Postremission sequential monitoring of minimal residual disease by WT1 Q-PCR and multiparametric flow cytometry assessment predicts relapse and may help to address risk-adapted therapy in acute myeloid leukemia patients

Risk stratification in acute myeloid leukemia (AML) patients using prognostic parameters at diagnosis is effective, but may be significantly improved by the use of on treatment parameters which better define the actual sensitivity to therapy in the single patient. Minimal residual disease (MRD) monitoring has been demonstrated crucial for the identification of AML patients at high risk of relapse, but the best method and timing of MRD detection are still discussed. Thus, we retrospectively analyzed 104 newly diagnosed AML patients, consecutively treated and monitored by quantitative polymerase chain reactions (Q-PCR) on WT1 and by multiparametric flow cytometry (MFC) on leukemia-associated immunophenotypes (LAIPs) at baseline, after induction, after 1st consolidation and after 1st intensification. By multivariate analysis, the factors independently associated with adverse relapse-free survival (RFS) were: bone marrow (BM)-WT1 ≥ 121/10(4) ABL copies (P = 0.02) and LAIP ≥ 0.2% (P = 0.0001) (after 1st consolidation) (RFS at the median follow up of 12.5 months: 51% vs. 82% [P < 0.0001] and 57% vs. 81%, respectively [P = 0.0003]) and PB-WT1 ≥ 16/10(4) ABL copies (P = 0.0001) (after 1st intensification) (RFS 43% vs. 95% [P < 0.0001]) Our data confirm the benefits of sequential MRD monitoring with both Q-PCR and MFC. If confirmed by further prospective trials, they may significantly improve the possibility of a risk-adapted, postinduction therapy of AML

Oxidative stress and growth-regulating intracellular signaling pathways in cardiac myocytes

The toxic effects of oxidative stress on cells (including cardiac myocytes, the contractile cells of the heart) are well known. However, an increasing body of evidence has suggested that increased production of reactive oxygen species (ROS) promotes cardiac myocyte growth. Thus, ROS may be 'second messenger' molecules in their own right, and growth-promoting neurohumoral agonists might exert their effects by stimulating production of ROS. The authors review the principal growth-promoting intracellular signaling pathways that are activated by ROS in cardiac myocytes, namely the mitogen-activated protein kinase cascades (extracellular signal-regulated kinases 1/2, c-Jun N-terminal kinases, and p38-mitogen-activated protein kinases) and the phosphoinositide 3-kinase/protein kinase B (Akt) pathway. Possible mechanisms are discussed by which these pathways are activated by ROS, including the oxidation of active site cysteinyl residues of protein and lipid phosphatases with their consequent inactivation, the potential involvement of protein kinase C or the apoptosis signal-regulating kinase 1, and the current models for the activation of the guanine nucleotide binding protein Ras

Serum posaconazole levels during acute myeloid leukaemia induction therapy: correlations with breakthrough invasive fungal infections

9The usefulness of posaconazole therapeutic drug monitoring (TDM) is still a matter of debate. A correlation between posaconazole serum levels and breakthrough invasive fungal infections (IFI) has not been clearly demonstrated so far. We analysed posaconazole serum levels in patients with acute myeloid leukaemia (AML) during induction therapy and correlated them with the incidence of breakthrough IFI and the need of systemic antifungal therapy. Overall, 77 AML patients receiving posaconazole were evaluated for serum levels; breakthrough IFI were observed in five with at least one posaconazole TDM (6.5%). Median serum level was 534 ng ml(-1) (IQ range: 298.5-750.5 ng ml(-1) ) and did not change significantly over time. Four of the 40 patients with median posaconazole levels <500 ng ml(-1) developed IFI, as compared with only 1 of the 37 patients with median levels ≥500 (10% vs. 2.7%, P = 0.19). Median posaconazole levels on day 7 were 384.5 ng ml(-1) (IQ range: 207-659 ng ml(-1) ) and 560.5 ng ml(-1) (IQ range: 395-756 ng ml(-1) ) in patients requiring or not systemic antifungal treatment respectively (P = 0.067). These results seem to confirm that higher median serum levels of posaconazole correlate with higher prophylactic efficacy against proven/probable IFI and with lesser need of systemic antifungal therapy.nonenoneCattaneo, Chiara; Panzali, Annafranca; Passi, Angela; Borlenghi, Erika; Lamorgese, Cinzia; Petullà, Marta; Re, Alessandro; Caimi, Luigi; Rossi, GiuseppeCattaneo, Chiara; Panzali, Annafranca; Passi, Angela; Borlenghi, Erika; Lamorgese, Cinzia; Petullà, Marta; Re, Alessandro; Caimi, Luigi; Rossi, Giusepp

Adult onset hemophagocytic lymphohistiocytosis prognosis is affected by underlying disease and coexisting viral infection: analysis of a single institution series of 35 patients

Adult onset hemophagocytic lymphohistiocytosis (HLH) is a hyperinfiammatory syndrome, which can develop as a complication of many disorders. Early diagnosis is essential in order to avoid a fatal outcome. To confirm the diagnosis of acquired IILII made in a single institution series of adult patients with IILII-04 criteria, we applied the IlScore and evaluated prognostic factors associated with clinical outcome. The median age of 35 patients was 54 (range 17-81), M/F ratio was 20/15. In 26/35 (74.3%) patients, an underlying haematological disease was present (2 Multicentric Castleman Disease, 10 B-cell NonHodgkin Lymphoma INIILI and 14 T/NK-cell NHL); an autoimmune disorder was observed in four (11.4%) patients (one Still Disease, one undifferentiated connective tissue disease and two haemolytic anaemia); in five (14.3%), no underlying disease was identified. A concomitant infection by EBV was observed in 10 patients (28.6%), CMV in 8 (22.9%), HIM in 6 (17.1%) and HIV in 1 (2.9%). Hyperferritinemia, fever and splenomegaly were present in more than 90% of patients, whereas bone marrow hemophagocytosis in 51% of cases only. According to HScore, 34/35 patients had a >75% and 32/35 >93% probability of IILII. Four-year overall survival and IILII-free survival were 17.8% (CI 1.9-33.8) and 23.8% (CI 7.3-40.3), respectively. By multivariate analysis, presence of oedema and hyperbilirubinemia were predictors of death, whereas there was a statistically significant trend for viral infection as predictor of poor prognosis. B-NIIL diagnosis was confirmed as associated to a better prognosis in comparison with T/NK lymphoma (4-year 11FS 53.3% vs. 0%, p =0.09) and similar to other aetiologies. Copyright (C) 2016 John Wiley & Sons, Ltd