No abstract

A B S T R A C T PurposeCurrent prognostic tools in myelofibrosis (MF) fail to identify patients at the highest risk of death and are limited by their applicability only to the time of diagnosis. We aimed to define an accelerated phase (AP) in MF by characterizing disease features that can identify patients with median overall survival of Յ 12 months at any time in the disease course. Patients and MethodsBaseline characteristics of 370 consecutive patients with MF from a single center were analyzed to identify features associated with a median overall survival of Յ 12 months. These putative AP features were then validated by following the course of chronic-phase patients (no AP features at baseline) until the development of one or more AP features and determining their subsequent survival. ResultsThe following three characteristics were associated with poor survival at baseline and were selected as putative AP features: blasts in blood or bone marrow Ն 10%, platelets less than 50 ϫ 10 9 /L, and chromosome 17 aberrations (median overall survival, 10, 12, and 5 months, respectively). In the validation phase, chronic-phase patients who developed AP features during follow-up were found to have short subsequent survival times (median overall survival, 12, 15, and 6 months, respectively). AP was a necessary step in the progression to blast phase, with leukemic transformation being exceedingly rare (3% risk at 10 years) in patients who remained persistently in chronic phase. ConclusionBlood or bone marrow blasts Ն 10%, platelets less than 50 ϫ 10 9 /L, and chromosome 17 aberrations defined AP in patients with MF. Patients in AP should be candidates for intensive therapeutic interventions.

Aim African-Asian disjunctions are common in palaeotropical taxa, and are typically explained by reference to three competing hypotheses: (1) 'rafting' on the Indian tectonic plate, enabling Africa-to-Asia dispersal; (2) migration via Eocene boreotropical forests; and (3) transoceanic long-distance dispersal. These hypotheses are tested using Uvaria (Annonaceae), which is distributed in tropical regions of Africa, Asia and Australasia. Recent phylogenetic reconstructions of the genus show a clear correlation with geographical provenance, indicating a probable origin in Africa and subsequent dispersal to Asia and then Australasia. Ancestral areas and migration routes are inferred and compared with estimates of divergence times in order to distinguish between the prevailing dispersal hypotheses.Location Palaeotropics.Methods Divergence times in Uvaria are estimated by analysing the sequences of four DNA regions (matK, psbA-trnH spacer, rbcL and trnL-F) from 59 Uvaria species and 77 outgroup species, using a Bayesian uncorrelated lognormal (UCLD) relaxed molecular clock. The ancestral area of Uvaria and subsequent dispersal routes are inferred using statistical dispersal-vicariance analysis (s-diva). ResultsUvaria is estimated to have originated in continental Africa 31.6 Ma [95% highest posterior density (HPD): 38.4-25.1 Ma] between the Middle Eocene and Late Oligocene. Two main migration events during the Miocene are identified: dispersal into Madagascar around 17.0 Ma (95% HPD: 22.3-12.3 Ma); and dispersal into Asia between 21.4 Ma (95% HPD: 26.7-16.7 Ma) and 16.

Uvaria (Annonaceae), a large palaeotropical genus of woody climbers, closely resembles several other smaller genera, including Anomianthus, Cyathostemma, Ellipeia, Ellipeiopsis and Rauwenhoffia. A molecular phylogenetic analysis of this group was undertaken using maximum parsimony, maximum likelihood and Bayesian methods based on four chloroplast DNA regions (matK, psbA-trnH spacer, rbcL and trnL-F). The resultant trees were moderately well resolved with significant statistical support for most nodes. Uvaria is shown unequivocally to be paraphyletic, with all representatives of the other five genera nested within it. The distinguishing morphological characteristics of the related genera are re-evaluated, and interpreted as no more than specialised adaptations of the basic Uvaria structure. The generic names Anomianthus, Cyathostemma, Ellipeia, Ellipeiopsis and Rauwenhoffia are accordingly reduced to synonymy with Uvaria, necessitating 11 new nomenclatural combinations and four replacement names.

With the use of the International Working Group for Myelofibrosis Treatment andResearch consensus criteria, we reassessed the efficacy of thalidomide and lenalidomide in 125 patients with myelofibrosis treated in 3 consecutive phase 2 trials: 44 received single-agent thalidomide, 41 single-agent lenalidomide, and 40 a combination of lenalidomide plus prednisone. The thalidomide group included significantly more untreated patients and patients with performance status of 2. The Lenalidomide-based therapy produced higher efficacy (34%-38%) than thalidomide (16%; P ‫؍‬ .06). Responses to thalidomide were seen within 3-15 weeks, whereas responses to the lenalidomidebased therapy were also seen after a prolonged course of therapy (range, 2-45 weeks). Lenalidomide plus prednisone therapy resulted in significantly longer response duration (median, 34 months) than single-agent lenalidomide or thalidomide (median, 7 and 13 months, respectively; P ‫؍‬ .042). Fewer patients (P ‫؍‬ .001) discontinued the lenalidomide plus prednisone therapy (13%) because of side effects then patients on single-agents therapy (32%-39%). In conclusion, the combination of lenalidomide plus prednisone appears to be more effective and safer than single-agent thalidomide or lenalidomide. (Blood. 2011; 118(4):899-902)

An extended molecular phylogenetic analysis of Uvaria (Annonaceae) is presented, using maximum parsimony, maximum likelihood and Bayesian methods, based on sequences of four plastid DNA regions (matK, psbA-trnH spacer, rbcL and trnL-F). The additional taxa include the monotypic West African genus Balonga, the monotypic South-East Asian genus Dasoclema and seven Australian representatives of the genus Melodorum. The results indicate that all of these taxa are nested within a well-supported clade otherwise consisting of Uvaria species, indicating that their taxonomic treatment needs to be reassessed. The distinguishing morphological characteristics of the taxa are re-evaluated and interpreted as specialized adaptations of the basic Uvaria structure. The genus Uvaria is accordingly extended following the transfer of these species, necessitating six new nomenclatural combinations and two replacement names.

No abstract

Ruxolitinib (RUX)-based combinations may provide benefit for patients with myelofibrosis (MF). In this open-label, nonrandomized, prospective phase 2 study, patients with MF initially received RUX twice per day continuously in 28-day cycles for the first 3 cycles. Azacitidine (AZA) 25 mg/m (days 1-5) was added starting with cycle 4 and could be subsequently increased to 75 mg/m (days 1-5). Forty-six patients were enrolled with a median follow-up of 28 months (range, 4-50+ months). An International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) response was achieved in 33 patients (72%), with a median time to response of 1.8 months (range, 0.7-19.0 months). One-fourth (7 of 33) of the IWG-MRT responses occurred after the addition of AZA. A reduction of >50% in palpable spleen length at 24 weeks and at any time on the study was achieved in 62% and 71% of the evaluable patients, respectively. Among patients who achieved a >50% reduction in spleen length at 24 weeks, 95% had maintained it at 48 weeks. Notably, improvements in bone marrow reticulin fibrosis grade occurred in 57% of the patients at 24 months. Treatment discontinuations as a result of drug-related toxicities occurred in 4 patients (9%), all as a result of cytopenias. New onset grade 3 to 4 anemia and thrombocytopenia occurred in 35% and 26% of patients, respectively. RUX and AZA were safe, with encouraging spleen response rates and improvement in bone marrow fibrosis in patients with MF. This trial was registered at www.clinicaltrials.gov as #NCT01787487.