to acute leukemia. With a median follow-up of 23 months, overall survival was 48% at 2 years. Mutations in ASXL1, TET2, AML1, NRAS, KRAS, CBL, FLT3, and janus kinase 2 (JAK2) genes, and hypermethylation of the promoter of the tumor suppressor gene TIF1γ, did not predict response or survival on DAC therapy. Lower CJUN and CMYB gene expression levels independently predicted improved overall survival. This trial confirmed DAC efficacy in approximately 40% of CMML patients with advanced myeloproliferative or myelodysplastic features and suggested that CJUN and CMYB expression could be potential biomarkers in this setting. This trial is registered at EudraCT (eudract.ema.europa.eu) as #2008-000470-21 and www.clinicaltrials.gov as #NCT01098084.

  14. Chronic migraine.

    PubMed

    Schwedt, Todd J

    2014-03-24

    Chronic migraine is a disabling neurologic condition that affects 2% of the general population. Patients with chronic migraine have headaches on at least 15 days a month, with at least eight days a month on which their headaches and associated symptoms meet diagnostic criteria for migraine. Chronic migraine places an enormous burden on patients owing to frequent headaches; hypersensitivity to visual, auditory, and olfactory stimuli; nausea; and vomiting. It also affects society through direct and indirect medical costs. Chronic migraine typically develops after a slow increase in headache frequency over months to years. Several factors are associated with an increased risk of transforming to chronic migraine. The diagnosis requires a carefully performed patient interview and neurologic examination, sometimes combined with additional diagnostic tests, to differentiate chronic migraine from secondary headache disorders and other primary chronic headaches of long duration. Treatment takes a multifaceted approach that may include risk factor modification, avoidance of migraine triggers, drug and non-drug based prophylaxis, and abortive migraine treatment, the frequency of which is limited to avoid drug overuse. This article provides an overview of current knowledge regarding chronic migraine, including epidemiology, risk factors for its development, pathophysiology, diagnosis, management, and guidelines. The future of chronic migraine treatment and research is also discussed.

  15. Chronic kidney disease

    MedlinePlus

    Kidney failure - chronic; Renal failure - chronic; Chronic renal insufficiency; Chronic kidney failure; Chronic renal failure ... Chronic kidney disease (CKD) slowly gets worse over months or years. You may not notice any symptoms for some ...

  16. Light-Emitting Diode Therapy in Preventing Mucositis in Children Receiving Chemotherapy With or Without Radiation Therapy Before Bone Marrow Transplantation

    ClinicalTrials.gov

    2013-09-19

    Chronic Myeloproliferative Disorders; Kidney Cancer; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Neuroblastoma; Oral Complications; Ovarian Cancer; Pain; Sarcoma

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

    ClinicalTrials.gov

    2016-08-30

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

  18. Caregiver Support in the Coping of Patients Who Are Undergoing a Donor Bone Marrow Transplant

    ClinicalTrials.gov

    2011-03-28

    Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic-Myeloproliferative Diseases; Psychosocial Effects of Cancer and Its Treatment

  19. Caregiver Support in the Quality of Life of Patients Who Are Undergoing Donor Bone Marrow Transplantation

    ClinicalTrials.gov

    2012-03-13

    Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases; Psychosocial Effects of Cancer and Its Treatment

  20. A Standardized Nursing Intervention Protocol for HCT Patients

    ClinicalTrials.gov

    2015-06-03

    Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Psychosocial Effects of Cancer and Its Treatment; Therapy-related Toxicity

  1. Sirolimus, Tacrolimus, Thymoglobulin and Rituximab as Graft-versus-Host-Disease Prophylaxis in Patients Undergoing Haploidentical and HLA Partially Matched Donor Hematopoietic Cell Transplantation

    ClinicalTrials.gov

    2015-12-09

    Chronic Myeloproliferative Disorders; Graft Versus Host Disease; Leukemia; Lymphoma; Lymphoproliferative Disorder; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms

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

    ClinicalTrials.gov

    2015-03-18

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

  3. Combination Chemotherapy and Donor Stem Cell Transplant in Treating Patients With Aplastic Anemia or Hematologic Cancer

    ClinicalTrials.gov

    2016-08-03

    Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases; Nonmalignant Neoplasm; Unspecified Adult Solid Tumor, Protocol Specific; Unspecified Childhood Solid Tumor, Protocol Specific

  4. Tissue, Blood, and Body Fluid Sample Collection From Patients With Hematologic Cancer

    ClinicalTrials.gov

    2016-07-01

    Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Lymphoproliferative Disorder; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Nonmalignant Neoplasm

  5. Immunologic Diagnostic Blood Test in Predicting Side-Effects in Patients Undergoing a Donor Stem Cell Transplant for Hematologic Cancer or Other Diseases

    ClinicalTrials.gov

    2011-03-03

    Chronic Myeloproliferative Disorders; Graft Versus Host Disease; Infection; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic-Myeloproliferative Diseases; Neuroblastoma; Therapy-related Toxicity

  6. Non-Ablative Allo HSCT For Hematologic Malignancies or SAA

    ClinicalTrials.gov

    2011-12-07

    Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases; Precancerous/Nonmalignant Condition; Small Intestine Cancer

  7. A Web-Based Stem Cell Transplant Support System or Standard Care in Young Patients Undergoing Stem Cell Transplant and Their Families

    ClinicalTrials.gov

    2011-07-11

    Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Neuroblastoma; Ovarian Cancer; Psychosocial Effects of Cancer and Its Treatment; Sarcoma

  8. 12-O-Tetradecanoylphorbol-13-acetate in Treating Patients With Hematologic Cancer or Bone Marrow Disorder

    ClinicalTrials.gov

    2010-01-25

    Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases; Precancerous/Nonmalignant Condition

  9. Presence of Donor-Derived DNA in Semen Samples From Cancer Survivors Who Underwent Donor Stem Cell Transplant

    ClinicalTrials.gov

    2014-12-08

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

  10. Baclofen-Amitriptyline Hydrochloride-Ketamine Gel in Treating Peripheral Neuropathy Caused by Chemotherapy in Patients With Cancer

    ClinicalTrials.gov

    2015-07-03

    Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Lymphoproliferative Disorder; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Neurotoxicity; Pain; Unspecified Adult Solid Tumor, Protocol Specific

  11. Donor Umbilical Cord Blood Transplant in Treating Patients With Hematologic Cancer

    ClinicalTrials.gov

    2012-10-09

    Chronic Myeloproliferative Disorders; Diamond-blackfan Anemia; Fanconi Anemia; Graft Versus Host Disease; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases

  12. Methemoglobinemia in Young Patients With Hematologic Cancer or Aplastic Anemia Treated With Dapsone

    ClinicalTrials.gov

    2010-11-04

    Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Lymphoproliferative Disorder; Methemoglobinemia; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Nonmalignant Neoplasm

  13. Donor Stem Cell Transplant or Donor White Blood Cell Infusions in Treating Patients With Hematologic Cancer

    ClinicalTrials.gov

    2012-07-02

    Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Unusual Cancers of Childhood

  14. American Ginseng in Treating Patients With Fatigue Caused by Cancer

    ClinicalTrials.gov

    2014-07-14

    Chronic Myeloproliferative Disorders; Fatigue; Leukemia; Lymphoma; Lymphoproliferative Disorder; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Precancerous Condition; Unspecified Adult Solid Tumor, Protocol Specific

  15. Antimicrobial Solution or Saline Solution in Maintaining Catheter Patency and Preventing Catheter-Related Blood Infections in Patients With Malignancies

    ClinicalTrials.gov

    2013-02-13

    Chronic Myeloproliferative Disorders; Infection; Leukemia; Lymphoma; Lymphoproliferative Disorder; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Unspecified Adult Solid Tumor, Protocol Specific

  16. Donor Peripheral Stem Cell Transplant in Treating Patients With Advanced Hematologic Cancer or Other Disorders

    ClinicalTrials.gov

    2016-09-16

    Chronic Myeloproliferative Disorders; Graft Versus Host Disease; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases; Precancerous/Nonmalignant Condition

  17. The mutation profile of JAK2 and CALR in Chinese Han patients with Philadelphia chromosome-negative myeloproliferative neoplasms

    PubMed Central

    2014-01-01

    Mutations in JAK2, MPL and CALR are highly relevant to the Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs). We performed high resolution melting analysis and Sanger sequencing together with T-A cloning to elucidate the unique mutation profile of these genes, in Chinese patients with MPNs. Peripheral blood DNA samples were obtained from 80 patients with polycythemia vera (PV), 80 patients with essential thrombocytosis (ET) and 50 patients with primary myelofibrosis (PMF). Ten PV patients were identified with diverse JAK2 exon 12 mutations. Five novel JAK2 Exon 12 mutation patterns (M532V/E543G, N533D, M535I/H538Y/K549I, E543G and D544N) were described. JAK2 V617F was detected in 140 samples (66 PV, 45 ET and 29 PMF). JAK2 Exon 12 mutations were prevalent (13%) and variable in the Chinese patients. Compared with PV patients with JAK2 V617F mutations, PV patients with JAK2 exon 12 mutations had an earlier median onset of disease (P = 0.0013). MPL W515L/K mutations were discerned in 4 ET and 3 PMF patients. Two kinds of CALR mutation, c. 1179_1230del and c. 1234_1235insTTGTC were detected in 20 ET and 16 PMF patients. A novel CALR mutation pattern (c. 1173_1223del/c. 1179_1230del) was identified in 2 PMF samples. In addition, 17 scattered point mutations in CALR c.1153 to c.1255 were also detected in 13 cases with CALR frame-shifting variations and 2 cases without CALR frame-shifting variations. Female patients showed a predisposition to CALR mutations (P = 0.0035). Chinese Ph-negative MPN patients have a unique mutation landscape in the common molecular markers of MPN diagnosis. Validation of the molecular diagnostic pipeline should be emphasized since there is a considerable ethnical diversity in the molecular profiles of Ph-negative MPNs. PMID:25023898

  18. [Chronicity, chronicization, systematization of delusions].

    PubMed

    Trapet, P; Fernandez, C; Galtier, M C; Gisselmann, A

    1984-05-01

    Chronicity in psychopathology is indicative of a term, a decay. Chronicization only leads the way to this term. Here, chronicization is taken literally as an inscription in the time course of delusions. The mechanism of systematization seems to be a central mark in the approach to chronic delusions. It is not an alienation or an irreversible closing but an attempted accommodation with reality in the life of psychotic subjects, irrespective of the delusional structure. The role of therapy and drug treatment as a follow-up may in that case assume another meaning.

  19. Chronic pancreatitis.

    PubMed

    Chari, S T; DiMagno, E P

    2001-09-01

    An increasing number of novel mutations are associated with chronic pancreatitis. Some cause a high-penetrance, autosomal dominant type of clinical picture (eg, mutations at codons 29 and 122 of the cationic trypsinogen gene), whereas others have a low penetrance or are frequent in the general population (eg, mutations in Kazal type 1 [SPINK1] and in codons 16, 22, and 23 of the cationic trypsinogen gene) and act as disease modifiers. The results of recent studies indicate that smoking adversely affects the course and complications of chronic pancreatitis (more frequent and faster rate of calcification and higher risk of development of pancreatic cancer). Thus, regardless of the cause of chronic pancreatis, patients with this condition should not smoke. Using current diagnostic criteria, the accuracy of endoscopic ultrasound for the diagnosis of chronic pancreatitis is not good. For example, 39% of dyspeptic persons without any other evidence of chronic pancreatitis fulfilled the endoscopic ultrasound criteria for chronic pancreatitis. Diabetes frequently occurs in chronic pancreatitis, but it is not prevented or increased by pancreatic surgery. Islet cell autotransplantation holds promise for the prevention of diabetes in patients requiring total pancreatectomy if the pancreas is not extensively fibrotic. Splenic vein occlusion is present in 7% of patients undergoing surgery for chronic pancreatitis, but fewer than one fifth of these patients have variceal bleeding before or after surgery.

  20. Chronic pancreatitis.

    PubMed

    Majumder, Shounak; Chari, Suresh T

    2016-05-01

    Chronic pancreatitis describes a wide spectrum of fibro-inflammatory disorders of the exocrine pancreas that includes calcifying, obstructive, and steroid-responsive forms. Use of the term chronic pancreatitis without qualification generally refers to calcifying chronic pancreatitis. Epidemiology is poorly defined, but incidence worldwide seems to be on the rise. Smoking, drinking alcohol, and genetic predisposition are the major risk factors for chronic calcifying pancreatitis. In this Seminar, we discuss the clinical features, diagnosis, and management of chronic calcifying pancreatitis, focusing on pain management, the role of endoscopic and surgical intervention, and the use of pancreatic enzyme-replacement therapy. Management of patients is often challenging and necessitates a multidisciplinary approach. PMID:26948434

  1. Veliparib and Topotecan With or Without Carboplatin in Treating Patients With Relapsed or Refractory Acute Leukemia, High-Risk Myelodysplasia, or Aggressive Myeloproliferative Disorders

    ClinicalTrials.gov

    2016-08-23

    Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndrome; Essential Thrombocythemia; Hematopoietic and Lymphoid Cell Neoplasm; Philadelphia Chromosome Negative, BCR-ABL1 Positive Chronic Myelogenous Leukemia; Polycythemia Vera; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Disease; Secondary Myelodysplastic Syndrome

  2. PD166326, a novel tyrosine kinase inhibitor, has greater antileukemic activity than imatinib mesylate in a murine model of chronic myeloid leukemia.

    PubMed

    Wolff, Nicholas C; Veach, Darren R; Tong, William P; Bornmann, William G; Clarkson, Bayard; Ilaria, Robert L

    2005-05-15

    Imatinib mesylate is highly effective in newly diagnosed chronic myeloid leukemia (CML), but BCR/ABL (breakpoint cluster region/abelson murine leukemia)-positive progenitors persist in most patients with CML treated with imatinib mesylate, indicating the need for novel therapeutic approaches. In this study, we have used the murine CML-like myeloproliferative disorder as a platform to characterize the pharmacokinetic, signal transduction, and antileukemic properties of PD166326, one of the most potent members of the pyridopyrimidine class of protein tyrosine kinase inhibitors. In mice with the CML-like disease, PD166326 rapidly inhibited Bcr/Abl kinase activity after a single oral dose and demonstrated marked antileukemic activity in vivo. Seventy percent of PD166326-treated mice achieved a white blood cell (WBC) count less than 20.0 x 10(9)/L (20,000/microL) at necropsy, compared with only 8% of imatinib mesylate-treated animals. Further, two thirds of PD166326-treated animals had complete resolution of splenomegaly, compared with none of the imatinib mesylate-treated animals. Consistent with its more potent antileukemic effect in vivo, PD166326 was also superior to imatinib mesylate in inhibiting the constitutive tyrosine phosphorylation of numerous leukemia-cell proteins, including the src family member Lyn. PD166326 also prolonged the survival of mice with imatinib mesylate-resistant CML induced by the Bcr/Abl mutants P210/H396P and P210/M351T. Altogether, these findings demonstrate the potential of more potent Bcr/Abl inhibitors to provide more effective antileukemic activity. Clinical development of PD166326 or a related analog may lead to more effective drugs for the treatment of de novo and imatinib mesylate-resistant CML.

  3. Chronic pancreatitis.

    PubMed

    Chari, S T; DiMagno, E P

    2000-09-01

    In the past year, there has been at least one important clinical paper that sheds light on the character and natural history of painful chronic pancreatitis, which has important clinical implications. In addition, several novel mutations have been described in the cationic trypsinogen gene in patients with hereditary pancreatitis. The mechanism by which these mutations cause pancreatic disease remains speculative. The diagnosis of early chronic pancreatitis is controversial. A novel noninvasive pancreatic function test (measurement of postprandial APOB-48) was reported but is unlikely to be a sensitive test of pancreatic function. Pancreatic fibrosis is frequently seen in alcoholics without chronic pancreatitis, and this makes it difficult to interpret the findings on endoscopic ultrasonogram. Recent studies highlight the difficulty in abolishing pancreatic steatorrhea. Recently fibrosing colonopathy in adult patients has been reported. Extracorporeal shockwave lithotripsy combined with endoscopic therapy failed to benefit patients with calcific chronic pancreatitis.

  4. Chronic Pain

    MedlinePlus

    ... adults. Common chronic pain complaints include headache, low back pain, cancer pain, arthritis pain, neurogenic pain (pain resulting ... Institute of Neurological Disorders and Stroke (NINDS). Low Back Pain Fact Sheet Back Pain information sheet compiled by ...

  5. Ear infection - chronic

    MedlinePlus

    Middle ear infection - chronic; Otitis media - chronic; Chronic otitis media; Chronic ear infection ... Chole RA. Chronic otitis media, mastoiditis, and petrositis. In: Flint PW, Haughey BH, Lund V, et al, eds. Cummings Otolaryngology: Head & Neck Surgery . 6th ed. ...

  6. Emerging Therapeutic Strategies for Targeting Chronic Myeloid Leukemia Stem Cells

    PubMed Central

    El Sabban, Maya; Mouteirik, Maha; Nasr, Rihab

    2013-01-01

    Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder. Current targeted therapies designed to inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein have made a significant breakthrough in the treatment of CML patients. However, CML remains a chronic disease that a patient must manage for life. Although tyrosine kinase inhibitors (TKI) therapy has completely transformed the prognosis of CML, it has made the therapeutic management more complex. The interruption of TKI treatment results in early disease progression because it does not eliminate quiescent CML stem cells which remain a potential reservoir for disease relapse. This highlights the need to develop new therapeutic strategies for CML to achieve a permanent cure, and to allow TKI interruption. This review summarizes recent research done on alternative targeted therapies with a particular focus on some important signaling pathways (such as Alox5, Hedgehog, Wnt/b-catenin, autophagy, and PML) that have the potential to target CML stem cells and potentially provide cure for CML. PMID:23935640

  7. Targeted treatment of chronic myeloid leukemia: role of imatinib

    PubMed Central

    Tamascar, Ila; Ramanarayanan, Jeyanthi

    2009-01-01

    Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by clonal expansion of pleuripotent hematopoetic stem cells. The incidence of CML is 1 to 2 cases per 100,000 people per year; in the Western Hemisphere, CML accounts for 15% of leukemias in adults. Discovery of the specific karyotypic abnormality of the Philadelphia (Ph) chromosome in the pathogenesis of CML has led to a better understanding of the disease and hence to an advancement of targeted therapeutics. Availability of imatinib as an accepted targeted therapy in newly diagnosed patients has changed the treatment paradigm in CML. The majority of CML patients in chronic phase achieve excellent and durable responses with standard-dose imatinib. Mechanisms of primary and secondary resistance to imatinib in CML have been extensively studied and newer tyrosine kinase inhibitors are now being evaluated for clinical use. It is important that at any time the CML treatment and response remain optimal and thus patients on imatinib require continuous monitoring for early detection of resistance. This review will discuss the treatment and guidelines for monitoring CML patients in the imatinib era. PMID:20616895

  8. Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents.

    PubMed

    Merlevede, Jane; Droin, Nathalie; Qin, Tingting; Meldi, Kristen; Yoshida, Kenichi; Morabito, Margot; Chautard, Emilie; Auboeuf, Didier; Fenaux, Pierre; Braun, Thorsten; Itzykson, Raphael; de Botton, Stéphane; Quesnel, Bruno; Commes, Thérèse; Jourdan, Eric; Vainchenker, William; Bernard, Olivier; Pata-Merci, Noemie; Solier, Stéphanie; Gayevskiy, Velimir; Dinger, Marcel E; Cowley, Mark J; Selimoglu-Buet, Dorothée; Meyer, Vincent; Artiguenave, François; Deleuze, Jean-François; Preudhomme, Claude; Stratton, Michael R; Alexandrov, Ludmil B; Padron, Eric; Ogawa, Seishi; Koscielny, Serge; Figueroa, Maria; Solary, Eric

    2016-01-01

    The cytidine analogues azacytidine and 5-aza-2'-deoxycytidine (decitabine) are commonly used to treat myelodysplastic syndromes, with or without a myeloproliferative component. It remains unclear whether the response to these hypomethylating agents results from a cytotoxic or an epigenetic effect. In this study, we address this question in chronic myelomonocytic leukaemia. We describe a comprehensive analysis of the mutational landscape of these tumours, combining whole-exome and whole-genome sequencing. We identify an average of 14±5 somatic mutations in coding sequences of sorted monocyte DNA and the signatures of three mutational processes. Serial sequencing demonstrates that the response to hypomethylating agents is associated with changes in DNA methylation and gene expression, without any decrease in the mutation allele burden, nor prevention of new genetic alteration occurence. Our findings indicate that cytosine analogues restore a balanced haematopoiesis without decreasing the size of the mutated clone, arguing for a predominantly epigenetic effect.

  9. Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents

    PubMed Central

    Merlevede, Jane; Droin, Nathalie; Qin, Tingting; Meldi, Kristen; Yoshida, Kenichi; Morabito, Margot; Chautard, Emilie; Auboeuf, Didier; Fenaux, Pierre; Braun, Thorsten; Itzykson, Raphael; de Botton, Stéphane; Quesnel, Bruno; Commes, Thérèse; Jourdan, Eric; Vainchenker, William; Bernard, Olivier; Pata-Merci, Noemie; Solier, Stéphanie; Gayevskiy, Velimir; Dinger, Marcel E.; Cowley, Mark J.; Selimoglu-Buet, Dorothée; Meyer, Vincent; Artiguenave, François; Deleuze, Jean-François; Preudhomme, Claude; Stratton, Michael R.; Alexandrov, Ludmil B.; Padron, Eric; Ogawa, Seishi; Koscielny, Serge; Figueroa, Maria; Solary, Eric

    2016-01-01

    The cytidine analogues azacytidine and 5-aza-2'-deoxycytidine (decitabine) are commonly used to treat myelodysplastic syndromes, with or without a myeloproliferative component. It remains unclear whether the response to these hypomethylating agents results from a cytotoxic or an epigenetic effect. In this study, we address this question in chronic myelomonocytic leukaemia. We describe a comprehensive analysis of the mutational landscape of these tumours, combining whole-exome and whole-genome sequencing. We identify an average of 14±5 somatic mutations in coding sequences of sorted monocyte DNA and the signatures of three mutational processes. Serial sequencing demonstrates that the response to hypomethylating agents is associated with changes in DNA methylation and gene expression, without any decrease in the mutation allele burden, nor prevention of new genetic alteration occurence. Our findings indicate that cytosine analogues restore a balanced haematopoiesis without decreasing the size of the mutated clone, arguing for a predominantly epigenetic effect. PMID:26908133

  10. Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents.

    PubMed

    Merlevede, Jane; Droin, Nathalie; Qin, Tingting; Meldi, Kristen; Yoshida, Kenichi; Morabito, Margot; Chautard, Emilie; Auboeuf, Didier; Fenaux, Pierre; Braun, Thorsten; Itzykson, Raphael; de Botton, Stéphane; Quesnel, Bruno; Commes, Thérèse; Jourdan, Eric; Vainchenker, William; Bernard, Olivier; Pata-Merci, Noemie; Solier, Stéphanie; Gayevskiy, Velimir; Dinger, Marcel E; Cowley, Mark J; Selimoglu-Buet, Dorothée; Meyer, Vincent; Artiguenave, François; Deleuze, Jean-François; Preudhomme, Claude; Stratton, Michael R; Alexandrov, Ludmil B; Padron, Eric; Ogawa, Seishi; Koscielny, Serge; Figueroa, Maria; Solary, Eric

    2016-01-01

    The cytidine analogues azacytidine and 5-aza-2'-deoxycytidine (decitabine) are commonly used to treat myelodysplastic syndromes, with or without a myeloproliferative component. It remains unclear whether the response to these hypomethylating agents results from a cytotoxic or an epigenetic effect. In this study, we address this question in chronic myelomonocytic leukaemia. We describe a comprehensive analysis of the mutational landscape of these tumours, combining whole-exome and whole-genome sequencing. We identify an average of 14±5 somatic mutations in coding sequences of sorted monocyte DNA and the signatures of three mutational processes. Serial sequencing demonstrates that the response to hypomethylating agents is associated with changes in DNA methylation and gene expression, without any decrease in the mutation allele burden, nor prevention of new genetic alteration occurence. Our findings indicate that cytosine analogues restore a balanced haematopoiesis without decreasing the size of the mutated clone, arguing for a predominantly epigenetic effect. PMID:26908133

  11. PPAR-gamma in overcoming kinase resistance in chronic myeloid leukemia.

    PubMed

    Yousefi, B; Shafiei-Irannejad, V; Azimi, A; Samadi, N; Zarghami, N

    2016-01-01

    Peroxisome proliferator-activated receptor gamma (PPARγ) plays key roles in regulating cellular differentiation, proliferation and apoptosis pathways. As such, they are considered promising targets for anticancer drug development, especially for breast cancer, multiple myeloma and hematologic malignancies. Chronic myeloid leukemia (CML) is a myeloproliferative disorder arising from an oncogenic Bcr-Abl tyrosine kinase. Inhibitors of this oncogene by small molecules such as imatinib are effective only in 75% of the patient's population. One of the potential strategies to overcome this resistance is to devise combination therapy protocols with other therapeutic agents including PPAR ligands. Since PPAR ligands are potentially interesting in different hematologic malignancies, this article will review the potential of PPAR ligands for use in CML treatment. PMID:27545215

  12. A highly specific q-RT-PCR assay to address the relevance of the JAK2WT and JAK2V617F expression levels and control genes in Ph-negative myeloproliferative neoplasms.

    PubMed

    Fantasia, Francesca; Di Capua, Emma Nora; Cenfra, Natalia; Pessina, Gloria; Mecarocci, Sergio; Rago, Angela; Cotroneo, Ettore; Busanello, Anna; Equitani, Francesco; Lo-Coco, Francesco; Nervi, Clara; Cimino, Giuseppe

    2014-04-01

    In Ph- myeloproliferative neoplasms, the quantification of the JAK2V617F transcripts may provide some advantages over the DNA allele burden determination. We developed a q-RT-PCR to assess the JAK2WT and JAK2V617F mRNA expression in 105 cases (23 donors, 13 secondary polycythemia, 22 polycythemia vera (PV), 38 essential thrombocythemia (ET), and 9 primary myelofibrosis (PMF)). Compared with the standard allele-specific oligonucleotide (ASO)-PCR technique, our assay showed a 100 % concordance rate detecting the JAK2V617F mutation in 22/22 PV (100 %), 29/38 (76.3 %) ET, and 5/9 (55.5 %) PMF cases, respectively. The sensitivity of the assay was 0.01 %. Comparing DNA and RNA samples, we found that the JAK2V617F mutational ratios were significantly higher at the RNA level both in PV (p = 0.005) and ET (p = 0.001) samples. In PV patients, JAK2WT expression levels positively correlated with the platelets (PLTs) (p = 0.003) whereas a trend to negative correlation was observed with the Hb levels (p = 0.051). JAK2V617F-positive cases showed the lowest JAK2WT and ABL1 mRNA expression levels. In all the samples, the expression pattern of beta-glucoronidase (GUSB) was more homogeneous than that of ABL1 or β2 microglobulin (B2M). Using GUSB as normalizator gene, a significant increase of the JAK2V617F mRNA levels was seen in two ET patients at time of progression to PV. In conclusion, the proposed q-RT-PCR is a sensitive and accurate method to quantify the JAK2 mutational status that can also show clinical correlations suggesting the impact of the residual amount of the JAK2WT allele on the Ph- MPN disease phenotype. Our observations also preclude the use of ABL1 as a housekeeping gene for these neoplasms.

  13. Chronic urticaria.

    PubMed Central

    Leznoff, A.

    1998-01-01

    OBJECTIVE: To review the pathophysiology of chronic urticaria in light of recent evidence for it being an autoimmune disease, and to recommend appropriate management. QUALITY OF EVIDENCE: An extensive literature review was supplemented with a MEDLINE search. Articles from easily available journals were preferred. These consisted of the most recent basic articles on autoimmunity in relation to chronic urticaria and a selection of previous articles on pathophysiology, which illustrate consistencies with recent evidence. The investigation and management protocol is supported by original and relevant literature. MAIN FINDINGS: The histopathology and immunohistology of chronic urticaria and certain clinical studies were a prelude to definitive evidence that most instances of chronic urticaria are autoimmune. Although allergic and other causes are uncommon, these must be sought because identification can lead to cure or specific treatment. Management of the much more common autoimmune urticaria is based on principles derived from the demonstrated pathogenesis and on results of published clinical trials. CONCLUSIONS: In most instances, chronic urticaria is an autoimmune disease, but uncommon allergic or other causes must be considered. PMID:9805172

  14. Chronic pain.

    PubMed

    Russo, C M; Brose, W G

    1998-01-01

    Chronic pain is an emotional experience and is defined as pain lasting greater than six months. It is important to understand the neurophysiology of pain in order to treat it. Nociceptors in the periphery travel to the substantia gelatinosa of the spinal cord while secondary and tertiary afferents transmit information from the dorsal horn to the brain. Modification of pain information may take place in these ascending pathways or in descending pathways. Treatment of chronic pain is most successful when it is approached in a multidisciplinary fashion with the focus not only on treatment of underlying etiology, but also on the secondary impacts of pain on the patient's life. The management of chronic pain requires special expertise. Most of the experts in chronic pain assessment and management organize themselves into pain treatment centers. These centers vary widely in their approach to the problem. The most sophisticated is a multidisciplinary center that is university-based and includes teaching and research. Treatment of chronic pain includes a variety of medications, psychological support, and rehabilitation. Multidisciplinary pain management is also an integral part of the palliative care and hospice concept used to treat cancer pain.

  15. Nilotinib and Imatinib Mesylate After Donor Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia or Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2014-12-09

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Chronic Phase Chronic Myelogenous Leukemia; Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia; Philadelphia Chromosome Positive Childhood Precursor Acute Lymphoblastic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Relapsing Chronic Myelogenous Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

  16. Nursing Positions

    MedlinePlus

    ... Story" 5 Things to Know About Zika & Pregnancy Nursing Positions KidsHealth > For Parents > Nursing Positions Print A ... and actually needs to feed. Getting Comfortable With Breastfeeding Nursing can be one of the most challenging ...

  17. Positive Psychology

    ERIC Educational Resources Information Center

    Peterson, Christopher

    2009-01-01

    Positive psychology is a deliberate correction to the focus of psychology on problems. Positive psychology does not deny the difficulties that people may experience but does suggest that sole attention to disorder leads to an incomplete view of the human condition. Positive psychologists concern themselves with four major topics: (1) positive…

  18. [Chronic cough].

    PubMed

    Schafroth Török, Salome

    2013-09-18

    In non-smokers without intake of an ACE-inhibitor, the three most common causes of chronic cough are eosinophilic airways disease (asthma or eosinophilic bronchitis), Upper-airway-cough-syndrome (UACS) and Gastro-esophageal-reflux desease (GERD). In smokers, chronic bronchitis and COPD are common causes as well. In patients with a normal chest X-ray and lack of information on a less frequent cause in history and physical examination, it is recommended therefore to routinely look for these diseases and/or to treat them empirically. PMID:24025176

  19. Chronic Cough.

    PubMed

    Pacheco, Adalberto; de Diego, Alfredo; Domingo, Christian; Lamas, Adelaida; Gutierrez, Raimundo; Naberan, Karlos; Garrigues, Vicente; López Vime, Raquel

    2015-11-01

    Chronic cough (CC), or cough lasting more than 8 weeks, has attracted increased attention in recent years following advances that have changed opinions on the prevailing diagnostic and therapeutic triad in place since the 1970s. Suboptimal treatment results in two thirds of all cases, together with a new notion of CC as a peripheral and central hypersensitivity syndrome similar to chronic pain, have changed the approach to this common complaint in routine clinical practice. The peripheral receptors involved in CC are still a part of the diagnostic triad. However, both convergence of stimuli and central nervous system hypersensitivity are key factors in treatment success.

  20. Chronic Cough.

    PubMed

    Pacheco, Adalberto; de Diego, Alfredo; Domingo, Christian; Lamas, Adelaida; Gutierrez, Raimundo; Naberan, Karlos; Garrigues, Vicente; López Vime, Raquel

    2015-11-01

    Chronic cough (CC), or cough lasting more than 8 weeks, has attracted increased attention in recent years following advances that have changed opinions on the prevailing diagnostic and therapeutic triad in place since the 1970s. Suboptimal treatment results in two thirds of all cases, together with a new notion of CC as a peripheral and central hypersensitivity syndrome similar to chronic pain, have changed the approach to this common complaint in routine clinical practice. The peripheral receptors involved in CC are still a part of the diagnostic triad. However, both convergence of stimuli and central nervous system hypersensitivity are key factors in treatment success. PMID:26165783

  1. Total-Body Irradiation With or Without Fludarabine Phosphate Followed By Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer

    ClinicalTrials.gov

    2016-02-02

    Acute Lymphoblastic Leukemia in Remission; Acute Myeloid Leukemia in Remission; Aggressive Non-Hodgkin Lymphoma; Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Diffuse Large B-Cell Lymphoma; Hematopoietic and Lymphoid Cell Neoplasm; Indolent Non-Hodgkin Lymphoma; Mantle Cell Lymphoma; Myelodysplastic/Myeloproliferative Neoplasm; Plasma Cell Myeloma; Refractory Chronic Lymphocytic Leukemia; Refractory Hodgkin Lymphoma; Waldenstrom Macroglobulinemia

  2. Positional plagiocephaly

    PubMed Central

    Cummings, Carl

    2011-01-01

    Cranial asymmetry occurring as a result of forces that deform skull shape in the supine position is known as deformational plagiocephaly. The risk of plagiocephaly may be modified by positioning the baby on alternate days with the head to the right or the left side, and by increasing time spent in the prone position during awake periods. When deformational plagiocephaly is already present, physiotherapy (including positioning equivalent to the preventive positioning, and exercises as needed for torticollis and positional preference) has been shown to be superior to counselling about preventive positioning only. Helmet therapy (moulding therapy) to reduce skull asymmetry has some drawbacks: it is expensive, significantly inconvenient due to the long hours of use per day and associated with skin complications. There is evidence that helmet therapy may increase the initial rate of improvement of asymmetry, but there is no evidence that it improves the final outcome for patients with moderate or severe plagiocephaly. PMID:23024590

  3. Chronic Bronchitis

    MedlinePlus

    ... risk for emphysema or chronic obstructive pulmonary disease (COPD)? What medicines will help relieve my symptoms? What lifestyle changes should I make at home to help relieve my symptoms? Is it safe for me to exercise? What kind of exercise should I do? What ...

  4. Chronic gastritis

    PubMed Central

    Sipponen, Pentti; Maaroos, Heidi-Ingrid

    2015-01-01

    Abstract Prevalence of chronic gastritis has markedly declined in developed populations during the past decades. However, chronic gastritis is still one of the most common serious pandemic infections with such severe killing sequelae as peptic ulcer or gastric cancer. Globally, on average, even more than half of people may have a chronic gastritis at present. Helicobacter pylori infection in childhood is the main cause of chronic gastritis, which microbial origin is the key for the understanding of the bizarre epidemiology and course of the disease. A life-long and aggressive inflammation in gastritis results in destruction (atrophic gastritis) of stomach mucosa with time (years and decades). The progressive worsening of atrophic gastritis results subsequently in dysfunctions of stomach mucosa. Atrophic gastritis will finally end up in a permanently acid-free stomach in the most extreme cases. Severe atrophic gastritis and acid-free stomach are the highest independent risk conditions for gastric cancer known so far. In addition to the risks of malignancy and peptic ulcer, acid-free stomach and severe forms of atrophic gastritis may associate with failures in absorption of essential vitamins, like vitamin B12, micronutrients (like iron, calcium, magnesium and zinc), diet and medicines. PMID:25901896

  5. Satellite positioning

    NASA Technical Reports Server (NTRS)

    Colombo, Oscar L.; Watkins, Michael M.

    1991-01-01

    Developments in satellite positioning techniques and their applications are reviewed on the basis of the theoretical and practical work published by U.S. researchers in 1987-1990. Current techniques are classified into two main categories: satellite laser tracking and radio tracking. Particular attention is given to the Geoscience Laser Ranging System, the Lunar Laser Ranging concept; GPS ephemerides determination, fiducial networks, and reference frame; static GPS positioning; and kinematic GPS positioning.

  6. Chronic motor tic disorder

    MedlinePlus

    Chronic vocal tic disorder; Tic - chronic motor tic disorder ... Chronic motor tic disorder is more common than Tourette syndrome . Chronic tics may be forms of Tourette syndrome. Tics usually start ...

  7. Chronic obstructive pulmonary disease

    MedlinePlus

    COPD; Chronic obstructive airways disease; Chronic obstructive lung disease; Chronic bronchitis; Emphysema; Bronchitis - chronic ... can do to relieve symptoms and keep the disease from getting worse. If you smoke, now is ...

  8. Chronic pain - resources

    MedlinePlus

    Pain - resources; Resources - chronic pain ... The following organizations are good resources for information on chronic pain: American Chronic Pain Association -- www.theacpa.org National Fibromyalgia and Chronic Pain Association -- www.fmcpaware.org ...

  9. Positive Psychotherapy

    ERIC Educational Resources Information Center

    Seligman, Martin E. P.; Rashid, Tayyab; Parks, Acacia C.

    2006-01-01

    Positive psychotherapy (PPT) contrasts with standard interventions for depression by increasing positive emotion, engagement, and meaning rather than directly targeting depressive symptoms. The authors have tested the effects of these interventions in a variety of settings. In informal student and clinical settings, people not uncommonly reported…

  10. Establishing optimal quantitative-polymerase chain reaction assays for routine diagnosis and tracking of minimal residual disease in JAK2-V617F-associated myeloproliferative neoplasms: a joint European LeukemiaNet/MPN&MPNr-EuroNet (COST action BM0902) study

    PubMed Central

    Jovanovic, J V; Ivey, A; Vannucchi, A M; Lippert, E; Oppliger Leibundgut, E; Cassinat, B; Pallisgaard, N; Maroc, N; Hermouet, S; Nickless, G; Guglielmelli, P; van der Reijden, B A; Jansen, J H; Alpermann, T; Schnittger, S; Bench, A; Tobal, K; Wilkins, B; Cuthill, K; McLornan, D; Yeoman, K; Akiki, S; Bryon, J; Jeffries, S; Jones, A; Percy, M J; Schwemmers, S; Gruender, A; Kelley, T W; Reading, S; Pancrazzi, A; McMullin, M F; Pahl, H L; Cross, N C P; Harrison, C N; Prchal, J T; Chomienne, C; Kiladjian, J J; Barbui, T; Grimwade, D

    2013-01-01

    Reliable detection of JAK2-V617F is critical for accurate diagnosis of myeloproliferative neoplasms (MPNs); in addition, sensitive mutation-specific assays can be applied to monitor disease response. However, there has been no consistent approach to JAK2-V617F detection, with assays varying markedly in performance, affecting clinical utility. Therefore, we established a network of 12 laboratories from seven countries to systematically evaluate nine different DNA-based quantitative PCR (qPCR) assays, including those in widespread clinical use. Seven quality control rounds involving over 21 500 qPCR reactions were undertaken using centrally distributed cell line dilutions and plasmid controls. The two best-performing assays were tested on normal blood samples (n=100) to evaluate assay specificity, followed by analysis of serial samples from 28 patients transplanted for JAK2-V617F-positive disease. The most sensitive assay, which performed consistently across a range of qPCR platforms, predicted outcome following transplant, with the mutant allele detected a median of 22 weeks (range 6–85 weeks) before relapse. Four of seven patients achieved molecular remission following donor lymphocyte infusion, indicative of a graft vs MPN effect. This study has established a robust, reliable assay for sensitive JAK2-V617F detection, suitable for assessing response in clinical trials, predicting outcome and guiding management of patients undergoing allogeneic transplant. PMID:23860450

  11. Establishing optimal quantitative-polymerase chain reaction assays for routine diagnosis and tracking of minimal residual disease in JAK2-V617F-associated myeloproliferative neoplasms: a joint European LeukemiaNet/MPN&MPNr-EuroNet (COST action BM0902) study.

    PubMed

    Jovanovic, J V; Ivey, A; Vannucchi, A M; Lippert, E; Oppliger Leibundgut, E; Cassinat, B; Pallisgaard, N; Maroc, N; Hermouet, S; Nickless, G; Guglielmelli, P; van der Reijden, B A; Jansen, J H; Alpermann, T; Schnittger, S; Bench, A; Tobal, K; Wilkins, B; Cuthill, K; McLornan, D; Yeoman, K; Akiki, S; Bryon, J; Jeffries, S; Jones, A; Percy, M J; Schwemmers, S; Gruender, A; Kelley, T W; Reading, S; Pancrazzi, A; McMullin, M F; Pahl, H L; Cross, N C P; Harrison, C N; Prchal, J T; Chomienne, C; Kiladjian, J J; Barbui, T; Grimwade, D

    2013-10-01

    Reliable detection of JAK2-V617F is critical for accurate diagnosis of myeloproliferative neoplasms (MPNs); in addition, sensitive mutation-specific assays can be applied to monitor disease response. However, there has been no consistent approach to JAK2-V617F detection, with assays varying markedly in performance, affecting clinical utility. Therefore, we established a network of 12 laboratories from seven countries to systematically evaluate nine different DNA-based quantitative PCR (qPCR) assays, including those in widespread clinical use. Seven quality control rounds involving over 21,500 qPCR reactions were undertaken using centrally distributed cell line dilutions and plasmid controls. The two best-performing assays were tested on normal blood samples (n=100) to evaluate assay specificity, followed by analysis of serial samples from 28 patients transplanted for JAK2-V617F-positive disease. The most sensitive assay, which performed consistently across a range of qPCR platforms, predicted outcome following transplant, with the mutant allele detected a median of 22 weeks (range 6-85 weeks) before relapse. Four of seven patients achieved molecular remission following donor lymphocyte infusion, indicative of a graft vs MPN effect. This study has established a robust, reliable assay for sensitive JAK2-V617F detection, suitable for assessing response in clinical trials, predicting outcome and guiding management of patients undergoing allogeneic transplant. PMID:23860450

  12. Positioning Agility

    NASA Astrophysics Data System (ADS)

    Oza, Nilay; Abrahamsson, Pekka; Conboy, Kieran

    Agile methods are increasingly adopted by European companies. Academics too are conducting numerous studies on different tenets of agile methods. Companies often feel proud in marketing themselves as ‘agile’. However, the true notion of ‘being agile’ seems to have been overlooked due to lack of positioning of oneself for agility. This raises a call for more research and interactions between academia and the industry. The proposed workshop refers to this call. It will be highly relevant to participants, interested in positioning their company’s agility from organizational, group or project perspectives. The positioning of agility will help companies to better align their agile practices with stakeholder values. Results of the workshop will be shared across participants and they will also have opportunity to continue their work on agile positioning in their companies. At broader level, the work done in this workshop will contribute towards developing Agile Positioning System.

  13. Chronic urticaria.

    PubMed Central

    Burrall, B. A.; Halpern, G. M.; Huntley, A. C.

    1990-01-01

    Urticaria affects 15% to 20% of the population once or more during a lifetime. Chronic urticaria is a frequent recurrent eruption over a period greater than 6 weeks; the cause remains a mystery in more than 75% of cases. Urticaria and angioedema may be produced by immunologic or nonimmunologic means. Urticarial vasculitis, contact urticaria, mastocytosis, physical urticarias, dermatographism, cholinergic urticaria, localized heat urticaria, cold urticaria, aquagenic urticaria, and vibratory angioedema all require specific evaluation and treatment. Chronic idiopathic urticaria is usually controlled by antihistamines; depending on the circadian rhythm of the eruption, sedative or nonsedative antihistamines are prescribed. Some patients will require a combination of H1 and H2 antagonists, or even parenteral corticosteroids. PMID:1970697

  14. Position statement on cannabis.

    PubMed

    Stein For The Executive Committee Of The Central Drug Authority, Dan Joseph

    2016-05-16

    There is an ongoing national debate around cannabis policy. This brief position statement by the Executive Committee of the Central Drug Authorityoutlines some of the factors that have contributed to this debate, delineates reduction strategies, summarises the harms and benefits ofmarijuana, and provides recommendations. These recommendations emphasise an integrated and evidence-based approach, the need forresources to implement harm reduction strategies against continued and chronic use of alcohol and cannabis, and the potential value of afocus on decriminalisation rather than the legalisation of cannabis.

  15. Positive Proof.

    ERIC Educational Resources Information Center

    Auty, Geoffrey

    1988-01-01

    Presents experiments which show that in electrostatics there are logical reasons for describing charged materials as positive or negative. Indicates that static and current electricity are not separate areas of physics. Diagrams of experiments and circuits are included. (RT)

  16. Vaccine Therapy in Reducing the Frequency of Cytomegalovirus Events in Patients With Hematologic Malignancies Undergoing Donor Stem Cell Transplant

    ClinicalTrials.gov

    2016-08-02

    Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Hodgkin Lymphoma; Adult Non-Hodgkin Lymphoma; Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Cytomegaloviral Infection; Hematopoietic and Lymphoid Cell Neoplasm; HLA-A*0201 Positive Cells Present; Myelodysplastic Syndrome; Adult Lymphoblastic Lymphoma; Chronic Lymphocytic Leukemia; Myelofibrosis; Myeloproliferative Neoplasm

  17. Therapeutic benefit of decitabine, a hypomethylating agent, in patients with high-risk primary myelofibrosis and myeloproliferative neoplasm in accelerated or blastic/acute myeloid leukemia phase.

    PubMed

    Badar, Talha; Kantarjian, Hagop M; Ravandi, Farhad; Jabbour, Elias; Borthakur, Gautam; Cortes, Jorge E; Pemmaraju, Naveen; Pierce, Sherry R; Newberry, Kate J; Daver, Naval; Verstovsek, Srdan

    2015-09-01

    Myeloproliferative neoplasm (MPN) transformed to acute myeloid leukemia (MPN-AML), MPN in accelerated phase (MPN-AP), and high-risk primary myelofibrosis (PMF) are associated with a poor response to therapy and very short survival. Several reports have suggested clinical activity of hypomethylating agents in these patients. We conducted a retrospective study of 21 patients with MPN-AML, 13 with MPN-AP and 11 with DIPSS-plus high-risk PMF treated with decitabine at our institution over the last 7 years and evaluated their clinical outcomes. Six patients (29%) with MPN-AML responded to decitabine (3 CR, 2 CRi, and 1 PR); median response duration was 7 months. The median overall survival (OS) was significantly higher in those who responded (10.5 vs 4 months). Among patients with MPN-AP, 8 patients (62%) benefited; the median response duration was 6.5 months. The median OS was 11.8 months in responders vs 4.7 months in non-responders. Among patients with DIPSS-plus high-risk PMF, 9 (82%) benefited; the median response duration was 9 months. The median OS was 32 months in responders vs 16.3 months in non-responders. Decitabine is a viable therapeutic option for patients with MPN-AML, MP-AP and high-risk PMF. Prospective clinical studies combining decitabine with other clinically active agents are needed to improve overall outcome.

  18. Therapeutic benefit of decitabine, a hypomethylating agent, in patients with high-risk primary myelofibrosis and myeloproliferative neoplasm in accelerated or blastic/acute myeloid leukemia phase

    PubMed Central

    Badar, Talha; Kantarjian, Hagop M.; Ravandi, Farhad; Jabbour, Elias; Borthakur, Gautam; Cortes, Jorge E.; Pemmaraju, Naveen; Pierce, Sherry R.; Newberry, Kate J.; Daver, Naval; Verstovsek, Srdan

    2015-01-01

    Myeloproliferative neoplasm (MPN) transformed to acute myeloid leukemia (MPN-AML), MPN in accelerated phase (MPN-AP), and high-risk primary myelofibrosis (PMF) are associated with a poor response to therapy and very short survival. Several reports have suggested clinical activity of hypomethylating agents in these patients. We conducted a retrospective study of 21 patients with MPN-AML, 13 with MPN-AP and 11 with DIPSS-plus high-risk PMF treated with decitabine at our institution over the last 7 years and evaluated their clinical outcomes. Six patients (29%) with MPN-AML responded to decitabine (3 CR, 2 CRi, and 1 PR); median response duration was 7 months. The median overall survival (OS) was significantly higher in those who responded (10.5 vs 4 months). Among patients with MPN-AP, 8 patients (62%) benefited; median response duration was 6.5 months. The median OS was 11.8 months in responders vs 4.7 months in non-responders. Among patients with DIPSS-plus high-risk PMF, 9 (82%) benefited; median response duration was 9 months. The median OS was 32 months in responders vs 16.3 months in non-responders. Decitabine is a viable therapeutic option for patients with MPN-AML, MP-AP and high-risk PMF. Prospective clinical studies combining decitabine with other clinically active agents are needed to improve overall outcome. PMID:26183878

  19. Acquired copy-neutral loss of heterozygosity of chromosome 1p as a molecular event associated with marrow fibrosis in MPL-mutated myeloproliferative neoplasms

    PubMed Central

    Pietra, Daniela; Guglielmelli, Paola; Bordoni, Roberta; Casetti, Ilaria; Milanesi, Chiara; Sant’Antonio, Emanuela; Ferretti, Virginia; Pancrazzi, Alessandro; Rotunno, Giada; Severgnini, Marco; Pietrelli, Alessandro; Astori, Cesare; Fugazza, Elena; Pascutto, Cristiana; Boveri, Emanuela; Passamonti, Francesco; De Bellis, Gianluca; Vannucchi, Alessandro; Cazzola, Mario

    2013-01-01

    We studied mutations of MPL exon 10 in patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF), first investigating a cohort of 892 consecutive patients. MPL mutation scanning was performed on granulocyte genomic DNA by using a high-resolution melt assay, and the mutant allele burden was evaluated by using deep sequencing. Somatic mutations of MPL, all but one involving codon W515, were detected in 26/661 (4%) patients with ET, 10/187 (5%) with PMF, and 7/44 (16%) patients with post-ET myelofibrosis. Comparison of JAK2 (V617F)–mutated and MPL-mutated patients showed only minor phenotypic differences. In an extended group of 62 MPL-mutated patients, the granulocyte mutant allele burden ranged from 1% to 95% and was significantly higher in patients with PMF or post-ET myelofibrosis compared with those with ET. Patients with higher mutation burdens had evidence of acquired copy-neutral loss of heterozygosity (CN-LOH) of chromosome 1p in granulocytes, consistent with a transition from heterozygosity to homozygosity for the MPL mutation in clonal cells. A significant association was found between MPL-mutant allele burden greater than 50% and marrow fibrosis. These observations suggest that acquired CN-LOH of chromosome 1p involving the MPL location may represent a molecular mechanism of fibrotic transformation in MPL-mutated myeloproliferative neoplasms. PMID:23575445

  20. Histone deacetylases inhibitor sodium butyrate inhibits JAK2/STAT signaling through upregulation of SOCS1 and SOCS3 mediated by HDAC8 inhibition in myeloproliferative neoplasms.

    PubMed

    Gao, Shen-meng; Chen, Chi-qi; Wang, Lu-yao; Hong, Li-li; Wu, Jian-bo; Dong, Pei-hong; Yu, Fu-jun

    2013-03-01

    Constitutive activation of Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) signaling has an important role in the oncogenesis of myeloproliferative neoplasms (MPNs) and leukemia. Histone deacetylases (HDACs) inhibitors have been reported to possess anticancer activity through different mechanisms. However, whether HDACs inhibitors suppress JAK2/STAT signaling in MPNs is still unknown. In this study, we show that the HDAC inhibitor sodium butyrate (SB) inhibited JAK2/STAT signaling and increased the expression of suppressors of cytokine signaling 1 (SOCS1) and SOCS3, both of which are the potent feedback inhibitors of JAK2/STAT signaling. SB upregulated the expression of SOCS1 and SOCS3 by triggering the promoter-associated histone acetylation of SOCS1 and SOCS3 in K562 and HEL cell lines. Importantly, we found that upon knockdown of each class I HDACs, only knockdown of HDAC8 resulted in the increased expression of SOCS1 and SOCS3. Moreover, overexpression of SOCS1 and SOCS3 significantly inhibited cell growth and suppressed JAK2/STAT signaling in K562 and HEL cells. Furthermore, SB increased the transcript levels of SOCS1 and SOCS3 and inhibited the clonogenic activity of hematopoietic progenitors from patients with MPNs. Taken together, these data establish a new anticancer mechanism that SB inhibits JAK2/STAT signaling through HDAC8-mediated upregulation of SOCS1 and SOCS3. Thus, HDACs inhibitors may have therapeutic potential for the treatment of MPNs.

  1. Uses and abuses of JAK2 and MPL mutation tests in myeloproliferative neoplasms a paper from the 2010 William Beaumont hospital symposium on molecular pathology.

    PubMed

    Tefferi, Ayalew; Noel, Pierre; Hanson, Curtis A

    2011-09-01

    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.

  2. Givinostat and hydroxyurea synergize in vitro to induce apoptosis of cells from JAK2(V617F) myeloproliferative neoplasm patients.

    PubMed

    Amaru Calzada, Ariel; Pedrini, Olga; Finazzi, Guido; Leoni, Flavio; Mascagni, Paolo; Introna, Martino; Rambaldi, Alessandro; Golay, Josée

    2013-03-01

    We investigated whether clinically achievable concentrations of the histone deacetylase (HDAC) inhibitors givinostat and hydroxyurea induce synergistic cytotoxicity in Jak2(V617F) cells in vitro and through which possible mechanism. Givinostat and hydroxyurea at low doses potentiated the pro-apoptotic effects of each other in the Jak2(V617F) HEL and UKE1 cell lines. Givinostat induced 6.8%-20.8% and hydroxyurea (HU) 20.4%-42.4% cell death alone and 35.8%-75.3% in combination. The effect was statistically significant using the median effect Chou-Talalay method, resulting in a combination index less than 1, indicating synergy. Givinostat alone induced cell cycle arrest of the cell lines in G0/G1 and hydroxyurea in S phase, whereas both drugs together led to a G1 block. At the molecular level, hydroxyurea counteracted the induction of p21CDKN1A by Givinostat and potentiated caspase 3 activation, explaining at least in part the increased apoptosis observed in presence of both compounds. We also verified the effect of the same drugs in colony assays of freshly isolated Jak2(V617F) polycythemia vera cells. In this case, low doses of the compounds were additive to each other. These results suggest that combined treatment with givinostat and hydroxyurea is a potential strategy for the management of Jak2(V617F) myeloproliferative neoplasms. PMID:23111067

  3. Rapid Molecular Profiling of Myeloproliferative Neoplasms Using Targeted Exon Resequencing of 86 Genes Involved in JAK-STAT Signaling and Epigenetic Regulation.

    PubMed

    Magor, Graham W; Tallack, Michael R; Klose, Nathan M; Taylor, Debra; Korbie, Darren; Mollee, Peter; Trau, Matt; Perkins, Andrew C

    2016-09-01

    Myeloproliferative neoplasms (MPNs) are a heterogeneous group of blood disorders characterized by excess production of mature blood cells and an increased risk of late transformation to acute myeloid leukemia or primary myelofibrosis. Approximately 15% of MPN cases do not carry mutations in JAK2, CALR, or MPL and are thus often referred to as triple-negative cases. These are caused by a diverse set of rare mutations in cytokine receptors, JAK-STAT signaling pathway components, or epigenetic modifiers. In addition, some cases diagnosed as MPN are reactive rather than clonal disorders, so a negative result from a genetic screen can be informative. To obtain a comprehensive rapid molecular diagnosis for most MPNs, we developed an assay to detect genetic mutations (single nucleotide variants and/or small insertions/deletions) in 86 genes using targeted exon resequencing (AmpliSeq) and a bench-top semiconductor machine (Ion Torrent Personal Genome Machine). Our assay reliably detects well characterized mutations in JAK2, CALR, and MPL, but also rarer mutations in ASXL1, TET2, SH2B3, and other genes. Some of these mutations are novel. We find multiple mutations in advanced cases, suggesting co-operation between Janus kinase-STAT pathway mutations and epigenetic mutations in disease progression. This assay can be used to follow molecular progression, clonal heterogeneity, and drug resistance in MPNs. PMID:27449473

  4. Myeloproliferative Neoplasm or Reactive Process? A Rare Case of Acute Myeloid Leukemia and Transient Posttreatment Megakaryocytic Hyperplasia with JAK-2 Mutation

    PubMed Central

    Wang, Steven; Zhou, Guangde; Heintzelman, Rebecca

    2016-01-01

    Myeloproliferative neoplasms (MPNs) are hematopoietic malignancies characterized by unchecked proliferation of differentiated myeloid cells. The most common BCR-ABL1-negative MPNs are polycythemia vera, essential thrombocythemia, and primary myelofibrosis. The discovery of JAK2 V617F mutation has improved our understanding of the molecular basis of MPN. The high frequency of JAK2 mutation in MPN makes JAK2 mutation testing an essential diagnostic tool and potential therapeutic target for MPN. Here, we present a rare case of a 34-year-old patient who was initially diagnosed with acute myeloid leukemia (AML) with mutated NPM1. After chemotherapy treatment followed by granulocyte colony stimulating factor administration, the patient achieved complete remission of AML. However, the bone marrow showed hypercellularity with granulocytic hyperplasia, markedly increased atypical megakaryocytes (50.2/HPF) with focal clustering, and reticulin fibrosis (3/4). JAK2 V617F mutation was also detected. Considering the possibility of AML transformed from a previous undiagnosed MPN, patient underwent peripheral blood allogenic stem cell transplant. This case illustrates the diagnostic challenges of firmly establishing a diagnosis between similar, but distinct, disease entities and an accurate clinicopathological differentiation is crucial. PMID:27752371

  5. The 'WS motif' common to v-mpl and members of the cytokine receptor superfamily is dispensable for myeloproliferative leukemia virus pathogenicity.

    PubMed

    Bénit, L; Charon, M; Cocault, L; Wendling, F; Gisselbrecht, S

    1993-03-01

    Several motifs are conserved in the extracellular domain of the cloned chains of the recently described cytokine receptor superfamily. One of them, usually close to the transmembrane region, is the 'WS motif'. Its function remains unknown, but it has been recently shown that the integrity of this motif is essential for interleukin 2 receptor beta-chain and erythropoietin receptor activity [Miyazaki, T., Maruyama, M., Yamada, G., Hatakeyama, M. & Taniguchi, T. (1991). EMBO J., 10, 3191-3197; Watowich, S.S., Yoshimura, A., Longmore, G.D., Hilton, D.J., Hoshimura, Y. & Lodish, H.R. (1992). Proc. Natl. Acad. Sci. USA, 89, 2140-2144]. This WS motif is present in the v-mpl oncogene, which has been transduced in the myeloproliferative leukemia virus (MPLV). v-mpl encodes a truncated transmembrane protein that belongs to this growth factor receptor family. We demonstrate that determinants of MPLV pathogenesis are encoded by the env-mpl fusion gene and that the complete deletion of the WS motif does not abolish MPLV oncogenic properties. PMID:8382360

  6. Distinct effects of concomitant Jak2V617F expression and Tet2 loss in mice promote disease progression in myeloproliferative neoplasms

    PubMed Central

    Chen, Edwin; Schneider, Rebekka K.; Breyfogle, Lawrence J.; Rosen, Emily A.; Poveromo, Luke; Elf, Shannon; Ko, Amy; Brumme, Kristina; Levine, Ross; Ebert, Benjamin L.

    2015-01-01

    Signaling mutations (eg, JAK2V617F) and mutations in genes involved in epigenetic regulation (eg, TET2) are the most common cooccurring classes of mutations in myeloproliferative neoplasms (MPNs). Clinical correlative studies have demonstrated that TET2 mutations are enriched in more advanced phases of MPNs such as myelofibrosis and leukemic transformation, suggesting that they may cooperate with JAK2V617F to promote disease progression. To dissect the effects of concomitant Jak2V617F expression and Tet2 loss within distinct hematopoietic compartments in vivo, we generated Jak2V617F/Tet2 compound mutant genetic mice. We found that the combination of Jak2V617F expression and Tet2 loss resulted in a more florid MPN phenotype than that seen with either allele alone. Concordant with this, we found that Tet2 deletion conferred a strong functional competitive advantage to Jak2V617F-mutant hematopoietic stem cells (HSCs). Transcriptional profiling revealed that both Jak2V617F expression and Tet2 loss were associated with distinct and nonoverlapping gene expression signatures within the HSC compartment. In aggregate, our findings indicate that Tet2 loss drives clonal dominance in HSCs, and Jak2V617F expression causes expansion of downstream precursor cell populations, resulting in disease progression through combinatorial effects. This work provides insight into the functional consequences of JAK2V617F-TET2 comutation in MPNs, particularly as it pertains to HSCs. PMID:25281607

  7. Co-targeting the PI3K/mTOR and JAK2 signalling pathways produces synergistic activity against myeloproliferative neoplasms

    PubMed Central

    Bartalucci, Niccolò; Tozzi, Lorenzo; Bogani, Costanza; Martinelli, Serena; Rotunno, Giada; Villeval, Jean-Luc; Vannucchi, Alessandro M

    2013-01-01

    Aberrant JAK2 signalling plays a central role in myeloproliferative neoplasms (MPN). JAK2 inhibitors have proven to be clinically efficacious, however, they are not mutation-specific and competent enough to suppress neoplastic clonal haematopoiesis. We hypothesized that, by simultaneously targeting multiple activated signalling pathways, MPN could be more effectively treated. To this end we investigated the efficacy of BEZ235, a dual PI3K/mTOR inhibitor, alone and in combination with the JAK1/JAK2 inhibitor ruxolitinib, in different preclinical models of MPN. Single-agent BEZ235 inhibited the proliferation and induced cell cycle arrest and apoptosis of mouse and human JAK2V617F mutated cell lines at concentrations significantly lower than those required to inhibit the wild-type counterpart, and preferentially prevented colony formation from JAK2V617F knock-in mice and patients' progenitor cells compared with normal ones. Co-treatment of BEZ235 and ruxolitinib produced significant synergism in all these in-vitro models. Co-treatment was also more effective than single drugs in reducing the extent of disease and prolonging survival of immunodeficient mice injected with JAK2V617F-mutated Ba/F3-EPOR cells and in reducing spleen size, decreasing reticulocyte count and improving spleen histopathology in conditional JAK2V617F knock-in mice. In conclusion, combined inhibition of PI3K/mTOR and JAK2 signalling may represent a novel therapeutic strategy in MPN. PMID:24237791

  8. JAK2 p.V617F detection and allele burden measurement in peripheral blood and bone marrow aspirates in patients with myeloproliferative neoplasms

    PubMed Central

    Takahashi, Koichi; Patel, Keyur P.; Kantarjian, Hagop; Luthra, Rajyalakshmi; Pierce, Sherry; Cortes, Jorge

    2013-01-01

    Detection of the JAK2 p.V617F mutation and measurement of its allele burden can be performed using both peripheral blood (PB) and bone marrow (BM) samples from patients with myeloproliferative neoplasms (MPNs). However, the diagnostic accuracy of detecting the JAK2 p.V617F mutation and quantifying its allele burden in PB and BM samples has not been systematically compared. We retrospectively analyzed 388 patients with MPN who had been tested for JAK2 p.V617F allele burden using both PB and BM samples within 3 months of each other. The sensitivity and specificity of detecting JAK2 p.V617F in PB when compared with BM were both 100%. Furthermore, the JAK2 p.V617F allele burden measured in PB and BM were equivalent by linear regression analysis (R2 = 0.991; P < .0001). We therefore conclude that PB is a reliable source for testing for the JAK2 p.V617F mutation and quantifying its allele burden in patients with MPN. PMID:24068492

  9. Childhood Obesity Is a Chronic Disease Demanding Specific Health Care--a Position Statement from the Childhood Obesity Task Force (COTF) of the European Association for the Study of Obesity (EASO).

    PubMed

    Farpour-Lambert, Nathalie J; Baker, Jennifer L; Hassapidou, Maria; Holm, Jens Christian; Nowicka, Paulina; O'Malley, Grace; Weiss, Ram

    2015-01-01

    Childhood obesity is one of the greatest health challenges of the 21st century. The EASO COTF is convinced that classifying obesity as a chronic disease in children and adolescents is a crucial step for increasing individual and societal awareness, and for improving early diagnosis and intervention. Such a classification will enhance the development of novel preventive and treatment approaches, health care policies and systems, and the education of healthcare workers. The management of obesity prior to the appearance of co-morbidities may prevent their escalation into significant medical and psychosocial problems, and reduce their economic and societal impact. Childhood is a unique window of opportunity to influence lifetime effects on health, quality of life, prevention of non-communicable chronic diseases and disabilities. The Convention on the Rights of the Child by UNICEF states that parties shall strive to ensure that no child is deprived of his or her right of access to health care services. The EASO COTF is aiming to address these issues via educational activities for health care workers, identification of research agendas, and the promotion of collaborations among clinicians, researchers, health institutions, organizations and states across Europe.

  10. miRNAs as Biomarkers in Chronic Myelogenous Leukemia

    PubMed Central

    Kotagama, Kasuen; Chang, Yung; Mangone, Marco

    2015-01-01

    Strategy, Management and Health PolicyEnabling Technology, Genomics, ProteomicsPreclinical ResearchPreclinical Development Toxicology, Formulation Drug Delivery, PharmacokineticsClinical Development Phases I-III Regulatory, Quality, ManufacturingPostmarketing Phase IV Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm that is frequently characterized by the constitutive expression of the oncogenic protein BCR-ABL tyrosine kinase. Tyrosine kinase inhibitors (TKIs) targeting breakpoint cluster region-ABL are the first-line therapy for most CML patients and have drastically improved the prognosis of CML. However, some CML patients are unresponsive to TKI treatment, and a notable proportion of initially responsive patients develop drug resistance. Several molecular pathways have been correlated with resistance to TKI treatment, however, the exact mechanism of developing drug resistance remains ambiguous. Recently, microRNAs (miRNAs) have been implicated in the progression of CML and the development of resistance to TKI treatment based on their important regulatory function in cell homeostasis, and the deregulation observed in the initiation and progression of many leukemia subtypes. In this review, we summarize some of the major discoveries regarding miRNAs in CML, and their relevance as biomarkers for diagnosis, disease progression, and drug sensitivity. PMID:26284455

  11. Cytogenetic and molecular abnormalities in chronic myelomonocytic leukemia

    PubMed Central

    Patnaik, M M; Tefferi, A

    2016-01-01

    Chronic myelomonocytic leukemia (CMML) is a clonal stem cell disorder associated with peripheral blood monocytosis and an inherent tendency to transform to acute myeloid leukemia. CMML has overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms. Clonal cytogenetic changes are seen in ~30%, whereas gene mutations are seen in >90% of patients. Common cytogenetic abnormalities include; trisomy 8, -Y, -7/del(7q), trisomy 21 and del(20q), with the Mayo–French risk stratification effectively risk stratifying patients based on cytogenetic abnormalities. Gene mutations frequently involve epigenetic regulators (TET2 ~60%), modulators of chromatin (ASXL1 ~40%), spliceosome components (SRSF2 ~50%), transcription factors (RUNX1 ~15%) and signal pathways (RAS ~30%, CBL ~15%). Of these, thus far, only nonsense and frameshift ASXL1 mutations have been shown to negatively impact overall survival. This has resulted in the development of contemporary, molecularly integrated (inclusive of ASXL1 mutations) CMML prognostic models, including Molecular Mayo Model and the Groupe Français des Myélodysplasies model. Better understanding of the prevalent genetic and epigenetic dysregulation has resulted in emerging targeted treatment options for some patients. The development of an integrated (cytogenetic and molecular) prognostic model along with CMML-specific response assessment criteria are much needed future goals. PMID:26849014

  12. Position indicator

    DOEpatents

    Tanner, David E.

    1981-01-01

    A nuclear reactor system is described in which a position indicator is provided for detecting and indicating the position of a movable element inside a pressure vessel. The movable element may be a valve element or similar device which moves about an axis. Light from a light source is transmitted from a source outside the pressure vessel to a first region inside the pressure vessel in alignment with the axis of the movable element. The light is redirected by a reflector prism to a second region displaced radially from the first region. The reflector prism moves in response to movement of the movable element about its axis such that the second region moves arcuately with respect to the first region. Sensors are arrayed in an arc corresponding to the arc of movement of the second region and signals are transmitted from the sensors to the exterior of the reactor vessel to provide indication of the position of the movable element.

  13. Changes of nucleolar organizer regions in granulopoietic precursors during the course of chronic myeloid leukemia.

    PubMed

    Gilberti, M F; Metze, K; Lorand-Metze, I

    1995-12-01

    The aim of the present study was to analyze the nucleolar organizer region (AgNOR) pattern of granulopoietic precursors in chronic myeloid leukemia (CML) at diagnosis and during the course of the disease. Clusters of AgNORs and isolated dots were counted separately in 24 cases of CML at diagnosis, in 19 cases during the relapse of the chronic phase after treatment, and in 16 cases of blast crisis. For comparison, 20 cases of normal bone marrow were studied. Each cell type had its own characteristic AgNOR pattern, as has been described for normal bone marrow. There was no significant difference in the number of AgNORs between cells in the peripheral blood and bone marrow. Compared with normal granulopoiesis, myeloblasts in CML at diagnosis had lower numbers of clusters, which decreased further during relapse of chronic phase and in blast crisis. Promyelocytes and myelocytes showed significantly fewer dots. The number of AgNOR clusters correlates inversely with the duration of the cell cycle. Therefore, these findings are consistent with the progressive loss in proliferative activity of immature precursors described during the course of CML. As the number of dots indicates cellular maturation, their lower number in promyelocytes and myelocytes in CML favors the concept of a discordant maturation process described in this disease. The separate counting of clusters and dots provides a useful, simple, and cheap method of describing cytokinetic changes during the course of this myeloproliferative disorder.

  14. [Chronic prostatitis with chronic pelvic pain syndrome].

    PubMed

    Balvocius, Antanas

    2002-01-01

    Almost 10% of the adult male population suffer from prostatitis. The International Prostatitis Collaborative Network has devised and validated a clinically useful classification of prostatitis that urologists and primary care clinicians will find helpful. According to this schema, chronic bacterial prostatitis is clearly an infectious disease, and patients with chronic prostatitis associated with chronic pelvic pain syndrome can have either inflammatory or noninflammatory disease. Chronic bacterial prostatitis is uncommon, chronic nonbacterial prostatitis (CPPS) is extremely common. Antibiotic therapy is indicated in management of chronic bacterial prostatitis and inflammatory chronic pelvic pain syndrome. Fluoroquinolones are safe and effective in managing chronic bacterial prostatitis. Based on literature, noninflammatory chronic pelvic pain syndrome can be treated using adrenergic blockade, analgesic, tricyclic antidepressants, benzodiazepie, physical therapy. PMID:12556633

  15. Positive psychotherapy.

    PubMed

    Seligman, Martin E P; Rashid, Tayyab; Parks, Acacia C

    2006-11-01

    Positive psychotherapy (PPT) contrasts with standard interventions for depression by increasing positive emotion, engagement, and meaning rather than directly targeting depressive symptoms. The authors have tested the effects of these interventions in a variety of settings. In informal student and clinical settings, people not uncommonly reported them to be "life-changing." Delivered on the Web, positive psychology exercises relieved depressive symptoms for at least 6 months compared with placebo interventions, the effects of which lasted less than a week. In severe depression, the effects of these Web exercises were particularly striking. This address reports two preliminary studies: In the first, PPT delivered to groups significantly decreased levels of mild-to-moderate depression through 1-year follow-up. In the second, PPT delivered to individuals produced higher remission rates than did treatment as usual and treatment as usual plus medication among outpatients with major depressive disorder. Together, these studies suggest that treatments for depression may usefully be supplemented by exercises that explicitly increase positive emotion, engagement, and meaning. ((c) 2006 APA, all rights reserved). PMID:17115810

  16. Positively Adolescent!

    ERIC Educational Resources Information Center

    Williamson, Sue

    2000-01-01

    Believes that music teachers should reassess their views toward adolescent behavior in the music classroom by learning to see their behavior in a positive light. Describes teaching strategies that build on four adolescent behaviors: (1) desire for peer acceptance; (2) abundant energy; (3) love of fun; and (4) limited time-managing skills. (CMK)

  17. Position sensor

    NASA Technical Reports Server (NTRS)

    Auer, Siegfried (Inventor)

    1988-01-01

    A radiant energy angle sensor is provided wherein the sensitive portion thereof comprises a pair of linear array detectors with each detector mounted normal to the other to provide X and Y channels and a pair of slits spaced from the pair of linear arrays with each of the slits positioned normal to its associated linear array. There is also provided electrical circuit means connected to the pair of linear array detectors and to separate X and Y axes outputs.

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

    PubMed

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

    2015-04-01

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

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

    PubMed

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

    2015-04-01

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

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

    PubMed Central

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

    2015-01-01

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

  1. Graft-Versus-Host Disease Prophylaxis in Treating Patients With Hematologic Malignancies Undergoing Unrelated Donor Peripheral Blood Stem Cell Transplant

    ClinicalTrials.gov

    2016-08-18

    Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Aggressive Non-Hodgkin Lymphoma; Chronic Lymphocytic Leukemia; Diffuse Large B-Cell Lymphoma; Hematopoietic and Lymphoid Cell Neoplasm; Indolent Non-Hodgkin Lymphoma; Mantle Cell Lymphoma; Myelodysplastic Syndrome; Myeloproliferative Neoplasm; Prolymphocytic Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Plasma Cell Myeloma; Refractory Chronic Lymphocytic Leukemia; Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Refractory Hodgkin Lymphoma; Small Lymphocytic Lymphoma; T-Cell Chronic Lymphocytic Leukemia; Waldenstrom Macroglobulinemia

  2. Positive Psychologists on Positive Constructs

    ERIC Educational Resources Information Center

    Lyubomirsky, Sonja

    2012-01-01

    Comments on the original article by McNulty and Fincham (see record 2011-15476-001). In their article, the authors offered compelling evidence that constructs such as forgiveness and optimism can have both beneficial and adverse consequences, depending on the context. Their caution about labeling particular psychological processes as "positive" is…

  3. Ipilimumab or Nivolumab in Treating Patients With Relapsed Hematologic Malignancies After Donor Stem Cell Transplant

    ClinicalTrials.gov

    2016-09-21

    Myeloproliferative Neoplasm; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Recurrent Hodgkin Lymphoma; Recurrent Non-Hodgkin Lymphoma; Recurrent Plasma Cell Myeloma

  4. The HDAC inhibitor Givinostat modulates the hematopoietic transcription factors NFE2 and C-MYB in JAK2(V617F) myeloproliferative neoplasm cells.

    PubMed

    Amaru Calzada, Ariel; Todoerti, Katia; Donadoni, Luca; Pellicioli, Anna; Tuana, Giacomo; Gatta, Raffaella; Neri, Antonino; Finazzi, Guido; Mantovani, Roberto; Rambaldi, Alessandro; Introna, Martino; Lombardi, Luigia; Golay, Josée

    2012-08-01

    We investigated the mechanism of action of the histone deacetylase inhibitor Givinostat (GVS) in Janus kinase 2 (JAK2)(V617F) myeloproliferative neoplasm (MPN) cells. GVS inhibited colony formation and proliferation and induced apoptosis at doses two- to threefold lower in a panel of JAK2(V617F) MPN compared to JAK2 wild-type myeloid leukemia cell lines. By global gene expression analysis, we observed that at 6 hours, GVS modulated 293 common genes in the JAK2(V617F) cell lines HEL and UKE1, of which 19 are implicated in cell cycle regulation and 33 in hematopoiesis. In particular, the hematopoietic transcription factors NFE2 and C-MYB were downmodulated by the drug specifically in JAK2(V617F) cells at both the RNA and protein level. GVS also inhibited JAK2-signal transducer and activator of transcription 5-extracellular signal-regulated kinase 1/2 phosphorylation, but modulation of NFE2 and C-MYB was JAK2-independent, as shown using the JAK2 inhibitor TG101209. GVS had a direct effect on the NFE2 promoters, as demonstrated by specific enrichment of associated histone H3 acetylated at lysine 9. Modulation by GVS of NFE2 was also observed in freshly isolated CD34(+) cells from MPN patients, and was accompanied by inhibition of their proliferation and differentiation toward the erythroid lineage. We conclude that GVS acts on MPN cells through dual JAK2-signal transducer and activator of transcription 5-extracellular signal-regulated kinase 1/2 inhibition and downmodulation of NFE2 and C-MYB transcription. PMID:22579713

  5. Deletion of Stat3 enhances myeloid cell expansion and increases the severity of myeloproliferative neoplasms in Jak2V617F knock-in mice

    PubMed Central

    Yan, Dongqing; Jobe, Fatoumata; Hutchison, Robert E.; Mohi, Golam

    2015-01-01

    The JAK2V617F mutation commonly found in myeloproliferative neoplasms (MPNs) induces constitutive phosphorylation/activation of the signal transducer and activator of transcription 3 (Stat3). However, the contribution of Stat3 in MPN evoked by JAK2V617F remains unknown. To determine the role of Stat3 in JAK2V617F-induced MPN, we generated Stat3-deficient Jak2V617F-expressing mice. Whereas expression of Jak2V617F resulted in a PV-like disease characterized by increased red blood cells (RBC), hematocrit, neutrophils and platelets in the peripheral blood of Jak2V617F knock-in mice, deletion of Stat3 slightly reduced RBC, and hematocrit parameters and modestly increased platelet numbers in Jak2V617F knock-in mice. Moreover, deletion of Stat3 significantly increased the neutrophil counts/percentages and markedly reduced the survival of mice expressing Jak2V617F. These phenotypic manifestations were reproduced upon bone marrow transplantation into wild-type animals. Flow cytometric analysis showed increased hematopoietic stem cell and granulocyte-macrophage progenitor populations in the bone marrow and spleens of Stat3-deficient Jak2V617F mice. Stat3 deficiency also caused a marked expansion of Gr-1+/Mac-1+ myeloid cells in Jak2V617F knock-in mice. Histopathologic analysis revealed marked increase in granulocytes in the bone marrow, spleens and livers of Stat3-deficient Jak2V617F-expressing mice. Together, these results suggest that deletion of Stat3 increases the severity of MPN induced by Jak2V617F. PMID:26044284

  6. Prognostic significance of ASXL1, JAK2V617F mutations and JAK2V617F allele burden in Philadelphia-negative 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 Despite insights into the genetic basis of Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPNs), a significant proportion of essential thrombocythemia (ET) and primary myelofibrosis (PMF) patients present with no known MPN disease alleles. There were no previous studies investigating the impact of ASXL1 mutations in Ph-negative MPNs in Turkey. In the current study, we investigated the prognostic significance of ASXL1 mutations in Turkish MPN patients. We also aimed to determine the prognostic significance of JAK2V617F allele burden and the relationship of JAK2V617F mutation with ASXL1 mutations in Ph-negative MPNs. Methods About 184 patients from a single center diagnosed with Ph-negative MPNs were screened for ASXL1, JAK2V617F mutations, and JAK2V617F allele burden: 107 ET and 77 PMF. Results A total of 29 ASXL1 mutations were detected in 24.7% of PMF and 8.4% of ET patients. ASXL1-mutated ET patients showed a trend toward an increase in the incidence of cerebrovascular events and higher total leukocyte counts. ASXL1-mutation in PMF was associated with older age and a higher prevalence of bleeding complications. In univariate analysis, overall survival (OS) was significantly reduced in ASXL1-mutated PMF patients. In multivariate analysis, Dynamic International Prognostic Scoring System-plus high-risk category and ASXL1 mutation status were independently associated with shorter survival in PMF. In PMF, mutational status and allele burden of JAK2V617F showed no difference in terms of OS and leukemia-free survival. Conclusion We conclude that ASXL1 mutations are molecular predictors of short OS in PMF. PMID:26082670

  7. Determination of prognosis of Philadelphia chromosome-negative myeloproliferative neoplasms with a simple clinical examination: Retrospective analysis of 71 patients in a single institution

    PubMed Central

    ITO, SHINICHI; TSUTSUMI, YUTAKA; OHIGASHI, HIROYUKI; SHIRATORI, SOUICHI; TESHIMA, TAKANORI

    2016-01-01

    Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocytosis (ET) and primary myelofibrosis (PMF), are clonal hematopoietic diseases. A single-institution retrospective analysis was performed, including 71 MPN patients diagnosed at the Hakodate Municipal Hospital between April, 2001 and April, 2014, and certain clinical characteristics were identified as effective prognostic factors. The patients were categorized by risk factor scoring based on age, number of abnormal blood cell lineages and splenomegaly at diagnosis, and the association between this categorization and prognosis was analyzed using a statistical procedure. The effect of Janus kinase 2 (JAK2) V617F mutation on prognosis was also investigated. The MPN patients were consolidated into three risk groups based on the margin of intergroup survival differences: i) Score 1–2 (n=23), ii) score 3 (n=24) and iii) score 4–5 (n=24). MPN patients with scores of 4 or 5 exhibited poorer overall survival (OS) compared with those with lower scores (P<0.001). In addition, there were significant differences in event-free survival (EFS) among scoring groups (P=0.0059). PV and ET had a better prognosis compared with PMF, although this analysis suggested that PV and ET patients with scores of 4 or 5 may have a poorer prognosis in terms of OS (P=0.0052) and EFS (P=0.022) and should be closely followed up. We observed no significant prognostic effect of the JAK2V167F mutation for OS (P=0.28) or EFS (P=0.17). Our results suggested that a simple scoring system based on age, blood cell counts and presence of splenomegaly at diagnosis may be used for the long-term prognosis of MPN patients. PMID:26870357

  8. Efficacy of NS-018, a potent and selective JAK2/Src inhibitor, in primary cells and mouse models of myeloproliferative neoplasms

    PubMed Central

    Nakaya, Y; Shide, K; Niwa, T; Homan, J; Sugahara, S; Horio, T; Kuramoto, K; Kotera, T; Shibayama, H; Hori, K; Naito, H; Shimoda, K

    2011-01-01

    Aberrant activation of Janus kinase 2 (JAK2) caused by somatic mutation of JAK2 (JAK2V617F) or the thrombopoietin receptor (MPLW515L) plays an essential role in the pathogenesis of myeloproliferative neoplasms (MPNs), suggesting that inhibition of aberrant JAK2 activation would have a therapeutic benefit. Our novel JAK2 inhibitor, NS-018, was highly active against JAK2 with a 50% inhibition (IC50) of <1 n, and had 30–50-fold greater selectivity for JAK2 over other JAK-family kinases, such as JAK1, JAK3 and tyrosine kinase 2. In addition to JAK2, NS-018 inhibited Src-family kinases. NS-018 showed potent antiproliferative activity against cell lines expressing a constitutively activated JAK2 (the JAK2V617F or MPLW515L mutations or the TEL–JAK2 fusion gene; IC50=11–120 n), but showed only minimal cytotoxicity against most other hematopoietic cell lines without a constitutively activated JAK2. Furthermore, NS-018 preferentially suppressed in vitro erythropoietin-independent endogenous colony formation from polycythemia vera patients. NS-018 also markedly reduced splenomegaly and prolonged the survival of mice inoculated with Ba/F3 cells harboring JAK2V617F. In addition, NS-018 significantly reduced leukocytosis, hepatosplenomegaly and extramedullary hematopoiesis, improved nutritional status, and prolonged survival in JAK2V617F transgenic mice. These results suggest that NS-018 will be a promising candidate for the treatment of MPNs. PMID:22829185

  9. Chronic osteomyelitis examined by CT

    SciTech Connect

    Wing, V.W.; Jeffrey, R.B. Jr.; Federle, M.P.; Helms, C.A.; Trafton, P.

    1985-01-01

    CT examination of 25 patients who had acute exacerbations of chronic osteomyelitis allowed for the correct identification of single or multiple sequestra in 14 surgical patients. Plain radiographs were equivocal for sequestra in seven of these patients, because the sequestra were too small or because diffuse bony sclerosis was present. CT also demonstrated a foreign body and five soft tissue abscesses not suspected on the basis of plain radiographs. CT studies, which helped guide the operative approach, were also useful in treating those patients whose plain radiographs were positive for sequestra. The authors review the potential role of CT in evaluating patients with chronic osteomyelitis.

  10. Positioning apparatus

    DOEpatents

    Vogel, M.A.; Alter, P.

    1983-07-07

    An apparatus is provided for precisely adjusting the position of an article relative to a beam emerging from a neutron source disposed in a housing. The apparatus includes a support pivotably mounted on a movable base plate and freely suspended therefrom. The support is gravity biased toward the housing and carries an article holder movable in a first direction longitudinally of the axis of said beam and normally urged into engagement against said housing. Means are provided for moving the base plate in two directions to effect movement of the suspended holder in two mutually perpendicular directions, respectively, normal to the axis of the beam.

  11. Positioning apparatus

    DOEpatents

    Vogel, Max A.; Alter, Paul

    1986-05-06

    An apparatus for precisely positioning materials test specimens within the optimum neutron flux path emerging from a neutron source located in a housing. The test specimens are retained in a holder mounted on the free end of a support pivotably mounted and suspended from a movable base plate. The support is gravity biased to urge the holder in a direction longitudinally of the flux path against the housing. Means are provided for moving the base plate in two directions to effect movement of the holder in two mutually perpendicular directions normal to the axis of the flux path.

  12. Positioning apparatus

    DOEpatents

    Vogel, Max A.; Alter, Paul

    1986-01-01

    An apparatus for precisely positioning materials test specimens within the optimum neutron flux path emerging from a neutron source located in a housing. The test specimens are retained in a holder mounted on the free end of a support pivotably mounted and suspended from a movable base plate. The support is gravity biased to urge the holder in a direction longitudinally of the flux path against the housing. Means are provided for moving the base plate in two directions to effect movement of the holder in two mutually perpendicular directions normal to the axis of the flux path.

  13. POSITIONING DEVICE

    DOEpatents

    Wall, R.R.; Peterson, D.L.

    1959-09-15

    A positioner is described for a vertical reactor-control rod. The positioner comprises four grooved friction rotatable members that engage the control rod on all sides and shift it longitudinally. The four friction members are drivingly interconnected for conjoint rotation and comprise two pairs of coaxial members. The members of each pair are urged toward one another by hydraulic or pneumatic pressure and thus grip the control rod so as to hold it in any position or adjust it. Release of the by-draulic or pneumatic pressure permits springs between the friction members of each pair to force them apart, whereby the control rod moves quickly by gravity into the reactor.

  14. Chronic Pain Medicines

    MedlinePlus

    ... Treatment of chronic pain usually involves medicines and therapy. Medicines used for chronic pain include pain relievers, antidepressants and anticonvulsants. Different types of medicines help ...

  15. Whole-exome sequencing identifies novel MPL and JAK2 mutations in triple-negative myeloproliferative neoplasms

    PubMed Central

    Milosevic Feenstra, Jelena D.; Nivarthi, Harini; Gisslinger, Heinz; Leroy, Emilie; Rumi, Elisa; Chachoua, Ilyas; Bagienski, Klaudia; Kubesova, Blanka; Pietra, Daniela; Gisslinger, Bettina; Milanesi, Chiara; Jäger, Roland; Chen, Doris; Berg, Tiina; Schalling, Martin; Schuster, Michael; Bock, Christoph; Constantinescu, Stefan N.; Cazzola, Mario

    2016-01-01

    Essential thrombocythemia (ET) and primary myelofibrosis (PMF) are chronic diseases characterized by clonal hematopoiesis and hyperproliferation of terminally differentiated myeloid cells. The disease is driven by somatic mutations in exon 9 of CALR or exon 10 of MPL or JAK2-V617F in >90% of the cases, whereas the remaining cases are termed “triple negative.” We aimed to identify the disease-causing mutations in the triple-negative cases of ET and PMF by applying whole-exome sequencing (WES) on paired tumor and control samples from 8 patients. We found evidence of clonal hematopoiesis in 5 of 8 studied cases based on clonality analysis and presence of somatic genetic aberrations. WES identified somatic mutations in 3 of 8 cases. We did not detect any novel recurrent somatic mutations. In 3 patients with clonal hematopoiesis analyzed by WES, we identified a somatic MPL-S204P, a germline MPL-V285E mutation, and a germline JAK2-G571S variant. We performed Sanger sequencing of the entire coding region of MPL in 62, and of JAK2 in 49 additional triple-negative cases of ET or PMF. New somatic (T119I, S204F, E230G, Y591D) and 1 germline (R321W) MPL mutation were detected. All of the identified MPL mutations were gain-of-function when analyzed in functional assays. JAK2 variants were identified in 5 of 57 triple-negative cases analyzed by WES and Sanger sequencing combined. We could demonstrate that JAK2-V625F and JAK2-F556V are gain-of-function mutations. Our results suggest that triple-negative cases of ET and PMF do not represent a homogenous disease entity. Cases with polyclonal hematopoiesis might represent hereditary disorders. PMID:26423830

  16. [The effectiveness of anagrelide treatment in patients with Ph negative myeloproliferative diseases: influence on the incidence of thrombosis in the data from the Registry of patients with essential thrombocythemia and thrombocythemia associated with other myeloproliferative diseases treated with Thromboreductin® to the end of 2012].

    PubMed

    Penka, M; Schwarz, J; Ovesná, P; Cervinek, L; Dulíček, P; Pospíšilová, D; Kissová, J; Pavlík, T

    2013-06-01

    In the Czech Republic, anagrelide (Thromboreductin®) [29] is used according to the recommendations of the Czech Working Group on Myeloproliferative Disorders (CZEMP) for treatment of thrombocythemia associated with Ph negative myeloproliferative disorders (MPDs). The patient data are collected in the Registry of patients with essential thrombocythemia (ET) and thrombocythemia associated with other MPDs treated with Thromboreductin®. At the end of 2012, the Registry contained data on 1,161 patients. Out of these, 1,159 patients with the dia-gnosis of a Ph negative MPD were evaluated. In 844 patients, precise WHO based dia-gnosis was known at start of therapy: 442 (52.4%) had ET, 108 (12.8%) had polycythaemia vera (PV) and 243 had primary myelofibrosis (PMF). The median age was 51 years at the time of diagnosis. At the time of the evaluation of the population, the median was 59 years. Every year, the proportion of patients newly treated with anagrelide as a firstline treatment in accordance with the CZEMP guidelines has been increasing. A growing proportion of patients has been treated with an additional cytoreducing drug, such as hydroxyurea and interferon. The majority of the patients received also an antiaggregant (or anticoagulant). More than a half of patients harbors the JAK2 mutation. A prompt decrease of platelet counts (as the response to Thromboreductin® treatment) was documented in most of the patients. After one year, 86.9% of patients had a full or partial response. In poorer responders, combination cytoreductive treatment was administered rather then the escalation of the Thromboreductin® dosage. There were 461 thrombotic manifestations in 363 patients and 61 haemorrhagic events in 57 patients recorded in the patients history. In the course of treatment (followup; F U), thrombosis was diagnosed only 179-times in 136 patients. There were more haemorrhagic events during F U: 109 events in 83 patients. Upon comparison of the number of events

  17. CHRONIC URTICARIA

    PubMed Central

    Sachdeva, Sandeep; Gupta, Vibhanshu; Amin, Syed Suhail; Tahseen, Mohd

    2011-01-01

    Chronic urticaria (CU) is a disturbing allergic condition of the skin. Although frequently benign, it may sometimes be a red flag sign of a serious internal disease. A multitude of etiologies have been implicated in the causation of CU, including physical, infective, vasculitic, psychological and idiopathic. An autoimmune basis of most of the ‘idiopathic’ forms is now hypothesized. Histamine released from mast cells is the major effector in pathogenesis and it is clinically characterized by wheals that have a tendency to recur. Laboratory investigations aimed at a specific etiology are not always conclusive, though may be suggestive of an underlying condition. A clinical search for associated systemic disease is strongly advocated under appropriate circumstances. The mainstay of treatment remains H1 antihistaminics. These may be combined with complementary pharmacopeia in the form of H2 blockers, doxepin, nifedipine and leukotriene inhibitors. More radical therapy in the form of immunoglobulins, plasmapheresis and cyclophosphamide may be required for recalcitrant cases. Autologous transfusion and alternative remedies like acupuncture have prospects for future. A stepwise management results in favorable outcomes. An update on CU based on our experience with patients at a tertiary care centre is presented. PMID:22345759

  18. Chronic Pancreatitis

    PubMed Central

    DiMagno, Matthew J.; DiMagno, Eugene P.

    2012-01-01

    Purpose of review We review important new clinical observations in chronic pancreatitis (CP) reported in 2011. Recent findings Smoking increases the risk of non-gallstone acute pancreatitis (AP) and the progression of AP to CP. Binge drinking during Oktoberfest did not associate with increased hospital admissions for AP. The unfolded protein response is an adaptive mechanism to maintain pancreatic health in response to noxious stimuli such as alcohol. Onset of diabetes mellitus in CP is likely due to progressive disease rather than individual variables. Insufficient pancreatic enzyme dosing is common for treatment of pancreatic steatorrhea; 90,000 USP U of lipase should be given with meals. Surgical drainage provides sustained, superior pain relief compared to endoscopic treatment in patients advanced CP with a dilated main duct +/− pancreatic stones. The central acting gabapentoid pregabalin affords a modest 12% pain reduction in patients with CP but ~30% of patients have significant side effects. Summary Patients with non-gallstone related AP or CP of any etiology should cease smoking. Results of this year’s investigations further elucidated the pancreatic pathobiology due to alcohol, onset of diabetes mellitus in CP, and the mechanisms and treatment of neuropathic pain in CP. PMID:22782018

  19. [Latest advances in chronic pancreatitis].

    PubMed

    Domínguez-Muñoz, J Enrique

    2013-10-01

    This article summarizes some of the recent and clinically relevant advances in chronic pancreatitis. These advances mainly concern knowledge of the etiopathogenesis of the disease, the pharmacological treatment of pain, and knowledge of the natural history of autoimmune pancreatitis. New evidence supports the relatively low prevalence of chronic alcoholic pancreatitis, and the role of tobacco in triggering the etiopathogenic mechanisms of chronic pancreatitis is better understood. Some studies have identified certain factors that are associated with having a positive genetic test in adults with chronic idiopathic pancreatitis, which should help to select those patients who should undergo genetic studies. Antioxidant therapy has been shown to be effective in reducing pain secondary to chronic pancreatitis, although the type and optimal dose of antioxidants remains to be elucidated. Finally, the development of exocrine and endocrine pancreatic insufficiency is a very common finding during the long-term follow-up of patients with autoimmune pancreatitis. Smoking also seems to play a role in this type of pancreatitis.

  20. Fludarabine Phosphate and Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia or Chronic Myelogenous Leukemia That Has Responded to Treatment With Imatinib Mesylate, Dasatinib, or Nilotinib

    ClinicalTrials.gov

    2016-07-18

    Adult Acute Lymphoblastic Leukemia in Remission; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Chronic Phase Chronic Myelogenous Leukemia; Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia; Philadelphia Chromosome Positive Childhood Precursor Acute Lymphoblastic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Relapsing Chronic Myelogenous Leukemia