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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 Options for Chronic Myeloproliferative Neoplasms

    MedlinePlus

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

  4. 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 ...

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

    ClinicalTrials.gov

    2016-12-26

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

    PubMed Central

    Janssen, J W; Steenvoorden, A C; Lyons, J; Anger, B; Böhlke, J U; Bos, J L; Seliger, H; Bartram, C R

    1987-01-01

    We report on investigations aimed at detecting mutated RAS genes in a variety of preleukemic disorders and leukemias of myeloid origin. DNA transfection analyses (tumorigenicity assay) and hybridization to mutation-specific oligonucleotide probes established NRAS mutations in codon 12 or 61 of 4/9 acute myelocytic leukemias (AML) and three AML lines. Leukemic cells of another AML patient showed HRAS gene activation. By using a rapid and sensitive dot-blot screening procedure based on the combination of in vitro amplification of RAS-specific sequences and oligonucleotide hybridization we additionally screened 15 myelodysplastic syndromes, 26 Philadelphia chromosome-positive chronic myelocytic leukemias in chronic or acute phase, and 19 other chronic myeloproliferative disorders. A mutation within NRAS codon 12 could thus be demonstrated in a patient with idiopathic myelofibrosis and in another with chronic myelomonocytic leukemia. Moreover, mutated NRAS sequences were detected in lymphocytes, in granulocytes, as well as in monocytes/macrophages of the latter case. Images PMID:3122217

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

    SciTech Connect

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

    1987-12-01

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

  8. 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

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

    PubMed Central

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

    2006-01-01

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

  10. 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

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  13. 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

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

    PubMed Central

    Yildiz, Ismail; Yokuş, Osman; Gedik, Habip

    2017-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  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. 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

  18. Myelodysplastic/ Myeloproliferative Neoplasms Treatment

    MedlinePlus

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

  19. 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

  20. 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

  1. 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.

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    1996-11-16

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

  4. 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

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

    ClinicalTrials.gov

    2017-03-20

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

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

    PubMed Central

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

    2003-01-01

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

  7. 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.

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

    PubMed Central

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

    2017-01-01

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

  9. Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable

    MedlinePlus

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

  10. 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

  11. [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.

  12. 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

  13. 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

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

    PubMed

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

    2013-06-01

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

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

    PubMed

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

    2000-04-01

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

  16. 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.

  17. 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/ ...

  18. 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/ ...

  19. 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/ ...

  20. 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

  1. 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

  2. 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.

  3. 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.

  4. Eosinophilic Myeloproliferative Disorders

    PubMed Central

    Klion, Amy D.

    2014-01-01

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

  5. 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

  6. 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

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

    PubMed

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

    2008-09-15

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

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

    PubMed

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

    2017-02-15

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

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

    PubMed

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

    2013-07-01

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

  10. 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

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

    PubMed Central

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

    2017-01-01

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

  12. 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.

  13. Myeloproliferative neoplasm stem cells.

    PubMed

    Mead, Adam J; Mullally, Ann

    2017-03-23

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

  14. 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.

  15. Genomics of Myeloproliferative Neoplasms.

    PubMed

    Zoi, Katerina; Cross, Nicholas C P

    2017-03-20

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

  16. 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

  17. Enhancing Targeted Therapy for Myeloproliferative Neoplasms

    DTIC Science & Technology

    2013-10-01

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

  18. [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.

  19. 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.

  20. 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)

  1. 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

  2. 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

  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. Prospect of JAK2 inhibitor therapy in myeloproliferative neoplasms

    PubMed Central

    Atallah, Ehab; Verstovsek, Srdan

    2016-01-01

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

  5. 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…

  6. 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

  7. Myelodysplasia and myeloproliferative disorders in children.

    PubMed

    McKenna, Robert W

    2004-12-01

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

  8. 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.

  9. 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

  10. Molecular diagnostics of myeloproliferative neoplasms.

    PubMed

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

    2015-10-01

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

  11. Treatment for Chronic Pain in Patients With Advanced Cancer

    ClinicalTrials.gov

    2016-11-25

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

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

    PubMed

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

    2009-09-01

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

  13. 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

  14. 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

  15. 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

  16. 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

  17. Noninvasive Positive Pressure Ventilation in Chronic Heart Failure

    PubMed Central

    Han, Yi

    2016-01-01

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

  18. Atypical Chronic Myelogenous Leukemia

    MedlinePlus

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

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

    PubMed

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

    2011-01-01

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

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

    PubMed

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

    2007-05-01

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

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

    ClinicalTrials.gov

    2017-03-06

    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

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

    PubMed

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

    2004-12-01

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

  3. [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

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

    PubMed

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

    2016-01-01

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

  5. 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

  6. 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.

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2016-06-01

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

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

    DTIC Science & Technology

    2008-02-01

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

  10. 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:…

  11. 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

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

    PubMed

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

    2016-08-01

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

  13. 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

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

    PubMed

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

    2004-04-01

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

  15. 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

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

    PubMed

    Takenaka, Katsuto

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

  17. 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

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

    PubMed Central

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

    2017-01-01

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

  19. [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.

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

    PubMed

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

    2012-08-01

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

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

    PubMed

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

    2005-01-01

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

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

    PubMed

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

    2013-04-01

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

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

    PubMed Central

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

    2013-01-01

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

  4. 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

  5. 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

  6. 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

  7. CALR mutation characterization in myeloproliferative neoplasms

    PubMed Central

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

    2016-01-01

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

  8. 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

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

    PubMed Central

    Fox, Lisa; Hegde, Subramanya

    2010-01-01

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

  10. 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

  11. Targeting glutamine metabolism in myeloproliferative neoplasms

    PubMed Central

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

    2016-01-01

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

  12. 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

  13. 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

  14. Emerging treatments for classical myeloproliferative neoplasms.

    PubMed

    Vannucchi, Alessandro M; Harrison, Claire N

    2017-02-09

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

  15. Myeloproliferative neoplasms: Current molecular biology and genetics.

    PubMed

    Saeidi, Kolsoum

    2016-02-01

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

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

    SciTech Connect

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

    1991-06-01

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

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

    PubMed

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

    2017-03-01

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

  18. 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

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

    PubMed

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

    2012-12-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

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

    2010-01-01

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

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

    PubMed

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

    1983-09-01

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

  4. 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

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

    PubMed

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

    2013-08-29

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

  6. 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

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

    PubMed Central

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

    2016-01-01

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

  8. 3q26.2/EVI1 rearrangement is associated with poor prognosis in classical Philadelphia chromosome-negative myeloproliferative neoplasms.

    PubMed

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

    2017-03-24

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

  9. 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

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

    PubMed

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

    2006-12-01

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

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

    PubMed

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

    2014-01-22

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

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

    PubMed Central

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

    1977-01-01

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

  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. 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

  15. 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…

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

    PubMed

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

    2017-02-01

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

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

    PubMed

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

    2009-06-11

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

  18. 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

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

    PubMed Central

    Braunstein, Evan M.

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

  3. Targeted ex vivo reduction of CD64-positive monocytes in chronic myelomonocytic leukemia and acute myelomonocytic leukemia using human granzyme B-based cytolytic fusion proteins.

    PubMed

    Schiffer, Sonja; Rosinke, Reinhard; Jost, Edgar; Hehmann-Titt, Grit; Huhn, Michael; Melmer, Georg; Barth, Stefan; Thepen, Theo

    2014-09-15

    CMML (chronic myelomonocytic leukemia) belongs to the group of myeloid neoplasms known as myelodysplastic and myeloproliferative diseases. In some patients with a history of CMML, the disease transforms to acute myelomonocytic leukemia (AMML). There are no specific treatment options for patients suffering from CMML except for supportive care and DNA methyltransferase inhibitors in patients with advanced disease. New treatment strategies are urgently required, so we have investigated the use of immunotherapeutic directed cytolytic fusion proteins (CFPs), which are chimeric proteins comprising a selective domain and a toxic component (preferably of human origin to avoid immunogenicity). The human serine protease granzyme B is a prominent candidate for tumor immunotherapy because it is expressed in cytotoxic T lymphocytes and natural killer cells. Here, we report the use of CD64 as a novel target for specific CMML and AMML therapy, and correlate CD64 expression with typical surface markers representing these diseases. We demonstrate that CD64-specific human CFPs kill CMML and AMML cells ex vivo, and that the mutant granzyme B protein R201K is more cytotoxic than the wild-type enzyme in the presence of the granzyme B inhibitor PI9. Besides, the human CFP based on the granzyme B mutant was also able to kill AMML or CMML probes resistant to Pseudomonas exotoxin A.

  4. 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

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

    PubMed

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

    2017-04-01

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

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

    PubMed Central

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

    1989-01-01

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

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

    PubMed

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

    2003-09-01

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

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

    ClinicalTrials.gov

    2016-12-27

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Refractory Anemia With Excess Blasts; Untreated Adult Acute Myeloid Leukemia; Myeloproliferative Neoplasm With 10% Blasts or Higher

  9. 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

  10. 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

  11. 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

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

    ClinicalTrials.gov

    2017-03-21

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

  13. 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…

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

    PubMed

    Stein, Brady L; Moliterno, Alison R

    2010-06-23

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

  15. 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

  16. JAK2 GGCC haplotype in MPL mutated myeloproliferative neoplasms.

    PubMed

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

    2012-07-01

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

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

    PubMed

    Vainchenker, William; Kralovics, Robert

    2017-02-09

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

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

    PubMed

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

    1985-02-01

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

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

    PubMed

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

    2003-05-01

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

  20. 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

  1. Positioning.

    ERIC Educational Resources Information Center

    Conone, Ruth M.

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

  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. 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

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

    PubMed

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

    2013-07-01

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

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

    PubMed

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

    2011-12-01

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

  7. 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.

  8. 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…

  9. 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

  10. 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

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

    PubMed

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

    2017-03-01

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

  12. 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

  13. 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

  14. 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

  15. Impact of Inflammation on Myeloproliferative Neoplasm Symptom Development.

    PubMed

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

    2015-01-01

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

  16. AKT is a therapeutic target in myeloproliferative neoplasms

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2013-07-25

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

  18. Impact of Inflammation on Myeloproliferative Neoplasm Symptom Development

    PubMed Central

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

    2015-01-01

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

  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. 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.

  1. 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.

  2. 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

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

    PubMed Central

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

    2016-01-01

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

  4. 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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  7. 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

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

    PubMed

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

    2015-05-01

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

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

    PubMed Central

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

    2017-01-01

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

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

    PubMed Central

    2017-01-01

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

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

    PubMed

    Rumi, Elisa; Cazzola, Mario

    2017-02-09

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

  12. [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.

  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. 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

  15. 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…

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

    PubMed

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

    2010-05-01

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

  17. 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

  18. 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

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

    PubMed

    Ahn, SangNam; Kim, Seonghoon; Zhang, Hongmei

    2016-12-26

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

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

    PubMed Central

    Ahn, SangNam; Kim, Seonghoon; Zhang, Hongmei

    2016-01-01

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

  1. 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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2013-08-01

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

  4. 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

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

    PubMed

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

    2017-02-01

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

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

    PubMed

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

    2017-03-07

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

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

    PubMed

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

    2017-03-01

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

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

    PubMed

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

    2014-03-01

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

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

    DTIC Science & Technology

    2006-10-01

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

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

    PubMed Central

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

    2005-01-01

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

  11. The overwhelmingly positive response to Dasatinib of a patient with multiple blast crisis of chronic myeloid leukemia

    PubMed Central

    Xu, Zhengli; Zheng, Miao; Wu, Chaonan; Ma, Yujia; Meng, Li; Zhou, Jianfeng; Wang, Ying

    2015-01-01

    Blastic phase (BP), the terminal phase of chronic myeloid leukemia (CML), can occur in any of the hematopoietic lineages. Extramedullary blastic crisis (EBC) is a rare form of blastic crisis, which has an extremely poor prognosis. As the tyrosine kinase inhibitor (TKI), Dasatinib is a more effective treatment drug than Imatinib and Nilotinib for this type of CML, because it has greater potency and penetrates through the blood-brain barrier to reach the cerebrospinal fluid (CSF). This report examines the case of a 22-year-old woman with CML, who successively suffered from monocytic blast crisis, lymphoid blast crisis, and central nervous system EBC. She had an overwhelmingly positive response to taking Dasatinib and eventually achieved lasting complete remission. PMID:25785155

  12. 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.

  13. 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

  14. 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

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

    PubMed

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

    2017-04-01

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

  16. 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

  17. Heliox and noninvasive positive-pressure ventilation: a role for heliox in exacerbations of chronic obstructive pulmonary disease?

    PubMed

    Hess, Dean R

    2006-06-01

    Evidence-based respiratory therapy for exacerbations of chronic obstructive pulmonary disease (COPD) includes oxygen, inhaled bronchodilators, and noninvasive positive-pressure ventilation. Examining the physics of gas flow, a case can be made either for or against the use of helium-oxygen mixture (heliox) in the care of patients with COPD. The evidence for the use of heliox in patients with COPD exacerbation is not strong at present. Most of the peer-reviewed literature consists of case reports, case series, and physiologic studies in small samples of carefully selected patients. Some patients with COPD exacerbation have a favorable physiologic response to heliox therapy, but predicting who will be a responder is difficult. Moreover, the use of heliox is hampered by the lack of widespread availability of an approved heliox delivery system. Appropriately designed randomized controlled trials with patient-important outcomes, such as avoidance of intubation, decreased intensive-care-unit and hospital days, and decreased cost of therapy, are sorely needed to establish the role of heliox in patients with COPD exacerbation, including those receiving noninvasive positive-pressure ventilation. Lacking such evidence, the use of heliox in patients with COPD exacerbation cannot be considered standard therapy.

  18. Results of therapy with interferon alpha and cyclic combination chemotherapy in patients with philadelphia chromosome positive chronic myelogenous leukemia in early chronic phase.

    PubMed

    Giles, F J; Kantarjian, H; O'Brien, S; Rios, M B; Cortes, J; Beran, M; Koller, C; Keating, M; Talpaz, M

    2001-04-01

    The objective of the study was to investigate the toxicity and efficacy of cyclic combination therapy offered to patients with Ph-positive CML having a sub-optimal response to IFN-alpha. Patients in early chronic phase CML were treated with IFN-alpha at 5MU/m(2) daily. Patients who did not achieve cytogenetic response after 6 months of IFN-alpha therapy, or Ph-suppression to less than 35% Ph-positive cells (partial cytogenetic response) after 12 months of therapy were offered cyclic intensive chemotherapy every 6 months, with IFN-alpha maintenance between cycles. The initial 3 cycles included daunorubicin, vincristine, cytosine arabinoside (ara-C) and prednisone (DOAP). Later cycles were given with cyclophosphamide replacing daunorubicin (COAP). Of 74 patients treated, 61 (82%) achieved complete hematologic response (CHR): 51 (69%) had a cytogenetic response, which was major (Ph < 35%) in 31 (42%), and complete in 23 (31%). Fifty-five patients (74%) achieved CHR by 6 months of therapy, 38 (69%; 51% of total) with a cytogenetic response - 13 (24%) had a major cytogenetic response. Seventeen patients received at least 1 course of DOAP therapy. Median survival of the overall cohort of patients was 120 months. With a median follow-up of 145 months (103+ to 155+ months), 40 patients (54%) have died. The median duration of cytogenetic response was 35 months (range 3 to 149+ months) and the estimated 10-year cytogenetic response rate was 37%. A durable complete cytogenetic response was observed in 16 patients (20%) with a median duration of 139+ months (range 12+ to 149+ months), 11 of them (15%) are now off IFN-alpha therapy for a median of 57+ months (range 12+ to 128+ months). The projected 10-year survival was 50% for the study group versus 35% for 208 patients who received other IFN-alpha based regimens at the MD Anderson Cancer Center (p<.01). In conclusion, the addition of intensive chemotherapy may improve survival in patients with CML who have not obtained an

  19. 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

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

    PubMed

    O'Sullivan, Jennifer M; Harrison, Claire N

    2017-02-03

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

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

    PubMed

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

    2009-11-01

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

  2. 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

  3. Oscillating Positive Expiratory Pressure on Respiratory Resistance in Chronic Obstructive Pulmonary Disease With a Small Amount of Secretion

    PubMed Central

    Gastaldi, Ada Clarice; Paredi, Paolo; Talwar, Anjana; Meah, Sally; Barnes, Peter J.; Usmani, Omar S.

    2015-01-01

    Abstract This study aims to evaluate the acute effects of an oscillating positive expiratory pressure device (flutter) on airways resistance in patients with chronic obstructive pulmonary disease (COPD). Randomized crossover study: 15 COPD outpatients from Asthma Lab–Royal Brompton Hospital underwent spirometry, impulse oscillometry (IOS) for respiratory resistance (R) and reactance (X), and fraction exhaled nitric oxide (FeNO) measures. Thirty minutes of flutter exercises: a “flutter-sham” procedure was used as a control, and airway responses after a short-acting bronchodilator were also assessed. Respiratory system resistance (R): in COPD patients an increase in X5insp (−0.21 to −0.33 kPa/L/s) and Fres (24.95 to 26.16 Hz) occurred immediately after flutter exercises without bronchodilator. Following 20 min of rest, a decrease in the R5, ΔR5, R20, X5, and Ax was observed, with R5, R20, and X5 values lower than baseline, with a moderate effect size; there were no changes in FeNO levels or spirometry. The use of flutter can decrease the respiratory system resistance and reactance and expiratory flow limitation in stable COPD patients with small amounts of secretions. PMID:26496331

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

    PubMed Central

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

    2016-01-01

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

  5. 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

  6. 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

  7. False-positive PCR detection of Tropheryma whipplei in cerebrospinal fluid and biopsy samples from a child with chronic lymphocytic meningitis.

    PubMed

    Goyo, Daniel; Camacho, Ana; Gómez, Carmen; de Las Heras, Rogelio Simón; Otero, Joaquín R; Chaves, Fernando

    2009-11-01

    We report the case of a teenager with chronic lymphocytic meningitis for whom Tropheryma whipplei 16S rRNA PCR results were positive in two cerebrospinal fluid samples and one duodenal biopsy specimen. PCR targeting another specific sequence of Tropheryma whipplei and sequencing of the initially amplified 16S rRNA fragment did not confirm the results.

  8. Elastic Tape Improved Shoulder Joint Position Sense in Chronic Hemiparetic Subjects: A Randomized Sham-Controlled Crossover Study

    PubMed Central

    Souza, Matheus Bragança; Desloovere, Kaat; Russo, Thiago Luiz

    2017-01-01

    Background Elastic tape has been widely used in clinical practice in order to improve upper limb (UL) sensibility. However, there is little evidence that supports this type of intervention in stroke patients. Objective To verify the effect of elastic tape, applied to the paretic shoulder, on joint position sense (JPS) during abduction and flexion in subjects with chronic hemiparesis compared to sham tape (non-elastic tape). Furthermore, to verify if this potential effect is correlated to shoulder subluxation measurements and sensorimotor impairment. Methods A crossover and sham-controlled study was conducted with post-stroke patients who were randomly allocated into two groups: 1) those who received Sham Tape (ST) first and after one month they received Elastic Tape (ET); 2) those who received Elastic Tape (ET) first and after one month they received Sham Tape (ST). The JPS was evaluated using a dynamometer. The absolute error for shoulder abduction and flexion at 30° and 60° was calculated. Sensorimotor impairment was determined by Fugl-Meyer, and shoulder subluxation was measured using a caliper. Results Thirteen hemiparetic subjects (average time since stroke 75.23 months) participated in the study. At baseline (before interventions), the groups were not different for abduction at 30° (p = 0.805; p = 0.951), and 60° (p = 0.509; p = 0.799), or flexion at 30° (p = 0.872; p = 0.897) and 60° (p = 0.853; p = 0.970). For the ET group, differences between pre and post-elastic tape for abduction at 30° (p<0.010) and 60° (p<0.010), and flexion at 30° p<0.010) and 60° (p<0.010) were observed. For the ST group, differences were also observed between pre and post-elastic tape for abduction at 30° (p<0.010) and 60° (p<0.010), and flexion at 30° (p<0.010,) and 60° (p<0.010). Potential effects were only correlated with shoulder subluxation during abduction at 30° (p = 0.001, r = -0.92) and 60° (p = 0.020, r = -0.75). Conclusion Elastic tape improved shoulder

  9. 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

  10. Painful ANA-positive scleroderma-like disease with acral ulcerations: a case of chronic gangrenous ergotism.

    PubMed

    Wollina, Uwe; Hansel, Gesine; Gruner, Monika; Schönlebe, Jaqueline; Heinig, Birgit; Köstler, Erich

    2007-09-01

    Chronic ergotism is a rare cause of limb ischemia. In this case report, the authors present a 62-year-old woman with history of long-term use of ergotamine alkaloids for the treatment of menstrual pain, who developed a severe painful disease initially misdiagnosed as systemic sclerosis (scleroderma) for 3 decades. She presented with a combination of acral gangrene, foot ulcer, renal obstruction, mild pulmonary fibrosis, and reduced esophageal motility. Right-sided renal obstruction was evident. The condition was extremely painful and had led to muscular contractions and immobility, drug abuse, and anemia. After establishing the diagnosis of chronic gangrenous ergotism, changing drug therapy, mobilization, and treatment of chronic wounds, she showed a remarkable recovery. Eventually the foot ulcer was closed successfully using a mesh graft transplantation, and the patient was able to walk alone. Chronic ergotism is rare but has to be taken into account when presented with painful chronic digital and foot ulcers.

  11. Prevalence of chronic headache with and without medication overuse: associations with socioeconomic position and physical and mental health status.

    PubMed

    Westergaard, Maria Lurenda; Glümer, Charlotte; Hansen, Ebba Holme; Jensen, Rigmor Højland

    2014-10-01

    Near-daily intake of acute symptomatic medication for frequent headache increases the risk for medication-overuse headache (MOH). Chronic headache (CH) and MOH prevalences are inversely related to socioeconomic position (SEP). It is not known how SEP influences the health status of people with these headaches. This cross-sectional study examined the prevalence of CH in Denmark; possible associations between CH and education, work status, and income; and the health status of people with CH across socioeconomic strata. A total of 129,150 individuals aged ⩾ 16 years were invited to the 2010 Danish National Health Survey. Data on SEP indicators and purchases of prescription drugs in 2009 were retrieved from national registers. Respondents with headache ⩾ 15 days per month over 3 months were classified as having CH. Those with concurrent over-the-counter analgesic intake of ⩾ 15 days per month or prescription medication overuse (⩾ 20 or ⩾ 30 defined daily doses per month depending on the drug or drugs) were classified as having MOH. Associations between headache and SEP were analyzed by logistic regression, and associations between headache and health status scores, by linear regression. Physical and mental health composite scores (SF-12) were summarized per headache group, stratified by SEP, and compared to the sample mean. Analyses were adjusted for stratified sampling and nonresponse. The response rate was 53.1%. CH prevalence was 3.3% with 53.0% of cases having concurrent medication overuse (MOH prevalence 1.8%). CH was more prevalent among those individuals with low SEP. Health status scores were significantly lower among persons with CH in all SEP categories. The burden of CH can be reduced by preventing and treating MOH.

  12. Whole-exome sequencing reveals potential molecular predictors of relapse after discontinuation of the targeted therapy in chronic myeloid leukemia patients.

    PubMed

    Smirnikhina, Svetlana A; Lavrov, Alexander V; Chelysheva, Ekaterina Yu; Adilgereeva, Elmira P; Shukhov, Oleg A; Turkina, Anna; Kutsev, Sergey I

    2016-07-01

    Chronic myeloid leukemia (CML) is a myeloproliferative disease well treated by tyrosine kinase inhibitors (TKIs). The aim was to identify genes with a predictive value for relapse-free survival after TKI cessation in CML patients. We performed whole-exome sequencing of DNA from six CML patients in long-lasting deep molecular remission. Patients were divided into two groups with relapse (n = 3) and without relapse (n = 3) after TKI discontinuation. We found variants in genes CYP1B1, ALPK2, and IRF1 in group of patients with relapse and one variant in gene PARP9 in group of patients without relapse. We verified prognostic value of the found markers in a small group of patients with TKI discontinuation and demonstrated their high sensitivity (77%), specificity (86%), positive (85%), and negative (79%) predictive values. Thus we revealed genetic variants, which are potential markers of outcome prediction in CML patients after TKI discontinuation.

  13. 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

  14. 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.

  15. Evolving Therapeutic Strategies for the Classic Philadelphia-Negative Myeloproliferative Neoplasms

    PubMed Central

    Kaplan, Jason B.; Stein, Brady L.; McMahon, Brandon; Giles, Francis J.; Platanias, Leonidas C.

    2016-01-01

    Despite the emergence of JAK inhibitors, there is a need for disease-modifying treatments for Philadelphia-negative myeloproliferative neoplasms (MPNs). JAK inhibitors ameliorate symptoms and address splenomegaly, but because of the heterogeneous contributors to the disease process, JAK inhibitor monotherapy incompletely addresses the burden of disease. The ever-growing understanding of MPN pathogenesis has provided the rationale for testing novel and targeted therapeutic agents, as monotherapies or in combination, in preclinical and clinical settings. A number of intriguing options have emerged, and it is hoped that further progress will lead to significant changes in the natural history of MPNs. PMID:26870834

  16. 20 alpha-hydroxysteroid dehydrogenase expression in a murine virus-induced myeloproliferative syndrome.

    PubMed

    Marcovistz, R; Le Bousse-Kerdiles, M C; Maillere, B; Smadja-Joffe, F; Poirrier, V; Jasmin, C

    1991-11-01

    The myeloproliferative sarcoma virus (MPSV) infection in DBA/2 mice leads to important quantitative and qualitative changes in their hemopoiesis. These findings suggest a disturbance in the production and action of a certain hemopoietic factor similar to IL3. Here, we show that the level of the 20 alpha-hydroxysteroid dehydrogenase (20 alpha-SDH) expression, which can be induced by IL3, is dramatically increased in spleen and thymus of MPSV-infected mice. Our results suggest that quantification of 20 alpha-SDH activity can be used to indicate abnormal production of a growth factor similar to IL3 in hemopoietic system diseases.

  17. Myeloproliferative Neoplasms, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology.

    PubMed

    Mesa, Ruben; Jamieson, Catriona; Bhatia, Ravi; Deininger, Michael W; Gerds, Aaron T; Gojo, Ivana; Gotlib, Jason; Gundabolu, Krishna; Hobbs, Gabriela; Klisovic, Rebecca B; Kropf, Patricia; Mohan, Sanjay R; Oh, Stephen; Padron, Eric; Podoltsev, Nikolai; Pollyea, Daniel A; Rampal, Raajit; Rein, Lindsay A M; Scott, Bart; Snyder, David S; Stein, Brady L; Verstovsek, Srdan; Wadleigh, Martha; Wang, Eunice S; Bergman, Mary Anne; Gregory, Kristina M; Sundar, Hema

    2016-12-01

    Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are a group of heterogeneous disorders of the hematopoietic system collectively known as Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). The diagnosis and the management of patients with MPNs have evolved since the identification of mutations that activate the JAK pathway (JAK2, CALR, and MPL mutations) and the development of targeted therapies has resulted in significant improvements in disease-related symptoms and quality of life. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnostic workup of MPN (MF, PV, and ET), risk stratification, treatment, and supportive care strategies for the management of MF.

  18. Best Clinical Practices for the Sleep Center Adjustment of Noninvasive Positive Pressure Ventilation (NPPV) in Stable Chronic Alveolar Hypoventilation Syndromes

    PubMed Central

    2010-01-01

    Summary: Noninvasive positive pressure ventilation (NPPV) devices are used during sleep to treat patients with diurnal chronic alveolar hypoventilation (CAH). Bilevel positive airway pressure (BPAP) using a mask interface is the most commonly used method to provide ventilatory support in these patients. BPAP devices deliver separately adjustable inspiratory positive airway pressure (IPAP) and expiratory positive airway pressure (EPAP). The IPAP and EPAP levels are adjusted to maintain upper airway patency, and the pressure support (PS = IPAP-EPAP) augments ventilation. NPPV devices can be used in the spontaneous mode (the patient cycles the device from EPAP to IPAP), the spontaneous timed (ST) mode (a backup rate is available to deliver IPAP for the set inspiratory time if the patient does not trigger an IPAP/EPAP cycle within a set time window), and the timed (T) mode (inspiratory time and respiratory rate are fixed). During NPPV titration with polysomnography (PSG), the pressure settings, backup rate, and inspiratory time (if applicable) are adjusted to maintain upper airway patency and support ventilation. However, there are no widely available guidelines for the titration of NPPV in the sleep center. A NPPV Titration Task Force of the American Academy of Sleep Medicine reviewed the available literature and developed recommendations based on consensus and published evidence when available. The major recommendations derived by this consensus process are as follows: General Recommendations:The indications, goals of treatment, and side effects of NPPV treatment should be discussed in detail with the patient prior to the NPPV titration study.Careful mask fitting and a period of acclimatization to low pressure prior to the titration should be included as part of the NPPV protocol.NPPV titration with PSG is the recommended method to determine an effective level of nocturnal ventilatory support in patients with CAH. In circumstances in which NPPV treatment is initiated

  19. Activation of the thrombopoietin receptor by mutant calreticulin in CALR-mutant myeloproliferative neoplasms.

    PubMed

    Araki, Marito; Yang, Yinjie; Masubuchi, Nami; Hironaka, Yumi; Takei, Hiraku; Morishita, Soji; Mizukami, Yoshihisa; Kan, Shin; Shirane, Shuichi; Edahiro, Yoko; Sunami, Yoshitaka; Ohsaka, Akimichi; Komatsu, Norio

    2016-03-10

    Recurrent somatic mutations of calreticulin (CALR) have been identified in patients harboring myeloproliferative neoplasms; however, their role in tumorigenesis remains elusive. Here, we found that the expression of mutant but not wild-type CALR induces the thrombopoietin (TPO)-independent growth of UT-7/TPO cells. We demonstrated that c-MPL, the TPO receptor, is required for this cytokine-independent growth of UT-7/TPO cells. Mutant CALR preferentially associates with c-MPL that is bound to Janus kinase 2 (JAK2) over the wild-type protein. Furthermore, we demonstrated that the mutant-specific carboxyl terminus portion of CALR interferes with the P-domain of CALR to allow the N-domain to interact with c-MPL, providing an explanation for the gain-of-function property of mutant CALR. We showed that mutant CALR induces the phosphorylation of JAK2 and its downstream signaling molecules in UT-7/TPO cells and that this induction was blocked by JAK2 inhibitor treatment. Finally, we demonstrated that c-MPL is required for TPO-independent megakaryopoiesis in induced pluripotent stem cell-derived hematopoietic stem cells harboring the CALR mutation. These findings imply that mutant CALR activates the JAK2 downstream pathway via its association with c-MPL. Considering these results, we propose that mutant CALR promotes myeloproliferative neoplasm development by activating c-MPL and its downstream pathway.

  20. Chronic kidney disease as a global public health problem: approaches and initiatives - a position statement from Kidney Disease Improving Global Outcomes.

    PubMed

    Levey, A S; Atkins, R; Coresh, J; Cohen, E P; Collins, A J; Eckardt, K-U; Nahas, M E; Jaber, B L; Jadoul, M; Levin, A; Powe, N R; Rossert, J; Wheeler, D C; Lameire, N; Eknoyan, G

    2007-08-01

    Chronic kidney disease (CKD) is increasingly recognized as a global public health problem. There is now convincing evidence that CKD can be detected using simple laboratory tests, and that treatment can prevent or delay complications of decreased kidney function, slow the progression of kidney disease, and reduce the risk of cardiovascular disease (CVD). Translating these advances to simple and applicable public health measures must be adopted as a goal worldwide. Understanding the relationship between CKD and other chronic diseases is important to developing a public health policy to improve outcomes. The 2004 Kidney Disease Improving Global Outcomes (KDIGO) Controversies Conference on 'Definition and Classification of Chronic Kidney Disease' represented an important endorsement of the Kidney Disease Outcome Quality Initiative definition and classification of CKD by the international community. The 2006 KDIGO Controversies Conference on CKD was convened to consider six major topics: (1) CKD classification, (2) CKD screening and surveillance, (3) public policy for CKD, (4) CVD and CVD risk factors as risk factors for development and progression of CKD, (5) association of CKD with chronic infections, and (6) association of CKD with cancer. This report contains the recommendations from the meeting. It has been reviewed by the conference participants and approved as position statement by the KDIGO Board of Directors. KDIGO will work in collaboration with international and national public health organizations to facilitate implementation of these recommendations.

  1. Successful treatment with oseltamivir phosphate in a patient with chronic immune thrombocytopenia positive for anti-GPIb/IX autoantibody.

    PubMed

    Shao, Linlin; Wu, Yang; Zhou, Hai; Qin, Ping; Ni, Heyu; Peng, Jun; Hou, Ming

    2015-01-01

    The management of chronic immune thrombocytopenia (ITP) remains to be a challenge. Oseltamivir phosphate is a sialidase inhibitor agent used to treat influenza in the conventional sense. At present, we demonstrate for the first time that an adult chronic ITP patient with anti-GP Ib/IX autoantibody, who was resistant to corticosteroids, IVIG, recombinant human thrombopoietin, rituximab, danazol and vindesine, but was successfully treated with oseltamivir phosphate. Through flow cytometric analysis of β-galactose and β-GlcNAc exposure on platelet surfaces, we showed that oseltamivir phosphate could reduce the desialylation level of platelet glycoproteins in ITP patient. The substantial alleviation of thrombocytopenia in this case, though not leading to conclusions, lays a foundation for a novel approach for the treatment of ITP.

  2. 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

  3. 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

  4. Insulin resistance, selfish brain, and selfish immune system: an evolutionarily positively selected program used in chronic inflammatory diseases

    PubMed Central

    2014-01-01

    Insulin resistance (IR) is a general phenomenon of many physiological states, disease states, and diseases. IR has been described in diabetes mellitus, obesity, infection, sepsis, trauma, painful states such as postoperative pain and migraine, schizophrenia, major depression, chronic mental stress, and others. In arthritis, abnormalities of glucose homeostasis were described in 1920; and in 1950 combined glucose and insulin tests unmistakably demonstrated IR. The phenomenon is now described in rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, polymyalgia rheumatica, and others. In chronic inflammatory diseases, cytokine-neutralizing strategies normalize insulin sensitivity. This paper delineates that IR is either based on inflammatory factors (activation of the immune/ repair system) or on the brain (mental activation via stress axes). Due to the selfishness of the immune system and the selfishness of the brain, both can induce IR independent of each other. Consequently, the immune system can block the brain (for example, by sickness behavior) and the brain can block the immune system (for example, stress-induced immune system alterations). Based on considerations of evolutionary medicine, it is discussed that obesity per se is not a disease. Obesity-related IR depends on provoking factors from either the immune system or the brain. Chronic inflammation and/or stress axis activation are thus needed for obesity-related IR. Due to redundant pathways in stimulating IR, a simple one factor-neutralizing strategy might help in chronic inflammatory diseases (inflammation is the key), but not in obesity-related IR. The new considerations towards IR are interrelated to the published theories of IR (thrifty genotype, thrifty phenotype, and others). PMID:25608958

  5. 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

  6. Updated and Expanded Study of Polycythemia Vera and Other Myeloproliferative Neoplasms in the Tri-County Area

    PubMed Central

    Buchanich, J. M.; Mertz, K. J.; Washington, T. L.; Logue, J. N.; Marchetto, D.; Roda, P. I.; Irvin-Barnwell, E.

    2016-01-01

    Introduction The results of a 2001–2005 polycythemia vera (PV) investigation in Eastern Pennsylvania revealed a disease cluster plus underreporting and false reporting to the Pennsylvania Cancer Registry (PCR). Purpose The objectives of this study were 1) to assess PV reporting to the PCR in 2006–2009, 2) to determine whether a cancer cluster persisted, and 3) to determine whether other myeloproliferative neoplasms (MPNs), including essential thrombocytopenia (ET), were subject to similar reporting problems. Methods Cases were identified from: 1) PCR records from the Tri-County, 2) reviewing billing records at Tri-County hematologist/oncologist offices, and 3) self-identification. An expert panel of physicians reviewed medical records and determined “true,” “false,” or “indeterminate” cases reported to the PCR. The analyses were conducted to determine sensitivity and positive predictive value (PPV) of case reporting to the PCR, estimate cancer incidence rates, and evaluate the presence of cancer clusters. Results Of 290 cases identified, 90% were from the original PCR, 9% from billing records, and 1% from self-report. Fifty-five cases consented to participate, and medical records were obtained for 44. The expert panel determined that 45% were true cases, 32% were false cases, and 23% were indeterminate. PV had 100% (95% CI, 59–100) sensitivity, but only 47% PPV (95% CI, 20–70): ET had 78% (95% CI, 47–99) sensitivity and 100% PPV (95% CI, 59–100). Low participation and chart review rates led to rates with wide confidence intervals. We did not identify any PV cancer clusters, but we did identify a cluster of 9 ET cases in the Wilkes-Barre, Pennsylvania area. Conclusion The current study was limited by the low response rate (22%) from MPN patients in the Tri-County area. This study identified 47% PPV for PV reporting and 100% PPV for ET. PMID:25803630

  7. Increased intrahepatic quasispecies heterogeneity correlates with off-treatment sustained response to nucleos(t)ide analogues in e antigen-positive chronic hepatitis B patients.

    PubMed

    Chen, L; Gan, Q R; Zhang, D Q; Yao, L F; Lin, R S; Li, Q; Lin, M H; Yu, D M; Zhang, X X; Pan, C

    2016-02-01

    Finite treatment with nucleos(t)ide analogues (NAs) remains a great challenge for chronic hepatitis B in the clinic. This study aimed to investigate the relationship between intrahepatic quasispecies heterogeneity and the NAs off-treatment outcomes in a prospective cohort. Eighteen HBeAg-positive patients with chronic hepatitis B who achieved the cessation criteria underwent liver biopsy, and stopped treatment thereafter. Patients were followed up prospectively for 1 year. The reverse transcriptase (RT) gene of intrahepatic hepatitis B virus (HBV) was cloned and sequenced. Intrahepatic quasispecies heterogeneity and specific gene mutations were analysed using bioinformatic methods. Ten patients achieved sustained response, and eight patients developed viral relapse. The intrahepatic quasispecies Shannon entropy and nucleotide diversity within either RT or the surface (S) region of patients with sustained response were significantly higher (p < 0.05) than those of patients who had a viral relapse. Intrahepatic quasispecies Shannon entropy at the nucleotide level predicted the sustained off-treatment response (area under receiver operating characteristics curve 0.925; 95% CI 0.807-1.000; p 0.003). More positive selection sites and N-glycosylation mutations within the S region were found in patients with sustained response than in the patients with viral relapse (p < 0.01). Most of the positive selection sites in patients with sustained response were located in reported HLA-I-restricted or HLA-II-restricted epitopes. Intrahepatic quasispecies heterogeneity at the end of treatment was correlated with off-treatment outcomes in HBeAg-positive patients with chronic hepatitis B. More immune escape mutations were found within the S region in patients with sustained response. The higher intrahepatic quasispecies heterogeneity indicated a more robust immune control over HBV, which in turn maintained a sustained response after withdrawal of NAs.

  8. 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.

  9. 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.

  10. The effect of a cellulose dressing and topical vancomycin on methicillin-resistant Staphylococcus aureus (MRSA) and Gram-positive organisms in chronic wounds: a case series.

    PubMed

    Albaugh, Karen W; Biely, Scott A; Cavorsi, Joseph P

    2013-05-01

    High levels of persistent bacteria may contribute to wound chronicity and delayed healing. A prospective study was conducted to: 1) evaluate the effect of applying vancomycin topically on appropriately cultured chronic lower leg wounds, specifically methicillin-resistant Staphylococcus aureus (MRSA) and Gram-positive bacteria, and 2) evaluate its effect in combination with a cellulose dressing on healing. Twenty-three (23) outpatients (11 men, 12 women, average age 65 years [range 39-89 years]) with lower extremity wounds (15 venous ulcers, six chronic open wounds with a history of diabetes, and two chronic open trauma wounds) averaging 43.58 weeks' (range 5-121 weeks) duration and swab-cultured positive for MRSA or Gram-positive bacteria were provided 1 g vancomycin delivered by a cellulose dressing and changed every 72 hours. Patients served as their own control, and all wounds were debrided once a week. Wound surface area and bacterial and exudate levels were recorded weekly during the 3-week pretreatment period and compared to 3-week treatment period levels. Patients were followed until healed. Mean change in wound surface area was +14.5% (SD 71.91) per week before and -24.6% (SD 13.59) during the vancomycin treatment period (P = 0.014), average exudate levels decreased from 2.75 (range 1-4) to 1.81 (range 0-3) (P = 0.016), and the number of patients with positive wound cultures for MRSA or Gram-positive bacteria decreased from 23 to four after the 3-week study period. All wounds healed after an average of 8.18 weeks (SD 4.76, range 2-17 weeks). The results of this study suggest topical vancomycin applied using a dressing that retains moisture reduces wound bacterial load and may facilitate healing. Randomized, controlled clinical studies to evaluate the effectiveness and efficacy of this treatment modality and explore the relationship between wound culture results and healing are warranted.

  11. Aberrant let7a/HMGA2 signaling activity with unique clinical phenotype in JAK2-mutated myeloproliferative neoplasms.

    PubMed

    Chen, Chih-Cheng; You, Jie-Yu; Lung, Jrhau; Huang, Cih-En; Chen, Yi-Yang; Leu, Yu-Wei; Ho, Hsing-Ying; Li, Chian-Pei; Lu, Chang-Hsien; Lee, Kuan-Der; Hsu, Chia-Chen; Gau, Jyh-Pyng

    2017-03-01

    High mobility group AT-hook 2 (HMGA2) is an architectural transcription factor that is negatively regulated by let-7 microRNA through binding to it's 3'-untranslated region. Transgenic mice expressing Hmga2 with a truncation of its 3'-untranslated region has been shown to exhibit a myeloproliferative phenotype. To decipher the let-7-HMGA2 axis in myeloproliferative neoplasms, we employed an in vitro model supplemented with clinical correlation. Ba/F3 cells with inducible JAK2V617F expression (Ton.JAK2.V617F cells) showed upregulation of HMGA2 with concurrent let-7a repression. Ton.JAK2.V617F cells treated with a let-7a inhibitor exhibited further escalation of Hmga2 expression, while a let-7a mimic diminished the Hmga2 transcript level. Hmga2 overexpression conferred JAK2-mutated cells with a survival advantage through inhibited apoptosis. A pan-JAK inhibitor, INC424, increased the expression of let-7a, downregulated the level of Hmga2, and led to increased apoptosis in Ton.JAK2.V617F cells in a dose-dependent manner. In samples from 151 patients with myeloproliferative neoplasms, there was a modest inverse correlation between the expression levels of let-7a and HMGA2 Overexpression of HMGA2 was detected in 29 (19.2%) of the cases, and it was more commonly seen in patients with essential thrombocythemia than in those with polycythemia vera (26.9% vs 12.7%, P=0.044). Patients with upregulated HMGA2 showed an increased propensity for developing major thrombotic events, and they were more likely to harbor one of the 3 driver myeloproliferative neoplasm mutations in JAK2, MPL and CALR Our findings suggest that, in a subset of myeloproliferative neoplasm patients, the let-7-HMGA2 axis plays a prominent role in the pathogenesis of the disease that leads to unique clinical phenotypes.

  12. Acute myelomonocytic leukemia with inv(16)(p13q22) complicating Philadelphia chromosome positive chronic myeloid leukemia.

    PubMed

    Heim, S; Christensen, B E; Fioretos, T; Sørensen, A G; Pedersen, N T

    1992-03-01

    The reciprocal translocation (9;22)(q34;q11) is highly characteristic of chronic myeloid leukemia (CML) and the pericentric inversion inv(16)(p13q22) is almost only found in acute nonlymphocytic leukemia of the myelomonocytic subtype (ANLL M4). Only twice before have an inv(16) and a t(9;22) been found in the same cells, and both times the patients seemed to have de novo ANLL M4. We describe the case of a 21-year-old man who in July 1986 presented with a clinically and hematologically classic chronic phase CML. Treatment with busulfan led to no improvement; instead in September 1986 he developed blast crisis with ANLL M4Eo morphology. He was now cytogenetically examined and the karyotype 45,X,-Y,t(9;22)(q34;q11),inv(16)(p13q22) was found. Southern blot analysis of the bone marrow DNA sampled at this time revealed a standard rearrangement in the 3' end of the M-bcr. Intensive cytostatic treatment caused cytopenia followed by complete hematologic, clinical, and cytogenetic reversal to chronic phase CML, so that in January 1987 the bone marrow karyotype was 46,XY,t(9;22)(q34;q11). Persistent splenomegaly was treated with splenectomy, and a chloroma of the skin was removed by irradiation. In March 1987 he received an allogeneic bone marrow transplant. Since then his only medical problem has been mild graft-versus-host disease; he is well and is working full time as a blacksmith.

  13. Differences and similarities in the trajectories of self-esteem and positive and negative affect in persons with chronic illness: an explorative longitudinal study

    PubMed Central

    Bonsaksen, Tore; Lerdal, Anners; Småstuen, Milada Cvancarova; Fagermoen, May Solveig

    2016-01-01

    Background Chronic illness is a risk factor for low self-esteem, and the research literature needs to include more studies of self-esteem and its development in chronic illness groups using longitudinal and comparative designs. The aim of this study was to explore the trajectories of self-esteem and of positive and negative affect in persons with morbid obesity and in persons with chronic obstructive pulmonary disease (COPD). Methods Patient education course attendants in Norway having morbid obesity (n=139) or COPD (n=97) participated in the study. Data concerning self-esteem, positive and negative affect, and sociodemographic background were collected at the start and at the end of the patient education, with subsequent follow-ups at 3, 6, and 12 months. Data were analyzed using linear mixed models for repeated measures. Results Taking all measurements into account, our data revealed a statistically significant increase in self-esteem for participants with morbid obesity but not for those with COPD. There were no significant differences in levels of negative and positive affect between the two groups, and the time-trajectories were also similar. However, participants in both groups achieved lower levels of negative affect for all the successive measurement points. Conclusion An increase in self-esteem during the first year after the patient education course was observed for persons with morbid obesity, but not for persons with COPD. Initial higher levels of self-esteem in the participants with COPD may indicate that they are less troubled with low self-esteem than people with morbid obesity are. The pattern of reduced negative affect for both groups during follow-up is promising. PMID:27574438

  14. Self-Management and Quality of Life in Chronic Obstructive Pulmonary Disease (COPD): The Mediating Effects of Positive Affect

    PubMed Central

    Benzo, Roberto P.; Abascal-Bolado, Beatriz; Dulohery, Megan M.

    2015-01-01

    Objective This study aimed to increase our understanding of general self-management (SM) abilities in COPD by determining if SM can predict disease specific quality of life (QoL), by investigating whether specific SM domains are significant in COPD and by exploring the mediating effect of the positive/negative affect in the association between SM and QoL. Methods Cross-sectional study based on 292 patients with COPD. Measures included demographics, lung function, gait speed, health care utilization, positive/negative affect, SM abilities, breathlessness and disease specific QoL. We performed, correlation, multiple regression models and mediation analysis (positive/negative affect being mediator between SM and QoL association). Results After controlling for breathlessness, living alone, marital status, hospitalization history, age and lung function, SM related to QoL (p< 0.0001). Investment in behaviors (hobbies and social relationships) and self-efficacy are SM domains independently related to QoL in COPD. Positivity measured by the positive/negative affect ratio completely mediates the relationship of SM with QoL. Conclusion SM is independently associated with disease specific QoL in COPD after adjustment significant covariates but positive/negative affect ratio completely mediates the relationship of SM with QoL. Practice implications Measuring positive/negative affect and addressing investment behavior and self-efficacy are important in implementing COPD-SM programs. PMID:26632024

  15. Hypercalcemia as the presenting feature of t-cell lymphoid blast crisis of ph-positive chronic myeloid leukemia.

    PubMed

    Nadal, E; Cervantes, F; Rosiñol, L; Talarn, C; Montserrat, E

    2001-03-01

    Hypercalcemia is a rare complication of chronic myeloid leukemia (CML), usually seen in the accelerated or blastic phases of the disease and associated with a poor prognosis. T-cell lymphoid phenotype is also an infrequent finding in the blast crisis (BC) of CML. A CML patient who had hypercalcemia as the presenting feature of a T-cell BC is reported. She was a 78 year-old woman who, at four months of CML diagnosis, developed weakness, bone pain, and mental confusion, with hypercalcemia being subsequently found. Although the peripheral blood and bone marrow were consistent with the chronic phase of CML, mediastinal enlargement, a soft tissue mass adjacent to the iliac bone, and multiple osteolytic lesions were seen. Serum levels of parathyroid hormone (PTH) and PTH-related peptide were normal, whereas the search for a second neoplasm was negative. The hypercalcemia initially responded to conventional treatment, but it reappeared two weeks later. Coincidentally, a high proportion of blast cells of T-cell origin at the cortical thymocyte stage were observed in the patient's peripheral blood and bone marrow, and she died shortly afterwards.

  16. Mutations with epigenetic effects in myeloproliferative neoplasms and recent progress in treatment: Proceedings from the 5th International Post-ASH Symposium

    PubMed Central

    Tefferi, A; Abdel-Wahab, O; Cervantes, F; Crispino, J D; Finazzi, G; Girodon, F; Gisslinger, H; Gotlib, J; Kiladjian, J-J; Levine, R L; Licht, J D; Mullally, A; Odenike, O; Pardanani, A; Silver, R T; Solary, E; Mughal, T

    2011-01-01

    Immediately following the 2010 annual American Society of Hematology (ASH) meeting, the 5th International Post-ASH Symposium on Chronic Myelogenous Leukemia and BCR-ABL1-Negative Myeloproliferative Neoplasms (MPNs) took place on 7–8 December 2010 in Orlando, Florida, USA. During this meeting, the most recent advances in laboratory research and clinical practice, including those that were presented at the 2010 ASH meeting, were discussed among recognized authorities in the field. The current paper summarizes the proceedings of this meeting in BCR-ABL1-negative MPN. We provide a detailed overview of new mutations with putative epigenetic effects (TET oncogene family member 2 (TET2), additional sex comb-like 1 (ASXL1), isocitrate dehydrogenase (IDH) and enhancer of zeste homolog 2 (EZH2)) and an update on treatment with Janus kinase (JAK) inhibitors, pomalidomide, everolimus, interferon-α, midostaurin and cladribine. In addition, the new ‘Dynamic International Prognostic Scoring System (DIPSS)-plus' prognostic model for primary myelofibrosis (PMF) and the clinical relevance of distinguishing essential thrombocythemia from prefibrotic PMF are discussed. PMID:23471017

  17. 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.

  18. 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

  19. Vimentin-positive astrocytes in canine distemper: a target for canine distemper virus especially in chronic demyelinating lesions?

    PubMed

    Seehusen, Frauke; Orlando, Enzo A; Wewetzer, Konstantin; Baumgärtner, Wolfgang

    2007-12-01

    In canine distemper demyelinating leukoencephalitis (DL), caused by canine distemper virus (CDV), astrocytes represent the main virus target. In these cells, glial fibrillary acidic protein (GFAP) is the main intermediate filament, whereas vimentin occurs early in the astrocytic lineage and is replaced gradually by GFAP. To further characterize the role of astrocytic infection in dogs with DL, an animal model for multiple sclerosis, formalin-fixed paraffin-embedded cerebella were investigated immunohistochemically and by immunofluorescence. The expression and morphological alterations of these intermediate filaments were also determined by immunofluorescence studies of CDV-infected canine mixed brain cell cultures. In acute distemper lesions, the astrocytic response was mainly composed of GFAP- and CDV-positive cells. In contrast, vimentin-positive astrocyte-like cells were present in advanced lesions, which represented the main cell type harboring the pathogen, indicating a change in cell tropism and/or susceptibility of glial cells during lesion progression in CDV encephalomyelitis. Canine cell cultures were composed of GFAP-positive astrocytes, vimentin-positive cells and other glial cells. Following infection with the CDV-R252 strain, GFAP-positive astrocytes, especially multinucleated syncytial giant cells, displayed a disrupted cytoskeleton, whereas vimentin-positive cells though more frequently infected did not show any alteration in the filament network. This indicates increased vulnerability of mature GFAP-positive astrocytes compared to immature, vimentin-positive astrocytes. The latter, however, exhibited increased susceptibility to CDV. To conclude, the present findings indicate a change in cell tropism of CDV and/or the occurrence of less differentiated astrocytes representing a permanent source for virus infection and spread in advanced lesions of DL.

  20. 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.

  1. 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

  2. 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

  3. Monitoring Minimal Residual Disease in the Myeloproliferative Neoplasms: Current Applications and Emerging Approaches

    PubMed Central

    2016-01-01

    The presence of acquired mutations within the JAK2, CALR, and MPL genes in the majority of patients with myeloproliferative neoplasms (MPN) affords the opportunity to utilise these mutations as markers of minimal residual disease (MRD). Reduction of the mutated allele burden has been reported in response to a number of therapeutic modalities including interferon, JAK inhibitors, and allogeneic stem cell transplantation; novel therapies in development will also require assessment of efficacy. Real-time quantitative PCR has been widely adopted for recurrent point mutations with assays demonstrating the specificity, sensitivity, and reproducibility required for clinical utility. More recently, approaches such as digital PCR have demonstrated comparable, if not improved, assay characteristics and are likely to play an increasing role in MRD monitoring. While next-generation sequencing is increasingly valuable as a tool for diagnosis of MPN, its role in the assessment of MRD requires further evaluation. PMID:27840830

  4. Post-therapeutic acute malignant myeloproliferative syndrome and acute nonlymphocytic leukemia in non-Hodgkin's lymphoma

    SciTech Connect

    Gomez, G.A.; Aggarwal, K.K.; Han, T.

    1982-12-01

    In a prospective randomized study of treatment with radiation therapy (RT) or RT + chemotherapy (CT) for patients with non-Hodgkin's lymphoma Stages I-III, one patient developed an acute malignant myeloproliferative syndrome (AMMS) and four others acute nonlymphocytic leukemia (ANLL). There was correlation between the intensity of treatment and development of this complication: Among patients treated with local radiation with or without chemotherapy no cases of AMMS or ANLL were observed. However, patients treated with total lymphoid irradiation alone (TLI) had an observed to expected ratio of 162. Among patients treated with TLI plus CT this ratio increased to over 1000. The cytogenetic, clinical, and hematologic abnormalities of these patients are discussed.

  5. Health resource utilization and cost associated with myeloproliferative neoplasms in a large United States health plan.

    PubMed

    Mehta, Jyotsna; Wang, Hongwei; Fryzek, Jon P; Iqbal, Sheikh Usman; Mesa, Ruben

    2014-10-01

    Myelofibrosis (MF), polycythemia vera (PV) and essential thrombocythemia (ET) may lead to bone marrow fibrosis. Because the disease course of ET and PV are long and the disease course of MF may be fatal, healthcare resource utilization (HRU) associated costs of these neoplasms are especially important to understand. We used a large US health insurance claim database to describe the costs of these diseases. Compared to age-gender matched comparisons without myeloproliferative neoplasms (MPN), all aspects of HRU that we examined, including inpatient, outpatient and emergency room visits and pharmacy, as well as overall healthcare expenditures, were significantly higher in patients with MF, PV and ET (e.g. MF total costs = $54 168 vs. $10 203; PV = $14 903 vs. $7913; ET = $29 553 vs. $8026) than in matched comparisons. In order to reduce the burden of illness associated with these diseases, continued efforts in the development of more efficacious treatments for these disorders are needed.

  6. 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.

  7. Splanchnic vein thrombosis in myeloproliferative neoplasms: pathophysiology and molecular mechanisms of disease

    PubMed Central

    How, Joan; Zhou, Amy; Oh, Stephen T.

    2016-01-01

    Myeloproliferative neoplasms (MPNs) are the most common underlying prothrombotic disorder found in patients with splanchnic vein thrombosis (SVT). Clinical risk factors for MPN-associated SVTs include younger age, female sex, concomitant hypercoagulable disorders, and the JAK2 V617F mutation. These risk factors are distinct from those associated with arterial or deep venous thrombosis (DVT) in MPN patients, suggesting disparate disease mechanisms. The pathophysiology of SVT is thought to derive from local interactions between activated blood cells and the unique splanchnic endothelial environment. Other mutations commonly found in MPNs, including CALR and MPL, are rare in MPN-associated SVT. The purpose of this article is to review the clinical and molecular risk factors for MPN-associated SVT, with particular focus on the possible mechanisms of SVT formation in MPN patients. PMID:28246554

  8. Novel germline mutations in the calreticulin gene: implications for the diagnosis of myeloproliferative neoplasms.

    PubMed

    Szuber, Natasha; Lamontagne, Bruno; Busque, Lambert

    2016-07-27

    Mutations in the calreticulin (CALR) gene are found in the majority of Janus kinase 2-negative myeloproliferative neoplasms MPN and, thus far, have exclusively been reported as acquired, somatic mutations. We assessed the mutational status of exon 9 of the CALR gene in 2000 blood samples submitted to our centre and identified 12 subjects (0.6%) harbouring distinctive CALR mutations, all with an allelic frequency of 50% and all involving indels occurring as multiples of 3 bp. Buccal cell samples obtained from these patients confirmed the germline nature of the mutations. Importantly, these germline mutations were not diagnostic of MPN. We thus report for the first time the identification and confirmation of germline mutations in CALR distinct from those somatic mutations that define classical MPN. The finding of a non-standard CALR mutation with an allelic frequency of 50% should raise suspicion of the possibility of a germline CALR mutation and these cases investigated further.

  9. Myeloproliferative Disease: An Unusual Cause of Raynaud's Phenomenon and Digital Ischaemia

    PubMed Central

    Huws, Gwenan; Lawson, Tom

    2016-01-01

    We describe a 59-year-old female who presented with ischaemic digits, preceded by a 6-month history of Raynaud's phenomenon affecting her fingers and toes. There were no clinical or laboratory features of primary vasculitis or connective tissue disease, Doppler imaging was normal, and bloods were unremarkable aside from a platelet count of 786 × 109/L (150–400) and white cells of 16 × 109/L (4–11). In view of the thrombocytosis a JAK2 mutation assay was requested which confirmed a JAK2 V617F mutation, suggesting essential thrombocytosis (ET) as the cause. She received treatment with hydroxycarbamide which normalised her platelet count and led to a complete resolution of her Raynaud's symptoms. Raynaud's phenomenon is a rare manifestation of ET. Myeloproliferative disorders such as ET should be considered in the differential diagnosis of Raynaud's phenomenon and vasculitis. PMID:27895669

  10. Chasing down the triple-negative myeloproliferative neoplasms: Implications for molecular diagnostics.

    PubMed

    Langabeer, Stephen E

    2016-01-01

    The majority of patients with classical myeloproliferative neoplasms (MPN) of polycythemia vera, essential thrombocythemia, and primary myelofibrosis harbor distinct disease-driving mutations within the JAK2, CALR, or MPL genes. The term triple-negative has been recently applied to those MPN without evidence of these consistent mutations, prompting whole or targeted exome sequencing approaches to determine the driver mutational status of this subgroup. These strategies have identified numerous novel mutations that occur in alternative exons of both JAK2 and MPL, the majority of which result in functional activation. Current molecular diagnostic approaches may possess insufficient coverage to detect these alternative mutations, prompting further consideration of targeted exon sequencing into routine diagnostic practice. How to incorporate these illuminating findings into the expanding molecular diagnostic algorithm for MPN requires continual attention.

  11. Splanchnic vein thrombosis in myeloproliferative neoplasms: pathophysiology and molecular mechanisms of disease.

    PubMed

    How, Joan; Zhou, Amy; Oh, Stephen T

    2017-03-01

    Myeloproliferative neoplasms (MPNs) are the most common underlying prothrombotic disorder found in patients with splanchnic vein thrombosis (SVT). Clinical risk factors for MPN-associated SVTs include younger age, female sex, concomitant hypercoagulable disorders, and the JAK2 V617F mutation. These risk factors are distinct from those associated with arterial or deep venous thrombosis (DVT) in MPN patients, suggesting disparate disease mechanisms. The pathophysiology of SVT is thought to derive from local interactions between activated blood cells and the unique splanchnic endothelial environment. Other mutations commonly found in MPNs, including CALR and MPL, are rare in MPN-associated SVT. The purpose of this article is to review the clinical and molecular risk factors for MPN-associated SVT, with particular focus on the possible mechanisms of SVT formation in MPN patients.

  12. Myeloproliferative Disease: An Unusual Cause of Raynaud's Phenomenon and Digital Ischaemia.

    PubMed

    Beynon, Celia; Huws, Gwenan; Lawson, Tom

    2016-01-01

    We describe a 59-year-old female who presented with ischaemic digits, preceded by a 6-month history of Raynaud's phenomenon affecting her fingers and toes. There were no clinical or laboratory features of primary vasculitis or connective tissue disease, Doppler imaging was normal, and bloods were unremarkable aside from a platelet count of 786 × 109/L (150-400) and white cells of 16 × 109/L (4-11). In view of the thrombocytosis a JAK2 mutation assay was requested which confirmed a JAK2 V617F mutation, suggesting essential thrombocytosis (ET) as the cause. She received treatment with hydroxycarbamide which normalised her platelet count and led to a complete resolution of her Raynaud's symptoms. Raynaud's phenomenon is a rare manifestation of ET. Myeloproliferative disorders such as ET should be considered in the differential diagnosis of Raynaud's phenomenon and vasculitis.

  13. Ultrasound measurement of deep abdominal muscle activity in sitting positions with different stability levels in subjects with and without chronic low back pain.

    PubMed

    Rasouli, Omid; Arab, Amir Massoud; Amiri, Mohsen; Jaberzadeh, Shapour

    2011-08-01

    The purpose of this study was to investigate the changes in the thickness of the transversus abdominis (TrA) and internal oblique (IO) muscles in three sitting postures with different levels of stability. The technique of ultrasound imaging was used for individuals with and without chronic low back pain (LBP). A sample of 40 people participated in this study. Subjects were categorised into two groups: with LBP (N = 20) and without LBP (N = 20). Changes in the thickness of tested muscles were normalized under three different sitting postures to actual muscle thickness at rest in the supine lying position and were expressed as a percentage of thickness change. The percentage of thickness change in TrA and IO increased as the stability of the sitting position decreased in both groups. However, the percentages of thickness change in all positions were less in subjects with LBP. There was a significant difference in thickness change in TrA when sitting on a gym ball between subjects with and without LBP but no difference was found when sitting on a chair. There was no significant difference in thickness change in IO in all positions between the two groups. Our findings indicate that difference in the percentage of thickness change in TrA between subjects with and without LBP increases as the stability of sitting position decreases.

  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. 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

  16. [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.

  17. 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

  18. 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.

  19. 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

  20. Recombinant human erythropoietin treatment of chronic renal failure patients normalizes altered phenotype and proliferation of CD4-positive T lymphocytes.

    PubMed

    Lisowska, Katarzyna A; Debska-Slizien, Alicja; Radzka, Monika; Witkowski, Jacek M; Rutkowski, Boleslaw; Bryl, Ewa

    2010-03-01

    Patients with chronic renal failure (CRF) receive recombinant human erythropoietin (rhEPO) for the correction of anemia. However, rhEPO also has an immunomodulatory effect. Detailed changes of phenotype and function of CD4(+) T lymphocytes in CRF patients receiving rhEPO have not been reported yet; their study may bring insight into understanding of this immunomodulatory action of rhEPO. Two groups of CRF patients were included into the study: those treated; and those not receiving rhEPO. The expression of activation markers on CD4(+) lymphocytes was measured with flow cytometry, both ex vivo and in vitro. The kinetics of CD4(+) T lymphocytes proliferation was calculated using a dividing cells tracing method and numerical approach. Significantly higher percentages of CD4(+)CD95(+), CD4(+)HLA-DR(+) cells, and lower percentages of CD4(+)CD69(+) and CD4(+)CD28(+) cells were observed in both rhEPO-treated and untreated patients when compared with healthy controls. Changes in the proportions of CD4(+)CD28(+) and CD4(+)HLA-DR(+) subpopulations were dependent on the type of rhEPO, being more pronounced for rhEPObeta. CD4(+) lymphocytes from untreated patients exhibited decreased expression of CD28 and CD69 after stimulation in vitro, whereas the expression of these antigens on lymphocytes of rhEPO-treated patients was similar to that observed in healthy controls. Fewer CD4(+)CD28(+) T lymphocytes of untreated patients proliferated in vitro; these cells had longer G0-->G1 time, which negatively correlated with surface expression of CD28. Our study confirms that rhEPO treatment normalizes activation parameters of CD4(+) T lymphocytes and their proliferative capacity, which could explain earlier described immunomodulatory effects of rhEPO in patients suffering from CRF.

  1. 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

  2. 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

  3. 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

  4. An international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults.

    PubMed

    Savona, Michael R; Malcovati, Luca; Komrokji, Rami; Tiu, Ramon V; Mughal, Tariq I; Orazi, Attilio; Kiladjian, Jean-Jacques; Padron, Eric; Solary, Eric; Tibes, Raoul; Itzykson, Raphael; Cazzola, Mario; Mesa, Ruben; Maciejewski, Jaroslaw; Fenaux, Pierre; Garcia-Manero, Guillermo; Gerds, Aaron; Sanz, Guillermo; Niemeyer, Charlotte M; Cervantes, Francisco; Germing, Ulrich; Cross, Nicholas C P; List, Alan F

    2015-03-19

    Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) are hematologically diverse stem cell malignancies sharing phenotypic features of both myelodysplastic syndromes and myeloproliferative neoplasms. There are currently no standard treatment recommendations for most adult patients with MDS/MPN. To optimize efforts to improve the management and disease outcomes, it is essential to identify meaningful clinical and biologic end points and standardized response criteria for clinical trials. The dual dysplastic and proliferative features in these stem cell malignancies define their uniqueness and challenges. We propose response assessment guidelines to harmonize future clinical trials with the principal objective of establishing suitable treatment algorithms. An international panel comprising laboratory and clinical experts in MDS/MPN was established involving 3 independent academic MDS/MPN workshops (March 2013, December 2013, and June 2014). These recommendations are the result of this collaborative project sponsored by the MDS Foundation.

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

    PubMed

    Sachs, Zohar; Been, Raha A; DeCoursin, Krista J; Nguyen, Hanh T; Mohd Hassan, Nurul A; Noble-Orcutt, Klara E; Eckfeldt, Craig E; Pomeroy, Emily J; Diaz-Flores, Ernesto; Geurts, Jennifer L; Diers, Miechaleen D; Hasz, Diane E; Morgan, Kelly J; MacMillan, Margaret L; Shannon, Kevin M; Largaespada, David A; Wiesner, Stephen M

    2016-10-01

    Juvenile myelomonocytic leukemia is a rare myeloproliferative neoplasm characterized by hyperactive RAS signaling. Neurofibromin1 (encoded by the NF1 gene) is a negative regulator of RAS activation. Patients with neurofibromatosis type 1 harbor loss-of-function mutations in NF1 and have a 200- to 500-fold increased risk of juvenile myelomonocytic leukemia. Leukemia cells from patients with juvenile myelomonocytic leukemia display hypersensitivity to certain cytokines, such as granulocyte-macrophage colony-stimulating factor. The granulocyte-macrophage colony-stimulating factor receptor utilizes pre-associated JAK2 to initiate signals after ligand binding. JAK2 subsequently activates STAT5, among other downstream effectors. Although STAT5 is gaining recognition as an important mediator of growth factor signaling in myeloid leukemias, the contribution of STAT5 to the development of hyperactive RAS-initiated myeloproliferative disease has not been well described. In this study, we investigated the consequence of STAT5 attenuation via genetic and pharmacological approaches in Nf1-deficient murine models of juvenile myelomonocytic leukemia. We found that homozygous Stat5 deficiency extended the lifespan of Nf1-deficient mice and eliminated the development of myeloproliferative neoplasm associated with Nf1 gene loss. Likewise, we found that JAK inhibition with ruxolitinib attenuated myeloproliferative neoplasm in Nf1-deficient mice. Finally, we found that primary cells from a patient with KRAS-mutant juvenile myelomonocytic leukemia displayed reduced colony formation in response to JAK2 inhibition. Our findings establish a central role for STAT5 activation in the pathogenesis of juvenile myelomonocytic leukemia and suggest that targeting this pathway may be of clinical utility in these patients.

  6. Intravenous renal cell transplantation with SAA1-positive cells prevents the progression of chronic renal failure in rats with ischemic-diabetic nephropathy.

    PubMed

    Kelly, Katherine J; Zhang, Jizhong; Han, Ling; Wang, Mingsheng; Zhang, Shaobo; Dominguez, Jesus H

    2013-12-15

    Diabetic nephropathy, the most common cause of progressive chronic renal failure and end-stage renal disease, has now reached global proportions. The only means to rescue diabetic patients on dialysis is renal transplantation, a very effective therapy but severely limited by the availability of donor kidneys. Hence, we tested the role of intravenous renal cell transplantation (IRCT) on obese/diabetic Zucker/SHHF F1 hybrid (ZS) female rats with severe ischemic and diabetic nephropathy. Renal ischemia was produced by bilateral renal clamping of the renal arteries at 10 wk of age, and IRCT with genetically modified normal ZS male tubular cells was given intravenously at 15 and 20 wk of age. Rats were euthanized at 34 wk of age. IRCT with cells expressing serum amyloid A had strong and long-lasting beneficial effects on renal function and structure, including tubules and glomeruli. However, donor cells were found engrafted only in renal tubules 14 wk after the second infusion. The results indicate that IRCT with serum amyloid A-positive cells is effective in preventing the progression of chronic kidney disease in rats with diabetic and ischemic nephropathy.

  7. Philadelphia chromosome-negative non-Hodgkin's lymphoma occurring in Philadelphia chromosome-positive chronic myeloid leukemia: A case report and literature review

    PubMed Central

    SHEN, ZHENG-LEI; YIN, LIE-FEN; MAO, WEN-WEN; LIANG, JIN; YANG, LING

    2016-01-01

    The current study reports the case of a patient with Philadelphia chromosome-negative (Ph−) non-Hodgkin's lymphoma (NHL) and chronic phase (CP) Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) that also possessed characteristic enlarged lymph nodes. A lymph node biopsy resulted in the diagnosis of CP-CML, in addition to T-lymphoblastic cell NHL with negative break point cluster/Abelson tyrosine kinase fusion genes in the lymph node of the patient, which was diagnosed as Ph− NHL. A review of the literature was performed in the present study to investigate the genetic differences between Ph− NHL and Ph+ NHL in patients with CML. The median age of patients with NHL and CML was 41 years. The follow-up time of patients with Ph+ NHL was significantly shorter (mean, <6 months) compared to the follow-up time of patients with Ph− NHL (mean, >15 months). Therefore the present study concludes that Ph+ NHL may be more aggressive compared with Ph+ NHL. The present study suggests that additional studies are required to assess the clinical and genetic characteristics of NHL patients with CML. PMID:27073575

  8. 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.

  9. Prognostic and predictive implications of Sokal, Euro and EUTOS scores in chronic myeloid leukaemia in the imatinib era-experience from a tertiary oncology centre in Southern India.

    PubMed

    Kuntegowdanahalli, Lakshmaiah Chinnagiriyappa; Kanakasetty, Govind Babu; Thanky, Aditi Harsh; Dasappa, Lokanatha; Jacob, Linu Abraham; Mallekavu, Suresh Babu; Lakkavalli, Rajeev Krishnappa; Kadabur, Lokesh N; Haleshappa, Rudresha Antapura

    2016-01-01

    Chronic myeloid leukaemia (CML) is a myeloproliferative disorder. Over the years many prognostic models have been developed to better risk stratify this disease at baseline. Sokal, Euro, and EUTOS scores were developed in varied populations initially receiving various therapies. Here we try to identify their predictive and prognostic implication in a larger population of Indian patients with CML-CP (chronic phase) in the imatinib era.

  10. Imatinib Mesylate and Decitabine in Treating Patients With Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2013-01-22

    Accelerated Phase Chronic Myelogenous Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Childhood Chronic Myelogenous Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Relapsing Chronic Myelogenous Leukemia

  11. Effect of lamivudine treatment in patients with decompensated cirrhosis due to anti-HBe positive/HBeAg-negative chronic hepatitis B.

    PubMed

    Nikolaidis, Nikolaos; Vassiliadis, Themistoklis; Giouleme, Olga; Tziomalos, Konstantinos; Grammatikos, Nikolaos; Patsiaoura, Kalliopi; Orfanou-Koumerkeridou, Eleni; Balaska, Aikaterini; Eugenidis, Nikolaos

    2005-06-01

    Lamivudine has been shown to improve liver function and reduce the need for liver transplantation (LT) in patients with decompensated HBeAg-positive cirrhosis. Nevertheless, there is only limited experience with lamivudine in patients with anti-HBe-positive/HBeAg-negative cirrhosis. The primary aim of this study was to determine whether lamivudine treatment improves liver function and subsequently pre-LT survival or delays or obviates the need for LT in patients with anti-HBe-positive/HBeAg-negative cirrhosis. Between July 1998 and June 2003, 20 consecutive patients awaiting LT were enrolled in the study. All patients showed active viral replication and were treated with lamivudine 100 mg daily. Significant clinical improvement, defined as a decrease in the Child-Pugh-Turcotte score by >or=2 points, was observed in 11 (55%) patients. The median change in the Child-Pugh-Turcotte score was -2 (range -5 to +2). The median time required to achieve a 2-point or greater reduction in Child-Pugh-Turcotte score was 6 months (range 3-12 months). In nine patients (45%), the Child-Pugh-Turcotte score decreased to positive/HBeAg-negative cirrhosis caused by actively replicating chronic hepatitis B.

  12. Vitamin E for the treatment of children with hepatitis B e antigen-positive chronic hepatitis: A systematic review and meta-analysis

    PubMed Central

    Fiorino, Sirio; Bacchi-Reggiani, Maria Letizia; Leandri, Paolo; Loggi, Elisabetta; Andreone, Pietro

    2017-01-01

    AIM To assess vitamin E efficacy, defined as its ability to induce hepatitis B e antigen (HBeAg) seroconversion, in children with HBeAg-positive persistent hepatitis. METHODS In July 2016, we extracted articles published in MEDLINE and the Cochrane Library using the following search terms: “chronic hepatitis B”, “children”, “childhood”, “therapy”, “treatment”, “vitamin E”, “tocopherols”, “tocotrienols”. Only randomized controlled trials (RCTs) published in English language were collected. RESULTS Three RCTs met inclusion criteria and were considered in the present meta-analysis. Overall, 23/122 children in the treatment group underwent HBeAg seroconversion vs 3/74 in the control group (OR = 3.96, 95%CI: 1.18-13.25, P = 0.025). CONCLUSION Although our meta-analysis has several limits, including the very small number of available studies and enrolled children with HBeAg positivity-related hepatitis, it suggests that vitamin E use may enhance the probability to induce HBeAg seroconversion in these patients. Further well designed and adequately sized trials are required to confirm or deny these very preliminary results. PMID:28293383

  13. Positive Cervical Artery Testing in a Patient with Chronic Whiplash Syndrome: Clinical Decision-Making in the Presence of Diagnostic Uncertainty

    PubMed Central

    Graziano, David L.; Nitsch, Wanda; Huijbregts, Peter A.

    2007-01-01

    This case report describes the diagnosis and management of a 43-year-old female patient who had sustained an injury to her neck in a motor-vehicle accident two years earlier. The major symptoms described by the patient included headache and neck pain, but history and examination also revealed signs and symptoms potentially indicative of cervical artery compromise. Physical therapy management initially consisted of soft tissue and non-thrust joint manipulation of the lower cervical and thoracic spine, specific exercise prescription, and superficial heat. Cervical vascular compromise was re-evaluated by way of the sustained extension-rotation test. When at the fifth visit this test no longer produced symptoms potentially indicative of vascular compromise, upper cervical diagnosis and management consisting of soft tissue and non-thrust joint manipulation was added. A positive outcome was achieved both at the impairment level and with regard to limitations in activities, the latter including increased performance at work, a return to previous reading activities, improved length and quality of sleep, and greater comfort while driving. At discharge, the patient reported only occasional pain and mild limitations in activities. This report describes the positive outcomes in a patient with chronic whiplash syndrome; however, its main emphasis lies in the discussion and critical evaluation of clinical reasoning in the presence of diagnostic uncertainty with regard to cervical artery compromise. PMID:19066653

  14. Patients admitted with an acute exacerbation of chronic obstructive pulmonary disease had positive experiences exercising from the beginning of their hospital stay: a qualitative analysis.

    PubMed

    Tang, Clarice Y; Taylor, Nicholas F; Blackstock, Felicity C

    2013-01-01

    The aim of the study is to explore the experiences of inpatients with an acute exacerbation of chronic obstructive pulmonary disease, who participated in a very early exercise programme while acutely unwell. This qualitative study analysed responses from participant interviews as part of a mixed method trial whereby participants were randomly allocated into three groups: low intensity, moderate to high intensity aerobic and resistance exercises or a control group who received routine physiotherapy. Everyone allocated to the exercise groups were invited to participate in the qualitative study. Interviews were within a week post discharge and the results were analysed thematically. A total of 19 participants were interviewed and described their experience as positive and beneficial and reported an increased motivation towards exercising. These findings converged with the high levels of exercise adherence (83%) and within-group improvements in walking capacity observed in both exercise groups. Participants also reported commencement of a home exercise programme after discharge but intention to participate in community pulmonary rehabilitation remained low. Participation in a very early exercise programme while acutely unwell can lead to positive attitude towards exercise. The results converge with the quantitative results that provided preliminary evidence of programme feasibility and within-group improvement in exercise tolerance.

  15. C-Arm Computed Tomography Adds Diagnostic Information in Patients with Chronic Thromboembolic Pulmonary Hypertension and a Positive V/Q SPECT.

    PubMed

    Hinrichs, Jan B; Werncke, Thomas; Kaireit, Till; Hoeper, Marius M; Olsson, Karen M; Kamp, Jan-Christopher; Wacker, Frank K; Bengel, Frank; von Falck, Christian; Schatka, Imke; Meyer, Bernhard C

    2017-01-01

    Purpose To determine if C-Arm computed tomography (CACT) has added diagnostic value in patients suffering from chronic thromboembolic pulmonary hypertension (CTEPH) with a positive mismatch pattern in ventilation/perfusion single photon emission computed tomography (V/Q SPECT). Materials and Methods 28 patients (23 men, 5 women, 62 ± 18 years) with CTEPH who had undergone SPECT, followed by CACT and right heart catheterization (RHC) were included. Two independent readers reviewed SPECT and CACT. Findings indicating CTEPH and their location (segmental or sub-segmental) were identified (V/Q mismatch in SPECT and vascular pathologies in CACT). Inter-modality agreement was calculated (Cohen's Kappa). Findings were scored on a 3-point-scale. The sum of the score (pulmonary artery CTEPH severity score (PACSS)) was calculated for each patient and imaging modality, correlated to RHC (spearman's correlation) and compared to the final therapeutic decision of the CTEPH board (including the consensus of SPECT, selective pulmonary DSA and CACT). Results Overall, 504 pulmonary artery segments were assessed in SPECT and CACT. SPECT had identified 266/504 (53 %) arterial segments without and 238/504 (47 %) segments with a V/Q mismatch indicating CTEPH. CACT detected 131/504 (26 %) segments without abnormal findings and 373/504 (74 %) segments with findings indicating CTEPH. Inter-modality agreement was fair (ĸ = 0.38). PACSS of CACT correlated mildly significantly with the mean pulmonary artery pressure (PAPmean; rho = 0.48, p = 0.01), while SPECT missed significance (rho = 0.32, p = 0.1). Discrepant findings were mostly attributed to a higher frequency of sub-segmental pulmonary arterial pathologies on CACT (145 sub-segmental findings indicating CTEPH) rated as normal on SPECT. Conclusion In patients with CTEPH, contrast-enhanced CACT detects additional findings with a better correlation to the severity of PAPmean than V/Q SPECT. CACT

  16. 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.

  17. 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

  18. 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

  19. 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

  20. 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

  1. Splanchnic vein thrombosis in myeloproliferative neoplasms: risk factors for recurrences in a cohort of 181 patients

    PubMed Central

    De Stefano, V; Vannucchi, A M; Ruggeri, M; Cervantes, F; Alvarez-Larrán, A; Iurlo, A; Randi, M L; Pieri, L; Rossi, E; Guglielmelli, P; Betti, S; Elli, E; Finazzi, M C; Finazzi, G; Zetterberg, E; Vianelli, N; Gaidano, G; Nichele, I; Cattaneo, D; Palova, M; Ellis, M H; Cacciola, E; Tieghi, A; Hernandez-Boluda, J C; Pungolino, E; Specchia, G; Rapezzi, D; Forcina, A; Musolino, C; Carobbio, A; Griesshammer, M; Barbui, T

    2016-01-01

    We retrospectively studied 181 patients with polycythaemia vera (n=67), essential thrombocythaemia (n=67) or primary myelofibrosis (n=47), who presented a first episode of splanchnic vein thrombosis (SVT). Budd–Chiari syndrome (BCS) and portal vein thrombosis were diagnosed in 31 (17.1%) and 109 (60.3%) patients, respectively; isolated thrombosis of the mesenteric or splenic veins was detected in 18 and 23 cases, respectively. After this index event, the patients were followed for 735 patient years (pt-years) and experienced 31 recurrences corresponding to an incidence rate of 4.2 per 100 pt-years. Factors associated with a significantly higher risk of recurrence were BCS (hazard ratio (HR): 3.03), history of previous thrombosis (HR: 3.62), splenomegaly (HR: 2.66) and leukocytosis (HR: 2.8). Vitamin K-antagonists (VKA) were prescribed in 85% of patients and the recurrence rate was 3.9 per 100 pt-years, whereas in the small fraction (15%) not receiving VKA more recurrences (7.2 per 100 pt-years) were reported. Intracranial and extracranial major bleeding was recorded mainly in patients on VKA and the corresponding rate was 2.0 per 100 pt-years. In conclusion, despite anticoagulation treatment, the recurrence rate after SVT in myeloproliferative neoplasms is high and suggests the exploration of new avenues of secondary prophylaxis with new antithrombotic drugs and JAK-2 inhibitors. PMID:27813534

  2. New Strategies in Myeloproliferative Neoplasms: The Evolving Genetic and Therapeutic Landscape

    PubMed Central

    Patel, Ami B.; Vellore, Nadeem A.; Deininger, Michael W.

    2015-01-01

    The classical BCR-ABL1-negative myeloproliferative neoplasms (MPNs) include essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF). While these clonal disorders share certain clinical and genetic features, MF in particular is distinct for its complex mutational landscape, severe disease phenotype and poor prognosis. The genetic complexity inherent to MF has made this disease extremely challenging to treat. Pharmacologic JAK inhibition has proven to be a transformative therapy in MPNs, alleviating symptom burden and improving survival, but has been hampered by off-target toxicities and, as monotherapy, has shown limited effects on mutant allele burden. In this review, we discuss the genetic heterogeneity contributing to the pathogenesis of MPNs, focusing on novel driver and epigenetic mutations and how they relate to combination therapeutic strategies. We discuss results from ongoing studies of new JAK inhibitors and report on new drugs and drug combinations that have demonstrated success in early preclinical and clinical trials, including Type II JAK inhibitors, anti-fibrotic agents and telomerase inhibitors. PMID:26933174

  3. Targeted next-generation sequencing identified novel mutations in triple-negative myeloproliferative neoplasms.

    PubMed

    Chang, Yu-Cheng; Lin, Huan-Chau; Chiang, Yi-Hao; Chen, Caleb Gon-Shen; Huang, Ling; Wang, Wei-Ting; Cheng, Chun-Chia; Lin, Johnson; Chang, Yi-Fang; Chang, Ming-Chih; Hsieh, Ruey-Kuen; Chen, Shu-Jen; Lim, Ken-Hong; Kuo, Yuan-Yeh

    2017-05-01

    Mutations in JAK2, MPL and CALR genes have been identified in the majority of myeloproliferative neoplasm (MPN) patients, and patients negative for these three mutations are the so-called triple-negative (TN) MPN. In this study, we examined the mutational profiles of 16 triple-negative MPN patients including 7 essential thrombocythemia (ET), 1 primary myelofibrosis and 8 polycythemia vera (PV). Targeted next-generation sequencing was performed using the ACTOnco Comprehensive Cancer Panel (Ion AmpliSeq Comprehensive Cancer Panel, Life Technologies) to target all coding exons of 409 cancer-related genes. Overall, 30 nonsynonymous somatic mutations were detected in 12 (75%) patients with a range of 1-5 mutations per sample. Notably, one ET patient was found to have JAK2V617F and KITP551L mutations at very low allele frequency. One MPLP70L and 1 MPLM602T mutations were identified each in 1 ET and 1 PV, respectively. Other recurrent mutations were also identified including KMT2C, KMT2D, IRS2, SYNE1, PDE4DIP, SETD2, ATM, TNFAIP3 and CCND2. In addition, germline mutations were also found in some cancer-related genes. Copy number changes were rare in this cohort of TN MPNs. In conclusion, both somatic and germline mutations can be detected in TN MPN patients.

  4. The Mutation Profile of Calreticulin in Patients with Myeloproliferative Neoplasms and Acute Leukemia

    PubMed Central

    Wang, Jingyi; Hao, Jianguo; He, Na; Ji, Chunyan; Ma, Daoxin

    2016-01-01

    Objective: Calreticulin (CALR) plays important roles in cell proliferation, apoptosis, and immune responses. CALR mutations were described recently in Janus kinase 2 gene (JAK2)-negative or MPL-negative primary myelofibrosis (PMF) and essential thrombocythemia (ET) patients. CALR trails JAK2 as the second most mutated gene in myeloproliferative neoplasms (MPNs). However, little is known about CALR mutation in Chinese patients with leukemia. In the present study, a cohort of 305 Chinese patients with hematopoietic neoplasms was screened for CALR mutations, with the aim of uncovering the frequency of CALR mutations in leukemia and MPNs. Materials and Methods: Polymerase chain reaction and direct sequencing were performed to analyze mutations of CALR in 305 patients with hematopoietic malignancies, including 135 acute myeloid leukemia patients, 57 acute lymphoblastic leukemia patients, and 113 MPN patients. Results: CALR mutations were found in 10.6% (12 of 113) of samples from patients with MPNs. CALR mutations were determined in 11.3% (6 of 53), 21.7% (5 of 23), and 9.1% (1/11) of patients with ET, PMF, and unclassifiable MPN, respectively. Conclusion: We showed that MPN patients carrying CALR mutations presented with higher platelet counts and lower hemoglobin levels compared to those with mutated JAK2. However, all of the leukemia patients had negative results for CALR mutations. PMID:26377485

  5. 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

  6. 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

  7. 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

  8. Study of the oipA genetic diversity and EPIYA motif patterns in cagA-positive Helicobacter pylori strains from Venezuelan patients with chronic gastritis.

    PubMed

    Torres, Keila; Valderrama, Elvis; Sayegh, Marjorie; Ramírez, José Luis; Chiurillo, Miguel Angel

    2014-11-01

    CagA and OipA are involved, among other virulence factors, in the ability of Helicobacter pylori to colonize the gastric mucosa and to modulate the host environment during the establishment of chronic infection. The number and type of EPIYA phosphorylation motifs and the presence and functional status of oipA have been involved in the induction of cellular transformations playing an important role in the development of H. pylori associated gastric diseases. This work determined the prevalence of the oipA virulence factor and EPIYA motif patterns in cagA-positive H. pylori gastric biopsies from chronic gastritis patients from the Central-Western region of Venezuela. DNA was extracted directly from gastric biopsies collected by upper endoscopy from 113 patients. The EPIYA motif genotyping and oipA gene functional status was determined by PCR and sequencing. Phylogenetic analysis with the 3' variable region of cagA sequences was performed. Only Western-type EPIYA variants were detected: ABC (68.14%), ABCC (29.20%) and ABCCC (2.66%). High prevalence of strains with the oipA gene (93.8%) and its functional status "ON" (83%) was observed. No significant association between EPIYA motif patterns or oipA functional status with the histological changes in the gastric mucosa was found. Our study demonstrated the absolute predominance of the Western-type cagA gene in a Venezuelan admixed population. This is the first report showing oipA status of H. pylori strains in Venezuela. Further studies with a larger number of samples and including other pathologies are necessary to continue evaluating the role of the H. pylori virulence factors in the prevalence of gastric diseases in our country.

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

    PubMed Central

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

    2010-01-01

    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 x Norway rats were loaded 3 times weekly for 4.5 weeks using 80 maximal stretch-shortening contractions per session. The contralateral 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 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 (H2O2, 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 improve the positive work output of muscles in aged rodents. PMID:20705127

  10. 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.

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

    PubMed

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

    2008-04-01

    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/mm(3) 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.

  12. 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

  13. Patan hospital experience in treating philadelphia chromosome/BCR-ABL1 positive chronic myeloid leukemia patients with gleevec (imatinib mesylate); the first generation specific tyrosine kinase inhibitor

    PubMed Central

    2010-01-01

    Background Chronic Myeloid Leukemia (CML) is caused by the abnormal fusion protein BCR-ABL1, a constitutively active tyrosine kinase and product of the Philadelphia chromosome. Gleevec (Imatinib mesylate) is a selective inhibitor of this kinase. Treatment with this agent is known to result in hematologic, cytogenetic, and molecular responses. Patan hospital (Patan, Nepal) is one of the Gleevec International Patient Assistance Program (GIPAP) centers for patients with CML. Methods A total of 106 Philadelphia positive CML patients were enrolled in our center between Feb 2003 and Jun 2008, and 103 of them were eligible for cytogenetic and/or hematologic response analyses. Results Out of 103 patients, 27% patients underwent cytogenetic analysis. Imatinib induced major cytogenetic responses in 89% and complete hematologic responses in almost 100% of the patients with confirmed CML. After a mean follow up of 27 months, an estimated 90% of the patients on imatinib remained in hematologic remission and more than 90% of the patients are still alive. About 30% of patients developed some form of manageable myelosuppression. A few patients developed non-hematologic toxic side effects such as edema and hepatotoxicity. Conclusions Our study demonstrates that imatinib is safe to use in a developing country. Furthermore, we demonstrate that imatinib is very effective and induced long lasting responses in a high proportion of patients with Ph chromosome/BCR-ABL1 positive CML. Imatinib is well tolerated by our patients. The lack of cytogenetic analysis in the majority of our patients hindered our ability to detect inadequate responses to imatinib and adjust therapy appropriately. PMID:21138592

  14. Analysis of Th17 and Tc17 Frequencies and Antiviral Defenses in Gut-Associated Lymphoid Tissue of Chronic HIV-1 Positive Patients

    PubMed Central

    d'Ettorre, Gabriella; Ceccarelli, Giancarlo; Andreotti, Mauro; Selvaggi, Carla; Giustini, Noemi; Serafino, Sara; Schietroma, Ivan; Nunnari, Giuseppe; Antonelli, Guido; Vullo, Vincenzo; Scagnolari, Carolina

    2015-01-01

    The complex relationship between both the Th1/Th17 and Tc1/Tc17 axis and innate defences in the intestinal mucosa during HIV-1 infection has not been well characterized. This study examined the frequency, phenotype, and functional status of T cell populations in the gut-associated lymphoid tissue and peripheral blood of virologically suppressed HIV-1-infected patients on therapy, focusing on the Th1, Th17, Tc1, and Tc17 cell subsets. We found a persistent immune cell activation (CD38 and HLADR expression) into the GALT despite the higher levels of Th17 and Tc17 in respect to peripheral blood. An upregulation of type I IFN response in GALT compared to the peripheral blood compartment was also recorded. Furthermore, IFN-α/β levels were negatively related to the frequencies of Th1 naïve cells and Tc1 cell subsets (naïve, central memory, and effector memory) in the GALT. In contrast, no relationships between type I IFN response and Th1 or Tc1 cell subsets in peripheral blood compartment and between IFN-α/β and Th17/Tc17 in both GALT and peripheral blood district were recorded. These data indicate that prolonged antiretroviral treatment improves GALT immune function despite the persistence of immune activation and type I IFN response in chronic HIV-1 positive patients. PMID:26221062

  15. 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

  16. Routine blood examinations combined with morphological analysis for the diagnosis of myelodysplastic/myeloproliferative neoplasms

    PubMed Central

    Wu, Huanling; Sun, Hui; Zhang, Zhifen; Li, Xiangli; Li, Yuantang; Li, Li; Xu, Rui; Wang, Zie; Tian, Wenjun

    2016-01-01

    In 2008, the World Health Organization (WHO) introduced a new hematological neoplasm category; myelodysplastic/myeloproliferative neoplasms (MDS/MPN), which included four main subcategories. This disease is often misdiagnosed, which delays effective therapy. The present study evaluated the role of routine blood examinations and morphological analysis of peripheral blood cells in the reliable diagnosis of MDS/MPN. In total, 236 adult MDS/MPN patients were analyzed. The analysis included 10 routine blood parameters measured using a Sysmex XE-2100™, 3 differential percentage parameters and 7 morphological features of peripheral blood cells which were analyzed by optical microscopy, and 3 differential absolute count numbers obtained based on the corresponding differential percentages and absolute count of blood cells. The parameters were compared among the subcategories and a value of P<0.05 was considered to indicate a statistically significant difference. The median white blood cell and hemoglobin counts of the patients were 18.0×109/l and 88 g/l, respectively. The proportion of monocytes increased to 8% (1.82×109/l), the proportion of blast cells increased to 1% (0.5×109/l) and that of neutrophil precursors increased to 10% (1.98×109/l). A total of 87% of all patients presented with hypogranulation and 71% presented with abnormal condensed nuclear chromatin in granulocytes. Atypical monocytes were observed in 73% of all patients and Pseudo-Pelger cells were observed in 60%. Significant differences were detected among the subcategories. The present study demonstrated that combining blood routine parameters and the morphological analysis of peripheral blood cells have an essential role in the reliable diagnosis of MDS/MPN based on WHO categories. PMID:27895799

  17. 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

  18. 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

  19. Hormonal and Reproductive Factors and Risk of Myeloproliferative Neoplasms in Postmenopausal Women

    PubMed Central

    Leal, Alexis D.; Thompson, Carrie A.; Wang, Alice H.; Vierkant, Robert A.; Habermann, Thomas M.; Ross, Julie A.; Mesa, Ruben A.; Virnig, Beth A.; Cerhan, James R.

    2015-01-01

    Background Hormonal and reproductive history has been associated with risk of some hematologic malignancies, but their role in myeloproliferative neoplasms (MPN) is largely unknown. Methods Using a population-based cohort study, we evaluated the association of these factors with risk of MPN overall, and for essential thrombocythemia (ET) and polycythemia vera (PV) specifically. Incident MPN cases from 1993–2004 were identified via linkage to Medicare. Relative risks (RR) and 95% confidence intervals (CI) were estimated utilizing Cox proportional hazard regression. Results After >250,000 person-years of follow-up, 257 cases of MPN were identified (172 ET, 64 PV). Ever use of hormone therapy (HT) was associated with an increased risk of ET (RR=1.63; 95%CI 1.19–2.23) but a decreased risk of PV (RR=0.58; 95%CI 0.34–0.98). There were no statistically significant associations of oral contraceptives or reproductive factors with MPN risk overall, or by MPN subtype. Bilateral oophorectomy was associated with increased risk of ET (RR=1.58; 95%CI 1.11–2.25) and decreased risk of PV (RR=0.32; 95%CI 0.12–0.88). There was no association of ovulatory years with ET risk, however there was increased risk of PV (RR=1.68 for >36.8 compared to ≤27.6 years; p-trend=0.045). Adjustment for potential confounding factors did not alter these associations. Conclusions HT use and bilateral oophorectomy had opposite associations for ET and PV. Except for ovulatory years and PV risk, reproductive history did not appear to play a role in the etiology of MPN. PMID:26564251

  20. 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

  1. Absence of SKP2 expression attenuates BCR-ABL–induced myeloproliferative disease

    PubMed Central

    Agarwal, Anupriya; Bumm, Thomas G. P.; Corbin, Amie S.; O'Hare, Thomas; Loriaux, Marc; VanDyke, Jonathan; Willis, Stephanie G.; Deininger, Jutta; Nakayama, Keiichi I.; Druker, Brian J.

    2008-01-01

    BCR-ABL is proposed to impair cell-cycle control by disabling p27, a tumor suppressor that inhibits cyclin-dependent kinases. We show that in cell lines p27 expression is inversely correlated with expression of SKP2, the F-box protein of SCFSKP2 (SKP1/Cul1/F-box), the E3 ubiquitin ligase that promotes proteasomal degradation of p27. Inhibition of BCR-ABL kinase causes G1 arrest, down-regulation of SKP2, and accumulation of p27. Ectopic expression of wild-type SKP2, but not a mutant unable to recognize p27, partially rescues cell-cycle progression. A similar regulation pattern is seen in cell lines transformed by FLT3-ITD, JAK2V617F, and TEL-PDGFRβ, suggesting that the SKP2/p27 conduit may be a universal target for leukemogenic tyrosine kinases. Mice that received transplants of BCR-ABL–infected SKP2−/− marrow developed a myeloproliferative syndrome but survival was significantly prolonged compared with recipients of BCR-ABL-expressing SKP2+/+ marrow. SKP2−/− leukemic cells demonstrated higher levels of nuclear p27 than SKP2+/+ counterparts, suggesting that the attenuation of leukemogenesis depends on increased p27 expression. Our data identify SKP2 as a crucial mediator of BCR-ABL–induced leukemogenesis and provide the first in vivo evidence that SKP2 promotes oncogenesis. Hence, stabilization of p27 by inhibiting its recognition by SCFSKP2 may be therapeutically useful. PMID:18559973

  2. Safety and efficacy of ruxolitinib in splanchnic vein thrombosis associated with myeloproliferative neoplasms.

    PubMed

    Pieri, Lisa; Paoli, Chiara; Arena, Umberto; Marra, Fabio; Mori, Fabio; Zucchini, Mery; Colagrande, Stefano; Castellani, Alessandro; Masciulli, Arianna; Rosti, Vittorio; De Stefano, Valerio; Betti, Silvia; Finazzi, Guido; Ferrari, Maria Luisa; Rumi, Elisa; Ruggeri, Marco; Nichele, Ilaria; Guglielmelli, Paola; Fjerza, Rajmonda; Mannarelli, Carmela; Fanelli, Tiziana; Merli, Lucia; Corbizi Fattori, Giuditta; Massa, Margherita; Cimino, Giuseppe; Rambaldi, Alessandro; Barosi, Giovanni; Cazzola, Mario; Barbui, Tiziano; Vannucchi, Alessandro M

    2017-02-01

    Splanchnic vein thrombosis (SVT) is one of the vascular complications of myeloproliferative neoplasms (MPN). We designed a phase 2 clinical trial to evaluate safety and efficacy of ruxolitinib in reducing splenomegaly and improving disease-related symptoms in patients with MPN-associated SVT. Patients diagnosed with myelofibrosis (12 cases), polycythemia vera (5 cases) and essential thrombocythemia (4 cases) received ruxolitinib for 24 weeks in the core study period. Spleen volume was assessed by magnetic resonance imaging (MRI) and splanchnic vein circulation by echo-Doppler analysis. Nineteen patients carried JAK2V617F, one had MPLW515L, and one CALRL367fs*46 mutation. Eighteen patients had spleno-portal-mesenteric thrombosis, two had Budd-Chiari syndrome, and one had both sites involved; 16 patients had esophageal varices. Ruxolitinib was well tolerated with hematological toxicities consistent with those of patients without SVT and no hemorrhagic adverse events were recorded. After 24 weeks of treatment, spleen volume reduction ≥35% by MRI was achieved by 6/21 (29%) patients, and a ≥50% spleen length reduction by palpation at any time up to week 24 was obtained by 13/21 (62%) patients. At week 72, 8 of the 13 (62%) patients maintained the spleen response by palpation. No significant effect of treatment on esophageal varices or in splanchnic circulation was observed. MPN-related symptoms, evaluated by MPN-symptom assessment form (SAF) TSS questionnaire, improved significantly during the first 4 weeks and remained stable up to week 24. In conclusion, this trial shows that ruxolitinib is safe in patients with MPN-associated SVT, and effective in reducing spleen size and disease-related symptoms.

  3. 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

  4. 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

  5. Critical appraisal of the role of ruxolitinib in myeloproliferative neoplasm-associated myelofibrosis

    PubMed Central

    Barosi, Giovanni; Rosti, Vittorio; Gale, Robert Peter

    2015-01-01

    The recent approval of molecular-targeted therapies for myeloproliferative neoplasm-associated myelofibrosis (MPN-MF) has dramatically changed its therapeutic landscape. Ruxolitinib, a JAK1/JAK2 tyrosine kinase inhibitor, is now widely used for first- and second-line therapy in persons with MPN-MF, especially those with disease-related splenomegaly, intermediate- or high-risk disease, and constitutional symptoms. The goal of this work is to critically analyze data supporting use of ruxolitinib in the clinical settings approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). We systematically reviewed the literature and analyzed the risk of biases in the two randomized studies (COMFORT I and COMFORT II) on which FDA and EMA approval was based. Our strategy was to apply the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) approach by evaluating five dimensions of evidence: (1) overall risk of bias, (2) imprecision, (3) inconsistency, (4) indirectness, and (5) publication bias. Based on these criteria, we downgraded the evidence from the COMFORT I and COMFORT II trials for performance, attrition, and publication bias. In the disease-associated splenomegaly sphere, we upgraded the quality of evidence because of large effect size but downgraded it because of comparator choice and outcome indirectness (quality of evidence, low). In the sphere of treating persons with intermediate- or high-risk disease, we downgraded the evidence because of imprecision in effect size measurement and population indirectness. In the sphere of disease-associated symptoms, we upgraded the evidence because of the large effect size, but downgraded it because of comparator indirectness (quality of evidence, moderate). In conclusion, using the GRADE technique, we identified factors affecting the quality of evidence that were otherwise unstated. Identifying and evaluating these factors should influence the confidence with which physicians

  6. 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

  7. TET2, ASXL1, IDH1 and IDH2 single nucleotide polymorphisms in Turkish patients with chronic myeloproliferative neoplasms.

    PubMed

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

    2017-02-20

    We aimed to determine the genotype distribution, allele frequency and prognostic impact of IDH1/2(Isocitrate dehydrogenase), TET2(Ten-Eleven-Translocation2) and ASXL1(Additional Sex Combs-Like 1) single nucleotide polymorphisms (SNPs) in MPNs. TET2(rs763480), ASXL1(rs2208131) and IDH1(rs11554137) variant homozygous genotype frequencies were 1.5%, 9.2% and 2.3%, respectively. No IDH2 SNP was identified. IDH1 and TET2 frequencies were 5% in ET and 1.7% in ET, 5% in PMF, respectively. ASXL1 frequencies were 8.3-10% in MPN subgroups. TET2 mutant allele T and ASXL1 mutant allele G were the highest frequency with 0.272 in PMF and with 0.322 in the PV group, respectively. There was no impact of the SPNs on prognosis. IDH1 frequency in MPNs is found similar to the literature. ASXL1 frequencies were similar between ET, PV and PMF patients. Turkish population ASXL1 and TET2 allele frequency are similar to European population. The role of SNPs in MPNs might be further evaluated in larger, multicenter studies.

  8. sEPCR Levels in Chronic Myeloproliferative Diseases and Their Association with Thromboembolic Events: A Case-Control Study.

    PubMed

    Atalay, Figen; Toprak, Selami Koçak; Koca, Ebru; Karakuş, Sema

    2014-06-01

    Amaç: Esansiyel trombositemi (ET) ve polisitemi vera (PV)’nin klinik seyrinde venöz, arteriyel ve mikrosirkülatuar trombotik olaylara sık olarak rastlanmaktadır. Biz, tromboembolik olay öyküsü olan ve olmayan hastalardaki çözünür endotelyal protein C reseptörü (sEPCR) düzeyleri açısından bir fark olup olmadığını araştırmayı amaçladık.Gereç ve Yöntemler: Çalışmaya polisitemia vera (12) ve esansiyel trombositozu (13) toplam 25 hasta ile kontrol grubunu oluşturmak üzere 29 sağlıklı kişi alındı. Her iki grupta da, protein C, S, antitrombin ve sEPCR ile düzeyleri ile trombin-antitrombin kompleks (TAT), protrombin fragmanı 1+2 ve D-Dimer plazma konsantrasyonları ölçülmüştür.Bulgular:Tromboembolik atak öyküsü olan ve olmayan hastalar karşılaştırıldığında sEPCR, D-dimer, TAT, protrombin fragman 1 +2 (F1+2) ve hematokrit düzeyleri açısından istatistiksel olarak anlamlı fark gözlenmemiştir (sırasıyla p=0,318; 0,722; 0,743; 0,324; 0,065).Sonuç: sEPCR, TAT, F1+2 ve D-Dimer gibi pıhtılaşma aktivasyonunu yansıtan parametrelerinde anlamlı artış görülmesi, parametrelerde literatür ile uyumlu olarark kontrol grubuna göre anlamlı artış gösterilmiş olması ET ve PV hastalarında tromboza eğilim oluşturan bazal bir durumun varlığına işaret etmektedir.

  9. Aberrant activation of ROS1 represents a new molecular defect in chronic myelomonocytic leukemia.

    PubMed

    Cilloni, Daniela; Carturan, Sonia; Bracco, Enrico; Campia, Valentina; Rosso, Valentina; Torti, Davide; Calabrese, Chiara; Gaidano, Valentina; Niparuck, Pimjai; Favole, Alessandra; Signorino, Elisabetta; Iacobucci, Ilaria; Morano, Annalisa; De Luca, Luciana; Musto, Pellegrino; Frassoni, Francesco; Saglio, Giuseppe

    2013-05-01

    Chronic myelomonocytic leukemia (CMML) is a clonal disorder sharing features of myelodysplastic syndromes and chronic myeloproliferative neoplasms. Although rare chromosomal aberrations and point mutations are reported in CMML, the molecular defects underlying CMML are largely unknown. ROS1 encodes a tyrosine kinase that is abnormally expressed and translocated in brain and lung cancers. In this study we show that ROS1 is abnormally activated in the CD34+ compartment of approximately 70% of CMML patients resulting in the activation of the Erk/Akt pathways through the Grb2/SOS complex thus revealing a central oncogenic role for ROS1 in CMML which might represent a molecular target.

  10. 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

  11. Urinary Sodium Excretion Has Positive Correlation with Activation of Urinary Renin Angiotensin System and Reactive Oxygen Species in Hypertensive Chronic Kidney Disease

    PubMed Central

    Ahn, Shin-Young; Kim, Sejoong; Kim, Dong Ki; Shin, Sung Joon; Lee, Sang Ho; Choi, Bum Soon; Lim, Chun Soo

    2014-01-01

    It is not well described the pathophysiology of renal injuries caused by a high salt intake in humans. The authors analyzed the relationship between the 24-hr urine sodium-to-creatinine ratio (24HUna/cr) and renal injury parameters such as urine angiotensinogen (uAGT/cr), monocyte chemoattractant peptide-1 (uMCP1/cr), and malondialdehyde-to-creatinine ratio (uMDA/cr) by using the data derived from 226 hypertensive chronic kidney disease patients. At baseline, the 24HUna/cr group or levels had a positive correlation with uAGT/cr and uMDA/cr adjusted for related factors (P<0.001 for each analysis). When we estimated uAGT/cr in the 24HUna/cr groups by ANCOVA, the uAGT/cr in patients with ≥200 mEq/g cr was higher than in patients with <100 mEq/g cr (708 [95% CI, 448-967] vs. 334 [95% CI, 184-483] pg/mg cr, P=0.014). Similarly, uMDA/cr was estimated as 0.17 (95% CI, 0.14-0.21) pM/mg cr in patients with <100 mEq/g cr and 0.27 (95% CI, 0.20-0.33) pM/mg cr in patients with ≥200 mEq/g cr (P=0.016). During the 16-week follow-up period, an increase in urinary sodium excretion predicted an increase in urinary angiotensinogen excretion. In conclusion, high salt intake increases renal renin-angiotensin-system (RAS) activation, primarily, and directly or indirectly affects the production of reactive oxygen species through renal RAS activation. PMID:25317016

  12. Immunological effects of nilotinib prophylaxis after allogeneic stem cell transplantation in patients with advanced chronic myeloid leukemia or philadelphia chromosome-positive acute lymphoblastic leukemia

    PubMed Central

    Shouval, Roni; Eldror, Shiran; Lev, Atar; Davidson, Jacqueline; Rosenthal, Esther; Volchek, Yulia; Shem-Tov, Noga; Yerushalmi, Ronit; Shimoni, Avichai; Somech, Raz; Nagler, Arnon

    2017-01-01

    Allogeneic stem cell transplantation remains the standard treatment for resistant advanced chronic myeloid leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia. Relapse is the major cause of treatment failure in both diseases. Post-allo-SCT administration of TKIs could potentially reduce relapse rates, but concerns regarding their effect on immune reconstitution have been raised. We aimed to assess immune functions of 12 advanced CML and Ph+ ALL patients who received post-allo-SCT nilotinib. Lymphocyte subpopulations and their functional activities including T-cell response to mitogens, NK cytotoxic activity and thymic function, determined by quantification of the T cell receptor (TCR) excision circles (TREC) and TCR repertoire, were evaluated at several time points, including pre-nilotib-post-allo-SCT, and up to 365 days on nilotinib treatment. NK cells were the first to recover post allo-SCT. Concomitant to nilotinib administration, total lymphocyte counts and subpopulations gradually increased. CD8 T cells were rapidly reconstituted and continued to increase until day 180 post SCT, while CD4 T cells counts were low until 180−270 days post nilotinib treatment. T-cell response to mitogenic stimulation was not inhibited by nilotinib administration. Thymic activity, measured by TREC copies and surface membrane expression of 24 different TCR Vβ families, was evident in all patients at the end of follow-up after allo-SCT and nilotinib treatment. Finally, nilotinib did not inhibit NK cytotoxic activity. In conclusion, administration of nilotinib post allo-SCT, in attempt to reduce relapse rates or progression of Ph+ ALL and CML, did not jeopardize immune reconstitution or function following transplantation. PMID:27880933

  13. Vibration response imaging: a novel noninvasive tool for evaluating the initial therapeutic effect of noninvasive positive pressure ventilation in patients with acute exacerbation of chronic obstructive pulmonary disease

    PubMed Central

    2012-01-01

    Background The popular methods for evaluating the initial therapeutic effect (ITE) of noninvasive positive pressure ventilation (NPPV) can only roughly reflect the therapeutic outcome of a patient’s ventilation because they are subjective, invasive and time-delayed. In contrast, vibration response imaging (VRI) can monitor the function of a patient’s ventilation over the NPPV therapy in a non-invasive manner. This study aimed to investigate the value of VRI in evaluating the ITE of NPPV for patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Methods Thirty-six AECOPD patients received VRI at three time points: before NPPV treatment (T1), at 15 min of NPPV treatment (T2), and at 15 min after the end of NPPV treatment (T4). Blood gas analysis was also performed at T1 and at 2 hours of NPPV treatment (T3). Thirty-nine healthy volunteers also received VRI at T1 and T2. VRI examination at the time point T2 in either the patients or volunteers did not require any interruption of the on-going NPPV. The clinical indices at each time point were compared between the two groups. Moreover, correlations between the PaCO2 changes (T3 vs T1) and abnormal VRI scores (AVRIS) changes (T2 vs T1) were analyzed. Results No significant AVRIS differences were found between T1 and T2 in the healthy controls (8.51 ± 3.36 vs. 8.53 ± 3.57, P > 0.05). The AVRIS, dynamic score, MEF score and EVP score showed a significant decrease in AECOPD patients at T2 compared with T1 (P < 0.05), but a significant increase at T4 compared with T2 (P < 0.05). We also found a positive correlation (R2 = 0.6399) between the PaCO2 changes (T3 vs T1) and AVRIS changes (T2 vs T1). Conclusions VRI is a promising noninvasive tool for evaluating the initial therapeutic effects of NPPV in AECOPD patients and predicting the success of NPPV in the early stage. PMID:22856613

  14. Improved diagnosis of the transition to JAK2 (V⁶¹⁷F) homozygosity: the key feature for predicting the evolution of myeloproliferative neoplasms.

    PubMed

    Gonzalez, Mariana Selena; De Brasi, Carlos Daniel; Bianchini, Michele; Gargallo, Patricia; Stanganelli, Carmen; Zalcberg, Ilana; Larripa, Irene Beatriz

    2014-01-01

    Most cases of BCR-ABL1-negative myeloproliferative neoplasms (MPNs), essential thrombocythemia, polycythemia vera and primary myelofibrosis are associated with JAK2 (V617F) mutations. The outcomes of these cases are critically influenced by the transition from JAK2 (V617F) heterozygosity to homozygosity. Therefore, a technique providing an unbiased assessment of the critical allele burden, 50% JAK2 (V617F), is highly desirable. In this study, we present an approach to assess the JAK2 (V617F) burden from genomic DNA (gDNA) and complementary DNA (cDNA) using one-plus-one template references for allele-specific quantitative-real-time-PCR (qPCR). Plasmidic gDNA and cDNA constructs encompassing one PCR template for JAK2 (V617F) spaced from one template for JAK2(Wild Type) were constructed by multiple fusion PCR amplifications. Repeated assessments of the 50% JAK2(V617F) burden within the dynamic range of serial dilutions of gDNA and cDNA constructs resulted in 52.53 ± 4.2% and 51.46 ± 4.21%, respectively. The mutation-positive cutoff was estimated to be 3.65% (mean +2 standard deviation) using 20 samples from a healthy population. This qPCR approach was compared with the qualitative ARMS-PCR technique and with two standard methods based on qPCR, and highly significant correlations were obtained in all cases. qPCR assays were performed on paired gDNA/cDNA samples from 20 MPN patients, and the JAK2 (V617F) expression showed a significant correlation with the allele burden. Our data demonstrate that the qPCR method using one-plus-one template references provides an improved assessment of the clinically relevant transition of JAK2 (V617F) from heterozygosity to homozygosity.

  15. pSTAT5 and ERK exhibit different expression in myeloproliferative neoplasms.

    PubMed

    Wiśniewska-Chudy, Ewa; Szylberg, Łukasz; Dworacki, Grzegorz; Mizera-Nyczak, Ewa; Marszałek, Andrzej

    2017-04-01

    Myeloproliferative neoplasms (MPNs) are clonal hematopoietic progenitor cell disorders characterized by the proliferation of one or more hematopoietic lineages. The classical MPNs include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) entities. These disorders are characterized by bone marrow morphology typical for each disease, and by the presence of JAK2V617F mutation in the marrow and blood. However, JAK2V617F cannot account for the phenotypic heterogeneity of MPNs because approximately half of all cases of ET and PMF show no evidence of this molecular marker. Therefore, the search for novel markers of these diseases is necessary to improve pathomorphological and molecular diagnostics. This study aimed to investigate the changes in expression patterns of the proteins STAT5 (the signal transducers and activators of transcription 5) and ERK (extracellular signal-regulated kinase) in bone marrow trephine specimens, derived both from patients with wild-type and mutant (V617F) forms of JAK2 kinase. Furthermore, the changes in STAT5 and ERK2 gene expression levels in the same patients were also investigated. The results of our immunohistochemical, immunoblotting and RT-qPCR studies revealed at least four major unique features of three types of MPNs. These include: i) more pronounced expression of phosphoSTAT5 protein in patients with JAK2V617F mutation compared to patients with wild-type of JAK2 kinase ii) different expression pattern of pSTAT5 in the nucleus and the cytoplasm of megakaryocytes and other bone marrow cells; iii) approximately 5-fold higher expression level of STAT5a gene in PV in comparison to patients with PMF and approximately 2-fold higher than in ET patients; iv) different, intracellular expression patterns of ERK2 and ERK1/2 antigens allowed to distinguish each subtype of MPN. These abnormalities in expression patterns of STAT5 and ERK proteins and genes provide some novel molecular features of MPNs and

  16. Analysis of the erythropoietin receptor gene in patients with myeloproliferative and myelodysplastic syndromes.

    PubMed

    Mittelman, M; Gardyn, J; Carmel, M; Malovani, H; Barak, Y; Nir, U

    1996-06-01

    The human erythropoietin receptor (EpoR) gene has been cloned and characterized. Very few EpoR genetic abnormalities have been reported so far. Polycythemia vera (PV) is characterized by low/normal serum erythropoietin (Epo) levels with proposed Epo hypersensitivity. Myelodysplastic syndromes (MDS) are characterized by refractory anemia with variable serum Epo levels. Several reports have suggested EpoR abnormalities in both types of stem cell disorders. We analyzed DNA obtained from peripheral blood mononuclear cells of seven healthy controls, 20 patients with myeloproliferative disorders (MPD, 11 patients with PV, five agnogenic myeloid metaplasia with myelofibrosis, four essential thrombocytosis) and eight patients with refractory anemia with ringed sideroblasts (RARS), an MDS variant. The DNA was digested with four restriction enzymes (BamHI, Bgl II, Sacl and HindIII), followed by Southern blot, using a 32P radiolabeled probe, containing 1.5 kb of the human EpoR cDNA. All 20 MPD patients and seven out of the eight MDS patients demonstrated a restriction pattern which was identical to the seven normal controls, as well as to the erythroid cell line K562, and also consistent with the expected restriction map, for all four enzymes tested. One RARS patient had a normal pattern with three enzymes but a different one with HindIII. The HindIII 12 kb large band was replaced by a faint 12 kb band and a new (about 9 kb) band appeared. The EpoR restriction map and the normal pattern obtained with the other three enzymes suggest that this patient has a 3 kb upstream deletion in one allelic EpoR gene. The same molecular pattern was detected in the patient's sister, who suffers from anemia with mild bone marrow (BM) dyserythropoiesis and plasmacytosis. Northern blot analysis showed that the patient's BM RNA carried normal EpoR message. This familial pattern may represent polymorphism. However, the patient's very high serum Epo level, her resistance to treatment with

  17. Chronic prostatitis

    PubMed Central

    2011-01-01

    Introduction Chronic prostatitis can cause pain and urinary symptoms, and usually occurs without positive bacterial cultures from prostatic secretions (known as chronic abacterial prostatitis or chronic pelvic pain syndrome [CP/CPPS]). Bacterial infection can result from urinary tract instrumentation, but the cause and natural history of CP/CPPS are unknown. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for chronic bacterial prostatitis? What are the effects of treatments for chronic abacterial prostatitis/chronic pelvic pain syndrome? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 33 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review, we present information relating to the effectiveness and safety of the following interventions: 5 alpha-reductase inhibitors, allopurinol, alpha-blockers, biofeedback, local injections of antimicrobial drugs, mepartricin, non-steroidal anti-inflammatory drugs (NSAIDs), oral antimicrobial drugs, pentosan polysulfate, prostatic massage, quercetin, radical prostatectomy, sitz baths, transurethral microwave thermotherapy, and transurethral resection. PMID:21736764

  18. Increased reactive oxygen species production and p47phox phosphorylation in neutrophils from myeloproliferative disorders patients with JAK2 (V617F) mutation

    PubMed Central

    Hurtado-Nedelec, Margarita; Csillag-Grange, Marie-José; Boussetta, Tarek; Belambri, Sahra Amel; Fay, Michèle; Cassinat, Bruno; Gougerot-Pocidalo, Marie-Anne; Dang, Pham My-Chan; El-Benna, Jamel

    2013-01-01

    Myeloproliferative disorders are associated with increased risk of thrombosis and vascular complications. The pathogenesis of these complications is not completely known. Reactive oxygen species produced by the neutrophil NADPH oxidase could have a role in this process. The aim of this study was to evaluate reactive oxygen species production by neutrophils of myeloproliferative disorder patients. Patients with or without the JAK2 V617F mutation were characterized. Reactive oxygen species production was assessed by chemiluminescence, and phosphorylation of the NADPH oxidase subunit p47phox was analyzed by Western blots. In a comparison of controls and myeloproliferative disorder patients without the JAK2 V617F mutation, reactive oxygen species production by neutrophils from patients with the JAK2 V617F mutation was dramatically increased in non-stimulated and in stimulated conditions. This increase was associated with increased phosphorylation of the p47phox on Ser345 and of the uspstream kinase ERK1/2. In neutrophils from healthy donors, JAK2 can be activated by GM-CSF. GM-CSF-induced p47phox phosphorylation and priming of reactive oxygen species production are inhibited by the selective JAK2 inhibitors AG490 and lestaurtinib (CEP-701), supporting a role for JAK2 in the upregulation of NADPH oxidase activation. These findings show an increase in reactive oxygen species production and p47phox phosphorylation in neutrophils from myeloproliferative disorder patients with the JAK2 V617F mutation, and demonstrate that JAK2 is involved in GM-CSF-induced NADPH oxidase hyperactivation. As neutrophil hyperactivation could be implicated in the thrombophilic status of patients with myeloproliferative disorders, aberrant activation of JAK2 V617F, leading to excessive neutrophil reactive oxygen species production might play a role in this setting. PMID:23975181

  19. 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

  20. Tacrolimus, Bortezomib, & Thymoglobulin in Preventing Low Toxicity GVHD in Donor Blood Stem Cell Transplant Patients

    ClinicalTrials.gov

    2016-10-21

    Acute Leukemia; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Diffuse Large B-Cell Lymphoma; Follicular Lymphoma; Graft Versus Host Disease; Mantle Cell Lymphoma; Marginal Zone Lymphoma; Myelodysplastic Syndrome; Myelofibrosis; Myeloproliferative Neoplasm; Small Lymphocytic Lymphoma

  1. 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

  2. Positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors reverses sub-chronic PCP-induced deficits in the novel object recognition task in rats.

    PubMed

    Damgaard, Trine; Larsen, Dorrit Bjerg; Hansen, Suzanne L; Grayson, Ben; Neill, Jo C; Plath, Niels

    2010-02-11

    Cognitive deficits are a major clinical unmet need in schizophrenia. The psychotomimetic drug phencyclidine (PCP) is widely applied in rodents to mimic symptoms of schizophrenia, including cognitive deficits. Previous studies have shown that sub-chronic PCP induces an enduring episodic memory deficit in female Lister Hooded rats in the novel object recognition (NOR) task. Here we show that positive modulation of AMPA receptor (AMPAR) mediated glutamate transmission alleviates cognitive deficits induced by sub-chronic PCP treatment. Female Lister hooded rats were treated sub-chronically with either vehicle (0.9% saline) or PCP (2mg/kg two doses per day for 7 days), followed by a 7 days washout period. 30 min prior to the acquisition trial of the NOR task animals were dosed with either vehicle, CX546 (10, 40 or 80 mg/kg) or CX516 (0.5, 2.5, 10, 40 or 80 mg/kg). Our results show that sub-chronic PCP treatment induced a significant decrease in the discrimination index (DI) and both ampakines CX546 and CX516 were able to reverse this disruption of object memory in rats in the novel object recognition task. These data suggest that positive AMPAR modulation may represent a mechanism for treatment of cognitive deficits in schizophrenia.

  3. Increased CD34+/KDR+ cells are not associated with carotid artery intima-media thickness progression in chronic HIV-positive subjects

    PubMed Central

    Papasavvas, Emmanouil; Hsue, Priscilla; Reynolds, Griffin; Pistilli, Maxwell; Hancock, Aidan; Martin, Jeffrey N; Deeks, Steven G; Montaner, Luis J

    2012-01-01

    Background Endothelial progenitor cells (EPCs) are involved in the endothelium repair. Low circulating EPC levels are predictive of cardiovascular events in HIV-negative subjects. The impact of HIV infection on EPCs, and the role of EPCs in HIV-associated cardiovascular disease, is not known. We hypothesized that circulating EPCs would be inversely associated with carotid artery intima-media thickness (c-IMT) changes in HIV-infected subjects. Methods EPCs (CD34+/KDR+, CD133+/KDR+ and CD34+/CD133+/KDR+) were defined retrospectively by flow cytometry in cryopreserved peripheral blood mononuclear cells collected longitudinally from 66 chronic HIV-infected subjects and cross-sectionally from 50 at-risk HIV-negative subjects. The HIV-infected subjects participated in the Study of the Consequences of the Protease Inhibitor Era (SCOPE) cohort, were receiving antiretroviral therapy (59/66) and had two sequential measurements of c-IMT 1 year apart. Two distinct groups of HIV-infected subjects were identified a priori: rapid c-IMT progressors (subjects with rapid c-IMT progression, n=13, Δc-IMT>0.2 mm) and slow c-IMT progressors (subjects with slow or no c-IMT progression, n=53, Δc-IMT<0.2 mm). Results Although cryopreservation reduced sensitivity of detection, EPC frequency in HIV-infected subjects was still significantly higher compared to at-risk HIV-negative subjects (CD34+/KDR+; P=0.01) and correlated positively with CD4+ T-cell count (CD34+/KDR+, r=0.27; P=0.03). No association was found between the change of EPC frequencies over time (ΔEPC) and Δc-IMT or between EPC frequencies and c-IMT or Δc-IMT. Conclusions The lack of an association between EPCs and c-IMT in our cohort does not support HIV-associated reductions in EPC frequency as a cause of accelerated atherosclerosis. PMID:22300770

  4. Early use of noninvasive techniques for clearing respiratory secretions during noninvasive positive-pressure ventilation in patients with acute exacerbation of chronic obstructive pulmonary disease and hypercapnic encephalopathy

    PubMed Central

    Wang, Jinrong; Cui, Zhaobo; Liu, Shuhong; Gao, Xiuling; Gao, Pan; Shi, Yi; Guo, Shufen; Li, Peipei

    2017-01-01

    Abstract Noninvasive positive-pressure ventilation (NPPV) might be superior to conventional mechanical ventilation (CMV) in patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPDs). Inefficient clearance of respiratory secretions provokes NPPV failure in patients with hypercapnic encephalopathy (HE). This study compared CMV and NPPV combined with a noninvasive strategy for clearing secretions in HE and AECOPD patients. The present study is a prospective cohort study of AECOPD and HE patients enrolled between October 2013 and August 2015 in a critical care unit of a major university teaching hospital in China. A total of 74 patients received NPPV and 90 patients received CMV. Inclusion criteria included the following: physician-diagnosed AECOPD, spontaneous airway clearance of excessive secretions, arterial blood gas analysis requiring intensive care, moderate-to-severe dyspnea, and a Kelly–Matthay scale score of 3 to 5. Exclusion criteria included the following: preexisting psychiatric/neurological disorders unrelated to HE, upper gastrointestinal bleeding, upper airway obstruction, acute coronary syndromes, preadmission tracheostomy or endotracheal intubation, and urgent endotracheal intubation for cardiovascular, psychomotor agitation, or severe hemodynamic conditions. Intensive care unit participants were managed by NPPV. Participants received standard treatment consisting of controlled oxygen therapy during NPPV-free periods; antibiotics, intravenous doxofylline, corticosteroids (e.g., salbutamol and ambroxol), and subcutaneous low-molecular-weight heparin; and therapy for comorbidities if necessary. Nasogastric tubes were inserted only in participants who developed gastric distension. No pharmacological sedation was administered. The primary and secondary outcome measures included comparative complication rates, durations of ventilation and hospitalization, number of invasive devices/patient, and in-hospital and 1-year mortality

  5. Efficiency and outcome of non-invasive versus invasive positive pressure ventilation therapy in respiratory failure due to chronic obstructive pulmonary disease.

    PubMed Central

    Amri Maleh, Valiollah; Monadi, Mahmood; Heidari, Behzad; Maleh, Parviz Amri; Bijani, Ali

    2016-01-01

    Background: Application noninvasive ventilation in the patients with exacerbation of chronic obstructive pulmonary disease (COPD) reduced mortality. This case-control study was designed to compare efficiency and outcome of non-invasive (NIV) versus invasive positive pressure ventilation (IPPV) in respiratory failure due to COPD. Methods: The patients were assigned to NIV or IPPV intermittantly.The clinical parameters, including RR (respiratory rate), BP (blood pressure), HR (heart rate) and PH, PaCO2, PaO2 before and 1, 4 and 24 h after treatment were measured. Demographic information such as age, sex, severity of disease based on APACHE score, length of stay and outcome were recorded. Results: Fifty patients were enrolled in the NIV group and 50 patients in IPPV. The mean age was 70.5 in NIV and 63.9 in invasive ventilation group (p>0.05). In IPPV group, the average values of PH: PCO2: and PO2, were 7.22±0.11, 69.64 + 24.25: and 68.86±24.41 .In NIV, the respective values were 7.30±0.07, 83.94±18.95, and 60.60±19.88. In NIV group, after 1, 4 and 24 h treatment, the clinical and ventilation parameters were stable. The mean APACHE score in was IPPV, 26.46±5.45 and in NIV was 12.26±5.54 (p<0.05). The average length of hospital stay in IPPV was 15.90±10 and in NIV 8.12±6.49 days (p<0.05). The total mortality in the NIV was 4 (8%) and in IPPV, 27 patients (54%) (p<0.05). Conclusion: This study indicates that using NIPPV is a useful therapeutic mode of treatment for respiratory failure with acceptable success rate and lower mortality. The application of NIPPV reduces hospital stay, intubation and its consequent complications. PMID:27386061

  6. Effectiveness of temporary positive expiratory pressure (T-PEP) at home and at hospital in patients with severe chronic obstructive pulmonary disease

    PubMed Central

    Mascardi, Valentina; Grecchi, Bruna; Barlascini, Cornelius; Banfi, Paolo

    2016-01-01

    Background Temporary positive airway pressure (T-PEP) is a tool recently introduced in the treatment of chronic obstructive pulmonary disease (COPD) or bronchiectasis. It demonstrated encouraging results also in severe COPD patients. The aim of this study is verify if adding T-PEP to best bronchodilator therapy both in clinic and home administering could reduce disease exacerbations and improve lung function in patients with severe COPD. Methods A total of 142 patients with severe COPD (FEV1 <50%) were enrolled; 120 were randomized in three groups: a group treated with T-PEP at home, a group with T-PEP at hospital and a group with medical therapy only (control group). Number of acute exacerbations COPD (AECOPD) after 1 month and 3 months were the primary outcomes. Secondary outcomes were changes in respiratory function parameters (FVC, FEV1, TLC, RV), arterial blood gases, dyspnea and health status assessment scales (Modified Medical Research Council (MMRC), Breathlessness, Cough and Sputum scale (BCSS) and COPD Assessment Test (CAT). The time of daily use of the T-PEP was registered as well as its acceptance using a Likert scale. Results Ninety-nine patients completed the study. Both the groups who used T-PEP showed a statistical lower number of AECOPD after 1 month and 3 months (P<0.01). Some respiratory functional parameters improved in the two groups treated with T-PEP (FVC, FEV1, RV) (P<0.02) and dyspnea and health status assessment scales (MMRC, BCSS, CAT) (P<0.04; P<0.01; P<0.009). The time of daily using was similar in the two T-PEP groups. Patients treated at home showed a greater acceptance than those treated at hospital (Likert scale 4.7 vs. 5.9) (P<0.01). Conclusions Patients treated with T-PEP showed a lower number of AECOPD. T-PEP improves functional respiratory parameters and improves dyspnea and health status assessment scales. No adherence difference in hospital and home treatment was found. Patients preferred home treatment. PMID:27867566

  7. 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

  8. 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

  9. Clinical use of ruxolitinib in an academic medical center in unselected patients with myeloproliferative neoplasms not on clinical study.

    PubMed

    Naqvi, Kiran; Daver, Naval; Pemmaraju, Naveen; Bose, Prithviraj; Garcia-Manero, Guillermo; Cortes, Jorge; Kantarjian, Hagop M; Verstovsek, Srdan

    2017-04-01

    Ruxolitinib is the only approved therapy for myelofibrosis (MF). However, its use in patients with myeloproliferative neoplasms (MPN) not participating in clinical studies has been poorly described. We reviewed the medical records of 45 patients (35 MF, 10 others) treated with ruxolitinib at our center, off clinical study, during the year after its approval. Patients had advanced features and were refractory to multiple therapies. Ruxolitinib was effective in reducing splenomegaly (51% response rate) and constitutional symptoms (42% response rate). It controlled blood counts in patients with polycythemia and thrombocythemia but was not effective in patients with non-classic MPNs. Ruxolitinib was an active therapy in patients previously treated with a JAK inhibitor and was safely combined with hypomethylating agents in patients with elevated blasts. Median overall survival was 24 months; 10 patients transformed to acute leukemia. Its use in combination with other active agents should be further explored in clinical studies.

  10. Social Media and Myeloproliferative Neoplasms (MPN): Analysis of Advanced Metrics From the First Year of a New Twitter Community: #MPNSM.

    PubMed

    Pemmaraju, Naveen; Utengen, Audun; Gupta, Vikas; Kiladjian, Jean-Jacques; Mesa, Ruben; Thompson, Michael A

    2016-12-01

    The social media platform Twitter has provided the hematology/oncology community with unprecedented, novel methods of interpersonal communication and increased ability for the dissemination of important updates in a rapidly moving field. The advent, and subsequent success, of disease-specific Twitter communities have further enabled interested healthcare stakeholders to become quickly organized around a unique set of rare medical conditions, such as hematologic malignancies, that, historically, generally lack large amounts of reliable online information. One example is the Twitter community #MPNSM (myeloproliferative neoplasms on social media), which was started approximately one and half years ago and has served as a recognized venue for discussion among many members of the MPN community, including patients, researchers, providers, and advocacy organizations. This article will focus on understanding the impact of the founding of this community via the analysis of advanced Twitter metrics of user experience, from the first year of use for this novel healthcare hashtag.

  11. Chronic pancreatitis

    MedlinePlus

    Chronic pancreatitis - chronic; Pancreatitis - chronic - discharge; Pancreatic insufficiency - chronic; Acute pancreatitis - chronic ... hospital for: Pain medicines Fluids given through a vein (IV) Stopping food or fluid by mouth to ...

  12. 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

  13. [A retrospective study on HBsAg clearance rate after antiviral therapy in children with HBeAg-positive chronic hepatitis B aged 1-7 years].

    PubMed

    Zhu, S S; Dong, Y; Xu, Z Q; Wang, L M; Chen, D W; Gan, Y; Wang, F C; Yan, J G; Cao, L L; Wang, P; Zhang, H F

    2016-10-20

    Objective: To investigate the HBsAg clearance rate after antiviral therapy in children with HBeAg-positive chronic hepatitis B (CHB) aged 1-7 years. Methods: A retrospective analysis was performed for the HBsAg clearance rate in 293 children who were hospitalized in 302 Hospital of PLA from June 2006 to December 2013, met the inclusion criteria, received antiviral therapy, and were followed up for at least 6 months after the withdrawal of antiviral therapy. The t-test or the rank sum test was applied according to the distribution of continuous data, and the chi-square test was used for comparison of categorical data. Results: The HBsAg positive rate of children's mothers was 91.1%. In the age groups of >1-≤2 years, >2-≤3 years, >3-≤4 years, >4-≤5 years, >5-≤6 years, and >6-≤7 years, the HBsAg clearance rates were 66.1%, 65.5%, 45.7%, 41.3%, 20.6%, and 27.6%, respectively. There were significant differences in HBsAg clearance rate between the age groups of >1-≤3 years and >3-≤5 years, >1-≤3 years and >5-≤7 years, and >3-≤5 years and >5-≤7 years (P = 0.001, 0.000, and 0.008). Of all children, 64.8% were boys, among whom 41.1% achieved HBsAg clearance, and 35.2% were girls, among whom 61.2% achieved HBsAg clearance; there was a significant difference in HBsAg clearance rate between boys and girls (P = 0.001). The children with pretreatment alanine aminotransferase (ALT) levels of ≤80 IU/L, > 80 IU/L, ≤200 IU/L, and > 200 IU/L had HBsAg clearance rates of 40.7%, 51.2%, 47.6%, and 49.4%, respectively; there were no significant differences in HBsAg clearance rate between the ALT ≤80 IU/L and ALT > 80 IU/L groups and the ALT ≤200 IU/L and ALT > 200 IU/L groups (P = 0.101 and 0.778). There was no significant difference in HBsAg clearance rate between the pretreatment HBV DNA load < 1×10(7) IU/ml and ≥1×10(7) IU/ml groups (54.9% vs 46.7%, P = 0.286). Of all children, 14.2% had genotype B and an HBsAg clearance rate of 57.1%, and 85% had

  14. 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.

  15. 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

  16. Cytogenetics in the management of Philadelphia-negative myeloproliferative neoplasms: an update by the Groupe francophone de cytogénétique hématologique (GFCH).

    PubMed

    Bilhou-Nabéra, Chrystèle; Bidet, Audrey; Eclache, Virginie; Lippert, Eric; Mozziconacci, Marie-Joëlle

    2016-10-01

    The recent years have witnessed tremendous progress in the molecular characterization of Philadelphia-negative myeloproliferative neoplasms (MPN). Beside a better understanding of pathophysiology, these abnormalities often constitute very useful diagnostic markers in diseases where exclusion of reactive states used to be the strongest argument. However, conventional and molecular cytogenetics keep a major interest in MPN, either as a second line exploration, in cases where no molecular marker is available, for differential diagnosis or as a proof of clonality or in first line for cases with hyperleukocytosis, for differential diagnosis (CML), to evidence druggable targets (ABL1, RET, PDGFR…) or as a prognosis marker. In this article, we will review the interest of cytogenetic techniques in myeloproliferative neoplasms.

  17. [A cohort study on the epidemiological characteristics of HBeAg sero-clearance in HBeAg positive chronic hepatitis B patients in Jiangsu province from 2012 to 2014].

    PubMed

    Zhu, L G; Jiang, J; Song, C; Zou, Y; Xu, J F; Liu, H J; Peng, H; Hu, Z B; Zhu, F C; Shen, H B; Zhai, X J

    2017-02-10

    Objective: To understand the epidemiological characteristics and influencing factors related to HBeAg sero-clearance in chronic hepatitis B patients so as to provide evidence for regular management on chronic HBV patients. Methods: From 2012 to 2014, a cohort study was conducted among HBeAg positive chronic HBV patients in Jiangsu province. Association between the characteristics and incidence of HBeAg sero-clearance was analyzed by Cox regression method. The changing trend on HBV DNA between patients with HBeAg sero-clearance and those with persistent HBeAg positive status was compared by repeated measure data variance analysis method. Results: In 2012, there were 721 HBeAg positive hepatitis B patients aged (45.2 ± 14.2) years enrolled in this study. By 2014, the follow-up observation period was 1 058 person-years, and 393 cases had lost their HBeAg status, with the rate as 37.2/100 person-years. The HBeAg sero-clearance rate was 32.4/100 person-years in hepatitis B patients who received antiviral treatment. The probability of HBeAg clearance in HBeAg positive hepatitis B patients aged ≥60 year (62.0/100 person-years) was higher than those of aged <20 year (7.0/100 person-years). The rate of HBeAg sero-clearance in HBeAg positive patients with HBV DNA <20 000 IU/ml (75.8/100 person-years) was higher than those whose HBV DNA were ≥200 000 IU/ml (16.1/100 person-years). By Cox regression analysis, the HBV DNA level was an important influencing factor on the progress of HBeAg sero-clearance. Patients with HBV DNA levle as ≥200 000 IU/ml, had a lower HBeAg clearance rate (HR=0.18, 95%CI: 0.13-0.23, P<0.001). Compared to the persistent HBeAg positive group, HBV DNA showed a more dramatic fall in the HBeAg-lost group (P<0.001). Conclusion: The rate of HBeAg sero-clearance among HBeAg positive hepatitis B patients was correlated with age and HBV DNA status of the patients that called for comprehensive management and intervention programs to develop for the HBe

  18. Associations between gender, disease features and symptom burden in patients with myeloproliferative neoplasms: an analysis by the MPN QOL International Working Group

    PubMed Central

    Geyer, Holly L.; Kosiorek, Heidi; Dueck, Amylou C.; Scherber, Robyn; Slot, Stefanie; Zweegman, Sonja; te Boekhorst, Peter AW; Senyak, Zhenya; Schouten, Harry C.; Sackmann, Federico; Fuentes, Ana Kerguelen; Hernández-Maraver, Dolores; Pahl, Heike L.; Griesshammer, Martin; Stegelmann, Frank; Döhner, Konstanze; Lehmann, Thomas; Bonatz, Karin; Reiter, Andreas; Boyer, Francoise; Etienne, Gabriel; Ianotto, Jean-Christophe; Ranta, Dana; Roy, Lydia; Cahn, Jean-Yves; Harrison, Claire N.; Radia, Deepti; Muxi, Pablo; Maldonado, Norman; Besses, Carlos; Cervantes, Francisco; Johansson, Peter L.; Barbui, Tiziano; Barosi, Giovanni; Vannucchi, Alessandro M.; Paoli, Chiara; Passamonti, Francesco; Andreasson, Bjorn; Ferrari, Maria L; Rambaldi, Alessandro; Samuelsson, Jan; Cannon, Keith; Birgegard, Gunnar; Xiao, Zhijian; Xu, Zefeng; Zhang, Yue; Sun, Xiujuan; Xu, Junqing; Kiladjian, Jean-Jacques; Zhang, Peihong; Gale, Robert Peter; Mesa, Ruben A.

    2017-01-01

    The myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia and myelofibrosis, are distinguished by their debilitating symptom profiles, life-threatening complications and profound impact on quality of life. The role gender plays in the symptomatology of myeloproliferative neoplasms remains under-investigated. In this study we evaluated how gender relates to patients’ characteristics, disease complications and overall symptom expression. A total of 2,006 patients (polycythemia vera=711, essential thrombocythemia=830, myelofibrosis=460, unknown=5) were prospectively evaluated, with patients completing the Myeloproliferative Neoplasm-Symptom Assessment Form and Brief Fatigue Inventory Patient Reported Outcome tools. Information on the individual patients’ characteristics, disease complications and laboratory data was collected. Consistent with known literature, most female patients were more likely to have essential thrombocythemia (48.6% versus 33.0%; P<0.001) and most male patients were more likely to have polycythemia vera (41.8% versus 30.3%; P<0.001). The rate of thrombocytopenia was higher among males than females (13.9% versus 8.2%; P<0.001) and males also had greater red-blood cell transfusion requirements (7.3% versus 4.9%; P=0.02) with shorter mean disease duration (6.4 versus 7.2 years, P=0.03). Despite there being no statistical differences in risk scores, receipt of most therapies or prior complications (hemorrhage, thrombosis), females had more severe and more frequent symptoms for most individual symptoms, along with overall total symptom score (22.8 versus 20.3; P<0.001). Females had particularly high scores for abdominal-related symptoms (abdominal pain/discomfort) and microvascular symptoms (headache, fatigue, insomnia, concentration difficulties, dizziness; all P<0.01). Despite complaining of more severe symptom burden, females had similar quality of life scores to those of males. The results of this study suggest

  19. The Jak2 inhibitor, G6, alleviates Jak2-V617F-mediated myeloproliferative neoplasia by providing significant therapeutic efficacy to the bone marrow.

    PubMed

    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

    2011-11-01

    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.

  20. 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

  1. Associations between gender, disease features and symptom burden in patients with myeloproliferative neoplasms: an analysis by the MPN QOL International Working Group.

    PubMed

    Geyer, Holly L; Kosiorek, Heidi; Dueck, Amylou C; Scherber, Robyn; Slot, Stefanie; Zweegman, Sonja; Te Boekhorst, Peter Aw; Senyak, Zhenya; Schouten, Harry C; Sackmann, Federico; Fuentes, Ana Kerguelen; Hernández-Maraver, Dolores; Pahl, Heike L; Griesshammer, Martin; Stegelmann, Frank; Döhner, Konstanze; Lehmann, Thomas; Bonatz, Karin; Reiter, Andreas; Boyer, Francoise; Etienne, Gabriel; Ianotto, Jean-Christophe; Ranta, Dana; Roy, Lydia; Cahn, Jean-Yves; Harrison, Claire N; Radia, Deepti; Muxi, Pablo; Maldonado, Norman; Besses, Carlos; Cervantes, Francisco; Johansson, Peter L; Barbui, Tiziano; Barosi, Giovanni; Vannucchi, Alessandro M; Paoli, Chiara; Passamonti, Francesco; Andreasson, Bjorn; Ferrari, Maria L; Rambaldi, Alessandro; Samuelsson, Jan; Cannon, Keith; Birgegard, Gunnar; Xiao, Zhijian; Xu, Zefeng; Zhang, Yue; Sun, Xiujuan; Xu, Junqing; Kiladjian, Jean-Jacques; Zhang, Peihong; Gale, Robert Peter; Mesa, Ruben A

    2017-01-01

    The myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia and myelofibrosis, are distinguished by their debilitating symptom profiles, life-threatening complications and profound impact on quality of life. The role gender plays in the symptomatology of myeloproliferative neoplasms remains under-investigated. In this study we evaluated how gender relates to patients' characteristics, disease complications and overall symptom expression. A total of 2,006 patients (polycythemia vera=711, essential thrombocythemia=830, myelofibrosis=460, unknown=5) were prospectively evaluated, with patients completing the Myeloproliferative Neoplasm-Symptom Assessment Form and Brief Fatigue Inventory Patient Reported Outcome tools. Information on the individual patients' characteristics, disease complications and laboratory data was collected. Consistent with known literature, most female patients were more likely to have essential thrombocythemia (48.6% versus 33.0%; P<0.001) and most male patients were more likely to have polycythemia vera (41.8% versus 30.3%; P<0.001). The rate of thrombocytopenia was higher among males than females (13.9% versus 8.2%; P<0.001) and males also had greater red-blood cell transfusion requirements (7.3% versus 4.9%; P=0.02) with shorter mean disease duration (6.4 versus 7.2 years, P=0.03). Despite there being no statistical differences in risk scores, receipt of most therapies or prior complications (hemorrhage, thrombosis), females had more severe and more frequent symptoms for most individual symptoms, along with overall total symptom score (22.8 versus 20.3; P<0.001). Females had particularly high scores for abdominal-related symptoms (abdominal pain/discomfort) and microvascular symptoms (headache, fatigue, insomnia, concentration difficulties, dizziness; all P<0.01). Despite complaining of more severe symptom burden, females had similar quality of life scores to those of males. The results of this study suggest that

  2. Action of temperature-sensitive mutants of myeloproliferative sarcoma virus suggests that fibroblast-transforming and hematopoietic transforming viral properties are related.

    PubMed

    Ostertag, W; Freshney, M; Vehmeyer, K; Jasmin, C; Rutter, G

    1984-01-01

    The myeloproliferative sarcoma virus is molecularly related to the Moloney sarcoma virus (Pragnell et al., J. Virol. 38:952-957, 1981), but causes both fibroblast transformation in vitro and leukemic changes--including spleen focus formation--in adult mice. The fibroblast transforming properties of myeloproliferative sarcoma virus were used to select viral temperature-sensitive mutants at 39.5 degrees C, the nonpermissive temperature. These mutants are temperature sensitive in the maintenance of the transformed state. This was also shown by cytoskeletal changes of the infected cells at permissive and nonpermissive temperatures. Viruses released from cells maintained at both the permissive and nonpermissive temperature are temperature sensitive in fibroblast transformation functions. All temperature-sensitive mutants show only a low reversion rate to wild-type transforming function. The myeloproliferative sarcoma virus temperature-sensitive mutants are inefficient in causing leukemic transformation (spleen enlargement, focus formation) in mice at the normal temperature. A method to maintain a low body temperature (33 to 34 degrees C) in mice is described. One temperature-sensitive mutant was checked at low body temperature and did not induce leukemia. These data thus indicate that the same or related viral functions are responsible for hematopoietic and fibroblast transformation.

  3. Action of temperature-sensitive mutants of myeloproliferative sarcoma virus suggests that fibroblast-transforming and hematopoietic transforming viral properties are related.

    PubMed Central

    Ostertag, W; Freshney, M; Vehmeyer, K; Jasmin, C; Rutter, G

    1984-01-01

    The myeloproliferative sarcoma virus is molecularly related to the Moloney sarcoma virus (Pragnell et al., J. Virol. 38:952-957, 1981), but causes both fibroblast transformation in vitro and leukemic changes--including spleen focus formation--in adult mice. The fibroblast transforming properties of myeloproliferative sarcoma virus were used to select viral temperature-sensitive mutants at 39.5 degrees C, the nonpermissive temperature. These mutants are temperature sensitive in the maintenance of the transformed state. This was also shown by cytoskeletal changes of the infected cells at permissive and nonpermissive temperatures. Viruses released from cells maintained at both the permissive and nonpermissive temperature are temperature sensitive in fibroblast transformation functions. All temperature-sensitive mutants show only a low reversion rate to wild-type transforming function. The myeloproliferative sarcoma virus temperature-sensitive mutants are inefficient in causing leukemic transformation (spleen enlargement, focus formation) in mice at the normal temperature. A method to maintain a low body temperature (33 to 34 degrees C) in mice is described. One temperature-sensitive mutant was checked at low body temperature and did not induce leukemia. These data thus indicate that the same or related viral functions are responsible for hematopoietic and fibroblast transformation. Images PMID:6537818

  4. 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

  5. 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.

  6. 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.

  7. Chronic Cough

    MedlinePlus

    Chronic cough Overview By Mayo Clinic Staff A chronic cough is a cough that lasts eight weeks or longer in adults, or four weeks in children. A chronic cough is more than just an annoyance. A chronic ...

  8. 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

  9. Iron Deposition Is Positively Related to Cognitive Impairment in Patients with Chronic Mild Traumatic Brain Injury: Assessment with Susceptibility Weighted Imaging

    PubMed Central

    Cao, Heli; Wei, Xiaoer; Li, Yuehua; Li, Wenbin

    2015-01-01

    Background. This study aimed to evaluate the usability of SWI in assessment of brain iron to detect cognitive dysfunction in patients with chronic mild traumatic brain injury (mTBI). Methods. 39 patients with mTBI and 37 normal controls were given the Mini-Mental State Examination (MMSE) and underwent SWI scanning at least 6 months after injury. Angle radian values were calculated with phase images. The angle radian values were compared between groups using analysis of covariance, and their association with MMSE scores was analyzed using Spearman correlations. Results. Significantly higher angle radian values (p < 0.05) were found in the head of the caudate nucleus, the lenticular nucleus, the hippocampus, the thalamus, the right substantia nigra, the red nucleus, and the splenium of the corpus callosum (SCC) in the mTBI group, compared to the control group. MMSE scores were negatively correlated with angle radian values in the right substantia nigra (r = −0.685, p < 0.001). Conclusions. Patients with chronic mTBI might have abnormally high accumulations of iron, and their MMSE scores are negatively associated with angle radian values in the right substantia nigra, suggesting a role of SWI in the assessment of cognitive impairments of these patients. PMID:26798636

  10. What Is Chronic Myelomonocytic Leukemia?

    MedlinePlus

    ... experts created a new category for it: myelodysplastic/myeloproliferative diseases. CMML is the most common disease in this group. ... American Cancer Society medical and editorial content team Our team ...

  11. 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

  12. Constitutional t(8;22)(q24;q11.2) that mimics the variant Burkitt-type translocation in Philadelphia chromosome-positive chronic myeloid leukemia.

    PubMed

    Kawamoto, Shinichiro; Yamamoto, Katsuya; Toyoda, Masanori; Yakushijin, Kimikazu; Matsuoka, Hiroshi; Minami, Hironobu

    2017-02-01

    Constitutional translocations that coincide with t(9;22)(q34;q11.2) may lead to unnecessary treatments in chronic myeloid leukemia (CML) patients, as, under the standard criteria, a diagnosis of CML with additional chromosomal abnormalities indicates an accelerated phase (AP). In the present report, a 47-year-old male had pain in the right foot due to gout. Peripheral blood examination showed leukocytosis with left shift. Bone marrow aspiration revealed myeloid hyperplasia with megakaryocytosis. RT-PCR revealed the major BCR-ABL fusion transcript, and CML in the chronic phase was diagnosed, followed by nilotinib treatment. Although WBC counts decreased immediately, G-banding analysis showed 46,XY,t(8;22)(q24;q11.2),t(9;22)(q34;q11.2) [20]. The t(8;22)(q24;q11.2) translocation is known to be recurrent in Burkitt's lymphoma. The diagnosis was changed to CML in AP, leading to B-lymphoid crisis. Unexpectedly, the karyotype was 46,XY,t(8;22)(q24;q11.2) [20] in hematological complete remission, even after 3 months. Fluorescence in situ hybridization on metaphase spreads revealed the MYC signal on the der(22)t(8;22), indicating that the 8q24 breakpoint was centromeric to MYC at 8q24.21. G-banding analysis of phytohemagglutinin-stimulated peripheral blood T-lymphocytes also indicated 46,XY,t(8;22)(q24.1;q11.2). We conclude that the t(8;22) is constitutional in this patient. As the tumor suppressor gene TRC8/RNF139 is disrupted by constitutional t(8;22)(q24.13;q11.21) in dysgerminoma, it may be associated with the onset of CML.

  13. Fibrin-associated EBV-positive Large B-Cell Lymphoma: An Indolent Neoplasm With Features Distinct From Diffuse Large B-Cell Lymphoma Associated With Chronic Inflammation.

    PubMed

    Boyer, Daniel F; McKelvie, Penelope A; de Leval, Laurence; Edlefsen, Kerstin L; Ko, Young-Hyeh; Aberman, Zachary A; Kovach, Alexandra E; Masih, Aneal; Nishino, Ha T; Weiss, Lawrence M; Meeker, Alan K; Nardi, Valentina; Palisoc, Maryknoll; Shao, Lina; Pittaluga, Stefania; Ferry, Judith A; Harris, Nancy Lee; Sohani, Aliyah R

    2017-03-01

    Incidental cases of localized fibrin-associated Epstein-Barr virus (EBV)+ large B-cell proliferations have been described at unusual anatomic sites and have been included in the category of diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) in the WHO Classification. We describe 12 cases and review the literature to define their clinicopathologic spectrum and compare features with typical cases of DLBCL-CI. Median age was 55.5 years with a M:F ratio of 3. In all 12 cases, the lymphoma was an incidental microscopic finding involving atrial myxomas (n=3), thrombi associated with endovascular grafts (n=3), chronic hematomas (n=2), and pseudocysts (n=4). All cases tested were nongerminal center B-cell origin, type III EBV latency, and were negative for MYC rearrangements and alternative lengthening of telomeres by FISH. Most showed high CD30, Ki67, and PD-L1, and low to moderate MYC and p53 expression. Among 11 patients with detailed follow-up, 6 were treated surgically, 3 with cardiac or vascular lesions had persistent/recurrent disease at intravascular sites, and 4 died of causes not directly attributable to lymphoma. Reports of previously published fibrin-associated cases showed similar features, whereas traditional DLBCL-CI cases with a mass lesion had significantly higher lymphoma-associated mortality. Fibrin-associated EBV+ large B-cell lymphoma is clinicopathologically distinct from DLBCL-CI, warranting separate classification. Most cases, particularly those associated with pseudocysts, behave indolently with the potential for cure by surgery alone and may represent a form of EBV+ lymphoproliferative disease rather than lymphoma. However, primary cardiac or vascular disease may have a higher risk of recurrence despite systemic chemotherapy.

  14. 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.

  15. Long-Term Outcome of Sequential Therapy with Lamivudine Followed by Interferon-β in Nucleoside-Naive, Hepatitis B e-Antigen-Positive Patients with Chronic Hepatitis B Virus Genotype C Infection.

    PubMed

    Enomoto, Masaru; Nishiguchi, Shuhei; Tamori, Akihiro; Kozuka, Ritsuzo; Hayashi, Takehiro; Kohmoto, Madoka Toyama; Jomura, Hisato; Morikawa, Hiroyasu; Murakami, Yoshiki; Shiomi, Susumu; Kawada, Norifumi

    2015-08-01

    It is unclear whether the combination of a nucleos(t)ide analog and interferon (IFN) is superior to monotherapy for treating chronic hepatitis B. In this study, we report the long-term outcomes of sequential therapy using lamivudine followed by IFN-β. This study included 24 hepatitis B e-antigen (HBeAg)-positive patients with chronic hepatitis B virus (HBV) genotype C infection who were treated with lamivudine alone for 16-32 weeks, then with both IFN-β and lamivudine for 4 weeks, and finally with IFN-β alone for 20 weeks. All patients were followed up for 7.1±2.8 years post-treatment. The rate of response, defined as transaminase normalization, HBeAg loss, and HBV DNA <10(4) copies/mL, was 5/24 (21%) at 24 weeks post-treatment. The patients with short-term responses were younger than those with no response (P=0.039). More short-term responders had undetectable HBV DNA at the start of IFN-β compared with the nonresponders (P=0.0059). Subsequently, 4 of the 5 short-term responders remained free of the need for further drug treatment for 4.2±3.5 years post-treatment; more short-term responders remained drug free than did nonresponders (P=0.035). In conclusion, the rate of response to sequential therapy was limited in HBeAg-positive patients with chronic HBV genotype C infection at 24 weeks post-treatment. In the majority of the short-term responders, however, the response was sustainable in the long term.

  16. 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.

  17. 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

  18. 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

  19. Functional analysis of JAK3 mutations in transient myeloproliferative disorder and acute megakaryoblastic leukaemia accompanying Down syndrome.

    PubMed

    Sato, Tomohiko; Toki, Tsutomu; Kanezaki, Rika; Xu, Gang; Terui, Kiminori; Kanegane, Hirokazu; Miura, Masayoshi; Adachi, Souichi; Migita, Masahiro; Morinaga, Shingo; Nakano, Takahide; Endo, Mikiya; Kojima, Seiji; Kiyoi, Hitoshi; Mano, Hiroyuki; Ito, Etsuro

    2008-05-01

    JAK3 mutations have been reported in transient myeloproliferative disorder (TMD) as well as in acute megakaryoblastic leukaemia of Down syndrome (DS-AMKL). However, functional consequences of the JAK3 mutations in TMD patients remain undetermined. To further understand how JAK3 mutations are involved in the development and/or progression of leukaemia in Down syndrome, additional TMD patients and the DS-AMKL cell line MGS were screened for JAK3 mutations, and we examined whether each JAK3 mutation is an activating mutation. JAK3 mutations were not detected in 10 TMD samples that had not previously been studied. Together with our previous report we detected JAK3 mutations in one in 11 TMD patients. Furthermore, this study showed for the first time that a TMD patient-derived JAK3 mutation (JAK3(I87T)), as well as two novel JAK3 mutations (JAK3(Q501H) and JAK3(R657Q)) identified in an MGS cell line, were activating mutations. Treatment of MGS cells and Ba/F3 cells expressing the JAK3 mutants with JAK3 inhibitors significantly decreased their growth and viability. These results suggest that the JAK3 activating mutation is an early event during leukaemogenesis in Down syndrome, and they provide proof-of-principle evidence that JAK3 inhibitors would have therapeutic effects on TMD and DS-AMKL patients carrying activating JAK3 mutations.

  20. CXCR4-independent rescue of the myeloproliferative defect of the Gata1low myelofibrosis mouse model by Aplidin.

    PubMed

    Verrucci, Maria; Pancrazzi, Alessandro; Aracil, Miguel; Martelli, Fabrizio; Guglielmelli, Paola; Zingariello, Maria; Ghinassi, Barbara; D'Amore, Emanuela; Jimeno, José; Vannucchi, Alessandro M; Migliaccio, Anna Rita

    2010-11-01

    The discovery of JAK2 mutations in Philadelphia-negative myeloproliferative neoplasms has prompted investigators to evaluate mutation-targeted treatments to restore hematopoietic cell functions in these diseases. However, the results of the first clinical trials with JAK2 inhibitors are not as promising as expected, prompting a search for additional drugable targets to treat these disorders. In this paper, we used the hypomorphic Gata1(low) mouse model of primary myelofibrosis (PMF), the most severe of these neoplasms, to test the hypothesis that defective marrow hemopoiesis and development of extramedullary hematopoiesis in myelofibrosis is due to insufficient p27(Kip1) activity and is treatable by Aplidin, a cyclic depsipeptide that activates p27(Kip1) in several cancer cells. Aplidin restored expression of Gata1 and p27(Kip1) in Gata1(low) hematopoietic cells, proliferation of marrow progenitor cells in vitro and maturation of megakaryocytes in vivo (reducing TGF-beta/VEGF levels released in the microenvironment by immature Gata1(low) megakaryocytes). Microvessel density, fibrosis, bone growth, and marrow cellularity were normal in Aplidin-treated mice and extramedullary hematopoiesis did not develop in liver although CXCR4 expression in Gata1(low) progenitor cells remained low. These results indicate that Aplidin effectively alters the natural history of myelofibrosis in Gata1(low) mice and suggest this drug as candidate for clinical evaluation in PMF.

  1. The role of thrombocytapheresis in the contemporary management of hyperthrombocytosis in myeloproliferative neoplasms: A case-based review.

    PubMed

    Boddu, Prajwal; Falchi, Lorenzo; Hosing, Chitra; Newberry, Kate; Bose, Prithviraj; Verstovsek, Srdan

    2017-03-22

    Extreme thrombocytosis induces an acquired thrombotic-hemorrhagic diathesis, and left uncontrolled is a harbinger of potentially fatal vascular complications. Currently, cytoreduction with medical therapy remains the mainstay of hyperthrombocytosis management. However, it offers a less-than-ideal option in situations where a rapid reduction in platelets is urgently needed, as in the presence of vital end-organ ischemia or to ameliorate of life-threatening hemorrhage. The role of thrombocytapheresis, or plateletpheresis, in hyperthrombocytosis has become increasingly obsolete given the proactive titration of cytoreductive therapies and early identification and correction of reversible causes of reactive thrombocytosis. Despite its narrowed indications, plateletpheresis continues to offer a valuable temporizing measure in platelet count reduction before cytoreductive agents exert their maximal effect. In this context, it is important for the treating physician to be aware of the symptoms and risks associated with hyperthrombocytosis to inform best clinical practices. In this review, we discuss the role of plateletpheresis in the modern-day management of hyperthrombocytosis in patients with myeloproliferative neoplasms through a case based review of the literature. It becomes apparent throughout the discussion that the decision to perform plateletpheresis should be individualized based upon the clinical scenario, degree of thrombocytosis, available infrastructure and every patient's risk profile.

  2. 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

  3. Comprehensive Gene expression meta-analysis and integrated bioinformatic approaches reveal shared signatures between thrombosis and myeloproliferative disorders

    PubMed Central

    Jha, Prabhash Kumar; Vijay, Aatira; Sahu, Anita; Ashraf, Mohammad Zahid

    2016-01-01

    Thrombosis is a leading cause of morbidity and mortality in patients with myeloproliferative disorders (MPDs), particularly polycythemia vera (PV) and essential thrombocythemia (ET). Despite the attempts to establish a link between them, the shared biological mechanisms are yet to be characterized. An integrated gene expression meta-analysis of five independent publicly available microarray data of the three diseases was conducted to identify shared gene expression signatures and overlapping biological processes. Using INMEX bioinformatic tool, based on combined Effect Size (ES) approaches, we identified a total of 1,157 differentially expressed genes (DEGs) (697 overexpressed and 460 underexpressed genes) shared between the three diseases. EnrichR tool’s rich library was used for comprehensive functional enrichment and pathway analysis which revealed “mRNA Splicing” and “SUMO E3 ligases SUMOylate target proteins” among the most enriched terms. Network based meta-analysis identified MYC and FN1 to be the most highly ranked hub genes. Our results reveal that the alterations in biomarkers of the coagulation cascade like F2R, PROS1, SELPLG and ITGB2 were common between the three diseases. Interestingly, the study has generated a novel database of candidate genetic markers, pathways and transcription factors shared between thrombosis and MPDs, which might aid in the development of prognostic therapeutic biomarkers. PMID:27892526

  4. The spleen microenvironment influences disease transformation in a mouse model of KITD816V-dependent myeloproliferative neoplasm

    PubMed Central

    Pelusi, Natalie; Kosanke, Maike; Riedt, Tamara; Rösseler, Corinna; Seré, Kristin; Li, Jin; Gütgemann, Ines; Zenke, Martin; Janzen, Viktor; Schorle, Hubert

    2017-01-01

    Activating mutations leading to ligand-independent signaling of the stem cell factor receptor KIT are associated with several hematopoietic malignancies. One of the most common alterations is the D816V mutation. In this study, we characterized mice, which conditionally express the humanized KITD816V receptor in the adult hematopoietic system to determine the pathological consequences of unrestrained KIT signaling during blood cell development. We found that KITD816V mutant animals acquired a myeloproliferative neoplasm similar to polycythemia vera, marked by a massive increase in red blood cells and severe splenomegaly caused by excessive extramedullary erythropoiesis. Moreover, we found mobilization of stem cells from bone marrow to the spleen. Splenectomy prior to KITD816V induction prevented expansion of red blood cells, but rapidly lead to a state of aplastic anemia and bone marrow fibrosis, reminiscent of post polycythemic myeloid metaplasia, the spent phase of polycythemia vera. Our results show that the extramedullary hematopoietic niche microenvironment significantly influences disease outcome in KITD816V mutant mice, turning this model a valuable tool for studying the interplay between functionally abnormal hematopoietic cells and their microenvironment during development of polycythemia vera-like disease and myelofibrosis. PMID:28128288

  5. Social Media and Myeloproliferative Neoplasms (MPN)--Focus on Twitter and the Development of a Disease-specific Community: #MPNSM.

    PubMed

    Pemmaraju, Naveen; Gupta, Vikas; Mesa, Ruben; Thompson, Michael A

    2015-12-01

    The advent of social media has led to the ability for individuals all over the world to communicate with each other, in real time, about mutual topics of interest in an unprecedented manner. Recently, the use of social media has increased among people interested in healthcare and medical research, particularly in the field of hematology and oncology, a field which frequently experiences rapid shifts of information and novel, practice-changing discoveries. Among the many social media platforms available to cancer patients and providers, one platform in particular, Twitter, has become the focus for the creation of disease-specific communities, especially for those interested in, affected by, or those who perform research in the fields of rare cancers, which historically have had a dearth of reliable information available. This article will focus on the initiation and progress of one such Twitter hematology/oncology community, #mpnsm, which was originally created for the purpose of serving as a venue for improving the interaction among patients, providers, researchers, and organizations with interest in the myeloproliferative neoplasms (MPNs) and to further the availability of reliable up-to-date analysis; relevant expert commentary; and readily usable information for patients, providers, and other groups interested in this field.

  6. 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

  7. Novel hematological parameters for the evaluation of patients with myeloproliferative neoplasms: the immature platelet and reticulocyte fractions.

    PubMed

    Strati, Paolo; Bose, Prithviraj; Lyle, Lindsey; Gaw, Katie; Zhou, Lingsha; Pierce, Sherry A; Huynh-Lu, Julie; Hirsch-Ginsberg, Cheryl F; Bueso-Mendoza, Daniel E; Bueso-Ramos, Carlos E; Verstovsek, Srdan

    2017-02-28

    New automated hematology analyzers have led to the availability of novel hematological parameters, including the immature platelet fraction (IPF) and the immature reticulocyte fraction (IRF), both of potential interest in patients with myeloproliferative neoplasms (MPNs). We performed a prospective analysis of 217 patients with MPN, including 32 (15%) with essential thrombocythemia (ET), 43 (20%) with polycythemia vera (PV), and 142 (65%) with myelofibrosis (MF); the IPF and IRF were measured by the Sysmex XN analyzer. As compared to patients with ET, both a higher IPF and IRF were observed among patients with PV and MF. Factors associated with high IPF among patients with PV/ET were male sex, thrombocytopenia, and diagnosis of PV; among patients with MF, they were elevated peripheral blasts, low platelet count, JAK2 V617F mutation, and previous therapy. Factors associated with high IRF among patients with PV/ET were low hemoglobin, high reticulocyte count, and PV diagnosis; among patients with MF, they were peripheral blasts and elevated reticulocytes. The IPF and IRF represent novel parameters in patients with MPN with potential relevant clinical implications. Comparison with healthy subjects and those with secondary polycythemia is needed to confirm our preliminary findings.

  8. Epstein-Barr virus-positive cytotoxic T-cell lymphoma followed by chronic active Epstein-Barr virus infection-associated T/NK-cell lymphoproliferative disorder: a case report.

    PubMed

    Kato, Seiichi; Miyata, Tomoko; Takata, Katsuyoshi; Shimada, Satoko; Ito, Yoshinori; Tomita, Akihiro; Elsayed, Ahmed Ali; Takahashi, Emiko; Asano, Naoko; Kinoshita, Tomohiro; Kimura, Hiroshi; Nakamura, Shigeo

    2013-12-01

    A 30-year-old female patient presented with intestinal Epstein-Barr virus (EBV)-positive cytotoxic T-cell lymphoma (EBV+ CTL), which was surgically resected. Fourteen years later, she returned to our hospital with hypersensitivity to mosquito bites and was diagnosed with chronic active EBV infection-associated T/NK-cell lymphoproliferative disorder (CAEBV/TNK-LPD). She developed systemic EBV+ CTL at age 47 years during the 2.5-year clinical course of CAEBV/TNK-LPD, despite multiagent chemotherapy and allogeneic stem cell transplantation. Afterward, she had a rapidly deteriorating clinical course and died at age 48 years. The immunophenotype of the EBV+ CTL was consistently a CD3, CD8, and cytotoxic molecule-positive type with the same clonality in polymerase chain reaction analysis of T-cell receptor-γ chain gene rearrangement. This is the first reported case of EBV+ CTL preceding the clinical presentation of CAEBV/TNK-LPD. The present case was unique in suggesting a close relationship between EBV+ CTL and chronic active EBV infection.

  9. 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.

  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

    2015-09-03

    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. D-cycloserine increases positive symptoms in chronic schizophrenic patients when administered in addition to antipsychotics: a double-blind, parallel, placebo-controlled study.

    PubMed

    van Berckel, B N; Evenblij, C N; van Loon, B J; Maas, M F; van der Geld, M A; Wynne, H J; van Ree, J M; Kahn, R S

    1999-08-01

    A hypofunction of the glutamatergic system and NMDA receptors in schizophrenia has been hypothesized. Therefore, stimulation of these receptors could be of benefit to patients with schizophrenia. D-cycloserine has been used for this purpose. This study reports the effects of 100 mg D-cycloserine, when added to typical antipsychotics in chronic schizophrenic patients exhibiting prominent negative symptoms, using a placebo-controlled, double-blind, parallel, design. D-cycloserine slightly worsened psychotic symptoms and general psychopathology as compared to placebo. D-cycloserine failed to change negative symptoms and had no effect on extrapyramidal symptoms. The exacerbation of schizophrenic symptoms may be explained by the antagonistic effects of this dose of D-cycloserine at the glycine recognition site of the NMDA receptor due to competition with the endogenous agonist glycine. Another explanation for the increase in psychopathology may be an interaction with the effects of antipsychotics on NMDA mediated neurotransmission. Thus, D-cycloserine in this study did not ameliorate schizophrenic symptoms. However, the fact that they actually worsened suggests that NMDA systems may be involved in the pathogenesis of schizophrenia. Further placebo-controlled studies with lower dosages of D-cycloserine, preferably in drug-free patients, are necessary to evaluate if D-cycloserine is of use for the treatment of patients with schizophrenia.

  12. [Overexpression of B7-1 amd B7-2 by LFA-1 positive lymphocytes in chronic inflammatory bowel diseases].

    PubMed

    Isbert, C; Germer, C T; Albrecht, D; Thomsen-Mund, K; Schuppan, D; Buhr, H J

    1998-01-01

    The B7/CD28 pathway is essential for initiating antigen-specific T-cell activation. LFA-1 (CD11a/CD18) is required for sufficient migration into inflammatory tissue. The aim of this study was to evaluate the role of B7 and LFA-1 in inflammatory bowel disease. Immunohistological single and double staining (PAP/APAAP) with monoclonal antibodies against HLA I/II, CD4, CD8, CD28, B7-1, B7-2, LFA-1 and CD68 were performed in tissue samples from patients with crohn's disease (n = 15), ulcerative colitis (n = 14), colorectal carcinoma (n = 5) and FAP (n = 3). The expression of B7-1 and B7-2 was generally much higher in ulcerative colitis and crohn's disease than in colorectal carcinoma and FAP. In crohn's disease multinucleated gigant cells in the granulomas express B7-1 and B7-2. Double staining showed a higher B7-1/B7-2 coexpression for CD4+ than for CD8+ T cells. In colitis ulcerosa and crohn's disease LFA-1 positive leucocytes showed a high coexpression of B7-1 and B7-2 in contrast to CD68 positive macrophages. These data suggest that overexpression of B7-1 and B7-2 on LFA-1 positive Leucocyts seems to play an important role in the pathogenesis of inflammatory bowel disease.

  13. Ferritin Level Is Positively Associated with Chronic Kidney Disease in Korean Men, Based on the 2010–2012 Korean National Health and Nutrition Examination Survey

    PubMed Central

    Kang, Hee-Taik; Linton, John A.; Kwon, Soon Kil; Park, Byoung-Jin; Lee, Jong Hun

    2016-01-01

    (1) Background: Oxidative stress and inflammation are associated with higher risk of chronic kidney disease (CKD). Serum ferritin concentrations correlate with total iron levels and systemic inflammation. (2) Methods: This study was cross-sectionally designed, based on the 2010–2012 Korean National Health and Nutrition Examination Survey (KNHANES). According to ferritin values, 13,462 participants (6082 men and 7380 women) were categorized into the normal- and high-ferritin groups (cut-off points: 200 ng/mL in men, 150 ng/mL in women). (3) Results: The mean ages of men and women were 44.5 and 48.4 years, respectively. The percentage of participants categorized into the high-ferritin group was 15.1% for men and 3.6% for women. The estimated glomerular filtration rate levels in the normal- and high-ferritin groups were 93.2 and 93.8 mL/min/1.73 m2 for men and 97.1 and 87.7 mL/min/1.73 m2 for women, respectively. The prevalence of CKD in the normal- and high-ferritin groups was 2.6% and 3.9% for men and 3.2% and 8.1% for women, respectively. Compared with the normal-ferritin group, the odds ratios (95% confidence intervals) for CKD of the high-ferritin group were 1.573 (1.014–2.441) in men and 1.061 (0.381–2.955) in women, after adjustments for age and other covariates. (4) Conclusions: High ferritin levels were associated with a higher risk of CKD in men but not in women. PMID:27801876

  14. α2δ ligands act as positive modulators of adult hippocampal neurogenesis and prevent depression-like behavior induced by chronic restraint stress.

    PubMed

    Valente, Maria Maddalena; Bortolotto, Valeria; Cuccurazzu, Bruna; Ubezio, Federica; Meneghini, Vasco; Francese, Maria Teresa; Canonico, Pier Luigi; Grilli, Mariagrazia

    2012-08-01

    Although the role of adult hippocampal neurogenesis remains to be fully elucidated, several studies suggested that the process is involved in cognitive and emotional functions and is deregulated in various neuropsychiatric disorders, including major depression. Several psychoactive drugs, including antidepressants, can modulate adult neurogenesis. Here we show for the first time that the α2δ ligands gabapentin [1-(aminomethyl)cyclohexaneacetic acid] and pregabalin (PGB) [(S)-(+)-3-isobutyl-GABA or (S)-3-(aminomethyl)-5-methylhexanoic acid] can produce concentration-dependent increases in the numbers of newborn mature and immature neurons generated in vitro from adult hippocampal neural progenitor cells and, in parallel, a decrease in the number of undifferentiated precursor cells. These effects were confirmed in vivo, because significantly increased numbers of adult cell-generated neurons were observed in the hippocampal region of mice receiving prolonged treatment with PGB (10 mg/kg i.p. for 21 days), compared with vehicle-treated mice. We demonstrated that PGB administration prevented the appearance of depression-like behaviors induced by chronic restraint stress and, in parallel, promoted hippocampal neurogenesis in adult stressed mice. Finally, we provided data suggesting involvement of the α2δ1 subunit and the nuclear factor-κB signaling pathway in drug-mediated proneurogenic effects. The new pharmacological activities of α2δ ligands may help explain their therapeutic activity as supplemental therapy for major depression and depressive symptoms in post-traumatic stress disorder and generalized anxiety disorders. These data contribute to the identification of novel molecular pathways that may represent potential targets for pharmacological modulation in depression.

  15. Heliox-Driven Nebulization Has a Positive Effect on the Lung Function in Lipopolysaccharide-Induced Chronic Obstructive Pulmonary Disease Rat Model

    PubMed Central

    Wu, Wenwen; Chen, Xi; Liu, Xiaohan; Liu, Chengyuan; Lu, Gendi

    2016-01-01

    Background Chronic obstructive pulmonary disease (COPD) is a serious lung disease that severely threatens people’s health. This study aimed to investigate the effects of heliox-driven nebulization (HDN) on lung function and arterial blood gases in a COPD rat model. Material/Methods Twelve healthy male Wistar rats were selected as controls and 34 rats were used to establish a COPD model induced by lipopolysaccharide. Then 6 rats each from the control and model groups were selected for their symptoms to be observed. The remaining 6 normal rats were used as control group (group A) and the remaining 28 experimental COPD rats were randomly assigned to 4 groups: experimental COPD group (group B), medical oxygen group (group C), and heliox groups (group D, He/O2=63%/37%; group E, He/O2=71%/29%). The lung function indicators and arterial blood gases were analyzed to evaluate the effects of different driving gases on COPD rats. Results The COPD model was successfully established with slow growth and severe lung dysfunction. Inspiratory resistance, expiratory resistance, and forced expiratory volume at 0.10 s (FEV0.10)/FVC were significantly decreased, whereas dynamic lung compliance was significantly increased in groups D and E, compared with the experimental COPD group (group B; P<0.05). Meanwhile, compared with the model group, the values of partial pressure of carbon dioxide in arterial blood were significantly higher, whereas the potential of hydrogen values were significantly lower after atomization in groups C and D but not in group E (P<0.05). The obvious increase in arterial oxygen saturation was found only in group E (P<0.05). Conclusions HDN improved the lung function and arterial blood gas analysis results in experimental COPD rats, with an optimal percentage of He/O2=71%/29%. PMID:27794584

  16. 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

  17. Chronic Sinusitis

    MedlinePlus

    Chronic sinusitis Overview By Mayo Clinic Staff Chronic sinusitis is a common condition in which the cavities around nasal passages (sinuses) become inflamed and swollen for at least 12 weeks, despite treatment attempts. Also known as chronic rhinosinusitis, this condition ...

  18. Quantitative Hepatitis B Core Antibody Level Is a New Predictor for Treatment Response In HBeAg-positive Chronic Hepatitis B Patients Receiving Peginterferon

    PubMed Central

    Hou, Feng-Qin; Song, Liu-Wei; Yuan, Quan; Fang, Lin-Lin; Ge, Sheng-Xiang; Zhang, Jun; Sheng, Ji-Fang; Xie, Dong-Ying; Shang, Jia; Wu, Shu-Huan; Sun, Yong-Tao; Wei, Shao-Feng; Wang, Mao-Rong; Wan, Mo-Bin; Jia, Ji-Dong; Luo, Guang-Han; Tang, Hong; Li, Shu-Chen; Niu, Jun-Qi; Zhou, Wei-dong; Sun, Li; Xia, Ning-Shao; Wang, Gui-Qiang

    2015-01-01

    A recent study revealed that quantitative hepatitis B core antibody (qAnti-HBc) level could serve as a novel marker for predicting treatment response. In the present study, we further investigated the predictive value of qAnti-HBc level in HBeAg-positive patients undergoing PEG-IFN therapy. A total of 140 HBeAg-positive patients who underwent PEG-IFN therapy for 48 weeks and follow-up for 24 weeks were enrolled in this study. Serum samples were taken every 12 weeks post-treatment. The predictive value of the baseline qAnti-HBc level for treatment response was evaluated. Patients were further divided into 2 groups according to the baseline qAnti-HBc level, and the response rate was compared. Additionally, the kinetics of the virological and biochemical parameters were analyzed. Patients who achieved response had a significantly higher baseline qAnti-HBc level (serological response [SR], 4.52±0.36 vs. 4.19±0.58, p=0.001; virological response [VR], 4.53±0.35 vs. 4.22±0.57, p=0.005; combined response [CR], 4.50±0.36 vs. 4.22±0.58, p=0.009)). Baseline qAnti-HBc was the only parameter that was independently correlated with SR (p=0.008), VR (p=0.010) and CR(p=0.019). Patients with baseline qAnti-HBc levels ≥30,000 IU/mL had significantly higher response rates, more HBV DNA suppression, and better hepatitis control in PEG-IFN treatment. In conclusion, qAnti-HBc level may be a novel biomarker for predicting treatment response in HBeAg-positive patients receiving PEG-IFN therapy. PMID:25553110

  19. A role of NF-E2 in chronic inflammation and clonal evolution in essential thrombocythemia, polycythemia vera and myelofibrosis?

    PubMed

    Hasselbalch, Hans C

    2014-02-01

    A novel murine model for myeloproliferative neoplasms (MPNs) generated by overexpression of the transcription factor NF-E2 has recently been described. Sustained overexpression of NF-E2 in this model induced myeloid expansion with anemia, leukocytosis and thrombocytosis. Herein, it is debated if NF-E2 overexpression also might have induced a sustained state of in vivo leukocyte and platelet activation with chronic and self-perpetuating production of inflammatory products from activated leukocytes and platelets. If so, this novel murine model also may excellently describe the deleterious impact of sustained chronic NF-E2 overexpression during uncontrolled chronic inflammation upon the hematopoietic system--the development of clonal myeloproliferation. Accordingly, this novel murine model may also have delivered the proof of concept of chronic inflammation as a trigger and driver of clonal evolution in MPNs.

  20. 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.

  1. Monocyte Chemoattractant Protein-1 (MCP-1) as a Potential Therapeutic Target and a Noninvasive Biomarker of Liver Fibrosis Associated With Transient Myeloproliferative Disorder in Down Syndrome.

    PubMed

    Kobayashi, Kenichiro; Yoshioka, Takako; Miyauchi, Jun; Nakazawa, Atsuko; Yamazaki, Shigeaki; Ono, Hiromi; Tatsuno, Michiko; Iijima, Kenta; Takahashi, Chiaki; Okada, Yoko; Teranishi, Kenji; Matsunaga, Takaaki; Matsushima, Chieko; Inagaki, Mayo; Suehiro, Minoru; Suehiro, Saori; Nishitani, Masahiko; Kubota, Hirohito; Iio, Jun; Nishida, Yoshinobu; Katayama, Tetsuo; Takada, Narito; Watanabe, Kentaro; Yamamoto, Tetsuro; Yasumizu, Ryoji; Matsuoka, Kentaro; Ohki, Kentaro; Kiyokawa, Nobutaka; Maihara, Toshiro; Usami, Ikuya

    2017-03-06

    Liver fibrosis is one of the common complications of transient myeloproliferative disorder (TMD) in Down syndrome (DS), but the exact molecular pathogenesis is largely unknown. We herein report a neonate of DS with liver fibrosis associated with TMD, in which we performed the serial profibrogenic cytokines analyses. We found the active monocyte chemoattractant protein-1 expression in the affected liver tissue and also found that both serum and urinary monocyte chemoattractant protein-1 concentrations are noninvasive biomarkers of liver fibrosis. We also showed a prospective of the future anticytokine therapy with herbal medicine for the liver fibrosis associated with TMD in DS.

  2. 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

  3. Loss of Ezh2 synergizes with JAK2-V617F in initiating myeloproliferative neoplasms and promoting myelofibrosis

    PubMed Central

    Nienhold, Ronny; Zmajkovic, Jakub; Hao-Shen, Hui; Geier, Florian; Dirnhofer, Stephan; Feenstra, Jelena D. Milosevic

    2016-01-01

    Myeloproliferative neoplasm (MPN) patients frequently show co-occurrence of JAK2-V617F and mutations in epigenetic regulator genes, including EZH2. In this study, we show that JAK2-V617F and loss of Ezh2 in hematopoietic cells contribute synergistically to the development of MPN. The MPN phenotype induced by JAK2-V617F was accentuated in JAK2-V617F;Ezh2−/− mice, resulting in very high platelet and neutrophil counts, more advanced myelofibrosis, and reduced survival. These mice also displayed expansion of the stem cell and progenitor cell compartments and a shift of differentiation toward megakaryopoiesis at the expense of erythropoiesis. Single cell limiting dilution transplantation with bone marrow from JAK2-V617F;Ezh2+/− mice showed increased reconstitution and MPN disease initiation potential compared with JAK2-V617F alone. RNA sequencing in Ezh2-deficient hematopoietic stem cells (HSCs) and megakaryocytic erythroid progenitors identified highly up-regulated genes, including Lin28b and Hmga2, and chromatin immunoprecipitation (ChIP)–quantitative PCR (qPCR) analysis of their promoters revealed decreased H3K27me3 deposition. Forced expression of Hmga2 resulted in increased chimerism and platelet counts in recipients of retrovirally transduced HSCs. JAK2-V617F–expressing mice treated with an Ezh2 inhibitor showed higher platelet counts than vehicle controls. Our data support the proposed tumor suppressor function of EZH2 in patients with MPN and call for caution when considering using Ezh2 inhibitors in MPN. PMID:27401344

  4. Ten years of cerebral venous thrombosis: male gender and myeloproliferative neoplasm is associated with thrombotic recurrence in unprovoked events.

    PubMed

    Lim, H Y; Ng, C; Donnan, G; Nandurkar, H; Ho, Prahlad

    2016-10-01

    Cerebral venous thrombosis (CVT) is a rare venous thrombotic event. We review our local experience in the management of CVT in comparison to other venous thromboembolism (VTE) with specific focus on risk factors for thrombotic recurrence. Retrospective evaluation of consecutive CVT presentations from January 2005 to June 2015, at two major tertiary hospitals in Northeast Melbourne, Australia. This population was compared to a separate audit of 1003 consecutive patients with DVT and PE. Fifty-two patients (30 female, 22 male) with a median age of 40 (18-83) years, presented with 53 episodes of CVT. Twenty-nine episodes (55 %) were associated with an underlying risk factor, with hormonal risk factors in females being most common. The median duration of anticoagulation was 6 months with 11 receiving life-long anticoagulation. Eighty-one percent had residual thrombosis on repeat imaging, which was not associated with recurrence at the same or distant site. Nine (17 %) had CVT-related haemorrhagic transformation with two resultant CVT-related deaths (RR 22.5; p = 0.04). All three VTE recurrences occured in males with unprovoked events (RR 18.2; p = 0.05) who were subsequently diagnosed with myeloproliferative neoplasm (MPN). Compared to the non-cancer VTE population, non-cancer CVT patients were younger, had similar rate of provoked events and VTE recurrence, although with significantly higher rate of MPN diagnosis (RR 9.30 (2.29-37.76); p = 0.002) CVT is a rare thrombotic disorder. All recurrences in this audit occurred in male patients with unprovoked events and subsequent diagnosis of MPN, suggesting further evaluation for MPN may be warranted in patients with unprovoked CVT.

  5. Correlative study between the JAK2V617F mutation and thrombosis in patients with myeloproliferative neoplasm.

    PubMed

    Li, Z C; Fu, H J; Wang, Z M; Yang, S; Xu, H Z

    2016-08-29

    In this study, we investigated the correlation between the JAK2V617F mutation and thrombosis in patients with myeloproliferative neoplasm (MPN) using real-time fluorescence quantitative PCR. The incidence of thrombus was monitored and blood and coagulation were routinely assayed in patients with MPN. The JAK2V617F mutation was found in 8/68 individuals in the control group (11.8%); it was expressed in 44/68 patients with MPN (64.7%), suggesting that the rate of this mutation was significantly higher in patients with MPN than that in the control group. Twenty-six MPN patients (38.2%) showed symptoms of thrombosis; MPN patients with thrombosis showed a significantly higher rate of the JAK2V617F mutation, were of a greater age, and had higher blood pressure than MPN patients without thrombosis. In addition, the white blood cells (WBC) (21.98 ± 1.95) and platelets (364.68 ± 97.72) were significantly higher in patients, expressing the mutated gene, with polycythemia vera than in the patients without the mutation. The WBC (32.89 ± 4.25) and hemoglobin (161.92 ± 16.19) were significantly increased in the essential thrombocythemia patients with gene mutation compared with the patients without mutation. MPN patients showed higher blood clotting ability than the control subjects; moreover, MPN patients with the JAK2V617F mutation showed higher blood clotting ability than those without the mutation. The findings of this study indicate that the JAK2V617F mutation is correlated with the incidence of thrombosis, and analysis of this mutation has important clinical significance in the diagnosis and treatment of MPN.

  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. Hepatitis B virus basal core promoter mutations A1762T/G1764A are associated with genotype C and a low serum HBsAg level in chronically-infected HBeAg-positive Chinese patients.

    PubMed

    Yan, Chun-Hui; Zhao, Cheng-Yu; Ding, Hai; Peng, Ya-Qin; Jin, Peng-Yuan; Yan, Ling; Zhuang, Hui; Li, Tong

    2012-11-01

    The present study was aimed to obtain baseline information of basal core promoter A1762T/G1764A and precore G1896A mutations of hepatitis B virus (HBV) in 192 HBeAg-positive chronically-infected Chinese patients, who were potential candidates for antiviral treatment. The detection of these mutations (including minor mutant subpopulations) was achieved by direct sequencing, whose sensitivity for minor mutant subpopulations identification was confirmed by clone sequencing. Patients enrolled were infected with either genotype B (46.35%) or C (53.65%) HBV identified by routine tests in our laboratory. The A1762T/G1764A or G1896A mutations were detected in 125specimens (125/192, 65.10%), in which 77 (77/125, 61.60%) existed as subpopulations. The A1762T/G1764A mutations were found to be more prevalent in genotype C than that in genotype B HBV [62.14% (64/103) vs. 20.22% (18/89), P<0.0001]. There is no statistically significant link between G1896A and genotypes. The emergence of A1762T/G1764A mutations was also found to be associated with an older age, an elevated ALT/AST level, and a lower HBsAg level in serum [wild-type vs. mutant: 4.57 (3.46-5.42) vs. 3.93 (2.51-5.36), P<0.0001]. In conclusion, HBV basal core promoter mutations A1762T/G1764A are associated with genotype C and a low serum HBsAg level in chronically-infected HBeAg-positive Chinese patients.

  8. 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

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

    ClinicalTrials.gov

    2017-01-31

    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

  10. Peginterferon add-on results in more HBsAg decline compared to monotherapy in HBeAg-positive chronic hepatitis B patients.

    PubMed

    Brouwer, W P; Sonneveld, M J; Xie, Q; Guo, S; Zhang, N; Zeuzem, S; Tabak, F; Zhang, Q; Simon, K; Akarca, U S; Streinu-Cercel, A; Hansen, B E; Janssen, H L A

    2016-06-01

    It is unknown whether peginterferon (PEG-IFN) add-on to entecavir (ETV) leads to more HBsAg decline compared to PEG-IFN monotherapy or combination therapy, and whether ETV therapy may prevent HBsAg increase after PEG-IFN cessation. We performed a post hoc analysis of 396 HBeAg-positive patients treated for 72 weeks with ETV + 24 weeks PEG-IFN add-on from week 24 to 48 (add-on, n = 85), 72 weeks with ETV monotherapy (n = 90), 52 weeks with PEG-IFN monotherapy (n = 111) and 52 weeks PEG-IFN + lamivudine (combination, n = 110) within 2 randomized trials. HBsAg decline was assessed at the end of PEG-IFN (EOP) and 6 months after PEG-IFN (EOF) discontinuation. Differences in baseline characteristics were accounted for using inversed probability of treatment weights. At EOP, a HBsAg reduction of ≥1log10 IU/mL was more frequently achieved for patients in the add-on or combination therapy arms (both 36%), compared to PEG-IFN mono (20%) or ETV (8%) (add-on vs PEG-IFN mono P = 0.050). At EOF, the HBsAg reduction ≥1log10 IU/mL was only sustained in patients treated with ETV consolidation (add-on vs combination and PEG-IFN mono: 40% vs 23% and 18%, P = 0.029 and P = 0.003, respectively). For add-on, combination, PEG-IFN mono and ETV, the mean HBsAg-level change at EOF was -0.84, -0.81, -0.68 and -0.33 log10 IU/mL, respectively (P > 0.05 for PEG-IFN arms). HBeAg loss at EOF was 36%, 31%, 33% and 20%, respectively (P > 0.05). PEG-IFN add-on for 24 weeks results in more on-treatment HBsAg decline than does 52 weeks of PEG-IFN monotherapy. ETV therapy may maintain the HBsAg reduction achieved with PEG-IFN.

  11. 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

  12. 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

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

    PubMed

    Wu, Zhiyuan; Zhang, Xinju; Xu, Xiao; Chen, Yuming; Hu, Tingting; Kang, Zhihua; Li, Shibao; Wang, Hua; Liu, Weiwei; Ma, Xiaochao; Guan, Ming

    2014-07-15

    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.

  14. Suspected myelodysplastic/myeloproliferative neoplasm in a feline leukemia virus-negative cat.

    PubMed

    Weeden, Amy L; Taylor, Kyle R; Terrell, Scott P; Gallagher, Alexander E; Wamsley, Heather L

    2016-12-01

    A 10-year-old castrated Domestic Short-Haired cat was presented to a primary care veterinarian for a wellness examination and laboratory examination for monitoring of diabetes mellitus. The CBC revealed marked thrombocytosis, leukopenia and macrocytic, normochromic anemia. The cat tested negative for FeLV and feline immunodeficiency virus, but was positive for Mycoplasma haemominutum by PCR. Hematologic abnormalities were not responsive to therapy, so a repeat CBC and a bone marrow aspiration for cytology were performed. Additional blood smear findings included anisocytosis with megaloblastic erythroid precursors, large platelets, eosinophilic myelocytes and metamyelocytes, and rare unidentified blasts. The bone marrow smear was highly cellular, and the cytologic pattern was consistent with myelodysplastic syndrome with an erythroid predominance. At that time, 15% blasts were present. The cat was treated with a vitamin K2 analog, doxycycline, and prednisolone, but without a clinical response. Within 3 months, euthanasia was elected due to declining quality of life, and a necropsy was performed. Postmortem bone marrow smears were highly cellular and dominated by monomorphic blasts of unknown line of origin (52%), persistent marked erythroid and megakaryocytic dysplasia, and ineffective erythropoiesis and granulopoiesis. Immunohistochemical, immunocytochemical, and cytochemical stains resulted in a diagnosis of acute myeloid leukemia of unclassified type. Additional histologic findings included mixed hepatitis with trematode infestation and lymphoplasmacytic interstitial nephritis with fibrosis. The marked thrombocytosis with myelodysplastic syndrome and the FeLV-negative status of this cat were unusual. The difficulty in classifying the myelodysplasia and subsequent leukemia highlights a need for further reporting and characterization of these types of disease.

  15. [Chronic myeloid leukemia after renal transplantation: report of a new case and review of the bibliography].

    PubMed

    Sanz, L; Cervantes, F; Esteve, J; Vilardell, J; Marín, P; Rozman, C; Montserrat, E

    1996-10-01

    The increase in cancer incidence in renal transplant recipients is a well recognized fact, which has been related to post-transplant immunosuppressive therapy. Solid tumors, skin cancer and non-Hodgkin's lymphomas account for most of the neoplasms in these patients, whereas chronic myeloproliferative disorders are infrequent. A patient is reported who developed chronic myelogenous leukemia (CML) six years after renal transplantation, which was followed by immunosuppressive with azathioprine, and the published data on such an association are reviewed. In all 10 cases reported azathioprine had been administered after transplantation. The amount and type of post-transplant immunosuppressive therapy seems to be the most important risk factor for the development of secondary CML in these patients, since no cases of CML in patients receiving cyclosporine A have been reported.

  16. Chronic Pain

    MedlinePlus

    ... a problem you need to take care of. Chronic pain is different. The pain signals go on for ... there is no clear cause. Problems that cause chronic pain include Headache Low back strain Cancer Arthritis Pain ...

  17. Chronic cholecystitis

    MedlinePlus

    Cholecystitis - chronic ... Most of the time, chronic cholecystitis is caused by repeated attacks of acute (sudden) cholecystitis. Most of these attacks are caused by gallstones in the gallbladder. These ...

  18. Chronic Bronchitis

    MedlinePlus

    ... a disease, often call Chronic Obstructive Pulmonary Disease (COPD) . A person with COPD may have either emphysema or chronic bronchitis, but many have both. Some people with COPD may also have asthma . Let’s take a look ...

  19. 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

  20. 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

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

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

    ClinicalTrials.gov

    2017-03-28

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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

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

    ClinicalTrials.gov

    2017-02-02

    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

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

    ClinicalTrials.gov

    2016-12-19

    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. 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

  16. 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

  17. 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

  18. 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

  19. G-CSF-Treated Donor Bone Marrow Transplant in Treating Patients With Hematologic Disorders

    ClinicalTrials.gov

    2012-05-24

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

  20. 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

  1. 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

  2. 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.

  3. 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.

  4. Recommendations for multimodal noninvasive and invasive screening for detection of extracranial venous abnormalities indicative of chronic cerebrospinal venous insufficiency: a position statement of the International Society for Neurovascular Disease.

    PubMed

    Zivadinov, Robert; Bastianello, Stefano; Dake, Michael D; Ferral, Hector; Haacke, E Mark; Haskal, Ziv J; Hubbard, David; Liasis, Nikolaos; Mandato, Kenneth; Sclafani, Salvatore; Siddiqui, Adnan H; Simka, Marian; Zamboni, Paolo

    2014-11-01

    Under the auspices of the International Society for Neurovascular Disease (ISNVD), four expert panel committees were created from the ISNVD membership between 2011 and 2012 to determine and standardize noninvasive and invasive imaging protocols for detection of extracranial venous abnormalities indicative of chronic cerebrospinal venous insufficiency (CCSVI). The committees created working groups on color Doppler ultrasound (US), magnetic resonance (MR) imaging, catheter venography (CV), and intravascular US. Each group organized a workshop focused on its assigned imaging modality. Non-ISNVD members from other societies were invited to contribute to the various workshops. More than 60 neurology, radiology, vascular surgery, and interventional radiology experts participated in these workshops and contributed to the development of standardized noninvasive and invasive imaging protocols for the detection of extracranial venous abnormalities indicative of CCSVI. This ISNVD position statement presents the MR imaging and intravascular US protocols for the first time and describes refined color Doppler US and CV protocols. It also emphasizes the need for the use of for noninvasive and invasive multimodal imaging to diagnose adequately and monitor extracranial venous abnormalities indicative of CCSVI for open-label or double-blinded, randomized, controlled studies.

  5. 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

    2011-10-06

    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.

  6. Zabofloxacin for chronic bronchitis.

    PubMed

    Kocsis, B; Szabo, D

    2016-09-01

    Treatment of lower respiratory tract infection poses as an ongoing challenge among respiratory tract diseases. Bacterial infections are causes of acute exacerbations in chronic bronchitis and indications for antibacterial therapy. Several antibiotics were applied to treat bacterial infections in chronic bronchitis, among them fluoroquinolones are considered potent, broad-spectrum agents with excellent tissue penetration. This monograph focuses on zabofloxacin, a novel fluoroquinolone agent recently approved and launched in South Korea, and summarizes the drug's antibacterial efficacy, pharmacokinetic properties and toxicity. Recent advances concerning fluoroquinolones in chronic bronchitis will be discussed, along with a comparison between zabofloxacin and moxifloxacin. Zabofloxacin has proved to be noninferior to moxifloxacin against major community-acquired Gram-positive and Gram-negative respiratory tract pathogens and found to be well tolerated in both oral and parenteral administrations. These features can make it a potential antimicrobial agent in therapy of chronic bronchitis and other lower respiratory tract infections.

  7. G-CSF priming, clofarabine, and high dose cytarabine (GCLAC) for upfront treatment of acute myeloid leukemia, advanced myelodysplastic syndrome or advanced myeloproliferative neoplasm.

    PubMed

    Becker, Pamela S; Medeiros, Bruno C; Stein, Anthony S; Othus, Megan; Appelbaum, Frederick R; Forman, Stephen J; Scott, Bart L; Hendrie, Paul C; Gardner, Kelda M; Pagel, John M; Walter, Roland B; Parks, Cynthia; Wood, Brent L; Abkowitz, Janis L; Estey, Elihu H

    2015-04-01

    Prior study of the combination of clofarabine and high dose cytarabine with granulocyte colony-stimulating factor (G-CSF) priming (GCLAC) in relapsed or refractory acute myeloid leukemia resulted in a 46% rate of complete remission despite unfavorable risk cytogenetics. A multivariate analysis demonstrated that the remission rate and survival with GCLAC were superior to FLAG (fludarabine, cytarabine, G-CSF) in the relapsed setting. We therefore initiated a study of the GCLAC regimen in the upfront setting in a multicenter trial. The objectives were to evaluate the rates of complete remission (CR), overall and relapse-free survival (OS and RFS), and toxicity of GCLAC. Clofarabine was administered at 30 mg m(-2) day(-1) × 5 and cytarabine at 2 g m(-2) day(-1) × 5 after G-CSF priming in 50 newly-diagnosed patients ages 18-64 with AML or advanced myelodysplastic syndrome (MDS) or advanced myeloproliferative neoplasm (MPN). Responses were assessed in the different cytogenetic risk groups and in patients with antecedent hematologic disorder. The overall CR rate was 76% (95% confidence interval [CI] 64-88%) and the CR + CRp (CR with incomplete platelet count recovery) was 82% (95% CI 71-93%). The CR rate was 100% for patients with favorable, 84% for those with intermediate, and 62% for those with unfavorable risk cytogenetics. For patients with an antecedent hematologic disorder (AHD), the CR rate was 65%, compared to 85% for those without an AHD. The 60 day mortality was 2%. Thus, front line GCLAC is a well-tolerated, effective induction regimen for AML and advanced myelodysplastic or myeloproliferative disorders.

  8. G-CSF Priming, Clofarabine, and High Dose Cytarabine (GCLAC) for Upfront Treatment of Acute Myeloid Leukemia, Advanced Myelodysplastic Syndrome or Advanced Myeloproliferative Neoplasm

    PubMed Central

    Becker, Pamela S.; Medeiros, Bruno C.; Stein, Anthony S.; Othus, Megan; Appelbaum, Frederick R.; Forman, Stephen J.; Scott, Bart L.; Hendrie, Paul C.; Gardner, Kelda M.; Pagel, John M.; Walter, Roland B.; Parks, Cynthia; Wood, Brent L.; Abkowitz, Janis L.; Estey, Elihu H.

    2016-01-01

    Prior study of the combination of clofarabine and high dose cytarabine with granulocyte colony-stimulating factor (G-CSF) priming (GCLAC) in relapsed or refractory acute myeloid leukemia resulted in a 46% rate of complete remission despite unfavorable risk cytogenetics. A multivariate analysis demonstrated that the remission rate and survival with GCLAC were superior to FLAG (fludarabine, cytarabine, G-CSF) in the relapsed setting. We therefore initiated a study of the GCLAC regimen in the upfront setting in a multicenter trial. The objectives were to evaluate the rates of complete remission (CR), overall and relapse-free survival (OS and RFS), and toxicity of GCLAC. Clofarabine was administered at 30 mg/m2/day × 5 and cytarabine at 2 gm/m2/day × 5 after G-CSF priming in 50 newly-diagnosed patients ages 18–64 with AML or advanced myelodysplastic syndrome (MDS) or advanced myeloproliferative neoplasm (MPN). Responses were assessed in the different cytogenetic risk groups and in patients with antecedent hematologic disorder. The overall CR rate was 76% (95% confidence interval [CI] 64–88%) and the CR + CRp (CR with incomplete platelet count recovery) was 82% (95% CI 71–93%). The CR rate was 100% for patients with favorable, 84% for those with intermediate, and 62% for those with unfavorable risk cytogenetics. For patients with an antecedent hematologic disorder (AHD), the CR rate was 65%, compared to 85% for those without an AHD. The 60 day mortality was 2%. Thus, front line GCLAC is a well-tolerated, effective induction regimen for AML and advanced myelodysplastic or myeloproliferative disorders. PMID:25545153

  9. 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.

  10. Prevalence of Abelson murine leukemia viral oncogene homolog-breakpoint cluster region fusions and correlation with peripheral blood parameters in chronic myelogenous leukemia patients in Lorestan Province, Iran

    PubMed Central

    Kiani, Ali Asghar; Shahsavar, Farhad; Gorji, Mojtaba; Ahmadi, Kolsoum; Nazarabad, Vahideh Heydari; Bahmani, Banafsheh

    2016-01-01

    Context: Chronic myelogenous leukemia (CML) is a chronic malignancy of myeloid linage associated with a significant increase in granulocytes in bone marrow and peripheral blood. CML diagnosis is based on detection of Philadelphia chromosome and “Abelson murine leukemia viral oncogene homolog” (ABL)-“breakpoint cluster region protein” fusions (ABL-BCR fusions). Aims: In this study, patients with CML morphology were studied according to ABL-BCR fusions and the relationship between the fusions and peripheral blood cell changes was examined. Materials and Methods: All patients suspected to chronic myeloproliferative disorders in Lorestan Province visiting subspecialist hematology clinics who were confirmed by oncologist were studied over a period of 5 years. After completing basic data questionnaire, blood samples were obtained with informed consent from the patients. Blood cell count and morphology were investigated and RNA was extracted from blood samples. cDNA was synthesized from RNA and ABL-BCR fusions including b3a2 and b2a2 (protein 210 kd or p210), e1a2 (protein 190 kdor p190), and e19a2 (protein 230 kdor p230) were studied by multiplex reverse transcription polymerase chain reaction method. Coexistence of e1a2 and b2a2 (p210/p190) fusions was also studied. The prevalence of mutations and their correlation with the blood parameters were statistically analyzed. Results: Of 58 patients positive for ABL-BCR fusion, 18 (30.5%) had b2a2 fusion, 37 (62.71%) had b3a2 fusion and three (3.08%) had e1a2 fusion. Coexistence of e1a2 and b2a2 (p210/p190) was not observed. There was no significant correlation between ABL-BCR fusions and white blood cell count, platelet count, and hemoglobin concentration. Conclusions: The ABL-BCR fusions in Lorestan Province were similar to other studies in Iran, and b3a2 fusion had the highest prevalence in the studied patients studied. PMID:27857896

  11. HBeAg Seroconversion in HBeAg-Positive Chronic Hepatitis B Patients Receiving Long-Term Nucleos(t)ide Analog Treatment: A Systematic Review and Network Meta-Analysis

    PubMed Central

    Xing, Tongjing; Xu, Hongtao; Cao, Lin; Ye, Maocong

    2017-01-01

    Background HBeAg seroconversion is an important intermediate outcome in HBeAg-positive chronic hepatitis B (CHB) patients. This study aimed to compare the effect of nucleos(t)ide analogs (NAs) on HBeAg seroconversion in treating CHB with lamivudine, adefovir, telbivudine, entecavir, and tenofovir. Methods Network meta-analysis of NA treatment-induced HBeAg seroconversion after 1–2 years of treatment was performed. In addition, NA treatment-induced HBeAg seroconversion after 3–5 years of treatment was systematically evaluated. Results A total of 31 articles were included in this study. Nine and five studies respectively reporting on 1- and 2-year treatment were included in our network meta-analysis. In addition, 6, 5, and 5 studies, respectively reporting on 3-, 4-, and 5-year treatment were included in our systematic evaluation. Telbivudine showed a significantly higher HBeAg seroconversion rate after a 1 year treatment period compared to the other NAs (odds ratio (OR) = 3.99, 95% CI 0.68–23.6). This was followed by tenofovir (OR = 3.36, 95% CI 0.70–16.75). Telbivudine also showed a higher seroconversion rate compared to the other NAs after a 2 year treatment period, (OR = 1.38, 95% CI 0.92–2.22). This was followed by entecavir (OR = 1.14, 95% CI 0.72–1.72). No significant difference was observed between spontaneous induction and long-term telbivudine treatment-induced HBeAg seroconversion. However, entecavir and tenofovir treatment-induced HBeAg seroconversions were significantly lower than spontaneous seroconversion. Conclusion Long-term treatment with potent anti-HBV drugs, especially tenofovir and entecavir, may reduce HBeAg seroconversion compared with spontaneous HBeAg seroconversion rate. Telbivudine treatment, whether short term or long term, is associated with higher HBeAg seroconversion compared with the other NAs. However, the high rates of drug resistance likely limit the application of telbivudine. PMID:28107377

  12. 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

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

    SciTech Connect

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

    2016-02-24

    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. Lastly, our findings indicate that cytosine analogues restore a balanced haematopoiesis without decreasing the size of the mutated clone, arguing for a predominantly epigenetic effect.

  14. 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

  15. Nursing Positions

    MedlinePlus

    ... breast with your other hand. The Clutch or Football Hold This is also a good position for ... same time may also choose this position. The football hold allows babies to take milk more easily — ...

  16. Chronic Pericarditis

    MedlinePlus

    ... unknown. However, it may be caused by cancer, tuberculosis , or an underactive thyroid gland ( hypothyroidism ), and it ... a previous injury, or a bacterial infection. Previously, tuberculosis was the most common cause of chronic pericarditis ...

  17. [Chronic migraine].

    PubMed

    Diener, H C; Holle, D; Müller, D; Nägel, S; Rabe, K

    2013-12-01

    The classification of the International Headache Society (IHS) generally differentiates episodic from chronic headache. Chronic migraine is defined as headache on 15 and more days a month over more than 3 months and headache on 8 days or more fulfils the criteria for migraine or were triptan/ergot-responsive when thought to be migrainous in early stages of the attack. The prevalence of chronic migraine is estimated at 2-4 %. The quality of life is highly compromised in this condition and comorbidities are much more frequent compared to episodic migraine. Data from prospective randomized studies are scarce as most patients with chronic migraine were excluded from previous trials and only few studies were conducted for this condition. The efficacy for prophylactic treatment compared with placebo is proven for topiramate and onabotulinum toxin A.

  18. 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…

  19. 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

  20. 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.

  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

    2017-01-31

    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; q22.1); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22.3;q23.3); MLLT3-KMT2A; 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. 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

  3. 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

  4. 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

  5. Application of an NGS-based 28-gene panel in myeloproliferative neoplasms reveals distinct mutation patterns in essential thrombocythaemia, primary myelofibrosis and polycythaemia vera.

    PubMed

    Delic, Sabit; Rose, Dominic; Kern, Wolfgang; Nadarajah, Niroshan; Haferlach, Claudia; Haferlach, Torsten; Meggendorfer, Manja

    2016-11-01

    Molecular routine diagnostics for BCR-ABL1-negative myeloproliferative neoplasms (MPN) currently focusses on mutations in JAK2, CALR and MPL. In recent years, recurrent mutations in MPNs have been identified in several other genes. We here present the validation of a next generation sequencing (NGS)-based 28-gene panel and its use in MPN. We analysed the mutation status of 28 genes in 100 MPN patients [40 essential thrombocythaemia (ET), 30 primary myelofibrosis (PMF), 30 polycythaemia vera (PV)] and found two or more mutated genes in 53 patients. Moreover, significantly more mutated splicing genes (SF3B1, SRSF2 and U2AF1) were present in PMF (0·60 mutated genes/patient) compared to ET (0·15) while no mutations in splicing genes were found in PV. Additionally, chromatin modification genes (ASXL1 and EZH2) were frequently mutated in PMF patients (0·50) and, to a significantly lesser extent, in ET (0·13) and PV (0·07). Contrarily, DNA methylation genes (DNMT3A, IDH1, IDH2 and TET2) were mutated most often in PV (0·5) and less frequently in ET (0·23) and PMF (0·20), but without reaching statistical significance. Our results demonstrate the feasibility and utility of NGS-based panel diagnostics for MPN. With 53% of the patients bearing two or more mutated genes, their prognostic relevance needs further studies.

  6. Concurrence of B-lymphoblastic leukemia and myeloproliferative neoplasm with copy neutral loss of heterozygosity at chromosome 1p harboring a MPL W515S mutation.

    PubMed

    Tao, Jiangchuan; Zhang, Xiaohui; Lancet, Jeffrey; Bennett, John M; Cai, Li; Papenhausen, Peter; Moscinski, Lynn; Zhang, Ling

    2014-01-01

    B-lymphoblastic leukemia (B-ALL) is a neoplasm of precursors committed to B-cell lineage, whereas myeloproliferative neoplasm (MPN) is a clonal proliferation derived from myeloid stem cells. Concurrent B-ALL with MPN is uncommon except in the presence of abnormalities of the PDGFRA, PDGFRB, or FGFR1 genes or the BCR-ABL1 fusion gene. Herein, we describe a rare concurrence, B-ALL with MPN without the aforementioned genetic aberrations, in a 64-year-old male patient. The patient was initially diagnosed with B-ALL with normal karyotype and responded well to aggressive chemotherapy but had sustained leukocytosis and splenomegaly. The posttreatment restaging bone marrow was free of B-ALL but remained hypercellular with myeloid predominance. Using a single nucleotide polymorphism microarray study, we identified a copy neutral loss of heterozygosity at the terminus of 1p in the bone marrow samples taken at diagnosis and again at remission, 49% and 100%, respectively. Several additional genetic abnormalities were present in the initial marrow sample but not in the remission marrow samples. Retrospective molecular studies detected a MPL W515S homozygous mutation in both the initial and remission marrows for B-ALL, at 30-40% and 80% dosage effect, respectively. In summary, we present a case of concurrent B-ALL and MPN and demonstrate a stepwise cytogenetic and molecular approach to the final diagnosis.

  7. 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

  8. 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.

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

    PubMed

    Rumi, Elisa; 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

    2013-05-23

    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.

  10. 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

  11. Conditional Expression of E2A-HLF Induces B-Cell Precursor Death and Myeloproliferative-Like Disease in Knock-In Mice

    PubMed Central

    Duque-Afonso, Jesús; Smith, Kevin S.; Cleary, Michael L.

    2015-01-01

    Chromosomal translocations are driver mutations of human cancers, particularly leukemias. They define disease subtypes and are used as prognostic markers, for minimal residual disease monitoring and therapeutic targets. Due to their low incidence, several translocations and their biological consequences remain poorly characterized. To address this, we engineered mouse strains that conditionally express E2A-HLF, a fusion oncogene from the translocation t(17;19) associated with 1% of pediatric B-cell precursor ALL. Conditional oncogene activation and expression were directed to the B-cell compartment by the Cre driver promoters CD19 or Mb1 (Igα, CD79a), or to the hematopoietic stem cell compartment by the Mx1 promoter. E2A-HLF expression in B-cell progenitors induced hyposplenia and lymphopenia, whereas expression in hematopoietic stem/progenitor cells was embryonic lethal. Increased cell death was detected in E2A-HLF expressing cells, suggesting the need for cooperating genetic events that suppress cell death for B-cell oncogenic transformation. E2A-HLF/Mb1.Cre aged mice developed a fatal myeloproliferative-like disorder with low frequency characterized by leukocytosis, anemia, hepatosplenomegaly and organ-infiltration by mature myelocytes. In conclusion, we have developed conditional E2A-HLF knock-in mice, which provide an experimental platform to study cooperating genetic events and further elucidate translational biology in cross-species comparative studies. PMID:26588248

  12. Depletion of Jak2V617F myeloproliferative neoplasm-propagating stem cells by interferon-α in a murine model of polycythemia vera

    PubMed Central

    Bruedigam, Claudia; Poveromo, Luke; Heidel, Florian H.; Purdon, Amy; Vu, Therese; Austin, Rebecca; Heckl, Dirk; Breyfogle, Lawrence J.; Kuhn, Catherine Paine; Kalaitzidis, Demetrios; Armstrong, Scott A.; Williams, David A.; Hill, Geoff R.; Ebert, Benjamin L.

    2013-01-01

    Interferon-α (IFNα) is an effective treatment of patients with myeloproliferative neoplasms (MPNs). In addition to inducing hematological responses in most MPN patients, IFNα reduces the JAK2V617F allelic burden and can render the JAK2V617F mutant clone undetectable in some patients. The precise mechanism underlying these responses is incompletely understood and whether the molecular responses that are seen occur due to the effects of IFNα on JAK2V617F mutant stem cells is debated. Using a murine model of Jak2V617F MPN, we investigated the effects of IFNα on Jak2V617F MPN-propagating stem cells in vivo. We report that IFNα treatment induces hematological responses in the model and causes depletion of Jak2V617F MPN-propagating cells over time, impairing disease transplantation. We demonstrate that IFNα treatment induces cell cycle activation of Jak2V617F mutant long-term hematopoietic stem cells and promotes a predetermined erythroid-lineage differentiation program. These findings provide insights into the differential effects of IFNα on Jak2V617F mutant and normal hematopoiesis and suggest that IFNα achieves molecular remissions in MPN patients through its effects on MPN stem cells. Furthermore, these results support combinatorial therapeutic approaches in MPN by concurrently depleting dormant JAK2V617F MPN-propagating stem cells with IFNα and targeting the proliferating downstream progeny with JAK2 inhibitors or cytotoxic chemotherapy. PMID:23487027

  13. 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

  14. 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

  15. 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…

  16. 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.

  17. Chronic myelogenous leukemia (CML)

    MedlinePlus

    CML; Chronic myeloid leukemia; Chronic granulocytic leukemia; Leukemia - chronic granulocytic ... nuclear disaster. It takes many years to develop leukemia from radiation exposure. Most people treated for cancer ...

  18. Chronic Bronchitis

    MedlinePlus

    ... breathing. You may also have other tests. Chronic bronchitis is a long-term condition that keeps coming back or never goes away completely. If you smoke, it is important to quit. Treatment can help with your symptoms. It often includes ...

  19. Chronic gastritis.

    PubMed

    Sipponen, Pentti; Maaroos, Heidi-Ingrid

    2015-06-01

    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.

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

    ClinicalTrials.gov

    2017-01-16

    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

  1. Nursing Positions

    MedlinePlus

    ... and actually needs to feed. Getting Comfortable With Breastfeeding Nursing can be one of the most challenging ... a mother. As you become more used to breastfeeding your baby, you can try different positions or ...

  2. 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)

  3. 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.

  4. 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.