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The current consensus on the diagnosis, prognosis, and treatment of essential thrombocythemia (ET) is based on experts' recommendations. However, several aspects of the diagnosis of, prognosis of, and therapy for ET are still controversial. The Delphi method was employed with an expert panel of members of the Spanish Group of Ph-negative Myeloproliferative Neoplasms in order to identify the degree of agreement on the diagnosis, prognosis, and treatment of ET. Nine leading experts selected a total of 41 clinical hematologists with well-known expertise in ET. An electronic questionnaire was used to collect the questions rated in a four-step scale. The questions were grouped into four blocks: diagnosis, risk stratification, goals of therapy, and treatment strategy. After the first round consisting of 80 questions, a second round including 14 additional questions focused on the recommendations advocated by experts of the European LeukemiaNet in 2011 was analyzed. The median and mean values for the first and second rounds were calculated. A summary of the conclusions considered as the most representative of each block of questions is presented. The Delphi method is a powerful instrument to address the current approaches and controversies surrounding ET. [ABSTRACT FROM AUTHOR]

The discovery of somatic mutations, primarily JAK2V617F and CALR, in classic BCR-ABL1-negative myeloproliferative neoplasms (MPNs) has generated interest in the development of molecularly targeted therapies, whose accurate assessment requires a standardized framework. A working group, comprised of members from European LeukemiaNet (ELN) and International Working Group for MPN Research and Treatment (IWG-MRT), prepared consensus-based recommendations regarding trial design, patient selection and definition of relevant end points. Accordingly, a response able to capture the long-term effect of the drug should be selected as the end point of phase II trials aimed at developing new drugs for MPNs. A time-to-event, such as overall survival, or progression-free survival or both, as co-primary end points, should measure efficacy in phase III studies. New drugs should be tested for preventing disease progression in myelofibrosis patients with early disease in randomized studies, and a time to event, such as progression-free or event-free survival should be the primary end point. Phase III trials aimed at preventing vascular events in polycythemia vera and essential thrombocythemia should be based on a selection of the target population based on new prognostic factors, including JAK2 mutation. In conclusion, we recommended a format for clinical trials in MPNs that facilitates communication between academic investigators, regulatory agencies and drug companies. [ABSTRACT FROM AUTHOR]

To explore the gene expression signature in essential thrombocythemia (ET) patients in relation to JAK2V617F mutational status, expression profiling in circulating granulocytes was performed. Twenty ET were studied by microarray analysis and the results were confirmed by real-time quantitative RT-PCR in 40 ET patients, not receiving cytoreductive treatment. A heterogeneous molecular signature characterized by two main gene expression patterns was found: one with an upregulation of inflammatory genes related to neutrophil activation and thrombosis, and the other with significantly lower expression of these genes. Supervised clustering analysis showed 30 genes differentially expressed between JAK2V617F-negative and JAK2V617F-positive ET patients. Among the JAK2V617F-negative, a set of 14 genes (CISH, C13orf18, CCL3, PIM1, MAFF, SOCS3, ID2, GADD45B, KLF5, TNF, LAMB3, HRH4, TAGAP and TRIB1) showed an abnormal expression pattern. In this group of patients, CISH, SOCS2, SOCS3 and PIM1 genes, all involved in JAK-STAT signalling pathway, presented a lower expression. A two-gene predictor model was built comprising FOSB and CISH genes, which were the best discriminators of JAK2V617F status. In conclusion, JAK2V617F-negative ET patients present a characteristic gene expression profile, different from JAK2V617F-positive patients. Other pathways, besides JAK-STAT, might be implicated in the pathophysiology of JAK2V617F-negative ET patients. Leukemia (2008) 22, 1368–1376; doi:10.1038/leu.2008.112; published online 15 May 2008 [ABSTRACT FROM AUTHOR]

The frequency of vascular events and evolution to myelofibrosis (MF) in young individuals with essential thrombocythemia (ET) is not well known. The incidence and predisposing factors to such complications was studied in 126 subjects diagnosed with ET at a median age of 31 years (range: 5–40). Overall survival and probability of survival free of thrombosis, bleeding and MF were analyzed by the Kaplan–Meier method and the presence of the Janus Kinase 2 (JAK2) V617F mutation correlated with the appearance of such complications. The JAK2 mutation (present in 43% of patients) was associated with higher hemoglobin (Hb) (P<0.001) and lower platelets at diagnosis. With a median follow-up of 10 years (range: 4–25), 31 thrombotic events were registered (incidence rate: 2.2 thromboses/100 patients/year). When compared with the general population, young ET patients showed a significant increase in stroke (odds ratio 50, 95% CI: 21.5–115) and venous thromboses (odds ratio 5.3, 95% CI: 3.9–10.6). Thrombosis-free survival was 84% at 10 years, with tobacco use being associated with higher risk of thrombosis. Actuarial freedom from evolution to MF was 97% at 10 years. In conclusion, young ET patients have thrombotic events, especially stroke and venous thrombosis, more frequently than generally considered, whereas they rarely transform to MF.Leukemia (2007) 21, 1218–1223. doi:10.1038/sj.leu.2404693; published online 12 April 2007 [ABSTRACT FROM AUTHOR]

A widely accepted definition of resistance or intolerance to hydroxyurea (HU) in patients with essential thrombocythemia (ET) is lacking. An international working group (WG) was convened to develop a consensus formulation of clinically significant criteria for defining resistance/intolerance to HU in ET. To this aim, an analytic hierarchy process (AHP), a multiple-attribute decision-making technique, was used. The steps consisted of selecting the candidate criteria for defining resistance/intolerance; identifying the motivations that could influence the preference of the WG for any individual criterion; comparing the candidate criteria in a pair-wise manner; and grading them according their ability to fulfill the motivations. Every step in the model was derived by questionnaires or group discussion. The WG proposed that the definition of resistance/intolerance should require the fulfillment of at least one of the following criteria: platelet count greater than 600 000/μl after 3 months of at least 2 g/day of HU (2.5 g/day in patients with a body weight over 80 kg); platelet count greater than 400 000/μl and WBC less than 2500/μl or Hb less than 10 g/dl at any dose of HU; presence of leg ulcers or other unacceptable muco-cutaneous manifestations at any dose of HU; HU-related fever.Leukemia (2007) 21, 277–280. doi:10.1038/sj.leu.2404473; published online 16 November 2006 [ABSTRACT FROM AUTHOR]

To determine the clinicohematological factors predictive for the appearance of major vascular complications (MVC) in patients with essential thrombocythemia (ET), 148 consecutive such patients were retrospectively assessed for the development of MVC during a median follow-up of 58.5 months. Seventy-seven patients had vascular risk factors, and 37 a history of MVC at ET diagnosis. Forty-nine MVC were registered in 33 patients during the follow-up period. The actuarial probability of MVC was 27% at 6 years in the whole series, 35.6% for patients above 60 years, and 21.4% for patients younger than 60 years, whereas only one of the 36 patients younger than 45 years had MVC. At multivariate analysis, age >60 years, history of major ischemia and hypercholesterolemia were the variables associated with an increased MVC risk. These results suggest that all ET patients above 60 years should be treated, whereas in younger patients treatment decisions should be primarily based on the existence of risk factors for MVC. [ABSTRACT FROM AUTHOR]

Between January 1985 and December 1988, 386 patients with multiple myeloma were randomized to receive either MP or combination chemotherapy based on alternating cycles of VCMP and VBAP. The major prognostic parameters did not differ significantly between both treatment groups. A significantly higher proportion of objective responses was observed with combination chemotherapy as compared to MP (47.8 vs 32.2, P = 0.01). The median survival for all patients was 33.5 months. So far no significant differences were found when comparing the survival curves from both groups of patients. However, the median survival of MP-treated patients is 26.8 months, whereas the median survival of patients receiving VCMP/VBAP has not yet been reached. The definitive analysis must await the evaluation of all patients entered into the study and a longer follow-up time. [ABSTRACT FROM AUTHOR]

The article presents a study on the occurrence of myeloid differentiation primary response gene 88 (MYD88) L265P mutation in older people with diffuse large B-cell lymphoma (DLBCL). The study shows that MYD88 L265P mutation led in higher risk of lymphoma progression and death, revealing that MYD88 mutation is related to poor DLBCL outcome. MYD88 leucine to proline exchange at position 265 (L265P) promotes malignant lymphoid cell survival through mechanisms resulting to NF-kB activation.

A letter to the editor is presented which talks about the role that JAK2 gene, JAK2 V617F play in the constitutive activation of its tyrosine kinase activity in cases of Philadelphia negative myeloproliferative disorders.

A letter to the editor is presented about the analysis of the presence of the Janus kinase 2 valine for phenylalanine at position 617 in megakaryocytic cells obtained from peripheral blood of patients with essential thrombocythemia.

The numerical and morphological findings of erythroid burst colonies from the peripheral blood and bone marrow of two patients with congenital dyserythropoietic anemia type II (CDA-II) are described. In both patients there was an increase of medullary and peripheral BFU-E that was explained by a compensating mechanism against the destruction of erythrocytes. In most of the colonies normal and abnormal erythroblasts co-existed. The ultrastructural analysis of erythroblasts showed, as in vivo, bi- and multinuclearity, autophagic vacuoles, and aberrant membranes that sometimes gave rise to the double-membrane appearance. These abnormalities were found in both patients simultaneously in the blood and bone marrow. These findings point to defective erythroid stem cells. The clinical expression of the disease may depend partly on the ratio of normal to abnormal erythroid colonies. [ABSTRACT FROM AUTHOR]

A response by A. Alvarez-Larrán, F. Cervantes and C. Besses to a letter to the editor about their article "Essential thrombocythemia in young individuals: frequency and risk factors for vascular events and evolution to myelofibrosis in 126 patients" is presented.

A response by A. Alvarez-Larrán, F. Cervantes and C. Besses to a letter to the editor about their article "Essential thrombocythemia in young individuals: frequency and risk factors for vascular events and evolution to myelofibrosis in 126 patients" is presented.

A letter to the editor about the presence of a higher JAK2 V617F-mutated gene clone in platelets of essential thrombocythemia patients is presented.

A letter to the editor discussing the relation of the molecular alteration to other biomarkers in the group of chronic myeloproliferative disorders is presented.

Reports on the results of in vitro cultures of circulating myeloid progenitor cells. Reactive thrombocytosis; Megakaryocytic progenitors; Lack of endogenous growth.

A 34-yr-old woman had clinical, radiological, gastroscopic, and histological evidence of infiltrative and erosive gastritis involving the antrum. Positive serological tests for syphilis suggested gastric lues. This diagnosis was confirmed by demonstrating spirochetes in gastric mucosa by silver impregnation. [ABSTRACT FROM AUTHOR]