A prospective randomized clinical trial assessed the efficacy and tolerance of micafungin compared with that of standard fluconazole treatment in patients undergoing hematopoietic stem cell transplantation (HSCT). Adult patients (n = 106) were randomly assigned to receive prophylaxis with either micafungin 150 mg (n = 52), or fluconazole 400 mg (n = 52). Success was defined as the absence of suspected, proven, or probable invasive fungal infection (IFI) through the end of therapy and the absence of proven or probable IFI through the end of the 4-week period following treatment. The overall efficacy of micafungin was comparable to that of fluconazole (94 vs. 88%; difference 6.0%; 95% confidence interval, -5.4 to +17.4%; P = 0.295). A total of 2 (4.0%) of 50 patients in the micafungin arm and 6 (12.0%) of 50 patients in the fluconazole arm received empirical antifungal therapy (P = 0.06). Micafungin treatment did not result in increasing adverse effects and had a safe profile as fluconazole in neutropenic patients. This randomized trial indicates that the efficacy and tolerance of micafungin 150 mg was comparable to that of fluconazole 400 mg, suggesting that micafungin at 150 mg daily represents a valuable new treatment option for antifungal prophylaxis in HSCT recipients.

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IntroductionThe production and lineage commitment of hematopoietic progenitor cells (HPCs) is controlled by the actions of a complex network of signaling pathways. 1 Mutations and translocations of tyrosine kinases within these pathways lead to constitutive signaling and enhanced proliferation. Classic examples are BCR-ABL in chronic myeloid leukemia, 2 JAK2 mutations in a group of myeloproliferative disorders, 3 and Fms-like tyrosine kinase 3 (FLT3) and c-KIT mutations in AML. 4 FLT3 belongs to a family of type III receptor tyrosine kinases 4,5 that also includes PDGFRs, FMS, and c-KIT. The structure of these kinases is characterized by an extracellular domain consisting of 5 Ig-like domains, a single transmembrane region, a cytoplasmic juxtamembrane (JXM) domain, and a tyrosine kinase domain. 6 FLT3 is expressed on hematopoietic progenitor cells and regulates early steps of HPC proliferation, survival, and differentiation. Mutations in the receptor, both in the form of internal tandem duplication (ITD) of the JXM domain and point mutations of the tyrosine kinase domain (TKD), result in constitutive activation. Compared with the ligand-activated wild-type FLT3 (FLT3-WT) receptor, oncogenic FLT3-ITD activates aberrant signaling and shows stronger transforming potential. 5,7 The downstream signaling pathways elicited by constitutive FLT3 activation have not been fully elucidated, but the STAT5, MAPK, and PI3K/AKT pathways have all been shown to be involved. 8-10 FLT3 mutations occur in approximately one-third of AML patients and are one of the most common alterations in AML. 11 FLT3-ITD and TKD mutations are also detectable in myeloproliferative neoplasms (MPNs), 12 and several animal studies indicate that expression of FLT3-ITD alone is sufficient to induce MPN. [13][14][15] Lnk (also known as SH2B3) is expressed in HPCs and plays a critical role in cytokine signaling and hematopoiesis. [16][17][18] Together with SH2-B (SH2B1) and APS (SH2B2), Lnk belongs to a family of adaptor proteins that modulate signaling of several cytokine and growth factor receptors. [19][20][21] These family members share common structural domains, including a dimerization domain (DD) at the amino (N)-terminus, a pleckstrin homology (PH) domain in the center, and an Src homology 2 (SH2) domain near the carboxylterminus. Lnk negatively modulates several important cytokineinduced signaling pathways, including the SCF/c-KIT, erythropoietin/JAK2, and thrombopoietin (TPO)/MPL-JAK2 pathways. 17,[22][23][24] Lnk also binds and regulates MPL-W515L-and JAK2-V617F-activated forms in hematopoetic cells. 25,26 Recently, Lnk mutations that result in partial loss of function have been identified in MPN patients, suggesting an important role of Lnk in the development of the disease. 27,28 Previously, we and others have shown that Lnk interacts with the JXM domain of c-KIT. 29 We also found that Lnk binds to PDGFRA, PDGFRB, and FMS, 30,31 all of which share a similar sequence in this domain. The fact that FLT3 harbors a conserved The online version of ...

Summary We examined serum levels of the angiogenic factors, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and hepatocyte growth factor (HGF), in normal donors for allogeneic peripheral blood stem cell (PBSC) transplantation. Granulocyte colony‐stimulating factor (G‐CSF) (filgrastim 400 μg/m2/d) was administered to 23 donors for 5 d and aphereses were performed on days 4 and 5. Although bFGF remained at similar levels after G‐CSF treatment, serum VEGF and HGF levels increased 1·5‐fold (n = 13; P = 0·02) and 6·8‐fold (n = 23; P < 0·0001) respectively. The serum HGF level before G‐CSF administration on day 1 correlated inversely with mobilized CD34+ cell numbers. Time course kinetics of HGF showed that on the day after G‐CSF administration (day 2), serum HGF levels increased to 3678 pg/ml. For auto PBSC mobilization with chemotherapy and G‐CSF 200 μg/m2/d (n = 8), we observed similar HGF elevation, which appeared to be dose‐dependent on the G‐CSF administered.