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After the identification of the anti-inflammatory properties of VA5-13l (2-benzyl-1- methyl-5-nitroindazolinone) in previous investigations, some of its analogous compounds were designed, synthesized and evaluated in two anti-inflammatory methods: LPS-enhanced leukocyte migration assay in zebrafish; and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema. The products evaluated (3, 6, 8, 9 and 10) showed the lower values of relative leukocyte migration at 30 µM (0.14, 0.07, 0.10, 0.13 and 0.07, respectively), while in ear edema and myeloperoxidase activity methods, all the compounds reduced inflammation, only 4 and 16 yielded unsatisfactory results. The relationship linking structure and activity (SAR analysis) was determinate by using SARANEA software. The importance of the 5-Nitro group of the indazole ring for the activity was evident, and showed modest reduction when benzyl (Bn) is changed by alkyl group. A substituted Bn moiety at N2 (R) is the best substituent (5-10); nevertheless, if methylene group of Bn is deleted, the activity is affected. Also, introduction of halogen atoms mainly at positions 3 or 4 of the benzyl moiety (6 and 10) leads in general to strong activities. In fact, compounds 7 and 8 (R = 4-FBn or 4-ClBn, respectively) exhibit satisfactory results in in vivo tests and appear promising. The production of IL-6 at all doses assayed was significantly reduced, except with 16. Nonetheless, the production of TNF-α was significantly inhibited only by this chemical (16) at concentration of 50 μM. On the other hand, compound 2 was the one that mostly inhibited the expression of COX-2 and iNOS. From these results, it can be concluded that the inhibition in the release of cytokines can be one of the mechanisms of action responsible for the anti-inflammatory effect for 2-benzyl derivates while other 2-alkyl derivatives can inhibit production of NO. Therefore, nitroindazolinone chemical prototype could be an interesting structural group with anti-inflammatory purposes in the therapeutic.

In acute promyelocytic leukemia (APL), differentiation therapy with all-trans retinoic acid (ATRA) and/or arsenic trioxide can induce a differentiation syndrome (DS) with massive pulmonary infiltration of differentiating leukemic cells. Because chemokines are implicated in migration and extravasation of leukemic cells, chemokines might play a role in DS. ATRA stimulation of the APL cell line NB4 induced expression of multiple CC-chemokines (CCLs) and their receptors (> 19-fold), resulting in increased chemokine levels and chemotaxis. Induction of CCL2 and CCL24 was directly mediated by ligand-activated retinoic acid receptors. In primary leukemia cells derived from APL patients at diagnosis, ATRA induced chemokine production as well. Furthermore, in plasma of an APL patient with DS, we observed chemokine induction, suggesting that chemokines might be important in DS. Dexamethasone, which efficiently reduces pulmonary chemokine production, did not inhibit chemokine induction in APL cells. Finally, chemokine production was also induced by arsenic trioxide as single agent or in combination with ATRA. We propose that differentiation therapy may induce chemokine production in the lung and in APL cells, which both trigger migration of leukemic cells. Because dexamethasone does not efficiently reduce leukemic chemokine production, pulmonary infiltration of leukemic cells may induce an uncontrollable hyperinflammatory reaction in the lung.

Five sets of 27membered combinatorial libraries of alicyclic βlactams were prepared vialiquidphase Ugi 4center 3component reactions U4C3CR utilizing 3 different cisβamino acids, 3 different isonitriles and 5×3 sets of aldehydes. Through combinations of the building blocks of one of these libraries, all of the possible sublibraries were also generated. A few azetidinone derivatives were synthesized individually by parallel synthesis.

Summary GM-CSF administration to patients with refractory anemia (RA) induces an increase in neutrophils and eosinophils. We studied cell kinetic mechanisms underlying this observation using clonogenic assays and in vivo iododeoxyuridine labeling of bone marrow cells. Cell cycle kinetics were studied in three patients before and during GM-CSF administration (two daily subcutaneous injections of 54 or 108 ?g). No consistent effect on the relative number of bone marrow CFU-GM was noticed. The DNA synthesis time and potential doubling time of low-density bone marrow cells remained essentially the same. A slight decrease (1.5–3.7%) in labeling index was found, originating from the myelo(-mono)cytic lineage. In all three patients the release time of labeled granulocytes from the bone marrow into the peripheral blood was shortened (before GM-CSF treatment 5–7 days and during GM-CSF 3–4 days). Cell cycle kinetics of CD34+ cells were studied in order to obtain kinetic information on immature precursor and progenitor cells. The DNA synthesis time of the CD34+ cells was shortened during GM-CSF therapy, resulting in a shorter potential doubling time. GM-CSF administration to patients with RA results in a rise in granulocytes that might be due partly to an accelerated release of granulocytes from the bone marrow compartment into the circulating blood and partly to an increased proliferative activity of the immature precursor and progenitor cells.

Background: Myelodysplastic syndrome is mainly a disease of the elderly, while the prevalence of Diabetes Mellitus (DM) in the aged population is about 25%.

Background: Midostaurin (M) is an oral, multi-targeted, small molecule FLT3 inhibitor with single agent activity in both internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutant (mut) FLT3AML. This global randomized, double-blinded placebo-controlled phase III trial demonstrated a statistically significant overall survival (OS) benefit when M was added to induction and consolidation chemotherapy followed by maintenance compared to standard chemotherapy in patients (pts) with activating FLT3muts (HR=0.78, one sided p=0.0001; Stone et al NEJM, 2017). We now report a detailed comparison of CIR in each arm to determine if M significantly lowered the risk of relapse.

Background: Bone marrow examination (BME) is the gold standard for diagnosing myelodysplastic syndromes (MDS). Because it is invasive, many physicians and patients (pts) avoid BME, and the MDS Diagnosis is missed. Recently (Oster et al. Int MDS, Valencia, May 2017), we proposed a non-invasive MDS diagnostic model, using logistic regression (LoR) with a small group of patients (47 BME-proven MDS vs 63 controls with no MDS by BME). The variables gender, age, Hb, MCV, PLT and WBC were found to be the most important. Putting the variables in the formula (Fig 1) yielded a score Y, reflecting the probability of having MDS. The area under the curve (AUC) for the ROC curve was 0.748, indicating a good model, but one insufficient to provide a single Y, above which MDS could be established clearly. We therefore established two cut-off values: Pts with Y≥0.633 were found to have high likelihood for MDS, and those with Y≤0.288, a low likelihood of having MDS. Those pts (about 50%) where Y fell between the two cutoffs were indeterminate. In this study, the large European MDS Registry (EUMDS) database was used to validate and improve the model.

Allogeneic stem cell transplantation (HSCT) is the only potential curative treatment for myelodysplastic syndromes (MDS). Non-relapse mortality (NRM) remains a matter of concern despite the introduction of reduced-intensity conditioning in this disease, occurring mainly in an elderly population. Disease features and status at transplant are cornerstones for the risk of relapse. Different pre-transplant parameters have been analysed in various population without resulting in consensus.

Background.A recent large retrospective study has observed that the presence of cytogenetic clonal heterogeneity, as detected by metaphase karyotyping, was associated with poor prognosis in patients (pts) with AML (Bochtler et al., J Clin Oncol 2013, 31: 3898-905).

Background: in vivo T-cell depletion (TCD) is frequently used in the setting of allogeneic hematopoietic stem cell in order to decrease acute and chronic GVHD incidence. Several randomized studies, enrolling patients with myeloid disease have concluded to a decreased risk of GVHD without increasing the relapse risk. The present study included only myelodysplastic syndrome patients and evaluated the impact of anti-thymoglobulin (ATG) or alemtuzumab on outcomes.

Background:Patients (pts) with AML harboring FLT3-ITD mutations have poor outcomes. The higher relapse rate and inferior overall survival (OS) largely depend on the ITD mutant to wild-type (wt) allelic ratio. Furthermore, there is a strong gene-gene interaction between NPM1mutation (NPM1mut) and FLT3-ITD. Consequently, the 2017 European LeukemiaNet (ELN) has included defined NPM1/FLT3-ITD genotypes for risk categorization. In the recent phase III RATIFY trial [NCT00651261; Stone et al., NEJM 2017] the addition of the multi-targeted kinase inhibitor midostaurin (M) to standard chemotherapy significantly prolonged OS and event-free survival (EFS) in pts with newly diagnosed AML and FLT3mutation. Here, we evaluated the prognostic impact in a post-hoc analysis of the NPM1/FLT3-ITD genotypes as defined by the 2017 ELN from randomized pts treated within the RATIFY trial.

BackgroundIron overload/toxicity due to red blood cell transfusions (RBCT) is associated with morbidity and mortality in various patient groups, including patients with lower-risk myelodysplastic syndrome (LR-MDS). Many studies suggested improved overall survival (OS) after iron chelation therapy (ICT), but most studies suffer from methodological problems. In daily practice, many transfused LR-MDS patients receive ICT according to (inter)national guidelines to counteract the effects of RBCT. The value of ICT in LR-MDS remains unproven. The aim of this study is to assess the effect of ICT on OS in LR-MDS patients.