Effect of tadalafil on erectile dysfunction in male patients with diabetes mellitus

BACKGROUND/AIM: [corrected] During the first 10 years over 50% of diabetes patients develop erectile dysfunction (ED). It is more severe and resistant to therapy than in male patients with normal glucoregulation. The purpose of this pilot study was to estimate the tadalafil (Cialis) efficacy and safety in male patients with diabetes mellitus (DM), together with moderate to severe ED. METHODS: The study included 30 male patients with diagnozed type 1 or type 2 DM together with ED. ED was estimated through the International Index of Erectile Function (IIEF-6), Sexual Encounter Profile (SEP) questionnaire and prostaglandin test, at the beginning of the research and three months after the 20 mg tadalafil therapy initiation, once a week (on Fridays). Glycosylated haemoglobin in blood (HbAlc) values were also monitored. According to the ED severity (IIEF values at the beginning of the therapy) the patients were divided into 2 groups. The previous experience with sildenafil citrate (Viagra) and prostaglandin E1 intracavernous therapy was recorded. RESULTS: Tadalafil significantly improved ED (p < 0.001) for 7.40 points of the IIEF score, i.e. for 58% and 60% towards SEP2 and SEP3 questionnaire, respectively. Compared to the previous ED therapy subjectively better tadalafil experience was recorded. Each group experienced a significant improvement in IIEF score (p < 0.001), more significantly in the group 2 (8.26+/-1.49 points) compared with the medium improvement in the group 1 (6.27+/-1.35 points). After three months HbA1c values decreased for 2.26+/-1.62 (p < 0.001). CONCLUSION: Tadalafil is an effective tool for treating ED in diabetes patients. In some situations tadalafil application could replace prostaglandin test. The sexual sphere motivation leads to the improvement of glucoregulation in DM patients.     

JAK2 inhibitors: are they the solution?

The discovery of the JAK2V617F mutation in patients with Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPN) started the era of targeted therapy for these diseases. Until now, patients had few treatment options available, which usually were restricted to hydroxyurea, interferon preparations, and chemotherapy in more aggressive cases. JAK2 inhibitors have been developed over the past 5 years, and the results of the first clinical trials with JAK2 inhibitors for patients with myelofibrosis were recently published. Current research results suggest that JAK2 inhibitors have a potential to decrease disease burden and its activity, as manifested by a decrease in splenomegaly and improvement in systemic disease-related symptoms, but they do not seem to be able to eradicate the malignant clone. However, JAK2 inhibitors help patients regardless of their mutation status, because patients without JAK2V617F mutation benefit to the same extent as patients with JAK2V617F mutation. A greater understanding of the pathophysiology of MPNs is needed before we can cure myelofibrosis with drug therapy. Currently, several new JAK2 inhibitors are in clinical trials for patients with myelofibrosis, and clinical trials for patients with polycythemia vera and essential thrombocythemia have also started. We review recent data on JAK2 inhibitors for the management of patients with Ph-negative MPNs.     

Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel

The Janus kinase 2 mutation, JAK2617V>F, is myeloid neoplasm-specific; its presence excludes secondary polycythemia, thrombocytosis, or bone marrow fibrosis from other causes. Furthermore, JAK2617V>F or a JAK2 exon 12 mutation is present in virtually all patients with polycythemia vera (PV), whereas JAK2617V>F also occurs in approximately half of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). Therefore, JAK2 mutation screening holds the promise of a decisive diagnostic test in PV while being complementary to histology for the diagnosis of ET and PMF; the combination of molecular testing and histologic review should also facilitate diagnosis of ET associated with borderline thrombocytosis. Accordingly, revision of the current World Health Organization (WHO) diagnostic criteria for PV, ET, and PMF is warranted; JAK2 mutation analysis should be listed as a major criterion for PV diagnosis, and the platelet count threshold for ET diagnosis can be lowered from 600 to 450 x 10(9)/L. The current document was prepared by an international expert panel of pathologists and clinical investigators in myeloproliferative disorders; it was subsequently presented to members of the Clinical Advisory Committee for the revision of the WHO Classification of Myeloid Neoplasms, who endorsed the document and recommended its adoption by the WHO.     

Phase II study of low-dose decitabine in combination with imatinib mesylate in patients with accelerated or myeloid blastic phase of chronic myelogenous leukemia

BACKGROUND: Resistance to imatinib is a frequent clinical problem in advanced phase chronic myelogenous leukemia (CML). A Phase II study was performed on low-dose decitabine, a DNA methyltransferase inhibitor, in combination with imatinib in patients with CML in accelerated phase (AP) and myeloid blastic phase (BP). METHODS: Patients received decitabine 15 mg/m(2) intravenously daily, 5 days a week for 2 weeks, and imatinib 600 mg orally daily. Global DNA methylation was measured by long interspersed nucleotide element (LINE) bisulfite/pyrosequencing. RESULTS: Twenty-eight patients were enrolled (25 with imatinib resistance; 18 in AP, 10 in BP). A total of 91 cycles (median, 2.5 cycles per patient) was administered. Complete hematologic responses, partial hematologic responses, and hematologic improvement were observed in 9 (32%), 1 (4%), and 2 (7%) patients. Major and minor cytogenetic responses were observed in 5 (18%) and 3 (11%) patients. The hematologic response rate was higher in patients without BCR-ABL kinase mutations (10 of 19, 53%) than in those with mutations (1 of 7, 14%). Median duration of hematologic response was 18 (range, 4 to 107+) weeks. Myelosuppression was the major adverse effect, with neutropenic fever in 9 patients (32%). LINE methylation decreased from 71.6% +/- 0.9% (mean +/- standard error of the mean) to 60.4% +/- 2.0% on Day 5, 60.5% +/- 1.8% on Day 12, and returned to 68.8% +/- 1.4% at peripheral blood recovery. A decrease in LINE methylation tended to be greater in nonresponders than in responders on Days 5 and 12. CONCLUSIONS: Combination therapy with decitabine and imatinib is well tolerated and active in advanced phase CML without BCR-ABL kinase mutations.     

Primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (post-PV MF), post essential thrombocythemia myelofibrosis (post-ET MF), blast phase PMF (PMF-BP): Consensus on terminology by the international working group for myelofibrosis research and treatment (IWG-MRT)

The International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) is comprised of hematologists, hematopathologists, and laboratory scientists and its main goal is to provide a forum for scientific exchange and collaboration. During its first general meeting in April 2006, the IWG-MRT established uniform treatment response criteria for chronic idiopathic myelofibrosis (CIMF); also known as agnogenic myeloid metaplasia (AMM), myelofibrosis with myeloid metaplasia (MMM), and many other names in the hematologic literature. This document summarizes the proceedings from the second meeting of the IWG-MRT, in November 2006, where the group discussed and agreed to standardize the nomenclature referring to CIMF: (i) the term primary myelofibrosis (PMF) was chosen over several other designations including CIMF, AMM, and MMM, (ii) myelofibrosis that develops in the setting of either polycythemia vera (PV) or essential thrombocythemia (ET) will be referred to as post-PV MF and post-ET MF, respectively, and (iii) "leukemic" transformation will be recognized as blast phase disease (PMF-BP, post-PV/ET MF in blast phase).     

Novel tumor antigens elicit anti-tumor humoral immune reactions in a subset of patients with polycythemia vera

We attempted to determine whether the immune reactions elicited by aberrantly expressed testis antigens contribute to the beneficial responses to interferon (IFN)-alpha therapy and other therapies in patients with polycythemia vera (PV). We screened a human testis cDNA library using SEREX (serological analysis of tumor antigens by screening an expression cDNA library with sera from three patients with PV who had undergone IFN-alpha-induced or other therapeutics-induced remission). We identified two novel PV associated tumor antigens, PV65 (eIF-2alpha) and PV13 (protamine 2). These 2 antigens elicited IgG antibody reactions in a subset of PV patients but not in healthy donors, suggesting that they are authentic tumor antigens. Increased phosphorylation of PV65 in response to stimulation of IFN-alpha, and upregulation of PV13 in tumor cells might enhance their abilities in elicitation of immune reactions in patients. These findings provide new insights into the mechanism underlying the regulation of the self-antigen repertoire in eliciting anti-tumor immune reactions in patients with polycythemia vera, and suggest their potential as the targets of novel immunotherapy.