Clinical epidemiology and survival of progressive multifocal leukoencephalopathy in the era of highly active antiretroviral therapy: Data from the Italian Registry Investigative Neuro AIDS (IRINA)

Human immunodeficiency virus (HIV)-associated progressive multifocal leukoencephalopathy (PML) remains a relevant clinical problem even in the era of highly active antiretroviral therapy (HAART). Aims of the study were to analyze clinical and treatment-related features and the survival probability of PML patients observed within the Italian Registry Investigative Neuro AIDS (IRINA) during a 29-month period of HAART. Intravenous drug use, the presence of focal signs, and the involvement of white matter at neuroradiology increased the risk of having PML. A reduced probability of PML was observed when meningeal signs were reported. Patients starting HAART at PML diagnosis and previously naïve for antiretrovirals showed significantly higher 1-year probability of survival (.58), compared to those continuing HAART (.24), or never receiving HAART (.00). Higher CD4 cell count were associated with a higher survival probability (.45). At multivariate analysis, a younger age, higher CD4, starting HAART at PML diagnosis, the absence of previous acquired immunodeficiency syndrome (AIDS)-defining events, and the absence of a severe neurologic impairment were all associated with a reduced hazard of death. The use of cidofovir showed a trend towards a reduced risk of death.     

Vascular and neoplastic risk in a large cohort of patients with polycythemia vera.

PURPOSE: The clinical course of polycythemia vera is often complicated by thrombosis as well as by the possible transition to myeloid metaplasia with myelofibrosis or acute myeloid leukemia. The aim of this study was to assess the rate of these complications in subjects receiving currently recommended treatments. PATIENTS AND METHODS: Overall, 1,638 patients from 12 countries were enrolled onto a large, prospective multicenter project aimed at describing the clinical history of polycythemia vera for the following outcomes: survival, the cumulative rate of cardiovascular death and thrombosis, the cumulative rate of leukemia, myelodysplasia, and myelofibrosis. The mean duration of the disease at entry and the duration of the follow-up were 4.9 and 2.7 years, respectively. RESULTS: The overall mortality rate of 3.7 deaths per 100 persons per year resulted from a moderate risk of cardiovascular death and a high risk of death from noncardiovascular causes (mainly hematologic transformations). Age older than 65 years and a positive history of thrombosis were the most important predictors of cardiovascular events. Antiplatelet therapy, but not cytoreductive treatment, was significantly associated with a lower risk of cardiovascular events. We found a consistent association between age and risk of leukemia, and between duration of the disease with risk of myelofibrosis. CONCLUSION: The European Collaboration on Low-Dose Aspirin in Polycythemia Vera study documents that large international collaborative studies are feasible in this field, in which few epidemiologic data are available. The persistently high mortality rate from hematologic malignancies characterizes the unmet therapeutic need of polycythemic patients and suggests a priority for future studies in this disease.     

Antiretroviral treatments used among adults with HIV infection in Europe

International guidelines for the treatment of human immunodeficiency virus (HIV) infection change rapidly. They are mainly based on results from large-scale randomized clinical trials, but also on hypotheses. The objective of the study was to look at the use of antiretrovirals (ARVs) in different HIV treatment centres in Europe. Between August 1996 and September 1997 self-administered anonymous questionnaires were distributed to persons with HIV infection at inpatient and outpatient departments in 11 European countries; 1,366 people completed the questionnaire. Important differences in use of ARVs were noted between different centres. Zidovudine was the drug that was used predominantly in all countries and by 77% of all patients; the use of didanosine, zalcitabine and stavudine differed widely. Use of ARVs was found to be lower for people who reported intravenous drug use (compared to homosexual transmission), people with a low education level, and those with a monthly income lower than 992 Euro. The use of a protease inhibitor containing ARV treatment regimen was significantly lower in the centres in the south of Europe. Between 1996 and 1997, many persons with HIV infection in Europe received a suboptimal ARV treatment regimen. Use of ARVs should be improved for intravenous drug users, persons with lower educational level and lower income.     

Diagnosis, pathogenesis and treatment of the myeloproliferative disorders essential thrombocythemia, polycythemia vera and essential megakaryocytic granulocytic metaplasia and myelofibrosis

According to strict clinical, hematological and morphological criteria, the Philadelphia (Ph) chromosome negative chronic myeloproliferative disorders essential thrombocythemia (ET), polycythemia vera (PV), and agnogenic myeloid (megakaryocytic/granulocytic) metaplasia (AMM) or idiopathic myelofibrosis (IMF) are three distinct disease entities with regard to clinical manifestations, natural history and outcome in terms of life expectancy. As clonality studies have clearly demonstrated that fibroblast proliferation in AMM, as well as in many other conditions such as advanced stages of Ph(+)-essential thrombocythemia, Ph(+)-granulocytic leukemia, and Ph(-)-polycythemia vera, is polyclonal indicating that myelofibrosis is secondary to the megakaryocytic granulocytic metaplasia in these various conditions, AMM is illogically labeled as IMF. As abnormal megakaryocytic granulocytic metaplasia is the essential feature preceding the early prefibrotic stage of AMM, the term essential megakaryocytic granulocytic metaplasia (EMGM) can readily be used to characterize this condition more appropriately at the biological level. Clinical, hematological and morphological characteristics, in particular megakaryocytopoiesis and bone marrow cellularity, reveal diagnostic features, which enable a clear-cut distinction between ET, PV and EMGM or classical IMF. The characteristic increase and clustering of enlarged megakaryocytes with mature cytoplasm and multilobulated nuclei and their tendency to cluster in a normal or only slightly increased cellular bone marrow represent the hallmark of ET. The characteristic increase and clustering of enlarged mature and pleiomorphic megakaryocytes with multilobulated nuclei and proliferation of erythropoiesis in a moderate to marked hypercellular bone marrow with hyperplasia of dilated sinuses are the specific diagnostic features of untreated PV. EMGM, including the early prefibrotic stages as well as the various myelofibrotic stages of classical IMF appear to be a distinct neoplastic dual proliferation of abnormal megakaryopoiesis and granulopoiesis. The histopathology of the bone marrow in prefibrotic EMGM and in classical IMF is dominated by atypical, enlarged and immature megakaryocytes with cloud-like immature nuclei, which are not seen in ET and PV at diagnosis and during follow-up. Myelofibrosis in ET, PV and EMGM is graded into: no reticulin fibrosis (MF0), early reticulin fibrosis (MF1), advanced reticulin sclerosis with minor or moderate collagen fibrosis (MF2) and advanced collagen fibrosis with osteosclerosis (MF3). Myelofibrosis is not a feature of ET at diagnosis and during long-term follow-up. Myelofibrosis may be present in a minority of PV-patients at diagnosis and usually becomes apparent during long-term follow-up in the majority of PV-patients. Myelofibrosis secondary to the abnormal megakaryocytic and granulocytic myeloproliferation constitutes a prominent feature in the majority of EMGM/IMF at time of diagnosis and usually progresses more or less rapidly during the natural history of the disease. Life expectancy is normal in ET, normal during the 1st ten years and compromised during the 2nd ten years follow-up in PV, but significantly shortened in the prefibrotic stage of EMGM as well as in the various myelosclerotic stages of classical IMF. First line treatment options in prospective randomized clinical trials of newly diagnosed MPD-patients are control of platelet function with low-dose aspirin versus reduction of platelet count with anagrelide, interferon or hydroxyurea in ET; control of platelet and erythrocyte counts by interferon alone versus bloodletting plus hydroxyurea on indication in PV; interferon versus no treatment in the early stages of EMGM; a wait and see strategy in the fibrotic stages of EMGM or classical IMF with favorable prognostic factors, and bone marrow transplantation in classical IMF with poor prognostic factors at presentation or during short-term follow-up.     

Thrombocytosis and leukocytosis interaction in vascular complications of essential thrombocythemia

To elucidate the role of thrombocytosis, alone or in combination with standard (age, previous cardiovascular events) and novel (leukocytosis, JAK2(V617F) mutational status) risk factors, in the cardiovascular events of essential thrombocythemia (ET), we analyzed a cohort of 1063 patients. We found that a platelet count at diagnosis greater than 1000 x 10(9)/L was associated with significantly lower rate of thrombosis in multivariable analysis and, if combined with leukocytes less than 11 x 10(9)/L, pointed to a "low-risk" category with a rate of thrombosis of 1.59% of patients/year. On the contrary, the highest risk category (thrombosis rate, 2.95% of patients/year) was constituted of patients with leukocytosis, lower platelet count, and a JAK2(V617F) mutated genotype in most cases (77% vs 26% in the low-risk group), independently from standard risk factors. These data challenge the theory that elevated platelet count increases thrombosis risk in ET and suggest prospective clinical trials to support this hypothesis.     

Thylakoid potassium channel is required for efficient photosynthesis in cyanobacteria

A potassium channel (SynK) of the cyanobacterium Synechocystis sp. PCC 6803, a photoheterotrophic model organism for the study of photosynthesis, has been recently identified and demonstrated to function as a potassium selective channel when expressed in a heterologous system and to be located predominantly to the thylakoid membrane in cyanobacteria. To study its physiological role, a SynK-less knockout mutant was generated and characterized. Fluorimetric experiments indicated that SynK-less cyanobacteria cannot build up a proton gradient as efficiently as WT organisms, suggesting that SynK might be involved in the regulation of the electric component of the proton motive force. Accordingly, measurements of flash-induced cytochrome b(6)f turnover and respiration pointed to a reduced generation of ΔpH and to an altered linear electron transport in mutant cells. The lack of the channel did not cause an altered membrane organization, but decreased growth and modified the photosystem II/photosystem I ratio at high light intensities because of enhanced photosensitivity. These data shed light on the function of a prokaryotic potassium channel and reports evidence, by means of a genetic approach, on the requirement of a thylakoid ion channel for optimal photosynthesis.     

Unraveling the genetic underpinnings of myeloproliferative neoplasms and understanding their effect on disease course and response to therapy: proceedings from the 6th International Post-ASH Symposium

Immediately after the annual scientific meeting of the American Society of Hematology (ASH), a select group of clinical and laboratory investigators in myeloproliferative neoplasms (MPN) is summoned to a post-ASH conference on chronic myeloid leukemia and the BCR-ABL1-negative MPN. The 6th such meeting occurred on December 13–14,2011, in La Jolla, California, USA, under the direction of its founder,Dr. Tariq Mughal. The current document is the first of two reports on this post-ASH event and summarizes the most recent preclinical and clinical advances in polycythemia vera, essential thrombocythemia,and primary myelofibrosis.     

Primary antithrombotic prevention in carriers of antiphospholipid antibodies without systemic autoimmune disorders

Primary antithrombotic prevention with aspirin is not indicated in asymptomatic patients with confirmed antiphospholipid (aPL) positivity without systemic autoimmune disorders because: a) the estimated prevalence of thrombosis in unselected cases is about 1% patient-years (range 0-2.8); b) this level of thrombotic risk is equivalent to that of major bleeding associated with the use of aspirin and therefore the expected benefit does not outweigh the risk; c) these expectations have been confirmed by at least one randomized clinical trial, although with methodological limits. The management of modifiable thrombotic risk factors can be an alternative and safer strategy, considering that many vascular events occur in the presence of concomitant non-aPL triggering conditions. Whether primary prophylaxis with aspirin may be useful for some subsets of aPL patients at particularly high thrombotic risk, such as those with overt systemic autoimmune disorders or with special patterns of antibodies ('triple positivity'), remains to be established.