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Sample records for post polycythemic myelofibrosis

  1. INC424 for Patients With Myelofibrosis, Post Polycythemia Myelofibrosis or Post-essential Thrombocythemia Myelofibrosis

    ClinicalTrials.gov

    2016-11-27

    Myelofibrosis (PMF); Post Polycythemia Myelofibrosis (PPV MF); Post-essential Thrombocythemia Myelofibrosis (PET-MF); Myelofibrosis; Post Polycythemia Myelofibrosis; Post-essential Thrombocythemia Myelofibrosis

  2. Myelofibrosis

    MedlinePlus

    ... metaplasia; Agnogenic myeloid metaplasia; Primary myelofibrosis; Secondary myelofibrosis; Bone marrow - myelofibrosis ... Bone marrow is the soft, fatty tissue inside your bones. Stem cells are immature cells in the bone ...

  3. Myelofibrosis

    MedlinePlus

    ... is an uncommon type of chronic leukemia — a cancer that affects the blood-forming tissues in the body. Myelofibrosis belongs to a group of diseases called myeloproliferative disorders. Many people with myelofibrosis get progressively worse, ...

  4. [Analysis of prognostic factors in Chinese patients with post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis].

    PubMed

    Chen, M; Xu, Z F; Xu, J Q; Li, B; Zhang, P H; Qin, T J; Zhang, Y; Wang, J Y; Zhang, H L; Fang, L W; Pan, L J; Hu, N B; Qu, S Q; Xiao, Z J

    2016-10-14

    Objective: To evaluate the performances of the prognostic scoring systems devised for primary myelofibrosis(PMF)and the new developed MYSEC- PM(Mysec Prognostic Model)and investigate the risk factors in Chinese patients with post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis(post- PV/ET MF). The most widely used prognostic scoring systems in PMF included the International Prognostic Scoring System(IPSS), dynamic International Prognostic Scoring System(DIPSS), refined DIPSS(DIPSS plus), modified IPSS for Chinese(IPSS-Chinese), and modified DIPSS for Chinese(DIPSS- Chinese). Methods: The clinical and hematologic information of 55 consecutive patients diagnosed with post- PV/ET MF from March 1984 to December 2013 were retrospectively collected. All post-PV/ET MF patients were categorized according to IPSS, DIPSS, DIPSS plus, IPSS-Chinese, DIPSS-Chinese and MYSEC-PM, and the possible prognostic factors were statistically analyzed. Results: Fifty five patients diagnosed with post-PV MF(n=32)or post-ET MF(n=23)were analyzed with a median age of 59(range: 20- 88)years old, including 20 males and 35 females. Median time from original diagnosis to myelofibrosis was 7.8(range: 1.1- 23.4)years. With a median follow up from post-PV/ET MF diagnosis of 37(range: 1-156)months, 44(80.0%)patients were censored alive, 11(20.0%)patients died. Median survival was 110(95% CI 87.5-132.8)months. Using IPSS, DIPSS, DIPSS plus, IPSS- Chinese and MYSEC- PM criteria, there were no statistically significances in survival among different risk groups(P>0.05). In univariate analyses HGB<100 g/L(P=0.003)was the only factor associated with poorer overall survival. The prognosis in subjects with HGB≥100 g/L was significantly better than that with HGB<100 g/L(median OS: not reached vs 47 months, P=0.003). Conclusion: IPSS, DIPSS, DIPSS plus, IPSS- Chinese and MYSEC- PM did not accurately discriminate different risk categories in post PV/ET MF patients. HGB< 100 g

  5. Successful treatment by selective arterial embolization of severe retroperitoneal hemorrhage secondary to bone marrow biopsy in post-polycythemic myelofibrosis.

    PubMed

    Arellano-Rodrigo, E; Real, M I; Muntañola, A; Burrel, M; Rozman, M; Fraire, G V; Cervantes, F

    2004-01-01

    Severe retroperitoneal hemorrhage represents an infrequent and serious complication of bone marrow biopsy. A 53-year-old man, diagnosed with polycythemia vera 12 years earlier, was submitted to a bone marrow biopsy due to the appearance of anemia with clinical and hematological features suggesting myelofibrotic transformation, a diagnosis that was confirmed by the marrow study. At 2 h of a right anterior iliac bone marrow trephine biopsy, the patient suddenly developed severe pain in the area of the biopsy, with antialgic flexion of the right leg. Computed tomographic (CT) scan of the abdomen showed a 5 x 9.5 cm hematoma in the right iliac and psoas muscles. The patient was initially managed with analgesics and transfusional support, but the pain persisted and a continuous fall in the hematocrit was observed in the following days. Angiographic examination of the right external iliac artery showed contrast extravasation arising from the circumflex iliac branch, which was embolized using polivinyl alcohol particles and one coil. Following such procedure, the patient recovered uneventfully and was discharged in good condition a few days later. This case illustrates the effectiveness of an endovascular approach in providing a fast and minimally invasive treatment for this life-threatening complication of bone marrow trephine biopsy.

  6. Evaluation of plitidepsin in patients with primary myelofibrosis and post polycythemia vera/essential thrombocythemia myelofibrosis: results of preclinical studies and a phase II clinical trial

    PubMed Central

    Pardanani, A; Tefferi, A; Guglielmelli, P; Bogani, C; Bartalucci, N; Rodríguez, J; Extremera, S; Pérez, I; Alfaro, V; Vannucchi, A M

    2015-01-01

    Previous data established that plitidepsin, a cyclic depsipeptide, exerted activity in a mouse model of myelofibrosis (MF). New preclinical experiments reported herein found that low nanomolar plitidepsin concentrations potently inhibited the proliferation of JAK2V617F-mutated cell lines and reduced colony formation by CD34+ cells of individuals with MF, at least in part through modulation of p27 levels. Cells of MF patients had significantly reduced p27 content, that were modestly increased upon plitidepsin exposure. On these premise, an exploratory phase II trial evaluated plitidepsin 5 mg/m2 3-h intravenous infusion administered on days 1 and 15 every 4 weeks (q4wk). Response rate (RR) according to the International Working Group for Myelofibrosis Research and Treatment consensus criteria was 9.1% (95% CI, 0.2–41.3%) in 11 evaluable patients during the first trial stage. The single responder achieved a red cell transfusion independence and stable disease was reported in nine additional patients (81.8%). Eight patients underwent a short-lasting improvement of splenomegaly. In conclusion, plitidepsin 5 mg/m2 3-h infusion q4wk was well tolerated but had a modest activity in patients with primary, post-polycythaemia vera or post-essential thrombocythaemia MF. Therefore, this trial was prematurely terminated and we concluded that further clinical trials with plitidepsin as single agent in MF are not warranted. PMID:25768401

  7. Evaluation of plitidepsin in patients with primary myelofibrosis and post polycythemia vera/essential thrombocythemia myelofibrosis: results of preclinical studies and a phase II clinical trial.

    PubMed

    Pardanani, A; Tefferi, A; Guglielmelli, P; Bogani, C; Bartalucci, N; Rodríguez, J; Extremera, S; Pérez, I; Alfaro, V; Vannucchi, A M

    2015-03-13

    Previous data established that plitidepsin, a cyclic depsipeptide, exerted activity in a mouse model of myelofibrosis (MF). New preclinical experiments reported herein found that low nanomolar plitidepsin concentrations potently inhibited the proliferation of JAK2V617F-mutated cell lines and reduced colony formation by CD34+ cells of individuals with MF, at least in part through modulation of p27 levels. Cells of MF patients had significantly reduced p27 content, that were modestly increased upon plitidepsin exposure. On these premise, an exploratory phase II trial evaluated plitidepsin 5 mg/m(2) 3-h intravenous infusion administered on days 1 and 15 every 4 weeks (q4wk). Response rate (RR) according to the International Working Group for Myelofibrosis Research and Treatment consensus criteria was 9.1% (95% CI, 0.2-41.3%) in 11 evaluable patients during the first trial stage. The single responder achieved a red cell transfusion independence and stable disease was reported in nine additional patients (81.8%). Eight patients underwent a short-lasting improvement of splenomegaly. In conclusion, plitidepsin 5 mg/m(2) 3-h infusion q4wk was well tolerated but had a modest activity in patients with primary, post-polycythaemia vera or post-essential thrombocythaemia MF. Therefore, this trial was prematurely terminated and we concluded that further clinical trials with plitidepsin as single agent in MF are not warranted.

  8. A phase II study of panobinostat in patients with primary myelofibrosis (PMF) and post-polycythemia vera/essential thrombocythemia myelofibrosis (post-PV/ET MF).

    PubMed

    Mascarenhas, John; Sandy, Lonette; Lu, Min; Yoon, James; Petersen, Bruce; Zhang, David; Ye, Fei; Newsom, Carrie; Najfeld, Vesna; Hochman, Tsivia; Goldberg, Judith D; Hoffman, Ronald

    2017-02-01

    Myelofibrosis is a chronic and progressive myeloproliferative neoplasm characterized by anemia, splenomegaly, debilitating symptoms and leukemic transformation. Ruxolitinib, an oral JAK1/2 inhibitor, is highly effective in ameliorating systemic symptoms and reducing splenomegaly. Current clinical research is focused on the evaluation of agents based on pre-clinical rationale that can result in disease course modification. Panobinostat is a pan-histone deacetylase inhibitor that has demonstrated clinical activity as a single agent in early phase trials of myelofibrosis. We previously conducted a phase I trial of panobinostat monotherapy in patients with myelofibrosis and determined 25mg thrice weekly as the recommended phase II dose. We then completed an investigator initiated, Simon 2-stage, phase II trial of 22 myelofibrosis patients at our single institution. After 6 cycles of therapy, the overall response rate by IWG-MRT criteria was 36% (8/22; 95% CI: 16-56%). The median percent reduction in spleen volume was 34% (range, 1.6%-73%) in eight evaluable patients. The average reduction in JAK2V617F allele burden was 6.8% (Range; -4.0% to 20.2%) and one patient obtained a complete molecular response. Six patients remained on therapy in the extension phase for a median of 18 months (range, 7-44). Treatment discontinuation was frequent due to patient/physician perception of therapy ineffectiveness. The optimal dosing of panobinostat for the treatment of MF remains somewhat ill-defined but appears to be most effective and better tolerated when administered at lower doses over a prolonged duration of therapy.

  9. Disruption of the ASXL1 gene is frequent in primary, post-essential thrombocytosis and post-polycythemia vera myelofibrosis, but not essential thrombocytosis or polycythemia vera: analysis of molecular genetics and clinical phenotypes

    PubMed Central

    Stein, Brady L.; Williams, Donna M.; O’Keefe, Christine; Rogers, Ophelia; Ingersoll, Roxann G.; Spivak, Jerry L.; Verma, Amit; Maciejewski, Jarek P.; McDevitt, Michael A.; Moliterno, Alison R.

    2011-01-01

    Background The myeloproliferative neoplasms, essential thrombocytosis, polycythemia vera and primary myelofibrosis, share the same acquired genetic lesion, but the concept of JAK2 V617F serving as the sole lesion responsible for these neoplasms is under question, and there has been interest in identifying additional mutations that may contribute to disease pathogenesis. Because ASXL1 lesions have been increasingly identified in myeloid neoplasms, we examined the relationships of ASXL1 mutation or deletion to both clinical phenotype and associated molecular features in 166 patients with myeloproliferative neoplasms. Design and Methods Exon 12 of ASXL1 was amplified from neutrophil genomic DNA and bidirectionally sequenced in 77 patients with myelofibrosis (including patients with primary and post-essential thrombocytosis or post-polycythemia myelofibrosis), 42 patients with polycythemia vera, 41 with essential thrombocytosis and 6 with post-myelofibrosis acute myeloid leukemia. Pyrosequencing assays were designed to determine the allele percentages of JAK2 V617F (G5073770T), ASXL1 2475dupA, and ASXL1 2846_2847del in neutrophil genomic DNA samples. Clinical and laboratory characteristics of patients with wild-type and ASXL1 mutations were then compared. Results We identified nonsense mutations or hemizygous deletion of ASXL1 in 36% of the patients with myelofibrosis, but very rarely among those with polycythemia vera or essential thrombocytosis. Among the patients with myelofibrosis, those with ASXL1 lesions were not distinguished from their wild-type counterparts with regard to JAK2 V617F status, exposure to chemotherapy or evolution to leukemia. Myelofibrosis patients with ASXL1 lesions were more likely to have received anemia-directed therapy compared to those without lesions [15/26 (58%) versus 11/39 (23%); P=0.02]. Using serial banked samples and quantitative ASXL1 mutant allele burden assays, we observed the acquisition and accumulation of ASXL1 mutations over

  10. Increased likelihood of post-polycythemia vera myelofibrosis in Ph-negative MPN patients with chromosome 12 abnormalities

    PubMed Central

    Benton, Christopher B; Tanaka, Maria; Wilson, Catherine; Pierce, Sherry; Zhou, Lingsha; Cortes, Jorge; Kantarjian, Hagop; Verstovsek, Srdan

    2016-01-01

    Chromosome 12 (Chr12) abnormalities have been described for individual patients with Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg MPN), however the frequency, characteristics, and outcomes of such patients as a whole have not been investigated. We reviewed a database of 1787 consecutive Ph-neg MPN patients seen at our institution and determined that 2% of Ph-neg MPN patients harbored an alteration involving Chr12 by cytogenetic evaluation. Retrospective chart review revealed that patients with Chr12 abnormalities had a higher likelihood of having myelofibrosis (MF) compared to patients without a Chr12 abnormality, and were more likely to have post-polycythemia vera MF. The most common alterations in Chr12 in MF patients involved 12q13, 12q15, 12q24, and trisomy 12, and >40% of Chr12 Ph-neg MPN patients had cytogenetic evolution. Chr12 abnormalities did not significantly correlate with JAK2 status, progression to acute myeloid leukemia, or survival, however patients with 12q24 abnormalities trended towards poorer outcomes. PMID:25687833

  11. A data-driven network model of primary myelofibrosis: transcriptional and post-transcriptional alterations in CD34+ cells

    PubMed Central

    Calura, E; Pizzini, S; Bisognin, A; Coppe, A; Sales, G; Gaffo, E; Fanelli, T; Mannarelli, C; Zini, R; Norfo, R; Pennucci, V; Manfredini, R; Romualdi, C; Guglielmelli, P; Vannucchi, A M; Bortoluzzi, S

    2016-01-01

    microRNAs (miRNAs) are relevant in the pathogenesis of primary myelofibrosis (PMF) but our understanding is limited to specific target genes and the overall systemic scenario islacking. By both knowledge-based and ab initio approaches for comparative analysis of CD34+ cells of PMF patients and healthy controls, we identified the deregulated pathways involving miRNAs and genes and new transcriptional and post-transcriptional regulatory circuits in PMF cells. These converge in a unique and integrated cellular process, in which the role of specific miRNAs is to wire, co-regulate and allow a fine crosstalk between the involved processes. The PMF pathway includes Akt signaling, linked to Rho GTPases, CDC42, PLD2, PTEN crosstalk with the hypoxia response and Calcium-linked cellular processes connected to cyclic AMP signaling. Nested on the depicted transcriptional scenario, predicted circuits are reported, opening new hypotheses. Links between miRNAs (miR-106a-5p, miR-20b-5p, miR-20a-5p, miR-17-5p, miR-19b-3p and let-7d-5p) and key transcription factors (MYCN, ATF, CEBPA, REL, IRF and FOXJ2) and their common target genes tantalizingly suggest new path to approach the disease. The study provides a global overview of transcriptional and post-transcriptional deregulations in PMF, and, unifying consolidated and predicted data, could be helpful to identify new combinatorial therapeutic strategy. Interactive PMF network model: http://compgen.bio.unipd.it/pmf-net/. PMID:27341078

  12. Myelofibrosis and benzene exposure.

    PubMed

    Tondel, M; Persson, B; Carstensen, J

    1995-02-01

    Petrol station attendants are exposed to benzene, a well-known carcinogen for blood malignancies. A case of myelofibrosis in a petrol station attendant is presented, along with other reports of myelofibrosis after benzene exposure obtained from the Swedish Cancer Environment Register. Findings of an increased risk for myelofibrosis in the transport sector also suggest a causal relationship with benzene.

  13. Novel Therapies for Myelofibrosis

    PubMed Central

    Stein, Brady L.; Cervantes, Francisco; Giles, Francis; Harrison, Claire N.; Verstovsek, Srdan

    2016-01-01

    Myelofibrosis (MF), including primary, post-essential thrombocythemia and post-polycythemia vera MF, associates with a reduced quality of life and shortened life expectancy. Dysregulation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is prominent, even in the absence of the JAK2V617F mutation. Therefore, all symptomatic MF patients may potentially derive benefit from JAK inhibitors. Despite the efficacy of JAK inhibitors in controlling signs and symptoms of MF, they do not eradicate the disease. Therefore, JAK inhibitors are currently being tested in combination with other novel therapies, a strategy which may be more effective in reducing disease burden, either by overcoming JAK inhibitor resistance or targeting additional mechanisms of pathogenesis. Additional targets include modulators of epigenetic regulation, pathways that work downstream from JAK/STAT (i.e., mammalian target of rapamycin/AKT/phosphoinositide 3-kinase,) heat shock protein 90, hedgehog signaling, pro-fibrotic factors, abnormal megakaryocytes and telomerase. In this review, we discuss novel MF therapeutic strategies. PMID:25860240

  14. Novel therapies for myelofibrosis.

    PubMed

    Stein, Brady L; Cervantes, Francisco; Giles, Francis; Harrison, Claire N; Verstovsek, Srdan

    2015-01-01

    Myelofibrosis (MF), including primary, post-essential thrombocythemia and post-polycythemia vera MF, associates with a reduced quality of life and shortened life expectancy. Dysregulation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is prominent, even in the absence of the JAK2(V617F) mutation. Therefore, all symptomatic MF patients may potentially derive benefit from JAK inhibitors. Despite the efficacy of JAK inhibitors in controlling signs and symptoms of MF, they do not eradicate the disease. Therefore, JAK inhibitors are currently being tested in combination with other novel therapies, a strategy which may be more effective in reducing disease burden, either by overcoming JAK inhibitor resistance or targeting additional mechanisms of pathogenesis. Additional targets include modulators of epigenetic regulation, pathways that work downstream from JAK/STAT (i.e. mammalian target of rapamycin/AKT/phosphoinositide 3-kinase) heat shock protein 90, hedgehog signaling, pro-fibrotic factors, abnormal megakaryocytes and telomerase. In this review, we discuss novel MF therapeutic strategies.

  15. Palliative splenic irradiation in primary and post PV/ET myelofibrosis: outcomes and toxicity of three radiation schedules

    PubMed Central

    Federico, Mario; Pagnucco, Guido; Russo, Antonio; Cardinale, Giovanni; Guerrieri, Patrizia; Sciumè, Francesco; Symonds, Catherine; Cito, Letizia; Siragusa, Sergio; Gebbia, Nicola; Lagalla, Roberto; Midiri, Massimo; Giordano, Antonio; Montemaggi, Paolo

    2009-01-01

    Splenectomy and splenic irradiation (SI) are the sole treatment modalities to control drug resistant splenomegaly in patients with myelofibrosis (MF). SI has been used in poor surgical candidates but optimal total dose and fractionation are unclear. We retrospectively reviewed 14 MF patients with symptomatic splenomegaly. Patients received a median of 10 fractions in two weeks. Fraction size ranged from 0.2–1.4 Gy, and total dose varied from 2–10.8 Gy per RT course. Overall results indicate that 81.8% of radiation courses achieved a significant spleen reduction. Splenic pain relief and gastrointestinal symptoms reduction were obtained in 94% and 91% of courses, respectively. Severe cytopenias occurred in 13% of radiation courses. Furthermore patients were divided in three groups according to the radiation dose they received: 6 patients in the low-dose group (LDG) received a normalized dose of 1.67 Gy; 4 patients in the intermediate-dose group (IDG) received a normalized dose 4.37 Gy; the remaining 4 patients in the high-dose group (HDG) received a normalized dose of 9.2 Gy. Subgroup analysis showed that if no differences in terms of treatment efficacy were seen among dose groups, hematologic toxicity rates distributed differently. Severe cytopenias occurred in 50% of courses in the HDG, and in the 14.3% and in 0% of the IDG and LDG, respectively. Spleen reduction and pain relief lasted for a median of 5.5 months in all groups. Due to the efficacy and tolerability of the low-dose irradiation 4 patients from the LDG and IDG were retreated and received on the whole 12 RT courses. Multiple retreatments did not show decremental trends in terms of rates of response to radiation nor in terms of duration of clinical response. Moreover, retreatment courses did not cause an increased rate of adverse effects and none of the retreated patients experienced severe hematologic toxicities. The average time of clinical benefit in retreated patients was much longer (21 months

  16. Acquired familial Mediterranean fever associated with a somatic MEFV mutation in a patient with JAK2 associated post-polycythemia myelofibrosis.

    PubMed

    Shinar, Yael; Tohami, Tali; Livneh, Avi; Schiby, Ginette; Hirshberg, Abraham; Nagar, Meital; Goldstein, Itamar; Cohen, Rinat; Kukuy, Olga; Shubman, Ora; Sharabi, Yehonatan; Gonzalez-Roca, Eva; Arostegui, Juan I; Rechavi, Gideon; Amariglio, Ninnette; Salomon, Ophira

    2015-06-30

    A study was designed to identify the source of fever in a patient with post-polycythemia myelofibrosis, associated with clonal Janus Kinase 2 (JAK2) mutation involving duplication of exon 12. The patient presented with 1-2 day long self-limited periodic episodes of high fever that became more frequent as the hematologic disease progressed. After ruling out other causes for recurrent fever, analysis of the pyrin encoding Mediterranean fever gene (MEFV) was carried out by Sanger sequencing in peripheral blood DNA samples obtained 4 years apart, in buccal cells, laser dissected kidney tubular cells, and FACS-sorted CD3-positive or depleted mononucleated blood cells. Hematopoeitc cells results were validated by targeted deep sequencing. A Sanger sequence based screen for pathogenic variants of the autoinflammatory genes NLRP3, TNFRSF1A and MVK was also performed. A rare, c.1955G>A, p.Arg652His MEFV gene variant was identified at negligible levels in an early peripheral blood DNA sample, but affected 46 % of the MEFV alleles and was restricted to JAK2-positive, polymorphonuclear and CD3-depleted mononunuclear DNA samples obtained 4 years later, when the patient experienced fever bouts. The patient was also heterozygous for the germ line, non-pathogenic NLRP3 gene variant, p.Q705K. Upon the administration of colchicine, the gold standard treatment for familial Mediterranean fever (FMF), the fever attacks subsided. This is the first report of non-transmitted, acquired FMF, associated with a JAK2 driven clonal expansion of a somatic MEFV exon 10 mutation. The non-pathogenic germ line NLRP3 p.Q705K mutation possibly played a modifier role on the disease phenotype.

  17. PRCA with myelofibrosis: an unusual case report.

    PubMed

    Kar, Rakhee; Mahapatra, Manoranjan; Pati, Hara P

    2008-03-01

    The association of PRCA and myelofibrosis is very rare with only two such cases reported in the literature. Leukemic transformation in myelofibrosis is known but the progression of PRCA to acute leukemia is very rare. We present an unusual case of PRCA with myelofibrosis which after 14 months of transfusion dependent anemia transformed to acute monocytic leukemia.

  18. Emerging drugs for myelofibrosis.

    PubMed

    Atallah, Ehab; Verstovsek, Srdan

    2012-12-01

    Myelofibrosis (MF), a Philadelphia chromosome-negative myeloproliferative neoplasm, is a life-threatening heterogeneous disorder characterized by dysregulation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling network. The clinical hallmarks of MF are progressive splenomegaly, anemia and debilitating symptoms attributable to ineffective hematopoiesis and excessive production of proinflammatory cytokines. This review describes the pathogenesis, clinical features and current treatment of MF, clinical data for ruxolitinib, a potent oral JAK1/JAK2 inhibitor and the only therapy approved for the treatment of MF, and agents in development for the treatment of MF. Information was derived from relevant MF articles identified in the published literature and abstracts of recent congresses. Ruxolitinib reduces spleen size and alleviates MF-related symptoms, thereby improving quality of life. Ruxolitinib may increase the risk of anemia and thrombocytopenia and does not appear to reverse bone marrow fibrosis. Studies are exploring ruxolitinib dosing strategies for patients with low platelet counts and combination therapies. Several other JAK inhibitors and other agents (i.e., immunomodulators, antifibrotic agents, anti-anemia agents, mammalian target of rapamycin [mTOR] inhibitors, epigenetic modifiers, pegylated interferon-α2a) to treat various aspects of MF (i.e., to improve blood counts or forestall marrow fibrosis) are in early clinical development.

  19. OUTCOME OF TRANSPLANTATION FOR MYELOFIBROSIS

    PubMed Central

    Ballen, Karen K.; Shrestha, Smriti; Sobocinski, Kathleen A; Zhang, Mei-Jie; Bashey, Asad; Bolwell, Brian J.; Cervantes, Francisco; Devine, Steven M.; Gale, Robert Peter; Gupta, Vikas; Hahn, Theresa E.; Hogan, William J.; Kröger, Nicolaus; Litzow, Mark R.; Marks, David I.; Maziarz, Richard T.; McCarthy, Philip L.; Schiller, Gary; Schouten, Harry C.; Roy, Vivek; Wiernik, Peter H.; Horowitz, Mary M.; Giralt, Sergio A.; Arora, Mukta

    2010-01-01

    Myelofibrosis is a myeloproliferative disorder incurable with conventional strategies. Several small series have reported long-term disease free survival after allogeneic hematopoietic cell transplantation. In this study, we analyze the outcomes of 289 patients receiving allogeneic transplantation for primary myelofibrosis between 1989 and 2002, from the database of the Center for International Bone Marrow Transplant Research (CIBMTR). The median age was 47 years (range 18-73 years). Donors were HLA identical siblings in 162 patients, unrelated individuals in 101 patients, and HLA non-identical family members in 26 patients. Patients were treated with a variety of conditioning regimens and graft versus host disease prophylaxis regimens. Splenectomy was performed in 65 patients prior to transplantation. The 100-day transplant related mortality was 18% for HLA identical sibling transplants, 35% for unrelated transplants, and 19% for transplants from alternative related donors. Corresponding 5 year overall survival rates were 37%, 30%, and 40% respectively. Disease-free survival rates were 33%, 27% and 22% respectively. Disease-free survival for patients receiving reduced intensity transplants was comparable, 39% for HLA identical sibling donors and 17% for unrelated donors at three years. In this large retrospective series, allogeneic transplantation for myelofibrosis resulted in long-term relapse-free survival in about one-third of patients. PMID:19879949

  20. The evolution and clinical relevance of prognostic classification systems in myelofibrosis.

    PubMed

    Bose, Prithviraj; Verstovsek, Srdan

    2016-03-01

    Primary myelofibrosis, the most aggressive of the classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), is a clonal disorder characterized by often debilitating constitutional symptoms and splenomegaly, bone marrow fibrosis and resultant cytopenias, extramedullary hematopoiesis, risk of leukemic transformation, and shortened survival. Post-polycythemia vera and post-essential thrombocythemia myelofibrosis represent similar entities, although some differences are being recognized. Attempts to classify patients with myelofibrosis into prognostic categories have been made since the late 1980s, and these scoring systems continue to evolve as new information becomes available. Over the last decade, the molecular pathogenesis of MPNs has been elucidated considerably, and the Janus kinase (JAK) 1/2 inhibitor ruxolitinib is the first drug specifically approved by the US Food and Drug Administration to treat patients with intermediate-risk and high-risk myelofibrosis. This article reviews the evolution of prognostic criteria in myelofibrosis, emphasizing the major systems widely in use today, as well as recently described, novel systems that incorporate emerging data regarding somatic mutations. Risk factors for thrombosis and conversion to MPN blast phase also are discussed. Finally, the practical usefulness of the current prognostic classification systems in terms of clinical decision making is discussed, particularly within the context of some of their inherent weaknesses. Cancer 2016;122:681-692. © 2015 American Cancer Society.

  1. Radioimmunoassay of erythropoietin: circulating levels in normal and polycythemic human beings

    SciTech Connect

    Garcia, J.F.; Ebbe, S.N.; Hollander, L.; Cutting, H.O.; Miller, M.E.; Cronkite, E.P.

    1982-05-01

    Techniques are described in detail for the RIA of human Ep in unextracted plasma or serum. With 100 ..mu..l of sample, the assay is sensitive at an Ep concentration of approximately 4 mU/ml, and when required, the sensitivity can be increased to 0.4 mU/ml, a range considerably less than the concentration observed in normal human beings. This is approximately 100 times more sensitive than existing in vivo bioassays for this hormone. Studies concerned with the validation of the Ep RIA show a high degree of correlation with the polycythemic mouse bioassay. Dilutions of a variety of human serum samples show a parallel relationship with the standard reference preparation for Ep. Validation of the RIA is further confirmed by observations of appropriate increases or decreases of circulating Ep levels in physiological and clinical conditions known to be associated with stimulation or suppression of Ep secretion. Significantly different mean serum concentrations of 17.2 mU/ml for normal male subjects and 18.8 mU/ml for normal female subjects were observed. Mean plasma Ep concentrations in patients with polycythemia vera are significantly decreased, and those of patients with secondary polycythemia are significantly increased as compared to plasma levels in normal subjects. These results demonstrate an initial practical value of the Ep RA in the hematology clinic, which will most certainly be expanded with its more extensive use.

  2. Erythropoietin assay: present status of methods, pitfalls, and results in polycythemic disorders.

    PubMed

    Popovic, W J; Adamson, J W

    1978-01-01

    Mammalian erythropoiesis is regulated primarily by the hormone erythropoietin (ESP). Studies of ESF have provided information about its biochemistry and its role in regulating hemoglobin synthesis. Such studies rely on assays for erythropoietic activity in biological fluid. The assay which has proven most valuable and is used most widely is based upon the incorporation of radioactive iron into newly-formed red cells of polycythemic mice. While this assay has gained wide acceptance, it is expensive, cumbersome, imprecise, and insensitive, capable of reliably detecting no less than 50 milliunits of erythropoietin. Improvements in assay techniques will require new methodology relying primarily on immunologic recognition for the determination of hormone activity. Currently under development and in experimental use are radioimmunoassays and a hemagglutination inhibition assay. While work has progressed in these areas, these assays are not of proven value at present and meaningful physiological correlations have not emerged from their use. Alternatively, assays for hormone activity using suspensions of hematopoietic cells and the measurement of incorporation of radioactive isotopes into hemoglobin have provided both improvement in sensitivity and precision. The disadvantage of these types of assays is that they are sensitive to factors other than ESF and may give misleading information, depending on whether the factors present stimulate or inhibit cellular proliferation and hemoglobin synthesis. While such techniques may provide a temporary solution to some problems associated with assaying ESF for purification or physiological studies, they are not the best answer to the overall problem of hormone detection and characterization. The most important contribution to this field will be the availability of large amounts of highly purified and well-characterized ESF.

  3. Recombinant interferon-α in myelofibrosis reduces bone marrow fibrosis, improves its morphology and is associated with clinical response.

    PubMed

    Pizzi, Marco; Silver, Richard T; Barel, Ariella; Orazi, Attilio

    2015-10-01

    Recombinant interferon-α represents a well-established therapeutic option for the treatment of polycythemia vera and essential thrombocythemia. Recent studies also suggest a role for recombinant interferon-α in the treatment of 'early stage' primary myelofibrosis, but few studies have reported the bone marrow changes after clinically successful interferon therapy. The aim of the present study is to detail the histological responses to recombinant interferon-α in primary myelofibrosis and post-polycythemia vera/post-essential thrombocythemia myelofibrosis and to correlate these with clinical findings. We retrospectively studied 12 patients with primary myelofibrosis or post-polycythemia vera/post-essential thrombocythemia myelofibrosis, who had been treated with recombinant interferon-α. Six patients had received other prior cytoreductive therapies. Bone marrow biopsy was assessed for the following histological parameters: (i) cellularity; (ii) myeloid-to-erythroid ratio; (iii) megakaryocyte tight clusters; (iv) megakaryocyte and naked nuclei density; (v) megakaryocytic atypia; (vi) fibrosis; and (vii) the percentage of blasts. Clinical and laboratory data were included: (i) constitutional symptoms; (ii) splenomegaly, if present; and (iii) complete cell blood count. The clinical response to therapy was evaluated using the International Working Group for Myelofibrosis Research and Treatment/European LeukemiaNet response criteria. The Dynamic International Prognostic Scoring System (DIPSS) score was calculated before and after recombinant interferon-α administration. Successful interferon therapy for myelofibrosis was associated with a significant reduction of marrow fibrosis, cellularity, megakaryocyte density and naked nuclei density. The presence of JAK2(V617F) mutation correlated with improved DIPSS score. JAK2(V617F)-negative cases showed worsening of such score or evolution to acute myeloid leukemia. Cytogenetic analysis documented a normal karyotype in all

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

    ClinicalTrials.gov

    2017-09-01

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

  5. 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

  6. Calreticulin mutations in Chinese with primary myelofibrosis

    PubMed Central

    Li, Bing; Xu, Junqing; Wang, Jingya; Gale, Robert Peter; Xu, Zefeng; Cui, Yajuan; Yang, Lin; Xing, Ruixian; Ai, Xiaofei; Qin, Tiejun; Zhang, Yue; Zhang, Peihong; Xiao, Zhijian

    2014-01-01

    We tested 357 Chinese with primary myelofibrosis for mutations in CALR, JAK2 and MPL. CALR mutations were detected in 76 subjects (21%). There were 24 (32%) type-1 (L367fs*46) and 49 (64%) type-2 (K385fs*47) mutations. Seventy-two of 168 subjects (43%) without a JAK2 or MPL mutation had a CALR mutation. Subjects with a type-2 CALR mutation had lower hemoglobin concentrations (P=0.001), lower WBC counts (P<0.001), a higher percentage of blood blasts (P=0.009), and higher conventional (P<0.001) and Chinese-adjusted Dynamic International Prognostic Scoring System (P<0.001) scores compared with subjects with JAK2 mutations. Subjects with a type-2 CALR mutation were also likely to have abnormal platelet levels (<100 × 109/L, P=0.01 or >450 × 109/L, P=0.042) and no splenomegaly (P=0.004). Type-2 CALR mutation or no detectable mutation was an independent high-risk factor for survival in multivariate analyses. These data suggest the ratio between type-1 and type-2 mutations is reversed in Chinese with primary myelofibrosis compared with populations of subjects with primary myelofibrosis of predominately European descent. The unfavorable prognostic impact of CALR mutations in Chinese with primary myelofibrosis is only seen in those with type-2 mutations. These data underscore the need to evaluate the prognostic impact of genetic mutations in different populations. PMID:24997152

  7. Impact of Molecular Genetics on Outcome in Myelofibrosis Patients after Allogeneic Stem Cell Transplantation.

    PubMed

    Kröger, Nicolaus; Panagiota, Victoria; Badbaran, Anita; Zabelina, Tatjana; Triviai, Ioanna; Araujo Cruz, Michelle Maria; Shahswar, Rabia; Ayuk, Francis; Gehlhaar, Marten; Wolschke, Christine; Bollin, Robin; Walter, Carolin; Dugas, Martin; Wiehlmann, Lutz; Lehmann, Ulrich; Koenecke, Christian; Chaturvedi, Anuhar; Alchalby, Haefaa; Stadler, Michael; Eder, Matthias; Christopeit, Max; Göhring, Gudrun; Koenigsmann, Michael; Schlegelberger, Brigitte; Kreipe, Hans-Heinrich; Ganser, Arnold; Stocking, Carol; Fehse, Boris; Thol, Felicitas; Heuser, Michael

    2017-07-01

    Molecular genetics may influence outcome for patients with myelofibrosis. To determine the impact of molecular genetics on outcome after allogeneic stem cell transplantation, we screened 169 patients with primary myelofibrosis (n = 110), post-essential thrombocythemia/polycythemia vera myelofibrosis (n = 46), and myelofibrosis in transformation (n = 13) for mutations in 16 frequently mutated genes. The most frequent mutation was JAK2V617F (n = 101), followed by ASXL1 (n = 49), calreticulin (n = 34), SRSF2 (n = 16), TET2 (n = 10), U2AF1 (n = 11), EZH2 (n = 7), MPL (n = 6), IDH2 (n = 5), IDH1 (n = 4), and CBL (n = 1). The cumulative incidence of nonrelapse mortality (NRM) at 1 year was 21% and of relapse at 5 years 25%. The 5-year rates progression-free (PFS) and overall survival (OS) were and 56%, respectively. In a multivariate analysis CALR mutation was an independent factor for lower NRM (HR, .415; P = .05), improved PFS (HR, .393; P = .01), and OS (HR, .448; P = .03). ASXL1 and IDH2 mutations were independent risk factors for lower PFS (HR, 1.53 [P = .008], and HR, 5.451 [P = .002], respectively), whereas no impact was observed for "triple negative" patients. Molecular genetics, especially CALR, IDH2, and ASXL1 mutations, may thus be useful to predict outcome independently from known clinical risk factors after allogeneic stem cell transplantation for myelofibrosis. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  8. How many JAK inhibitors in myelofibrosis?

    PubMed

    Ferreira, Bruna Velosa; Harrison, Claire

    2014-06-01

    The discovery of the activating mutation JAK2 V617F ushered a new era in MPN which included new diagnostic and prognostic criteria as well as a potential therapeutic target. JAK2 inhibition became a reality with first patients receiving drugs that targeted JAK2 in 2007 and was marked by the first approval in 2011 of Ruxolitinib a JAK 1 and 2-inhibitor to treat myelofibrosis (MF). In this article entitled "How many JAK inhibitors for myelofibrosis" we discuss JAK2 as a target, review briefly the benefits to patients with MF of JAK inhibition and highlight some of the differences between the number of JAK inhibitors currently being evaluated. Reflecting upon what we have learnt from the chronic myeloid leukaemia field and for MF regarding disease complexity as well as individual patient factors including resistance we discuss why it is likely we will need several different agents with JAK inhibitory activity. The next chapter discusses combination therapies for myelofibrosis which is a logical step in both trying to cure this disease and improve patient outcome and toxicities with JAK inhibitors. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

  9. Calreticulin mutation burden--is it a stable clone in patients with essential thrombocythemia and myelofibrosis?

    PubMed

    Shuly, Yulia; Nagar, Meital; Ben-Asaf, Lior; Kneller, Abraham; Steinberg, David M; Amariglio, Ninette; Salomon, Ophira

    2015-12-01

    Calreticulin mutation represents the second most frequent mutation after JAK2 V617F in myeloproliferative disorder and is considered to be a driving mutation. Herein the mutation burden was evaluated in patients with essential thrombocythemia or myelofibrosis and found to increase by 5.7% over time unrelated to the time elapsed from the initial to the final positive test. The longer the course of the disease when first tested (range 0-30 years, mean 7.9 years) the lower mutation burden was observed. The mutated clone was larger in type II in comparison with type I mutation when first tested but the difference in mutation burden from the final to the first positive test was significantly higher in those with type I. Similarly, the difference in mutation burden was higher in patients with essential thrombocythemia reaching almost 8% in comparison to 1.3% in post-essential thrombocythemia myelofibrosis. Thus a repeat calreticulin quantitative test is not warranted.

  10. Magnetic resonance imaging in myelofibrosis and essential thrombocythaemia: contribution to differential diagnosis.

    PubMed

    Rozman, C; Cervantes, F; Rozman, M; Mercader, J M; Montserrat, E

    1999-03-01

    To ascertain the value of magnetic resonance (MR) imaging in the differential diagnosis between myelofibrosis (MF) and essential thrombocythaemia (ET), 38 patients were analysed. 20 patients had MF (idiopathic myelofibrosis, 15 cases; post-ET myelofibrosis, four cases; post-polycythaemic MF, one case) and 18 ET. Mean age was 61.5 years (range 30-89) for patients with MF and 60.9 years (range 26-83) for ET patients. MR imaging was performed in the dorsal vertebrae in all cases, and also in both femurs in 2 5 of the patients. In most ET cases the MR signal of the dorsal vertebrae was not modified, whereas it was markedly reduced in MF (P=0.0000001). With regard to femoral marrow, it was usually fatty in ET, with an absent to moderate degree of reconversion seen in the 14 cases analysed, contrasting with the marked degree of reconversion noted in 10/11 patients with MF (P=0.000007). An inverse correlation was demonstrated between the vertebral signal and the degree of femoral reconversion. These differences were due to the fact that in ET the bone marrow adipose tissue is grossly preserved, whereas in MF it is usually markedly decreased or absent. The above results indicate that MR imaging is a useful tool for the differential diagnosis of ET and MF, with the usefulness of this technique increasing when vertebral and femoral bone marrow studies are combined.

  11. Role of the spleen in the exaggerated polycythemic response to hypoxia in chronic mountain sickness in rats.

    PubMed

    Kam, H Y; Ou, L C; Thron, C D; Smith, R P; Leiter, J C

    1999-11-01

    In a rat model of chronic mountain sickness, the excessive polycythemic response to hypoxic exposure is associated with profound splenic erythropoiesis. We studied the uptake and distribution of radioactive iron and red blood cell (RBC) morphology in intact and splenectomized rats over a 30-day hypoxic exposure. Retention of (59)Fe in the plasma was correlated with (59)Fe uptake by both spleen and marrow and the appearance of (59)Fe-labeled RBCs in the blood. (59)Fe uptake in both the spleen and the marrow paralleled the production of nucleated RBCs. Splenic (59)Fe uptake was approximately 10% of the total marrow uptake under normoxic conditions but increased to 60% of the total marrow uptake during hypoxic exposure. Peak splenic (59)Fe uptake and splenomegaly occurred at the most intense phase of erythropoiesis and coincided with the rapid appearance of (59)Fe-labeled RBCs in the blood. The bone marrow remains the most important erythropoietic organ under both resting and stimulated states, but inordinate splenic erythropoiesis in this rat strain accounts in large measure for the excessive polycythemia during the development of chronic mountain sickness in chronic hypoxia.

  12. Primary autoimmune myelofibrosis: definition of a distinct clinicopathologic syndrome.

    PubMed

    Pullarkat, Vinod; Bass, Randall D; Gong, Jerald Z; Feinstein, Donald I; Brynes, Russell K

    2003-01-01

    Myelofibrosis is characterized by reticulin fibrosis of the bone marrow with resulting features of myelophthisis. Besides hematopoietic malignancies and other neoplasms involving the bone marrow, myelofibrosis has been described in association with autoimmune disorders, especially systemic lupus erythematosus. We describe the clinicopathologic features of a primary form of autoimmune myelofibrosis (AIMF) in patients who do not have systemic lupus erythematosus or another well-defined autoimmune syndrome. Absence of marked splenomegaly, peripheral blood cytopenias with mild teardrop poikilocytosis and leukoerythroblastosis, bone marrow lymphoid aggregates, and presence of autoantibodies are some of the salient features of primary AIMF. AIMF should especially be differentiated from chronic idiopathic myelofibrosis, a neoplastic myeloproliferative disease. Primary AIMF appears to have an excellent prognosis, with all patients reported in this series responding to a short course of corticosteroid therapy.

  13. Idiopathic myelofibrosis associated with ulcerative colitis.

    PubMed

    Arellano-Rodrigo, Eduardo; Esteve, Jordi; Giné, Eva; Panés, Julián; Cervantes, Francisco

    2002-07-01

    A patient with ulcerative colitis (UC) who developed idiopathic myelofibrosis (IM) is reported. The initial diagnosis of UC was established by colonoscopy and large bowel biopsy, performed after a one-month history of abdominal pain and bloody diarrhea. The patient showed a favorable response to prednisone and mesalamine treatment and six months later he developed a new episode of UC, which was successfully controlled with treatment. However, two years later splenomegaly and anemia were observed, with aniso-poikilocytosis, tear-drop cells, immature myeloid precursors in the peripheral blood, and increased serum LDH, arising the suspicion of IM, a diagnosis that was confirmed by bone marrow biopsy. The present case represents a new association of IM with an autoimmune disease and gives support to the hypothesis of a possible immune basis of some IM cases.

  14. Idiopathic myelofibrosis associated with primary biliary cirrhosis.

    PubMed

    Hernández-Boluda, J C; Jiménez, M; Rosiñol, L; Cervantes, F

    2002-03-01

    A patient with primary biliary cirrhosis (PBC) who developed idiopathic myelofibrosis (IM) is reported. The initial diagnosis of PBC was established by liver biopsy, performed after a 2-month history of constitutional symptoms associated with abnormalities of the serum liver enzymes, with typical serum immunological markers being found. Although a favorable response of PBC to prednisone was observed, one and a half year later the patient developed anemia with anisocytosis and poikilocytosis, tear-drop cells, and leukoerythroblastic picture, and IM was diagnosed by bone marrow biopsy. A few months later, a rapid worsening of the patient's clinical condition was noted, with an increase in the constitutional symptoms and need for frequent packed RBC transfusions, and she finally died from an infectious complication. This case represents a new association of IM with an autoimmune disease, supporting the hypothesis of a possible immune basis of IM in some cases.

  15. Definition and management of ruxolitinib treatment failure in myelofibrosis.

    PubMed

    Pardanani, A; Tefferi, A

    2014-12-12

    Ruxolitinib, a Janus kinase (JAK)-1 and JAK-2 inhibitor, is the first-in-class drug to be licensed in the United States for the treatment of high- and intermediate-risk myelofibrosis (MF). Several other JAK inhibitors are in development with some currently undergoing phase-3 clinical trial testing. None of the currently available JAK inhibitors are specific to mutant JAK2; their mechanism of action involves attenuation of JAK-STAT signaling with downregulation of proinflammatory cytokines, rather than selective suppression of the disease clone. Accordingly, while ruxolitinib and other JAK inhibitors are effective in controlling splenomegaly and alleviating constitutional symptoms, their benefit in terms of reversing bone marrow fibrosis or inducing complete or partial remissions appears to be limited. The experience to date with ruxolitinib shows that despite its salutary effects on quality of life, over half of the patients discontinue treatment within 2-3 years. In the current perspective, we examine the incidence and causes of ruxolitinib 'treatment failure' in MF patients based on our personal experience as well as a review of the published literature. We also discuss the challenges in defining and classifying ruxolitinib failure, and within the context of several clinical scenarios, we provide recommendations for the post-ruxolitinib management of MF patients.

  16. Current Challenges in Stem Cell Transplantation in Myelofibrosis.

    PubMed

    Kröger, Nicolaus

    2015-12-01

    Primary or post-ET/PV myelofibrosis is one of the Philadelphia-negative myeloproliferative neoplasms with worst survival. Allogeneic stem cell transplantation (ASCT) can cure a substantial number of patients but is still not universally applicable due to toxicity which leads to therapy-related morbidity and mortality. In the more recent years, outcome of ASCT has improved by less toxic conditioning regimens and optimization of relapse prevention strategies. The introduction of novel therapies such as JAK2 inhibitors may also be helpful in preparation of the transplant by reducing spleen size and constitutional symptoms. To reduce the risk of relapse, molecular monitoring and adoptive immunotherapy with donor lymphocytes have been introduced. Despite lacking prospective randomized trials, it is justified to offer ASCT to eligible patients with PMF whose median survival is expected to be less than 5 years. This includes patients with intermediate-2 and high risk according to IPSS or DIPSS, respectively. The benefit/risk ratio should be considered in each patient taking also transplant- and patient-specific factors into account.

  17. Prostaglandin transporter mutations cause pachydermoperiostosis with myelofibrosis.

    PubMed

    Diggle, Christine P; Parry, David A; Logan, Clare V; Laissue, Paul; Rivera, Carolina; Restrepo, Carlos Martín; Fonseca, Dora J; Morgan, Joanne E; Allanore, Yannick; Fontenay, Michaela; Wipff, Julien; Varret, Mathilde; Gibault, Laure; Dalantaeva, Nadezhda; Korbonits, Márta; Zhou, Bowen; Yuan, Gang; Harifi, Ghita; Cefle, Kivanc; Palanduz, Sukru; Akoglu, Hadim; Zwijnenburg, Petra J; Lichtenbelt, Klaske D; Aubry-Rozier, Bérengère; Superti-Furga, Andrea; Dallapiccola, Bruno; Accadia, Maria; Brancati, Francesco; Sheridan, Eamonn G; Taylor, Graham R; Carr, Ian M; Johnson, Colin A; Markham, Alexander F; Bonthron, David T

    2012-08-01

    Pachydermoperiostosis, or primary hypertrophic osteoarthropathy (PHO), is an inherited multisystem disorder, whose features closely mimic the reactive osteoarthropathy that commonly accompanies neoplastic and inflammatory pathologies. We previously described deficiency of the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (HPGD) as a cause of this condition, implicating elevated circulating prostaglandin E(2) (PGE(2)) as causative of PHO, and perhaps also as the principal mediator of secondary HO. However, PHO is genetically heterogeneous. Here, we use whole-exome sequencing to identify recessive mutations of the prostaglandin transporter SLCO2A1, in individuals lacking HPGD mutations. We performed exome sequencing of four probands with severe PHO, followed by conventional mutation analysis of SLCO2A1 in nine others. Biallelic SLCO2A1 mutations were identified in 12 of the 13 families. Affected individuals had elevated urinary PGE(2), but unlike HPGD-deficient patients, also excreted considerable quantities of the PGE(2) metabolite, PGE-M. Clinical differences between the two groups were also identified, notably that SLCO2A1-deficient individuals have a high frequency of severe anemia due to myelofibrosis. These findings reinforce the key role of systemic or local prostaglandin excess as the stimulus to HO. They also suggest that the induction or maintenance of hematopoietic stem cells by prostaglandin may depend upon transporter activity. © 2012 Wiley Periodicals, Inc.

  18. Unique features of primary myelofibrosis in Chinese.

    PubMed

    Xu, Zefeng; Gale, Robert Peter; Zhang, Yue; Qin, Tiejun; Chen, Huishu; Zhang, Peihong; Zhang, Tianjiao; Liu, Liu; Qu, Shiqiang; Xiao, Zhijian

    2012-03-15

    Clinical and laboratory features of 642 consecutive Chinese subjects with primary myelofibrosis (PMF) were analyzed and compared with those of 1054 predominately white subjects with PMF. Chinese subjects were significantly younger, fewer had constitutional symptoms, and fewer had a palpable spleen or liver. Anemia, in contrast, was significantly more common in Chinese as was an increased white blood cell count and low platelet count. The reason for these differences is unclear, but it does not seem to be correlated with delayed diagnosis. A small but significantly increased proportion of Chinese had the JAK2(V617F) mutation but no difference in the frequency of haplotypes associated with PMF in whites. Survival of Chinese with PMF was also significantly longer than that of whites with PMF. We found commonly used staging systems for PMF such as the International Prognostic Scoring System and the Dynamic International Prognostic Scoring System were suboptimal predictors of survival in Chinese with PMF, and we developed a revised prognostic score that should help in comparison of data between studies of PMF in different populations and planning of clinical trials.

  19. Efficacy of ALK5 inhibition in myelofibrosis

    PubMed Central

    Zhao, Wanke; Ho, Wanting Tina; Han, Ying; Murdun, Cem; Mailloux, Adam W.; Zhang, Ling; Wang, Xuefeng; Budhathoki, Anjali; Pradhan, Kith; Rapaport, Franck; Wang, Huaquan; Shao, Zonghong; Ren, Xiubao; Steidl, Ulrich; Levine, Ross L.; Zhao, Zhizhuang Joe; Verma, Amit; Epling-Burnette, Pearlie K.

    2017-01-01

    Myelofibrosis (MF) is a bone marrow disorder characterized by clonal myeloproliferation, aberrant cytokine production, extramedullary hematopoiesis, and bone marrow fibrosis. Although somatic mutations in JAK2, MPL, and CALR have been identified in the pathogenesis of these diseases, inhibitors of the Jak2 pathway have not demonstrated efficacy in ameliorating MF in patients. TGF-β family members are profibrotic cytokines and we observed significant TGF-β1 isoform overexpression in a large cohort of primary MF patient samples. Significant overexpression of TGF-β1 was also observed in murine clonal MPLW515L megakaryocytic cells. TGF-β1 stimulated the deposition of excessive collagen by mesenchymal stromal cells (MSCs) by activating the TGF-β receptor I kinase (ALK5)/Smad3 pathway. MSCs derived from MPLW515L mice demonstrated sustained overproduction of both collagen I and collagen III, effects that were abrogated by ALK5 inhibition in vitro and in vivo. Importantly, use of galunisertib, a clinically active ALK5 inhibitor, significantly improved MF in both MPLW515L and JAK2V617F mouse models. These data demonstrate the role of malignant hematopoietic stem cell (HSC)/TGF-β/MSC axis in the pathogenesis of MF, and provide a preclinical rationale for ALK5 blockade as a therapeutic strategy in MF. PMID:28405618

  20. Sunitinib in Treating Patients With Idiopathic Myelofibrosis

    ClinicalTrials.gov

    2014-05-12

    Accelerated Phase Chronic Myelogenous Leukemia; Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Mast Cell Leukemia; Meningeal Chronic Myelogenous Leukemia; Primary Myelofibrosis; Progressive Hairy Cell Leukemia, Initial Treatment; Prolymphocytic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage II Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage IV Chronic Lymphocytic Leukemia; T-cell Large Granular Lymphocyte Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia; Untreated Hairy Cell Leukemia

  1. Idiopathic myelofibrosis associated with classic polyarteritis nodosa.

    PubMed

    Camós, Mireia; Arellano-Rodrigo, Eduardo; Abelló, Deborah; Muntañola, Ana; Ferrer, Ana; Grau, Josep Maria; Cervantes, Francisco

    2003-03-01

    A woman with scleroderma and classic polyarteritis nodosa (PAN) who developed idiopathic myelofibrosis (IM) is reported. The patient presented with a one-year history of weakness, polyarthritis, Raynaud phenomenon, dry cough, and epigastralgia. The diagnosis of scleroderma with visceral involvement was made and treatment with prednisone subsequently started, with good clinical response. Six years later, fever, weight loss, livedo reticularis, and dysesthesias developed. Electromyographic studies were consistent with sensory neuropathy and a sural nerve biopsy yielded the diagnosis of PAN. The patient received cyclophosphamide plus prednisone with a favorable response, but 11 years later she was admitted because of weakness, constitutional symptoms, and abdominal pain due to spleen infarcts. Marked anemia, with aniso-poikilocytosis, tear-drop cells, immature myeloid precursors in the peripheral blood, and an increased serum LDH, was observed and the diagnosis of IM established by bone marrow biopsy. This case represents a new association between IM and an autoimmune disease and supports the hypothesis of an immune basis of IM in some patients.

  2. Role of neoplastic monocyte-derived fibrocytes in primary myelofibrosis

    PubMed Central

    Bueso-Ramos, Carlos E.; Newberry, Kate J.; Knez, Liza; Post, Sean M.; Ahn, Jihae; Levine, Ross L.; Kantarjian, Hagop M.

    2016-01-01

    Primary myelofibrosis (PMF) is a fatal neoplastic disease characterized by clonal myeloproliferation and progressive bone marrow (BM) fibrosis thought to be induced by mesenchymal stromal cells stimulated by overproduced growth factors. However, tissue fibrosis in other diseases is associated with monocyte-derived fibrocytes. Therefore, we sought to determine whether fibrocytes play a role in the induction of BM fibrosis in PMF. In this study, we show that BM from patients with PMF harbors an abundance of clonal, neoplastic collagen- and fibronectin-producing fibrocytes. Immunodeficient mice transplanted with myelofibrosis patients’ BM cells developed a lethal myelofibrosis-like phenotype. Treatment of the xenograft mice with the fibrocyte inhibitor serum amyloid P (SAP; pentraxin-2) significantly prolonged survival and slowed the development of BM fibrosis. Collectively, our data suggest that neoplastic fibrocytes contribute to the induction of BM fibrosis in PMF, and inhibiting fibrocyte differentiation with SAP may interfere with this process. PMID:27481130

  3. Myelofibrosis: Review of clinical and pathological features in fourteen dogs

    PubMed Central

    Hoff, Brent; Lumsden, John H.; Valli, Victor E.O.; Kruth, Stephen A.

    1991-01-01

    A clinicopathological study was performed on 14 dogs with myelofibrosis (MF), in order to correlate clinical, laboratory, and histomorphological parameters and investigate factors of prognostic significance. The clinical signs included fatigue, weight loss, anorexia, and diarrhea. Physical findings included pale mucous membranes and wasting/emaciation. The major laboratory observations were moderate to severe, poorly-responsive anemia with various degrees of marrow cellularity and fibrosis. All dogs with severe, non-responsive anemia should have a bone marrow core biopsy, stained for connective tissue, in order to detect myelofibrosis. Myelofibrosis regressed in six dogs. ImagesFigure 1aFigure 1bFigure 1cFigure 1d PMID:17423803

  4. Myelofibrosis and acquired hemophilia A: a case report.

    PubMed

    Wrobel, Marie; Comio, Emilie; Gay, Valerie; Baroudi, Noureddine; Meyer, Pascal; Chuniaud-Louche, Christine; Hacini, Maya; Pica, Gian Matteo

    2016-05-07

    Myelofibrosis and acquired hemophilia A is a rare association. To the best of our knowledge only one case of myelofibrosis and acquired hemophilia A has been previously described. A 66-year-old Caucasian man diagnosed with myelofibrosis evolving in acute myeloid leukemia was referred to us for postoperative bleeding. Hemostatic studies showed prolonged activated partial thromboplastin time, decreased factor VIII coagulation, and a high factor VIII inhibitor titer; these findings led to a diagnosis of acquired hemophilia A for which he was treated with methylprednisolone and recombinant activated factor VII on admission. Due to a lack of response he was subsequently treated with rituximab combined with activated prothrombin complex concentrates. Furthermore, he received azacytidine to treat the underlying hematological malignancies. Immunosuppressive rituximab therapy resolved acquired hemophilia A with marked efficacy. Rapid and accurate diagnosis, effective hemostatic therapy, and timely treatment for underlying disease are important in the management of acquired hemophilia A secondary to hematological malignancy.

  5. Correlation between erythropoietic activity and body growth rate in hypertransfused polycythemic growing rats as the result of an erythropoietin-dependent operating mechanism

    SciTech Connect

    Bozzini, C.E.; Alippi, R.M.; Barcelo, A.C.; Caro, J.

    1989-02-01

    The established relationship between erythropoietic activity and body growth rate in the polycythemic growing rat could be the result of either an erythropoietin (EPO)-dependent or an EPO-independent operating mechanism. The present study was thus undertaken to elucidate the nature of the aforementioned mechanism by assessing the ratio between plasma immunoreactive EPO (iEPO) concentration and erythropoietic activity in young hypertransfused rats for different body growth rates. Red blood cell (RBC)-59Fe uptake was about 75% in 21-day-old rats; it rapidly decreased with time when the animals were placed on a protein-free diet, approaching a level of about 1% by the 10th day of protein starvation. Over the same period plasma iEPO decreased from 55 mU/ml to 7 mU/ml. Body growth rate was 0. Following this ''protein depletion period'' the rats received diets containing different amounts of casein (''protein repletion period'') added isocalorically to the protein-free diet to elicit a rise in body growth rate. Statistically significant relationships (p less than 0.001) were found between dietary casein concentration and body growth rate (r = 0.991), dietary casein concentration and RBC-59Fe uptake (r = 0.991), dietary casein concentration and plasma iEPO level (r = 0.992), body growth rate and RBC-59Fe (r = 0.986), and body growth rate and plasma iEPO level (r = 0.994) in hypertransfused polycythemic rats during the protein repletion period. These findings suggest that the correlation between erythropoietic activity and growth rate in the growing rat is the result of an erythropoietin-dependent operating mechanism, which appears to be independent of the ratio tissue oxygen supply/tissue oxygen demand.

  6. Spinal cord compression due to extramedullary haemopoiesis in myelofibrosis.

    PubMed Central

    Cook, G; Sharp, R A

    1994-01-01

    Extramedullary haemopoiesis resulting in spinal cord compression is rare. This report of extramedullary myeloid metaplasia in a patient with myelofibrosis serves to illustrate the value of magnetic resonance imaging (MRI) in the diagnosis and management of good neurological recovery. Images PMID:8027402

  7. [Acute panmyelosis with myelofibrosis: a rare cause of pancytopenia].

    PubMed

    Falé, Cláudia; Araújo, Ana; Lourenço, Sílvia; Pais, Maria

    2013-01-01

    Acute Panmyelosis with myelofibrosis is a rare and aggressive acute myeloid leukemia accounting for 2% of all acute leukemias. Clinically, it is characterized by an acute onset of cytopenias associated with extensive bone marrow fibrosis in the absence of splenomegaly and related morphological changes in the red blood cells such as dacryocytes. The presence of fibrosis further complicates the correct diagnosis of this rare disease, being important to differentiate this entity from other hematologic malignancies such as other acute myeloid leukemias and myelodysplastic syndromes associated with myelofibrosis. We report a case of a young adult of 16 years old, admitted with severe pancytopenia. The exposure of this case is justified by the rarity of this pathology associated with few cases reported in medical literature, allowing for a clinical sharing and a better understanding of the different clinical aspects of this entity of difficult diagnosis.

  8. A case of mistaken identity: When lupus masquerades as primary myelofibrosis

    PubMed Central

    Hasrouni, Edy; Rogers, Heesun J; Tabarroki, Ali; Visconte, Valeria; Traina, Fabiola; Afable, Manuel; Sekeres, Mikkael A; Maciejewski, Jaroslaw P

    2013-01-01

    Introduction: Autoimmune myelofibrosis is an uncommon hematologic disease characterized by anemia, bone marrow myelofibrosis, and an autoimmune feature. Myelofibrosis is often associated with other conditions, including infections, nutritional/endocrine dysfunction, toxin/drug exposure, and connective tissue diseases, including scleroderma and systemic lupus erythematosus. Absence of clonal markers (JAK2) and heterogeneity of the symptoms often complicate the diagnosis. Case presentation: Here, we present two cases of systemic lupus erythematosus–induced autoimmune myelofibrosis. The first case is of a 36-year-old African American female with diagnosis of systemic lupus erythematosus at the age of 12 years. The second patient is a 44-year-old African American male with family history of systemic lupus erythematosus who developed anemia and constitutional symptoms later on. Both patients showed hypercellularity and fibrotic changes of the bone marrow. Moreover, mutational analysis showed that both patients were wild type for JAK2 (V617F and exon 12) and MPL (exon 10). Conclusions: These two cases illustrate that anemic patients with fibrotic changes in the bone marrow without other clinicopathologic features associated with primary myelofibrosis in the presence of clinical manifestations and history of an autoimmune disease should suggest an autoimmune myelofibrosis. These cases demonstrate that a good clinical history combined with molecular technologies and pathomorphologic criteria are helpful in distinguishing between primary myelofibrosis and a nonclonal myelofibrosis from an associated condition. PMID:27489629

  9. Nontuberculous mycobacterial infection in a patient with myelofibrosis: case report and concise review.

    PubMed

    Henriquez-Camacho, Cesar; Martinez-Barranco, Pilar; Velasco, Maria; Villafuerte-Gutierrez, Paola; Losa, Juan

    2015-06-01

    A 70-year-old patient having massive refractory ascites in the course of idiopathic myelofibrosis was diagnosed of peritoneal extramedullary hematopoiesis and developed an overwhelming nontuberculous mycobacterial infection. The case describes this unusual infection and highlights the need for additional studies to confirm the etiology of ascites in primary myelofibrosis.

  10. Autoimmune myelofibrosis: report of three cases and review of the literature.

    PubMed

    Rizzi, Rita; Pastore, Domenico; Liso, Arcangelo; Liuzzi, Grazia M; Dalena, Anna M; Specchia, Giorgina; Ricco, Rosalia; Liso, Vincenzo

    2004-03-01

    Autoimmune myelofibrosis is a distinct clinicopathological entity, recognizing immunopathogenetic mechanisms and occurring isolately or in association with systemic and/or organ-specific autoimmune diseases. It results in chronic cytopenias, and is defined by a pattern including bone marrow, peripheral blood, serological and clinical features. It has to be distinguished from other disorders having myelofibrosis. Among these, the most relevant differential diagnosis is with chronic idiopathic myelofibrosis, particularly when disclosing autoimmune clinical and/or laboratory features as epiphenomenon related to a secondary immune-dysregulation. Here we report on 3 patients admitted because of chronic cytopenias. In all of them, the clinicopathological evaluation essentially demonstrated myelofibrosis, not clustered megakaryocytes, reactive lymphoid infiltration in marrow biopsies, absence of significant tear-drop poikilocytosis and leukoerythroblastosis on peripheral blood smears, normal-sized spleen, positive autoimmune serology. The resulting patterns met the diagnosis of autoimmune myelofibrosis occurring isolately in a patient and associated with Sjögren's syndrome or concomitant Sjögren's syndrome and Hashimoto's thyroiditis in the other two, respectively. Transient improvements in cytopenias and unmodified myelofibrosis were observed following corticosteroid treatment. It is noteworthy the lack of a specific therapy, being the underlying pathophisiology of myelofibrosis still unclear. In conclusion, increased awareness of the clinicopathological pattern identifying autoimmune myelofibrosis is recommended in order to improve basic and clinical knowledge of this emerging entity.

  11. Splenic irradiation as palliative treatment for symptomatic splenomegaly due to secondary myelofibrosis: a multi-institutional experience.

    PubMed

    Pistevou-Gombaki, Kiki; Zygogianni, Anna; Kantzou, Ioanna; Kyrgias, George; Mystakidou, Kyriaki; Kouvaris, John; Klonizakis, Ioannis; Tsirigotis, Panagiotis; Pappa, Vassiliki; Siakantari, Marina; Eleftheriadis, Nikos; Georgakopoulos, John; Sarris, George; Kelekis, Nikolaos; Kouloulias, Vassilios

    2015-01-01

    To evaluate the impact of splenic irradiation as a palliative treatment for symptomatic splenomegaly due to secondary myelofibrosis. Seventeen patients with chronic myelogenous leukemia and 3 with idiopathic polycythaemia presented with splenomegaly, splenic pain and anemia. Due to symptomatic splenomegaly, despite first-line treatment, the patients underwent splenic irradiation. Two patients received two different schedules of external radiotherapy (580 cGy in 5 fractions and 600 cGy in 6 fractions). Eight patients received 980 cGy in 14 fractions. Ten patients received two courses of 360 cGy in 6 fractions, 3 months apart. Median follow-up was 12 months post irradiation. The patients showed excellent response to treatment one month post-radiotherapy, while treatment was well tolerated without severe toxicity. The dimensions of the spleen decreased significantly. Pain-related Visual Analogue Score (VAS) regressed after completion of irradiation. During 12-month follow-up all patients maintained the benefit of radiotherapy. This study indicates that splenic irradiation could be a safe and effective palliative treatment for symptomatic splenomegaly due to secondary myelofibrosis.

  12. Tetraspanin CD9 participates in dysmegakaryopoiesis and stromal interactions in primary myelofibrosis.

    PubMed

    Desterke, Christophe; Martinaud, Christophe; Guerton, Bernadette; Pieri, Lisa; Bogani, Costanza; Clay, Denis; Torossian, Frederic; Lataillade, Jean-Jacques; Hasselbach, Hans C; Gisslinger, Heinz; Demory, Jean-Loup; Dupriez, Brigitte; Boucheix, Claude; Rubinstein, Eric; Amsellem, Sophie; Vannucchi, Alessandro M; Le Bousse-Kerdilès, Marie-Caroline

    2015-06-01

    Primary myelofibrosis is characterized by clonal myeloproliferation, dysmegakaryopoiesis, extramedullary hematopoiesis associated with myelofibrosis and altered stroma in the bone marrow and spleen. The expression of CD9, a tetraspanin known to participate in megakaryopoiesis, platelet formation, cell migration and interaction with stroma, is deregulated in patients with primary myelofibrosis and is correlated with stage of myelofibrosis. We investigated whether CD9 participates in the dysmegakaryopoiesis observed in patients and whether it is involved in the altered interplay between megakaryocytes and stromal cells. We found that CD9 expression was modulated during megakaryocyte differentiation in primary myelofibrosis and that cell surface CD9 engagement by antibody ligation improved the dysmegakaryopoiesis by restoring the balance of MAPK and PI3K signaling. When co-cultured on bone marrow mesenchymal stromal cells from patients, megakaryocytes from patients with primary myelofibrosis displayed modified behaviors in terms of adhesion, cell survival and proliferation as compared to megakaryocytes from healthy donors. These modifications were reversed after antibody ligation of cell surface CD9, suggesting the participation of CD9 in the abnormal interplay between primary myelofibrosis megakaryocytes and stroma. Furthermore, silencing of CD9 reduced CXCL12 and CXCR4 expression in primary myelofibrosis megakaryocytes as well as their CXCL12-dependent migration. Collectively, our results indicate that CD9 plays a role in the dysmegakaryopoiesis that occurs in primary myelofibrosis and affects interactions between megakaryocytes and bone marrow stromal cells. These results strengthen the "bad seed in bad soil" hypothesis that we have previously proposed, in which alterations of reciprocal interactions between hematopoietic and stromal cells participate in the pathogenesis of primary myelofibrosis. Copyright© Ferrata Storti Foundation.

  13. Tetraspanin CD9 participates in dysmegakaryopoiesis and stromal interactions in primary myelofibrosis

    PubMed Central

    Desterke, Christophe; Martinaud, Christophe; Guerton, Bernadette; Pieri, Lisa; Bogani, Costanza; Clay, Denis; Torossian, Frederic; Lataillade, Jean-Jacques; Hasselbach, Hans C.; Gisslinger, Heinz; Demory, Jean-Loup; Dupriez, Brigitte; Boucheix, Claude; Rubinstein, Eric; Amsellem, Sophie; Vannucchi, Alessandro M.; Le Bousse-Kerdilès, Marie-Caroline

    2015-01-01

    Primary myelofibrosis is characterized by clonal myeloproliferation, dysmegakaryopoiesis, extramedullary hematopoiesis associated with myelofibrosis and altered stroma in the bone marrow and spleen. The expression of CD9, a tetraspanin known to participate in megakaryopoiesis, platelet formation, cell migration and interaction with stroma, is deregulated in patients with primary myelofibrosis and is correlated with stage of myelofibrosis. We investigated whether CD9 participates in the dysmegakaryopoiesis observed in patients and whether it is involved in the altered interplay between megakaryocytes and stromal cells. We found that CD9 expression was modulated during megakaryocyte differentiation in primary myelofibrosis and that cell surface CD9 engagement by antibody ligation improved the dysmegakaryopoiesis by restoring the balance of MAPK and PI3K signaling. When co-cultured on bone marrow mesenchymal stromal cells from patients, megakaryocytes from patients with primary myelofibrosis displayed modified behaviors in terms of adhesion, cell survival and proliferation as compared to megakaryocytes from healthy donors. These modifications were reversed after antibody ligation of cell surface CD9, suggesting the participation of CD9 in the abnormal interplay between primary myelofibrosis megakaryocytes and stroma. Furthermore, silencing of CD9 reduced CXCL12 and CXCR4 expression in primary myelofibrosis megakaryocytes as well as their CXCL12-dependent migration. Collectively, our results indicate that CD9 plays a role in the dysmegakaryopoiesis that occurs in primary myelofibrosis and affects interactions between megakaryocytes and bone marrow stromal cells. These results strengthen the “bad seed in bad soil” hypothesis that we have previously proposed, in which alterations of reciprocal interactions between hematopoietic and stromal cells participate in the pathogenesis of primary myelofibrosis. PMID:25840601

  14. Dynamic International Prognostic Scoring System scores, pre-transplant therapy and chronic graft-versus-host disease determine outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis

    PubMed Central

    Ditschkowski, Markus; Elmaagacli, Ahmet H.; Trenschel, Rudolf; Gromke, Tanja; Steckel, Nina K.; Koldehoff, Michael; Beelen, Dietrich W.

    2012-01-01

    Background Myelofibrosis is a myeloproliferative stem cell disorder curable exclusively by allogeneic hematopoietic stem cell transplantation and is associated with substantial mortality and morbidity. The aim of this study was to assess disease-specific and transplant-related risk factors that influence post-transplant outcome in patients with myelofibrosis. Design and Methods We retrospectively assessed 76 consecutive patients with primary (n=47) or secondary (n=29) myelofibrosis who underwent bone marrow (n=6) or peripheral blood stem cell (n=70) transplantation from sibling (n=30) or unrelated (n=46) donors between January 1994 and December 2010. The median follow-up of surviving patients was 55±7.5 months. Results Primary graft failure occurred in 5% and the non-relapse mortality rate at 1 year was 28%. The relapse-free survival rate was 50% with a relapse rate of 19% at 5 years. The use of pharmacological pre-treatment and the post-transplant occurrence of chronic graft-versus-host disease were significant independent unfavourable risk factors for post-transplant survival in multivariate analysis. Using the Dynamic International Prognostic Scoring System for risk stratification, low-risk patients had significantly better overall survival (P=0.014, hazard ratio 1.4) and relapse-free survival (P=0.02, hazard ratio 1.3) compared to the other risk groups of patients. The additional inclusion of thrombocytopenia, abnormal karyotype and transfusion need (Dynamic International Prognostic Scoring System Plus) resulted in a predicted 5-year overall survival of 100%, 51%, 54% and 30% for low, intermediate-1, intermediate-2 and high-risk groups, respectively. The relapse incidence was significantly higher in the absence of chronic graft-versus-host disease (P=0.006), and pharmacological pre-treatment (n=43) was associated with reduced relapse-free survival (P=0.001). Conclusions The data corroborate a strong correlation between alloreactivity and long-term post

  15. Safety and Efficacy of Fedratinib in Patients With Primary or Secondary Myelofibrosis: A Randomized Clinical Trial.

    PubMed

    Pardanani, Animesh; Harrison, Claire; Cortes, Jorge E; Cervantes, Francisco; Mesa, Ruben A; Milligan, Donald; Masszi, Tamás; Mishchenko, Elena; Jourdan, Eric; Vannucchi, Alessandro M; Drummond, Mark W; Jurgutis, Mindaugas; Kuliczkowski, Kazimierz; Gheorghita, Emanuil; Passamonti, Francesco; Neumann, Frank; Patki, Abhay; Gao, Guozhi; Tefferi, Ayalew

    2015-08-01

    Myelofibrosis (MF) is a BCR-ABL-negative myeloproliferative neoplasm characterized by anemia, splenomegaly, debilitating constitutional symptoms, and shortened survival. Fedratinib, a JAK2-selective inhibitor, previously demonstrated clinically beneficial activity in patients with MF in early-phase trials. To evaluate the efficacy and safety of fedratinib therapy in patients with primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF. Double-blind, randomized, placebo-controlled phase 3 study in 94 sites in 24 countries in which 289 adult patients (≥18 years of age) with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF were randomly assigned between December 2011 and September 2012 to once-daily oral fedratinib, at a dose of 400 mg or 500 mg, or placebo, for at least 6 consecutive 4-week cycles. The primary end point was spleen response (≥35% reduction in spleen volume from baseline as determined by magnetic resonance imaging or computed tomography) at week 24 and confirmed 4 weeks later. The main secondary end point was symptom response (≥50% reduction in total symptom score, assessed using the modified Myelofibrosis Symptom Assessment Form). The primary end point was achieved by 35 of 96 (36% [95% CI, 27%-46%]) and 39 of 97 (40% [95% CI, 30%-50%]) patients in the fedratinib 400-mg and 500-mg groups, vs 1 of 96 (1% [95% CI, 0%-3%]) in the placebo group (P < .001). Symptom response rates at week 24 were 33 of 91 (36% [95% CI, 26%-46%]), 31 of 91 (34% [95% CI, 24%-44%]), and 6 of 85 (7% [95% CI, 2%-13%]) in the fedratinib 400-mg, 500-mg, and placebo groups, respectively (P < .001). Common adverse events with fedratinib treatment were anemia, gastrointestinal symptoms, and increased levels of liver transaminases, serum creatinine, and pancreatic enzymes. Encephalopathy was reported in 4 women who received fedratinib 500 mg/d. A diagnosis of Wernicke encephalopathy was

  16. Intrinsic resistance to JAK2 inhibition in myelofibrosis

    PubMed Central

    Kalota, Anna; Jeschke, Grace R.; Carroll, Martin; Hexner, Elizabeth O.

    2013-01-01

    Purpose Recent results have demonstrated that myeloproliferative neoplasms (MPN) are strongly associated with constitutive activation of the JAK2 tyrosine kinase. However, JAK2 inhibitors currently approved or under development for treating myeloproliferative neoplasms do not selectively deplete the malignant clone, and the inhibition of activity of the drug target (JAK2) has not been rigorously evaluated in clinical studies. Therefore in this study we developed an in vitro assay to gain insight into how effectively JAK2 activity is inhibited in patient samples. Experimental Design We treated primary cells from normal donors and patients with MPN with JAK2 inhibitors and measured phosphorylation of downstream targets STAT5 and STAT3 by flow cytometry. Obtained results were next correlated with JAK2 V617F allele burden and plasma cytokines level. Results We observed a dose-dependent decrease in pSTAT5 and pSTAT3 in ex vivo treated granulocytes. However, phosphorylation of STAT3 and STAT5 in cells from patients with myelofibrosis was significantly less inhibited when compared to cells from patients with polycythemia vera, essential thrombocytosis, and normal donors. Sensitivity to inhibition did not correlate with JAK2 V617F clonal burden. Mixing studies using plasma from patients with myelofibrosis did not transfer resistance to sensitive cells. Likewise, no single cytokine measured appeared to account for the observed pattern of resistance. Taken together these observations suggest that there are cell intrinsic mechanisms that define a priori resistance to JAK2 inhibition in myelofibrosis, and the lesion is localized upstream of STAT3 and STAT5. PMID:23386690

  17. Colorectal Liver Metastasis, Primary Gallbladder Carcinoma and Myelofibrosis Present Simultaneously in a Liver Resection Specimen

    PubMed Central

    Gray, Sophie A.; Raber, Menno H.; Provoost, Esther; Toes, Gert-Jan; Klaase, Joost M.

    2015-01-01

    Myelofibrosis and gallbladder carcinoma are both very rare diseases. This case report describes a patient with a history of myelofibrosis and colorectal carcinoma who was diagnosed with colorectal liver metastases. Surgery was performed to remove the metastases, and on site, the gallbladder was removed because of involvement in one of the liver lesions. After pathological examination, a primary gallbladder carcinoma and myelofibrosis were found in addition to the liver metastases. The combination of diseases was not likely to be interconnected but rather an unlucky course of events for the patient. PMID:26600770

  18. A rare cause of cytopenia in a patient with systemic lupus erythematosus: Autoimmune myelofibrosis

    PubMed Central

    Cansu, Döndü Üsküdar; Teke, Hava Üsküdar; Korkmaz, Cengiz

    2017-01-01

    Hematological abnormalities are very common in the course of systemic lupus erythematosus (SLE). Myelofibrosis is a bone marrow disorder in which there is excessive fibrous tissue formation in the bone marrow. Various benign and malignant disorders can cause or be associated with a diffuse increase in the bone marrow reticular tissue. Some diseases such as infections, neoplasms, and autoimmune diseases may also induce bone marrow fibrosis (secondary myelofibrosis). Cytopenia from autoimmune myelofibrosis (AIMF) in SLE is a rare condition. Here we present a case of AIMF associated with SLE and aim to emphasize on the other cause of cytopenia in SLE. PMID:28293461

  19. Treatment and management of myelofibrosis in the era of JAK inhibitors.

    PubMed

    Keohane, Clodagh; Radia, Deepti H; Harrison, Claire N

    2013-01-01

    Myelofibrosis (MF) can present as a primary disorder or evolve from polycythemia vera (PV) or essential thrombocythemia (ET) to post-PV MF or post-ET MF, respectively. MF is characterized by bone marrow fibrosis, splenomegaly, leukoerythroblastosis, extramedullary hematopoiesis, and a collection of debilitating symptoms. Until recently, the therapeutic options for patients with MF consisted of allogeneic hematopoietic stem cell transplant (alloHSCT), the use of cytoreductive agents (ie, hydroxyurea), splenectomy and splenic irradiation for treatment of splenomegaly, and management of anemia with transfusions, erythropoiesis-stimulating agents (ESAs), androgens, and immunomodulatory agents. However, with increased understanding of the pathogenesis of MF resulting from dysregulated Janus kinase (JAK) signaling, new targeted JAK inhibitor therapies, such as ruxolitinib, are now available. The purpose of this article is to review the clinical features of MF, discuss the use and future of JAK inhibitors, reassess when and how to use conventional MF treatments in the context of JAK inhibitors, and provide a perspective on the future of MF treatment.

  20. Treatment and management of myelofibrosis in the era of JAK inhibitors

    PubMed Central

    Keohane, Clodagh; Radia, Deepti H; Harrison, Claire N

    2013-01-01

    Myelofibrosis (MF) can present as a primary disorder or evolve from polycythemia vera (PV) or essential thrombocythemia (ET) to post-PV MF or post-ET MF, respectively. MF is characterized by bone marrow fibrosis, splenomegaly, leukoerythroblastosis, extramedullary hematopoiesis, and a collection of debilitating symptoms. Until recently, the therapeutic options for patients with MF consisted of allogeneic hematopoietic stem cell transplant (alloHSCT), the use of cytoreductive agents (ie, hydroxyurea), splenectomy and splenic irradiation for treatment of splenomegaly, and management of anemia with transfusions, erythropoiesis-stimulating agents (ESAs), androgens, and immunomodulatory agents. However, with increased understanding of the pathogenesis of MF resulting from dysregulated Janus kinase (JAK) signaling, new targeted JAK inhibitor therapies, such as ruxolitinib, are now available. The purpose of this article is to review the clinical features of MF, discuss the use and future of JAK inhibitors, reassess when and how to use conventional MF treatments in the context of JAK inhibitors, and provide a perspective on the future of MF treatment. PMID:23990704

  1. Hypocellular myelodysplastic syndrome with myelofibrosis in acute myeloid leukemia transformation: A case report.

    PubMed

    Song, Kui; Xu, Xiaojun; Li, Min

    2015-07-01

    Primary myelodysplastic syndrome (MDS) with myelofibrosis is a rare hematological disorder that should be classified as a distinct subgroup of MDS. Treatment of MDS with myelofibrosis remains problematic and the prognosis is poor in these patients, particularly following transformation into acute myeloid leukemia (AML). The current study presents the case of a 28-year-old male diagnosed with MDS associated with myelofibrosis, together with hypocellular bone marrow features. Following induction chemotherapy consisting of mitoxantrone and cytarabine, the patient achieved complete remission, but developed severe myelofibrosis. The patient relapsed and the disease transformed into AML 12 months later. However, the extent of the myelofibrosis was markedly alleviated upon administration of a FLAG regimen that consisted of fludarabine, cytarabine and granulocyte colony-stimulating factor during the AML transformation. After one course of the FLAG regimen, the patient achieved a second complete remission. As there was no suitable donor for hematopoietic stem cell transplantation (HSCT), the patient relapsed and succumbed shortly after. In conclusion, MDS with fibrosis is an aggressive disease, but the degree of myelofibrosis may not be associated with the progression of hypocellular MDS, and allogeneic HSCT remains a potentially curative option for affected patients.

  2. [Myelofibrosis in a benzene-exposed cleaning worker].

    PubMed

    Bausà, Roser; Navarro, Lydia; Cortès-Franch, Imma

    Long-term exposure to benzene has been associated with several blood malignancies, including aplastic anemia, myeloproliferative neoplasms, and different leukemias. We present a case of primary myelofibrosis in a 59-year-old woman who worked as a cleaner at a car dealership and automobile mechanic shop. For 25 years, she used gasoline as a degreaser and solvent to clean engine parts, floors and work desks on a daily basis. She was referred by her primary care provider to the Occupational Health Unit of Barcelona to assess whether her illness was work-related. Review of her job history and working conditions revealed chronic exposure to benzene in the absence of adequate preventive measures. An association between benzene exposure and myeloproliferative disease was established, suspicious for an occupational disease. Copyright belongs to the Societat Catalana de Salut Laboral.

  3. Comorbidities predict worse prognosis in patients with primary myelofibrosis

    PubMed Central

    Newberry, Kate J.; Naqvi, Kiran; Nguyen, Khanh T.; Cardenas-Turanzas, Marylou; Tanaka, Maria Florencia; Pierce, Sherry; Verstovsek, Srdan

    2016-01-01

    Background Comorbidities have been shown to play an important role in prognostic assessment of several hematologic conditions; however, the role of comorbidities in primary myelofibrosis has not been studied. The aim of our study was to evaluate the prevalence and impact of comorbidities in patients with primary myelofibrosis (PMF) using the Adult Comorbidity Evaluation-27 (ACE-27). Methods In this retrospective observational cohort study, we evaluated 349 consecutive patients with a confirmed diagnosis of PMF who presented to our institution from 2000 to 2008. We evaluated the frequency and severity of comorbidities in these patients and assessed their impact on survival in a bivariable model that included the ACE-27 and Dynamic International Prognostic Scoring System (DIPSS) scores as covariates. Results Sixty-four percent of patients had at least one comorbid condition, and diseases of the cardiovascular system (63%) were most common. Comorbidities had a significant negative impact on survival (P < 0.001). Patients with severe comorbidities had twice the risk of death as those with no comorbidities. When stratified by demographic and clinical characteristics, comorbidities were significantly associated with worse survival in patients younger than 65 years (P < 0.001) and those with performance status < 1 (P < 0.001). In a multivariable model that included the ACE-27 and Dynamic-International Prognostic Scoring System scores, comorbidities retained a significant association with shorter survival (P ≤ 0.001). Conclusions Assessment of comorbid conditions in patients with PMF, particularly those who are younger and with good performance status, has important implications for overall prognosis and treatment planning. PMID:24917509

  4. Clinical, histopathologic, and genetic features of pediatric primary myelofibrosis--an entity different from adults.

    PubMed

    DeLario, Melissa R; Sheehan, Andrea M; Ataya, Ramona; Bertuch, Alison A; Vega, Carlos; Webb, C Renee; Lopez-Terrada, Dolores; Venkateswaran, Lakshmi

    2012-05-01

    Primary myelofibrosis is a chronic myeloproliferative neoplasm characterized by cytopenias, leukoerythroblastosis, extramedullary hematopoiesis, hepatosplenomegaly and bone marrow fibrosis. Primary myelofibrosis is a rare disorder in adults; children are even less commonly affected by this entity, with the largest pediatric case series reporting on three patients. Most literature suggests spontaneous resolution of myelofibrosis without long term complications in the majority of affected children. We describe the clinical, pathologic, and molecular characteristics and outcomes of nineteen children with primary myelofibrosis treated in our center from 1984 to 2011. Most patients had cytopenia significant enough to require supportive therapy. No child developed malignant transformation and only five of the 19 children (26%) had spontaneous resolution of disease. Sequence analyses for JAK2V617F and MPLW515L mutations were performed on bone marrow samples from 17 and six patients, respectively, and the results were negative. In conclusion, analysis of this large series of pediatric patients with primary myelofibrosis demonstrates distinct clinical, hematologic, bone marrow, and molecular features from adult patients.

  5. Multiple esophageal variceal ruptures with massive ascites due to myelofibrosis-induced portal hypertension

    PubMed Central

    Tokai, Koichi; Miyatani, Hiroyuki; Yoshida, Yukio; Yamada, Shigeki

    2012-01-01

    A 75-year old man had been diagnosed at 42 years of age as having polycythemia vera and had been monitored at another hospital. Progression of anemia had been recognized at about age 70, and the patient was thus referred to our center in 2008 where secondary myelofibrosis was diagnosed based on bone marrow biopsy findings. Hematemesis due to rupture of esophageal varices occurred in January and February of 2011. The bleeding was stopped by endoscopic variceal ligation. Furthermore, in March of the same year, hematemesis recurred and the patient was transported to our center. He was in irreversible hemorrhagic shock and died. The autopsy showed severe bone marrow fibrosis with mainly argyrophilic fibers, an observation consistent with myelofibrosis. The liver weighed 1856 g the spleen 1572 g, indicating marked hepatosplenomegaly. The liver and spleen both showed extramedullary hemopoiesis. Myelofibrosis is often complicated by portal hypertension and is occasionally associated with gastrointestinal hemorrhage due to esophageal varices. A patient diagnosed as having myelofibrosis needs to be screened for esophageal/gastric varices. Myelofibrosis has a poor prognosis. Therefore, it is necessary to carefully decide the therapeutic strategy in consideration of the patient’s concomitant conditions, treatment invasiveness and quality of life. PMID:22851873

  6. 'JAK-ing' up the treatment of primary myelofibrosis: building better combination strategies.

    PubMed

    Assi, Rita; Verstovsek, Srdan; Daver, Naval

    2017-03-01

    The article discusses the promising agents that are approved or currently under investigation for the treatment of myelofibrosis and reviews the ongoing Janus kinase (JAK) inhibitors-based combinatorial strategies in this setting. Myelofibrosis is a Philadelphia-negative myeloproliferative neoplasm with constitutive JAK/STAT activation. The JAK-inhibitor ruxolitinib is the only approved drug for this disease in the United States and Europe based on two randomized phase III studies that demonstrated clinically meaningful reduction in spleen size, improvement in symptoms, quality of life, and an overall survival advantage with prolonged follow-up. Emerging data have revealed the complex molecular architecture of myelofibrosis with clonal evolution playing a central role in disease progression or transformation. These molecular pathways may explain the heterogeneous benefits obtained by JAK-inhibitors in patients with myelofibrosis. In addition, the genetic and epigenetic mutations appear to work in concert with overactive JAK/STAT signaling and contribute to myelofibrosis pathogenesis and prognosis, suggesting a potential to exploit them as potential therapeutic targets. Combining JAK-inhibitors with agents that target parallel prosurvival pathways or agents that enhance hematopoiesis may enhance efficacy and/or mitigate on-target myelosuppression, thereby extending the therapeutic benefits observed with JAK-inhibitors alone.

  7. [Urticarial vasculitis associated with essential thrombocythaemia progressing to myelofibrosis].

    PubMed

    Koudoukpo, C; Jachiet, M; Zini, J-M; Andreoli, A; Pinquier, L; Rybojad, M; Bosset, D; de Masson, A; Bagot, M; Lebbé, C; Bouaziz, J-D

    2014-12-01

    Urticarial vasculitis (UV) is a rare form of leukocytoclastic vasculitis in which skin lesions resemble urticaria. UV comprises hypocomplementemic and normocomplementemic subtypes. To date, only 4 cases of UV associated with myeloproliferative disorders have been described, including 3 cases with essential thrombocythaemia (ET) and one case with polycythaemia vera. We describe the case of a 59-year-old male patient with JAK2-positive TE and secondary myelofibrosis and who developed multiple urticarial papules persisting for more than 24hours. Skin biopsy showed perivascular neutrophilic infiltrate with margination of neutrophils in the lumen of vessels and some leukocytoclastic patterns, and with red cell extravasation consistent with UV. Treatment with ruxolitinib (a JAK2 inhibitor) induced transient and partial control of the haematological symptoms but did not prevent UV flare. Prednisolone 20mg once daily was added, with good clinical response. To our knowledge, this is the fourth reported case of UV associated with ET and the first case associated with MF. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  8. Interleukin-10 inhibits autonomous myelopoiesis in patients with myelofibrosis.

    PubMed

    Geissler, Klaus; Jäger, Eva; Öhler, Leopold; Gisslinger, Heinz; Jäger, Ulrich; Lechner, Klaus

    2015-09-01

    The spontaneous formation of colony-forming units granulocyte/macrophage (CFU-GM) in semisolid cultures has been shown to be due to the endogenous release of cytokines and/or to the hypersensitivity of cells against growth factors. We have reported that increased autonomous CFU-GM growth is an in vitro characteristic of myelofibrosis (MF) which may reflect aberrant hematopoiesis in vivo. Because of its cytokine synthesis-inhibiting action, we speculated that interleukin-10 (IL-10) may inhibit pathological overproduction of myeloid cells in MF by suppression of autonomous myelopoiesis. In this study, IL-10 significantly inhibited autonomous CFU-GM formation in vitro from peripheral blood mononuclear cells (PB MNC) in 10 of 11 patients with MF tested. In all patients, there was a mean inhibition of 69% ranging from 35% to 100%. Suppression of autonomous CFU-GM formation by IL-10 was dose dependent and reversible by the addition of anti-IL-10 antibodies. Our results indicate that IL-10 is a potentially useful molecule to affect aberrant myelopoiesis in patients with MF.

  9. Calreticulin mutation profile in Indian patients with primary myelofibrosis.

    PubMed

    Sazawal, Sudha; Singh, Neha; Mahapatra, Manoranjan; Saxena, Renu

    2015-12-01

    Somatic mutations in Calreticulin (CALR) have been recently discovered in JAK2/MPL unmutated patients with primary myelofibrosis (PMF) or essential thrombocythemia. Clinical and hematologic features were obtained for 80 patients with PMF. JAK2V617F mutation was analyzed by DNA tetra-primer amplification refractory mutation system (ARMS-PCR). CALR and MPL mutations were identified by bi-directional Sanger sequencing. CALR mutations were detected in 11.2% (9/80) of all PMF patients and 25.7% (9/35) of all JAK2V617F and MPL unmutated patients all of which were Type I mutation or deletions. A novel CALR mutation pattern (c.1241_1288del) was identified in one (1/9) patient. No case of Type II mutations or scattered point mutations was found in any of these patients. Uni-variate analysis at presentation showed that CALR mutations were significantly associated with younger age (P = 0.003) and larger spleen size (P = 0.001). No significant correlation was found between CALR mutation and clinico-hematologic characteristics or international prognostic scoring system (IPSS) scoring of the PMF patients. CALR mutations have a distinct molecular profile in Indian patients, different from that of other studies worldwide. Larger prospective studies need to be designed to establish the impact of paucity of Type II mutations in contributing to disease phenotype and prognostic outcome of patients.

  10. Myelofibrosis: an update on current pharmacotherapy and future directions.

    PubMed

    Cervantes, Francisco; Martinez-Trillos, Alejandra

    2013-05-01

    Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by symptoms mainly derived from anemia and splenomegaly and constitutional symptoms and associated with a median survival around 6 years. Allogeneic stem cell transplantation (allo-SCT) remains the only curative therapy of MF but is applicable to a minority of patients. Discovery of the JAK2 mutation has provided the basis for the introduction of a new class of drugs, the JAK inhibitors, in the treatment of MF. A literature review on the therapy of MF has been performed through a PubMed search, with special attention being paid to the available data on transplantation, the JAK inhibitors, and other new drugs. Conventional therapy of MF is usually adjusted to the predominant clinical symptoms in each patient, and its impact on survival is limited. Reduced-intensity conditioning regimens have increased the number of patients eligible for allo-SCT, but this procedure is still associated with substantial morbidity and mortality. The JAK inhibitors, such as ruxolitinib, can achieve profound symptomatic relief of the splenomegaly and the constitutional symptoms. However, they often accentuate the anemia and do not reduce the JAK2 allele burden, therefore lacking the potential to modify the natural history of MF.

  11. 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

  12. How we manage JAK inhibition in allogeneic transplantation for myelofibrosis.

    PubMed

    Ballinger, Tarah J; Savani, Bipin N; Gupta, Vikas; Kroger, Nicolaus; Mohty, Mohamad

    2015-02-01

    Hematopoietic stem cell transplantation (HCT) is currently the only curative treatment for myelofibrosis (MF), but this option is complicated by high incidences of associated morbidity and mortality. Ruxolitinib, a janus-activated kinase (JAK) 1/2 inhibitor, has proven to be beneficial in reduction of splenomegaly, improvement of constitutional symptoms, and possibly in overall survival. However, use of JAK inhibitors in the peritransplant period has been complicated by unpredictable response, return of MF symptoms or cytokine storm reaction upon discontinuation, and lack of long-term response data. This review considers the current limited available data on JAK inhibitor use prior to HCT, including common side effects and possible impact of severe adverse events on discontinuation of the drug. We provide our experience and recommendations regarding use of JAK inhibition in patients undergoing HCT. Additional studies are needed to determine the optimal schedule of JAK inhibitors in the transplant protocols and their impact on engraftment, graft-versus-host disease, and survival. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Practical management of patients with myelofibrosis receiving ruxolitinib.

    PubMed

    Harrison, Claire; Mesa, Ruben; Ross, David; Mead, Adam; Keohane, Clodagh; Gotlib, Jason; Verstovsek, Srdan

    2013-10-01

    Myelofibrosis (MF) is characterized by bone marrow fibrosis, progressive anemia and extramedullary hematopoiesis, primarily manifested as splenomegaly. Patients also experience debilitating constitutional symptoms, including sequelae of splenomegaly, night sweats and fatigue. Ruxolitinib (INC424, INCB18424, Jakafi, Jakavi), a JAK1 and JAK2 inhibitor, was approved in November 2011 by the US FDA for the treatment of intermediate- or high-risk MF, and more recently in Europe and Canada for the treatment of MF-related splenomegaly or symptoms. These approvals were based on data from two randomized Phase III studies: COMFORT-I randomized against placebo, and COMFORT-II randomized against best available therapy. In these studies, ruxolitinib rapidly improved multiple disease manifestations of MF, reducing splenomegaly and improving quality of life of patients and potentially prolonging survival. However, as with other chemotherapies, ruxolitinib therapy is associated with some adverse events, such as anemia and thrombocytopenia. The aims of this article are to provide a brief overview of ruxolitinib therapy, to discuss some common adverse events associated with ruxolitinib therapy and to provide clinical management recommendations to maximize patients' benefit from ruxolitinib.

  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. Myelofibrosis associated with prominent periosteal bone apposition. Report of two cases.

    PubMed

    Yu, J S; Greenway, G; Resnick, D

    1994-01-01

    Myelofibrosis is a myeloproliferative disorder that is characterized by splenomegaly and bone marrow replacement by fibrous tissue. The predominant radiographic feature is osteosclerosis; however, in rare instances, periosteal bone apposition or periostitis is apparent in the metaphysis of the distal femura and proximal tibiae. It has been suggested that periostitis, when associated with fever and bone pain, is indicative of more aggressive disease. We report this unusual radiographic finding and its similar appearance to hypertrophic osteoarthropathy in two patients with myelofibrosis. In our patients, the presence of periosteal bone apposition did not correlate with increased disease aggressiveness.

  16. Dynamic of bone marrow fibrosis regression predicts survival after allogeneic stem cell transplantation for myelofibrosis.

    PubMed

    Kröger, Nicolaus; Zabelina, Tatjana; Alchalby, Haefaa; Stübig, Thomas; Wolschke, Christine; Ayuk, Francis; von Hünerbein, Natascha; Kvasnicka, Hans-Michael; Thiele, Jürgen; Kreipe, Hans-Heinrich; Büsche, Guntram

    2014-06-01

    We correlate regression of bone marrow fibrosis (BMF) on day 30 and 100 after dose- reduced allogeneic stem cell transplantation (allo-SCT) in 57 patients with primary or post-essential thrombocythemia/polycythemia vera myelofibrosis with graft function and survival. The distribution of International Prognostic Scoring System (IPSS) risk score categories was 1 patient with low risk, 5 patients with intermediate-1 risk, 18 patients with intermediate-2 risk, and 33 patients with high risk. Before allo-SCT, 41 patients (72%) were classified as XXX [myclofibrosis (MF)]-3 and 16 (28%) were classified as MF-2 according to the World Health Organization criteria. At postengraftment day +30 (±10 days), 21% of the patients had near-complete or complete regression of BMF (MF-0/-1), and on day +100 (±20 days), 54% were MF-0/-1. The 5-year overall survival rate at day +100 was 96% in patients with MF-0/-1 and 57% for those with MF-2/-3 (P = .04). There was no difference in BMF regression at day +100 between IPSS high-risk and low/intermediate-risk patients. Complete donor cell chimerism at day +100 was seen in 81% of patients with MF-0/-1 and in 31% of those with MF-2/-3. Patients with MF-2/-3 at day +100 were more likely to be transfusion-dependent for either RBCs (P = .014) or platelets (P = .018). Rapid BMF regression after reduced-intensity conditioning allo-SCT resulted in a favorable survival independent of IPSS risk score at transplantation.

  17. Regression of myelofibrosis and osteosclerosis following hematopoietic cell transplantation assessed by magnetic resonance imaging and histologic grading.

    PubMed

    Sale, George E; Deeg, H Joachim; Porter, Bruce A

    2006-12-01

    Myelofibrosis is a reactive, often inhomogeneous process in the marrow cavity, and sampling errors on biopsies obtained to diagnose and monitor the course of myelofibrosis have been a constant problem in hematopathology. We investigated the potential utility of magnetic resonance imaging (MRI) of the lumbar spine, pelvis, and femora as a diagnostic and monitoring technique for assessment of myelofibrosis. Findings on serial marrow biopsies were correlated with T1-weighted spin-echo and short inversion time inversion recovery (STIR) images in patients with chronic idiopathic myelofibrosis or myelofibrosis developing from polycythemia vera or essential thrombocythemia who underwent hematopoietic cell transplantation (HCT). Thirty-five patients were studied before HCT; 11 were followed for 3 months and 10 patients for >/=1 year after HCT with sequential marrow biopsies and MRI studies. MRI allowed direct visualization of the biopsy sites and correlation of histologic and MRI findings. MRI also provided assessment of the extent and degree of myelofibrosis in a large volume of the skeletal marrow. There was good correlation between biopsy results and MRI findings at specific biopsy sites and between successful HCT and resolution of fibrosis and osteosclerosis as determined by MRI. We conclude that in patients with myelofibrosis, MRI of the skeleton provides a comprehensive assessment of the pattern and extent of fibrosis and allows for correlation with biopsy findings. In patients undergoing HCT, MRI accurately reflects response or progression of marrow disease.

  18. Pathologic interaction between megakaryocytes and polymorphonuclear leukocytes in myelofibrosis.

    PubMed

    Schmitt, A; Jouault, H; Guichard, J; Wendling, F; Drouin, A; Cramer, E M

    2000-08-15

    Idiopathic myelofibrosis (MF) is a myeloproliferative syndrome characterized by an increase in bone marrow collagen. Megakaryocytes (Mks), which store growth factors in their alpha granules, are known to be involved in the pathogenesis of MF. Previously, mice given bone marrow grafts infected with a retrovirus carrying murine thrombopoietin (TPO) complementary DNA developed a disease resembling human idiopathic MF. In this study, we used this murine model (TPO mice) to determine whether release of alpha granules is responsible for fibroblast activation and development of fibrosis. The intracellular trafficking of several alpha-granule proteins (von Willebrand factor, fibrinogen, and transforming growth factor beta (TGF beta), which are stored in the granule matrix; and alpha(IIb)beta(3) integrin and P-selectin (CD62p), which are located in the alpha-granule membrane) was studied with immune electron microscopy in bone marrow Mks from TPO mice. P-selectin immunolabeling increased consistently and was occasionally found lining the demarcation membrane system. Evidence of extensive emperipolesis was also found in TPO mouse Mks, involving almost exclusively neutrophil and eosinophil polymorphonuclear (PMN) cells with altered morphologic features. In parallel, the host Mks had myeloperoxidase-positive granules scattered in their cytoplasm, associated with marked ultrastructural cytoplasmic alterations and ruptured alpha-granule membranes. Similar observations were made in bone marrow biopsy specimens from 12 patients with idiopathic MF; indeed, there was an increased rate of emperipolesis involving mostly PMN cells, abnormal P-selectin expression, and mutual subcellular PMN and Mk alterations. This study indicates that in idiopathic MF, abnormal P-selectin distribution in Mks induces selective sequestration of PMN cells. This results in a release of alpha-granular proteins and growth factors, which in turn induces fibroblast activation and fibrosis deposition. (Blood

  19. Targeting hedgehog signaling in myelofibrosis and other hematologic malignancies

    PubMed Central

    2014-01-01

    Treatment of myelofibrosis (MF), a BCR-ABL–negative myeloproliferative neoplasm, is challenging. The only current potentially curative option, allogeneic hematopoietic stem cell transplant, is recommended for few patients. The remaining patients are treated with palliative therapies to manage MF-related anemia and splenomegaly. Identification of a mutation in the Janus kinase 2 (JAK2) gene (JAK2 V617F) in more than half of all patients with MF has prompted the discovery and clinical development of inhibitors that target JAK2. Although treatment with JAK2 inhibitors has been shown to improve symptom response and quality of life in patients with MF, these drugs do not alter the underlying disease; therefore, novel therapies are needed. The hedgehog (Hh) signaling pathway has been shown to play a role in normal hematopoiesis and in the tumorigenesis of hematologic malignancies. Moreover, inhibitors of the Hh pathway have been shown to inhibit growth and self-renewal capacity in preclinical models of MF. In a mouse model of MF, combined inhibition of the Hh and JAK pathways reduced JAK2 mutant allele burden, reduced bone marrow fibrosis, and reduced white blood cell and platelet counts. Preliminary clinical data also suggest that inhibition of the Hh pathway, alone or in combination with JAK2 inhibition, may enable disease modification in patients with MF. Future studies, including one combining the Hh pathway inhibitor sonidegib and the JAK2 inhibitor ruxolitinib, are underway in patients with MF and will inform whether this combination approach can lead to true disease modification. PMID:24598114

  20. CD133 marks a stem cell population that drives human primary myelofibrosis

    PubMed Central

    Triviai, Ioanna; Stübig, Thomas; Niebuhr, Birte; Hussein, Kais; Tsiftsoglou, Asterios; Fehse, Boris; Stocking, Carol; Kröger, Nicolaus

    2015-01-01

    Primary myelofibrosis is a myeloproliferative neoplasm characterized by bone marrow fibrosis, megakaryocyte atypia, extramedullary hematopoiesis, and transformation to acute myeloid leukemia. To date the stem cell that undergoes the spatial and temporal chain of events during the development of this disease has not been identified. Here we describe a CD133+ stem cell population that drives the pathogenesis of primary myelofibrosis. Patient-derived circulating CD133+ but not CD34+CD133− cells, with a variable burden for JAK2V617F mutation, had multipotent cloning capacity in vitro. CD133+ cells engrafted for up to 10 months in immunocompromised mice and differentiated into JAK2-V617F+ myeloid but not lymphoid progenitors. We observed the persistence of human, atypical JAK2-V617F+ megakaryocytes, the initiation of a prefibrotic state, bone marrow/splenic fibrosis and transition to acute myeloid leukemia. Leukemic cells arose from a subset of CD133+ cells harboring EZH2D265H but lacking a secondary JAK2V617F mutation, consistent with the hypothesis that deregulation of EZH2 activity drives clonal growth and increases the risk of acute myeloid leukemia. This is the first characterization of a patient-derived stem cell population that drives disease resembling both chronic and acute phases of primary myelofibrosis in mice. These results reveal the importance of the CD133 antigen in deciphering the neoplastic clone in primary myelofibrosis and indicate a new therapeutic target for myeloproliferative neoplasms. PMID:25724578

  1. Acute megakaryoblastic leukemia (acute 'malignant' myelofibrosis): An unusual cause of osteosclerosis

    SciTech Connect

    Karasick, S.; Karasick, D.; Schilling, J.

    1982-11-01

    Acute megakaryoblastic leukemia or acute 'malignant' myelosclerosis is an acute and rapidly progressive myeloproliferative syndrome characterized by minimal or absent splenomegaly, pancytopenia, diffuse marrow fibrosis, and circulating blasts of megakaryocytic origin. The disease must be differentiated from other hematologic malignancies especially myelofibrosis with myeloid metaplasia. The radiographic changes of osteosclerosis in our patient have not been previously reported in the literature.

  2. Primary hypertrophic osteoarthropathy with myelofibrosis and anemia: a case report and review of literature

    PubMed Central

    Li, Sheyu; Li, Qianrui; Wang, Qin; Chen, Decai; Li, Jianwei

    2015-01-01

    Primary hypertrophic osteoarthropathy (PHO) is a rare and usually benign disorder of bone and connective tissue growth. Here we present a 28-year-old male patient presenting to our hospital with PHO and symptomatic anemia. Bone marrow biopsy suggested myelofibrosis, a serious complication of PHO, which is often neglected upon admission, but may lead to life-threatening anemia. PMID:25785156

  3. Incidence of Myelofibrosis in Chronic Myeloid Leukemia, Multiple Myeloma, and Chronic Lymphoid Leukemia during Various Phases of Diseases.

    PubMed

    Dolgikh, T Yu; Domnikova, N P; Tornuev, Yu V; Vinogradova, E V; Krinitsyna, Yu M

    2017-02-01

    Pathomorphological study of trephinobiopsy specimens from 129 patients with lymphoproliferative and myeloproliferative diseases was carried out over the course of chemotherapy. Combinations of initial and manifest myelofibrosis (loose network of reticulin fibers and extensive network of reticulin and collagen fibers, respectively) predominated at the debut of chronic myeloid leukemia, chronic lymphoid leukemia, and multiple myeloma. Manifest myelofibrosis was detected in patients with chronic myeloid leukemia without hematological response (failure of normalization of hematological values) and in patients with progressing and relapsing multiple myeloma. Combinations of foci of initial and manifest myelofibrosis were most incident in patients with progressing and relapsing chronic lymphoid leukemia. The incidence of myelofibrosis was higher in patients with multiple myeloma and chronic lymphoid leukemia progression and relapses and in patients with chronic myeloid leukemia without hematological response than at the disease debut and in case of response to chemotherapy. The response to chemotherapy in patients with chronic myeloid leukemia and chronic lymphoid leukemia was associated with a decrease in the incidence of myelofibrosis. In patients with multiple myeloma responding to chemotherapy, the incidence of myelofibrosis did not change in comparison with the disease debut.

  4. Construction of gene/protein interaction networks for primary myelofibrosis and KEGG pathway-enrichment analysis of molecular compounds.

    PubMed

    Sun, C G; Cao, X J; Zhou, C; Liu, L J; Feng, F B; Liu, R J; Zhuang, J; Li, Y J

    2015-12-08

    The objective of this study was the development of a gene/protein interaction network for primary myelofibrosis based on gene expression, and the enrichment analysis of KEGG pathways underlying the molecular complexes in this network. To achieve this, genes involved in primary myelofibrosis were selected from the OMIM database. A gene/protein interaction network for primary myelofibrosis was obtained through Cytoscape with the literature mining performed using the Agilent Literature Search plugin. The molecular complexes in the network were detected by ClusterViz plugin and KEGG pathway enrichment of molecular complexes was performed using DAVID online. We found 75 genes associated with primary myelofibrosis in the OMIM database. The gene/protein interaction network of primary myelofibrosis contained 608 nodes, 2086 edges, and 4 molecular complexes with a correlation integral value greater than 4. Molecular complexes involved in KEGG pathways are related to cytokine regulation, immune function regulation, ECM-receptor interaction, focal adhesion, actin cytoskeleton regulation, cell adhesion molecules, and other biological behavior of tumors, which can provide a reliable direction for the treatment of primary myelofibrosis and the bioinformatic foundation for further understanding the molecular mechanisms of this disease.

  5. Laparoscopically assisted splenectomy following preoperative splenic artery embolization using contour emboli for myelofibrosis with massive splenomegaly.

    PubMed

    Iwase, K; Higaki, J; Mikata, S; Tanaka, Y; Yoshikawa, M; Hori, S; Osuga, K; Kosugi, S; Tamaki, T; Kamiike, W

    1999-06-01

    Laparoscopically assisted splenectomy with an 8- to 10-cm left upper paramedian laparotomy was performed following preoperative splenic artery embolization using painless contour emboli (super absorbent polymer microsphere) with early successful results in two men (46 and 37 years old) with myelofibrosis accompanied by massive splenomegaly. Dissection around the lower part of the spleen and the hilum initially was performed intracorporeally with the usual laparoscopic view under 12 mm Hg pneumoperitoneum. The alternating changes of viewpoints between the direct view through an 8- to 10-cm incision and the usual laparoscopic view with or without application of a retraction method were effective for safe hilar devascularization. Preoperative splenic artery embolization at the distal site was effective for safe dissection around the enlarged spleen. The patients did not complain of pain before operation. Preoperative painless embolization and laparoscopically assisted splenectomy with small laparotomy promotes the feasibility and safety of minimally invasive splenectomy for myelofibrosis with massive splenomegaly.

  6. Hematologic improvements in a myelodysplastic syndromes with myelofibrosis (MDS-F) patient treated with azacitidine.

    PubMed

    Okamura, Daisuke; Matsuda, Akira; Ishikawa, Maho; Maeda, Tomoya; Tanae, Ken; Kohri, Mika; Takahashi, Naoki; Kawai, Nobutaka; Asou, Norio; Bessho, Masami

    2014-01-01

    Myelodysplastic syndromes with myelofibrosis (MDS-F) is a poor prognostic hematopoietic disorder. Azacitidine was shown to prolong survival of high-risk MDS patients. However, the effects of azacitidine on MDS-F have yet to be elucidated. Azacitidine was administered to a 74-year-old man with MDS-F at a dose of 75 mg/m(2)/daily subcutaneously for 7 days every 28 days. Hematologic improvements were observed according to the International Working Group 2006 criteria after 8 cycles of the azacitidine treatment, and complete remission was achieved after 14 cycles. The grade of myelofibrosis was also improved. The therapeutic activity of azacitidine was confirmed in our MDS-F patient.

  7. Bone and bone-marrow blood flow in chronic granulocytic leukemia and primary myelofibrosis

    SciTech Connect

    Lahtinen, R.; Lahtinen, T.; Romppanen, T.

    1982-03-01

    Blood flow in hematopoietic bone marrow and in nonhematopoietic bone has been measured with a Xe-133 washout method in 20 patients with chronic granulocytic leukemia (CGL) and in seven with primary myelofibrosis. Age-matched healthy persons served as controls. Bone-marrow blood flow in CGL was dependent upon the phase of the disease. In the metamorphosis phase, bone-marrow blood flow was high compared with that in the well-controlled phase. Apart from the initial phase, the mean values for bone blood flow in CGL were increased compared with the values of the healthy controls. In myelofibrosis the bone blood flow was also increased. Bone-marrow blood flow in these diseases was dependent upon the cellularity of bone marrow as measured morphometrically.

  8. Resolution of myelofibrosis-associated pulmonary arterial hypertension following allogeneic hematopoietic stem cell transplantation

    PubMed Central

    Iliescu, Cezar; Lopez-Mattei, Juan; Patel, Bela; Bashoura, Lara; Popat, Uday

    2016-01-01

    Abstract We present the case of a 62-year-old man with myelofibrosis-associated pulmonary arterial hypertension (PAH) who underwent allogeneic hematopoietic stem cell transplantation with subsequent resolution of disease and PAH. Right heart catheterization was used to guide PAH therapy before and after transplantation. Drug interactions, adverse effects, and renal insufficiency posed clinical challenges for the management of PAH-specific medications after transplantation. PAH improved soon after transplantation, and vasoactive medications were tapered off. Resolution of PAH was confirmed with repeat measurement of pulmonary hemodynamic characteristics. Although the etiology and pathophysiology for the resolution of PAH was unclear, the myelopulmonary pathophysiologic link was likely to have contributed. This is the first report describing resolution of myelofibrosis-associated PAH after allogeneic hematopoietic stem cell transplantation. PMID:28090305

  9. Intense splenic 99mTc-MDP uptake in a patient with myelofibrosis.

    PubMed

    Chen, Ming; Liu, Chun; Yang, Jigang

    2013-12-01

    99mTc-MDP bone scan was performed in a 49-year-old woman with breast cancer. Whole-body bone scan showed multiple foci of increased MDP activity in the bone and intense splenic 99mTc-MDP uptake. Initial bone marrow aspiration in multiple locations yielded no blood cells. A subsequent bone marrow biopsy in the left anterior superior iliac spine showed myelofibrosis in addition to the known bone metastasis.

  10. Ruxolitinib is manageable in patients with myelofibrosis and severe thrombocytopenia: a report on 12 Danish patients.

    PubMed

    Bjørn, Mads Emil; Holmström, Morten Orebo; Hasselbalch, Hans Carl

    2016-01-01

    We report 12 Danish myelofibrosis patients who have been treated successfully with ruxolitinib despite having low platelet counts (< 50 × 10(9)/L) during their treatment-course. The majority of the patients experienced marked clinical improvement. Serious side effects were only recorded in a single patient. It is concluded that JAK-inhibition with ruxolitinib is manageable in patients with low platelet counts and should be considered in symptomatic patients who otherwise might not be candidates for treatment.

  11. Autoimmune myelofibrosis with pancytopenia as a presenting manifestation of systemic lupus erythematosus responsive to mycophenolate mofetil.

    PubMed

    Ungprasert, P; Chowdhary, V R; Davis, M D; Makol, A

    2016-04-01

    Hematological abnormalities, such as anemia, leucopenia, and thrombocytopenia, secondary to peripheral destruction, are common in systemic lupus erythematosus (SLE). However, cytopenias from autoimmune myelofibrosis (AIMF) are extremely uncommon in SLE, with less than 40 reported cases in the literature. We report the case of a 33-year-old female who presented with bullous skin lesions and pancytopenia as the presenting manifestation of what was ultimately diagnosed as SLE with AIMF. She responded well to glucocorticoids and mycophenolate mofetil.

  12. Acute Myeloid Leukemia with Isolated Trisomy 19 Associated with Diffuse Myelofibrosis and Osteosclerosis

    PubMed Central

    Stelling, Adam; Jonas, Brian A.; Rashidi, Hooman H.; Abedi, Mehrdad; Chen, Mingyi

    2015-01-01

    Primary myelofibrosis (PMF), per WHO criteria, is a clonal myeloproliferative neoplasm that usually presents with a proliferation of granulocytic and megakaryocytic lineages with an associated fibrous deposition and extramedullary hematopoiesis. The bone marrow histologic findings of this disorder are typically characterized by the presence of myeloid metaplasia with an associated reactive fibrosis, angiogenesis, and osteosclerosis. However, marked myelofibrosis is not solely confined to PMF and may also be associated with other conditions including but not limited to acute megakaryoblastic leukemias (FAB AML-M7). Here, we describe a rare case of a non-megakaryoblastic acute myeloid leukemia with marked myelofibrosis with osteosclerosis and an isolated trisomy 19. A 19-year-old male presented with severe bone pain of one week duration with a complete blood cell count and peripheral smear showing a mild anemia and occasional circulating blasts. A follow up computed tomography (CT) scan showed diffuse osteosclerosis with no evidence of hepatosplenomegaly or lymphadenopathy. Subsequently, the bone marrow biopsy showed markedly sclerotic bony trabeculae and a hypercellular marrow with marked fibrosis and intervening sheets of immature myeloid cells consistent with myeloblasts with monocytic differentiation. Importantly, these myeloblasts were negative for megakaryocytic markers (CD61 and vWF), erythroid markers (hemoglobin and E-cadherin), and lymphoid markers (CD3, CD19, and TdT). Metaphase cytogenetics showed an isolated triosomy 19 with no JAK2 V617F mutation. The patient was treated with induction chemotherapy followed by allogenic hematopoietic stem cell transplantation which subsequently resulted in a rapid resolution of bone marrow fibrosis, suggesting graft-anti-fibrosis effect. This is a rare case of a non-megakaryoblastic acute myeloid leukemia with myelofibrosis and osteosclerosis with trisomy 19 that may provide insights into the prognosis and therapeutic

  13. Ruxolitinib: a new JAK1/2 inhibitor that offers promising options for treatment of myelofibrosis

    PubMed Central

    Ostojic, Alen; Vrhovac, Radovan; Verstovsek, Srdan

    2016-01-01

    Ruxolitinib (INCB018424) is the first potent, selective, oral inhibitor of JAK1 and 2 being developed for clinical use. Its major cellular and systemic effects are proliferation inhibition, apoptosis induction and reduction in cytokine plasma levels, all mediated by the drug's inhibition of JAKs' ability to phosphorylate STAT. In initial clinical trials of its use in myelofibrosis, ruxolitinib exhibited durable efficacy in reduction of splenomegaly and alleviation of constitutional symptoms. Patients also showed weight gain and improvement in general physical condition. The dose-limiting toxicity was thrombocytopenia. In preliminary findings of a Phase III trial in patients with primary, postpolycythemia-vera, or postessential- thrombocythemia myelofibrosis, administration at an initial dosage of 15 or 20 mg twice daily led to a spleen-volume response rate (≥35% reduction at 24 weeks) of 41.9 versus 0.7% for placebo (p < 0.0001); furthermore, 45.9% of the ruxolitinib recipients had ≥50% improvement in symptom score (on the modified Myelofibrosis Symptom Assessment Form version 2.0) versus 5.3% for placebo (p < 0.0001). Ruxolitinib recipients also showed improvement in parameters of quality of life. PMID:21919691

  14. Ferrokinetic study of splenic erythropoiesis: Relationships among clinical diagnosis, myelofibrosis, splenomegaly, and extramedullary erythropoiesis

    SciTech Connect

    Beguin, Y.; Fillet, G.; Bury, J.; Fairon, Y. )

    1989-10-01

    Splenic erythropoiesis was demonstrated by surface counting of {sup 59}Fe in 129 of 1,350 ferrokinetic studies performed over a 15 year period. These 129 studies were carried out in 108 patients, including 40 with chronic myelogenous leukemia (CML), 24 with agnogenic myeloid metaplasia (AMM), 18 with polycythemia vera (PV), six with a myelodysplastic syndrome, five with acute leukemia, three with prostate or breast carcinoma, two each with aplastic anemia or Hodgkin's disease, and one each with idiopathic thrombocythemia, multiple myeloma, chronic renal failure, or treated hypopituitarism. Splenomegaly was present in 83% of the studies and hepatomegaly in 72%. Grade II-III myelofibrosis was demonstrated in 62% of the cases. Hepatic erythropoiesis was present in 77% of the studies (only 38% in PV), and marrow erythropoiesis was undetectable in 33%. Total erythropoiesis was about twice normal (range 0.2 to 8 times normal) but was ineffective to varying degrees in 86% of the studies. Relationships between organomegaly, myelofibrosis, and extramedullary erythropoiesis, as well as differences among clinical disorders, are discussed. Differences observed between CML in chronic or blastic phase suggested that the erythroid cell line was involved in the proliferative process. It is concluded that splenic erythropoiesis (1) is encountered in a variety of clinical conditions; (2) is not necessarily associated with splenomegaly or myelofibrosis, even in the myeloproliferative disorders; (3) is part of a predominantly extramedullary (in the liver as well as in the spleen), expanded, and largely inefficient total erythropoiesis; and (4) can be evaluated in a semiquantitative manner by surface counting.

  15. Outcome after Transplantation According to Reduced-Intensity Conditioning Regimen in Patients Undergoing Transplantation for Myelofibrosis.

    PubMed

    Robin, Marie; Porcher, Raphael; Wolschke, Christine; Sicre de Fontbrune, Flore; Alchalby, Haefaa; Christopeit, Maximilian; Cassinat, Bruno; Zabelina, Tatjana; Peffault de Latour, Régis; Ayuk, Francis; Socié, Gérard; Kröger, Nicolaus

    2016-07-01

    Allogeneic hematopoietic stem cell transplantation remains the sole curative option for myelofibrosis. Many transplantation recipients receive a reduced-intensity conditioning (RIC) regimen owing to age or comorbidities; however, there is little published evidence to guide the choice of RIC regimen. In this study, we compared outcomes in patients who received 1 of 2 frequently used RIC regimens for patients with myelofibrosis: fludarabine-busulfan (FB) and fludarabine-melphalan (FM). A total of 160 patients underwent a RIC allograft procedure (FB group, n = 105; FM group, n = 55). We have developed a complex statistical model involving weighting and adjustment to permit comparison between these 2 groups. After weighting, the incidence of acute graft-versus-host disease (GVHD) was 62% in the FM group and 31% in the FB group (P = .001), and the corresponding incidence of chronic GVHD was 49% and 53%, respectively. The 7-year progression-free survival was were 52% in the FM group versus 33% in the FB group, and the 7-year overall survival rate 52% in the FM group versus 59% in the FB group. Nonrelapse mortality (NRM) was 43% in the FM group and 31% in the FB group. Multivariable analyses revealed no significant differences in PFS between the 2 groups; however, the relapse rate was significantly lower in the FM group (hazard ratio, 9.21; P = .008), whereas a trend toward reduced NRM was seen in the FB group (hazard ratio, 0.51; P = .068). In conclusion, both regimens appear to be efficient in mediating disease control and can be used to successfully condition patients with myelofibrosis. The FM regimen appears to induce more NRM than the FB regimen, but with augmented control of disease, leading to comparable overall survival rates for both regimens. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  16. Mayor Erythropoietic Response after Deferasirox Treatment in a Transfusion-Dependent Anemic Patient with Primary Myelofibrosis

    PubMed Central

    Lisette, Del Corso; Enrico, Balleari; Eleonora, Arboscello; Riccardo, Ghio; Manlio, Mencoboni; Omar, Racchi

    2013-01-01

    Primary myelofibrosis (PMF) is a myeloproliferative neoplasm frequently complicated by transfusion dependent anemia. Both anemia and transfusion-dependence are associated with a poor outcome, at least in part because of toxic effects of iron overload (IOL). Iron-chelating therapy (ICT) is increasingly used in order to prevent IOL in this setting. Here, we describe the case of a 73-year-old man affected by PMF and severe transfusion-dependent anemia who experienced a dramatic erythroid response after being treated with deferasirox to prevent IOL. PMID:24307957

  17. Mayor erythropoietic response after deferasirox treatment in a transfusion-dependent anemic patient with primary myelofibrosis.

    PubMed

    Lisette, Del Corso; Enrico, Balleari; Eleonora, Arboscello; Riccardo, Ghio; Manlio, Mencoboni; Omar, Racchi

    2013-01-01

    Primary myelofibrosis (PMF) is a myeloproliferative neoplasm frequently complicated by transfusion dependent anemia. Both anemia and transfusion-dependence are associated with a poor outcome, at least in part because of toxic effects of iron overload (IOL). Iron-chelating therapy (ICT) is increasingly used in order to prevent IOL in this setting. Here, we describe the case of a 73-year-old man affected by PMF and severe transfusion-dependent anemia who experienced a dramatic erythroid response after being treated with deferasirox to prevent IOL.

  18. Discrepancy in Diagnosis of Primary Myelofibrosis between Referral and Tertiary Care Centers

    PubMed Central

    Yi, Cecilia Arana; Jeyakumar, Ghayathri; Medina, Pedro; Cortes, Jorge; Pierce, Sherry; Bueso-Ramos, Carlos; Kantarjian, Hagop; Verstovsek, Srdan

    2015-01-01

    Primary myelofibrosis (PMF) is myeloproliferative neoplasm whose diagnosis is based on a combination of clinical and pathology criteria. We evaluated 560 consecutive patients who were diagnosed with PMF upon a referral to our center and evaluated the frequency of and reasons for diagnostic discordance. Discordance in the diagnosis was found in 70 (12.5%) patients. Discordant cases had a significantly lower grade of bone marrow fibrosis (grade 0–1), more likely to be JAK2V617F-mutation negative, and have no peripheral blood blasts, possibly explaining the difficulty in making a proper diagnosis and underscoring the need for a complete evaluation at a tertiary center. PMID:24284333

  19. Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Myelofibrosis With Prior exposure to JAK1/2 Inhibitors

    PubMed Central

    Shanavas, Mohamed; Popat, Uday; Michaelis, Laura C; Fauble, Veena; McLornan, Donal; Klisovic, Rebecca; Mascarenhas, John; Tamari, Roni; Arcasoy, Murat O; Davies, James; Gergis, Usama; Ukaegbu, Oluchi C; Kamble, Rammurti T; Storring, John M; Majhail, Navneet S; Romee, Rizwan; Verstovsek, Srdan; Pagliuca, Antonio; Vasu, Sumithira; Ernst, Brenda; Atenafu, Eshetu G; Hanif, Ahmad; Champlin, Richard; Hari, Paremeswaran; Gupta, Vikas

    2016-01-01

    The impact of JAK1/2 inhibitor therapy prior to allogeneic hematopoietic cell transplantation (HCT) has not been studied in a large cohort in myelofibrosis (MF). In this retrospective multicenter study, we analyzed outcomes of patients who underwent HCT for MF with prior exposure to JAK1/2 inhibitors. One hundred consecutive patients from participating centers were analyzed, and based on clinical status and response to JAK1/2 inhibitors at the time of HCT, patients were stratified into five groups: (a) clinical improvement (n=23), (b) stable disease (n=31), (c) new cytopenia/increasing blasts/intolerance (n=15), (d) progressive disease: splenomegaly (n=18), and (e) progressive disease: leukemic transformation (LT) (n=13). Overall survival (OS) at two years was 61% (95%CI, 49–71). This was 91% (95% CI, 69–98) for those who experienced clinical improvement, and 32% (95% CI, 8–59) for those who developed LT on JAK1/2 inhibitors. In multivariable analysis, response to JAK1/2 inhibitors (p=0.03), DIPSS score (p=0.003), and donor type (p=0.006) were independent predictors of survival. Among the 66 patients who remained on JAK1/2 inhibitors until stopped for HCT, two patients developed serious adverse events necessitating delaying of HCT, and another 8 patients had symptoms with lesser severity. Adverse events were more common in patients who started tapering or abruptly stopped their regular dose ≥6 days prior to conditioning therapy. We conclude that prior exposure to JAK1/2 inhibitors did not adversely affect post-transplant outcomes. Our data suggest that JAK1/2 inhibitors should be continued near to the start of conditioning therapy. The favorable outcomes of patients who experienced clinical improvement with JAK1/2 inhibitor therapy prior to HCT were particularly encouraging, and need further prospective validation. PMID:26493563

  20. European Bone Marrow Working Group trial on reproducibility of World Health Organization criteria to discriminate essential thrombocythemia from prefibrotic primary myelofibrosis

    PubMed Central

    Buhr, Thomas; Hebeda, Konnie; Kaloutsi, Vassiliki; Porwit, Anna; Van der Walt, Jon; Kreipe, Hans

    2012-01-01

    Background The World Health Organization classification of myeloproliferative neoplasms discriminates between essential thrombocythemia and the prefibrotic phase of primary myelofibrosis. This discrimination is clinically relevant because essential thrombocythemia is associated with a favorable prognosis whereas patients with primary myelofibrosis have a higher risk of progression to myelofibrosis or blast crisis. Design and Methods To assess the reproducibility of the classification, six hematopathologists from five European countries re-classified 102 non-fibrotic bone marrow trephines, obtained because of sustained thrombocytosis. Results Consensus on histological classification defined as at least four identical diagnoses occurred for 63% of the samples. Inter-observer agreement showed low to moderate kappa values (0.28 to 0.57, average 0.41). The percentage of unclassifiable myeloproliferative neoplasms rose from 2% to 23% when minor criteria for primary myelofibrosis were taken into account. In contrast, the frequency of primary myelofibrosis dropped from 23% to 7%, indicating that the majority of patients with a histological diagnosis of primary myelofibrosis did not fulfill the complete criteria for this disease. Thus, over 50% of cases in this series either could not be reproducibly classified or fell into the category of unclassifiable myeloproliferative neoplasms. Conclusions World Health Organization criteria for discrimination of essential thrombocythemia from prefibrotic primary myelofibrosis are poorly to only moderately reproducible and lead to a higher proportion of non-classifiable myeloproliferative neoplasms than histology alone. PMID:22058215

  1. A multinational, open-label, phase 2 study of ruxolitinib in Asian patients with myelofibrosis: Japanese subset analysis.

    PubMed

    Oritani, Kenji; Okamoto, Shinichiro; Tauchi, Tetsuzo; Saito, Shigeki; Ohishi, Kohshi; Handa, Hiroshi; Takenaka, Katsuto; Gopalakrishna, Prashanth; Amagasaki, Taro; Ito, Kazuo; Akashi, Koichi

    2015-03-01

    Ruxolitinib is a potent Janus kinase (JAK) 1/JAK2 inhibitor that has demonstrated rapid and durable improvements in splenomegaly and symptoms and a survival benefit in 2 phase 3 trials in patients with myelofibrosis. Ruxolitinib was well tolerated and effectively reduced splenomegaly and symptom burden in Asian patients with myelofibrosis in the Asian multinational, phase 2 Study A2202. We present a subset analysis of Japanese patients (n = 30) in Study A2202. At data cutoff, 22 patients were ongoing; 8 discontinued, mainly due to adverse events (n = 4). At week 24, 33 % of patients achieved ≥35 % reduction from baseline in spleen volume; 56.0 % achieved ≥50 % reduction from baseline in total symptom score, as measured by the 7-day Myelofibrosis Symptom Assessment Form v2.0. The most common adverse events were anemia (63 %), thrombocytopenia (40 %), nasopharyngitis (37 %), decreased platelet counts (30 %), and diarrhea (30 %). Dose reductions or interruptions due to hemoglobin decreases were more frequent in Japanese patients; no loss of efficacy and no discontinuations due to hematologic abnormalities were observed. Ruxolitinib was well tolerated in Japanese patients and provided substantial reductions in splenomegaly and myelofibrosis-related symptoms similar to those observed in the overall Asian population and phase 3 COMFORT studies.

  2. Long-term results of prednisone treatment for the anemia of myelofibrosis.

    PubMed

    Hernández-Boluda, Juan-Carlos; Martínez-Trillos, Alejandra; García-Gutiérrez, Valentín; Ferrer-Marín, Francisca; Xicoy, Blanca; Alvarez-Larrán, Alberto; Kerguelen, Ana; Barba, Pere; Gómez, Montse; Herrera, Juan-Carlos; Correa, Juan-Gonzalo; Cervantes, Francisco

    2016-01-01

    This study has retrospectively analyzed the efficacy of single-agent prednisone, usually given after failure of other therapies, in 30 patients with myelofibrosis (MF) and severe anemia. Initial dose was 0.5-1 mg/kg daily, with tapering to the minimum effective dose in responders. Twelve patients (40%) achieved anemia response according to the revised International Working Group for Myelofibrosis Research and Treatment criteria, after a median time of 1.1 months on treatment. Median response duration was 12.3 months. Patients with constitutional symptoms or > 2% circulating blasts had a trend for a lower response rate. A platelet increase > 50 × 10(9)/L was observed in three out of 11 patients with baseline counts < 100 × 10(9)/L. Median survival from prednisone start was significantly longer in anemia responders (5.0 years, 95% CI = 3.5-6.5, vs 1.5 years, 95% CI = 0.2-2.8; p = 0.002). Prednisone can improve the anemia and thrombocytopenia in selected MF patients after failure to standard therapies.

  3. Bone-marrow imaging with indium-111 chloride in aplastic anemia and myelofibrosis: concise communication

    SciTech Connect

    Sayle, B.A.; Helmer, R.E.; Birdsong, B.A.; Balachandran, S.; Gardner, F.H.

    1982-02-01

    Twenty-nine patients with aplastic anemia and 11 patients with myelofibrosis were evaluated with indium-111 chloride bone-marrow imaging, ferrokinetics, and bone-marrow core biopsies. There was good correlation between the erythrocyte cellularity of the marrow and the In-111 bone-marrow scan grades in most patients. In some, the overall scan grade tended to underestimate the erythroid elements because the core biopsy had been taken from the area of the greatest radionuclide concentration on the scan. In patients with aplastic anemia, there was good correlation between the plasma iron clearance t1/2 and the scan grade. Less agreement was found in the comparison between the Fe-59 sacral and organ counts and the red-cell iron utilization. In patients with myelofibrosis, there was poor correlation between the surface counts over the sacrum and the red-cell iron utilization. Plasma iron clearances were abnormally short and were unrelated to the transferrin saturation levels. Eighteen patients were studied several times to evaluate their responses to steroid therapy. In all, there was good correlation between the bone-marrow imaging, the erythrocyte cellularity, ferrokinetics, and the patient's response to therapy. Indium-111 bone-marrow imaging is useful both in evaluating marrow erythroid activity and in following the response to therapy in patients with these diseases.

  4. Inflammation as a Keystone of Bone Marrow Stroma Alterations in Primary Myelofibrosis

    PubMed Central

    Desterke, Christophe; Martinaud, Christophe; Ruzehaji, Nadira; Le Bousse-Kerdilès, Marie-Caroline

    2015-01-01

    Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm where severity as well as treatment complexity is mainly attributed to a long lasting disease and presence of bone marrow stroma alterations as evidenced by myelofibrosis, neoangiogenesis, and osteosclerosis. While recent understanding of mutations role in hematopoietic cells provides an explanation for pathological myeloproliferation, functional involvement of stromal cells in the disease pathogenesis remains poorly understood. The current dogma is that stromal changes are secondary to the cytokine “storm” produced by the hematopoietic clone cells. However, despite therapies targeting the myeloproliferation-sustaining clones, PMF is still regarded as an incurable disease except for patients, who are successful recipients of allogeneic stem cell transplantation. Although the clinical benefits of these inhibitors have been correlated with a marked reduction in serum proinflammatory cytokines produced by the hematopoietic clones, further demonstrating the importance of inflammation in the pathological process, these treatments do not address the role of the altered bone marrow stroma in the pathological process. In this review, we propose hypotheses suggesting that the stroma is inflammatory-imprinted by clonal hematopoietic cells up to a point where it becomes “independent” of hematopoietic cell stimulation, resulting in an inflammatory vicious circle requiring combined stroma targeted therapies. PMID:26640324

  5. Mesenchymal Cell Reprogramming in Experimental MPLW515L Mouse Model of Myelofibrosis

    PubMed Central

    Wei, Max; Ren, Xiubao; Shao, Zonghong; Zhang, Ling; Levine, Ross L.; Epling-Burnette, Pearlie K.

    2017-01-01

    Myelofibrosis is an indicator of poor prognosis in myeloproliferative neoplasms (MPNs), but the precise mechanism(s) contributing to extracellular matrix remodeling and collagen deposition in the bone marrow (BM) niche remains unanswered. In this study, we isolated mesenchymal stromal cells (MSCs) from mice transplanted with wild-type thrombopoietin receptor (MPLWT) and MPLW515L retroviral-transduced bone marrow. Using MSCs derived from MPLW515-transplant recipients, excessive collagen deposition was maintained in the absence of the virus and neoplastic hematopoietic cells suggested that the MSCs were reprogrammed in vivo. TGFβ production by malignant megakaryocytes plays a definitive role promoting myelofibrosis in MPNs. However, TGFβ was equally expressed by MSCs derived from MPLWT and MPLW515L expressing mice and the addition of neutralizing anti-TGFβ antibody only partially reduced collagen secretion in vitro. Interestingly, profibrotic MSCs displayed increased levels of pSmad3 and pSTAT3 suggesting that inflammatory mediators cooperating with the TGFβ-receptor signaling may maintain the aberrant phenotype ex vivo. FGFb is a known suppressor of TGFβ signaling. Reduced collagen deposition by FGFb-treated MSCs derived from MPLW515L mice suggests that the activating pathway is vulnerable to this suppressive mediator. Therefore, our findings have implications for the future investigation of therapies to reverse fibrosis in MPNs. PMID:28135282

  6. Acute myelofibrosis in a patient with diffuse large cell non Hodgkin's lymphoma and renal cancer.

    PubMed

    Mohren, Martin; Essbach, Uwe; Franke, Astrid; Klink, Anne; Maas, Christian; Markmann, Ilka; Pelz, Antje F; Jentsch-Ullrich, Kathleen

    2003-09-01

    Relapse after anthracycline based combination chemotherapy is frequently seen in patients with aggressive non Hodgkin's Lymphomas (NHL), whereas complications such as secondary leukemia or solid tumor rarely occur. We report a patient with diffuse large cell (DLC) NHL and concurrent renal cancer, who developed acute myelofibrosis (AMF) later in the course of her disease. This 60-year-old female patient presented with pancytopenia and a right sided renal mass. Diagnostic work up revealed severe bone marrow infiltration by DLC NHL and renal cancer T1N0M0G2. Cytogenetic and molecular evaluation of bone marow cells showed three distinct clones, (a normal 46XX karyotype, a ringed chromosome 7 and a third clone with an enlarged chromosome 2 as well as several fragments). The patient underwent nephrectomy and eventually received 6 cycles of CHOP 14 chemotherapy. Anemia persisted followed by severe granulocytopenia and thrombocytopenia 6 weeks later. Repeated bone marrow biopsy showed absence of lymphoma and/or cancer metastasis, but massive myelofibrosis with an increased number of atypical megakaryocytes. Considering the short clinical course and the absence of hepatosplenomegaly AMF was diagnosed. The concurrence of three distinctneoplasms within a short period of time as well as the complex cytogenetic aberrations found in her bone marrow cells reflect a strong individual susceptibility to malignant disease in this patient.

  7. Ruxolitinib is effective in patients with intermediate-1 risk myelofibrosis: a summary of recent evidence.

    PubMed

    Harrison, Claire N; Talpaz, Moshe; Mead, Adam J

    2016-10-01

    Ruxolitinib is the only therapy with an approved indication for myelofibrosis (MF), a myeloproliferative neoplasm associated with progressive bone marrow fibrosis and extramedullary hematopoiesis. Although the pivotal phase 3 COMFORT studies included only patients with intermediate-2 or high-risk MF, the US indication includes all patients with intermediate- or high-risk disease. Data from recent nonrandomized studies confirm that the benefits of ruxolitinib established in the COMFORT studies in terms of spleen size reduction and symptom improvement also extend to patients with intermediate-1 risk MF, who tend to have less advanced disease than patients with higher-risk MF. Given the disease-modifying potential of ruxolitinib therapy, timely initiation of ruxolitinib therapy may not only improve patients' current clinical status but also lead to better long-term outcomes. The decision of whether or when to initiate ruxolitinib treatment should be based on the expected benefit-risk ratio for each patient, specifically considering potential adverse effects.

  8. Janus kinase inhibition and its effect upon the therapeutic landscape for myelofibrosis: from palliation to cure?

    PubMed

    Harrison, Claire; Verstovsek, Srdan; McMullin, Mary F; Mesa, Ruben

    2012-05-01

    Following the discovery of the Janus kinase (JAK) 2 V617F mutation in 2005 the explosion of research and drug development activity has not only advanced our understanding of the pathogenesis of myeloproliferative neoplasms (MPNs) but also triggered debate about classification, allowed revised diagnostic and response criteria, provided a target for treatment and a mode of monitoring its success. These changes and the resultant clinical research are discussed in this article where we argue that discovery of the JAK2 V617F mutation has signalled the much delayed change in therapeutic paradigm for myelofibrosis and possibly other MPNs from palliation and allowing us to move closer to, but not yet attain, a cure.

  9. Primary autoimmune myelofibrosis with severe thrombocytopenia mimicking immune thrombocytopenia: A case report

    PubMed Central

    Hua, Jian; Matayoshi, Shu; Uchida, Tomoyuki; Inoue, Morihiro; Hagihara, Masao

    2016-01-01

    Patients presenting with bone marrow fibrosis not accompanied by well-established autoimmune diseases, such as systemic lupus erythematosus, or malignant diseases, are considered to have primary autoimmune myelofibrosis (AIMF). Primary AIMF has been reported to follow a benign course and responds well to treatment with immunosuppressive agents. Immune thrombocytopenia (ITP) is also an autoimmune disorder characterized by antiplatelet-antibody-mediated thrombocytopenia in the absence of other causes of thrombocytopenia. We herein present a rare case of a female patient who was diagnosed with primary AIMF. The patient presented with severe thrombocytopenia, which was initially misdiagnosed as ITP. The symptoms of the disease resolved completely following steroid treatment. After withdrawal of the treatment at 1 year from the diagnosis, the bone marrow examination showed no evidence of bone marrow fibrosis or other abnormalities. To date, the patient has been followed up for 2 years without evidence of disease. PMID:28105358

  10. Ruxolitinib in myelofibrosis: to be or not to be an immune disruptor

    PubMed Central

    Manduzio, Palma

    2017-01-01

    Primary myelofibrosis (PMF) is a myeloproliferative neoplasm classified according to the 2016 revision of World Health Organization Classification of Tumors and Haematopoietic and Lymphoid Tissue. Ruxolitinib is an oral inhibitor of Janus kinase approved in the USA for the treatment of intermediate or high-risk PMF and approved in Europe for the treatment of splenomegaly and constitutional symptoms of the disease. More recently, case reports described serious opportunistic infections in this neoplasm treated with ruxolitinib. Research studies demonstrated the immunological derangement of this compound mainly based on T, dendritic, and natural killer cell defects. The purpose of this review of the literature was to analyze the relationship among ruxolitinib, immune system and bacterial, viral, fungal, and protozoan infections. A literature search was conducted using PubMed articles published between January 2010 and November 2016. The efficacy of drug in patients with PMF was demonstrated in two phase III studies, Controlled MyeloFibrosis Study with ORal Jak inhibitor Treatment (COMFORT-I and COMFORT-II). Grade 3 and 4 neutropenia were recognized in 7.1% and 2% of patients in the ruxolitinib and placebo arm of COMFORT-I. Grade 3 or 4 neutropenia or leukopenia were observed in 8.9% and 6.3% of ruxolitinib treated patients of 5-year follow-up of COMFORT-II. In addition, leukocyte subpopulations, lymphocyte functions, or antibody deficiency were not documented in either of the studies. The complex interactions between ruxolitinib, bone marrow, immune system, and infections in PMF need further investigation, robust data from a randomized clinical trial, registry, or large case-series. PMID:28243106

  11. Calreticulin mutants in mice induce an MPL-dependent thrombocytosis with frequent progression to myelofibrosis.

    PubMed

    Marty, Caroline; Pecquet, Christian; Nivarthi, Harini; El-Khoury, Mira; Chachoua, Ilyas; Tulliez, Micheline; Villeval, Jean-Luc; Raslova, Hana; Kralovics, Robert; Constantinescu, Stefan N; Plo, Isabelle; Vainchenker, William

    2016-03-10

    Frameshift mutations in the calreticulin (CALR) gene are seen in about 30% of essential thrombocythemia and myelofibrosis patients. To address the contribution of the CALR mutants to the pathogenesis of myeloproliferative neoplasms, we engrafted lethally irradiated recipient mice with bone marrow cells transduced with retroviruses expressing these mutants. In contrast to wild-type CALR, CALRdel52 (type I) and, to a lesser extent, CALRins5 (type II) induced thrombocytosis due to a megakaryocyte (MK) hyperplasia. Disease was transplantable into secondary recipients. After 6 months, CALRdel52-, in contrast to rare CALRins5-, transduced mice developed a myelofibrosis associated with a splenomegaly and a marked osteosclerosis. Monitoring of virus-transduced populations indicated that CALRdel52 leads to expansion at earlier stages of hematopoiesis than CALRins5. However, both mutants still specifically amplified the MK lineage and platelet production. Moreover, a mutant deleted of the entire exon 9 (CALRdelex9) did not induce a disease, suggesting that the oncogenic property of CALR mutants was related to the new C-terminus peptide. To understand how the CALR mutants target the MK lineage, we used a cell-line model and demonstrated that the CALR mutants, but not CALRdelex9, specifically activate the thrombopoietin (TPO) receptor (MPL) to induce constitutive activation of Janus kinase 2 and signal transducer and activator of transcription 5/3/1. We confirmed in c-mpl- and tpo-deficient mice that expression of Mpl, but not of Tpo, was essential for the CALR mutants to induce thrombocytosis in vivo, although Tpo contributes to disease penetrance. Thus, CALR mutants are sufficient to induce thrombocytosis through MPL activation.

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

    ClinicalTrials.gov

    2014-04-03

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

  13. Primary Myelofibrosis

    MedlinePlus

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

  14. Expanding the SHOC2 Mutation Associated Phenotype of Noonan Syndrome with Loose Anagen Hair: Structural Brain Anomalies and Myelofibrosis

    PubMed Central

    Gripp, Karen W.; Zand, Dina J.; Demmer, Laurie; Anderson, Carol E.; Dobyns, William B.; Zackai, Elaine H.; Denenberg, Elizabeth; Jenny, Kim; Stabley, Deborah L.; Sol-Church, Katia

    2013-01-01

    Noonan syndrome is a heterogenous rasopathy typically presenting with short stature, characteristic facial features, cardiac abnormalities including pulmonic valve stenosis, ASD and hypertrophic cardiomyopathy (HCM), cryptorchidism, ectodermal abnormalities and learning differences. The phenotype is variable, and limited genotype phenotype correlation exists with SOS1 mutations often associated with normal cognition and stature, RAF1 mutations entailing a high HCM risk, and certain PTPN11 mutations predisposing to juvenile myelomonocytic leukemia. The recently identified SHOC2 mutation (p.Ser2Gly) causes Noonan syndrome with loose anagen hair. We report five patients with this mutation. All had skin hyperpigmentation, sparse light colored hair, increased fine wrinkles, ligamentous laxity, developmental delay and 4/4 had a structural cardiac anomaly. Hypotonia and macrocephaly occurred in 4/5 (80%); 3/5 (60%) had polyhydramnios, increased birth weight or required use of a feeding tube. Distinctive brain abnormalities included relative megalencephaly and enlarged subarachnoid spaces suggestive of benign external hydrocephalus, and a relatively small posterior fossa as indicated by a vertical tentorium. The combination of a large brain with a small posterior fossa likely resulted in the high rate of cerebellar tonsillar ectopia (3/4) (75%). Periventricular nodular heterotopia was seen in one patient with a thick and dysplastic corpus callosum. We report on the first hematologic neoplasm, myelofibrosis, in a 2-year-old patient with SHOC2 mutation. Myelofibrosis is exceedingly rare in children and young adults. The absence of a somatic JAK2 mutation, seen in the majority of patients with myelofibrosis, is noteworthy as it suggests that germline or somatic SHOC2 mutations are causally involved in myelofibrosis. PMID:23918763

  15. Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: structural brain anomalies and myelofibrosis.

    PubMed

    Gripp, Karen W; Zand, Dina J; Demmer, Laurie; Anderson, Carol E; Dobyns, William B; Zackai, Elaine H; Denenberg, Elizabeth; Jenny, Kim; Stabley, Deborah L; Sol-Church, Katia

    2013-10-01

    Noonan syndrome is a heterogenous rasopathy typically presenting with short stature, characteristic facial features, cardiac abnormalities including pulmonic valve stenosis, ASD and hypertrophic cardiomyopathy (HCM), cryptorchidism, ectodermal abnormalities, and learning differences. The phenotype is variable, and limited genotype phenotype correlation exists with SOS1 mutations often associated with normal cognition and stature, RAF1 mutations entailing a high HCM risk, and certain PTPN11 mutations predisposing to juvenile myelomonocytic leukemia. The recently identified SHOC2 mutation (p.Ser2Gly) causes Noonan syndrome with loose anagen hair. We report five patients with this mutation. All had skin hyperpigmentation, sparse light colored hair, increased fine wrinkles, ligamentous laxity, developmental delay, and 4/4 had a structural cardiac anomaly. Hypotonia and macrocephaly occurred in 4/5 (80%); 3/5 (60%) had polyhydramnios, increased birth weight or required use of a feeding tube. Distinctive brain abnormalities included relative megalencephaly and enlarged subarachnoid spaces suggestive of benign external hydrocephalus, and a relatively small posterior fossa as indicated by a vertical tentorium. The combination of a large brain with a small posterior fossa likely resulted in the high rate of cerebellar tonsillar ectopia (3/4; 75%). Periventricular nodular heterotopia was seen in one patient with a thick and dysplastic corpus callosum. We report on the first hematologic neoplasm, myelofibrosis, in a 2-year-old patient with SHOC2 mutation. Myelofibrosis is exceedingly rare in children and young adults. The absence of a somatic JAK2 mutation, seen in the majority of patients with myelofibrosis, is noteworthy as it suggests that germline or somatic SHOC2 mutations are causally involved in myelofibrosis.

  16. An accurate, simple prognostic model consisting of age, JAK2, CALR, and MPL mutation status for patients with primary myelofibrosis.

    PubMed

    Rozovski, Uri; Verstovsek, Srdan; Manshouri, Taghi; Dembitz, Vilma; Bozinovic, Ksenija; Newberry, Kate; Zhang, Ying; Bove, Joseph E; Pierce, Sherry; Kantarjian, Hagop; Estrov, Zeev

    2017-01-01

    In most patients with primary myelofibrosis, one of three mutually exclusive somatic mutations is detected. In approximately 60% of patients, the Janus kinase 2 gene is mutated, in 20%, the calreticulin gene is mutated, and in 5%, the myeloproliferative leukemia virus gene is mutated. Although patients with mutated calreticulin or myeloproliferative leukemia genes have a favorable outcome, and those with none of these mutations have an unfavorable outcome, prognostication based on mutation status is challenging due to the heterogeneous survival of patients with mutated Janus kinase 2. To develop a prognostic model based on mutation status, we screened primary myelofibrosis patients seen at the MD Anderson Cancer Center, Houston, USA, between 2000 and 2013 for the presence of Janus kinase 2, calreticulin, and myeloproliferative leukemia mutations. Of 344 primary myelofibrosis patients, Janus kinase 2(V617F) was detected in 226 (66%), calreticulin mutation in 43 (12%), and myeloproliferative leukemia mutation in 16 (5%); 59 patients (17%) were triple-negatives. A 50% cut-off dichotomized Janus kinase 2-mutated patients into those with high Janus kinase 2(V617F) allele burden and favorable survival and those with low Janus kinase 2(V617F) allele burden and unfavorable survival. Patients with a favorable mutation status (high Janus kinase 2(V617F) allele burden/myeloproliferative leukemia/calreticulin mutation) and aged 65 years or under had a median survival of 126 months. Patients with one risk factor (low Janus kinase 2(V617F) allele burden/triple-negative or age >65 years) had an intermediate survival duration, and patients aged over 65 years with an adverse mutation status (low Janus kinase 2(V617F) allele burden or triple-negative) had a median survival of only 35 months. Our simple and easily applied age- and mutation status-based scoring system accurately predicted the survival of patients with primary myelofibrosis. Copyright© Ferrata Storti Foundation.

  17. An accurate, simple prognostic model consisting of age, JAK2, CALR, and MPL mutation status for patients with primary myelofibrosis

    PubMed Central

    Rozovski, Uri; Verstovsek, Srdan; Manshouri, Taghi; Dembitz, Vilma; Bozinovic, Ksenija; Newberry, Kate; Zhang, Ying; Bove, Joseph E.; Pierce, Sherry; Kantarjian, Hagop; Estrov, Zeev

    2017-01-01

    In most patients with primary myelofibrosis, one of three mutually exclusive somatic mutations is detected. In approximately 60% of patients, the Janus kinase 2 gene is mutated, in 20%, the calreticulin gene is mutated, and in 5%, the myeloproliferative leukemia virus gene is mutated. Although patients with mutated calreticulin or myeloproliferative leukemia genes have a favorable outcome, and those with none of these mutations have an unfavorable outcome, prognostication based on mutation status is challenging due to the heterogeneous survival of patients with mutated Janus kinase 2. To develop a prognostic model based on mutation status, we screened primary myelofibrosis patients seen at the MD Anderson Cancer Center, Houston, USA, between 2000 and 2013 for the presence of Janus kinase 2, calreticulin, and myeloproliferative leukemia mutations. Of 344 primary myelofibrosis patients, Janus kinase 2V617F was detected in 226 (66%), calreticulin mutation in 43 (12%), and myeloproliferative leukemia mutation in 16 (5%); 59 patients (17%) were triple-negatives. A 50% cut-off dichotomized Janus kinase 2-mutated patients into those with high Janus kinase 2V617F allele burden and favorable survival and those with low Janus kinase 2V617F allele burden and unfavorable survival. Patients with a favorable mutation status (high Janus kinase 2V617F allele burden/myeloproliferative leukemia/calreticulin mutation) and aged 65 years or under had a median survival of 126 months. Patients with one risk factor (low Janus kinase 2V617F allele burden/triple-negative or age >65 years) had an intermediate survival duration, and patients aged over 65 years with an adverse mutation status (low Janus kinase 2V617F allele burden or triple-negative) had a median survival of only 35 months. Our simple and easily applied age- and mutation status-based scoring system accurately predicted the survival of patients with primary myelofibrosis. PMID:27686378

  18. A phase 1/2, open-label study evaluating twice-daily administration of momelotinib in myelofibrosis

    PubMed Central

    Gupta, Vikas; Mesa, Ruben A.; Deininger, Michael W.N.; Rivera, Candido E.; Sirhan, Shireen; Brachmann, Carrie Baker; Collins, Helen; Kawashima, Jun; Xin, Yan; Verstovsek, Srdan

    2017-01-01

    Momelotinib, a small-molecule inhibitor of Janus kinase 1 and Janus kinase 2, has demonstrated efficacy in myelofibrosis patients with 300 mg, once-daily dosing. This open-label, non-randomized, phase 1/2 study evaluated the safety and therapeutic benefit of momelotinib with twice-daily dosing. A total of 61 subjects with primary myelofibrosis or post–polycythemia vera/post–essential thrombocythemia myelofibrosis with intermediate- or high-risk disease received momelotinib. A phase 1 dose escalation identified 200 mg twice daily as the optimal dose to be expanded in phase 2. The most frequent adverse events were diarrhea (45.9%), peripheral neuropathy (44.3%), thrombocytopenia (39.3%), and dizziness (36.1%), the latter primarily due to a first-dose effect. The response assessment according to the 2006 International Working Group criteria (≥8 weeks duration at any time point) demonstrated spleen response by palpation of 72% (36/50) and anemia response of 45% (18/40). Spleen response by magnetic resonance imaging obtained at 24 weeks was 45.8% (27/59) for all subjects and 54.0% (27/50) for those with palpable splenomegaly at baseline. The symptoms of myelofibrosis were improved in most subjects. Cytokine analysis showed a rapid decline in interleukin-6 with momelotinib treatment, and a slower reduction in other inflammatory cytokines. In the subgroup of subjects with the JAK2V617F mutation at baseline (n=41), momelotinib significantly reduced the allele burden by 21.1% (median) at 24 weeks. These results provide evidence of tolerability and a potential therapeutic activity of momelotinib for subjects that support further evaluation in ongoing, phase 3 randomized trials. (clinicaltrials. gov identifier:01423058). PMID:27634203

  19. Danazol therapy for the anemia of myelofibrosis: assessment of efficacy with current criteria of response and long-term results.

    PubMed

    Cervantes, Francisco; Isola, Ignacio M; Alvarez-Larrán, Alberto; Hernández-Boluda, Juan-Carlos; Correa, Juan-Gonzalo; Pereira, Arturo

    2015-11-01

    The efficacy of danazol was assessed in 50 patients with myelofibrosis and anemia using the recently revised criteria of the International Working Group for Myelofibrosis Research and Treatment. According to them, anemia response (clinical improvement) is defined as transfusion cessation in transfusion-dependent patients or an Hb increase >2 g/dl in patients without transfusion requirements, both maintained for at least 12 weeks. Median follow-up from danazol start was 36 months (interquartile range [IQR] 19.2-58.8). Anemia response was achieved in 15 patients (30 %), including 5 of the 27 with transfusion dependency (18.5 %) and 10 of the 23 without transfusion requirements (43.5 %). Median time to response was 5 months (IQR 4-7) and median duration of the response 14 months (IQR 10-21). Among responder patients, 5 discontinued therapy due to toxicity or personal decision and 1 died from spleen rupture while being in response. A trend for worse response was seen in transfusion-dependent patients (p = 0.055). A platelet increase >50 × 10(9)/l was observed in 3 of 13 thrombocytopenic patients, all of whom had moderate thrombocytopenia. Toxicity was usually moderate, leading to treatment withdrawal in only 4 patients. Danazol is effective in 30 % of patients with anemia-associated myelofibrosis. The responses are less frequent in patients with transfusion dependency.

  20. The impact of ruxolitinib on thrombosis in patients with polycythemia vera and myelofibrosis: a meta-analysis.

    PubMed

    Samuelson, Bethany T; Vesely, Sara K; Chai-Adisaksopha, Chatree; Scott, Bart L; Crowther, Mark; Garcia, David

    2016-09-01

    The Food and Drug Administration approval of ruxolitinib for treatment of myelofibrosis and polycythemia vera has changed the management of patients with myeloproliferative neoplasms. Yet the impact of this therapy on risk of thrombosis, a major cause of morbidity and mortality among these patients, remains unknown. The aim of this study was to evaluate the impact of ruxolitinib on the risk of thrombosis among patients with polycythemia vera or myelofibrosis. Following identification of randomized controlled trials comparing ruxolitinib to standard care or placebo, rates of thrombosis, including venous and arterial thrombosis, were analyzed using fixed effects models. Rates of thrombosis were significantly lower among patients treated with ruxolitinib [risk ratio 0.45, 95% confidence interval (CI) 0.23-0.88]. Subgroup analysis of venous and arterial thrombosis demonstrated similar risk ratios, which did not reach statistical significance (risk ratio 0.46, 95% CI 0.14-1.48 and RR 0.42, 95% CI 0.18-1.01, respectively). In conclusion, our analysis suggests that JAK2 inhibition with ruxolitinib decreases the risk of arterial and/or venous thrombosis in patients with polycythemia vera or myelofibrosis. These findings will require confirmation in a prospective study.

  1. CXCR4-Independent Rescue of the Myeloproliferative Defect of the Gata1low Myelofibrosis Mouse Model by Aplidin®

    PubMed Central

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

    2013-01-01

    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 Gata1low 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 p27Kip 1 activity and is treatable by Aplidin®, a cyclic depsipeptide that activates p27 kip 1 in several cancer cells. Aplidin® restored expression of Gata1 and p27Kip 1 in Gata1 low hematopoietic cells, proliferation of marrow progenitor cells in vitro and maturation of megakaryocytes in vivo (reducing TGF-β/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 Gata1low progenitor cells remained low. These results indicate that Aplidin® effectively alters the natural history of myelofibrosis in Gata1low mice and suggest this drug as candidate for clinical evaluation in PMF. PMID:20458749

  2. 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. (c) 2010 Wiley-Liss, Inc.

  3. Serial 18F-FDG PET for Monitoring Treatment Response After Allogeneic Stem Cell Transplantation for Myelofibrosis.

    PubMed

    Derlin, Thorsten; Alchalby, Haefaa; Bannas, Peter; Laqmani, Azien; Ayuk, Francis; Triviai, Ioanna; Kreipe, Hans-Heinrich; Bengel, Frank M; Kröger, Nicolaus

    2016-10-01

    Our objective was to assess the feasibility of (18)F-FDG PET/CT for noninvasive monitoring of treatment response after allogeneic stem cell transplantation (SCT) for myelofibrosis. Twelve patients with myelofibrosis underwent (18)F-FDG PET/CT before and after SCT. Bone marrow uptake, spleen uptake, and spleen size were assessed before and after SCT and compared with hematologic response criteria and bone marrow biopsies. All patients who did not achieve complete remission remained PET-positive (P = 0.02). Extent of disease, bone marrow metabolism, spleen metabolism, and spleen volume decreased significantly in patients with complete remission (P = 0.03). PET/CT after SCT had a sensitivity of 1.0 (95% confidence interval [CI], 0.54-1.0), a specificity of 0.83 (95% CI, 0.36-1.0), a negative predictive value of 1.0 (95% CI, 0.48-1.0), and a positive predictive value of 0.86 (95% CI, 0.42-1.0) for diagnosis of residual disease. (18)F-FDG PET/CT is feasible for noninvasive monitoring of treatment response after allogeneic SCT for myelofibrosis. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  4. The Small Molecule Inhibitor G6 Significantly Reduces Bone Marrow Fibrosis and the Mutant Burden in a Mouse Model of Jak2-Mediated Myelofibrosis

    PubMed Central

    Kirabo, Annet; Park, Sung O.; Wamsley, Heather L.; Gali, Meghanath; Baskin, Rebekah; Reinhard, Mary K.; Zhao, Zhizhuang J.; Bisht, Kirpal S.; Keserű, György M.; Cogle, Christopher R.; Sayeski, Peter P.

    2013-01-01

    Philadelphia chromosome–negative myeloproliferative neoplasms, including polycythemia vera, essential thrombocytosis, and myelofibrosis, are disorders characterized by abnormal hematopoiesis. Among these myeloproliferative neoplasms, myelofibrosis has the most unfavorable prognosis. Furthermore, currently available therapies for myelofibrosis have little to no efficacy in the bone marrow and hence, are palliative. We recently developed a Janus kinase 2 (Jak2) small molecule inhibitor called G6 and found that it exhibits marked efficacy in a xenograft model of Jak2-V617F–mediated hyperplasia and a transgenic mouse model of Jak2-V617F–mediated polycythemia vera/essential thrombocytosis. However, its efficacy in Jak2-mediated myelofibrosis has not previously been examined. Here, we hypothesized that G6 would be efficacious in Jak2-V617F–mediated myelofibrosis. To test this, mice expressing the human Jak2-V617F cDNA under the control of the vav promoter were administered G6 or vehicle control solution, and efficacy was determined by measuring parameters within the peripheral blood, liver, spleen, and bone marrow. We found that G6 significantly reduced extramedullary hematopoiesis in the liver and splenomegaly. In the bone marrow, G6 significantly reduced pathogenic Jak/STAT signaling by 53%, megakaryocytic hyperplasia by 70%, and the Jak2 mutant burden by 68%. Furthermore, G6 significantly improved the myeloid to erythroid ratio and significantly reversed the myelofibrosis. Collectively, these results indicate that G6 is efficacious in Jak2-V617F–mediated myelofibrosis, and given its bone marrow efficacy, it may alter the natural history of this disease. PMID:22796437

  5. Abnormal P-selectin localization during megakaryocyte development determines thrombosis in the gata1low model of myelofibrosis

    PubMed Central

    Zetterberg, Eva; Verrucci, Maria; Martelli, Fabrizio; Zingariello, Maria; Sancillo, Laura; D’Amore, Emanuela; Rana, Rosa Alba; Migliaccio, Anna Rita

    2014-01-01

    Patients with primary myelofibrosis have increased risk for bleeding and thrombosis. It is debated whether propensity to thrombosis is due to increased numbers of platelet microparticles and/or to pathological platelet-neutrophil interactions. Platelet neutrophil interactions are mediated by P-selectin and even though the megakaryocytes of myelofibrosis patients express normal levels of P-selectin, it remains abnormally localized to the demarcation membrane system rather than being assembled into the α-granules in platelets. Mice carrying the hypomorphic Gata1low mutation express the same megakaryocyte abnormalities presented by primary myelofibrosis patients, including abnormal P-selectin localization to the DMS and develop with age myelofibrosis, a disease that closely resembles human primary myelofibrosis. Whether these mice would also develop thrombosis has not been investigated as yet. The aim of this study was to determine whether Gata1low mice would develop thrombosis with age and, in this case, the role played by P-selectin in the development of the trait. To this aim, Gata1low mice were crossed with P-selnull mice according to standard genetic protocols and Gata1lowP-selwt, Gata1lowP-selnull and Gata1WTP-selnull or Gata1wtP-selwt (as controls) littermates obtained. It was shown that platelet counts, but not hematocrit, are reduced in Gata1low mice. Moreover, platelet microparticles are reduced in Gata1low mice and P-selectin positive platelet microparticles were not found. To determine the phenotypic implications of the different mutations, bleeding time was estimated by a tail cut procedure. Mutant mice were sacrificed and presence of thrombosis was determined by immunohistological staining of organs. Gata1low mice with or without the P-selectin null trait had a prolonged bleeding time compared to wild type mice. However, in Gata1low mice significantly higher frequency of thrombotic events was seen in adult and old Gata1low mice compared to Gata1low

  6. The role of zinc protoporphyrin measurement in the differentiation between primary myelofibrosis and essential thrombocythaemia.

    PubMed

    Metzgeroth, Georgia; Kanders, Eva-Maria; Erben, Philipp; Hofmann, Wolf-Karsten; Hastka, Jan

    2011-04-01

    The differentiation between primary myelofibrosis (PMF) and essential thrombocythaemia (ET) may be difficult especially in early-stage disease. In PMF, increased levels of inflammatory cytokines induce impaired iron utilisation and disturbed erythropoiesis. In conditions with impaired iron support to erythropoiesis, zinc protoporphyrin (ZPP) is produced instead of heme. Here, we investigate whether ZPP concentration can be useful in the differentiation between PMF and ET. Seventy newly diagnosed patients (PMF, n=24; ET, n=46) were analysed. Intraerythrocytic ZPP concentration (normal≤40 μmol/mol heme) was measured by an Aviv front-face haematofluorometer. In PMF, ZPP concentrations were significantly increased when compared to ET (99±37 μmol/mol heme vs. 36±13 μmol/mol heme, p<0.0001). There was also a significant difference between early-stage PMF and advanced disease (77±30 μmol/mol heme vs. 122±31 μmol/mol heme, p=0.003). ZPP>76 μmol/mol heme as observed in 71% of PMF patients were not seen in ET. In PMF patients responding to immunosuppressive treatment (n=4), the increase in haemoglobin was accompanied by declining ZPP. In summary, by detecting the disturbed iron metabolism common in PMF, ZPP may assist in the differentiation between PMF and ET. Concentrations>60 μmol/mol heme are unlikely in ET if iron deficiency is excluded. ZPP determination is also useful for monitoring the effect of therapy in PMF.

  7. Myelofibrosis-associated complications: pathogenesis, clinical manifestations, and effects on outcomes

    PubMed Central

    Mughal, Tariq I; Vaddi, Kris; Sarlis, Nicholas J; Verstovsek, Srdan

    2014-01-01

    Myelofibrosis (MF) is a rare chronic BCR-ABL1 (breakpoint cluster region-Abelson murine leukemia viral oncogene homologue 1)-negative myeloproliferative neoplasm characterized by progressive bone marrow fibrosis, inefficient hematopoiesis, and shortened survival. The clinical manifestations of MF include splenomegaly, consequent to extramedullary hematopoiesis, cytopenias, and an array of potentially debilitating abdominal and constitutional symptoms. Dysregulated Janus kinase (JAK)-signal transducer and activator of transcription signaling underlies secondary disease-associated effects in MF, such as myeloproliferation, bone marrow fibrosis, constitutional symptoms, and cachexia. Common fatal complications of MF include transformation to acute leukemia, thrombohemorrhagic events, organ failure, and infections. Potential complications from hepatosplenomegaly include portal hypertension and variceal bleeding, whereas extramedullary hematopoiesis outside the spleen and liver – depending on the affected organ – may result in intracranial hypertension, spinal cord compression, pulmonary hypertension, pleural effusions, lymphadenopathy, skin lesions, and/or exacerbation of abdominal symptoms. Although allogeneic stem cell transplantation is the only potentially curative therapy, it is suitable for few patients. The JAK1/JAK2 inhibitor ruxolitinib is effective in improving splenomegaly, MF-related symptoms, and quality-of-life measures. Emerging evidence that ruxolitinib may be associated with a survival benefit in intermediate- or high-risk MF suggests the possibility of a disease-modifying effect. Consequently, ruxolitinib could provide a treatment backbone to which other (conventional and novel) therapies may be added for the prevention and effective management of specific MF-associated complications. PMID:24501543

  8. Myelofibrosis-associated complications: pathogenesis, clinical manifestations, and effects on outcomes.

    PubMed

    Mughal, Tariq I; Vaddi, Kris; Sarlis, Nicholas J; Verstovsek, Srdan

    2014-01-01

    Myelofibrosis (MF) is a rare chronic BCR-ABL1 (breakpoint cluster region-Abelson murine leukemia viral oncogene homologue 1)-negative myeloproliferative neoplasm characterized by progressive bone marrow fibrosis, inefficient hematopoiesis, and shortened survival. The clinical manifestations of MF include splenomegaly, consequent to extramedullary hematopoiesis, cytopenias, and an array of potentially debilitating abdominal and constitutional symptoms. Dysregulated Janus kinase (JAK)-signal transducer and activator of transcription signaling underlies secondary disease-associated effects in MF, such as myeloproliferation, bone marrow fibrosis, constitutional symptoms, and cachexia. Common fatal complications of MF include transformation to acute leukemia, thrombohemorrhagic events, organ failure, and infections. Potential complications from hepatosplenomegaly include portal hypertension and variceal bleeding, whereas extramedullary hematopoiesis outside the spleen and liver - depending on the affected organ - may result in intracranial hypertension, spinal cord compression, pulmonary hypertension, pleural effusions, lymphadenopathy, skin lesions, and/or exacerbation of abdominal symptoms. Although allogeneic stem cell transplantation is the only potentially curative therapy, it is suitable for few patients. The JAK1/JAK2 inhibitor ruxolitinib is effective in improving splenomegaly, MF-related symptoms, and quality-of-life measures. Emerging evidence that ruxolitinib may be associated with a survival benefit in intermediate- or high-risk MF suggests the possibility of a disease-modifying effect. Consequently, ruxolitinib could provide a treatment backbone to which other (conventional and novel) therapies may be added for the prevention and effective management of specific MF-associated complications.

  9. Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis

    PubMed Central

    Rumi, Elisa; Pietra, Daniela; Pascutto, Cristiana; Guglielmelli, Paola; Martínez-Trillos, Alejandra; Casetti, Ilaria; Colomer, Dolors; Pieri, Lisa; Pratcorona, Marta; Rotunno, Giada; Sant’Antonio, Emanuela; Bellini, Marta; Cavalloni, Chiara; Mannarelli, Carmela; Milanesi, Chiara; Boveri, Emanuela; Ferretti, Virginia; Astori, Cesare; Rosti, Vittorio; Cervantes, Francisco; Barosi, Giovanni; Vannucchi, Alessandro M.

    2014-01-01

    We studied the impact of driver mutations of JAK2, CALR, (calreticulin gene) or MPL on clinical course, leukemic transformation, and survival of patients with primary myelofibrosis (PMF). Of the 617 subjects studied, 399 (64.7%) carried JAK2 (V617F), 140 (22.7%) had a CALR exon 9 indel, 25 (4.0%) carried an MPL (W515) mutation, and 53 (8.6%) had nonmutated JAK2, CALR, and MPL (so-called triple-negative PMF). Patients with CALR mutation had a lower risk of developing anemia, thrombocytopenia, and marked leukocytosis compared with other subtypes. They also had a lower risk of thrombosis compared with patients carrying JAK2 (V617F). At the opposite, triple-negative patients had higher incidence of leukemic transformation compared with either CALR-mutant or JAK2-mutant patients. Median overall survival was 17.7 years in CALR-mutant, 9.2 years in JAK2-mutant, 9.1 years in MPL-mutant, and 3.2 years in triple-negative patients. In multivariate analysis corrected for age, CALR-mutant patients had better overall survival than either JAK2-mutant or triple-negative patients. The impact of genetic lesions on survival was independent of current prognostic scoring systems. These observations indicate that driver mutations define distinct disease entities within PMF. Accounting for them is not only relevant to clinical decision-making, but should also be considered in designing clinical trials. PMID:24986690

  10. Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis.

    PubMed

    Rumi, Elisa; Pietra, Daniela; Pascutto, Cristiana; Guglielmelli, Paola; Martínez-Trillos, Alejandra; Casetti, Ilaria; Colomer, Dolors; Pieri, Lisa; Pratcorona, Marta; Rotunno, Giada; Sant'Antonio, Emanuela; Bellini, Marta; Cavalloni, Chiara; Mannarelli, Carmela; Milanesi, Chiara; Boveri, Emanuela; Ferretti, Virginia; Astori, Cesare; Rosti, Vittorio; Cervantes, Francisco; Barosi, Giovanni; Vannucchi, Alessandro M; Cazzola, Mario

    2014-08-14

    We studied the impact of driver mutations of JAK2, CALR, (calreticulin gene) or MPL on clinical course, leukemic transformation, and survival of patients with primary myelofibrosis (PMF). Of the 617 subjects studied, 399 (64.7%) carried JAK2 (V617F), 140 (22.7%) had a CALR exon 9 indel, 25 (4.0%) carried an MPL (W515) mutation, and 53 (8.6%) had nonmutated JAK2, CALR, and MPL (so-called triple-negative PMF). Patients with CALR mutation had a lower risk of developing anemia, thrombocytopenia, and marked leukocytosis compared with other subtypes. They also had a lower risk of thrombosis compared with patients carrying JAK2 (V617F). At the opposite, triple-negative patients had higher incidence of leukemic transformation compared with either CALR-mutant or JAK2-mutant patients. Median overall survival was 17.7 years in CALR-mutant, 9.2 years in JAK2-mutant, 9.1 years in MPL-mutant, and 3.2 years in triple-negative patients. In multivariate analysis corrected for age, CALR-mutant patients had better overall survival than either JAK2-mutant or triple-negative patients. The impact of genetic lesions on survival was independent of current prognostic scoring systems. These observations indicate that driver mutations define distinct disease entities within PMF. Accounting for them is not only relevant to clinical decision-making, but should also be considered in designing clinical trials.

  11. Pros and cons of splenectomy in patients with myelofibrosis undergoing stem cell transplantation.

    PubMed

    Li, Z; Deeg, H J

    2001-03-01

    During fetal development, the spleen is a major hemopoietic organ. In the adult human, this task is relinquished to the bone marrow. However, under the stress of certain pathologic conditions, extramedullary hemopoiesis may again occur in the spleen. This is especially true for diseases of the marrow, in particular, myeloproliferative disorders such as agnogenic myeloid metaplasia, which is associated with severe fibrosis of the marrow space. At the same time, the spleen sequesters blood cells and contributes to peripheral blood cytopenias, which may improve following splenectomy. However, success is unpredictable, and the operative mortality of splenectomy is on the order of 10%. As a growing number of patients undergo hemopoietic stem cell transplantation as definitive therapy for myelofibrosis, the decision on splenectomy has additional ramifications since the spleen plays an important role in the kinetics of engraftment of donor cells and in immune reconstitution. We conclude from our analysis of available information that the benefit of splenectomy is difficult to predict, although after transplantation splenectomized patients have faster hemopoietic recovery. It appears that the most important indication for splenectomy in these patients is the relief of symptoms from massive spleen enlargement.

  12. Looking forward: novel therapeutic approaches in chronic and advanced phases of myelofibrosis.

    PubMed

    Mascarenhas, John

    2015-01-01

    Myelofibrosis (MF) is complex at the pathobiologic level and heterogeneous at the clinical level. The advances in molecular characterization of MF provide important insight into the mechanisms driving this chronic myeloid malignancy, refine risk stratification, offer novel therapeutic targets, and serve to measure therapeutic response. Although JAK2 inhibition has been the focus of laboratory and clinical efforts over the last decade, current experimental therapeutic approaches have broadened to include inhibitors of key alternative signaling pathways, epigenetic modulators, anti-fibrotics, and immunotherapies. Based on compelling preclinical rationale, a number of JAK2 inhibitor based combination therapies are now actively being evaluated in the clinic with the goal of disease course modification. The role and timing of hematopoietic stem cell transplant (HSCT) for MF has been challenged with the availability of commercial ruxolitinib and the plethora of experimental treatment options that exist. Integration of preconditioning JAK2 inhibition, reduced intensity conditioning regimens, and alternative donor sources are all being explored in an attempt to optimize this potentially curative modality. This review will summarize modern MF risk stratification, current clinical research approaches to chronic and advance phase MF focusing on novel agents alone and in combination, and update the reader on new directions in HSCT.

  13. Does primary myelofibrosis involve a defective stem cell niche? From concept to evidence.

    PubMed

    Lataillade, Jean-Jacques; Pierre-Louis, Olivier; Hasselbalch, Hans Carl; Uzan, Georges; Jasmin, Claude; Martyré, Marie-Claire; Le Bousse-Kerdilès, Marie-Caroline

    2008-10-15

    Primary myelofibrosis (PMF) is the rarest and the most severe Philadelphia-negative chronic myeloproliferative syndrome. By associating a clonal proliferation and a mobilization of hematopoietic stem cells from bone marrow to spleen with profound alterations of the stroma, PMF is a remarkable model in which deregulation of the stem cell niche is of utmost importance for the disease development. This paper reviews key data suggesting that an imbalance between endosteal and vascular niches participates in the development of clonal stem cell proliferation. Mechanisms by which bone marrow niches are altered with ensuing mobilization and homing of neoplastic hematopoietic stem cells in new or reinitialized niches in the spleen and liver are examined. Differences between signals delivered by both endosteal and vascular niches in the bone marrow and spleen of patients as well as the responsiveness of PMF stem cells to their specific signals are discussed. A proposal for integrating a potential role for the JAK2 mutation in their altered sensitivity is made. A better understanding of the cross talk between stem cells and their niche should imply new therapeutic strategies targeting not only intrinsic defects in stem cell signaling but also regulatory hematopoietic niche-derived signals and, consequently, stem cell proliferation.

  14. Identification of 'short-lived' and 'long-lived' patients at presentation of idiopathic myelofibrosis.

    PubMed

    Cervantes, F; Pereira, A; Esteve, J; Rafel, M; Cobo, F; Rozman, C; Montserrat, E

    1997-06-01

    To contribute to a better knowledge of the prognosis of idiopathic myelofibrosis (IM), the prognostic value of the presenting features in 106 patients diagnosed with IM at a single institution during a 21-year period was retrospectively analysed. Median survival was 59.4 months (95% CI 40.7-75.4). Using univariate analysis, age > 64 years, constitutional symptoms (fever, night sweats, weight loss), Hb < 10 g/dl, circulating blasts (> or= 1%), and serum LDH > 3 times upper normal level were associated with a significantly shorter survival; male sex, platelet count < 100 x 10(9)/l, blood percentage of immature granulocytes (excluding blasts), low cholesterol levels and advanced marrow histological stage had borderline significance. Using multivariate study, only age > 64 years, constitutional symptoms, Hb < 10 g/dl, and circulating blasts retained their prognostic relevance. The latter three variables confirmed their predictive value in patients above and below the series median age, and were able to identify two groups of patients: a low-risk group of 67 patients with none or one bad prognostic factor, in whom IM had an indolent course (median survival 98.8 months, 95% CI 68.7-127.6), and a high-risk group, including 39 patients with two or three factors, with a more aggressive disease (median survival 20.6 months, 95% CI 10-28.2). Finally, the application of two recently proposed scoring systems (in which three prognostic groups are considered) was unable to separate intermediate- from high-risk patients.

  15. Clinicopathologic characteristics of prefibrotic-early primary myelofibrosis in Chinese patients.

    PubMed

    Gong, Xubo; Lu, Xingguo; Xiao, Xibin; Wang, Weiqin; Yang, Jin; Fu, Yanbiao; Zheng, Yanbo; Tang, Qiusu; Zhang, Xiaohong

    2014-03-01

    The clinicopathologic features of patients with prefibrotic-early primary myelofibrosis (PEPMF) are still uncertain, and the characteristics of PEPMF in Asian patients are rarely reported. This study analyzed the clinicopathologic characteristics of 42 Chinese patients with PMF newly diagnosed according to the 2008 World Health Organization criteria. Some clinical and laboratory features of the patients differed significantly from those of the predominantly white patients in Western countries. Chinese patients with PEPMF were more often male (1.28:1) and younger, less likely to have higher median hemoglobin concentrations (126 g/L), less frequently had palpable spleens (35.7%), and had longer median times between prefibrotic-early and classical PEPMF (64 months). On bone marrow trephine sections, Chinese patients were more likely to have increased granulopoiesis (78.6%) and less frequently had balloon-like megakaryocytes (61.9%), giant and staghorn megakaryocytes (35.7%), or megakaryocytes with hyperchromatic and dysplastic nuclei (40.4%). In conclusion, some clinicopathologic characteristics of PEPMF in Chinese patients in China differ substantially from those seen in predominantly white patients in Western countries, and more clinicopathologic studies involving different ethnic populations and geographic regions of the world should help unfold the characteristics of this disease.

  16. Fatal hepatic failure associated with graft rejection following reduced-intensity stem-cell transplantation for chronic idiopathic myelofibrosis (CIMF).

    PubMed

    Miyakoshi, Shigesaburo; Kami, Masahiro; Kishi, Yukiko; Murashige, Naoko; Yuji, Koichiro; Kusumi, Eiji; Matsumura, Tomoko; Onishi, Yasushi; Kobayashi, Kazuhiko; Kim, Sung-Won; Hamaki, Tamae; Takaue, Yoichi; Taniguchi, Shuichi

    2004-12-01

    A 54-year-old man with chronic idiopathic myelofibrosis (CIMF) underwent RIST. His clinical course had been uneventful until day 60, when splenomegaly reappeared. Hepatic dysfunction developed on day 75. Recipient-type hematopoiesis increased to 51% on day 90. After rapid tapering of cyclosporin, serum levels of AST and ALP normalized in parallel with recovery of complete chimerism on day 134. Yet, jaundice progressed. He died of liver failure on day 176. Postmortem examination revealed neither GVHD nor VOD. Graft rejection following RIST for CIMF may lead to fatal hepatic damage through extramedullary hematopoiesis in the liver or cytokine-mediated immune dysregulations.

  17. Autoimmune myelofibrosis accompanied by Sjögren's syndrome in a 47, XXX/46, XX mosaic woman.

    PubMed

    Takahashi, Tohru

    2014-01-01

    This report describes a patient with autoimmune myelofibrosis accompanied by Sjögren's syndrome (SS). A 36-year-old woman was admitted due to petechiae, purpura, gingival bleeding, dyspnea on exertion, and a lack of concentration. She had pancytopenia and was diagnosed with SS. A bone marrow study showed hypercellular marrow with reticulin fibrosis. Lymphocytic infiltrates and aggregates composed of a mixture of T and B cells in the marrow were also observed. A chromosomal analysis of the marrow cells showed 47, XXX and an analysis of peripheral lymphocytes revealed 47, XXX/46, XX mosaic results. The patient's cytopenia resolved following treatment with oral prednisolone.

  18. Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN international working group.

    PubMed

    Kröger, N M; Deeg, J H; Olavarria, E; Niederwieser, D; Bacigalupo, A; Barbui, T; Rambaldi, A; Mesa, R; Tefferi, A; Griesshammer, M; Gupta, V; Harrison, C; Alchalby, H; Vannucchi, A M; Cervantes, F; Robin, M; Ditschkowski, M; Fauble, V; McLornan, D; Ballen, K; Popat, U R; Passamonti, F; Rondelli, D; Barosi, G

    2015-11-01

    The aim of this work is to produce recommendations on the management of allogeneic stem cell transplantation (allo-SCT) in primary myelofibrosis (PMF). A comprehensive systematic review of articles released from 1999 to 2015 (January) was used as a source of scientific evidence. Recommendations were produced using a Delphi process involving a panel of 23 experts appointed by the European LeukemiaNet and European Blood and Marrow Transplantation Group. Key questions included patient selection, donor selection, pre-transplant management, conditioning regimen, post-transplant management, prevention and management of relapse after transplant. Patients with intermediate-2- or high-risk disease and age <70 years should be considered as candidates for allo-SCT. Patients with intermediate-1-risk disease and age <65 years should be considered as candidates if they present with either refractory, transfusion-dependent anemia, or a percentage of blasts in peripheral blood (PB) >2%, or adverse cytogenetics. Pre-transplant splenectomy should be decided on a case by case basis. Patients with intermediate-2- or high-risk disease lacking an human leukocyte antigen (HLA)-matched sibling or unrelated donor, should be enrolled in a protocol using HLA non-identical donors. PB was considered the most appropriate source of hematopoietic stem cells for HLA-matched sibling and unrelated donor transplants. The optimal intensity of the conditioning regimen still needs to be defined. Strategies such as discontinuation of immune-suppressive drugs, donor lymphocyte infusion or both were deemed appropriate to avoid clinical relapse. In conclusion, we provided consensus-based recommendations aimed to optimize allo-SCT in PMF. Unmet clinical needs were highlighted.

  19. An interesting case of pachydermoperiostosis with idiopathic myelofibrosis associated with monosomy 22.

    PubMed

    Arikan, Senay; Sen, Ilker; Bahceci, Mithat; Tuzcu, Alpaslan; Ayli, Meltem

    2009-08-01

    A 24-year-old man was referred to our clinic in August 2003 with complaints of weakness, dizziness, and bilateral knee pain of 3 years' duration. Bilateral digital clubbing had been found on routine physical examination during his military service 4 years earlier. There were no cardiorespiratory or abdominal symptoms. There was no compromise in the activities of everyday life. The patient was not a chronic smoker. In the family history of the patient, his brother had been diagnosed with pachydermoperiostosis in another center 2 years earlier, but did not return to the hospital for a follow-up investigation of myelofibrosis. On physical examination, the patient showed marked drumstick clubbing of the hands (Fig. 1), and a pale general appearance. The causes of digital clubbing are shown in Table 1 (Fawcett RS, Linford S, Stulberg DL. Nail abnormalities: clues to systemic disease. Am Fam Physician 2004; 69: 1417-1424). Deep nasolabial folds were seen on the face. Skin hypertrophy, cutis verticis gyrata, and seborrhea on the face were also observed. The patient also complained of hyperhidrosis. Examination of the cardiovascular system was normal. There was bilateral swelling of the ankle and knee (Fig. 2). Hepatosplenomegaly was found on abdominal examination. Investigations showed hypochromic microcytic anemia [hemoglobin, 8.58 g/dL (normal, 12.2-18.1 g/dL); hematocrit, 28.1% (normal, 37.7-53.7%); white blood cell count, 3430/mm(3) (normal, 4600-10,200/mm(3)); neutrophils, 2470/mm(3) (normal, 2000-6900/mm(3)); lymphocytes, 820/mm(3) (normal, 600-3400/mm(3)); platelets, 162,000/mm(3) (normal, 142,000-424,000 mm(3)); mean corpuscular volume, 73.7 fL (normal, 80-97 fL)]. Anisocytosis, poikilocytosis, microcytosis, and hypochromia were observed on peripheral blood examination, and the erythrocyte sedimentation rate was 37 mm/h. The serum C-reactive protein level was 50.1 mg/L (normal, 0-5 mg/L). Biochemical parameters, including serum calcium, phosphate, alkaline

  20. The role of growth differentiation factor 15 in the pathogenesis of primary myelofibrosis

    PubMed Central

    Uchiyama, Tatsuki; Kawabata, Hiroshi; Miura, Yasuo; Yoshioka, Satoshi; Iwasa, Masaki; Yao, Hisayuki; Sakamoto, Soichiro; Fujimoto, Masakazu; Haga, Hironori; Kadowaki, Norimitsu; Maekawa, Taira; Takaori-Kondo, Akifumi

    2015-01-01

    Growth differentiation factor 15 (GDF15) is a pleiotropic cytokine that belongs to the transforming growth factor-β superfamily. Elevated serum concentrations of this cytokine have been reported in patients with various malignancies. To assess the potential roles of GDF15 in hematologic malignancies, we measured its serum levels in patients with these diseases. We found that serum GDF15 levels were elevated in almost all these patients, particularly in patients with primary myelofibrosis (PMF). Immunohistochemical staining of bone marrow (BM) specimens revealed that GDF15 was strongly expressed by megakaryocytes, which may be sources of increased serum GDF15 in PMF patients. Therefore, we further assessed the contribution of GDF15 to the pathogenesis of PMF. Recombinant human (rh) GDF15 enhanced the growth of human BM mesenchymal stromal cells (BM-MSCs), and it enhanced the potential of these cells to support human hematopoietic progenitor cell growth in a co-culture system. rhGDF15 enhanced the growth of human primary fibroblasts, but it did not affect their expression of profibrotic genes. rhGDF15 induced osteoblastic differentiation of BM-MSCs in vitro, and pretreatment of BM-MSCs with rGDF15 enhanced the induction of bone formation in a xenograft mouse model. These results suggest that serum levels of GDF15 in PMF are elevated, that megakaryocytes are sources of this cytokine in BM, and that GDF15 may modulate the pathogenesis of PMF by enhancing proliferation and promoting osteogenic differentiation of BM-MSCs. PMID:26276681

  1. 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

  2. Tie2 Expressing Monocytes in the Spleen of Patients with Primary Myelofibrosis

    PubMed Central

    Campanelli, Rita; Fois, Gabriela; Catarsi, Paolo; Poletto, Valentina; Villani, Laura; Erba, Benedetta Gaia; Maddaluno, Luigi; Jemos, Basilio; Salmoiraghi, Silvia; Guglielmelli, Paola; Abbonante, Vittorio; Di Buduo, Christian Andrea; Balduini, Alessandra; Iurlo, Alessandra; Barosi, Giovanni; Rosti, Vittorio; Massa, Margherita

    2016-01-01

    Primary myelofibrosis (PMF) is a Philadelphia-negative (Ph−) myeloproliferative disorder, showing abnormal CD34+ progenitor cell trafficking, splenomegaly, marrow fibrosis leading to extensive extramedullary haematopoiesis, and abnormal neoangiogenesis in either the bone marrow or the spleen. Monocytes expressing the angiopoietin-2 receptor (Tie2) have been shown to support abnormal angiogenic processes in solid tumors through a paracrine action that takes place in proximity to the vessels. In this study we investigated the frequency of Tie2 expressing monocytes in the spleen tissue samples of patients with PMF, and healthy subjects (CTRLs), and evaluated their possible role in favouring spleen angiogenesis. We show by confocal microscopy that in the spleen tissue of patients with PMF, but not of CTRLs, the most of the CD14+ cells are Tie2+ and are close to vessels; by flow cytometry, we found that Tie2 expressing monocytes were Tie2+CD14lowCD16brightCDL62−CCR2− (TEMs) and their frequency was higher (p = 0.008) in spleen tissue-derived mononuclear cells (MNCs) of patients with PMF than in spleen tissue-derived MNCs from CTRLs undergoing splenectomy for abdominal trauma. By in vitro angiogenesis assay we evidenced that conditioned medium of immunomagnetically selected spleen tissue derived CD14+ cells of patients with PMF induced a denser tube like net than that of CTRLs; in addition, CD14+Tie2+ cells sorted from spleen tissue derived single cell suspension of patients with PMF show a higher expression of genes involved in angiogenesis than that found in CTRLs. Our results document the enrichment of Tie2+ monocytes expressing angiogenic genes in the spleen of patients with PMF, suggesting a role for these cells in starting/maintaining the pathological angiogenesis in this organ. PMID:27281335

  3. Initial (prefibrotic) stages of idiopathic (primary) myelofibrosis (IMF) - a clinicopathological study.

    PubMed

    Thiele, J; Kvasnicka, H M; Boeltken, B; Zankovich, R; Diehl, V; Fischer, R

    1999-11-01

    A clinicopathological follow-up study including sequential bone marrow biopsies was performed on 79 patients with idiopathic (primary) myelofibrosis (IMF) to characterize initial (prefibrotic) stages and to elucidate whether development of fibrosis was accompanied by corresponding clinical findings. For this purpose our cohort of patients was divided into two groups of which the first presented with the generally accepted signs and symptoms of IMF (group I; n = 60). Most patients of the second group (group II; n = 19) showed mild to moderate therapy-refractory anemia, minimal to slight splenomegaly and frequently thrombocytosis, but no bone marrow fibrosis at onset. Hematopoiesis was consistent with a striking hypercellularity in comparison to the age-related involution by adipose tissue, a conspicuous clustering and histotopographic dislocation of megakaryocytes, a neutrophil granulocytic proliferation and a reduction of erythropoietic islets with arrest of maturation. Most remarkable was the dysplastic cytology of megakaryocytes with a definitive deviation of differentiation resulting in bizarre forms. Follow-up examinations revealed that at later stages group II patients were not distinguishable from the first group with more advanced IMF. For this reason, these patients were regarded as presenting initial, prefibrotic IMF characterized by distinctive bone marrow features at the beginning. The prominent abnormalities of megakaryopoiesis together with the granulocytic proliferation were extremely helpful to differentiate prefibrotic IMF with accompanying thrombocythemia from essential thrombocythemia (ET). Dynamics of fiber progression were calculated by regarding increase in density per time. Speed of progression during the first year of observation proved to be significantly higher in group II patients with prefibrotic IMF in comparison to full-blown cases (group I). In conclusion, with respect to prospective clinical trials, diagnostic criteria for IMF should

  4. Iron Chelation Therapy with Deferasirox in the Management of Iron Overload in Primary Myelofibrosis

    PubMed Central

    Elli, Elena Maria; Belotti, Angelo; Aroldi, Andrea; Parma, Matteo; Pioltelli, Pietro; Pogliani, Enrico Maria

    2014-01-01

    Deferasirox (DSX) is the principal option currently available for iron-chelation-therapy (ICT), principally in the management of myelodysplastic syndromes (MDS), while in primary myelofibrosis (PMF) the expertise is limited. We analyzed our experience in 10 PMF with transfusion-dependent anemia, treated with DSX from September 2010 to December 2013. The median dose tolerated of DSX was 750 mg/day (10 mg/kg/day), with 3 transient interruption of treatment for drug-related adverse events (AEs) and 3 definitive discontinuation for grade 3/4 AEs. According to IWG 2006 criteria, erythroid responses with DSX were observed in 4/10 patients (40%), 2 of them (20%) obtaining transfusion independence. Absolute changes in median serum ferritin levels (Delta ferritin) were greater in hematologic responder (HR) compared with non-responder (NR) patients, already at 6 months of ICT respect to baseline. Our preliminary data open new insights regarding the benefit of ICT not only in MDS, but also in PMF with the possibility to obtain an erythroid response, overall in 40 % of patients. HR patients receiving DSX seem to have a better survival and a lower incidence of leukemic transformation (PMF-BP). Delta ferritin evaluation at 6 months could represent a significant predictor for a different survival and PMF-BP. However, the tolerability of the drug seems to be lower compared to MDS, both in terms of lower median tolerated dose and for higher frequency of discontinuation for AEs. The biological mechanism of action of DSX in chronic myeloproliferative setting through an independent NF-κB inhibition could be involved, but further investigations are required. PMID:24959339

  5. Endogenous retrovirus induces leukemia in a xenograft mouse model for primary myelofibrosis

    PubMed Central

    Triviai, Ioanna; Ziegler, Marion; Bergholz, Ulla; Oler, Andrew J.; Stübig, Thomas; Prassolov, Vladimir; Fehse, Boris; Kozak, Christine A.; Kröger, Nicolaus; Stocking, Carol

    2014-01-01

    The compound immunodeficiencies in nonobese diabetic (NOD) inbred mice homozygous for the Prkdcscid and Il2rgnull alleles (NSG mice) permit engraftment of a wide-range of primary human cells, enabling sophisticated modeling of human disease. In studies designed to define neoplastic stem cells of primary myelofibrosis (PMF), a myeloproliferative neoplasm characterized by profound disruption of the hematopoietic microenvironment, we observed a high frequency of acute myeloid leukemia (AML) in NSG mice. AML was of mouse origin, confined to PMF-xenografted mice, and contained multiple clonal integrations of ecotropic murine leukemia virus (E-MuLV). Significantly, MuLV replication was not only observed in diseased mice, but also in nontreated NSG controls. Furthermore, in addition to the single ecotropic endogenous retrovirus (eERV) located on chromosome 11 (Emv30) in the NOD genome, multiple de novo germ-line eERV integrations were observed in mice from each of four independent NSG mouse colonies. Analysis confirmed that E-MuLV originated from the Emv30 provirus and that recombination events were not necessary for virus replication or AML induction. Pathogenicity is thus likely attributable to PMF-mediated paracrine stimulation of mouse myeloid cells, which serve as targets for retroviral infection and transformation, as evidenced by integration into the Evi1 locus, a hotspot for retroviral-induced myeloid leukemia. This study thus corroborates a role of paracrine stimulation in PMF disease progression, underlines the importance of target cell type and numbers in MuLV-induced disease, and mandates awareness of replicating MuLV in NOD immunodeficient mice, which can significantly influence experimental results and their interpretation. PMID:24912157

  6. Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib

    PubMed Central

    Patel, Keyur P.; Newberry, Kate J.; Luthra, Rajyalakshmi; Jabbour, Elias; Pierce, Sherry; Cortes, Jorge; Singh, Rajesh; Mehrotra, Meenakshi; Routbort, Mark J.; Luthra, Madan; Manshouri, Taghi; Santos, Fabio P.; Kantarjian, Hagop

    2015-01-01

    Although most patients with myelofibrosis (MF) derive benefit from ruxolitinib, some are refractory, have a suboptimal response, or quickly lose their response. To identify genes that may predict response to ruxolitinib, we performed targeted next-generation sequencing (NGS) of a panel of 28 genes recurrently mutated in hematologic malignancies in a cohort of patients with MF who were treated with ruxolitinib in a phase 1/2 study. We also tested for CALR deletions by standard polymerase chain reaction methods. Ninety-eight percent of patients had a mutation in ≥1 gene. Seventy-nine (82.1%) patients had the JAK2V617F mutation, 9 (9.5%) had CALR mutations (7 type 1, 2 type 2), 3 (3.1%) had MPL mutations, and 4 (4.2%) were negative for all 3. ASXL1/JAK2 and TET2/JAK2 were the most frequently comutated genes. Mutations in NRAS, KRAS, PTPN11, GATA2, TP53, and RUNX1 were found in <5% of patients. Spleen response (≥50% reduction in palpable spleen size) was inversely correlated with the number of mutations; patients with ≤2 mutations had ninefold higher odds of a spleen response than those with ≥3 mutations (odds ratio = 9.37; 95% confidence interval, 1.86-47.2). Patients with ≥3 mutations also had a shorter time to treatment discontinuation and shorter overall survival than those with fewer mutations. In multivariable analysis, only number of mutations and spleen response remained associated with time to treatment discontinuation. Patients with ≥3 mutations had the worst outcomes, suggesting that multigene profiling may be useful for therapeutic planning for MF. PMID:26124496

  7. A 7-Gene Signature Depicts the Biochemical Profile of Early Prefibrotic Myelofibrosis

    PubMed Central

    Skov, Vibe; Burton, Mark; Thomassen, Mads; Stauffer Larsen, Thomas; Riley, Caroline H.; Brinch Madelung, Ann; Kjær, Lasse; Bondo, Henrik; Stamp, Inger; Ehinger, Mats; Dahl-Sørensen, Rasmus; Brochmann, Nana; Nielsen, Karsten; Thiele, Jürgen; Jensen, Morten K.; Weis Bjerrum, Ole; Kruse, Torben A.; Hasselbalch, Hans Carl

    2016-01-01

    Recent studies have shown that a large proportion of patients classified as essential thrombocythemia (ET) actually have early primary prefibrotic myelofibrosis (prePMF), which implies an inferior prognosis as compared to patients being diagnosed with so-called genuine or true ET. According to the World Health Organization (WHO) 2008 classification, bone marrow histology is a major component in the distinction between these disease entities. However, the differential diagnosis between them may be challenging and several studies have not been able to distinguish between them. Most lately, it has been argued that simple blood tests, including the leukocyte count and plasma lactate dehydrogenase (LDH) may be useful tools to separate genuine ET from prePMF, the latter disease entity more often being featured by anemia, leukocytosis and elevated LDH. Whole blood gene expression profiling was performed in 17 and 9 patients diagnosed with ET and PMF, respectively. Using elevated LDH obtained at the time of diagnosis as a marker of prePMF, a 7-gene signature was identified which correctly predicted the prePMF group with a sensitivity of 100% and a specificity of 89%. The 7 genes included MPO, CEACAM8, CRISP3, MS4A3, CEACAM6, HEMGN, and MMP8, which are genes known to be involved in inflammation, cell adhesion, differentiation and proliferation. Evaluation of bone marrow biopsies and the 7-gene signature showed a concordance rate of 71%, 79%, 62%, and 38%. Our 7-gene signature may be a useful tool to differentiate between genuine ET and prePMF but needs to be validated in a larger cohort of “ET” patients. PMID:27579896

  8. Effect of Ruxolitinib Therapy on Myelofibrosis-Related Symptoms and Other Patient-Reported Outcomes in COMFORT-I: A Randomized, Double-Blind, Placebo-Controlled Trial

    PubMed Central

    Mesa, Ruben A.; Gotlib, Jason; Gupta, Vikas; Catalano, John V.; Deininger, Michael W.; Shields, Alan L.; Miller, Carole B.; Silver, Richard T.; Talpaz, Moshe; Winton, Elliott F.; Harvey, Jimmie H.; Hare, Thomas; Erickson-Viitanen, Susan; Sun, William; Sandor, Victor; Levy, Richard S.; Kantarjian, Hagop M.; Verstovsek, Srdan

    2013-01-01

    Purpose To assess the effects of ruxolitinib on symptom burden and quality of life (QoL) and to evaluate the ability of the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 to measure meaningful changes in myelofibrosis-related symptoms in patients with myelofibrosis. Patients and Methods COMFORT-I (Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment–I) is a double-blind, placebo-controlled phase III study evaluating ruxolitinib in patients with intermediate-2 or high-risk myelofibrosis. Exploratory analyses were conducted on the following patient-reported outcomes (PROs) assessments: modified MFSAF v2.0 (individual symptoms and Total Symptom Score [TSS]), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Scale, and Patient Global Impression of Change (PGIC). Results Patients receiving ruxolitinib experienced improvements in individual myelofibrosis-related symptoms, although patients receiving placebo experienced worsening (P < .001). The majority (91%) of ruxolitinib-treated patients designated as ≥ 50% TSS responders (≥ 50% TSS improvement) self-reported their condition as either “Much improved” or “Very much improved” on the PGIC. These patients achieved significant improvements in the EORTC QLQ-C30 functional domains and Global Health Status/QoL versus patients receiving placebo, who experienced worsening on these measures (P ≤ .0135). Ruxolitinib-treated patients with a lesser degree of symptom improvement (< 50% TSS responders) also achieved improvements over placebo on these measures. The degree of spleen volume reduction with ruxolitinib correlated with improvements in TSS, PGIC, PROMIS Fatigue Scale, and EORTC Global Health Status/QoL. Ruxolitinib-treated patients who achieved a ≥ 35% reduction in spleen volume experienced the greatest improvements in these PROs. Conclusion

  9. Assessing Bone Marrow Activity in Patients with Myelofibrosis: Results of a Pilot Study of (18)F-FLT PET.

    PubMed

    Vercellino, Laetitia; Ouvrier, Matthieu John; Barré, Emmanuelle; Cassinat, Bruno; de Beco, Virginie; Dosquet, Christine; Chevret, Sylvie; Meignin, Véronique; Chomienne, Christine; Toubert, Marie-Elisabeth; Merlet, Pascal; Kiladjian, Jean-Jacques

    2017-10-01

    An emerging noninvasive approach to assess tissue proliferation uses the PET tracer 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT). To evaluate the diagnostic value of this technique in myelofibrosis, (18)F-FLT PET imaging results were compared with bone marrow histology and bone marrow scintigraphy (BMS), the gold standard techniques in this clinical situation. Methods: Fifteen patients with histology-proven myelofibrosis were included consecutively in the study. Tracers' distributions were assessed using a visual grading assessment score of the uptake in the axial skeleton, proximal and distal limbs, liver, and spleen. This visual score was used to define patterns of tracer distribution and to compare the information provided either by PET or by BMS. A semiquantitative analysis with determination of SUVmax in the same localizations was performed for (18)F-FLT PET. Results: The histology grade of fibrosis correlated with the SUVmax in the axial skeleton (spine and iliac crests) and proximal limbs. (18)F-FLT uptake in these areas was much lower in patients with grade 3 fibrosis than in patients with grade 1 or 2 fibrosis. (18)F-FLT PET showed the same distribution of uptake as BMS in 13 of 14 patients (1 patient did not undergo BMS). In 1 patient, (18)F-FLT PET clearly showed an intense abnormal splenic uptake, whereas spleen uptake was inconclusive with BMS. Conclusion:(18)F-FLT PET appears to be a reliable and convenient technique to assess hematopoietic activity in bone marrow. It yields results close to those observed with BMS. In our study population, (18)F-FLT uptake in the axial skeleton and proximal limbs assessed by SUVmax correlated with the grade of fibrosis. Thus, (18)F-FLT PET may be a useful tool to measure the severity of myelofibrosis, and to monitor noninvasively the patients' status during follow-up. Finally, (18)F-FLT PET may be foreseen as an alternative to BMS. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

  10. Allogeneic hematopoietic stem cell transplantation in myelofibrosis: the 20-year experience of the Gruppo Italiano Trapianto di Midollo Osseo (GITMO).

    PubMed

    Patriarca, Francesca; Bacigalupo, Andrea; Sperotto, Alessandra; Isola, Miriam; Soldano, Franca; Bruno, Barbara; van Lint, Maria Teresa; Iori, Anna Paola; Santarone, Stella; Porretto, Ferdinando; Pioltelli, Pietro; Visani, Giuseppe; Iacopino, Pasquale; Fanin, Renato; Bosi, Alberto

    2008-10-01

    Allogeneic stem cell transplantation is a potentially curative treatment for myelofibrosis, although its use is limited by a high rate of transplant-related mortality. In this study, we evaluated the outcome of patients with myelofibrosis who underwent allogeneic stem cell transplantation, and the impact of prognostic factors. One hundred patients were transplanted in 26 Italian centers between 1986 and 2006. We analyzed the influence of the patients' characteristics and the clinical features of their disease before stem cell transplantation and of transplant procedures on transplant-related mortality, overall survival, and relapse-free survival by means of univariate and multivariate analyses. The median age of the patients at the time of stem cell transplantation was 49 years (range, 21-68) and 90% of them had an intermediate or high Dupriez score. Forty-eight percent received a myeloablative conditioning regimen and 78% received stem cells from matched sibling donors. The cumulative incidence of engraftment at day 90 after transplant was 87% (95% CI, 0.87-0.97). The cumulative 1-year and 3-year incidences of transplant-related mortality were 35% and 43%, respectively. The estimated 3-year overall and relapse-free survival rates after stem cell transplantation were 42% and 35%, respectively. In multivariate analysis, negative predictors of transplant-related mortality were year of stem cell transplantation before 1995, unrelated donor, and a long interval between diagnosis and transplantation. There was a trend towards longer overall and relapse-free survival in patients receiving peripheral blood stem cells rather than bone marrow as the source of their graft (p=0.070 and p=0.077, respectively). The intensity of the conditioning regimen (myeloablative versus reduced intensity regimens) did not significantly influence the outcome. We conclude that the outcome of myelofibrosis patients who underwent allogeneic stem cell transplantation significantly improved after

  11. CALR exon 9 mutations are somatically acquired events in familial cases of essential thrombocythemia or primary myelofibrosis.

    PubMed

    Rumi, Elisa; Harutyunyan, Ashot S; Pietra, Daniela; Milosevic, Jelena D; Casetti, Ilaria C; Bellini, Marta; Them, Nicole C C; Cavalloni, Chiara; Ferretti, Virginia V; Milanesi, Chiara; Berg, Tiina; Sant'Antonio, Emanuela; Boveri, Emanuela; Pascutto, Cristiana; Astori, Cesare; Kralovics, Robert; Cazzola, Mario

    2014-04-10

    Somatic mutations in the calreticulin (CALR) gene were recently discovered in patients with sporadic essential thrombocythemia (ET) and primary myelofibrosis (PMF) lacking JAK2 and MPL mutations. We studied CALR mutation status in familial cases of myeloproliferative neoplasm. In a cohort of 127 patients, CALR indels were identified in 6 of 55 (11%) subjects with ET and in 6 of 20 (30%) with PMF, whereas 52 cases of polycythemia vera had nonmutated CALR. All CALR mutations were somatic, found in granulocytes but not in T lymphocytes. Patients with CALR-mutated ET showed a higher platelet count (P = .017) and a lower cumulative incidence of thrombosis (P = .036) and of disease progression (P = .047) compared with those with JAK2 (V617F). In conclusion, a significant proportion of familial ET and PMF nonmutated for JAK2 carry a somatic mutation of CALR.

  12. [Review of evidence of thalidomide and lenalidomide in different hematological diseases: chronic lymphocytic leukemia, primary amyloidosis, myelofibrosis and syndrome myelodysplastic].

    PubMed

    Jiménez Lozano, I; Juárez Jiménez, J C

    2013-01-01

    Lenalidomide is an immunomodulatory drug approved by the AEMPS and the EMA, in combination with dexamethasone, for the treatment of multiple myeloma in adult patients who have received at least one prior therapy. Moreover, it has recently been approved for the treatment of patients with transfusion-dependent anaemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate. It has also shown to be active in other hematologic and no hematologic diseases. Growing evidence of its use entails a challenge when situating the drug in a cost-effective way to treat these diseases. On this article we review the available evidence on the use of lenalidomide in the second line treatment of patients with chronic lymphocytic leukemia, primary amyloidosis and primary myelofibrosis, and in the first line treatment of patients with myelodysplastic syndrome, and also the evidence of other immunomodulators. Different clinical practice guidelines and scientific evidence portals consider lenalidomide a valid alternative in the first-line treatment of patients with myelodysplastic syndromes, specially those with the deletion of 5q, and in second line for patients with chronic lymphocytic leukemia. However, the available evidence of lenalidomide in the treatment of patients with primary amyloidosis and primary myelofibrosis is limited, ant thus is not considered as the first choice treatment. In any case, the treatment of choice should consider the safety profile in each patient, the previous treatments that has received and the own therapeutic protocols of each center.

  13. Synergism between fibronectin and transforming growth factor-β1 in the production of substance P in monocytes of patients with myelofibrosis.

    PubMed

    Chang, Victor T; Yook, Clara; Rameshwar, Pranela

    2013-03-01

    Substance P (SP), also considered a proinflammatory cytokine, as well as others such as transforming growth factor-β1 (TGF-β1) and interleukin-1 (IL-1), and the extracellular matrix protein fibronectin (FN) have been associated with the pathophysiology of myelofibrosis. SP is encoded by the TAC1 gene. The relationships among SP, TGF-β1, IL-1 and FN are poorly understood. This study determined the mechanisms for concomitant production of IL-1, TGF-β1 and SP and also determined the synergistic role of FN in SP release. Enzyme-linked immunosorbent assay (ELISA) indicated increased levels of SP and TGF-β1 in the blood of patients with myelofibrosis. Monocytes, shown to be activated in patients with bone marrow (BM) fibrosis, expressed the TAC1 gene for SP release, in a nuclear factor-κB (NFκB)-dependent manner. Reporter gene assay with the 5' regulatory region of TAC1 indicated its expression by high levels of FN and TGF-β1. Immunohistochemical studies of paraffin-embedded BM biopsies from patients with myelofibrosis, and age-matched controls without fibrosis, indicated co-localization of SP and its receptor neurokinin-1 (NK1). In summary, myelofibrotic monocytes have autocrine loops that stimulate the release of SP and TGF-β1, and that are potentiated by fibronectin. The FN-mediated induction of SP in turn stimulates monocytes through autostimulation by NK1 receptors. These findings, combined with those of previous studies, demonstrate an adhesion-mediated NFκB/IL-1/TGF-β1 axis that can be initiated by increased FN in patients with myelofibrosis for the production of SP. These findings show how TGF-β1 and SP production are coupled, and suggest new therapeutic targets to reverse immune-mediated fibrosis.

  14. A phase I, open-label, dose-escalation, multicenter study of the JAK2 inhibitor NS-018 in patients with myelofibrosis

    PubMed Central

    Verstovsek, S; Talpaz, M; Ritchie, E; Wadleigh, M; Odenike, O; Jamieson, C; Stein, B; Uno, T; Mesa, R A

    2017-01-01

    NS-018 is a Janus-activated kinase 2 (JAK2)-selective inhibitor, targeting the JAK–signal transducer and activator of transcription (STAT) pathway that is deregulated in myelofibrosis. In this phase I, dose-escalation portion of a phase I/II study, patients with myelofibrosis received oral NS-018 in continuous 28-day cycles. The primary study objective was to evaluate safety, tolerability and clinically active dose of NS-018. Forty-eight patients were treated; 23 (48%) had previously received a JAK inhibitor (JAKi). The most common drug-related adverse events were thrombocytopenia (27%)/anemia (15%) for hematologic events, and dizziness (23%)/nausea (19%) for non-hematologic events. Once daily NS-018 at 300 mg was chosen as the phase II study dose based on improved tolerability compared with higher doses. A ⩾50% reduction in palpable spleen size was achieved in 56% of patients (47% of patients with prior JAKi treatment), and improvements were observed in myelofibrosis-associated symptoms. Bone marrow fibrosis grade (local assessment) improved from baseline in 11/30 evaluable patients (37%) after 3 cycles of NS-018. JAK2 allele burden was largely unchanged. Changes in cytokine/protein levels were noted after 4 weeks of treatment. NS-018 reached peak plasma concentration in 1–2 h and did not accumulate with multiple dosing. NS-018 will be assessed in patients with previous JAKi exposure in the phase II portion. PMID:27479177

  15. Study of cytogenetic abnormalities in G-CSF stimulated peripheral blood cells and non-stimulated bone marrow cells of patients with myelofibrosis.

    PubMed

    Lozynskyy, R Y; Lozynska, M R; Hontar, Y V; Huleyuk, N L; Maslyak, Z V; Novak, V L

    2016-03-01

    The aim of the study was to improve cytogenetic diagnostics and monitoring of myelofibrosis and to reveal the spectrum of cytogenetic abnormalities in patients from Ukraine. A total of 42 patients (23 females and 19 males) with myelofibrosis was studied using different cytogenetic methods. Granulocyte colony-stimulating factor (G-CSF) was added by the new method during cultivation of peripheral blood (PB) cells from 31 patients for specific stimulation of mitotic divisions. Two patients underwent examination by fluorescent in situ hybridization method. In cell cultures of PB stimulated in vitro with G-CSF and in non-stimulated bone marrow chromosome abnormalities were found in 19 (45.2%) of all the patients. The spectrum of cytogenetic abnormalities of bone marrow and PB was the same in all of the patients. Aspiration of bone marrow was unsuccessful due to significant fibrosis in 10 (29.4%) of 34 patients. The study by fluorescent in situ hybridization method confirmed cytogenetic abnormalities revealed by G-method and discovered additional possibly normal subclone. Cytogenetic study of PB using in vitro G-CSF as a specific stimulant of mitosis instead of phytohemagglutinin revealed significant variety of chromosomal abnormalities in Ukrainian patients with myelofibrosis. This method could be a less invasive alternative to cytogenetic examination of bone marrow in the subgroup of patients with considerable fibrosis and consecutive changes. The usage of fluorescent in situ hybridization method supplemented karyotyping by G-banding method.

  16. Impact of allogeneic stem cell transplantation on survival of patients less than 65 years of age with primary myelofibrosis

    PubMed Central

    Giorgino, Toni; Scott, Bart L.; Ditschkowski, Markus; Alchalby, Haefaa; Cervantes, Francisco; Vannucchi, Alessandro; Cazzola, Mario; Morra, Enrica; Zabelina, Tatjana; Maffioli, Margherita; Pereira, Arturo; Beelen, Dietrich; Deeg, H. Joachim; Passamonti, Francesco

    2015-01-01

    Allogeneic hematopoietic stem cell transplantation (SCT) is the only curative option for patients with primary myelofibrosis (PMF), but information on its net advantage over conventional therapies is lacking. Using ad hoc statistical analysis, we determined outcomes in 438 patients <65 years old at diagnosis who received allogenic SCT (n = 190) or conventional therapies (n = 248). Among patients at low risk per the Dynamic International Prognostic Scoring System (DIPSS) model, the relative risk of death after allogenic SCT vs those treated with nontransplant modalities was 5.6 (95% CI, 1.7-19; P = .0051); for intermediate-1 risk it was 1.6 (95% CI, 0.79-3.2; P = .19), for intermediate-2 risk, 0.55 (95% CI, 0.36-0.83; P = .005), and for high risk, 0.37 (95% CI, 0.21-0.66; P = .0007). Thus, patients with intermediate-2 or high-risk PMF clearly benefit from allogenic SCT. Patients at low risk should receive nontransplant therapy, whereas individual counseling is indicated for patients at intermediate-1 risk. PMID:25784679

  17. Impact of allogeneic stem cell transplantation on survival of patients less than 65 years of age with primary myelofibrosis.

    PubMed

    Kröger, Nicolaus; Giorgino, Toni; Scott, Bart L; Ditschkowski, Markus; Alchalby, Haefaa; Cervantes, Francisco; Vannucchi, Alessandro; Cazzola, Mario; Morra, Enrica; Zabelina, Tatjana; Maffioli, Margherita; Pereira, Arturo; Beelen, Dietrich; Deeg, H Joachim; Passamonti, Francesco

    2015-05-21

    Allogeneic hematopoietic stem cell transplantation (SCT) is the only curative option for patients with primary myelofibrosis (PMF), but information on its net advantage over conventional therapies is lacking. Using ad hoc statistical analysis, we determined outcomes in 438 patients <65 years old at diagnosis who received allogenic SCT (n = 190) or conventional therapies (n = 248). Among patients at low risk per the Dynamic International Prognostic Scoring System (DIPSS) model, the relative risk of death after allogenic SCT vs those treated with nontransplant modalities was 5.6 (95% CI, 1.7-19; P = .0051); for intermediate-1 risk it was 1.6 (95% CI, 0.79-3.2; P = .19), for intermediate-2 risk, 0.55 (95% CI, 0.36-0.83; P = .005), and for high risk, 0.37 (95% CI, 0.21-0.66; P = .0007). Thus, patients with intermediate-2 or high-risk PMF clearly benefit from allogenic SCT. Patients at low risk should receive nontransplant therapy, whereas individual counseling is indicated for patients at intermediate-1 risk. © 2015 by The American Society of Hematology.

  18. X-linked thrombocytopenia with thalassemia displays bone marrow reticulin fibrosis and enhanced angiogenesis: comparisons with primary myelofibrosis.

    PubMed

    Åström, Maria; Hahn-Strömberg, Victoria; Zetterberg, Eva; Vedin, Inger; Merup, Mats; Palmblad, Jan

    2015-03-01

    X-linked thrombocytopenia with thalassemia (XLTT) is caused by the mutation 216R > Q in exon 4 of the GATA1 gene. Male hemizygous patients display macrothrombocytopenia, splenomegaly, and a β-thalassemia trait. We describe two XLTT families where three males were initially misdiagnosed as having primary myelofibrosis (PMF) and all five investigated males showed mild-moderate bone marrow (BM) reticulin fibrosis. Comparative investigations were performed on blood samples and BM biopsies from males with XLTT, PMF patients and healthy controls. Like PMF, XLTT presented with high BM microvessel density, low GATA1 protein levels in megakaryocytes, and elevated blood CD34+ cell counts. But unlike PMF, the BM microvessel pericyte coverage was low in XLTT, and no collagen fibrosis was found. Further, as evaluated by immunohistochemistry, expressions of the growth factors VEGF, AGGF1, and CTGF were low in XLTT megakaryocytes and microvessels but high in PMF. Thus, although the reticulin fibrosis in XLTT might simulate PMF, opposing stromal and megakaryocyte features may facilitate differential diagnosis. Additional comparisons between these disorders may increase the understanding of mechanisms behind BM fibrosis in relation to pathological megakaryopoiesis.

  19. Clonal Evolution Revealed by Whole Genome Sequencing in a Case of Primary Myelofibrosis Transformed to Secondary Acute Myeloid Leukemia

    PubMed Central

    Engle, Elizabeth K.; Fisher, Daniel A.C.; Miller, Christopher A.; McLellan, Michael D.; Fulton, Robert S.; Moore, Deborah M.; Wilson, Richard K.; Ley, Timothy J.; Oh, Stephen T.

    2014-01-01

    Clonal architecture in myeloproliferative neoplasms (MPNs) is poorly understood. Here we report genomic analyses of a patient with primary myelofibrosis (PMF) transformed to secondary acute myeloid leukemia (sAML). Whole genome sequencing (WGS) was performed on PMF and sAML diagnosis samples, with skin included as a germline surrogate. Deep sequencing validation was performed on the WGS samples and an additional sample obtained during sAML remission/relapsed PMF. Clustering analysis of 649 validated somatic single nucleotide variants revealed four distinct clonal groups, each including putative driver mutations. The first group (including JAK2 and U2AF1), representing the founding clone, included mutations with high frequency at all three disease stages. The second clonal group (including MYB) was present only in PMF, suggesting the presence of a clone that was dispensable for transformation. The third group (including ASXL1) contained mutations with low frequency in PMF and high frequency in subsequent samples, indicating evolution of the dominant clone with disease progression. The fourth clonal group (including IDH1 and RUNX1) was acquired at sAML transformation and was predominantly absent at sAML remission/relapsed PMF. Taken together, these findings illustrate the complex clonal dynamics associated with disease evolution in MPNs and sAML. PMID:25252869

  20. Hematopoietic cell transplantation as curative therapy for patients with myelofibrosis: Long-term success in all age groups

    PubMed Central

    Deeg, H. Joachim; Bredeson, Christopher; Farnia, Stephanie; Ballen, Karen; Gupta, Vikas; Mesa, Ruben A.; Popat, Uday; Saber, Wael; Seftel, Matthew; Tamari, Roni; Pertersdorf, Effie

    2015-01-01

    Myeloproliferative neoplasms (MPN) are chronic marrow disorders with variable prognosis. Most patients with Polycythemia Vera, Essential Thrombocythemia or even Primary Myelofibrosis (PMF) are successfully managed by conservative strategies for years or even decades, and recent data suggest that even in patients with high-risk disease, in particular those with PMF, life expectancy can be extended by treatment with JAK2 inhibitors. However, none of those modalities are curative, and once marrow failure develops, the disease “accelerates” or transforms to acute leukemia, the only treatment option able to effectively treat and, in fact, cure MPN is allogeneic hematopoietic cell transplantation (HCT). Outcome is superior if HCT is performed before leukemic transformation occurs. Several reports document survival in unmaintained remission beyond 10 years. The most recent analyses show reduced regimen-related mortality (less than 10% or even 5% at day 100), and progressively improved survival with both HLA-identical sibling and unrelated donors. The development of low/reduced intensity conditioning regimens has contributed to the improved success rate and has allowed to successfully carry out HCT in patients in the 7th and even 8th decade of life. We propose, therefore, that HCT should be offered to fit patients in these age groups and should be covered by their respective insurance carriers. PMID:26371371

  1. Different expression patterns of LGALS1 and LGALS3 in polycythemia vera, essential thrombocythemia and primary myelofibrosis.

    PubMed

    Moura, L G; Tognon, R; Nunes, N S; Rodrigues, L Cataldi; Ferreira, A F; Kashima, S; Covas, D T; Santana, M; Souto, E X; Perobelli, L; Simões, B P; Dias-Baruffi, M; Castro, F A

    2016-10-01

    Despite all the knowledge, the cellular and molecular mechanisms involved in myeloproliferative neoplasm (MPN) pathophysiology remain unclear. Authors have shown galectin-1 (Gal-1) and 3 playing roles in tumour angiogenesis and fibrosis, which were correlated with poor prognosis in patients with MPN. In the present study LGALS1 and LGALS3 were differently expressed between polycythemia vera, essential thrombocythemia (ET) and primary myelofibrosis (PMF) diseases. Increased LGALS3 expression was associated with a negative JAK2 V617F status mutation in leucocytes from PMF but not in patients with ET without this mutation. However, a positive Janus kinase 2 (JAK2) V617F cell line established from patients with ET (SET-2 cells) when treated with JAK inhibitor presented high levels of LGALS3. Additionally, high LGALS1 expression was found in CD34(+) cells but not in leucocytes from patients with PMF, in absence of JAK2 V617F mutation, and also in SET-2 cells treated with JAK inhibitor. Thus, our findings indicate that differential expression of LGALS1 and/or LGALS3 in patients with MPN is linked with JAK2 V617F status mutation in these diseases and state of cell differentiation. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  2. Dualism of mixed chimerism between hematopoiesis and stroma in chronic idiopathic myelofibrosis after allogeneic stem cell transplantation.

    PubMed

    Thiele, J; Varus, E; Siebolts, U; Kvasnicka, H M; Wickenhauser, C; Metz, K A; Beelen, D W; Ditschkowski, M; Zander, A; Kröger, N

    2007-04-01

    Scant knowledge exists concerning lineage-restricted mixed chimerism (mCh) after allogeneic peripheral blood stem cell transplantation (PSCT) in patients with chronic idiopathic myelofibrosis (CIMF). Following a sex-mismatched PSCT, a combined immunopheno- and genotyping by fluorescence in-situ hybridization (FISH) was performed on sequential bone marrow (BM) biopsies at standardized intervals. Results were compared with PCR analysis of corresponding peripheral blood samples in five patients. According to FISH, pretransplant specimens revealed a gender congruence of more than 99%, while in the first three months the total BM exhibited a persistent fraction of host cells (30% to 40%) with a tendency to decline after about one year. It is noteworthy that the majority of endothelial cells maintained a recipient origin, whereas CD34+ progenitors and especially CD61+ megakaryocytes exhibited only very few host-derived cells. In keeping with the prevalence of donor cells in the hematopoietic compartment, PCR analysis of peripheral blood cells displayed a non-significant degree of mCh. In conclusion, according to FISH and PCR analysis, successful PSCT in CIMF results in an almost complete chimeric (donor-derived) state of the hematopoietic cell population. The non-transplantable stromal compartment includes the vascular endothelium with a predominance of recipient cells. The minimal mCh of this population implies probably a donor-derived origin (endothelial progenitor cells).

  3. 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

  4. Medical complications, resource utilization and costs in patients with myelofibrosis by frequency of blood transfusion and iron chelation therapy.

    PubMed

    Vekeman, Francis; Cheng, Wendy Y; Sasane, Medha; Huynh, Lynn; Duh, Mei Sheng; Paley, Carole; Mesa, Ruben A

    2015-01-01

    Iron chelation therapies (ICTs) can help eliminate iron surplus in erythrocyte transfusion-dependent (TD) patients with myelofibrosis (MF). The study assessed adjusted incidence rate ratios (aIRRs) of MF-related complications and resource utilization (RU) and adjusted mean monthly inpatient cost differences in patients with TD MF treated with versus without ICT (ICT+ vs. ICT-) using data from two healthcare claims databases. Patients with ≥ 2 MF International Classification of Diseases, 9th Revision (ICD-9) diagnosis codes ≥ 30 days apart were included. Among 571 patients with TD MF, 103 (18%) were ICT+ and 468 (82%) were ICT-. ICT+ patients had lower rates of thrombocytopenia (aIRR: 0.55; p < 0.001), pancytopenia (0.53; p < 0.001), emergency room visits (0.84 [95% confidence interval: 0.74-0.96]) and inpatient stays (0.75 [0.64-0.87]), but higher rates of outpatient visits (1.21 [1.18-1.23]). Adjusted mean complication-related inpatient cost difference per month was lower in ICT+ patients (-$1804 [$570]; p = 0.004). ICT+ patients had significantly lower rates of acute care, but higher rates of outpatient care.

  5. Long-term results of a phase II trial of lenalidomide plus prednisone therapy for patients with myelofibrosis.

    PubMed

    Chihara, Dai; Masarova, Lucia; Newberry, Kate J; Maeng, Hoyoung; Ravandi, Farhad; Garcia-Manero, Guillermo; Ferrajoli, Alessandra; Cortes, Jorge; Kantarjian, Hagop; Verstovsek, Srdan

    2016-09-01

    Lenalidomide, with or without prednisone, is an active therapy for patients with myelofibrosis (MF). We provide an update of a phase II study of lenalidomide plus prednisone in patients with MF, after median follow up of 9 years. Forty patients were enrolled in the study and all patients were evaluable for response. Response to the treatment was reevaluated using IWG response criteria published in 2013: quality of response improved over time and overall response rate was 35%. Response in splenomegaly was seen in 39% of patients and anemia response in 32%. The median time to treatment failure (TTF) in all patients was 8.2 months and the median duration of response was 34.6 months. Response was highly durable in some patients: six patients (15%) had TTF for more than 60 months (5 years) and three patients are still on the treatment beyond 109 months (9 years). Complete and partial responses were seen in one and five patients, respectively, but achieving deeper response was not necessary for the response to be durable. New clinical studies are needed to explore safe and well tolerated lenalidomide-based combination strategies for patients with MF.

  6. The changing profile of idiopathic myelofibrosis: a comparison of the presenting features of patients diagnosed in two different decades.

    PubMed

    Cervantes, F; Pereira, A; Esteve, J; Cobo, F; Rozman, C; Montserrat, E

    1998-02-01

    In an attempt to ascertain whether the presenting features of idiopathic myelofibrosis (IM) have changed in recent years, 2 groups of patients diagnosed with IM in a single institution in different time periods were compared. The first group included 53 patients diagnosed from 1975 to 1986, and the second included 56 patients diagnosed from 1987 to 1997. No significant differences were observed between the two groups with regard to age, gender, delay from first symptoms to disease diagnosis, peripheral blood hematological values and serum biochemical parameters. Patients diagnosed prior to 1987 presented more often with constitutional symptoms (fever, night sweats, weight loss), but the difference did not reach statistical significance. These latter patients had, however, a higher frequency of splenomegaly (91% vs. 73%, p=0.01) and hepatomegaly (79% vs. 48%, p=0.002), and were more often in the osteosclerotic phase at diagnosis (p=0.05) than patients more recently diagnosed. Finally, no significant differences were found between both groups in either the distribution by prognostic scores or survival. The above results seem to indicate a trend towards a less florid clinical picture of IM at presentation in recent years. This, however, does not result in a longer patient survival.

  7. Safety and efficacy of splenic irradiation in the treatment of patients with idiopathic myelofibrosis: a report on 15 patients.

    PubMed

    Bouabdallah, R; Coso, D; Gonzague-Casabianca, L; Alzieu, C; Resbeut, M; Gastaut, J A

    2000-06-01

    Splenic irradiation in idiopathic myelofibrosis (IMF) has often been use d in selected situations when other therapies were unefficient or contraindicated. This could improve quality of life of patients, but literature remains rare in this field. We have assessed the impact of splenic irradiation in 15 patients with IMF. All of them were no longer responsive to usual treatments, and they presented at least one of the following features: constitutional symptoms, splenic pain, large splenic size, and anemia requiring >2 units of red blood cell transfusion per month. The planned schedule of radiotherapy consisted in daily fractions of 0.4-1 Gy. The median dose of radiotherapy per treatment was 9.8 Gy (range, 0.6-30.5). The overall response rate was 59% with a median duration of 10 months (range, 1-19). Splenic irradiation was more effective on constitutional symptoms, splenic pain, and spleen size. The best responses were noted when full doses of radiotherapy could be delivered, and when patients were previously fewly transfused. Splenic irradiation effectively palliates IMF-related symptoms, and constitute an alternative therapy for patients refractory to usual treatments.

  8. Role of Myelofibrosis in Hematotoxicity of Munition RDX Environmental Degradation Product MNX

    DTIC Science & Technology

    2008-09-01

    consequence of anemia in the absence of sufficient regeneration from bone marrow erythroid precursors is recruitment of extramedullatory sites of...Another event associated with a successful regeneration of an anemic episode is increased reticulocytes in the peripheral blood. We quantitated...planned. Statistics: Effects of MNX and RDX on endpoints with normally distributed data ( EPO , BUN, liver weights) were determined by ANOVA with post

  9. Risk factors for infections in myelofibrosis: role of disease status and treatment. A multicenter study of 507 patients.

    PubMed

    Polverelli, Nicola; Breccia, Massimo; Benevolo, Giulia; Martino, Bruno; Tieghi, Alessia; Latagliata, Roberto; Sabattini, Elena; Riminucci, Mara; Godio, Laura; Catani, Lucia; Nicolosi, Maura; Perricone, Margherita; Sollazzo, Daria; Colafigli, Gioia; Campana, Anna; Merli, Francesco; Vitolo, Umberto; Alimena, Giuliana; Martinelli, Giovanni; Lewis, Russell E; Vianelli, Nicola; Cavo, Michele; Palandri, Francesca

    2017-01-01

    Although infectious complications represent a relevant cause of morbidity and mortality in patients with myelofibrosis (MF), little is known about their incidence, outcome and risk factors. We retrospectively evaluated a cohort of 507 MF patients, diagnosed between 1980 and 2014 in five Italian hematology centers, to define the epidemiology of infections and describe the impact of ruxolitinib (RUX) treatment. Overall, 112 patients (22%) experienced 160 infectious events (grade 3-4, 45%) for an incidence rate of 3.9% per patient-year. Infections were mainly bacterial (78%) and involving the respiratory tract (52% of cases). Also, viral (11%) and fungal infections (2%) were recorded. Overall, infections were fatal in 9% of the cases. Among baseline features, high/intermediate-2 IPSS category (HR 1.8, 95%CI:1.2-2.7; P = 0.02) and spleen length ≥10 cm below left costal margin (HR 1.6, 95%CI:1.1-2.5; P = 0.04) were associated with higher infectious risk in multivariate analysis. Overall, the rate of infections was higher in the cohort of 128 RUX-treated patients (44% vs. 20%, P < 0.001). In conclusion, IPSS-category and splenomegaly, emerged as the main risk factors for infections in MF. RUX-treated patients experienced significantly more infection episodes; however, future prospective studies are needed to isolate the confounding contribution of other risk factors such as disease stage. Am. J. Hematol. 92:37-41, 2017. © 2016 Wiley Periodicals, Inc.

  10. The loss of Ezh2 drives the pathogenesis of myelofibrosis and sensitizes tumor-initiating cells to bromodomain inhibition

    PubMed Central

    Kanai, Akinori; Mochizuki-Kashio, Makiko; Harada, Hironori; Shimoda, Kazuya

    2016-01-01

    EZH2 is a component of polycomb repressive complex 2 (PRC2) and functions as an H3K27 methyltransferase. Loss-of-function mutations in EZH2 are associated with poorer outcomes in patients with myeloproliferative neoplasms (MPNs), particularly those with primary myelofibrosis (MF [PMF]). To determine how EZH2 insufficiency is involved in the pathogenesis of PMF, we generated mice compound for an Ezh2 conditional deletion and activating mutation in JAK2 (JAK2V617F) present in patients with PMF. The deletion of Ezh2 in JAK2V617F mice markedly promoted the development of MF, indicating a tumor suppressor function for EZH2 in PMF. The loss of Ezh2 in JAK2V617F hematopoietic cells caused significant reductions in H3K27 trimethylation (H3K27me3) levels, resulting in an epigenetic switch to H3K27 acetylation (H3K27ac). These epigenetic switches were closely associated with the activation of PRC2 target genes including Hmga2, an oncogene implicated in the pathogenesis of PMF. The treatment of JAK2V617F/Ezh2-null mice with a bromodomain inhibitor significantly attenuated H3K27ac levels at the promoter regions of PRC2 targets and down-regulated their expression, leading to the abrogation of MF-initiating cells. Therefore, an EZH2 insufficiency not only cooperated with active JAK2 to induce MF, but also conferred an oncogenic addiction to the H3K27ac modification in MF-initiating cells that was capable of being restored by bromodomain inhibition. PMID:27401345

  11. A Pilot Study of Quantitative MRI Parametric Response Mapping of Bone Marrow Fat for Treatment Assessment in Myelofibrosis

    PubMed Central

    Luker, Gary D.; Nguyen, Huong (Marie); Hoff, Benjamin A.; Galbán, Craig J.; Hernando, Diego; Chenevert, Thomas L.; Talpaz, Moshe; Ross, Brian D.

    2016-01-01

    Myelofibrosis (MF) is a hematologic neoplasm arising as a primary disease or secondary to other myeloproliferative neoplasms (MPNs). Both primary and secondary MF are uniquely associated with progressive bone marrow fibrosis, displacing normal hematopoietic cells from the marrow space and disrupting normal production of mature blood cells. Activation of the JAK2 signaling pathway in hematopoietic stem cells commonly causes MF, and ruxolitinib, a drug targeting this pathway, is the treatment of choice for many patients. However, current measures of disease status in MF do not necessarily predict response to treatment with ruxolitinib or other drugs in MF. Bone marrow biopsies are invasive and prone to sampling error, while measurements of spleen volume only indirectly reflect bone marrow status. Toward the goal of developing an imaging biomarker for treatment response in MF, we present preliminary results from a prospective clinical study evaluating parametric response mapping (PRM) of quantitative Dixon MRI bone marrow fat fraction maps in four MF patients treated with ruxolitinib. PRM allows for the voxel-wise identification of significant change in quantitative imaging readouts over time, in this case the bone marrow fat content. We identified heterogeneous response patterns of bone marrow fat among patients and within different bone marrow sites in the same patient. We also observed discordance between changes in bone marrow fat fraction and reductions in spleen volume, the standard imaging metric for treatment efficacy. This study provides initial support for PRM analysis of quantitative MRI of bone marrow fat to monitor response to therapy in MF, setting the stage for larger studies to further develop and validate this method as a complementary imaging biomarker for this disease. PMID:27213182

  12. 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

  13. Impact of JAK2V617F Mutational Status on Phenotypic Features in Essential Thrombocythemia and Primary Myelofibrosis

    PubMed Central

    Yönal, İpek; Dağlar-Aday, Aynur; Akadam-Teker, Başak; Yılmaz, Ceylan; Nalçacı, Meliha; Yavuz, Akif Selim; Sargın, Fatma Deniz

    2016-01-01

    Objective: The JAK2V617F mutation is present in the majority of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF). The impact of this mutation on disease phenotype in ET and PMF is still a matter of discussion. This study aims to determine whether there are differences in clinical presentation and disease outcome between ET and PMF patients with and without the JAK2V617F mutation. Materials and Methods: In this single-center study, a total of 184 consecutive Philadelphia-negative chronic myeloproliferative neoplasms, 107 cases of ET and 77 cases of PMF, were genotyped for JAK2V617F mutation using the JAK2 Ipsogen MutaScreen assay, which involves allele-specific polymerase chain reaction. Results: ET patients positive for JAK2V617F mutation had higher hemoglobin (Hb) and hematocrit (Hct) levels, lower platelet counts, and more prevalent splenomegaly at diagnosis compared to patients negative for the JAK2V617F mutation, but rates of major thrombotic events, arterial thrombosis, and venous thrombosis were comparable between the groups. At presentation, PMF patients with JAK2V617F mutation had significantly higher Hb and Hct levels and leukocyte counts than patients without the mutation. Similar to the findings of ET patients, thromboembolic rates were similar in PMF patients with and without theJAK2V617F mutation. For ET and PMF patients, no difference was observed in rates of death with respect to JAK2V617F mutational status. Moreover, leukemic transformation rate was not different in our PMF patients with and without JAK2V617F mutation. Conclusion: We conclude that JAK2V617F-mutated ET patients express a polycythemia vera-like phenotype and JAK2V617F mutation in PMF patients is associated with a more pronounced myeloproliferative phenotype. PMID:25913509

  14. Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I.

    PubMed

    Verstovsek, Srdan; Mesa, Ruben A; Gotlib, Jason; Levy, Richard S; Gupta, Vikas; DiPersio, John F; Catalano, John V; Deininger, Michael W N; Miller, Carole B; Silver, Richard T; Talpaz, Moshe; Winton, Elliott F; Harvey, Jimmie H; Arcasoy, Murat O; Hexner, Elizabeth O; Lyons, Roger M; Raza, Azra; Vaddi, Kris; Sun, William; Peng, Wei; Sandor, Victor; Kantarjian, Hagop

    2015-04-01

    In the phase III COMFORT-I study, the Janus kinase 1 (JAK1)/JAK2 inhibitor ruxolitinib provided significant improvements in splenomegaly, key symptoms, and quality-of-life measures and was associated with an overall survival benefit relative to placebo in patients with intermediate-2 or high-risk myelofibrosis. This planned analysis assessed the long-term efficacy and safety of ruxolitinib at a median follow-up of 149 weeks. At data cutoff, approximately 50% of patients originally randomized to ruxolitinib remained on treatment whereas all patients originally assigned to placebo had discontinued or crossed over to ruxolitinib. At week 144, mean spleen volume reduction was 34% with ruxolitinib. Previously observed improvements in quality-of-life measures were sustained with longer-term ruxolitinib therapy. Overall survival continued to favor ruxolitinib despite the majority of placebo patients crossing over to ruxolitinib [hazard ratio 0.69 (95% confidence interval: 0.46-1.03); P = 0.067]. Exploratory analyses suggest that crossover may have contributed to an underestimation of the true survival difference between the treatment groups. Ruxolitinib continued to be generally well tolerated; there was no pattern of worsening grade ≥ 3 anemia or thrombocytopenia with longer-term ruxolitinib exposure. These longer-term data continue to support the efficacy and safety of ruxolitinib in patients with myelofibrosis. The study is registered at clinicaltrials.gov: NCT00952289. Copyright© Ferrata Storti Foundation.

  15. Enhanced Expression of Stim, Orai, and TRPC Transcripts and Proteins in Endothelial Progenitor Cells Isolated from Patients with Primary Myelofibrosis

    PubMed Central

    Dragoni, Silvia; Laforenza, Umberto; Bonetti, Elisa; Reforgiato, Marta; Poletto, Valentina; Lodola, Francesco; Bottino, Cinzia; Guido, Daniele; Rappa, Alessandra; Pareek, Sumedha; Tomasello, Mario; Guarrera, Maria Rosa; Cinelli, Maria Pia; Aronica, Adele; Guerra, Germano; Barosi, Giovanni; Tanzi, Franco

    2014-01-01

    Background An increase in the frequency of circulating endothelial colony forming cells (ECFCs), the only subset of endothelial progenitor cells (EPCs) truly belonging to the endothelial phenotype, occurs in patients affected by primary myelofibrosis (PMF). Herein, they might contribute to the enhanced neovascularisation of fibrotic bone marrow and spleen. Store-operated Ca2+ entry (SOCE) activated by the depletion of the inositol-1,4,5-trisphosphate (InsP3)-sensitive Ca2+ store drives proliferation in ECFCs isolated from both healthy donors (N-ECFCs) and subjects suffering from renal cellular carcinoma (RCC-ECFCs). SOCE is up-regulated in RCC-ECFCs due to the over-expression of its underlying molecular components, namely Stim1, Orai1, and TRPC1. Methodology/Principal Findings We utilized Ca2+ imaging, real-time polymerase chain reaction, western blot analysis and functional assays to evaluate molecular structure and the functional role of SOCE in ECFCs derived from PMF patients (PMF-ECFCs). SOCE, induced by either pharmacological (i.e. cyclopiazonic acid or CPA) or physiological (i.e. ATP) stimulation, was significantly higher in PMF-ECFCs. ATP-induced SOCE was inhibited upon blockade of the phospholipase C/InsP3 signalling pathway with U73111 and 2-APB. The higher amplitude of SOCE was associated to the over-expression of the transcripts encoding for Stim2, Orai2–3, and TRPC1. Conversely, immunoblotting revealed that Stim2 levels remained constant as compared to N-ECFCs, while Stim1, Orai1, Orai3, TRPC1 and TRPC4 proteins were over-expressed in PMF-ECFCs. ATP-induced SOCE was inhibited by BTP-2 and low micromolar La3+ and Gd3+, while CPA-elicited SOCE was insensitive to Gd3+. Finally, BTP-2 and La3+ weakly blocked PMF-ECFC proliferation, while Gd3+ was ineffective. Conclusions Two distinct signalling pathways mediate SOCE in PMF-ECFCs; one is activated by passive store depletion and is Gd3+-resistant, while the other one is regulated by the InsP3-sensitive Ca2

  16. Primary analysis of a phase II open-label trial of INCB039110, a selective JAK1 inhibitor, in patients with myelofibrosis.

    PubMed

    Mascarenhas, John O; Talpaz, Moshe; Gupta, Vikas; Foltz, Lynda M; Savona, Michael R; Paquette, Ronald; Turner, A Robert; Coughlin, Paul; Winton, Elliott; Burn, Timothy C; O'Neill, Peter; Clark, Jason; Hunter, Deborah; Assad, Albert; Hoffman, Ronald; Verstovsek, Srdan

    2017-02-01

    Combined Janus kinase 1 (JAK1) and JAK2 inhibition therapy effectively reduces splenomegaly and symptom burden related to myelofibrosis but is associated with dose-dependent anemia and thrombocytopenia. In this open-label phase II study, we evaluated the efficacy and safety of three dose levels of INCB039110, a potent and selective oral JAK1 inhibitor, in patients with intermediate- or high-risk myelofibrosis and a platelet count ≥50×10(9)/L. Of 10, 45, and 32 patients enrolled in the 100 mg twice-daily, 200 mg twice-daily, and 600 mg once-daily cohorts, respectively, 50.0%, 64.4%, and 68.8% completed week 24. A ≥50% reduction in total symptom score was achieved by 35.7% and 28.6% of patients in the 200 mg twice-daily cohort and 32.3% and 35.5% in the 600 mg once-daily cohort at week 12 (primary end point) and 24, respectively. By contrast, two patients (20%) in the 100 mg twice-daily cohort had ≥50% total symptom score reduction at weeks 12 and 24. For the 200 mg twice-daily and 600 mg once-daily cohorts, the median spleen volume reductions at week 12 were 14.2% and 17.4%, respectively. Furthermore, 21/39 (53.8%) patients who required red blood cell transfusions during the 12 weeks preceding treatment initiation achieved a ≥50% reduction in the number of red blood cell units transfused during study weeks 1-24. Only one patient discontinued for grade 3 thrombocytopenia. Non-hematologic adverse events were largely grade 1 or 2; the most common was fatigue. Treatment with INCB039110 resulted in clinically meaningful symptom relief, modest spleen volume reduction, and limited myelosuppression.

  17. Primary analysis of a phase II open-label trial of INCB039110, a selective JAK1 inhibitor, in patients with myelofibrosis

    PubMed Central

    Mascarenhas, John O.; Talpaz, Moshe; Gupta, Vikas; Foltz, Lynda M.; Savona, Michael R.; Paquette, Ronald; Turner, A. Robert; Coughlin, Paul; Winton, Elliott; Burn, Timothy C.; O’Neill, Peter; Clark, Jason; Hunter, Deborah; Assad, Albert; Hoffman, Ronald; Verstovsek, Srdan

    2017-01-01

    Combined Janus kinase 1 (JAK1) and JAK2 inhibition therapy effectively reduces splenomegaly and symptom burden related to myelofibrosis but is associated with dose-dependent anemia and thrombocytopenia. In this open-label phase II study, we evaluated the efficacy and safety of three dose levels of INCB039110, a potent and selective oral JAK1 inhibitor, in patients with intermediate- or high-risk myelofibrosis and a platelet count ≥50×109/L. Of 10, 45, and 32 patients enrolled in the 100 mg twice-daily, 200 mg twice-daily, and 600 mg once-daily cohorts, respectively, 50.0%, 64.4%, and 68.8% completed week 24. A ≥50% reduction in total symptom score was achieved by 35.7% and 28.6% of patients in the 200 mg twice-daily cohort and 32.3% and 35.5% in the 600 mg once-daily cohort at week 12 (primary end point) and 24, respectively. By contrast, two patients (20%) in the 100 mg twice-daily cohort had ≥50% total symptom score reduction at weeks 12 and 24. For the 200 mg twice-daily and 600 mg once-daily cohorts, the median spleen volume reductions at week 12 were 14.2% and 17.4%, respectively. Furthermore, 21/39 (53.8%) patients who required red blood cell transfusions during the 12 weeks preceding treatment initiation achieved a ≥50% reduction in the number of red blood cell units transfused during study weeks 1–24. Only one patient discontinued for grade 3 thrombocytopenia. Non-hematologic adverse events were largely grade 1 or 2; the most common was fatigue. Treatment with INCB039110 resulted in clinically meaningful symptom relief, modest spleen volume reduction, and limited myelosuppression. PMID:27789678

  18. Safety and efficacy of ruxolitinib in an open-label, multicenter, single-arm phase 3b expanded-access study in patients with myelofibrosis: a snapshot of 1144 patients in the JUMP trial

    PubMed Central

    Al-Ali, Haifa Kathrin; Griesshammer, Martin; le Coutre, Philipp; Waller, Cornelius F.; Liberati, Anna Marina; Schafhausen, Philippe; Tavares, Renato; Giraldo, Pilar; Foltz, Lynda; Raanani, Pia; Gupta, Vikas; Tannir, Bayane; Ronco, Julian Perez; Ghosh, Jagannath; Martino, Bruno; Vannucchi, Alessandro M.

    2016-01-01

    JUMP is a phase 3b expanded-access trial for patients without access to ruxolitinib outside of a clinical study; it is the largest clinical trial to date in patients with myelofibrosis who have been treated with ruxolitinib. Here, we present safety and efficacy findings from an analysis of 1144 patients with intermediate- or high-risk myelofibrosis, as well as a separate analysis of 163 patients with intermediate-1-risk myelofibrosis – a population of patients not included in the phase 3 COMFORT studies. Consistent with ruxolitinib’s mechanism of action, the most common hematologic adverse events were anemia and thrombocytopenia, but these led to treatment discontinuation in only a few cases. The most common non-hematologic adverse events were primarily grade 1/2 and included diarrhea, pyrexia, fatigue, and asthenia. The rates of infections were low and primarily grade 1/2, and no new or unexpected infections were observed. The majority of patients achieved a ≥50% reduction from baseline in palpable spleen length. Improvements in symptoms were rapid, with approximately half of all patients experiencing clinically significant improvements, as assessed by various quality-of-life questionnaires. The safety and efficacy profile in intermediate-1-risk patients was consistent with that in the overall JUMP population and with that previously reported in intermediate-2- and high-risk patients. Overall, ruxolitinib provided clinically meaningful reductions in spleen length and symptoms in patients with myelofibrosis, including those with intermediate-1-risk disease, with a safety and efficacy profile consistent with that observed in the phase 3 COMFORT studies. This trial was registered as NCT01493414 at ClinicalTrials.gov. PMID:27247324

  19. Allogeneic haematopoietic stem cell transplantation for myelofibrosis: a report of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

    PubMed

    Robin, Marie; Tabrizi, Reza; Mohty, Mohamad; Furst, Sabine; Michallet, Mauricette; Bay, Jacques-Olivier; Cahn, Jean-Yves; De Coninck, Eric; Dhedin, Nathalie; Bernard, Marc; Rio, Bernard; Buzyn, Agnès; Huynh, Anne; Bilger, Karin; Bordigoni, Pierre; Contentin, Nathalie; Porcher, Raphaël; Socié, Gérard; Milpied, Noel

    2011-02-01

    Allogeneic haematopoietic stem-cell transplantation (HSCT) is the only curative treatment for myelofibrosis. We report an analysis of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) registry including patients with myelofibrosis transplanted between 1997 and 2008. Potential risk factors affecting engraftment, non-relapse mortality (NRM), overall survival (OS) and progression-free survival (PFS) were analysed. One hundred and forty-seven patients, aged 20-68 (median 53) years, diagnosed with primary (53%) or secondary myelofibrosis underwent HSCT; 59% of patients were transplanted from a matched sibling donor. The conditioning regimen was myeloablative in 31% of patients. Ninety percent of the patients engrafted. Factors affecting favourably engraftment were splenectomy before HSCT, human leucocyte antigen (HLA) matched sibling donor, peripheral stem cell use as source of stem cells and absence of pre-transplant thrombocytopenia. Four-year OS, PFS and NRM survival were 39% (95%confidence interval [CI]: 31-50), 32% (95%CI: 24-43) and 39% (95%CI 30-48), respectively. Multivariate analysis indicated that HLA-identical sibling donor, chronic phase disease and splenectomy in men had favourable impact on OS.

  20. Splenic irradiation in the treatment of patients with chronic myelogenous leukemia or myelofibrosis with myeloid metaplasia. Results of daily and intermittent fractionation with and without concomitant hydroxyurea

    SciTech Connect

    Wagner, H. Jr.; McKeough, P.G.; Desforges, J.; Madoc-Jones, H.

    1986-09-15

    Seventeen patients with either chronic myelogenous leukemia (CML) or myelofibrosis with myeloid metaplasia (MMM) received 24 courses of splenic irradiation at this institution from 1973 to 1982. Eleven of the 17 patients had received prior chemotherapy. Patients were treated with /sup 60/Co gamma rays or 6 MV photons. The fraction size ranged from 15 to 100 rad and the total dose per treatment course from 15 to 650 rad, with the exception of one patient who received 1650 rad. Fourteen of 19 courses (71%) given for splenic pain yielded significant subjective relief while 17 of 26 courses given for splenomegaly obtained at least 50% regression of splenic size. Blood counts were carefully monitored before each treatment to limit hematologic toxicity. From this experience, the authors conclude that splenic irradiation effectively palliates splenic pain and reverses splenomegaly in the majority of patients with CML and MMM. Intermittent fractionation (twice or thrice weekly) is more convenient for the patient, appears to be as effective as daily treatment, and may be associated with less hematologic toxicity. Preliminary results of concurrent treatment with splenic irradiation and oral hydroxyurea show promise and warrant further study.

  1. 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.

  2. Translocation t(3;12)(q26;q21) in JAK2V617F Point Mutation Negative Chronic Idiopathic Myelofibrosis: A Case Report

    PubMed Central

    Mešanović, S.; Šahović, H.; Perić, M.

    2014-01-01

    The myeloproliferative diseases (MPDs) or myelo-proliferative neoplasms (MPNs) are a group of diseases of the bone marrow in which excess cells are produced. Chronic idiopathic myelofibrosis (CIMF) is a stem cell defect characterized by splenomegaly with multiorgan extramedullary hematopoiesis, immature peripheral blood granulocytes and erythrocytes and progressive bone marrow fibrosis. The most common chromosomal abnormalities seen in CIMF patients include numerical changes of chromosomes 7, 8 and 9, and structural changes of 1q, 5q, 13q and 20q. At least 75.0% of patients with bone marrow abnormalities have one or more of these chromosomal anomalies. Detection of the Janus kinase 2 (JAK2) mutation may be a potential major breakthrough for understanding the pathobiology of MPNs, and is an essential part of the diagnostic algorithm. In this study, we describe a JAK2V617F mutation negative CIMF patient who has the chromosomal translocation t(3;12)(q26;q21) in her karyotype. PMID:25741217

  3. REDUCED INTENSITY HEMATOPOIETIC CELL TRANSPLANTATION FOR PATIENTS WITH PRIMARY MYELOFIBROSIS: A COHORT ANALYSIS FROM THE CENTER FOR INTERNATIONAL BLOOD AND MARROW TRANSPLANT RESEARCH

    PubMed Central

    Gupta, Vikas; Malone, Adriana K.; Hari, Parameswaran N.; Ahn, Kwang Woo; Hu, Zhen-Huan; Gale, Robert Peter; Ballen, Karen K.; Hamadani, Mehdi; Olavarria, Eduardo; Gerds, Aaron T.; Waller, Edmund K.; Costa, Luciano J.; Antin, Joseph H.; Kamble, Rammurti T.; van Besien, Koen M.; Savani, Bipin N.; Schouten, Harry C.; Szer, Jeffrey; Cahn, Jean-Yves; de Lima, Marcos J.; Wirk, Baldeep; Aljurf, Mahmoud D.; Popat, Uday; Bejanyan, Nelli; Litzow, Mark R.; Norkin, Maxim; Lewis, Ian D.; Hale, Gregory A.; Woolfrey, Ann E.; Miller, Alan M.; Ustun, Celalettin; Jagasia, Madan H.; Lill, Michael; Maziarz, Richard T.; Cortes, Jorge; Kalaycio, Matt E.; Saber, Wael

    2014-01-01

    We evaluated the outcomes and associated prognostic factors in 233 patients undergoing allogeneic hematopoietic cell transplantation (HCT) for primary myelofibrosis (MF) using reduced intensity conditioning (RIC). Median age at HCT was 55 years. Donors were: matched sibling donor (MSD), 34%; HLA-well-matched unrelated donors (URD), 45%; and partially/mismatched URD, 21%. Risk stratification according to Dynamic International Prognostic Scoring System (DIPSS): low, 12%; intermediate-1, 49%; intermediate-2, 37%; and high, 1%. The probability of survival at 5-years was 47% (95% CI 40–53). In a multivariate analysis, donor type was the only independent factor associated with survival. Adjusted probabilities of survival at 5-years for MSD, well matched URD and partially matched/mismatched URD were 56% (95% CI 44–67), 48% (95% CI 37–58), and 34% (95% CI 21–47), respectively (p=0.002). Relative risks (RR) for NRM for well-matched URD and partially matched/mismatched URD were 3.92 (p=0.006) and 9.37 (p<0.0001), respectively. A trend towards increased NRM (RR 1.7, p=0.07) and inferior survival (RR 1.37, p=0.10) was observed in DIPSS-intermediate-2/high-risk patients compared to DIPSS-low/intermediate-1 risk patients. RIC HCT is a potentially curative option for patients with MF, and donor type is the most important factor influencing survival in these patients. PMID:24161923

  4. Results of a phase 2 study of pacritinib (SB1518), a JAK2/JAK2(V617F) inhibitor, in patients with myelofibrosis

    PubMed Central

    Seymour, John F.; Roberts, Andrew W.; Wadleigh, Martha; To, L. Bik; Scherber, Robyn; Turba, Elyce; Dorr, Andrew; Zhu, Joy; Wang, Lixia; Granston, Tanya; Campbell, Mary S.; Mesa, Ruben A.

    2015-01-01

    Pacritinib (SB1518) is a Janus kinase 2 (JAK2), JAK2(V617F), and Fms-like tyrosine kinase 3 inhibitor that does not inhibit JAK1. It demonstrated a favorable safety profile with promising efficacy in phase 1 studies in patients with primary and secondary myelofibrosis (MF). This multicenter phase 2 study further characterized the safety and efficacy of pacritinib in the treatment of patients with MF. Eligible patients had clinical splenomegaly poorly controlled with standard therapies or were newly diagnosed with intermediate- or high-risk Lille score. Patients with any degree of cytopenia were eligible. Thirty-five patients were enrolled. At entry, 40% had hemoglobin <10 g/dL and 43% had platelets <100 000× 109/L. Up to week 24, 8 of 26 evaluable patients (31%) achieved a ≥35% decrease in spleen volume determined by magnetic resonance imaging and 14 of 33 (42%) attained a ≥50% reduction in spleen size by physical examination. Median MF symptom improvement was ≥50% for all symptoms except fatigue. Grade 1 or 2 diarrhea (69%) and nausea (49%) were the most common treatment-emergent adverse events. The study drug was discontinued in 9 patients (26%) due to adverse events (4 severe). Pacritinib is an active agent in patients with MF, offering a potential treatment option for patients with preexisting anemia and thrombocytopenia. This trial was registered at www.clinicaltrials.gov as #NCT00745550. PMID:25762180

  5. Bone geometry, bone mineral density, and micro-architecture in patients with myelofibrosis: a cross-sectional study using DXA, HR-pQCT, and bone turnover markers.

    PubMed

    Farmer, Sarah; Vestergaard, Hanne; Hansen, Stinus; Shanbhogue, Vikram Vinod; Shanbhoque, Vikram Vinod; Stahlberg, Claudia Irene; Hermann, Anne Pernille; Frederiksen, Henrik

    2015-07-01

    Primary myelofibrosis (MF) is a severe chronic myeloproliferative neoplasm, progressing towards a terminal stage with insufficient haematopoiesis and osteosclerotic manifestations. Whilst densitometry studies have showed MF patients to have elevated bone mineral density, data on bone geometry and micro-structure assessed with non-invasive methods are lacking. We measured areal bone mineral density (aBMD) using dual-energy X-ray absorptiometry (DXA). Bone geometry, volumetric BMD, and micro-architecture were measured using high-resolution peripheral quantitative computed tomography (HR-pQCT). We compared the structural parameters of bones by comparing 18 patients with MF and healthy controls matched for age, sex, and height. Blood was analysed for biochemical markers of bone turnover in patients with MF. There were no significant differences in measurements of bone geometry, volumetric bone mineral density, and micro-structure between MF patients and matched controls. Estimated bone stiffness and bone strength were similar between MF patients and controls. The level of pro-collagen type 1 N-terminal pro-peptide (P1NP) was significantly increased in MF, which may indicate extensive collagen synthesis, one of the major diagnostic criteria in MF. We conclude that bone mineral density, geometry, and micro-architecture in this cohort of MF patients are comparable with those in healthy individuals.

  6. Post clamp

    NASA Technical Reports Server (NTRS)

    Ramsey, John K. (Inventor); Meyn, Erwin H. (Inventor)

    1990-01-01

    A pair of spaced collars are mounted at right angles on a clamp body by retaining rings which enable the collars to rotate with respect to the clamp body. Mounting posts extend through aligned holes in the collars and clamp body. Each collar can be clamped onto the inserted post while the clamp body remains free to rotate about the post and collar. The clamp body is selectively clamped onto each post.

  7. A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis

    PubMed Central

    Vannucchi, Alessandro M.; Kantarjian, Hagop M.; Kiladjian, Jean-Jacques; Gotlib, Jason; Cervantes, Francisco; Mesa, Ruben A.; Sarlis, Nicholas J.; Peng, Wei; Sandor, Victor; Gopalakrishna, Prashanth; Hmissi, Abdel; Stalbovskaya, Viktoriya; Gupta, Vikas; Harrison, Claire; Verstovsek, Srdan

    2015-01-01

    Ruxolitinib, a potent Janus kinase 1/2 inhibitor, resulted in rapid and durable improvements in splenomegaly and disease-related symptoms in the 2 phase III COMFORT studies. In addition, ruxolitinib was associated with prolonged survival compared with placebo (COMFORT-I) and best available therapy (COMFORT-II). We present a pooled analysis of overall survival in the COMFORT studies using an intent-to-treat analysis and an analysis correcting for crossover in the control arms. Overall, 301 patients received ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146) and 227 patients received placebo (n=154) or best available therapy (n=73). After a median three years of follow up, intent-to-treat analysis showed that patients who received ruxolitinib had prolonged survival compared with patients who received placebo or best available therapy [hazard ratio=0.65; 95% confidence interval (95%CI): 0.46–0.90; P=0.01]; the crossover-corrected hazard ratio was 0.29 (95%CI: 0.13–0.63). Both patients with intermediate-2– or high-risk disease showed prolonged survival, and patients with high-risk disease in the ruxolitinib group had survival similar to that of patients with intermediate-2–risk disease in the control group. The Kaplan-Meier estimate of overall survival at week 144 was 78% in the ruxolitinib arm, 61% in the intent-to-treat control arm, and 31% in the crossover-adjusted control arm. While larger spleen size at baseline was prognostic for shortened survival, reductions in spleen size with ruxolitinib treatment correlated with longer survival. These findings are consistent with previous reports and support that ruxolitinib offers a survival benefit for patients with myelofibrosis compared with conventional therapies. (clinicaltrials.gov identifiers: COMFORT-I, NCT00952289; COMFORT-II, NCT00934544) PMID:26069290

  8. Crucial factors of the inflammatory microenvironment (IL-1β/TNF-α/TIMP-1) promote the maintenance of the malignant hemopoietic clone of myelofibrosis: an in vitro study

    PubMed Central

    Polverelli, Nicola; Romano, Marco; Perricone, Margherita; Rossi, Lara; Ottaviani, Emanuela; Luatti, Simona; Martinelli, Giovanni; Vianelli, Nicola; Cavo, Michele

    2016-01-01

    Along with molecular abnormalities (mutations in JAK2, Calreticulin (CALR) and MPL genes), chronic inflammation is the major hallmark of Myelofibrosis (MF). Here, we investigated the in vitro effects of crucial factors of the inflammatory microenvironment (Interleukin (IL)-1β, Tumor Necrosis Factor (TNF)-α, Tissue Inhibitor of Metalloproteinases (TIMP)-1 and ATP) on the functional behaviour of MF-derived circulating CD34+ cells. We found that, regardless mutation status, IL-1β or TNF-α increases the survival of MF-derived CD34+ cells. In addition, along with stimulation of cell cycle progression to the S-phase, IL-1β or TNF-α ± TIMP-1 significantly stimulate(s) the in vitro clonogenic ability of CD34+ cells from JAK2V617 mutated patients. Whereas in the JAK2V617F mutated group, the addition of IL-1β or TNF-α + TIMP-1 decreased the erythroid compartment of the CALR mutated patients. Megakaryocyte progenitors were stimulated by IL-1β (JAK2V617F mutated patients only) and inhibited by TNF-α. IL-1β + TNF-α + C-X-C motif chemokine 12 (CXCL12) ± TIMP-1 highly stimulates the in vitro migration of MF-derived CD34+ cells. Interestingly, after migration toward IL-1β + TNF-α + CXCL12 ± TIMP-1, CD34+ cells from JAK2V617F mutated patients show increased clonogenic ability. Here we demonstrate that the interplay of these inflammatory factors promotes and selects the circulating MF-derived CD34+ cells with higher proliferative activity, clonogenic potential and migration ability. Targeting these micro-environmental interactions may be a clinically relevant approach. PMID:27304059

  9. Increased risks of polycythemia vera, essential thrombocythemia, and myelofibrosis among 24 577 first-degree relatives of 11 039 patients with myeloproliferative neoplasms in Sweden

    PubMed Central

    Goldin, Lynn R.; Kristinsson, Sigurdur Y.; Helgadottir, Elin A.; Samuelsson, Jan; Björkholm, Magnus

    2008-01-01

    Previous small studies have reported familial clustering of myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). We identified 6217 PV, 2838 ET, 1172 MF, and 812 MPN unclassifiable (NOS) patients diagnosed in Sweden, 43 550 controls, and first-degree relatives of cases (n = 24 577) and controls (n = 99 542). Using a marginal survival model, we calculated relative risks (RRs) and 95% confidence intervals as measures of familial aggregation. Relatives of MPN patients had significantly increased risks of PV (RR = 5.7; 3.5-9.1), ET (RR = 7.4; 3.7-14.8), and MPN NOS (RR = 7.5; 2.7-20.8). Analyses stratified by type of first-degree relative revealed consistently higher risks for siblings, compatible with a model of recessive genetic inheritance, which can be confirmed only by identifying the susceptibility gene(s). Mean age at MPN diagnosis was not different (P = .20) for affected relatives of cases (57.5 years) versus controls (60.6 years), and risk of MPN by age was not different for parents versus offspring of MPN cases (P = .10), providing no support for anticipation. Relatives of MPN patients had a borderline increased risk of chronic myeloid leukemia (CML; RR = 1.9; 0.9-3.8; P = .09). Our findings of 5- to 7-fold elevated risk of MPNs among first-degree relatives of MPN patients support the hypothesis that common, strong, shared susceptibility genes predispose to PV, ET, MF, and possibly CML. PMID:18451307

  10. IDH mutations in primary myelofibrosis predict leukemic transformation and shortened survival: clinical evidence for leukemogenic collaboration with JAK2V617F.

    PubMed

    Tefferi, A; Jimma, T; Sulai, N H; Lasho, T L; Finke, C M; Knudson, R A; McClure, R F; Pardanani, A

    2012-03-01

    Isocitrate dehydrogenase (IDH) mutations are frequent in blast-phase myeloproliferative neoplasms and might therefore contribute to leukemic transformation. We examined this possibility in 301 consecutive patients with chronic-phase primary myelofibrosis (PMF). The mutant IDH was detected in 12 patients (4%): 7 IDH2 (5 R140Q, 1 R140W and 1 R172G) and 5 IDH1 (3 R132S and 2 R132C). In all, 6 (50%) of the 12 IDH-mutated patients also expressed JAK2V617F. Overall, 18 (6%) patients displayed only MPL and 164 (54.3%) only JAK2 mutations. Multivariable analysis that accounted for conventional risk factors disclosed inferior overall survival (OS; P=0.03) and leukemia-free survival (LFS; P=0.003) in IDH-mutated patients: OS hazard ratio (HR) was 0.39 (95% confidence interval (95% CI) 0.2-0.75), 0.50 (95% CI 0.27-0.95) and 0.53 (95% CI 0.23-1.2) for patients with no, JAK2 or MPL mutations, respectively. Further analysis disclosed a more pronounced effect for the mutant IDH on OS and LFS in the presence (P=0.0002 and P<0.0001, respectively) as opposed to the absence (P=0.34 and P=0.64) of concomitant JAK2V617F. Analysis of paired samples obtained during chronic- and blast-phase disease revealed the presence of both IDH and JAK2 mutations at both time points. Our observations suggest that IDH mutations in PMF are independent predictors of leukemic transformation and raise the possibility of leukemogenic collaboration with JAK2V617F.

  11. JAK2 Exon 14 Skipping in Patients with Primary Myelofibrosis: A Minor Splice Variant Modulated by the JAK2-V617F Allele Burden

    PubMed Central

    Catarsi, Paolo; Rosti, Vittorio; Morreale, Giacomo; Poletto, Valentina; Villani, Laura; Bertorelli, Roberto; Pedrazzini, Matteo; Zorzetto, Michele; Barosi, Giovanni

    2015-01-01

    Background Primary myelofibrosis (PMF) is an acquired clonal disease of the hematopoietic stem cell compartment, characterized by bone marrow fibrosis, anemia, splenomegaly and extramedullary hematopoiesis. About 60% of patients with PMF harbor a somatic mutation of the JAK2 gene (JAK2-V617F) in their hematopoietic lineage. Recently, a splicing isoform of JAK2, lacking exon 14 (JAK2Δ14) was described in patients affected by myeloproliferative diseases. Materials and Methods By using a specific RT-qPCR method, we measured the ratio between the splicing isoform and the JAK2 full-length transcript (JAK2+14) in granulocytes, isolated from peripheral blood, of forty-four patients with PMF and nine healthy donors. Results We found that JAK2Δ14 was only slightly increased in patients and, at variance with published data, the splicing isoform was also detectable in healthy controls. We also found that, in patients bearing the JAK2-V617F mutation, the percentage of mutated alleles correlated with the observed increase in JAK2Δ14. Homozygosity for the mutation was also associated with a higher level of JAK2+14. Bioinformatic analysis indicates the possibility that the G>T transversion may interfere with the correct splicing of exon 14 by modifying a splicing regulatory sequence. Conclusions Increased levels of JAK2 full-length transcript and a small but significant increase in JAK2 exon 14 skipping, are associated with the JAK2-V617F allele burden in PMF granulocytes. Our data do not confirm a previous claim that the production of the JAK2Δ14 isoform is related to the pathogenesis of PMF. PMID:25617626

  12. Outcome of Allogeneic Stem Cell Transplantation Following Reduced-Intensity Conditioninig Regimen in Patients With Idiopathic Myelofibrosis: the G.I.T.M.O. Experience

    PubMed Central

    Patriarca, Francesca; Bacigalupo, Andrea; Sperotto, Alessandra; Isola, Miriam; Bruno, Barbara; van Lint, Maria Teresa; Iori, Anna Paola; Di Bartolomeo, Paolo; Musso, Maurizio; Pioltelli, Pietro; Visani, Giuseppe; Iacopino, Pasquale; Fanin, Renato; Bosi., Alberto

    2010-01-01

    Background: Allogeneic stem cell transplantation (SCT) is a potentially curative treatment for myelofibrosis (MI), though limited by a high rate of transplant-related mortality (TRM). In the present study we evaluate the outcome of MI patients undergoing an allogenic SCT after reduced intensity conditioning (RIC) regimens, and the impact of prognostic factors. Design and methods: Fifty two patients were transplanted in 26 Italian centres between 1998 and 2006. We analyzed the influence of patient and disease clinical features before SCT and of transplant procedures on TRM and overall survival (OS) by means of univariate and multivariate analyses. Results: At SCT, median age was 52,5 years (32–68) and 89% of the patients had an intermediate or high Dupriez score. Conditioning regimens were based on fludarabine plus busulphan in 27% of patients, thiotepa plus cyclophosphamide in 46% and miscellaneous drug combinations in the other 27% of cases. Stem cells came from matched sibling donors for 75% of the patients and mismatched sibling or unrelated donors for the remaining 25%. The cumulative incidence of engraftment at day 90 after transplant was 83% (95% CI, 0.87–0.97). The estimated 1-year TRM was 30%. The estimated 3-year event-free-survival (EFS) and OS after hematopoietic SCT was 44% and 38% respectively. In multivariate analysis, an higher leukocyte count and circulating blasts in the peripheral blood before SCT significantly reduced EFS and OS respectively. Interpretation and conclusions: We conclude that the extension of the disease before transplantation based on the presence of circulating blasts and high leukocyte counts significantly affected the outcome after HSCT PMID:21415963

  13. A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis.

    PubMed

    Vannucchi, Alessandro M; Kantarjian, Hagop M; Kiladjian, Jean-Jacques; Gotlib, Jason; Cervantes, Francisco; Mesa, Ruben A; Sarlis, Nicholas J; Peng, Wei; Sandor, Victor; Gopalakrishna, Prashanth; Hmissi, Abdel; Stalbovskaya, Viktoriya; Gupta, Vikas; Harrison, Claire; Verstovsek, Srdan

    2015-09-01

    Ruxolitinib, a potent Janus kinase 1/2 inhibitor, resulted in rapid and durable improvements in splenomegaly and disease-related symptoms in the 2 phase III COMFORT studies. In addition, ruxolitinib was associated with prolonged survival compared with placebo (COMFORT-I) and best available therapy (COMFORT-II). We present a pooled analysis of overall survival in the COMFORT studies using an intent-to-treat analysis and an analysis correcting for crossover in the control arms. Overall, 301 patients received ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146) and 227 patients received placebo (n=154) or best available therapy (n=73). After a median three years of follow up, intent-to-treat analysis showed that patients who received ruxolitinib had prolonged survival compared with patients who received placebo or best available therapy [hazard ratio=0.65; 95% confidence interval (95%CI): 0.46-0.90; P=0.01]; the crossover-corrected hazard ratio was 0.29 (95%CI: 0.13-0.63). Both patients with intermediate-2- or high-risk disease showed prolonged survival, and patients with high-risk disease in the ruxolitinib group had survival similar to that of patients with intermediate-2-risk disease in the control group. The Kaplan-Meier estimate of overall survival at week 144 was 78% in the ruxolitinib arm, 61% in the intent-to-treat control arm, and 31% in the crossover-adjusted control arm. While larger spleen size at baseline was prognostic for shortened survival, reductions in spleen size with ruxolitinib treatment correlated with longer survival. These findings are consistent with previous reports and support that ruxolitinib offers a survival benefit for patients with myelofibrosis compared with conventional therapies. (clinicaltrials.gov identifiers: COMFORT-I, NCT00952289; COMFORT-II, NCT00934544). Copyright© Ferrata Storti Foundation.

  14. 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.

  15. Reduced-intensity hematopoietic cell transplantation for patients with primary myelofibrosis: a cohort analysis from the center for international blood and marrow transplant research.

    PubMed

    Gupta, Vikas; Malone, Adriana K; Hari, Parameswaran N; Ahn, Kwang Woo; Hu, Zhen-Huan; Gale, Robert Peter; Ballen, Karen K; Hamadani, Mehdi; Olavarria, Eduardo; Gerds, Aaron T; Waller, Edmund K; Costa, Luciano J; Antin, Joseph H; Kamble, Rammurti T; van Besien, Koen M; Savani, Bipin N; Schouten, Harry C; Szer, Jeffrey; Cahn, Jean-Yves; de Lima, Marcos J; Wirk, Baldeep; Aljurf, Mahmoud D; Popat, Uday; Bejanyan, Nelli; Litzow, Mark R; Norkin, Maxim; Lewis, Ian D; Hale, Gregory A; Woolfrey, Ann E; Miller, Alan M; Ustun, Celalettin; Jagasia, Madan H; Lill, Michael; Maziarz, Richard T; Cortes, Jorge; Kalaycio, Matt E; Saber, Wael

    2014-01-01

    We evaluated outcomes and associated prognostic factors in 233 patients undergoing allogeneic hematopoietic cell transplantation (HCT) for primary myelofibrosis (MF) using reduced-intensity conditioning (RIC). The median age at RIC HCT was 55 yr. Donors were a matched sibling donor (MSD) in 34% of RIC HCTs, an HLA well-matched unrelated donor (URD) in 45%, and a partially matched/mismatched URD in 21%. Risk stratification according to the Dynamic International Prognostic Scoring System (DIPSS) was 12% low, 49% intermediate-1, 37% intermediate-2, and 1% high. The probability of survival at 5 yr was 47% (95% confidence interval [CI], 40% to 53%). In a multivariate analysis, donor type was the sole independent factor associated with survival. Adjusted probabilities of survival at 5-yr were 56% (95% CI, 44% to 67%) for MSD, 48% (95% CI, 37% to 58%) for well-matched URD, and 34% (95% CI, 21% to 47%) for partially matched/mismatched URD (P = .002). The relative risk (RR) for NRM was 3.92 (P = .006) for well-matched URD and 9.37 (P < .0001) for partially matched/mismatched URD. Trends toward increased NRM (RR, 1.7; P = .07) and inferior survival (RR, 1.37; P = .10) were observed in DIPSS intermediate-2/high-risk patients compared with DIPSS low/intermediate-1 risk patients. Our data indicate that RIC HCT is a potentially curative option for patients with MF, and that donor type is the most important factor influencing survival in these patients. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  16. Role of miR-34a-5p in Hematopoietic Progenitor Cells Proliferation and Fate Decision: Novel Insights into the Pathogenesis of Primary Myelofibrosis

    PubMed Central

    Bianchi, Elisa; Ruberti, Samantha; Rontauroli, Sebastiano; Guglielmelli, Paola; Salati, Simona; Rossi, Chiara; Zini, Roberta; Tagliafico, Enrico; Vannucchi, Alessandro Maria; Manfredini, Rossella

    2017-01-01

    Primary Myelofibrosis (PMF) is a chronic Philadelphia-negative myeloproliferative neoplasm characterized by a skewed megakaryopoiesis and an overproduction of proinflammatory and profibrotic mediators that lead to the development of bone marrow (BM) fibrosis. Since we recently uncovered the upregulation of miR-34a-5p in PMF CD34+ hematopoietic progenitor cells (HPCs), in order to elucidate its role in PMF pathogenesis here we unravelled the effects of miR-34a-5p overexpression in HPCs. We showed that enforced expression of miR-34a-5p partially constrains proliferation and favours the megakaryocyte and monocyte/macrophage commitment of HPCs. Interestingly, we identified lymphoid enhancer-binding factor 1 (LEF1) and nuclear receptor subfamily 4, group A, member 2 (NR4A2) transcripts as miR-34a-5p-targets downregulated after miR-34a-5p overexpression in HPCs as well as in PMF CD34+ cells. Remarkably, the knockdown of NR4A2 in HPCs mimicked the antiproliferative effects of miR-34a-5p overexpression, while the silencing of LEF1 phenocopied the effects of miR-34a-5p overexpression on HPCs lineage choice, by favouring the megakaryocyte and monocyte/macrophage commitment. Collectively our data unravel the role of miR-34a-5p in HPCs fate decision and suggest that the increased expression of miR-34a-5p in PMF HPCs could be important for the skewing of megakaryopoiesis and the production of monocytes, that are key players in BM fibrosis in PMF patients. PMID:28098757

  17. Rare congenital chromosomal aberration dic(X;Y)(p22.33;p11.32) in a patient with primary myelofibrosis.

    PubMed

    Pavlistova, Lenka; Izakova, Silvia; Zemanova, Zuzana; Bartuskova, Lucie; Langova, Martina; Malikova, Pavlina; Michalova, Kyra

    2016-01-01

    Constitutional translocations between sex chromosomes are rather rare in humans with breakpoints at Xp11 and Yq11 as the most frequent. Breakpoints on the short arm of the Y chromosome form one subgroup of t(X;Y), giving rise to a derived chromosome with the centromeres of both the X and Y chromosomes, dic(X;Y). Here, we report a rare congenital chromosomal aberration, 46,X,dic(X;Y)(p22.33;p11.32)[20]/45,X[10], in an adult male. Primary myelofibrosis, a malignant haematological disease, was diagnosed in a 63-year-old man following liver transplantation after hepatocellular carcinoma. By the analysis of the bone marrow sample, the karyotype 46,X,dic(X;Y)(p22.33;p11.32) was detected in all the mitoses analysed and verified with multicolour fluorescence in situ hybridization (mFISH). A cytogenetic examination of stimulated peripheral blood cells revealed the constitutional karyotype 46,X,dic(X;Y)(p22.33;p11.32)[20]/45,X[10]. The cell line 45,X was confirmed with FISH in 35 % of interphase nuclei. The SRY locus was present on the dicentric chromosome. A CGH/SNP array (Illumina) revealed a gain of 153,7 Mbp of the X chromosome and a 803-kbp microdeletion (including the SHOX gene), which were also confirmed with FISH. SHOX encodes a transcriptional factor that regulates the growth of the long bones. The deletion of the SHOX gene together with the Madelung deformity of the forearm and the short stature of the proband led to a diagnosis of Léri-Weill dyschondrosteosis (LWD). The gain of almost the whole X chromosome (153,7 Mbp) was considered a variant of Klinefelter syndrome (KS). The levels of gonadotropins and testosterone were consistent with gonadal dysfunction. A malformation of the right external ear was detected. We have reported a structural aberration of the sex chromosomes, dic(X;Y)(p22.33;p11.32). The related genomic imbalance is associated with two known hereditary syndromes, LWD and a KS variant, identified in our proband at an advanced age. Because the

  18. Ruxolitinib in clinical practice for primary and secondary myelofibrosis: an analysis of safety and efficacy of Gruppo Laziale of Ph-negative MPN.

    PubMed

    Breccia, Massimo; Andriani, Alessandro; Montanaro, Marco; Abruzzese, Elisabetta; Buccisano, Francesco; Cedrone, Michele; Centra, Antonietta; Villivà, Nicoletta; Celesti, Francesca; Trawinska, Malgorzata Monica; Massaro, Fulvio; Di Veroli, Ambra; Anaclerico, Barbara; Colafigli, Gioia; Molica, Matteo; Spadea, Antonio; Petriccione, Luca; Cimino, Giuseppe; Latagliata, Roberto

    2017-03-01

    Ruxolitinib, a JAK1 and JAK2 inhibitor, has been tested and approved for the treatment of primary and secondary myelofibrosis (MF). Aim of our study is to report safety and efficacy of ruxolitinib in 98 patients affected by MF treated outside clinical trials and collected and treated consecutively by the Lazio Cooperative Group for Ph negative myeloproliferative diseases.There were 45 males and 53 females; median age was 61.8 years (range 35.3-88). Forty-five patients were diagnosed as primary MF and 53 as secondary MF. Seventy-seven patients (78.5%) experienced constitutional symptoms at baseline, and out of 94 patients tested, 66 (70%) were JAK2(V617F) mutated. Overall, 40 patients received hydroxyurea as firstline treatment, 30 patients received other chemotherapeutic approaches, whereas 28 were treated with ruxolitinib frontline. Median time from diagnosis to start of ruxolitinib in the whole cohort was 34.6 months. Fifty-eight patients (59%) required a dose reduction during the first 3 months due to hematological toxicity in the majority of cases. At 48 weeks, 52% of patients obtained a clinical benefit: of them 7 patients (7%) had a CR, 10 (10%) a PR, 6 patients (6%) a CI, and 28 patients (28.5%) a spleen response. Overall, 66% of patients had disappearance of baseline symptoms burden. After 1 year, of 72 evaluable patients, 52% achieved and maintained a clinical benefit. Adverse events of special interest at any grade included anemia (39.7%), thrombocytopenia (25.5%), infections (16.3%, of which 10 were bronchopneumonia), fluid retention (3%), diarrhea (2%) and abdominal pain (2%). After a median follow-up of 16 months from start of ruxolitinib, median daily dose decreased to 10 mg BID and 21 patients (21%) discontinued the drug. The results of this retrospective multicentric analysis confirmed the efficacy of ruxolitinib outside clinical trials with more than half of treated patients achieving and maintaining a clinical benefit and most of them

  19. Loss of Ezh2 cooperates with Jak2V617F in the development of myelofibrosis in a mouse model of myeloproliferative neoplasm

    PubMed Central

    Yang, Yue; Akada, Hajime; Nath, Dipmoy; Hutchison, Robert E.

    2016-01-01

    An activating JAK2V617F mutation has been found in ∼50% patients with myelofibrosis (MF). Inactivating mutations in histone methyltransferase enhancer of zeste homolog 2 (EZH2) also have been observed in patients with MF. Interestingly, inactivating EZH2 mutations are often associated with JAK2V617F mutation in MF, although their contributions in the pathogenesis of MF remain elusive. To determine the effects of concomitant loss of EZH2 and JAK2V617F mutation in hematopoiesis, we generated Ezh2-deficient Jak2V617F-expressing mice. Whereas expression of Jak2V617F alone induced a polycythemia vera–like disease, concomitant loss of Ezh2 significantly reduced the red blood cell and hematocrit parameters but increased the platelet counts in Jak2V617F knock-in mice. Flow cytometric analysis showed impairment of erythroid differentiation and expansion of megakaryocytic precursors in Ezh2-deficient Jak2V617F mice. Moreover, loss of Ezh2 enhanced the repopulation capacity of Jak2V617F-expressing hematopoietic stem cells. Histopathologic analysis revealed extensive fibrosis in the bone marrow (BM) and spleen of Ezh2-deleted Jak2V617F mice. Transplantation of BM from Ezh2-deleted Jak2V617F mice into wild-type animals resulted in even faster progression to MF. Gene expression profiling and chromatin immunoprecipitation sequence analysis revealed that S100a8, S100a9, Ifi27l2a, and Hmga2 were transcriptionally derepressed, and the H3K27me3 levels in these gene promoters were significantly reduced on Ezh2 deletion in hematopoietic progenitors of Jak2V617F mice. Furthermore, overexpression of S100a8, S100a9, Ifi27l2a, or Hmga2 significantly increased megakaryocytic colonies in the BM of Jak2V617F mice, indicating a role for these Ezh2 target genes in altered megakaryopoiesis involved in MF. Overall, our results suggest that loss of Ezh2 cooperates with Jak2V617F in the development of MF in Jak2V617F-expressing mice. PMID:27081096

  20. Genetics Home Reference: primary myelofibrosis

    MedlinePlus

    ... from gene mutations that occur in early blood-forming cells after conception. These alterations are called somatic ... Free article on PubMed Central Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, ...

  1. Time Course and Variability of Polycythemic Response in Men at High Altitude

    NASA Technical Reports Server (NTRS)

    Grover, R. F.; Seiland, M.; McCullough, R. G.; Greenleaf, J. E.; Dahms, T. E.; Wolfel, E.; Reeves, J. T.

    2000-01-01

    Ten young men were exposed to 4,300 m (PB 460 Torr) for three weeks. Plasma volume (PV, Evans Blue dye). and blood volume (BV, carbon monoxide) measured simultaneously, and red cell volume (RCV) calculated from hematocrit, were determined twice at sea level and after 9-11 and 19-20 days at high altitude. After 19-20 days. half the subjects increased RCV +19.4 +/- 1.8% (p<0.001); the other 5 subjects had no significant change in RCV. All 10 subjects had a sustained decrease in PV (-16.2 +/- 1.9%, p<0.05) at altitude. Consequently, compared with sea level values, BV was unchanged (-3.1 +/- 1.8%) in the group with increased RCV, but BV decreased significantly (-12.2 +/- 1.4%, p<0.05) in the other group. Variability in RCV response was not explained by differences, in hypoxemic stimulus or the erythropoictin and reticulocyte responses. Since RCV reflects the balance between red cell. production and destruction, accelerated red cell destruction may have occurred in those individuals with no net change in RCV.

  2. Time Course and Variability of Polycythemic Response in Men at High Altitude

    NASA Technical Reports Server (NTRS)

    Grover, R. F.; Seiland, M.; McCullough, R. G.; Greenleaf, J. E.; Dahms, T. E.; Wolfel, E.; Reeves, J. T.

    2000-01-01

    Ten young men were exposed to 4,300 m (PB 460 Torr) for three weeks. Plasma volume (PV, Evans Blue dye). and blood volume (BV, carbon monoxide) measured simultaneously, and red cell volume (RCV) calculated from hematocrit, were determined twice at sea level and after 9-11 and 19-20 days at high altitude. After 19-20 days. half the subjects increased RCV +19.4 +/- 1.8% (p<0.001); the other 5 subjects had no significant change in RCV. All 10 subjects had a sustained decrease in PV (-16.2 +/- 1.9%, p<0.05) at altitude. Consequently, compared with sea level values, BV was unchanged (-3.1 +/- 1.8%) in the group with increased RCV, but BV decreased significantly (-12.2 +/- 1.4%, p<0.05) in the other group. Variability in RCV response was not explained by differences, in hypoxemic stimulus or the erythropoictin and reticulocyte responses. Since RCV reflects the balance between red cell. production and destruction, accelerated red cell destruction may have occurred in those individuals with no net change in RCV.

  3. 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

  4. Post-traumatic Stress Disorder Post Partum

    PubMed Central

    Schwab, W.; Marth, C.; Bergant, A. M.

    2012-01-01

    Traumatic birth experiences may lead to serious psychological impairment. Recent studies show that a considerable number of women can develop post-traumatic stress disorder (PTSD), in some cases in a subsyndromal form. Until now, the possibility that postpartum psychological symptoms might be a continuum of a pre-existing disorder in pregnancy has rarely been considered. This study therefore aimed to evaluate the proportion of women who develop post-traumatic stress disorder as a result of childbirth. Materials and Methods: 56 multiparous women were recruited for the study. The diagnosis of PTSD was made according to the criteria for psychological disorders in the DSM-IV (Diagnostics and Statistical Manual of Mental Disorders). The data were collected in structured interviews in the 30th to 38th week of gestation and in the 6th week post partum. Results: Of the 56 women participating, 52 (93 %) completed the survey. Uncontrolled results showed that 21.15 % of the multiparous women met the full diagnostic PTSD criteria in the 6th week post partum. After the exclusion of all cases already characterised by all criteria or a subsyndromal form of PTSD caused by previous traumatisation, the PTSD rate was below 8 % at 6 weeks postpartum (= incidence rate of PTSD post partum). Conclusions: The present study is the first prospective longitudinal study to demonstrate the occurrence of full criteria PTSD in multiparous women as a result of childbirth after having excluded pre-existing PTSD. The results of our study show a high prevalence rate of PTSD during pregnancy. A number of women report all aspects of post-traumatic stress disorder as a result of childbirth. PMID:25253905

  5. Post-Error Adjustments

    PubMed Central

    Danielmeier, Claudia; Ullsperger, Markus

    2011-01-01

    When our brain detects an error, this process changes how we react on ensuing trials. People show post-error adaptations, potentially to improve their performance in the near future. At least three types of behavioral post-error adjustments have been observed. These are post-error slowing (PES), post-error reduction of interference, and post-error improvement in accuracy (PIA). Apart from these behavioral changes, post-error adaptations have also been observed on a neuronal level with functional magnetic resonance imaging and electroencephalography. Neuronal post-error adaptations comprise activity increase in task-relevant brain areas, activity decrease in distracter-encoding brain areas, activity modulations in the motor system, and mid-frontal theta power increases. Here, we review the current literature with respect to these post-error adjustments, discuss under which circumstances these adjustments can be observed, and whether the different types of adjustments are linked to each other. We also evaluate different approaches for explaining the functional role of PES. In addition, we report reanalyzed and follow-up data from a flanker task and a moving dots interference task showing (1) that PES and PIA are not necessarily correlated, (2) that PES depends on the response–stimulus interval, and (3) that PES is reliable on a within-subject level over periods as long as several months. PMID:21954390

  6. Fence Posts and Rails

    ERIC Educational Resources Information Center

    Turton, Roger

    2016-01-01

    "Mathematical Lens" uses photographs as a springboard for mathematical inquiry and appears in every issue of "Mathematics Teacher." Recently while dismantling an old wooden post-and-rail fence, Roger Turton noticed something very interesting when he piled up the posts and rails together in the shape of a prism. The total number…

  7. Fence Posts and Rails

    ERIC Educational Resources Information Center

    Turton, Roger

    2016-01-01

    "Mathematical Lens" uses photographs as a springboard for mathematical inquiry and appears in every issue of "Mathematics Teacher." Recently while dismantling an old wooden post-and-rail fence, Roger Turton noticed something very interesting when he piled up the posts and rails together in the shape of a prism. The total number…

  8. Myelofibrosis 2012: it’s complicated

    PubMed Central

    Hubbeling, Harper G.; Frank, Dale M.

    2012-01-01

    Major advances in myeloproliferative neoplasms in the last decade have cast light on their complexity. The identification of JAK2V617F briefly promised a unifying mechanism of pathogenesis with a single pathway that could be efficiently targeted. Instead, there have been major advances in understanding acquired and background genetic and epigenetic contributors to this group of disorders, with refined risk prediction models and experimental therapeutics that have provided a more nuanced model of disease. In aggregate these observations likely explain the heterogeneity of these disorders and their generally unpredictable response to therapy. Molecular studies, beginning with the identification of JAK2V617F, have led to a concept of MPN subtypes existing on a continuum, and additional discoveries such as TET2 and EZH2 mutations have provided the molecular underpinnings to begin to explain overlapping phenotypes in myeloid malignancies more generally. In many ways the pace of molecular discovery is outstripping our ability to integrate these observations into clinical care, both in terms of molecular diagnostics and medical decision making. This review will attempt to summarize, within a clinical context, our evolving understanding of myeloproliferative neoplasms. It focuses on biology, histopathology, prognostic scoring systems, stem cell transplantation as well as selected clinical/preclinical therapeutic observations. PMID:23556120

  9. Post-quantum cryptography.

    PubMed

    Bernstein, Daniel J; Lange, Tanja

    2017-09-13

    Cryptography is essential for the security of online communication, cars and implanted medical devices. However, many commonly used cryptosystems will be completely broken once large quantum computers exist. Post-quantum cryptography is cryptography under the assumption that the attacker has a large quantum computer; post-quantum cryptosystems strive to remain secure even in this scenario. This relatively young research area has seen some successes in identifying mathematical operations for which quantum algorithms offer little advantage in speed, and then building cryptographic systems around those. The central challenge in post-quantum cryptography is to meet demands for cryptographic usability and flexibility without sacrificing confidence.

  10. [Post-partum thyroiditis].

    PubMed

    Neves, Celestino; Alves, Marta; Delgado, Luís; Medina, J Luís

    2009-01-01

    In the post-partum period the immune alterations are associated with the multiple autoimmune diseases relapse. After birth, immune-tolerance variation slowly disappear, and is observed a return to a normal state - after an exacerbation period - of autoimmune reactivity, during which a great increase in T cells and autoantibodies is observed. In this period - 3 to 9 months after birth - the thyroid autoimmune disease relapses or reappears. The reactivation of the immune system in the post-partum period unchains an acute phase of celular destruction which characterizes the post-partum thyroiditis.

  11. Post-quantum cryptography

    NASA Astrophysics Data System (ADS)

    Bernstein, Daniel J.; Lange, Tanja

    2017-09-01

    Cryptography is essential for the security of online communication, cars and implanted medical devices. However, many commonly used cryptosystems will be completely broken once large quantum computers exist. Post-quantum cryptography is cryptography under the assumption that the attacker has a large quantum computer; post-quantum cryptosystems strive to remain secure even in this scenario. This relatively young research area has seen some successes in identifying mathematical operations for which quantum algorithms offer little advantage in speed, and then building cryptographic systems around those. The central challenge in post-quantum cryptography is to meet demands for cryptographic usability and flexibility without sacrificing confidence.

  12. Strain balanced quantum posts

    SciTech Connect

    Alonso-Alvarez, D.; Alen, B.; Ripalda, J. M.; Llorens, J. M.; Taboada, A. G.; Briones, F.; Roldan, M. A.; Hernandez-Saz, J.; Hernandez-Maldonado, D.; Herrera, M.; Molina, S. I.

    2011-04-25

    Quantum posts are assembled by epitaxial growth of closely spaced quantum dot layers, modulating the composition of a semiconductor alloy, typically InGaAs. In contrast with most self-assembled nanostructures, the height of quantum posts can be controlled with nanometer precision, up to a maximum value limited by the accumulated stress due to the lattice mismatch. Here, we present a strain compensation technique based on the controlled incorporation of phosphorous, which substantially increases the maximum attainable quantum post height. The luminescence from the resulting nanostructures presents giant linear polarization anisotropy.

  13. Post-Concussion Syndrome

    MedlinePlus

    ... those often experienced by people diagnosed with depression, anxiety or post-traumatic stress disorder. In many cases, both physiological effects of brain trauma and emotional reactions to these ...

  14. Post-splenectomy syndrome

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/001290.htm Post-splenectomy syndrome To use the sharing features on ... Sabiston Textbook of Surgery: The Biological Basis of Modern Surgical Practice . 20th ed. Philadelphia, PA: Elsevier; 2017: ...

  15. CRITICALITY SAFETY POSTING GUIDELINES

    SciTech Connect

    JENSEN, M.A.

    2001-11-01

    This document provides a set of guidelines in the preparation of criticality safety postings. Guidance is provided in word choice, word arrangement, common human factors considerations. and use of color to highlight limits, cautions, and permissives.

  16. Post-Polio Syndrome

    MedlinePlus

    ... first episode of polio. Currently, the most accepted theory regarding the cause of post-polio syndrome rests ... conserve your energy. Moving from one frame of mind to another can be difficult. Here are some ...

  17. Post adoption depression.

    PubMed

    Fields, Eve S; Meuchel, Jennifer M; Jaffe, Chiara J; Jha, Manish; Payne, Jennifer L

    2010-04-01

    We sought to evaluate the prevalence rate and factors associated with post adoption depression. One hundred and twelve adoptive mothers of infants under 12 months of age were recruited from local and national adoption organizations. A modified Edinburgh Postnatal Depression Scale (EPDS) and a questionnaire collecting medical and psychiatric history, perceived stress, and demographics were administered retrospectively. The rates of significant depressive symptoms (defined as EPDS >or=12) were calculated at three time points post adoption, and associations with specific clinical variables (personal or family psychiatric history, stress, and adjustment difficulty) were assessed. Eighty-six mothers were included. Rates of significant depressive symptoms (EPDS >or=12) were found in 27.9% of subjects at 0-4 weeks, 25.6% at 5-12 weeks, and 12.8% at 13-52 weeks post adoption. Significant depressive symptoms were not associated with personal or family psychiatric history but were associated with stress (p = 0.0011) and adjustment difficulties (p = 0.042) post adoption. Significant depressive symptoms were relatively common in adoptive mothers within the first year after adoption and were associated with environmental stress. Prospective studies are needed to confirm the existence of post adoption depression and the factors associated with it.

  18. Esthetic Intracanal Posts

    PubMed Central

    Parčina, Ivana; Amižić

    2016-01-01

    The primary function of an endodontic post is to provide retention for the core and enable full sealing of the coronal portion of the root canal. Traditionally used metal posts do not meet the requirements of modern dental medicine due to some fairly significant drawbacks such as color, corrosion potential, non-adhesive bonding and high modulus of elasticity which can lead to root fracture. Recently, esthetic ceramic and fiber reinforced posts have been manufactured in order to avoid such imperfections. Since much attention has been devoted to the esthetic aspects of dental medicine, the use of these posts with composite/ceramic cores is very common in restorative dentistry and it is actually becoming a standard. This is due to the fact that, apart from being an esthetically pleasing material, they are also biocompatible, have good physical properties and the capacity of adhesive bonding to tooth tissue and core buildup. Nonetheless, a good clinician should know how to spot the difference between them in order to select and use the appropriate post system in each specific situation. PMID:27789912

  19. The "Post-Post Period" and Environmental Education Research

    ERIC Educational Resources Information Center

    McKenzie, Marcia

    2005-01-01

    Described as "post-experimental" and of the "post-post period," the current moment in social science research is typified by multi-voiced texts, researcher reflexivity, cultural criticism, and experimental works; characteristics in keeping with post-structurally informed understandings of social science research as contingent, evolving and messy.…

  20. Unmanipulated haploidentical bone marrow transplantation and post-transplant cyclophosphamide for hematologic malignanices following a myeloablative conditioning: an update.

    PubMed

    Bacigalupo, A; Dominietto, A; Ghiso, A; Di Grazia, C; Lamparelli, T; Gualandi, F; Bregante, S; Van Lint, M T; Geroldi, S; Luchetti, S; Grasso, R; Pozzi, S; Colombo, N; Tedone, E; Varaldo, R; Raiola, A M

    2015-06-01

    This is a report of 148 patients with hematologic malignancies who received an unmanipulated haploidentical bone marrow transplant (BMT), followed by post-transplant high-dose cyclophosphamide (PT-CY). All patients received a myeloablative conditioning consisting of thiotepa, busulfan, fludarabine (n=92) or TBI, fludarabine (n=56). The median age was 47 years (17-74); 47 patients were in first remission (CR1), 37 in second remission (CR2) and 64 had an active disease; all patients were first grafts. The diagnosis was acute leukemia (n=75), myelodisplastic syndrome (n=24), myelofibrosis (n=16), high-grade lymphoma (n=15) and others (n=18). GVHD prophylaxis consisted in PT-CY on days +3 and +5, cyclosporine (from day 0), and mycophenolate (from day +1). The median day for neutrophil engraftment was day +18 (13-32). The cumulative incidence of grades II-IV acute GVHD was 24%, and of grades III-IV GVHD 10%. The incidence of moderate-severe chronic GVHD was 12%. With a median follow-up for the surviving patients of 313 days (100-1162), the cumulative incidence of transplant-related mortality (TRM) is 13%, and the relapse-related death is 23%. The actuarial 22 months overall survival is 77% for CR1 patients, 49% for CR2 patients and 38% for patients grafted in relapse (P<0.001). Major causes of death were relapse (22%), GVHD (2%) and infections (6%). We confirm our initial results, suggesting that a myeloablative conditioning regimen followed by unmanipulated haploidentical BMT with PT-CY, results in a low risk of acute and chronic GVHD and encouraging rates of TRM and overall survival, also for patients with active disease at the time of transplant.

  1. Post-wildfire management

    Treesearch

    Jonathan W. Long; Carl Skinner; Susan Charnley; Ken Hubbert; Lenya Quinn-Davidson; Marc Meyer

    2014-01-01

    Wildfires, especially large, severe, and unmanageable events, exert major influences on socioecological systems, not only through risks to life and property, but also losses of important values associated with mature forest stands. These events prompt decisions about post-wildfire management interventions, including short-term emergency responses, salvage logging, and...

  2. [Post-transfusional AIDS].

    PubMed

    Azzini, M; Maccabruni, A; Marcellini, M; Michelone, G; Dei Cas, A

    1987-01-01

    Two cases of post-transfusional AIDS in two premature babies who received blood of the same seropositive donor, are reported. The risk of the susceptibility to HIV infection of these patients, in relation to the immaturity of immune system and to the transfusional treatment often necessary in premature newborns, is stressed.

  3. Post-Concussion Syndrome

    MedlinePlus

    ... even if you never lost consciousness. If a concussion occurs while you're playing a sport, don't go back in the game. Seek medical attention so that you don't risk worsening your injury. Causes Some experts believe post-concussion symptoms are caused by structural damage to the ...

  4. Castleman-Kojima disease (TAFRO syndrome) : a novel systemic inflammatory disease characterized by a constellation of symptoms, namely, thrombocytopenia, ascites (anasarca), microcytic anemia, myelofibrosis, renal dysfunction, and organomegaly : a status report and summary of Fukushima (6 June, 2012) and Nagoya meetings (22 September, 2012).

    PubMed

    Kawabata, Hiroshi; Takai, Kazue; Kojima, Masaru; Nakamura, Naoya; Aoki, Sadao; Nakamura, Shigeo; Kinoshita, Tomohiro; Masaki, Yasufumi

    2013-01-01

    Recently, a unique clinicopathologic variant of multicentric Castleman's disease (MCD) has been identified in Japan. This disease is characterized by a constellation of symptoms, as listed in the title, and multiple lymphadenopathy of mild degree with a pathologic diagnosis of atypical CD, often posing diagnostic and therapeutic problems for pathologists and hematologists, respectively. These findings suggest that this disease represents a novel clinical entity belonging to systemic inflammatory disorders with a background of immunological abnormality beyond the ordinal spectrum of MCD. To define this disorder more clearly, Japanese participants presented clinicopathologic data at the Fukushima and Nagoya meetings. Many of the patients presented by the participants were significantly accompanied by a combination of thrombocytopenia, ascites (anasarca), pleural effusions, microcytic anemia, fever, myelofibrosis, renal dysfunction, and organomegaly (TAFRO). Multiple lymphadenopathies were generally of mild degree, less than 1.5 cm in diameter, and consistently featured the histopathology of mixed- or less hyaline vascular-type CD. Autoantibodies were often detected. However, this disease did not fulfill the diagnostic criteria for well-known autoimmune diseases including systemic lupus erythematosus. Castleman-Kojima disease and TAFRO syndrome (the favored clinical term) were proposed for this disease. The patients were sensitive to steroid and anti-interleukin-6 receptor antibody (tocilizumab), but some exhibited a deteriorated clinical course despite the treatment. The participants proposed a future nationwide survey and a Japanese consortium to facilitate further clinical and therapeutic studies of this novel disease. [J Clin Exp Hematop 53(1): 57-61, 2013].

  5. [Post-traumatic stress].

    PubMed

    Ogłodek, Ewa; Araszkiewicz, Aleksander

    2012-01-01

    As civilization advanced, the number of disasters, including their types and size of the threat to humanity. In addition to natural disasters and wars, there are currently a disaster communication, environmental and technological. Disasters "new generation" include increasingly frequent bombings and terrorist attacks. These events are an impediment to long-lasting and deep impact on the mental functioning of the victims of the event. This represents a potential risk of a variety of psychopathological symptoms, which go beyond the limits of human suffering. ICD-I0 classification includes individuals sickness arising as a consequence of pathological after surviving the disaster, which include: acute stress disorder (ASD), post-traumatic stress disorder (PTSD), post-traumatic stress disorder linked to depression, symptoms anxiety, addictions, dissociative disorders and personality changes and permanent after the disaster.

  6. Post-stroke dyskinesias

    PubMed Central

    Nakawah, Mohammad Obadah; Lai, Eugene C

    2016-01-01

    Strokes, whether ischemic or hemorrhagic, are among the most common causes of secondary movement disorders in elderly patients. Stroke-related (vascular) movement disorders, however, are uncommon complications of this relatively common disease. The spectrum of post-stroke movement disorders is broad and includes both hypo- and hyperkinetic syndromes. Post-stroke dyskinesias are involuntary hyperkinetic movements arising from cerebrovascular insults and often present with mixed phenotypes of hyperkinesia which can sometimes be difficult to classify. Nevertheless, identification of the most relevant motor phenotype, whenever possible, allows for a more specific phenomenological categorization of the dyskinesia and thus helps guide its treatment. Fortunately, post-stroke dyskinesias are usually self-limiting and resolve within 6 to 12 months of onset, but a short-term pharmacotherapy might sometimes be required for symptom control. Functional neurosurgical interventions targeting the motor thalamus or globus pallidus interna might be considered for patients with severe, disabling, and persistent dyskinesias (arbitrarily defined as duration longer than 12 months). PMID:27853372

  7. 10. FLOOR 1; CENTER POST AND POSTS UNDER STONE BEAMS ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    10. FLOOR 1; CENTER POST AND POSTS UNDER STONE BEAMS WHICH SUPPORT BRIDGE BEAMS FOR BRIDGE TREES; WEDGES FOR ADJUSTING HEIGHT OF BRIDGE TREE CAN BE SEEN - Shelter Island Windmill, Manwaring Road, Shelter Island, Suffolk County, NY

  8. 1. Post card view of the bridge, c. 1910. Post ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    1. Post card view of the bridge, c. 1910. Post card courtesy Carol Poh Miller. Photocopy by Berni Rich, Score Photographers Cleveland, OH - B & O Railroad Bridge Number 464, Spanning Old Ship Canal & Cuyahoga River, Cleveland, Cuyahoga County, OH

  9. Typical Newel Post, First Floor Newel Post, Typical Baluster, Typical ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Typical Newel Post, First Floor Newel Post, Typical Baluster, Typical Nosing, First Floor Stringer Profile, Second Floor Stringer Profile - National Home for Disabled Volunteer Soldiers - Battle Mountain Sanitarium, Treasurer's Quarters, 500 North Fifth Street, Hot Springs, Fall River County, SD

  10. POST-MENOPAUSAL OSTEOPOROSIS

    PubMed Central

    Hogg, C. Alison

    1997-01-01

    Millions of women will be prescribed hormone replacement therapy (HRT) and be told that it will prevent osteoporosis occuring, despite the fact that there is doubt about its long term usefulness. Preventive measures outlined in this article are much more preferable, but need to be directed towards the whole population, not just menopausal women. The prevention of osteoporosis is an important public health issue which needs to be addressed now, not in the next century. This article explores the issues that surround the medicalisation of post-menopausal osteoporosis. PMID:17987149

  11. [Post-stripping telangiectasis].

    PubMed

    Hutinel, B; Maraval, M

    1985-01-01

    These telangiectasia appear between one and six months after the operation, especially in cases of capillary fragility. The most common localizations are the antero-internal and external sides of the thighs and knees. Unnecessary strippings, of continent saphenous veins, are the most frequent cause of these. Their prevention consists of the least possible traumatising stripping, using a fine stripper, a very rigorous post-operative support, and the wearing of light varicose stockings or tights for between one and three months. The treatment using microsclerosis, often delicate, should not be undertaken before six months.

  12. Perioperative post graduate education.

    PubMed

    Kapnoullas, J

    1997-04-01

    This article describes post-graduate perioperative education in Australia at the Australian Catholic University and St. Vincent's Public Hospital: The Graduate Certificate in Perioperative Practice. The Australian Catholic University operates from eight campuses along the east coast of Australia. There are approximately 9000 students along with 1000 staff. The University consists of major faculties that all have clear relevance to the workplace-namely Arts and Sciences, Education and Health Sciences. Qualifications are offered at Certificate of Doctoral level studies in the areas of business, education, ethics, human movement, management, information systems, music, nursing, religion, social work and theology.

  13. [Post-traumatic tics].

    PubMed

    Alegre, S; Chacón, J; Redondo, L; Navarro-Busto, C; Solana, B

    1996-10-01

    Secondary tics are those in which an aetiology justifying them can be found, as compared to idiopathic tics, which make up the majority, and the Gilles de la Tourette syndrome (SGT), which is, at the moment, of unknown origin. Of the possible aetiologies described as causing tics, craneo-encephalic trauma has been mentioned on very few occasions. We present a case of post-traumatic tics (verbal and neck) in a young man of 24, and review the published cases which can be considered to be of post-traumatic tics. We have found six cases of tics secondary to traumas, all craneo-encephalic, like ours (the one under study). The time interval between the blow and the appearance of the tic or tics varied between 2 weeks and 3 months. The absence of significant lesions seen in the complementary investigations make it impossible for us to discover the site of the lesion caused by the trauma. However, the presence in some cases of other tics before the trauma, and of family histories of tics, supports the idea of a genetic basis or predisposition to suffer this disorder.

  14. [Post-abortion contraception].

    PubMed

    Ohannessian, A; Jamin, C

    2016-12-01

    To establish guidelines of the French National College of Gynecologists and Obstetricians about post-abortion contraception. A systematic review of the literature about post-abortion contraception was performed on Medline and Cochrane Database between 1978 and March 2016. The guidelines of the French and foreign scientific societies were also consulted. After an abortion, if the woman wishes to use a contraception, it should be started as soon as possible because of the very early ovulation resumption. The contraception choice must be done in accordance with the woman's expectations and lifestyle. The contraindications of each contraception must be respected. The long-acting reversible contraception, intra-uterine device (IUD) and implant, could be preferred (grade C) as the efficacy is not dependent on compliance. Thus, they could better prevent repeat abortion (LE3). In case of surgical abortion, IUD should be proposed and inserted immediately after the procedure (grade A), as well as the implant (grade B). In case of medical abortion, the implant can be inserted from the day of mifépristone, the IUD after an ultrasound examination confirming the success of the abortion (no continuing pregnancy or retained sac) (grade C). Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  15. Post herpetic neuralgia.

    PubMed

    Philip, Annie; Thakur, Rajbala

    2011-06-01

    During the past decade, important advances have been made in understanding the epidemiology, pathogenesis, prevention and treatment of post herpetic neuralgia pain as well as treatment of other neuropathic pain conditions. PHN is accepted as a model for management and clinical trials of neuropathic pain of less clear etiologies. In palliative medicine, where the etiology of pain may be nociceptive, neuropathic, or mixed, it is frequently to the research on PHN that we turn in order to extrapolate the data to the patients at hand. To review and summarize what is known about epidemiology, pathogenesis, clinical features and prevention strategies for post herpetic neuralgia. Discuss the available including the most recent therapeutic options as regards to their mechanism of action, efficacy, safety and tolerability in an attempt to explain the rationale for their use. A multidisciplinary and integrative approach has the best chance of success in the management of patients with PHN pain, a problem that can be often frustrating to the patient and challenging to the clinician. Prevention strategies for PHN include administration of zoster vaccine, treatment with antiviral therapy within 72 hours of rash onset and aggressive pain control. First and second line pharmacotherapy include anticonvulsants, antidepressants, topical lidocaine, high dose capsaicin, and opioids either used individually or in combination. Interventional techniques play a limited role in the management of PHN although some data indicate that Intrathecal methylprednisolone and spinal cord stimulation may be effective.

  16. Post Falls Dam stabilization

    SciTech Connect

    Gorny, R.H.; Gibson, J.Z.

    1995-12-31

    The stability of Washington Water Power`s (WWP) Middle Channel and South Channel Dams at Post Falls, Idaho, were evaluated as required by the Federal Energy Regulatory Commission (FERC) and did not meet guideline stability criteria under Probable Maximum Flood (PMF) loading. This paper describes the stability analysis, stabilization design, design parameters, construction of the anchors, and compares the design and as-built conditions. Value engineering was used to select the optimal stabilization measure. Constructibility, cost, and schedule were major considerations. The value engineering study evaluated 41 potential stabilization alternatives, selected post tensioning, and used scheduling criteria to optimize the design. Access considerations required the installation of five 47 strand, 7400 kN (1645{sup k}) anchors in the Middle Dam, and installation of six anchors with different capacities anchors in the South Channel Dam. The Washington Water Power - Black & Veatch team used value engineering, contractor prequalification, resident engineering services provided by the engineer, and strong construction support provided by the Owner to successfully complete the project on a very tight schedule.

  17. Isolated post resonator mesogyroscope

    NASA Technical Reports Server (NTRS)

    Challoner, Dorian; Peay, Chris; Wellman, Joanne; Shcheglov, Kirill; Hayworth, Ken; Wiberg, Dean; Yee, Karl; Sipppola, Clayton

    2004-01-01

    A new symmetric vibratory gyroscope principle has been devised in which a central post proof mass is counter-rocked against an outer sensing plate such that the motion is isolated from the gyroscope case. Prototype gyroscopes have been designed and fabricated with micromachined silicon at mesoscale (20-cm resonator width), vs. microscale (e.g., 2-mm resonator width) to achieve higher sensitivity and machined precision. This novel mesogyro design arose out of an ongoing technical cooperation between JPL and Boeing begun in 1997 to advance the design of micro-inertial sensors for low-cost space applications. This paper describes the theory of operation of the mesogyro and relationships with other vibratory gyroscopes, the mechanical design, closed loop electronics design, bulk silicon fabrication and packaged gyroscope assembly and test methods. The initial packaged prototype test results are reported for what is believed to be the first silicon mesogyroscope.

  18. Post-16 update

    NASA Astrophysics Data System (ADS)

    1999-07-01

    (post16) Faces of Physics To study a physics course post-16 is take out an option on your future. But physics itself is very varied, and so is what you might do with it. It seems right that post-16 physics courses reflect important aspects of this variety. Physics varies with why people do it. As reliable knowledge, physics is often essential to making things happen. This is physics as feeding into technology, and quite often feeding off technology. The human urge here is the urge to create things that work. It drives individual inventors; it drives large teams in multinational companies. At the opposite end of this spectrum is physics driven by curiosity, by the urge to find out. The stock examples are the grand discoveries from the expansion of the universe to the discovery of the nucleus of atoms. But the physicist's curiosity is often on a more detailed, even finicky scale: how exactly do the molecules of this polymer respond to stress?; just how do ions implanted in this material modify its conductivity? It is clear to me that a decent post-16 physics course must respect and reflect both. This is by no means a matter of `basic laws and their applications'. It is a matter of recognizing two fundamental interests, in doing and in explaining, and of recognizing that they are at once closely interdependent and worlds apart. Ideas in physics are also not of one kind. One opposition is the idea of describing Nature in terms of deterministic physical laws, as against describing Nature as the predictable outcome of probabilistic behaviour `underneath'. The first has gripped the Western imagination since at least the time of Descartes. The second has increasingly come to the fore, especially in thermodynamics with the idea that we can only make processes work by fixing the circumstances so that uncaring atoms and molecules happen by chance to do what we want. Now in quantum theory both ideas - determinism and randomness - co-exist. Post-16 physics courses are not in

  19. Post-16 update

    NASA Astrophysics Data System (ADS)

    1999-01-01

    Post-16 Initiative logo This is the first of a regular series of contributions from the Institute's Post-16 Initiative. The Initiative is taking a hard and searching look at the physics taught in schools and colleges from age 16 to age 19. To start with, it is responding to Government initiatives, but hopes to encourage and stimulate good practice in physics teaching on a longer time scale than can be afforded in making responses to current developments. Here Jon Ogborn writes about what AS courses need to be, while Peter Campbell gives his thoughts about teaching matter. Advanced Subsidiary physics: what should it be? From September 2000 all A-levels will be new. Students can take the first Advanced Subsidiary (AS) year and stop there - or decide to go on. In the Institute of Physics post-16 Initiative, we have been thinking how to provide a satisfying one-year experience of physics at the new AS level, and what it should achieve. The students will decide. So the AS course must give a decent picture of what physics is, what it offers for their futures, what interests it can satisfy. That all says breadth, with enough depth to see what is in store later. And this sounds like the right recipe for someone who is taking a single AS year of physics to broaden their A-level experience. It must also be attractive. A way forward is shown by the Salters - Horners course, attracting interest through leading from applications. Why does that work? It gives physics a story to tell, into which ideas fit and make sense. Our own new A-level, Advancing Physics, must also have interesting stories to tell, which must in addition build up an honest picture of physics. An example: teach electric circuits through modern sensing devices. Sensor instrumentation is a key activity of physicists, full of new ideas, but also simple. It makes essential use of circuits such as the potential divider. Practical work gets better things to do than checking the equation for resistors in parallel

  20. Post removal techniques part 1.

    PubMed

    Dickie, Jamie; McCrosson, John

    2014-01-01

    Dismantling restorations from teeth which require endodontic re-treatment can be difficult. Many dentists are reluctant to remove posts through fear of weakening, perforating or fracturing the remaining root structure. A variety of techniques have been described and developed for post removal. This is the first in a series of two papers which provide an overview of these techniques.The rationale for endodontic re-treatment, pre-operative assessment and factors affecting post removal are discussed. Techniques are illustrated with clinical case reports. The second paper describes the use of specific post removal devices and the removal of fibre posts. Endodontic re-treatment has a more successful long-term outcome than surgical treatment for failed root canal treatment. This may involve the removal of existing post restorations or portions thereof.

  1. IVGEN Post Flight Analysis

    NASA Technical Reports Server (NTRS)

    Mcquillen, John; Brown, Dan; Hussey, Sam; Zoldak, John

    2014-01-01

    The Intravenous Fluid Generation (IVGEN) Experiment was a technology demonstration experiment that purified ISS potable water, mixed it with salt, and transferred it through a sterilizing filter. On-orbit performance was verified as appropriate and two 1.5 l bags of normal saline solution were returned to earth for post-flight testing by a FDA certified laboratory for compliance with United States Pharmacopiea (USP) standards. Salt concentration deviated from required values and an analysis identified probable causes. Current efforts are focused on Total Organic Content (TOC) testing, and shelf life.The Intravenous Fluid Generation (IVGEN) Experiment demonstrated the purification of ISS potable water, the mixing of the purified water with sodium chloride, and sterilization of the solution via membrane filtration. On-orbit performance was monitored where feasible and two 1.5-liter bags of normal saline solution were returned to earth for post-flight testing by a FDA-registered laboratory for compliance with United States Pharmacopeia (USP)standards [1]. Current efforts have been focused on challenge testing with identified [2] impurities (total organic-carbon), and shelf life testing. The challenge testing flowed known concentrations of contaminants through the IVGEN deionizing cartridge and membrane filters to test their effectiveness. One finding was that the filters and DI-resin themselves contribute to the contaminant load during initial startup, suggesting that the first 100 ml of fluid be discarded. Shelf life testing is ongoing and involves periodic testing of stored DI cartridges and membrane filters that are capped and sealed in hermetic packages. The testing is conducted at six month intervals measuring conductivity and endotoxins in the effluent. Currently, the packaging technique has been successfully demonstrated for one year of storage testing. The USP standards specifies that the TOC be conducted at point of generation as opposed to point of

  2. NEWS: Post-16 update

    NASA Astrophysics Data System (ADS)

    Campbell, Peter

    2000-07-01

    post16.gif As a teacher of physics it is very easy to become preoccupied with particulars of courses, or topics or even single concepts. Concerned with imminent student audiences and desired learning outcomes, the daily challenge is to summon satisfactory teaching approaches and resources for the job at hand. For the conscientious teacher, assessment outcomes may too often seem a judgment on our own efforts rather than those of our students. From time to time we may step back and think bigger, for example while planning a recruitment event, or while away from work on holiday. We may be successful locally. But why, at a time when books and television documentaries popularizing science have a large following, has physics education been facing declining numbers? Many recognize that physics has an essential contribution to make to the training of science or engineering specialists, but we know that it is also important for the skilled worker, the informed citizen and, in fact, for anyone trying to make sense of the world. So what are the best ways forward for post-16 physics? To make any impact on the bigger picture requires organization, thinking and meeting time among people in diverse roles: teachers and curriculum managers; university lecturers; employers and professional bodies; unitary awarding bodies; regulatory and funding agencies; and even Government. For the past few years, the Institute of Physics post-16 Initiative has created an unrivalled opportunity to address the wider issues. Its Shaping the Future booklets series was designed to stimulate informed discussion and debate, by providing background information and analysis. Taken together, the booklets should help all those concerned with physics education to understand where we are now, and why. Literally dozens of people have contributed to a review and analysis of physics education. Each booklet is a 48-page smorgasbord in A4 landscape format, containing many examples of good practice, basic but

  3. Nuclear Power - Post Fukushima

    NASA Astrophysics Data System (ADS)

    Reyes, Jose, Jr.

    2011-10-01

    The extreme events that led to the prolonged power outage at the Fukushima Daiicchi nuclear plant have highlighted the importance of assuring a means for stable long term cooling of the nuclear fuel and containment following a complete station blackout. Legislative bodies, regulatory agencies and industry are drawing lessons from those events and considering what changes, if any, are needed to nuclear power, post Fukushima. The enhanced safety of a new class of reactor designed by NuScale Power is drawing significant attention in light of the Fukushima events. During normal operation, each NuScale containment is fully immersed in a water-filled stainless steel lined concrete pool that resides underground. The pool, housed in a Seismic Category I building, is large enough to provided 30 days of core and containment cooling without adding water. After 30 days, the decay heat generations coupled with thermal radiation heat transfer is completely adequate to remove core decay heat for an unlimited period of time. These passive power systems can perform their function without requiring an external supply of water of power. An assessment of the NuScale passive systems is being performed through a comprehensive test program that includes the NuScale integral system test facility at Oregon State University

  4. [Post traumatic partial seizures].

    PubMed

    Carvajal, P; Almárcegui, C; Pablo, M J; Peralta, P; Bernal, M; Valdizán, J R

    Post traumatic epilepsy represents 4% of the prevalence of the disorder and is one of the sequelas which is most difficult to prevent. Risk factors have been described to predict the appearance of seizures. A seven year old boy with a severe head injury was admitted to the Intensive Care Unit. On neuroimaging studies there were multiple foci of contusion, mainly in the left hemisphere, and blood in the III and IV ventricles and frontal horn of the left lateral ventricle. The patient had severe sequelae of head injury with a right spastic hemiplegia and hemiparesia with hypertony of the left side, together with complete blindness of both eyes due to bilateral atrophy of the optic nerve. Serial EEG were done, in which a recording showed alternating periods of hypervoltage grapho elements superimposed on a trace of very low voltage, with continuous activity of low voltage and low frequency. There were no grapho elements with acute morphology. However, the patient had a first partial seizure a year and a half after his head injury. On the EEG an epileptogenic focus was identified in the left hemisphere. Within two years of his head injury he had seven seizures. He had not received prophylactic antiepileptic treatment after the head injury. We report a case of epilepsy secondary to a head injury, in which the first seizure occurred one and a half years after injury. In view of the risk factors, we discuss whether prophylactic anti epileptic treatment might have been beneficial.

  5. Recovery post ICU.

    PubMed

    Jones, Christina

    2014-10-01

    Many ICU patients struggle to recovery following critical illness and may be left with physical, cognitive and psychological problems, which have a negative impact on their quality of life. Gross muscle mass loss and weakness can take some months to recover after the patients' Intensive Care Unit (ICU) discharge, in addition critical illness polyneuropathies can further complicate physical recovery. Psychological problems such as anxiety, depression and post traumatic stress disorder (PTSD) are common and have an negative impact on the patients' ability to engage in rehabilitation after ICU discharge. Finally cognitive deficit affecting memory can be a significant problem. The first step in helping patients to recover from such a devastating illness is to recognise those who have the greatest need and target interventions. Research now suggests that there are interventions that can accelerate physical recovery and reduce the incidence of psychological problems such as anxiety, depression and PTSD. Cognitive rehabilitation, however, is still in its infancy. This review will look at the research into patients' recovery and what can be done to improve this where needed.

  6. [POST MORTEM PATERNITY].

    PubMed

    Marguénaud, Jean-Pierre

    2015-07-01

    Post mortem paternity, namely the procreation after the death of the man whom is part of the couple, is one of the questions which raised the most hesitations since the first bioethics laws of 1994. The National Assembly, encouraged by several opinions of the CCNE (National advisory committee of ethics) had let itself convince that the transfer had, at least, to be authorized in utero embryos preserved at the regard of which no one could not claim to have rights equal or higher than those of the woman concerned. However, the Senate always ended up obtaining the maintenance of an absolute prohibition of posthumous procreation (starting) from the spermatozoids or frozen embryos. This indifference with the cruelty of the application of the law to the women plunged into mourning--based on a paradoxical appreciation of the interest of the child not to be born orphan, and on a not very glorious taking into account of the interest of the Body of notaries not to change its practices--is particularly debatable. One can, nevertheless, try to understand it according to the obsession of the legalization of surrogate motherhood by application of the principle of nondiscrimination which could justify the requests of the men who, thanks to a surrogate mother, would wish to become fathers starting from gametes or embryos taken or created before the death of their wife or partner.

  7. Post-16 update

    NASA Astrophysics Data System (ADS)

    1999-11-01

    (Post-16 Initiative) Engineering Physics? Many A-level physics students do not go on to study physics. For them physics is a support subject, either just for fun or just for the grade. Where physics is a lead subject some students go on to study physics but many more go on to study engineering. So can we deliberately give some aspects of an A-level course an engineering flavour? Electromagnetism would seem a good place to start. There is a clear `physics' route into this topic, a microscopic forces and fields view of the situation. But do our students really need to look at it this way? All electromagnetic machines are linked magnetic and electric circuits. The design idea is to link these circuits as closely as possible. The electric circuits must be as good as possible, with a high conductivity. The magnetic circuits must be as good as possible, with high permeance. Conductivity depends on area/length. So does permeance. The goodness of an electromagnetic machine (how good it is at its job, which is linking electric and magnetic circuits) scales as the square of its linear dimensions. That means small electromagnetic machines are harder to make, and so the very smallest nanomotors are electrostatic. None of this is new, but many teachers are uncomfortable with it. We are thinking like physicists. Many of our students are not. They deserve us to take the trouble every now and again to encourage them to think a bit differently about a topic, to look at practical ways of discussing design and to give their course an engineering flavour. Philip Britton Coursework in A-level Physics The criteria for the new AS and A-levels have provided the teams developing the specifications with an opportunity to think creatively about how internal assessment is used within post-16 physics courses. Teachers may be concerned that allowing 30% of the marks to be internally assessed will create a burden for them. However, it is possible to look at this in a much more positive light

  8. NEWS: Post-16 update

    NASA Astrophysics Data System (ADS)

    1999-05-01

    (post16) Making physics connect Doesn't Melvyn Bragg do a wonderful job, engaging both scientists and artists in sensitive discussion on Radio 4 about their methods and their purposes? But every week teachers have the chance to show their students that physics is a way of seeing the world that is well-connected with other aspects of knowledge and culture. The stakes are high: students who fail to appreciate this generally choose not to study the subject beyond GCSE. Most students find our preoccupation with technical detail off-putting. Accepting that we have a syllabus to cover, it's still a question of balance. In our teaching we should aim for variety in order to find ways to connect with every student's interests. Also, we can show that we (the nearest embodiment of a physicist some students will experience) are multidimensional and so fully human. Most important, teachers need flexibility to both encourage and respond to student comment and questions. The first booklet in the discussion series Shaping the Future takes up these themes. Rich in ideas for both immediate use and the longer term, it aims to stimulate debate and improve teaching. Copies cost £5.50 including postage and are available from Ingrid Ebeyer, Post-16 Initiative, Institute of Physics, 76 Portland Place, London W1N 3DH. How far is it? This question is asked in many family cars and school minibuses at the start of a journey, and answered by most in terms of hours and minutes rather than miles. What a good idea for introducing a social and historical perspective to a lesson on distance, velocity and time. How far can you actually get in a day? What is the range of human activity? Walking for eight hours will get many people about 25 miles. A pack horse will progress at much the same rate, but fast riding or a coach and team of horses will get further. Motorway driving (when the cones are on holiday) would take you nearly 500 miles. The 05.15 am train from Penzance arrives in Inverness at 7

  9. Redefining Post-Secondary Education

    ERIC Educational Resources Information Center

    Turpin, David H.

    2005-01-01

    For at least a brief period of time, the release of Bob Rae's review of post-secondary education in Ontario served to focus public attention on the importance of post-secondary education not only in Ontario, but across Canada. This article elaborates further on Rae's review which stresses the crucial importance of the higher studies and recommends…

  10. Post-16 Science in England

    ERIC Educational Resources Information Center

    Swinscoe, David

    2012-01-01

    Science education at post-16 has had a high profile recently. Increasing the quality and quantity of STEM education is seen as a route to economic prosperity for both the individual and the nation. The post-16 sector is being encouraged to produce more STEM undergraduates and more STEM-skilled entrants to the industry with an emphasis on…

  11. Redefining Post-Secondary Education

    ERIC Educational Resources Information Center

    Turpin, David H.

    2005-01-01

    For at least a brief period of time, the release of Bob Rae's review of post-secondary education in Ontario served to focus public attention on the importance of post-secondary education not only in Ontario, but across Canada. This article elaborates further on Rae's review which stresses the crucial importance of the higher studies and recommends…

  12. On Post-Hoc Blocking.

    ERIC Educational Resources Information Center

    Bonett, Douglas G.

    1982-01-01

    Post-hoc blocking and analysis of covariance (ANCOVA) both employ a concomitant variable to increase statistical power relative to the completely randomized design. It is argued that the advantages attributed to the block design are not always valid and that there are circumstances when the ANCOVA would be preferred to post-hoc blocking.…

  13. Post-Baccalaureate Fellowship Program.

    ERIC Educational Resources Information Center

    Cadbury, Jr., William E.

    The Post-Baccalaureate Fellowship Program provides an opportunity for students who went to college with inferior preparation to supplement their education by studying for 1 year at an academically demanding liberal arts college before entering graduate or professional school. The post-baccalaureate fellows take regular courses in a program that is…

  14. Post-16 update

    NASA Astrophysics Data System (ADS)

    1999-03-01

    Post-16 Initiative logo Physics in Mathematical Mood Later this year, as part of the post-16 initiative of the Institute of Physics, a booklet with the above title will be published. In draft form, the booklet was discussed at the ASE conference in January. Some of the issues raised are briefly set out here. If you have any views to contribute, please write to Simon Carson at the Institute of Physics or e-mail simon.carson@physics.org. A mathematical view of the world is intrinsically a part of physics and therefore physics should be studied in an appropriately mathematical way. However, we all know that, to some students at least, mathematics proves to be a stumbling block rather than a powerful aid to understanding. So how can we help? Realizing that as physics teachers we need to deliver the mathematics necessary to an understanding of our subject is a start. Its corollary is that we need to find the space within the physics core. We may wish to use supplementary courses such as AS mathematics or QCA's new free-standing mathematics units, but requiring additional courses as a prerequisite to a study of A-level physics may deter students. Teaching the mathematics in context may aid understanding but we also must ensure that techniques are seen in a variety of contexts and that at some point the tool is abstracted from the background. As teachers we need to be aware of the very basic mathematical difficulties that students bring with them: the use of calculators, standard form, simple algebraic manipulation, for example. Mathematical arguments need to be developed fully and carefully. Encouraging cooperation and discussion between students may help the less able to understand and the more able to appreciate and develop their own understanding through making explicit their reasoning by explaining it to others. And what of new technology? Software tools allow students to develop their understanding about graphs, for example, enabling them to investigate the

  15. Coagulopathy post peritoneovenous shunt.

    PubMed Central

    LeVeen, H H; Ip, M; Ahmed, N; Hutto, R B; LeVeen, E G

    1987-01-01

    In 1942, 53% of medically treated patients with cirrhosis were dead 6 months after the onset of ascites. Only 30% survived 1 year. This dismal outlook has improved only slightly with advances in medicine. Yet, some internists reject the peritoneovenous shunt (PVS) for this fatal condition even if they are aware that a diminished blood volume causes the abnormal sodium retention responsible for ascites. Their objections are based on life-threatening complications of PVS, especially post shunt coagulopathy (PSC). Blood shed into the peritoneal cavity becomes incoagulable. Such blood is immediately coagulated by a protocoagulant (soluble collagen) and concurrently lysed by tissue plasminogen activator (TPA) secreted by the peritoneal serosa. Wide zones of lysis surround peritoneal tissue placed on fibrin plates. Large volumes of ascitic fluid infused into circulating blood simulates the fate of blood shed into the peritoneal cavity with lysis playing the major role. Addition of ascitic fluid to normal platelet-rich plasma in vitro initiates clot lysis on thromboelastogram (TEG). Epsilon-aminocaproic acid (EACA) counteracts this lysis. EACA and clotting factors normalize the TEG and arrest PSC. Disposal of ascitic fluid at surgery prevents or ameliorates PSC. Mild PSC was encountered only twice in 150+ consecutive patients (1.3%) with only one case being clinically significant (0.6%). Severe PSC occurred seven times in 98 early shunt patients whose ascitic fluid was not discarded. Severe PSC requires shunt interruption and control of bleeding with clotting factors and EACA. Peritoneal lavage with saline prevents the recurrence of PSC on reopening the shunt. In four patients, EACA and clotting factors were adequate to arrest coagulopathy. Three earlier patients died of PSC before its cause and treatment were understood. Proper management eliminates this life-threatening complication, and PSC cannot be considered a deterrent to PVS. Disseminated intravascular

  16. Reviewing Canadian Post-Secondary Education: Post-Secondary Education Policy in Post-Industrial Canada

    ERIC Educational Resources Information Center

    Kirby, Dale

    2007-01-01

    Since 2004, a number of Canadian provinces have initiated comprehensive reviews of their respective public post-secondary education systems. This paper examines the ways in which these provincial post-secondary education reviews are consistent with the pervasive influence of economic globalization on higher education and a more market-driven and…

  17. Post-Tropical Cyclone Matthew

    NASA Image and Video Library

    2017-09-28

    NASA Gets a Last Look at Post-Tropical Cyclone Matthew Before It was Swallowed Up Post-Tropical Cyclone Matthew was swallowed up or absorbed by a cold front on Oct. 10, but NASA's Terra satellite captured a last look at the storm before that happened. On Sunday, Oct. 9, 2016 at 11:45 a.m. EDT (1545 UTC) NASA's Terra satellite captured a last look at Post-Tropical Cyclone Matthew as it was being absorbed by a cold front along the U.S. Eastern Seaboard. Read more: go.nasa.gov/2dfhQg9 Credits: NASA Goddard MODIS Rapid Response Team

  18. 32 CFR 643.120 - Post offices.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 4 2010-07-01 2010-07-01 true Post offices. 643.120 Section 643.120 National... Additional Authority of Commanders § 643.120 Post offices. Title 10 U.S.C. 4779b, provides that the SA shall assign suitable space for post office purposes at military posts where post offices have been...

  19. Takotsubo cardiomyopathy post liver transplantation.

    PubMed

    Vachiat, Ahmed; McCutcheon, Keir; Mahomed, Adam; Schleicher, Gunter; Brand, Liezl; Botha, Jean; Sussman, Martin; Manga, Pravin

    2016-10-23

    A patient with end-stage liver disease developed stress-induced Takotsubo cardiomyopathy post liver transplantation, with haemodynamic instability requiring a left ventricular assist device. We discuss the diagnosis and management of this condition.

  20. [Post-mortem microbiology analysis].

    PubMed

    Fernández-Rodríguez, Amparo; Alberola, Juan; Cohen, Marta Cecilia

    2013-12-01

    Post-mortem microbiology is useful in both clinical and forensic autopsies, and allows a suspected infection to be confirmed. Indeed, it is routinely applied to donor studies in the clinical setting, as well as in sudden and unexpected death in the forensic field. Implementation of specific sampling techniques in autopsy can minimize the possibility of contamination, making interpretation of the results easier. Specific interpretation criteria for post-mortem cultures, the use of molecular diagnosis, and its fusion with molecular biology and histopathology have led to post-mortem microbiology playing a major role in autopsy. Multidisciplinary work involving microbiologists, pathologists, and forensic physicians will help to improve the achievements of post-mortem microbiology, prevent infectious diseases, and contribute to a healthier population.

  1. Post-MI pericarditis (image)

    MedlinePlus

    Post-MI pericarditis is inflammation of the pericardium (the sac-like covering of the heart). Any previous injury to the heart muscle can cause pericarditis. Incidences of pericarditis are associated with ...

  2. Post-tubal sterilization syndrome.

    PubMed

    Lethbridge, D J

    1992-01-01

    This article presents a review of the literature on post-tubal sterilization syndrome. Although studies have shortcomings they suggest the majority of women undergoing tubal sterilization do not experience changes in menstrual patterns after the procedure, but a minority do. Suggestions are made for further research, conducted from a nursing perspective. Implications for practice are suggested, given the tentative information on post-tubal sterilization syndrome.

  3. Post-16 update

    NASA Astrophysics Data System (ADS)

    1999-09-01

    Institute of Physics post-16 initiative, shaping the future Physics education based in IT - sorry ICT! Which, of course, makes for a nifty headline, but as is so often the case with neat slogans, little else. Two formative questions: What, in another decade, will the government of the day call `What you lot should be doing with computers'? and What, of the many things that currently exercise our intellects, will there be anything special to say about in a decade, concerning the use of computers in the teaching of physics? Advancing Physics represents some attempts to come to grips with the second of the two questions above. The first is left to a higher wisdom. In thinking about learning, what can we do with the huge processing power, increasingly available in smaller and less obtrusive packages? What will we do that helps people learn physics, both tomorrow and in 2009? Here are a few suggestions based on development work so far. Wide, reliable and shared access to well ordered learning resources. We have created a CD-ROM, with versions for both student and teacher, that provides a wide range of resources. These do not teach, but do provide. A commitment to allowing a course to evolve and adapt. Electronic publication puts the costs into origination, and not into publication and distribution. A website allows for the community of users to contribute. E-mail networks support individuals and propagate good practice. You can create and explore your own microworlds. The interactive nature of models, and the crafted relationships between the models and the natural world give an insight into the creative imaginary worlds of the physicist. The unreasonable, but pleasurable, success of mathematics in describing the natural world can come to the fore. Measurements that were not possible before are now possible. What was previously indirect, and inaccessible, now becomes a direct measurement, making relationships transparent in new and fruitful ways. The dichotomy between

  4. 39 CFR 241.1 - Post offices.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... July 1 each year, post offices are classified by the Postmaster General based on the allowable postal...) Third Class. Post offices having 36 but less 190 revenue units. (4) Fourth Class. Post offices having...

  5. Post-mortem clinical pharmacology

    PubMed Central

    Ferner, R E

    2008-01-01

    Clinical pharmacology assumes that deductions can be made about the concentrations of drugs from a knowledge of the pharmacokinetic parameters in an individual; and that the effects are related to the measured concentration. Post-mortem changes render the assumptions of clinical pharmacology largely invalid, and make the interpretation of concentrations measured in post-mortem samples difficult or impossible. Qualitative tests can show the presence of substances that were not present in life, and can fail to detect substances that led to death. Quantitative analysis is subject to error in itself, and because post-mortem concentrations vary in largely unpredictable ways with the site and time of sampling, as a result of the phenomenon of post-mortem redistribution. Consequently, compilations of ‘lethal concentrations’ are misleading. There is a lack of adequate studies of the true relationship between fatal events and the concentrations that can be measured subsequently, but without such studies, clinical pharmacologists and others should be wary of interpreting post-mortem measurements. PMID:18637886

  6. Post-operative urinary retention.

    PubMed

    Steggall, Martin; Treacy, Colm; Jones, Mark

    Urinary retention is a common complication of surgery and anaesthesia. The risk of post-operative urinary retention is increased following certain surgical procedures and anaesthetic modalities, and with patients' advancing age. Patients at increased risk of post-operative urinary retention should be identified before surgery or the condition should be identified and treated in a timely manner following surgery. If conservative measures do not help the patient to pass urine, the bladder will need to be drained using either an intermittent catheter or an indwelling urethral catheter, which can result in catheter-associated urinary tract infections. This article provides an overview of normal bladder function, risk factors for developing post-operative urinary retention, and treatment options. Guidance drawn from the literature aims to assist nurses in identifying at-risk patients and inform patient care.

  7. What about ex post facto

    SciTech Connect

    McKee, H.C.

    1992-07-01

    This note presents a legal question in an attempt to find an answer. The author hopes that some legal scholar can explain the principle of ex post facto in the US Constitution as it applies to some of the environmental laws. One of the major advantages of the Association is that it provides a forum for communication among members with different backgrounds and experience. An ex post facto law is one that is applied retroactively. Under such a law, a person could be punished for some act that violated a law passed after the act was committed, even though the act was legal when committed. The US Constitution prohibits such laws, as will be discussed later. States are also prohibited from enacting ex post facto laws.

  8. 75 FR 5036 - Proposed Posting, Posting and Deposting of Stockyards

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-01

    .... The document shows the facility number for Shamrock Livestock Commission, Shamrock, Texas is the same... number for Shamrock Livestock Commission, Shamrock, Texas as follows: Stockyard name and Facility number location Date of posting TX-355 Shamrock Livestock November 3, 2003 Commission, Shamrock, Texas. J....

  9. Hydrodynamics of post CHF region

    SciTech Connect

    Ishii, M.; De Jarlais, G.

    1984-04-01

    Among various two-phase flow regimes, the inverted flow in the post-dryout region is relatively less well understood due to its special heat transfer conditions. The review of existing data indicates further research is needed in the areas of basic hydrodynamics related to liquid core disintegration mechanisms, slug and droplet formations, entrainment, and droplet size distributions. In view of this, the inverted flow is studied in detail both analytically and experimentally. Criteria for initial flow regimes in the post-dryout region are given. Preliminary models for subsequent flow regime transition criteria are derived together with correlations for a mean droplet diameter based on the adiabatic simulation data.

  10. Post-processing of data

    NASA Astrophysics Data System (ADS)

    Pfeifer, Hans-Joachim

    The post processing of Laser Doppler Anemometer (LDA) data has comparable influence on the final results, e.g. reliability, accuracy etc., as well as all the other aspects of LDA instruments. This is due to the fact that signal statistics in LDA are completely different from signal statistics well known in other measuring procedures where the continuous time history of the physical quantity under consideration is available. Four topics are presented: statistical quantities such as mean velocity, turbulence intensity, and histograms; filter control for both counter processors and FFT processors; auto and cross correlation and their Fourier transform; post processing of photon correlograms.

  11. 32 CFR 643.120 - Post offices.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 4 2011-07-01 2011-07-01 false Post offices. 643.120 Section 643.120 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) REAL PROPERTY REAL ESTATE... assign suitable space for post office purposes at military posts where post offices have been established...

  12. 39 CFR 241.1 - Post offices.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... revenue units for the second preceding fiscal year as follows: (1) First Class. Post offices having 950 or more revenue units. (2) Second Class. Post offices having 190 but less than 950 revenue units. (3) Third Class. Post offices having 36 but less 190 revenue units. (4) Fourth Class. Post offices having...

  13. [Gastrobronchial fistula post sleeve gastrectomy].

    PubMed

    Barboza Besada, Eduardo; Barboza Beraún, Aurelio; Castillo-Ángeles, Manuel; Málaga, Germán; Tan Kuong, Jesús; Valdivia Retamozo, José; Portugal Vivanco, José; Contardo Zambrano, Manuel; Montes, Martín; Kaemena, María Luisa

    2013-01-01

    A 35 years old female with morbid obesity IMC 45 was referred because of a gastrobronchial fistula developed post sleeve gastrectomy initially treated with endoscopic techniques without improvement, reason why a total resection of the gastric remanent with a Roux en Y reconstruction was done as an option with successful result.

  14. East Texas post oak region

    Treesearch

    Herbert S. Sternitzke

    1967-01-01

    This report summarizes information on forest area and timber volume in a 26-county area designated as the post oak region of east Texas. These counties are on the western fringe of lands capable of supporting productive southern forests. The information here is from the first detailed forest inventory of the region, made during 1965 in cooperation with the Texas...

  15. Issues in post-literacy

    NASA Astrophysics Data System (ADS)

    Dave, Ravindra H.; Ouane, Adama; Sutton, Peter

    1989-12-01

    While school enrolments have been rising, the absolute number of illiterates in the world has grown too. Eradication of adult illiteracy and universalization of primary education are hindered by high drop-out in schools and relapse into illiteracy among adults. Post-literacy programmes seek to stop this reversal by ensuring retention, application and continuation of literacy skills. The Unesco Institute for Education (UIE) has been researching and promoting post-literacy strategies since 1980, but finds that most projects do not include provision for post-literacy from the outset, despite the evident need. Those programmes which have been mounted use a variety of strategies, which UIE has analysed in 12 categories. The exact delimitation of the post-literacy stage in the lifelong education continuum differs from project to project, and the emphasis on individual or societal advance depends on local perceptions of the goals of development. Examples are given of successful programmes, and the challenges of increasing participation and motivation, securing adequate funding, and making efficient and flexible use of institutional facilities are discussed.

  16. Reconsidering Post-Traumatic Stress

    ERIC Educational Resources Information Center

    Berman, Dene S.; Davis-Berman, Jennifer

    2005-01-01

    This article serves to challenge the prevailing wisdom that suggests that most trauma is followed by post-traumatic stress disorder (PTSD), and is best treated with critical incident stress debriefing (CISD). Instead, recent evidence suggests that many individuals exposed to stress do not experience stress responses. Even those who do, however,…

  17. Chaos Theory and Post Modernism

    ERIC Educational Resources Information Center

    Snell, Joel

    2009-01-01

    Chaos theory is often associated with post modernism. However, one may make the point that both terms are misunderstood. The point of this article is to define both terms and indicate their relationship. Description: Chaos theory is associated with a definition of a theory dealing with variables (butterflies) that are not directly related to a…

  18. Fence Posts for Southern Farms

    Treesearch

    H. H. Muntz

    1950-01-01

    Of the more common woods native to the South, the heartwood of osageorange (bois d'arc), black locust, red mulberry, cedar, and baldcypress is most desirable and makes good fence posts without any preservative treatment. The heartwood of other southern tree species, and all sapwood is much less durable and will give only a few years of service when used for fence...

  19. Post Occupancy Evaluation in Scotland

    ERIC Educational Resources Information Center

    Watson, Chris; Thomson, Keith

    2004-01-01

    The Scottish Executive, the devolved government for Scotland, is engaging with stakeholders to achieve excellence in the school estate through Post Occupancy Evaluation (POE). Design of the school environment has a direct impact on teaching and learning, activities which can be supported or frustrated by many building elements. Through a…

  20. STS-80 Post Flight Presentation

    NASA Technical Reports Server (NTRS)

    1996-01-01

    The flight crew of STS-80, Cmdr. Kenneth D. Cockrell, Pilot Kent V. Rominger, Mission Specialists, Tamara E. Jernigan, Thomas D. Jones, and F. Story Musgrave give a post flight presentation of their mission. This presentation is divided into two parts first a slide presentation of still shots, and the second is a video presentation.

  1. Reconsidering Post-Traumatic Stress

    ERIC Educational Resources Information Center

    Berman, Dene S.; Davis-Berman, Jennifer

    2005-01-01

    This article serves to challenge the prevailing wisdom that suggests that most trauma is followed by post-traumatic stress disorder (PTSD), and is best treated with critical incident stress debriefing (CISD). Instead, recent evidence suggests that many individuals exposed to stress do not experience stress responses. Even those who do, however,…

  2. Chaos Theory and Post Modernism

    ERIC Educational Resources Information Center

    Snell, Joel

    2009-01-01

    Chaos theory is often associated with post modernism. However, one may make the point that both terms are misunderstood. The point of this article is to define both terms and indicate their relationship. Description: Chaos theory is associated with a definition of a theory dealing with variables (butterflies) that are not directly related to a…

  3. A Post-Occidental Globe?

    ERIC Educational Resources Information Center

    Esen, Huseyin; Sanchez, Alejandra; Araya, Daniel; Gallaga, Drea; Kanogoiw, Fungai; Geary, James; Choe, Keecheng; Ullah, Khan Grogan; Carbajo, Lisa; Fitzpatrick, Margaret; Pour-Previti, Mercedes; Peters, Michael A.; Mukherjee, Mousumi; Britez, Rodrigo

    2012-01-01

    This is an experiment in conversation on the topic of "a post-occidental globe". It emerges from a moderated discussion group where members of a class--master's and PhD students--reflected upon a set of resources provided as part of a course in Global Studies in Education at the University of Illinois. The conversation threads were moderated and…

  4. Estonianization Efforts Post-Independence

    ERIC Educational Resources Information Center

    Rannut, Mart

    2008-01-01

    The purpose of this paper is to provide an overview of the sociolinguistic situation in Estonia. The paper opens with a historic overview, followed by an overview of the current demographic situation and of post-Soviet language and education policies and practices. It is argued that Estonia represents a success story in terms of language policy,…

  5. A Post-Occidental Globe?

    ERIC Educational Resources Information Center

    Esen, Huseyin; Sanchez, Alejandra; Araya, Daniel; Gallaga, Drea; Kanogoiw, Fungai; Geary, James; Choe, Keecheng; Ullah, Khan Grogan; Carbajo, Lisa; Fitzpatrick, Margaret; Pour-Previti, Mercedes; Peters, Michael A.; Mukherjee, Mousumi; Britez, Rodrigo

    2012-01-01

    This is an experiment in conversation on the topic of "a post-occidental globe". It emerges from a moderated discussion group where members of a class--master's and PhD students--reflected upon a set of resources provided as part of a course in Global Studies in Education at the University of Illinois. The conversation threads were moderated and…

  6. Post-Newtonian Jeans Analysis

    NASA Astrophysics Data System (ADS)

    Nazari, Elham; Kazemi, Ali; Roshan, Mahmood; Abbassi, Shahram

    2017-04-01

    The Jeans analysis is studied in the first post-Newtonian limit. In other words, the relativistic effects on local gravitational instability are considered for systems whose characteristic velocities and corresponding gravitational fields are higher than those permitted in the Newtonian limit. The dispersion relation for the propagation of small perturbations is found in the post-Newtonian approximation using two different techniques. A new Jeans mass is derived and compared to the standard Jeans mass. In this limit, the relativistic effects make the new Jeans mass smaller than the Newtonian Jeans mass. Furthermore, the fractional difference between these two masses increases when the temperature/pressure of the system increases. Interestingly, in this limit, pressure can enhance gravitational instability instead of preventing it. Finally, the results are applied to high-temperature astrophysical systems, and the possibility of local fragmentation in some relativistic systems is investigated.

  7. Post-Lyme disease syndrome

    PubMed Central

    Dąbek, Józefa; Cieślik, Paweł

    2015-01-01

    About 10% of patients with Lyme disease continue to experience musculoskeletal pain and cognitive dysfunction after recommended antibiotic treatment. This condition is called post-Lyme disease syndrome (PLDS) or post-treatment Lyme disease syndrome. These two terms are used interchangeably. The pathogenesis of PLDS has been controversial. The hypothesis that patients with PLDS may harbor hidden reservoirs of Borrelia burgdorferi after their initial antibiotic treatment is difficult to accept. The prospective, double-blind studies contradict this point of view. Also, recently published research applying xenodiagnosis to PLDS supports the opinion that PLDS most likely has an autoimmune background. Lengthy courses of antibiotics are not justified in patients with PLDS because of the lack of benefit, and they are fraught with hazards. Most patients with PLDS recover from persistent symptoms with time. However, it can take months before they feel completely well. PMID:27407225

  8. The ISAC post-accelerator

    NASA Astrophysics Data System (ADS)

    Laxdal, R. E.; Marchetto, M.

    2014-01-01

    The acceleration chain of the ISAC facility boosts the energy of both radioactive and stable light and heavy ions for beam delivery to both a medium energy area in ISAC-I and a high energy area in ISAC-II. The post-accelerator comprises a 35.4 MHz RFQ to accelerate beams of A/q ≤ 30 from 2 keV/u to 150 keV/u and a post stripper, 106.1 MHz variable energy drift tube linac (DTL) to accelerate ions of A/q ≤ 6 to a final energy between 0.15 MeV/u to 1.5 MeV/u. A 40 MV superconducting linac further accelerates beam from 1.5 MeV/u to energies above the Coulomb barrier. All linacs operate cw to preserve beam intensity.

  9. Post-Lyme disease syndrome.

    PubMed

    Ścieszka, Joanna; Dąbek, Józefa; Cieślik, Paweł

    2015-01-01

    About 10% of patients with Lyme disease continue to experience musculoskeletal pain and cognitive dysfunction after recommended antibiotic treatment. This condition is called post-Lyme disease syndrome (PLDS) or post-treatment Lyme disease syndrome. These two terms are used interchangeably. The pathogenesis of PLDS has been controversial. The hypothesis that patients with PLDS may harbor hidden reservoirs of Borrelia burgdorferi after their initial antibiotic treatment is difficult to accept. The prospective, double-blind studies contradict this point of view. Also, recently published research applying xenodiagnosis to PLDS supports the opinion that PLDS most likely has an autoimmune background. Lengthy courses of antibiotics are not justified in patients with PLDS because of the lack of benefit, and they are fraught with hazards. Most patients with PLDS recover from persistent symptoms with time. However, it can take months before they feel completely well.

  10. OCO-2 Post Launch Briefing

    NASA Image and Video Library

    2014-07-02

    NASA Kennedy Space Center Public Affairs Officer George Diller, moderates a post-launch press briefing, following the successful launch of the Orbiting Carbon Observatory-2 (OCO-2), NASA’s first spacecraft dedicated to studying carbon dioxide, Wednesday, July 2, 2014, at the Vandenberg Air Force Base, Calif. OCO-2 will measure the global distribution of carbon dioxide, the leading human-produced greenhouse gas driving changes in Earth’s climate. Photo Credit: (NASA/Bill Ingalls)

  11. Post-penetrating keratoplasty glaucoma

    PubMed Central

    Aggarwal, Anand; Minudath, KB; Vanathi, M; Choudhary, Sunil; Gupta, Viney; Sihota, Ramanjit; Panda, Anita

    2008-01-01

    Post-penetrating keratoplasty (post-PK) glaucoma is an important cause of irreversible visual loss and graft failure. The etiology for this disorder is multifactorial, and with the use of new diagnostic equipment, it is now possible to elucidate the exact pathophysiology of this condition. A clear understanding of the various mechanisms that operate during different time frames following PK is essential to chalk out the appropriate management algorithms. The various issues with regard to its management, including the putative risk factors, intraocular pressure (IOP) assessment post-PK, difficulties in monitoring with regard to the visual fields and optic nerve evaluation, are discussed. A step-wise approach to management starting from the medical management to surgery with and without metabolites and the various cycloablative procedures in cases of failed filtering procedures and excessive perilimbal scarring is presented. Finally, the important issue of minimizing the incidence of glaucoma following PK, especially through the use of oversized grafts and iris tightening procedures in the form of concomitant iridoplasty are emphasized. It is important to weigh the risk-benefit ratio of any modality used in the treatment of this condition as procedures aimed at IOP reduction, namely trabeculectomy with antimetabolites, and glaucoma drainage devices can trigger graft rejection, whereas cyclodestructive procedures can not only cause graft failure but also precipitate phthisis bulbi. Watchful expectancy and optimal time of intervention can salvage both graft and vision in this challenging condition. PMID:18579984

  12. The SPOOKI post production system

    NASA Astrophysics Data System (ADS)

    Beauchemin, M.; Klasa, M.; Fortier, S.; Fortin, F.; Hardy, G.; Pelletier, L.; Edouard, S.; Archambault, B.; Yazidi, H.

    2010-09-01

    The Canadian Meteorological Centre (CMC) delivers a large number of numerical weather prediction products to the various weather offices and clients throughout Canada and abroad. The current post production system was built according to the needs and ideology of the 1980's and it is becoming obsolete with time. Its cumbersome architecture is difficult to maintain and requires a lot of human and computing resources. The "Weather Elements" section of CMC is aware of the problems associated with its maintenance in the long term and has therefore decided to review in depth the whole approach to the operational post production. The analysis of present and future needs have led to the development of an innovative concept in the operational production field inspired by the "Plug and Play" process. SPOOKI (Système de Production Orienté-Objet contennant une Kyrielle d'Informations - Object oriented production system containing a myriad of information) was created in its present form in 2007. It is based on a modular approach where each plug-in component is specialized, reusable and autonomous. These object oriented programming characteristics greatly simplify the maintenance of the system. Particular attention was also given to create a user-friendly system for novice users. An experimental version of SPOOKI is currently running in development mode and an operational one is planned to be implemented in the coming year. The poster presentation will describe SPOOKI, the future CMC operational post production system. Several examples of usage will be shown.

  13. Vehicle Support Posts Installation at Mobile Launcher

    NASA Image and Video Library

    2017-05-11

    Construction workers at the Mobile Launcher at NASA's Kennedy Space Center in Florida, prepare to install vehicle support posts. A total of eight support posts are being installed to support the load of the Space Launch System's (SLS) solid rocket boosters, with four posts for each of the boosters. The support posts are about five feet tall and each weigh about 10,000 pounds. The posts will structurally support the SLS rocket through T-0 and liftoff. The Ground Systems Development and Operations Program is overseeing installation of the support posts to prepare for the launch of the Orion spacecraft atop the SLS rocket.

  14. Reactivation of Pulmonary Tuberculosis following Treatment of Myelofibrosis with Ruxolitinib.

    PubMed

    Abidi, Maheen Z; Haque, Javeria; Varma, Parvathi; Olteanu, Horatiu; Guru Murthy, Guru Subramanian; Dhakal, Binod; Hari, Parameswaran

    2016-01-01

    Ruxolitinib is widely in use for treatment of myeloproliferative disorders. It causes inhibition of the Janus kinase (JAK) signal transducer and activation of transcription (STAT) pathway, which plays a key role in the underlying pathophysiology of myeloproliferative diseases. We describe a case of reactivation pulmonary tuberculosis in a retired physician while on treatment with ruxolitinib. We also review the literature on opportunistic infections following use of ruxolitinib. Our case highlights the importance of screening for latent tuberculosis in patients from highly endemic areas prior to start of therapy with ruxolitinib.

  15. Reactivation of Pulmonary Tuberculosis following Treatment of Myelofibrosis with Ruxolitinib

    PubMed Central

    Haque, Javeria; Varma, Parvathi; Guru Murthy, Guru Subramanian; Dhakal, Binod; Hari, Parameswaran

    2016-01-01

    Ruxolitinib is widely in use for treatment of myeloproliferative disorders. It causes inhibition of the Janus kinase (JAK) signal transducer and activation of transcription (STAT) pathway, which plays a key role in the underlying pathophysiology of myeloproliferative diseases. We describe a case of reactivation pulmonary tuberculosis in a retired physician while on treatment with ruxolitinib. We also review the literature on opportunistic infections following use of ruxolitinib. Our case highlights the importance of screening for latent tuberculosis in patients from highly endemic areas prior to start of therapy with ruxolitinib. PMID:27843657

  16. The future of JAK inhibition in myelofibrosis and beyond.

    PubMed

    Mascarenhas, John O; Cross, Nicholas C P; Mesa, Ruben A

    2014-09-01

    The identification of aberrant JAK-STAT signaling in patients with myeloproliferative neoplasms has served as the basis for the development of a new class of targeted agents. Ruxolitinib, the first-in-class oral small molecule JAK1/2 inhibitor, has demonstrated clinical efficacy and shown a potential overall survival benefit in two randomized phase III clinical trials. However, this agent has not been associated with improvements in cytopenias, molecular remissions, or resolution of bone marrow fibrosis. Therefore, further translational research is needed to improve the understanding of the pathogenetic mechanisms driving this myeloid malignancy to ultimately address remaining unmet clinical needs. A number of novel JAK inhibitors are being evaluated in ongoing clinical trials and the full clinical potential of these newer agents remains incompletely understood. The use of JAK inhibition in combination therapy approaches, as well as mono- and combination therapies in the treatment of advanced forms of polycythemia vera are also under active investigation. This review will update the reader on the current understanding of oncogenic JAK-STAT pathway activity in the pathogenesis of myeloproliferative neoplasms and the current success and limitations of anti-JAK therapy. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Abnormal erythroid cell proliferation and myelofibrosis in a cat.

    PubMed

    Iwanaga, Tomoko; Miura, Naoki; Miyoshi, Noriaki; Endo, Yasuyuki; Momoi, Yasuyuki

    2012-07-01

    A cat was presented with severe progressive anemia despite marked erythroblastosis. The cat was negative for feline leukemia virus antigen and feline immunodeficiency virus antibody. Bone marrow cytology revealed an excess of erythroid cells with a predominance of prorubricytes and basophilic rubricytes. No response to immunosuppressive therapy was obtained, and a tentative diagnosis of myelodysplastic syndrome was made. The cat showed a partial response to low-dose cytarabine (20 mg/m(2) subcutaneously q24) but died 51 days after the 1st admission. Histopathological examination revealed fibrosis in the bone marrow and marked infiltration of erythroid cells into other organs.

  18. 76 FR 45882 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-01

    ... informs the public that an appeal of the closing of the Goodwin, Arkansas post office has been filed. It... Service's determination to close the post office in Goodwin, Arkansas. The petition was filed by Randy...

  19. 76 FR 44385 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-25

    ... informs the public that an appeal of the closing of the Peach Orchard, Arkansas post office has been filed... review of the closing of the Peach Orchard, Arkansas post office. The petition, which was filed by...

  20. 42 CFR 124.604 - Posted notice.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... facility shall post notices, which the Secretary supplies in English and Spanish, in appropriate areas of... other than English or Spanish, the facility shall translate the notice into that language and post the...

  1. 76 FR 19149 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-06

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Wesleyville Post Office in...

  2. 75 FR 77921 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-14

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice; correction. SUMMARY: The... an appeal of the closing of the Graves Mill, Virginia post office. The procedural schedule...

  3. 76 FR 11824 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-03

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Mitchellville Post Office in...

  4. 77 FR 3806 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-25

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document... Station post office in Yerington, Nevada. The first petition for review received December 28, 2011,...

  5. 76 FR 58057 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-19

    ... informs the public that an appeal of the closing of the Burnt Prairie, Illinois post office has been filed... for review of the Postal Service's determination to close the Burnt Prairie post office in...

  6. 42 CFR 124.604 - Posted notice.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... facility shall post notices, which the Secretary supplies in English and Spanish, in appropriate areas of... other than English or Spanish, the facility shall translate the notice into that language and post...

  7. 42 CFR 124.604 - Posted notice.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... facility shall post notices, which the Secretary supplies in English and Spanish, in appropriate areas of... other than English or Spanish, the facility shall translate the notice into that language and post...

  8. 76 FR 53984 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-30

    ... informs the public that an appeal of the closing of the Prairie Hill, Texas post office has been filed. It... for review of the Postal Service's determination to close the Prairie Hill post office in Prairie...

  9. 76 FR 55425 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-07

    ... informs the public that an appeal of the closing of the Watson, Alabama post office has been filed. It... for review of the Postal Service's determination to close the Watson post office in Watson,...

  10. Protracted refractory pain post-TEVAR: post-implantation syndrome?

    PubMed Central

    Waweru, Peter; Gill, Hardeep; Abeid, Chris

    2016-01-01

    Aortic dissection is a life-threatening condition and has one of the highest mortality rates of cardiovascular diseases. It remains a devastating disease; with multiple unanswered questions concerning treatment modalities. The role of thoracic endovascular aortic repair (TEVAR) in these patients; especially those with uncomplicated acute aortic Type B dissections (AAD-B) is especially controversial although it has been shown to have better long-term outcomes compared to medical therapy alone. For those who have TEVAR, up to 60% may develop an acute, transient systemic inflammatory response syndrome that remains vaguely defined. The role of local inflammation in this post-implantation syndrome (PIS) has not been highlighted. We present a case of a 57-year-old male patient with an uncomplicated AAD-B who developed an ‘atypical’ PIS post-TEVAR with severe refractory abdominal pains; leukocytosis and raised C-reactive protein. The role of local inflammation in PIS is highlighted. PMID:28344762

  11. Hyperbaric post weld heat treatment

    SciTech Connect

    Saunderson, S.; Waller, D.

    1983-05-01

    This paper describes a sub-sea hyperbaric Post Weld Heat Treatment (PWHT) system developed jointly by SHELL UK EXPLORATION and PRODUCTION and COMEX DIVING. It discusses: assessment of power requirements and equipment, initial tests conducted in the COMEX hydrosphere and in shallow water in Marseille, and full scale North Sea trials at - 150 m, comparing the performance and results of two separate power sources and control units. Particular attention is drawn to the importance of the elements, insulation and controls used to achieve uniform distribution of heat at the required temperature in a HELIOX environment.

  12. Cascading Post-coronal Loops

    NASA Image and Video Library

    2017-04-24

    An active region that had just rotated into view blasted out a coronal mass ejection, which was immediately followed by a bright series of post-coronal loops seeking to reorganize that region's magnetic field (April 19, 2017). We have observed this phenomenon numerous times, but this one was one of the longest and clearest sequences we have seen in years. The bright loops are actually charged particles spinning along the magnetic field lines. The action was captured in a combination of two wavelengths of extreme ultraviolet light over a period of about 20 hours. Movies are available at https://photojournal.jpl.nasa.gov/catalog/PIA21598

  13. STS-112 Post Flight Presentation

    NASA Technical Reports Server (NTRS)

    2002-01-01

    The STS-112 post flight presentation begins with a shot of the moonrise over the Earth's Limb. A photograph of the STS-112 crew is shown. The crew consists of Mission Specialists Sandy Magnus, David Wolf, Piers Sellers and Fodor Yurchikhin, Pilot Pam Melroy and Commander Jeff Ashby. The crew departs from the Operations and Control Building to the launch pad at Kennedy Space Center in Florida. Sandy Magnus is shown preparing to board the Space Shuttle Atlantis. The actual STS-112 launch with flight deck activity during rendezvous with the International Space Station is also presented.

  14. Midwest Guardrail System with round timber posts

    Treesearch

    Ronald K. Faller; John D. Reid; David E. Kretschmann; Jason A. Hascall; Dean L. Sicking

    2009-01-01

    A modified Midwest Guardrail System (MGS) was developed by using small-diameter round wood posts. The barrier system was configured with three timber species: Douglas fir (DF), ponderosa pine (PP), and southern yellow pine (SYP). Barrier VII computer simulation, combined with cantilever post testing in a rigid sleeve and soil, was used to determine the required post...

  15. Post-Colonial Theory and Action Research

    ERIC Educational Resources Information Center

    Parsons, Jim B.; Harding, Kelly J.

    2011-01-01

    This essay explores connections between post-colonial theory and action research. Post-colonial theory is committed to addressing the plague of colonialism. Action research, at its core, promises to problematize uncontested "colonial" hegemonies of any form. Both post-colonial theory and action research engage dialogic, critically reflective and…

  16. 10 CFR 160.6 - Posting.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 2 2014-01-01 2014-01-01 false Posting. 160.6 Section 160.6 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) TRESPASSING ON COMMISSION PROPERTY § 160.6 Posting. Notices stating the pertinent prohibitions of §§ 160.3 and 160.4 and penalties of § 160.5 will be conspicuously posted at all entrances...

  17. 10 CFR 20.1902 - Posting requirements.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... HIGH RADIATION AREA.” (d) Posting of airborne radioactivity areas. The licensee shall post each airborne radioactivity area with a conspicuous sign or signs bearing the radiation symbol and the words “CAUTION, AIRBORNE RADIOACTIVITY AREA” or “DANGER, AIRBORNE RADIOACTIVITY AREA.” (e) Posting of areas...

  18. 10 CFR 20.1902 - Posting requirements.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... HIGH RADIATION AREA.” (d) Posting of airborne radioactivity areas. The licensee shall post each airborne radioactivity area with a conspicuous sign or signs bearing the radiation symbol and the words “CAUTION, AIRBORNE RADIOACTIVITY AREA” or “DANGER, AIRBORNE RADIOACTIVITY AREA.” (e) Posting of areas...

  19. 10 CFR 20.1902 - Posting requirements.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... HIGH RADIATION AREA.” (d) Posting of airborne radioactivity areas. The licensee shall post each airborne radioactivity area with a conspicuous sign or signs bearing the radiation symbol and the words “CAUTION, AIRBORNE RADIOACTIVITY AREA” or “DANGER, AIRBORNE RADIOACTIVITY AREA.” (e) Posting of areas...

  20. 10 CFR 20.1902 - Posting requirements.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... HIGH RADIATION AREA.” (d) Posting of airborne radioactivity areas. The licensee shall post each airborne radioactivity area with a conspicuous sign or signs bearing the radiation symbol and the words “CAUTION, AIRBORNE RADIOACTIVITY AREA” or “DANGER, AIRBORNE RADIOACTIVITY AREA.” (e) Posting of areas...

  1. 10 CFR 20.1902 - Posting requirements.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... HIGH RADIATION AREA.” (d) Posting of airborne radioactivity areas. The licensee shall post each airborne radioactivity area with a conspicuous sign or signs bearing the radiation symbol and the words “CAUTION, AIRBORNE RADIOACTIVITY AREA” or “DANGER, AIRBORNE RADIOACTIVITY AREA.” (e) Posting of areas...

  2. 37 CFR 2.81 - Post publication.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 37 Patents, Trademarks, and Copyrights 1 2012-07-01 2012-07-01 false Post publication. 2.81 Section 2.81 Patents, Trademarks, and Copyrights UNITED STATES PATENT AND TRADEMARK OFFICE, DEPARTMENT OF COMMERCE RULES OF PRACTICE IN TRADEMARK CASES Publication and Post Publication § 2.81 Post publication....

  3. 37 CFR 2.81 - Post publication.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 37 Patents, Trademarks, and Copyrights 1 2013-07-01 2013-07-01 false Post publication. 2.81 Section 2.81 Patents, Trademarks, and Copyrights UNITED STATES PATENT AND TRADEMARK OFFICE, DEPARTMENT OF COMMERCE RULES OF PRACTICE IN TRADEMARK CASES Publication and Post Publication § 2.81 Post publication....

  4. 37 CFR 2.81 - Post publication.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 37 Patents, Trademarks, and Copyrights 1 2010-07-01 2010-07-01 false Post publication. 2.81 Section 2.81 Patents, Trademarks, and Copyrights UNITED STATES PATENT AND TRADEMARK OFFICE, DEPARTMENT OF COMMERCE RULES OF PRACTICE IN TRADEMARK CASES Publication and Post Publication § 2.81 Post publication....

  5. 37 CFR 2.81 - Post publication.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 37 Patents, Trademarks, and Copyrights 1 2011-07-01 2011-07-01 false Post publication. 2.81 Section 2.81 Patents, Trademarks, and Copyrights UNITED STATES PATENT AND TRADEMARK OFFICE, DEPARTMENT OF COMMERCE RULES OF PRACTICE IN TRADEMARK CASES Publication and Post Publication § 2.81 Post publication....

  6. 37 CFR 2.81 - Post publication.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 37 Patents, Trademarks, and Copyrights 1 2014-07-01 2014-07-01 false Post publication. 2.81 Section 2.81 Patents, Trademarks, and Copyrights UNITED STATES PATENT AND TRADEMARK OFFICE, DEPARTMENT OF COMMERCE RULES OF PRACTICE IN TRADEMARK CASES Publication and Post Publication § 2.81 Post publication....

  7. 75 FR 54192 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-03

    ...] [FR Doc No: 2010-22040] POSTAL REGULATORY COMMISSION [Docket No. A2010-5; Order No. 526] Post Office... that an appeal of the closing of the Rentiesville Post Office, Rentiesville, Oklahoma 74459 has been... closing of the Rentiesville Post Office, Rentiesville, Oklahoma 74459. The appeal, postmarked August...

  8. 76 FR 59451 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-26

    ... informs the public that an appeal of the closing of the Coyote, New Mexico post office has been filed. It... Postal Service's determination to close the Coyote post office in Coyote, New Mexico. The petition was filed by Manuelita Trujillo on behalf of the Concerned Citizens of the Coyote Post Office (Petitioner...

  9. Post-Tenure Review. SPEC Kit 261.

    ERIC Educational Resources Information Center

    Hook, Sara Anne, Comp.; Lees, N. Doug, Comp.; Powers, Gerald, Comp.

    2000-01-01

    This SPEC (Systems and Procedures Exchange Center) Kit reports results of a survey of ARL (Association of Research Libraries) that examined post-tenure review of librarians throughout higher education in North America. The purpose of the survey was to identify which institutions apply post-tenure or post-continuing appointment review to library…

  10. 36 CFR 261.51 - Posting.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 36 Parks, Forests, and Public Property 2 2012-07-01 2012-07-01 false Posting. 261.51 Section 261.51 Parks, Forests, and Public Property FOREST SERVICE, DEPARTMENT OF AGRICULTURE PROHIBITIONS Prohibitions in Areas Designated by Order § 261.51 Posting. Posting is accomplished by: (a) Placing a copy of...

  11. Clinical issues in post-abortion care.

    PubMed

    Cappiello, Joyce D; Beal, Margaret W; Simmonds, Katherine E

    2011-05-01

    This article provides an overview of the clinical issues in post-abortion care, including types of abortion procedures, expected post-abortion course, possible complications, and the components of the post-abortion visit. By providing follow-up care to their patients, NPs can increase continuity of care and promote successful contraceptive use.

  12. 49 CFR 238.211 - Collision posts.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... structural protection described in paragraph (a) of this section, either: (1) Two forward collision posts... structural protection described in paragraphs (a) and (b) of this section, two forward collision posts... body structure. (3) Prior to or during structural deformation, each collision post acting together with...

  13. 49 CFR 238.211 - Collision posts.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... structural protection described in paragraph (a) of this section, either: (1) Two forward collision posts... structural protection described in paragraphs (a) and (b) of this section, two forward collision posts... body structure. (3) Prior to or during structural deformation, each collision post acting together with...

  14. 49 CFR 238.211 - Collision posts.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... structural protection described in paragraph (a) of this section, either: (1) Two forward collision posts... structural protection described in paragraphs (a) and (b) of this section, two forward collision posts... body structure. (3) Prior to or during structural deformation, each collision post acting together with...

  15. 39 CFR 241.1 - Post offices.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 39 Postal Service 1 2012-07-01 2012-07-01 false Post offices. 241.1 Section 241.1 Postal Service UNITED STATES POSTAL SERVICE ORGANIZATION AND ADMINISTRATION ESTABLISHMENT CLASSIFICATION, AND DISCONTINUANCE § 241.1 Post offices. (a) Establishment. Post Offices are established and maintained at...

  16. In vitro evaluation of glass fiber post

    PubMed Central

    Sharma, Navneet; Singh, Harpal

    2012-01-01

    Statement of problem: Techniques and recommendations for the restoration of endodontically treated teeth have changed from the use of custom cast metal post and core system to glass fiber-reinforced (GFRC) post and composite core system. Has this latest prefabricated glass fiber reinforced post and composite core system increased the fracture resistance of teeth and reduced the incidence of unrestorable root fractures. Purpose: The purpose of this study was to evaluate the incidence of root fracture and mode of failure of endodontically treated teeth restored with two different post and core systems. Material and Methods: Forty maxillary central incisors were randomly divided into two groups. (n=20). All teeth received endodontic treatment. First group was restored with custom cast post and core system. Second group was restored with glass fiber post and composite core system. In Both the groups posts were cemented with adhesive resin cement. Compressive load was applied at an angle of 130 to the long axis of teeth at a cross head speed of 1 mm/min until fracture occurred. Data were analyzed with student “t” test P<.001. Results: The mean value for fracture resistance was (331.4025) N in Group -I Custom cast Ni-Cr post and core and (237.0625) N in Group -II Glass fiber reinforced post and composite core system. Students “t” test shows the significant difference in fracture resistance of two groups. Conclusion: This study showed that the incidence of root fracture was significantly higher in custom cast Ni-Cr post and core system than glass fiber post and composite core system. A more favourable mode of failure was observed in teeth restored with Group II glass fiber post system. Key words:Post-and-core technique, glass fiber post, cast post and-core system, fracture resistance, endodontically treated teeth. PMID:24558556

  17. [Post-Lyme disease syndrome].

    PubMed

    Błaut-Jurkowska, Justyna; Jurkowski, Marcin

    2016-02-01

    Lyme disease is a chronic infectious disease caused by the bacteria, spirochete of the Borrelia type. Skin, nervous system, musculoskeletal system and heart may be involved in the course of the disease. The prognosis for properly treated Lyme disease is usually good. However, in about 5% of patients so called Post-Lyme disease syndrome (PLSD) develops. It is defined as a syndrome of subjective symptoms persisting despite proper treatment of Borrelia burgdorferi infection. The most common symptoms include: fatigue, muscle and joint pain, and problems with memory and concentration. Pathogenesis of PLDS remains unknown. The differential diagnosis should include neurological, rheumatic and mental diseases. Till now there is no causative treatment of PLDS. In relieving symptom rehabilitation, painkillers, anti-inflammatory and antidepressants medicines are recommended. Emotional and psychological supports are also necessary. Non-specific symptoms reported by patients with post- Lyme disease syndrome raise the suspicion of other pathologies. This can lead to misdiagnosis and implementation of unnecessary, potentially harmful to the patient's therapy. An increase in tick-borne diseases needs to increase physicians awareness of these issues. © 2016 MEDPRESS.

  18. Sterile post-traumatic immunosuppression

    PubMed Central

    Islam, Md Nahidul; Bradley, Benjamin A; Ceredig, Rhodri

    2016-01-01

    After major trauma, the human immune system initiates a series of inflammatory events at the injury site that is later followed by suppression of local inflammation favoring the repair and remodeling of the damaged tissues. This local immune response involves complex interactions between resident cells such as macrophages and dendritic cells, soluble mediators such as cytokines and chemokines, and recruited cells such as neutrophils, monocytes and mesenchymal stromal cells. If of sufficient magnitude, these initial immune responses nevertheless have systemic consequences resulting in a state called post-traumatic immunosuppression (PTI). However, controversy exists regarding the exact immunological changes occurring in systemic compartments triggered by these local immune responses. PTI is one of the leading causes of post-surgical mortality and makes patients vulnerable to hospital-acquired infections, multiple organ failure and many other complications. In addition, hemorrhage, blood transfusion, immunesenescence and immunosuppressant drugs aggravate PTI. PTI has been intensively studied, but published results are frequently cloudy. The purpose of this review is to focus on the contributions made by different responsive modalities to immunosuppression following sterile trauma and to try to integrate these into an overall scheme of PTI. PMID:27195120

  19. Parameterized post-Newtonian cosmology

    NASA Astrophysics Data System (ADS)

    Sanghai, Viraj A. A.; Clifton, Timothy

    2017-03-01

    Einstein’s theory of gravity has been extensively tested on solar system scales, and for isolated astrophysical systems, using the perturbative framework known as the parameterized post-Newtonian (PPN) formalism. This framework is designed for use in the weak-field and slow-motion limit of gravity, and can be used to constrain a large class of metric theories of gravity with data collected from the aforementioned systems. Given the potential of future surveys to probe cosmological scales to high precision, it is a topic of much contemporary interest to construct a similar framework to link Einstein’s theory of gravity and its alternatives to observations on cosmological scales. Our approach to this problem is to adapt and extend the existing PPN formalism for use in cosmology. We derive a set of equations that use the same parameters to consistently model both weak fields and cosmology. This allows us to parameterize a large class of modified theories of gravity and dark energy models on cosmological scales, using just four functions of time. These four functions can be directly linked to the background expansion of the universe, first-order cosmological perturbations, and the weak-field limit of the theory. They also reduce to the standard PPN parameters on solar system scales. We illustrate how dark energy models and scalar-tensor and vector-tensor theories of gravity fit into this framework, which we refer to as ‘parameterized post-Newtonian cosmology’ (PPNC).

  20. Post-stroke urinary incontinence.

    PubMed

    Mehdi, Z; Birns, J; Bhalla, A

    2013-11-01

    To provide a comprehensive review of the current evidence on post-stroke urinary incontinence. An electronic database search was performed to identify relevant studies and review articles related to Urinary Incontinence (UI) in the stroke population between the years 1966 and 2012. Urinary incontinence following stroke is a common problem affecting more than one-third of acute stroke patients and persisting in up to a quarter at 1 year. It is well established that this condition is a strong marker of stroke severity and is associated with poorer functional outcomes and increased institutionalisation and mortality rates compared with those who remain continent. Despite evidence linking better outcomes to those patients who regain continence, the results of national audits have demonstrated that the management of UI following stroke is suboptimal, with less than two-thirds of stroke units having a documented plan to promote continence. Current evidence supports a thorough assessment to categorise the type and severity of post-stroke urinary incontinence. An individually tailored, structured management strategy to promote continence should be employed. This has been associated with better stroke outcomes and should be the aim of all stroke health professionals. © 2013 John Wiley & Sons Ltd.

  1. Hot Post-AGB Stars

    NASA Astrophysics Data System (ADS)

    Parthasarathy, M.; Gauba, G.; Fujii, T.; Nakada, Y.

    2001-08-01

    From the study of IRAS sources with far-IR colors similar to planetary nebulae (PNe), several proto-planetary nebulae with hot (OB) post-AGB central stars have been detected. These stars form an evolutionary link between the cooler G,F,A supergiant stars that have evolved off the Asymptotic Giant Branch (AGB) and the hot (OB) central stars of PNe. The optical spectra of these objects show strong Balmer emission lines and in some cases low excitation nebular emission lines such as [NII] and [SII] superposed on the OB stellar continuum. The absence of of [OIII] 5007Å line and the presence of low excitation nebular emission lines indicate that photoionisation has just started. The UV(IUE) spectra of some of these objects revealed violet shifted stellar wind P-Cygni profiles of CIV, SiIV and NV, indicating hot and fast stellar wind and post-AGB mass loss. These objects appear to be rapildy evolving into the early stages of PNe similar to that observed in the case of Hen1357 IRAS 17119-5926 (Stingray Nebula) and IRAS 18062+2410 SAO85766.

  2. An SEM Approach for the Evaluation of Intervention Effects Using Pre-Post-Post Designs

    ERIC Educational Resources Information Center

    Mun, Eun Young; von Eye, Alexander; White, Helene R.

    2009-01-01

    This study analyzes latent change scores using latent curve models (LCMs) for evaluation research with pre-post-post designs. The article extends a recent article by Willoughby, Vandergrift, Blair, and Granger (2007) on the use of LCMs for studies with pre-post-post designs, and demonstrates that intervention effects can be better tested using…

  3. Post-Secularism, Religious Knowledge and Religious Education

    ERIC Educational Resources Information Center

    Carr, David

    2012-01-01

    Post-secularism seems to follow in the wake of other (what are here called) "postal" perspectives--post-structuralism, postmodernism, post-empiricism, post-positivism, post-analytical philosophy, post-foundationalism and so on--in questioning or repudiating what it takes to be the epistemic assumptions of "modernism." To be sure, post-secularism…

  4. Post-Secularism, Religious Knowledge and Religious Education

    ERIC Educational Resources Information Center

    Carr, David

    2012-01-01

    Post-secularism seems to follow in the wake of other (what are here called) "postal" perspectives--post-structuralism, postmodernism, post-empiricism, post-positivism, post-analytical philosophy, post-foundationalism and so on--in questioning or repudiating what it takes to be the epistemic assumptions of "modernism." To be sure, post-secularism…

  5. Morphological Changes in Bone Marrow Post Imatinib Therapy in Chronic Phase CML: A Follow up Study on Sequential Bone Marrow Aspirates and Biopsies

    PubMed Central

    Narang, Neha Chopra; Sikka, Meera; Kotru, Mrinalini

    2017-01-01

    Introduction Imatinib mesylate is used extensively for first line treatment of Chronic Myeloid Leukemia (CML). However, not many studies have documented morphological changes in bone marrow biopsies produced during Imatinib therapy with reference to myelofibrosis. Aim To document the morphological changes produced in the bone marrow during Imatinib therapy. Materials and Methods This longitudinal study followed up 75 Philadelphia Chromosome Positive Chronic Myeloid Leukemia with chronic phase(Ph+ CML- CP) patients sequentially, receiving 400-600mg Imatinib over a period of 12 or more months. Haematologic parameters were measured at admission, 2 weeks, 1 month, 3 months, 6 months and 12 or more months. Morphologic changes in bone marrow aspirate and biopsy were evaluated at admission, 6 months and ≥12 months of treatment in accordance with National Comprehensive Cancer Network(NCCN) guidelines. Results Complete Haematologic Response (CHR) was seen in 47.1%, 80%, 85.4%, 90.4% at ≥1 month, 3 months, 6 months and 12 months respectively after therapy. It was noted that patients not showing CHR by 3 months were less likely to show CHR at 6 months and beyond. Bone marrow aspirates and biopsies showed reduction in cellularity and myeloid precursors with regeneration of erythroid precursors in 70-83% at ≥12 months. A significant decrease in myelofibrosis (p-value< 0.04) was noted as early as 6 months. Mild to moderate hypoplasia was noted in 31.8% of biopsies within 6 months. Pseudo gaucher cells and benign lymphoid nodules were also seen. Conclusion Sequential analysis showed that Imatinib reduced the grade of myelofibrosis significantly (p-value< 0.04). It also prevented development of myelofibrosis in patients who did not have it at presentation. Hence Imatinib is effective when used early in the course of CML-CP. PMID:28571145

  6. Morphological Changes in Bone Marrow Post Imatinib Therapy in Chronic Phase CML: A Follow up Study on Sequential Bone Marrow Aspirates and Biopsies.

    PubMed

    Narang, Neha Chopra; Rusia, Usha; Sikka, Meera; Kotru, Mrinalini

    2017-04-01

    Imatinib mesylate is used extensively for first line treatment of Chronic Myeloid Leukemia (CML). However, not many studies have documented morphological changes in bone marrow biopsies produced during Imatinib therapy with reference to myelofibrosis. To document the morphological changes produced in the bone marrow during Imatinib therapy. This longitudinal study followed up 75 Philadelphia Chromosome Positive Chronic Myeloid Leukemia with chronic phase(Ph+ CML- CP) patients sequentially, receiving 400-600mg Imatinib over a period of 12 or more months. Haematologic parameters were measured at admission, 2 weeks, 1 month, 3 months, 6 months and 12 or more months. Morphologic changes in bone marrow aspirate and biopsy were evaluated at admission, 6 months and ≥12 months of treatment in accordance with National Comprehensive Cancer Network(NCCN) guidelines. Complete Haematologic Response (CHR) was seen in 47.1%, 80%, 85.4%, 90.4% at ≥1 month, 3 months, 6 months and 12 months respectively after therapy. It was noted that patients not showing CHR by 3 months were less likely to show CHR at 6 months and beyond. Bone marrow aspirates and biopsies showed reduction in cellularity and myeloid precursors with regeneration of erythroid precursors in 70-83% at ≥12 months. A significant decrease in myelofibrosis (p-value< 0.04) was noted as early as 6 months. Mild to moderate hypoplasia was noted in 31.8% of biopsies within 6 months. Pseudo gaucher cells and benign lymphoid nodules were also seen. Sequential analysis showed that Imatinib reduced the grade of myelofibrosis significantly (p-value< 0.04). It also prevented development of myelofibrosis in patients who did not have it at presentation. Hence Imatinib is effective when used early in the course of CML-CP.

  7. Post-Newtonian quasirigid body

    NASA Astrophysics Data System (ADS)

    Xu, Chongming; Tao, Jin-He; Wu, Xuejun

    2004-01-01

    In this paper, we construct for the first time, in the first post-Newtonian (1PN) approximation, a complete model of a quasirigid body by means of a new constraint on the mass current density and mass density. In our 1PN quasirigid body model most of the relations, such as the spin vector proportional to the angular velocity, the definition of the moment of inertia tensor, the key relation between the mass quadrupole moment and the moment of inertia tensor, the rigid rotating formulas for the mass quadrupole moment, and the moment of inertia tensor, are just an extension of the main relations in the Newtonian rigid body model. When all of the 1/c2 terms are neglected, the 1PN quasirigid body model and the corresponding formulas reduce to the Newtonian version. A key relation is obtained in this paper for the first time, which might be very useful in future applications to problems in geodynamics and astronomy.

  8. [Post-tubal ligation syndrome].

    PubMed

    Satoh, K; Osada, H

    1993-01-01

    Post-tubal ligation syndrome includes pain during intercourse, aching lower back, premenstrual tension syndrome, difficulty in menstruating, uterine hemorrhage, and absence of menstruation. The syndrome is caused by blood circulation problems in and around the Fallopian tubes and ovaries, pressure on nerves, and intrapelvic adhesion. Differentiating between this syndrome and endometritis during diagnosis and differentiating between functional hemorrhage due to hormonal abnormality and anatomical hemorrhage due to polyp or tumor is very important. Since the symptoms of this syndrome are mild, simple symptomatic treatment is sufficient in most cases. In some cases, however, desquamation surgery or reversal of tubal ligation may be necessary. Endoscopic surgery is also available. In Japan, because of widespread use of condoms and IUDs, tubal ligation is not very common.

  9. STS-78 Post Flight Presentation

    NASA Technical Reports Server (NTRS)

    1996-01-01

    The flight crew of the STS-78 mission, Cmdr. Terence T. Henricks, Pilot Kevin R. Kregel, Payload Cmdr. Susan J. Helms, Mission Specialists Richard M. Linnehan, Charles E. Brady, Jr., and Payload Specialists Jean-Jacques Favier, Ph.D. and Robert B. Thirsk, M.D., back from their seventeen day mission, offer a video and still photo presentation of their journey. Included in the presentation are pre-launch, launch, and post-launch activities; experiments performed in the Spacelab; and re-entry; and the landing at KSC. Each of the STS-78 crew members discuss particular aspects of the mission including the 22 LMS life science and microgravity experiments. The experiments address human physiology, metallic alloys and protein crystal growth, and the study of the behavior of fluids and materials processing in the near-weightless environment of space.

  10. Lethal post-tonsillectomy hemorrhage.

    PubMed

    Windfuhr, Jochen P

    2003-12-01

    Post-tonsillectomy hemorrhage (PTH) seems to be a rare but unavoidable complication. Due to the frequency of performed tonsillectomies, it can be estimated that a certain amount may result in a lethal outcome. This study was undertaken to evaluate the clinical features of these rare cases. Retrospective case series of five patients with lethal post-tonsillectomy hemorrhage are reported after they had undergone tonsillectomy by four different surgeons. The relevant literature was reviewed. The youngest patient was 42 months and the oldest almost 13 years old. All patients were male. Three patients had left the hospital against surgeon's recommendation 5 days following tonsillectomy. Preceding episodes of bleeding prior to the lethal bleeding occurred in two patients. Lethal PTH occurred in four patients within 5-9 days, the latest bleeding 39 days after surgery. In the literature, lethal PTH was described for eight patients since 1958. The youngest patient was 4 years, the oldest 18 years old (mean: 8.6 years; median: 6.5 years). In three patients, lethal PTH occurred on the day of surgery and the latest bleeding 54 days after surgery. Due to the paucity of reports, little reliable information can be obtained from the literature. It remains unclear, whether or not this reflects the true incidence of this complication. The experience with the five reported cases suggests, that immediate surgical treatment may have avoided lethal outcome in most cases. Therefore, a close postoperative follow-up is advisable to detect any episode of bleeding as soon as possible which should be referred to a specialist. Certainly, the collected data do not suffice to establish general guidelines, indicating that further collection of cases is required to assess characteristics of lethal PTH.

  11. [Fiber reinforced composite posts: literature review].

    PubMed

    Frydman, G; Levatovsky, S; Pilo, R

    2013-07-01

    FRC (Fiber-reinforced composite) posts have been used since the beginning of the 90s with the introduction of carbon fiber posts. Fiber posts are widely used to restore endodontically treated teeth that have insufficient coronal tooth structure. Many in vitro and in vivo studies have shown the advantage of using FRC over prefabricated and cast metal post especially indicated in narrow root canals which are prone to vertically root fracture. The most frequent failure of FRC is debonding of a post at the resin cement/dentin interface. Bonding to dentin may be achieved by using etch-and-rinse and self-etch adhesives. The bond strength formed by self-adhesive cements is noticeably lower in comparison to the bond strength formed with resin cements applied in combination with etch-and-rinse adhesives. In an attempt to maximize resin bonding to fiber posts, several surface treatments have been suggested. Sandblasting with alumina particles results in an increased surface roughness and surface area without affecting the integrity of the post as long as it is applied by 50 microm alumina particles at 2.5 bars for maximally 5 seconds at a distance of 30 mm. The efficiency of post salinization is controversial and its contribution to the retention is of minor importance. Hydrofluoric acid has recently been proposed for etching glass fiber posts but this technique produced substantial damage to the glass fibers and affected the integrity of the post. Delayed cementation of fiber post (at least 24h post endodontic treatment) resulted in higher retentive strengths in comparison to immediate cementation and the best results were obtained when the luting agent was brought into the post space with lentulo spirals or specific syringes. The resin cement film thickness also influences the pullout strengths of fiber-reinforced posts .The highest bond strength values were obtained when the cement layer oversized the post spaces but not larger than 0.3 mm. The use of core build

  12. Factors affecting the cement-post interface.

    PubMed

    Zicari, F; De Munck, J; Scotti, R; Naert, I; Van Meerbeek, B

    2012-03-01

    To evaluate the effect of different factors on the push-out bond strength of glass fiber posts luted in simulated (standard) root canals using different composite cements. Three types of glass-fiber root-canal posts with a different matrix, namely an epoxy resin (RelyX post, 3M ESPE), a proprietary composite resin (FRC-Plus post, Ivoclar-Vivadent), and a methacrylate resin (GC post, GC), and three types of composite cements, namely an etch-and-rinse Bis-GMA-based (Variolink II, Ivoclar-Vivadent), a self-etch 10-MDP-based (Clearfil Esthetic Cement, Kuraray) and a self-adhesive (RelyX Unicem, 3M ESPE) cement, were tested. Posts were either left untreated (control), were treated with silane, or coated with silicated alumina particles (Cojet system, 3M ESPE). Posts were inserted up to 9-mm depth into composite CAD-CAM blocks (Paradigm, 3M ESPE) in order to solely test the strength of the cement-post interface, while excluding interference of the cement-dentin interface. After 1-week storage at 37 °C, three sections (coronal, middle, apical) of 2-mm thickness were subjected to a push-out bond-strength test. All three variables, namely the type of post, the composite cement and the post-surface pre-treatment, were found to significantly affect the push-out bond strength (p<0.001). Regarding the type of post, a significantly lower push-out bond strength was recorded for the FRC-Plus post (Ivoclar-Vivadent); regarding the composite cement, a significantly higher push-out bond strength was recorded for the self-adhesive cement Unicem (3M ESPE); and regarding the post-surface treatment, a significantly higher push-out bond strength was recorded when the post-surface was beforehand subjected to a Cojet (3M ESPE) combined sandblasting/silicatization surface pre-treatment. Many interactions between these three variables were found to be significant as well (p<0.001). Finally, the push-out bond strength was found to significantly reduce with depth from coronal to apical

  13. Vehicle Support Posts Installation onto Mobile Launcher

    NASA Image and Video Library

    2017-05-25

    At NASA's Kennedy Space Center in Florida, the final four vehicle support posts are being installed on the deck of the mobile launcher. A total of eight support posts are being installed to support the load of the Space Launch System's (SLS) solid rocket boosters, with four posts for each of the boosters. The support posts are about five feet tall and each weigh about 10,000 pounds. The posts will structurally support the SLS rocket through T-0 and liftoff, and will drop down before vehicle liftoff to avoid contact with the flight hardware. The Ground Systems Development and Operations Program is overseeing installation of the support posts to prepare for the launch of the Orion spacecraft atop the SLS rocket.

  14. Vehicle Support Posts Installation onto Mobile Launcher

    NASA Image and Video Library

    2017-05-25

    Construction workers on the deck of the mobile launcher at NASA's Kennedy Space Center in Florida, prepare to install a vehicle support post. A total of eight support posts are being installed to support the load of the Space Launch System's (SLS) solid rocket boosters, with four posts for each of the boosters. The support posts are about five feet tall and each weigh about 10,000 pounds. The posts will structurally support the SLS rocket through T-0 and liftoff, and will drop down before vehicle liftoff to avoid contact with the flight hardware. The Ground Systems Development and Operations Program is overseeing installation of the support posts to prepare for the launch of the Orion spacecraft atop the SLS rocket.

  15. Vehicle Support Posts Installation onto Mobile Launcher

    NASA Image and Video Library

    2017-05-11

    In view are three vehicle support posts installed on the deck of the mobile launcher at NASA's Kennedy Space Center in Florida. A total of eight support posts will be installed to support the load of the Space Launch System's (SLS) solid rocket boosters, with four posts for each of the boosters. The support posts are about five feet tall and each weigh about 10,000 pounds. The posts will structurally support the SLS rocket through T-0 and liftoff, and will drop down before vehicle liftoff to avoid contact with the flight hardware. The Ground Systems Development and Operations Program is overseeing installation of the support posts to prepare for the launch of the Orion spacecraft atop the SLS rocket.

  16. Vehicle Support Posts Installation onto Mobile Launcher

    NASA Image and Video Library

    2017-05-11

    A vehicle support post will lifted up by crane and lowered onto the deck of the mobile launcher at NASA's Kennedy Space Center in Florida. A total of eight support posts will be installed to support the load of the Space Launch System's (SLS) solid rocket boosters, with four posts for each of the boosters. The support posts are about five feet tall and each weigh about 10,000 pounds. The posts will structurally support the SLS rocket through T-0 and liftoff, and will drop down before vehicle liftoff to avoid contact with the flight hardware. The Ground Systems Development and Operations Program is overseeing installation of the support posts to prepare for the launch of the Orion spacecraft atop the SLS rocket.

  17. Vehicle Support Posts Installation onto Mobile Launcher

    NASA Image and Video Library

    2017-05-11

    A construction worker on the deck of the mobile launcher welds a portion of a platform for installation of a vehicle support post at NASA's Kennedy Space Center in Florida. A total of eight support posts will be installed to support the load of the Space Launch System's (SLS) solid rocket boosters, with four posts for each of the boosters. The support posts are about five feet tall and each weigh about 10,000 pounds. The posts will structurally support the SLS rocket through T-0 and liftoff, and will drop down before vehicle liftoff to avoid contact with the flight hardware. The Ground Systems Development and Operations Program is overseeing installation of the support posts to prepare for the launch of the Orion spacecraft atop the SLS rocket.

  18. Vehicle Support Posts Installation onto Mobile Launcher

    NASA Image and Video Library

    2017-05-11

    Construction workers on the deck of the mobile launcher at NASA's Kennedy Space Center in Florida, prepare a platform for installation of a vehicle support post. A total of eight support posts will be installed to support the load of the Space Launch System's (SLS) solid rocket boosters, with four posts for each of the boosters. The support posts are about five feet tall and each weigh about 10,000 pounds. The posts will structurally support the SLS rocket through T-0 and liftoff, and will drop down before vehicle liftoff to avoid contact with the flight hardware. The Ground Systems Development and Operations Program is overseeing installation of the support posts to prepare for the launch of the Orion spacecraft atop the SLS rocket.

  19. Vehicle Support Posts Installation onto Mobile Launcher

    NASA Image and Video Library

    2017-05-11

    Four vehicle support posts have been installed on the deck of the mobile launcher at NASA's Kennedy Space Center in Florida. A total of eight support posts will be installed to support the load of the Space Launch System's (SLS) solid rocket boosters, with four posts for each of the boosters. The support posts are about five feet tall and each weigh about 10,000 pounds. The posts will structurally support the SLS rocket through T-0 and liftoff, and will drop down before vehicle liftoff to avoid contact with the flight hardware. The Ground Systems Development and Operations Program is overseeing installation of the support posts to prepare for the launch of the Orion spacecraft atop the SLS rocket.

  20. Vehicle Support Posts Installation onto Mobile Launcher

    NASA Image and Video Library

    2017-05-25

    At NASA's Kennedy Space Center in Florida, construction workers on the deck of the mobile launcher install the final four vehicle support posts. A total of eight support posts are being installed to support the load of the Space Launch System's (SLS) solid rocket boosters, with four posts for each of the boosters. The support posts are about five feet tall and each weigh about 10,000 pounds. The posts will structurally support the SLS rocket through T-0 and liftoff, and will drop down before vehicle liftoff to avoid contact with the flight hardware. The Ground Systems Development and Operations Program is overseeing installation of the support posts to prepare for the launch of the Orion spacecraft atop the SLS rocket.

  1. Nurses management of post-operative pain.

    PubMed

    Buckley, H

    2000-06-01

    Nurses have the responsibility of adequately managing patients' post-operative pain. This literature review assesses whether nurses' management of post-operative pain is adequate or not, according to the literature findings. The findings reveal that nurses' management of patients' post-operative pain is not adequate and implies the concurrent need for improved nurse education and practice. The findings also indicate a need for ongoing research of this phenomenon.

  2. [Post-traumatic stress disorder after childbirth].

    PubMed

    Korábová, I; Masopustová, Z

    2016-01-01

    The aim of this paper is to introduce the issue of post-traumatic stress disorder after childbirth to health care professionals. The text focuses on the diagnostic definition of post-traumatic stress disorder after childbirth, symptoms, physiological background, prevalence, course, risk factors and consequences of post-traumatic stress disorder after childbirth for a woman, her child and her partner. Options for interventions and therapy are outlined as well.

  3. The Management of Post-Term Pregnancy

    PubMed Central

    Iwanicki, Stanislaw; Akierman, Albert

    1988-01-01

    Although post-term pregnancy is associated with an increased incidence of fetal distress, oligohydramnios, fetal macrosomia, fetal dysmaturity, and perinatal mortality, as many as 80% of post-term fetuses appear completely normal. The authors of this article discuss the three sub-groups of post-term pregnancies, and deal with the diagnosis and antepartum and intrapartum management of the condition. Recommendations and a protocol for management are provided. PMID:21253236

  4. Post-grouting bored pile technology

    NASA Astrophysics Data System (ADS)

    Zheng, A. R.

    2017-04-01

    Post-grouting is an effective technology to modify the shortcomings of thick bottom slime and shaft mudcake for the slurry bored pile. Construction procedure, parameter selection and strengthening mechanism of post-grouting bored pile had been introduced in this paper. Development of study on physical and mechanical properties of surrounding soil post-grouted was summarized. The bearing capacity behaviour and deformation properties of the pile were also analyzed. It will provide some advice for the research and application of post-grouting bored pile.

  5. Fabricating fiber-reinforced composite posts.

    PubMed

    Manhart, Jürgen

    2011-03-01

    Endodontic posts do not increase the strength of the remaining tooth structure in endodontically treated teeth. On the contrary, depending on the post design employed (tapered versus parallel-sided), the root can be weakened relative to the amount of tooth removed during preparation. In many cases, if there has been a high degree of damage to the clinical crown, conservative preparation for an anatomic tapered (biomimetic) post with the incorporation of a ferrule on solid tooth structure is necessary to protect the reaming root structure as well as for the long-term retention of the composite resin core and the definitive restoration. Adhesively luted endodontic posts reinforced with glass or quartz fiber lead to better homogeneous tension distribution when loaded than rigid metal or zirconium oxide ceramic posts. Fiber-reinforced posts also possess advantageous optical properties over metal or metal oxide post systems. The clinician should realize that there are admittedly substantial differences in the mechanical loading capacity of the different fiber-reinforced endodontic posts and should be aware of such differences in order to research and select a suitable post system for use.

  6. MRO DKF Post-Processing Tool

    NASA Technical Reports Server (NTRS)

    Ayap, Shanti; Fisher, Forest; Gladden, Roy; Khanampompan, Teerapat

    2008-01-01

    This software tool saves time and reduces risk by automating two labor-intensive and error-prone post-processing steps required for every DKF [DSN (Deep Space Network) Keyword File] that MRO (Mars Reconnaissance Orbiter) produces, and is being extended to post-process the corresponding TSOE (Text Sequence Of Events) as well. The need for this post-processing step stems from limitations in the seq-gen modeling resulting in incorrect DKF generation that is then cleaned up in post-processing.

  7. A laboratory comparison of individual Targis/Vectris posts with standard fiberglass posts.

    PubMed

    Corsalini, Massimo; Genovese, Katia; Lamberti, Luciano; Pappalettere, Carmine; Carella, Mauro; Carossa, Stefano

    2007-01-01

    This article presents an in vitro analysis of a specific occlusal loading test on endodontically treated teeth restored with 2 different composite post materials. Individual, customized posts (IFPs) were compared to standard fiberglass posts (SFPs). The selected IFPs (standard cylindric Targis/Vectris posts) were compared to SFPs (Conic 6% Post, Ghimas). The posts were first subjected to a 3-point bending test to compare their flexural elastic properties. They were then used to restore 22 endodontically treated artificial maxillary central incisors and subjected to a specific occlusal loading simulation test. The loading test showed that IFP restorations performed better than SFP restorations. A clinical evaluation of this laboratory observation is suggested.

  8. STS-113 Post Flight Presentation

    NASA Technical Reports Server (NTRS)

    2002-01-01

    The STS-113 post-flight presentation begins with a view of Mission Specialists Michael E. Lopez-Alegria and John B. Herrington getting suited for the space mission. The STS-113 crew consists of: Commander James D. Wetherbee, Pilot Paul Lockhart, Mission Specialists Michael Lopez-Alegria and John Herrington. Cosmonauts Valery Korzun, and Sergei Treschev, and astronaut Peggy Whitson who are all members of the expedition five crew, and Commander Kenneth Bowersox, Flight Engineers Nikolai Budarin and Donald Pettit, members of Expedition Six. The main goal of this mission is to take Expedition Six up to the International Space Station and Return Expedition Five to the Earth. The second objective is to install the P(1) Truss segment. Three hours prior to launch, the crew of Expedition Six along with James Wetherbee, Paul Lockhart, Michael Lopez-Alegria and John Herrington are shown walking to an astrovan, which takes them to the launch pad. The actual liftoff is presented. Three Extravehicular Activities (EVA)'s are performed on this mission. Michael Lopez-Alegria and John Herrington are shown performing EVA 1 and EVA 2 which include making connections between the P1 and S(0) Truss segments, and installing fluid jumpers. A panoramic view of the ISS with the Earth in the background is shown. The grand ceremony of the crew exchange is presented. The astronauts performing everyday duties such as brushing teeth, washing hair, sleeping, and eating pistachio nuts are shown. The actual landing of the Space Shuttle is presented.

  9. Post orgasmic illness syndrome (POIS).

    PubMed

    Waldinger, Marcel D

    2016-08-01

    Men with post orgasmic illness syndrome (POIS) become ill rather immediately after ejaculation, whether spontaneously at night, during sexual intercourse or masturbation. Two subtypes are distinguished: primary and secondary POIS. It also occurs before or after a man has been sterilized. POIS is an invalidating most probably auto-immune disease leading to much distress in males and their partners. It is characterized by five criteria. Its symptoms are described by seven clusters. However, the manifestation of these symptoms varies from one male to the other but is relatively constant in the person himself. Among men the symptoms vary in intensity, durations and sort of symptoms. POIS is a chronic disorder that manifests itself in POIS "attacks" that occur within a few minutes to a few hours after ejaculation, and disappear spontaneously after 3 to 7 days. POIS is not associated with increased total serum IgE concentrations. On the contrary, there are indications that POIS is triggered by specific cytokines that are released by an auto-immune reaction to the man's seminal fluid. Indirect clinical evidence suggests that the antigen (Ag) triggering the POIS systemic reaction is not bound to spermatozoa but to seminal fluid produced by prostatic tissue. In addition, POIS may also occur-although rarely-in females. In those cases, it is hypothesized that the Ag is associated with female prostatic tissue around the vagina.

  10. STS-113 Post Flight Presentation

    NASA Astrophysics Data System (ADS)

    2002-01-01

    The STS-113 post-flight presentation begins with a view of Mission Specialists Michael E. Lopez-Alegria and John B. Herrington getting suited for the space mission. The STS-113 crew consists of: Commander James D. Wetherbee, Pilot Paul Lockhart, Mission Specialists Michael Lopez-Alegria and John Herrington. Cosmonauts Valery Korzun, and Sergei Treschev, and astronaut Peggy Whitson who are all members of the expedition five crew, and Commander Kenneth Bowersox, Flight Engineers Nikolai Budarin and Donald Pettit, members of Expedition Six. The main goal of this mission is to take Expedition Six up to the International Space Station and Return Expedition Five to the Earth. The second objective is to install the P(1) Truss segment. Three hours prior to launch, the crew of Expedition Six along with James Wetherbee, Paul Lockhart, Michael Lopez-Alegria and John Herrington are shown walking to an astrovan, which takes them to the launch pad. The actual liftoff is presented. Three Extravehicular Activities (EVA)'s are performed on this mission. Michael Lopez-Alegria and John Herrington are shown performing EVA 1 and EVA 2 which include making connections between the P1 and S(0) Truss segments, and installing fluid jumpers. A panoramic view of the ISS with the Earth in the background is shown. The grand ceremony of the crew exchange is presented. The astronauts performing everyday duties such as brushing teeth, washing hair, sleeping, and eating pistachio nuts are shown. The actual landing of the Space Shuttle is presented.

  11. STS-73 Post Flight Presentation

    NASA Technical Reports Server (NTRS)

    1995-01-01

    The post flight presentation of the STS-73 Space Shuttle's United States Microgravity Lab. (USML) mission was presented by the flight crew, Cmdr. Kenneth Bowersox, Pilot Kent Rominger, Payload Specialists Albert Sacco and Fred Gregory, and Mission Specialists Kathryn Thornton, Catherine 'Cady' Collman, and Michael Lopez-Alegria, using color video and slides. Film footage includes the prelaunch and launch activities, the USML and Middeck experiments (Advanced Protein Crystallization Facility (APCF), the Astroculture(tm) (ASC) hardware and experiment, the Commercial Generic Bioprocessing Apparatus (CGBA), the Crystal Growth Furnace (CGF), the Drop Physics Module (DPM), the Geophysical Fluid Flow Cell (GFFC), the Glovebox (GBX), the Zeolite Crystal Growth (ZCG) experiment, the Surface Tension Driven Convection Experiment (STDCE), the Protein Crystal Growth (PCG) experiment, three Measuring Microgravity experiments (the Space Acceleration Measurement System (SAMS), the Three Dimensional Microgravity Accelerometer (3DMA), and the Orbital Acceleration Research Experiment (OARE)), and the High-Packed Digital Television (HI-PAC) demonstration system), pre-return flight systems checkout, reentry, and space shuttle landing. The USML experiments were monitored via the HI-PAC system downlink. Earth views included mostly geographical locations (Mediterranean Sea; Turkey; Lake Powell, Arizona/Utah area; San Francisco Bay; Baltimore, Maryland; Washington, DC; India; Tibet; China; Bhutan; Philadelphia; and the Himalayas).

  12. Carbohydrate post-glycosylational modifications

    PubMed Central

    Yu, Hai; Chen, Xi

    2008-01-01

    Carbohydrate modification is a common phenomenon in nature. Many carbohydrate modifications such as some epimerization, O-acetylation, O-sulfation, O-methylation, N-deacetylation, and N-sulfation, take place after the formation of oligosaccharide or polysaccharide backbones. These modifications can be categorized as carbohydrate post-glycosylational modifications (PGMs). Carbohydrate PGMs further extend the complexity of the structures and the synthesis of carbohydrates and glycoconjugates. They also increase the capacity of the biological information that can be controlled by finely tuning the structures of carbohydrates. Developing efficient methods to obtain structurally defined naturally occurring oligosaccharides, polysaccharides, and glycoconjugates with carbohydrate PGMs is essential for understanding the biological significance of carbohydrate PGMs. Combine with high-throughput screening methods, synthetic carbohydrates with PGMs are invaluable probes in structure-activity relationship studies. We illustrate here several classes of carbohydrates with PGMs and their applications. Recent progress in chemical, enzymatic, and chemoenzymatic syntheses of these carbohydrates and their derivatives are also presented. PMID:17340000

  13. STS 63: Post Flight Presentation

    NASA Technical Reports Server (NTRS)

    1995-01-01

    At a post flight conference, Captain Jim Wetherbee, of STS Flight 63, introduces each of the other members of the STS 63 crew (Eileen Collins, Pilot; Dr. Bernard Harris, Payload Commander; Dr. Michael Foale, Mission Specialist from England; Dr. Janice Voss, Misssion Specialist; and Colonel Vladimir Titor, Misssion Specialist from Russia. A short biography of each member and a brief description of their assignment during this mission is given. A film was shown that included the preflight suit-up, a view of the launch site, the actual night launch, a tour of the Space Shuttle and several of the experiment areas, several views of earth and the MIR Space Station and cosmonauts, the MIR-Space Shuttle rendezvous, the deployment of the Spartan Ultraviolet Telescope, Foale and Harris's EVA and space walk, the retrieval of Spartan, and the night entry home, including the landing. Several spaceborne experiments were introduced: the radiation monitoring experiment, environment monitoring experiment, solid surface combustion experiment, and protein crystal growth and plant growth experiments. This conference ended with still, color pictures, taken by the astronauts during the entire STS 63 flight, being shown.

  14. Post-traumatic stress disorder.

    PubMed

    Yehuda, Rachel; Hoge, Charles W; McFarlane, Alexander C; Vermetten, Eric; Lanius, Ruth A; Nievergelt, Caroline M; Hobfoll, Stevan E; Koenen, Karestan C; Neylan, Thomas C; Hyman, Steven E

    2015-10-08

    Post-traumatic stress disorder (PTSD) occurs in 5-10% of the population and is twice as common in women as in men. Although trauma exposure is the precipitating event for PTSD to develop, biological and psychosocial risk factors are increasingly viewed as predictors of symptom onset, severity and chronicity. PTSD affects multiple biological systems, such as brain circuitry and neurochemistry, and cellular, immune, endocrine and metabolic function. Treatment approaches involve a combination of medications and psychotherapy, with psychotherapy overall showing greatest efficacy. Studies of PTSD pathophysiology initially focused on the psychophysiology and neurobiology of stress responses, and the acquisition and the extinction of fear memories. However, increasing emphasis is being placed on identifying factors that explain individual differences in responses to trauma and promotion of resilience, such as genetic and social factors, brain developmental processes, cumulative biological and psychological effects of early childhood and other stressful lifetime events. The field of PTSD is currently challenged by fluctuations in diagnostic criteria, which have implications for epidemiological, biological, genetic and treatment studies. However, the advent of new biological methodologies offers the possibility of large-scale approaches to heterogeneous and genetically complex brain disorders, and provides optimism that individualized approaches to diagnosis and treatment will be discovered.

  15. Post orgasmic illness syndrome (POIS)

    PubMed Central

    2016-01-01

    Men with post orgasmic illness syndrome (POIS) become ill rather immediately after ejaculation, whether spontaneously at night, during sexual intercourse or masturbation. Two subtypes are distinguished: primary and secondary POIS. It also occurs before or after a man has been sterilized. POIS is an invalidating most probably auto-immune disease leading to much distress in males and their partners. It is characterized by five criteria. Its symptoms are described by seven clusters. However, the manifestation of these symptoms varies from one male to the other but is relatively constant in the person himself. Among men the symptoms vary in intensity, durations and sort of symptoms. POIS is a chronic disorder that manifests itself in POIS “attacks” that occur within a few minutes to a few hours after ejaculation, and disappear spontaneously after 3 to 7 days. POIS is not associated with increased total serum IgE concentrations. On the contrary, there are indications that POIS is triggered by specific cytokines that are released by an auto-immune reaction to the man’s seminal fluid. Indirect clinical evidence suggests that the antigen (Ag) triggering the POIS systemic reaction is not bound to spermatozoa but to seminal fluid produced by prostatic tissue. In addition, POIS may also occur—although rarely—in females. In those cases, it is hypothesized that the Ag is associated with female prostatic tissue around the vagina. PMID:27652231

  16. Post-transplant lymphoproliferative disorders.

    PubMed

    Dharnidharka, Vikas R; Webster, Angela C; Martinez, Olivia M; Preiksaitis, Jutta K; Leblond, Veronique; Choquet, Sylvain

    2016-01-28

    Post-transplant lymphoproliferative disorders (PTLDs) are a group of conditions that involve uncontrolled proliferation of lymphoid cells as a consequence of extrinsic immunosuppression after organ or haematopoietic stem cell transplant. PTLDs show some similarities to classic lymphomas in the non-immunosuppressed general population. The oncogenic Epstein-Barr virus (EBV) is a key pathogenic driver in many early-onset cases, through multiple mechanisms. The incidence of PTLD varies with the type of transplant; a clear distinction should therefore be made between the conditions after solid organ transplant and after haematopoietic stem cell transplant. Recipient EBV seronegativity and the intensity of immunosuppression are among key risk factors. Symptoms and signs depend on the localization of the lymphoid masses. Diagnosis requires histopathology, although imaging techniques can provide additional supportive evidence. Pre-emptive intervention based on monitoring EBV levels in blood has emerged as the preferred strategy for PTLD prevention. Treatment of established disease includes reduction of immunosuppression and/or administration of rituximab (a B cell-specific antibody against CD20), chemotherapy and EBV-specific cytotoxic T cells. Despite these strategies, the mortality and morbidity remains considerable. Patient outcome is influenced by the severity of presentation, treatment-related complications and risk of allograft loss. New innovative treatment options hold promise for changing the outlook in the future.

  17. STS-70 Post Flight Presentation

    NASA Technical Reports Server (NTRS)

    Peterson, Glen (Editor)

    1995-01-01

    In this post-flight overview, the flight crew of the STS-70 mission, Tom Henricks (Cmdr.), Kevin Kregel (Pilot), Major Nancy Currie (MS), Dr. Mary Ellen Weber (MS), and Dr. Don Thomas (MS), discuss their mission and accompanying experiments. Pre-flight, launch, and orbital footage is followed by the in-orbit deployment of the Tracking and Data Relay Satellite (TDRS) and a discussion of the following spaceborne experiments: a microgravity bioreactor experiment to grow 3D body-like tissue; pregnant rat muscular changes in microgravity; embryonic development in microgravity; Shuttle Amateur Radio Experiment (SAREX); terrain surface imagery using the HERCULES camera; and a range of other physiological tests, including an eye and vision test. Views of Earth include: tropical storm Chantal; the Nile River and Red Sea; lightning over Brazil. A three planet view (Earth, Mars, and Venus) was taken right before sunrise. The end footage shows shuttle pre-landing checkout, entry, and landing, along with a slide presentation of the flight.

  18. CID Post-impact fireball

    NASA Technical Reports Server (NTRS)

    1984-01-01

    Following its controlled impact on posts imbedded in the lakebed, the B-720 is sliding sideways and almost enveloped in the large fireball with only the aircraft's nose and right wing-tip exposed. In a typical aircraft crash, fuel spilled from ruptured fuel tanks forms a fine mist that can be ignited by a number of sources at the crash site. In 1984 the NASA Dryden Flight Research Facility (after 1994 a full-fledged Center again) and the Federal Aviation Administration (FAA) teamed-up in a unique flight experiment called the Controlled Impact Demonstration (CID), to test crash a Boeing 720 aircraft using standard fuel with an additive designed to supress fire. The additive, FM-9, a high-molecular-weight long-chain polymer, when blended with Jet-A fuel had demonstrated the capability to inhibit ignition and flame propagation of the released fuel in simulated crash tests. This anti-misting kerosene (AMK) cannot be introduced directly into a gas turbine engine due to several possible problems such as clogging of filters. The AMK must be restored to almost Jet-A before being introduced into the engine for burning. This restoration is called 'degradation' and was accomplished on the B-720 using a device called a 'degrader.' Each of the four Pratt & Whitney JT3C-7 engines had a 'degrader' built and installed by General Electric (GE) to break down and return the AMK to near Jet-A quality. In addition to the AMK research the NASA Langley Research Center was involved in a structural loads measurement experiment, which included having instrumented dummies filling the seats in the passenger compartment. Before the final flight on December 1, 1984, more than four years of effort passed trying to set-up final impact conditions considered survivable by the FAA. During those years while 14 flights with crews were flown the following major efforts were underway: NASA Dryden developed the remote piloting techniques necessary for the B-720 to fly as a drone aircraft; General

  19. Post-Retrofit Residential Assessments

    SciTech Connect

    Lancaster, Ross; lutzenhiser, Loren; Moezzi, Mithra; Widder, Sarah H.; Chandra, Subrato; Baechler, Michael C.

    2012-04-30

    This study examined a range of factors influencing energy consumption in households that had participated in residential energy-efficiency upgrades. The study was funded by a grant from the U.S. Department of Energy’s Pacific Northwest National Laboratory and was conducted by faculty and staff of Portland State University Center for Urban Studies and Department of Economics. This work was made possible through the assistance and support of the Energy Trust of Oregon (ETO), whose residential energy-efficiency programs provided the population from which the sample cases were drawn. All households in the study had participated in the ETO Home Performance with Energy Star (HPwES) program. A number of these had concurrently pursued measures through other ETO programs. Post-retrofit energy outcomes are rarely investigated on a house-by-house basis. Rather, aggregate changes are ordinarily the focus of program impact evaluations, with deviation from aggregate expectations chalked up to measurement error, the vagaries of weather and idiosyncrasies of occupants. However, understanding how homes perform post-retrofit on an individual basis can give important insights to increase energy savings at the participant and the programmatic level. Taking a more disaggregated approach, this study analyzed energy consumption data from before and after the retrofit activity and made comparisons with engineering estimates for the upgrades, to identify households that performed differently from what may have been expected based on the estimates. A statistical analysis using hierarchal linear models, which accounted for weather variations, was performed looking separately at gas and electrical use during the periods before and after upgrades took place. A more straightforward comparison of billing data for 12-month periods before and after the intervention was also performed, yielding the majority of the cases examined. The later approach allowed total energy use and costs to be

  20. Explosive signatures: Pre & post blast

    NASA Astrophysics Data System (ADS)

    Bernier, Evan Thomas

    Manuscripts 1 and 2 of this dissertation both involve the pre-blast detection of trace explosive material. The first manuscript explores the analysis of human hair as an indicator of exposure to explosives. Field analysis of hair for trace explosives is quick and non-invasive, and could prove to be a powerful linkage to physical evidence in the form of bulk explosive material. Individuals tested were involved in studies which required handling or close proximity to bulk high explosives such as TNT, PETN, and RDX. The second manuscript reports the results of research in the design and application of canine training aids for non-traditional, peroxide-based explosives. Organic peroxides such as triacetonetriperoxide (TATP) and hexamethylenetriperoxidediamine (HMTD) can be synthesized relatively easily with store-bought ingredients and have become popular improvised explosives with many terrorist groups. Due to the hazards of handling such sensitive compounds, this research established methods for preparing training aids which contained safe quantities of TATP and HMTD for use in imprinting canines with their characteristic odor. Manuscripts 3 and 4 of this dissertation focus on research conducted to characterize pipe bombs during and after an explosion (post-blast). Pipe bombs represent a large percentage of domestic devices encountered by law enforcement. The current project has involved the preparation and controlled explosion of over 90 pipe bombs of different configurations in order to obtain data on fragmentation patterns, fragment velocity, blast overpressure, and fragmentation distance. Physical data recorded from the collected fragments, such as mass, size, and thickness, was correlated with the relative power of the initial device. Manuscript 4 explores the microstructural analysis of select pipe bomb fragments. Shock-loading of the pipe steel led to plastic deformation and work hardening in the steel grain structure as evidenced by optical microscopy and

  1. 76 FR 53159 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-25

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Ida, Arkansas post office has been filed. It... (from Postal Service): September 1, 2011; deadline for notices to intervene: September 12, 2011. See the...

  2. 76 FR 61403 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-04

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Redfield, New York post office has been filed. It... due (from Postal Service): October 11, 2011; deadline for notices to intervene: October 21, 2011. See...

  3. 10 CFR 76.70 - Post issuance.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 2 2014-01-01 2014-01-01 false Post issuance. 76.70 Section 76.70 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) CERTIFICATION OF GASEOUS DIFFUSION PLANTS Certification § 76.70 Post issuance. (a) Amendment of certificate terms and conditions. The terms and conditions of a certificate...

  4. 10 CFR 76.70 - Post issuance.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 2 2013-01-01 2013-01-01 false Post issuance. 76.70 Section 76.70 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) CERTIFICATION OF GASEOUS DIFFUSION PLANTS Certification § 76.70 Post issuance. (a) Amendment of certificate terms and conditions. The terms and conditions of a certificate...

  5. 10 CFR 76.70 - Post issuance.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 2 2011-01-01 2011-01-01 false Post issuance. 76.70 Section 76.70 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) CERTIFICATION OF GASEOUS DIFFUSION PLANTS Certification § 76.70 Post issuance. (a) Amendment of certificate terms and conditions. The terms and conditions of a certificate...

  6. 10 CFR 76.70 - Post issuance.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 2 2010-01-01 2010-01-01 false Post issuance. 76.70 Section 76.70 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) CERTIFICATION OF GASEOUS DIFFUSION PLANTS Certification § 76.70 Post issuance. (a) Amendment of certificate terms and conditions. The terms and conditions of a certificate...

  7. 10 CFR 76.70 - Post issuance.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 2 2012-01-01 2012-01-01 false Post issuance. 76.70 Section 76.70 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) CERTIFICATION OF GASEOUS DIFFUSION PLANTS Certification § 76.70 Post issuance. (a) Amendment of certificate terms and conditions. The terms and conditions of a certificate...

  8. 76 FR 78318 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-16

    ... informs the public that an appeal of the closing of the Harris, Iowa post office has been filed. It... close the Harris post office in Harris, Iowa. The petition for review was filed by Jeff Loring, Mayor of the City of Harris (Petitioner) and is postmarked November 17, 2011. The Commission hereby institutes...

  9. 10 CFR 34.53 - Posting.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 1 2010-01-01 2010-01-01 false Posting. 34.53 Section 34.53 Energy NUCLEAR REGULATORY COMMISSION LICENSES FOR INDUSTRIAL RADIOGRAPHY AND RADIATION SAFETY REQUIREMENTS FOR INDUSTRIAL RADIOGRAPHIC OPERATIONS Radiation Safety Requirements § 34.53 Posting. All areas in which industrial radiography is...

  10. 10 CFR 34.53 - Posting.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 1 2011-01-01 2011-01-01 false Posting. 34.53 Section 34.53 Energy NUCLEAR REGULATORY COMMISSION LICENSES FOR INDUSTRIAL RADIOGRAPHY AND RADIATION SAFETY REQUIREMENTS FOR INDUSTRIAL RADIOGRAPHIC OPERATIONS Radiation Safety Requirements § 34.53 Posting. All areas in which industrial radiography is...

  11. 10 CFR 34.53 - Posting.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 1 2012-01-01 2012-01-01 false Posting. 34.53 Section 34.53 Energy NUCLEAR REGULATORY COMMISSION LICENSES FOR INDUSTRIAL RADIOGRAPHY AND RADIATION SAFETY REQUIREMENTS FOR INDUSTRIAL RADIOGRAPHIC OPERATIONS Radiation Safety Requirements § 34.53 Posting. All areas in which industrial radiography is...

  12. 10 CFR 34.53 - Posting.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 1 2013-01-01 2013-01-01 false Posting. 34.53 Section 34.53 Energy NUCLEAR REGULATORY COMMISSION LICENSES FOR INDUSTRIAL RADIOGRAPHY AND RADIATION SAFETY REQUIREMENTS FOR INDUSTRIAL RADIOGRAPHIC OPERATIONS Radiation Safety Requirements § 34.53 Posting. All areas in which industrial radiography is...

  13. 10 CFR 34.53 - Posting.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 1 2014-01-01 2014-01-01 false Posting. 34.53 Section 34.53 Energy NUCLEAR REGULATORY COMMISSION LICENSES FOR INDUSTRIAL RADIOGRAPHY AND RADIATION SAFETY REQUIREMENTS FOR INDUSTRIAL RADIOGRAPHIC OPERATIONS Radiation Safety Requirements § 34.53 Posting. All areas in which industrial radiography is...

  14. Post Training Needs of Urban School Counselors.

    ERIC Educational Resources Information Center

    Henderson, Phyllis

    The post-training needs of school counselors employed in urban settings were investigated in this study. A questionnaire was completed by a total of 275 school counselors from 9 urban school districts in Ohio. The top four post-training needs reported by the school counselors were the desire for training in counseling students who: (1)…

  15. Post-Lie Algebras and Isospectral Flows

    NASA Astrophysics Data System (ADS)

    Ebrahimi-Fard, Kurusch; Lundervold, Alexander; Mencattini, Igor; Munthe-Kaas, Hans Z.

    2015-11-01

    In this paper we explore the Lie enveloping algebra of a post-Lie algebra derived from a classical R-matrix. An explicit exponential solution of the corresponding Lie bracket flow is presented. It is based on the solution of a post-Lie Magnus-type differential equation.

  16. 76 FR 62461 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-07

    ... informs the public that an appeal of the closing of the Oak Hill, Alabama post office has been filed. It... Postal Service's determination to close the Oak Hill post office in Oak Hill, Alabama. The petition for review was filed by the Patrons of Oak Hill (Petitioner) and is postmarked September 19, 2011. The...

  17. Post-Colonialism Perspectives on Educational Competition

    ERIC Educational Resources Information Center

    Yeh, Chuan-Rong

    2016-01-01

    Educational competition has always been the puzzle issue of educational researches. In this article, I analyze several aspects of educational competition within the perspective of post-colonialism discourse. In the political aspect, Taiwanese education is linked with political power, to present the post-colonial spirit by continuing dynastic…

  18. 75 FR 74109 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-30

    ... informs the public that an appeal of the closing of the Graves Mill, Virginia post office has been filed... for review of the closing of the Graves Mill Post Office located in Graves Mill, Virginia. The petition, which was filed by Douglas M. Graves (Petitioner), is postmarked November 15, 2010, and...

  19. 77 FR 1750 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-11

    ... informs the public that an appeal of the closing of the Elk River, Idaho post office has been filed. It... Commission received a petition for review of the Postal Service's determination to close the Elk River post office in Elk River, Idaho. The petition for review received December 20, 2011, was filed by Dawn...

  20. 76 FR 71085 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-16

    ... informs the public that an appeal of the closing of the Deer Grove, Illinois post office has been filed... received a petition for review of the Postal Service's determination to close the Deer Grove post office in Deer Grove, Illinois. The petition for review was filed by Galen R. Hooper (Petitioner) and...

  1. 76 FR 71084 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-16

    ... informs the public that an appeal of the closing of the Orchard, Iowa post office has been filed. It... received two petitions for review of the Postal Service's determination to close the Orchard post office in Orchard, Iowa. The first petition for review was filed by Judith ] A. Schimpf. The second petition for...

  2. 76 FR 76447 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-07

    ... informs the public that an appeal of the closing of the Miller, Nebraska post office has been filed. It... received a petition for review of the Postal Service's determination to close the Miller post office in Miller, Nebraska. The petition for review was filed by Teresa Saathoff, (Petitioner) and is...

  3. 77 FR 3807 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-25

    ... informs the public that an appeal of the closing of the Badger, Iowa post office has been filed. It... Commission received four petitions for review of the Postal Service's determination to close the Badger post office in Badger, Iowa. The first petition for review received December 30, 2011, was filed by Myron...

  4. A Short Course in Post-Structuralism.

    ERIC Educational Resources Information Center

    Tompkins, Jane

    1988-01-01

    Asserts that post-structuralism cannot be applied to literary texts because to talk about applying post-structuralism assumes: (1) free-standing subjects; (2) free-standing objects of investigation; (3) free-standing methods; and (4) free-standing interpretation. (RAE)

  5. 76 FR 64127 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-17

    ... informs the public that an appeal of the closing of the Basalt, Idaho post office has been filed. It... received two petitions for review of the Postal Service's determination to close the Basalt post office in Basalt, Idaho. The petitions for review were filed by Franklyn and Nancy Freeman, and Paul and Joy...

  6. 76 FR 58545 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-21

    ... Postal Service): September 28, 2011; deadline for notices to intervene: October 11, 2011. See the... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Woodgate, New York post office has been filed. It...

  7. 76 FR 61405 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-04

    ... Commission. Shoshana M. Grove, Secretary. Procedural Schedule September 23, 2011 Filing of Appeal. October 11... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Pomfret Center, Connecticut post office has been...

  8. 46 CFR 196.12-1 - Posting.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 7 2010-10-01 2010-10-01 false Posting. 196.12-1 Section 196.12-1 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OCEANOGRAPHIC RESEARCH VESSELS OPERATIONS Stability Letter § 196.12-1 Posting. If a stability letter is issued in accordance with the requirements in § 170.120 of...

  9. 76 FR 64134 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-17

    ... informs the public that an appeal of the closing of the Conception Junction, Missouri post office has been... Junction post office in Conception Junction, Missouri. The petition for review was filed by Richard L... Federal government holidays. Docket section personnel may be contacted via electronic mail at...

  10. 76 FR 67768 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-02

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Sattley/Calpine, California post office has...

  11. 76 FR 70174 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-10

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Amoret, Missouri post office has been filed....

  12. 76 FR 46857 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-03

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Still Pond, Maryland post office has been...

  13. 76 FR 77273 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-12

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Burns, Colorado post office has been filed....

  14. 76 FR 75916 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-05

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Prince, West Virginia post office has been...

  15. 76 FR 64132 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-17

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Saint Lucas, Iowa post office has been filed....

  16. 76 FR 76202 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-06

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Little America, Wyoming post office has been...

  17. 77 FR 4381 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-27

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Peterson, Minnesota post office has been filed....

  18. 76 FR 67773 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-02

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Ozan, Arkansas post office has been filed....

  19. 76 FR 28104 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-13

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Tateville, Kentucky post office has been filed....

  20. 76 FR 70173 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-10

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the West Edmeston, New York post office has been...

  1. 76 FR 64129 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-17

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Balm, Florida post office has been filed....

  2. 76 FR 75917 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-05

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Fort Meade, South Dakota post office has...

  3. 76 FR 70175 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-10

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the New Boston, Illinois post office has been...

  4. 76 FR 67772 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-02

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Lodi, Texas post office has been filed....

  5. 76 FR 72985 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-28

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Witten, South Dakota post office has been...

  6. 76 FR 67002 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-28

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the New Hampton, Missouri post office has been...

  7. 76 FR 55951 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-09

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Bentonville, Ohio post office has been filed....

  8. 76 FR 73744 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-29

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Port Kent, New York post office has been filed....

  9. 76 FR 75569 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-02

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Prescott, Iowa post office has been filed....

  10. 76 FR 73746 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-29

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Rippey, Iowa post office has been filed....

  11. 76 FR 62097 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-06

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the West Stockholm, New York post office has...

  12. 77 FR 1754 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-11

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the St. Anthony, Iowa post office has been filed....

  13. 76 FR 73745 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-29

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Deering, Missouri post office has been filed....

  14. 77 FR 4377 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-27

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Randolph, Iowa post office has been filed....

  15. 76 FR 64131 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-17

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Bloomington, Idaho post office has been filed....

  16. 77 FR 3809 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-25

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Pierceville, Indiana post office has been...

  17. 76 FR 67767 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-02

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Glenwood, Alabama post office has been filed....

  18. 76 FR 61758 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-05

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Argyle, Florida post office has been filed....

  19. 77 FR 4383 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-27

    ... From the Federal Register Online via the Government Publishing Office ] POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Elwell, Michigan post office has been filed....

  20. 76 FR 75918 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-05

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Lanagan, Missouri post office has been filed....

  1. 76 FR 67766 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-02

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Saratoga, Arkansas post office has been filed....

  2. 76 FR 67770 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-02

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Fairfield, Kentucky post office has been filed....

  3. 76 FR 55952 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-09

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Velpen, Indiana post office has been filed....

  4. 76 FR 28103 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-13

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Gywnedd, Pennsylvania post office has been...

  5. 76 FR 44054 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-22

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Ukiah, California Main Post Office has been...

  6. 77 FR 3808 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-25

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Chilo, Ohio post office has been filed....

  7. 77 FR 1755 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-11

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Halsey, Nebraska post office has been filed....

  8. 76 FR 64130 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-17

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Scott, Mississippi post office has been filed....

  9. 76 FR 71083 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-16

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Andover, Illinois post office has been filed....

  10. 76 FR 78320 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-16

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the South Greenfield, Missouri post office has...

  11. 76 FR 78319 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-16

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Phippsburg, Colorado post office has been...

  12. 76 FR 73742 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-29

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the consolidation of the Slayden, Tennessee post office has...

  13. 76 FR 67000 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-28

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Jenkinjones, West Virginia post office has...

  14. 75 FR 66804 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-29

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This notice advises... issues raised include: Failure to follow the post office closure requirements. See 39 U.S.C....

  15. 76 FR 67001 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-28

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Witter, Arkansas post office has been filed....

  16. 76 FR 64133 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-17

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Campaign, Tennessee post office has been filed....

  17. 75 FR 78778 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-16

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Holmes Mill (Kentucky) Post Office has been...

  18. 77 FR 1752 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-11

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Ashton, Iowa, post office has been filed....

  19. 77 FR 1751 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-11

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Strandquist, Minnesota post office has been...

  20. 76 FR 75568 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-02

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the New Cambria, Kansas post office has been filed....

  1. 77 FR 3805 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-25

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Bovill, Idaho post office has been filed....

  2. 77 FR 4380 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-27

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Ponce de Leon, Missouri post office has been...

  3. 76 FR 73743 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-29

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Nemaha, Nebraska post office has been filed....

  4. 76 FR 82003 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-29

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Fostoria, Iowa post office has been filed....

  5. 77 FR 4379 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-27

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Highfalls, North Carolina post office has...

  6. 76 FR 67003 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-28

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Adona, Arkansas post office has been filed....

  7. 76 FR 67771 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-02

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the St. Olaf, Iowa post office has been filed....

  8. 77 FR 7213 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-10

    ... informs the public that an appeal of the closing of the Santa Fe, Missouri post office has been filed. It... Commission received two petitions for review of the Postal Service's determination to close the Santa Fe post office in Santa Fe, Missouri. The first petition for review received January 18, 2012, was filed...

  9. 76 FR 65545 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-21

    ... informs the public that an appeal of the closing of the Agate, Colorado post office has been filed. It... received a petition for review of the Postal Service's determination to close the Agate post office in Agate, Colorado. The petition for review was filed online on October 12, 2011 by Gail Pitzer (Petitioner...

  10. Post-Colonialism Perspectives on Educational Competition

    ERIC Educational Resources Information Center

    Yeh, Chuan-Rong

    2016-01-01

    Educational competition has always been the puzzle issue of educational researches. In this article, I analyze several aspects of educational competition within the perspective of post-colonialism discourse. In the political aspect, Taiwanese education is linked with political power, to present the post-colonial spirit by continuing dynastic…

  11. Post-Traumatic Stress Disorder - Multiple Languages

    MedlinePlus

    ... Are Here: Home → Multiple Languages → All Health Topics → Post-Traumatic Stress Disorder URL of this page: https://medlineplus.gov/languages/ ... V W XYZ List of All Topics All Post-Traumatic Stress Disorder - Multiple Languages To use the sharing features on ...

  12. 46 CFR Sec. 4 - Posting of bond.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 8 2011-10-01 2011-10-01 false Posting of bond. Sec. 4 Section 4 Shipping MARITIME ADMINISTRATION, DEPARTMENT OF TRANSPORTATION A-NATIONAL SHIPPING AUTHORITY BONDING OF SHIP'S PERSONNEL Sec. 4 Posting of bond. The General Agent shall retain an executed copy of each such bond in its principal...

  13. 77 FR 58592 - Modified Norway Post Agreement

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-21

    ... Modified Norway Post Agreement AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: The Commission is noticing a recently-filed Postal Service request to include a modified Norway Post Agreement... existing bilateral agreement for inbound competitive services with Posten Norge AS (Modified Norway...

  14. Constructing Relationships in Post-Divorce Therapy.

    ERIC Educational Resources Information Center

    Chenail, Ronald J.; And Others

    This paper introduces a post-divorce therapy project in which therapists focus on communication patterns and help families resolve their problematic post-divorce situations by co-creating more useful ways of dealing with their disputes and conflicts. The paper also examines how therapists attempt to construct alternative relationships with and…

  15. 77 FR 1962 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-12

    ... informs the public that an appeal of the closing of the Daisy, Georgia post office has been filed. It... Commission received eleven petitions for review of the Postal Service's determination to close the Daisy post office in Daisy, Georgia. The first petition for review received December 27, 2011, was filed by...

  16. 76 FR 44384 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-25

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Ben Franklin, Texas post office has been filed. It...

  17. 76 FR 44383 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-25

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Rosser, Texas post office has been filed. It...

  18. Academic Community and Post-Tenure Review.

    ERIC Educational Resources Information Center

    Tierney, William G.

    1997-01-01

    Discusses the need for post-tenure faculty review to root out "dead wood" faculty and increase faculty accountability, focusing on the time frame for such reviews, who gets reviewed, and the intensity and ramifications of the review. Also notes criticisms of post-tenure reviews and the need to build community through self-regulation.…

  19. 76 FR 72727 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-25

    ... informs the public that an appeal of the closing of the Lafayette, Kentucky post office has been filed. It... received a petition for review of the Postal Service's determination to close the Lafayette post office in Lafayette, Kentucky. The petition for review was filed by Ellin Francis, Mayor of Lafayette (Petitioner)...

  20. Post-emergence herbicides useful in calendula

    USDA-ARS?s Scientific Manuscript database

    Easy and effective weed control is required by growers who are considering new industrial crops. Post-emergence herbicides typically are the products of choice by today’s growers. Unfortunately, post-emergence herbicides with proven safety margins are not known for calendula (Calendula officinalis),...

  1. 46 CFR 169.217 - Posting.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Certification Certificate of Inspection § 169.217 Posting. The certificate of inspection must be framed under glass or other suitable transparent material and posted in a conspicuous place on the vessel except on open boats where the certificate may be retained in a watertight container, which is secured to the...

  2. 46 CFR 189.01-5 - Posting.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Certificate of Inspection § 189.01-5 Posting. (a) The original certificate of inspection shall, in general, be framed under glass or other transparent material and posted in a conspicuous place where it will be most likely to be observed. On other vessels such as barges, where the framing of the certificate under glass...

  3. Enacting Post-Reflexive Teacher Education

    ERIC Educational Resources Information Center

    Vagle, Mark D.; Monette, Rachel; Thiel, Jaye Johnson; Wester-Neal, Katie

    2017-01-01

    The purpose of this article is to re-conceptualize Schön's call for a phenomenology of practice--moving away from reflection and towards "post-reflexion"--by explicitly drawing on philosophical and methodological tenets of phenomenology, specifically some of Vagle's theorizing of a "post-intentional phenomenology." Finally, we…

  4. Vaccination in a post earthquake crisis.

    PubMed

    Wiwanitkit, Viroj

    2010-07-01

    Earthquakes are a kind of natural disaster. Several infectious diseases should be considered important emerging diseases in post-disaster situations and adequate prevention measures should be implemented in these circumstances. For prevention, vaccination is an important infection control method. In this brief article, the author will discuss the importance of vaccination in a post-earthquake situation.

  5. Nondestructive evaluation of timber highway guardrail posts

    Treesearch

    James P. Wacker; Xiping Wang; David E. Kretschmann; Douglas R. Rammer

    2010-01-01

    Timber post guardrail systems have been utilized in several regions of the U.S. due to their beneficial energy absorbing characteristics during vehicle impacts. These posts are not routinely inspected and replacement decisions are rather arbitrary. The Federal Highway Administration recently placed emphasis on new asset management strategies that actively assess...

  6. 77 FR 5582 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-03

    ... informs the public that an appeal of the closing of the Balm, Florida post office has been filed. It... Commission received a petition for review of the Postal Service's determination to close the Balm post office in Balm, Florida. The petition for review received January 26, 2012, was filed by George and Marilyn...

  7. 46 CFR 196.12-1 - Posting.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 7 2011-10-01 2011-10-01 false Posting. 196.12-1 Section 196.12-1 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OCEANOGRAPHIC RESEARCH VESSELS OPERATIONS Stability Letter § 196.12-1 Posting. If a stability letter is issued in accordance with the requirements in § 170.120...

  8. 46 CFR 189.01-5 - Posting.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 7 2011-10-01 2011-10-01 false Posting. 189.01-5 Section 189.01-5 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OCEANOGRAPHIC RESEARCH VESSELS INSPECTION AND CERTIFICATION Certificate of Inspection § 189.01-5 Posting. (a) The original certificate of inspection shall, in general,...

  9. 42 CFR 124.604 - Posted notice.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... room. (b) If in the service area of the facility the “usual language of households” of ten percent or... other than English or Spanish, the facility shall translate the notice into that language and post the translated notice on signs substantially similar in size and legibility to, and posted with, those...

  10. 10 CFR 1048.6 - Posting.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 4 2011-01-01 2011-01-01 false Posting. 1048.6 Section 1048.6 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) TRESPASSING ON STRATEGIC PETROLEUM RESERVE FACILITIES AND OTHER PROPERTY § 1048.6 Posting. Notices stating the pertinent prohibitions of §§ 1048.3 and 1048.4 and the penalties of §...

  11. 10 CFR 1048.6 - Posting.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false Posting. 1048.6 Section 1048.6 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) TRESPASSING ON STRATEGIC PETROLEUM RESERVE FACILITIES AND OTHER PROPERTY § 1048.6 Posting. Notices stating the pertinent prohibitions of §§ 1048.3 and 1048.4 and the penalties of §...

  12. 76 FR 69297 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-08

    ... informs the public that an appeal of the closing of the East Poland, Maine post office has been filed. It... received two petitions for review of the Postal Service's determination to close the East Poland post office in East Poland, Maine. The first petition for review was filed by Carl E. Duchette. The...

  13. Fiber post techniques for anatomical root variations.

    PubMed

    Boksman, Leendert; Hepburn, Alejandro Bertoldi; Kogan, Enrique; Friedman, Manny; de Rijk, Waldemar

    2011-05-01

    In contemporary dental practice, there is no remaining reason to use metallic posts, custom or prefabricated. Many cases that several years ago would have required a retentive post will not require that post today, because of the many improvements in bonding agents and composite resin restoratives. However, in cases where less than 50% of coronal tooth structure remains--or in other cases wherein the judgment of the clinician a post is indicated--there are now aesthetic, non-corrosive, fracture resistant and radiopaque alternatives for all varieties that save time and money without compromise. Their most compelling advantage, regardless of the geometry or amount of residual tooth structure, is the protection from root fracture that a low modulus restoration provides. In selecting the materials (posts, resins) for these techniques, the dentist is advised not to cut corners, and to seek the strongest and most radiopaque products available.

  14. Image post-processing in dental practice.

    PubMed

    Gormez, Ozlem; Yilmaz, Hasan Huseyin

    2009-10-01

    Image post-processing of dental digital radiographs, a function which used commonly in dental practice is presented in this article. Digital radiography has been available in dentistry for more than 25 years and its use by dental practitioners is steadily increasing. Digital acquisition of radiographs enables computer-based image post-processing to enhance image quality and increase the accuracy of interpretation. Image post-processing applications can easily be practiced in dental office by a computer and image processing programs. In this article, image post-processing operations such as image restoration, image enhancement, image analysis, image synthesis, and image compression, and their diagnostic efficacy is described. In addition this article provides general dental practitioners with a broad overview of the benefits of the different image post-processing operations to help them understand the role of that the technology can play in their practices.

  15. Flexural properties, morphology and bond strength of fiber-reinforced posts: influence of post pretreatment.

    PubMed

    Braga, Neilor Mateus Antunes; Souza-Gabriel, Aline Evangelista; Messias, Danielle Cristine Furtado; Rached-Junior, Fuad Jacob Abi; Oliveira, Camila Fávero; Silva, Ricardo Gariba; Silva-Sousa, Yara T Corrêa

    2012-01-01

    The aim of this study was to assess the influence of surface pretreatments of fiber-reinforced posts on flexural strength (FS), modulus of elasticity (ME) and morphology of these posts, as well as the bond strength (BS) between posts and core material. Fifty-two fiber posts (smooth and serrated) were assigned to 4 groups (n=13): no treatment (control), 10% hydrogen peroxide (HP) for 10 min (HP-10), 24% HP for 1 min (HP-24) and airborne-particle abrasion (Al(2)O(3)). To evaluate FS and ME, a 3-point bending test was performed. Three posts of each group were examined by scanning electron microscopy. Composite resin was used as the core build-up and samples were sectioned to obtain microtensile sticks. Data were analyzed by ANOVA and Tukey's test (α=0.05). For FS, significant differences were observed between posts type and surface pretreatment (p<0.05), with the highest means for the smooth posts. Al2O3 provided higher FS than HP-24. Al(2)O(3) promoted higher ME than HP-24 and control. SEM images revealed partial dissolution of the resin matrix in all treated groups. The smooth posts had higher BS and FS than serrated posts (p<0.05). Mechanical properties of the glass fiber posts and the bond strength between posts and composite material were not altered by the surface treatments, except for airborne-particle abrasion that increased the post elastic modulus.

  16. Recovery from post-operative anaemia.

    PubMed

    Wallis, J P; Wells, A W; Whitehead, S; Brewster, N

    2005-10-01

    Acceptance of lower transfusion thresholds and shorter post-operative stays results in patients leaving hospital after surgery with lower haemoglobin (Hb) than previously. We undertook a prospective observational study to assess the haematological response to post-operative anaemia and to determine the utility of quality of life (QoL) measures in assessing the impact of anaemia on such patients. Thirty patients undergoing unilateral hip arthroplasty had blood samples taken and QoL questionnaires administered pre-operatively and at 7, 28 and 56 days post-operatively. Increased erythropoiesis was evident at day 7 post-operatively. Approximately two-thirds of the post-operative Hb deficit was corrected by day 28. There was evidence of functional iron deficiency in more than one-quarter of patients at day 56. QoL scores used did not show any relationship with Hb in the post-operative period. Red cell 2,3-diphosphoglycerate (2,3DPG) levels increased in proportion to the degree of post-operative anaemia. We concluded that substantial recovery of Hb occurs between day 7 and day 28 post-operatively. Complete recovery of Hb may be delayed beyond day 56 due to development of iron deficiency. Patients are at significant risk of developing post-operative iron deficiency depending on operative blood loss and pre-operative iron stores. Increased red cell 2,3DPG may offset the effect of anaemia on oxygen delivery. We found no evidence that anaemia produces a measurable effect on chosen QoL scores in the post-operative period.

  17. Quick response airborne command post communications

    NASA Astrophysics Data System (ADS)

    Blaisdell, Randy L.

    1988-08-01

    National emergencies and strategic crises come in all forms and sizes ranging from natural disasters at one end of the scale up to and including global nuclear warfare at the other. Since the early 1960s the U.S. Government has spent billions of dollars fielding airborne command posts to ensure continuity of government and the command and control function during times of theater conventional, theater nuclear, and global nuclear warfare. Unfortunately, cost has prevented the extension of the airborne command post technology developed for these relatively unlikely events to the lower level, though much more likely to occur, crises such as natural disasters, terrorist acts, political insurgencies, etc. This thesis proposes the implementation of an economical airborne command post concept to address the wide variety of crises ignored by existing military airborne command posts. The system is known as the Quick Response Airborne Command Post (QRAC Post) and is based on the exclusive use of commercially owned and operated aircraft, and commercially available automated data processing and communications resources. The thesis addresses the QRAC Post concept at a systems level and is primarily intended to demonstrate how current technology can be exploited to economically achieve a national objective.

  18. Post-harvest proteomics and food security.

    PubMed

    Pedreschi, Romina; Lurie, Susan; Hertog, Maarten; Nicolaï, Bart; Mes, Jurriaan; Woltering, Ernst

    2013-06-01

    To guarantee sufficient food supply for a growing world population, efforts towards improving crop yield and plant resistance should be complemented with efforts to reduce post-harvest losses. Post-harvest losses are substantial and occur at different stages of the food chain in developed and developing countries. In recent years, a substantially increasing interest can be seen in the application of proteomics to understand post-harvest events. In the near future post-harvest proteomics will be poised to move from fundamental research to aiding the reduction of food losses. Proteomics research can help in reducing food losses through (i) identification and validation of gene products associated to specific quality traits supporting marker-assisted crop improvement programmes, (ii) delivering markers of initial quality that allow optimisation of distribution conditions and prediction of remaining shelf-life for decision support systems and (iii) delivering early detection tools of physiological or pathogen-related post-harvest problems. In this manuscript, recent proteomics studies on post-harvest and stress physiology are reviewed and discussed. Perspectives on future directions of post-harvest proteomics studies aiming to reduce food losses are presented. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Post-caesarean analgesia: What is new?

    PubMed

    Kerai, Sukhyanti; Saxena, Kirti Nath; Taneja, Bharti

    2017-03-01

    Adequate post-operative analgesia after caesarean section (CS) is vital as it impacts the distinct surgical recovery requirements of the parturient. Although newer analgesic modalities and drugs for post-caesarean analgesia have been introduced over the recent years, review of the literature suggests suggests that we are far from achieving the goals of optimum post-operative analgesia. We conducted a systematic review of recent advances in modalities for post-caesarean analgesia. After systematic search and quality assessment of studies, we included a total of 51 randomised controlled trials that evaluated the role of opioids, transversus abdominis plane (TAP) block, wound infiltration/infusion, ketamine, gabapentin and ilioinguinal-iliohypogastric nerve block (II-IH NB) for post-caesarean analgesia. Administration of opioids still remains the gold standard for post-operative analgesia, but the associated troublesome side effects have led to the mandatory incorporation of non-opioid analgesics in post-CS analgesia regime. Among the non-opioid techniques, TAP block is the most investigated modality of the last decade. The analgesic efficacy of TAP block as a part of multimodal analgesia is established in post-CS cases where intrathecal morphine is not employed and in CS under general anaesthesia. Among non-steroidal anti-inflammatory drugs, COX-I inhibitors and intravenous paracetamol are found to be useful in post-operative analgesic regimen. The perioperative use of ketamine is found useful only in CS done under spinal anaesthesia; no benefit is seen where general anaesthesia is employed. Wound infiltration with local anaesthetics, systemic gabapentin and II-IH NB need further trials to assess their efficacy.

  20. Development of new radiopaque glass fiber posts.

    PubMed

    Furtos, Gabriel; Baldea, Bogdan; Silaghi-Dumitrescu, Laura

    2016-02-01

    The aim of this study was to analyze the radiopacity and filler content of three experimental glass fiber posts (EGFP) in comparison with other glass/carbon fibers and metal posts from the dental market. Three EGFP were obtained by pultrusion of glass fibers in a polymer matrix based on 2,2-bis[4-(2-hydroxy-3-methacryloyloxypropoxy)-phenyl]propane (bis-GMA) and triethyleneglycol dimethacrylate (TEGDMA) monomers. Using intraoral sensor disks 27 posts, as well as mesiodistal sections of human molar and aluminum step wedges were radiographed for evaluation of radiopacity. The percentage compositions of fillers by weight and volume were investigated by combustion analysis. Two EGFP showed radiopacity higher than enamel. The commercial endodontic posts showed radiopacity as follows: higher than enamel, between enamel and dentin, and lower than dentin. The results showed statistically significant differences (p b 0.05)when evaluatedwith one-way ANOVA statistical analysis. According to combustion analyses, the filler content of the tested posts ranges between 58.84wt.% and 86.02wt.%. The filler content of the tested EGFP ranged between 68.91 wt.% and 79.04 wt.%. EGFP could be an alternative to commercial glass fiber posts. Futureglass fiber posts are recommended to present higher radiopacity than dentin and perhaps ideally similar to or higher than that of enamel, for improved clinical detection. The posts with a lower radiopacity than dentin should be considered insufficiently radiopaque. The radiopacity of some glass fiber posts is not greatly influenced by the amount of filler.