We genotyped 370 subjects with primary myelofibrosis (PMF) and 148 with postpolycythemia vera/postessential thrombocythemia (PPV/PET) MF for mutations of EZH2. Mutational status at diagnosis was correlated with hematologic parameters, clinical manifestations, and outcome. A total of 25 different EZH2 mutations were detected in 5.9% of PMF, 1.2% of PPV-MF, and 9.4% of PET-MF patients; most were exonic heterozygous missense changes. EZH2 mutation coexisted with JAK2V617F or ASXL1 mutation in 12 of 29 (41.4%) and 6 of 27 (22.2%) evaluated patients; TET2 and CBL mutations were found in 2 and 1 patients, respectively. EZH2-mutated PMF patients had significantly higher leukocyte counts, blast-cell counts, and larger spleens at diagnosis, and most of them (52.6%) were in the high-risk International Prognostic Score System (IPSS) category. After a median follow-up of 39 months, 128 patients (25.9%) died, 81 (63.3%) because of leukemia. Leukemia-free survival (LFS) and overall survival (OS) were significantly reduced in EZH2-mutated PMF patients (P ‫؍‬ .028 and P < .001, respectively); no such impact was seen for PPV/ PET-MF patients, possibly due to the low number of mutated cases. In multivariate analysis, survival of PMF patients was predicted by IPSS high-risk category, a < 25% JAK2V617F allele burden, and EZH2 mutation status. We conclude that EZH2 mutations are independently associated with shorter survival in patients with PMF. (Blood. 2011;118(19):5227-5234) IntroductionThe identification of the JAK2V617F mutation 1-4 represented a seminal discovery in the field of Philadelphia-chromosomenegative chronic myeloproliferative neoplasms (MPNs), 5 providing clues to the pathogenesis, 6 prompting a revision of the diagnostic criteria, 7 and culminating in the development of clinical trials with JAK2 (and JAK1) inhibitors. 8,9 The JAK2V617F mutation occurs in almost all patients with polycythemia vera (PV) and in 50%-70% of those with essential thrombocythemia (ET) and primary myelofibrosis (PMF). Soon after the identification of the JAK2V617F mutation, mutations in JAK2 exon 12 were described in rare patients with JAK2V617F-negative PV and mutations in MPL were reported in 5%-10% of ET or PMF subjects. The complexity of the molecular pathogenesis of MPNs is reinforced by discovery of additional mutations in TET2, 10 ASXL1, 11 CBL, 12 IDH1/IDH2, 13 and IKZF1. 14 These mutations are detected in a minority of patients at different phases of the disorder, including leukemic transformation, and are variably associated each other and with JAK2 or MPL mutations.We recently identified novel loss-of-function mutations in EZH2 in 1 of 30 (3%) PV and in 4 of 30 PMF patients (13%), as well as in 11%-25% of patients with myelodysplastic syndromes (MDS) and in 10% of patients with MDS/MPN. 15 Mutations were spread throughout the gene and included missense, nonsense, and premature stop codons; both monoallelic and biallelic mutations were described. Among patients with MDS/MPN, survival was significantly worse in those with EZH2 muta...

equivocal zone, that is, between blue-green and yellow, other factors in the clinical picture were considered to be more important; however, when the reaction color was yellow, and especially when the same reaction was pro¬ duced with 0.05 ml. of serum, the diagnosis of acute pancreatitis was considered to be definite. 550 Fifty white male adults were studied. A 25% solution of "Thorazine" was applied to the skin and covered with occlusive dressing. This was repeated after 3 days and again 3 days later.

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