The purpose of this study was to conduct a two-stage case control association study including 654 acute myeloid leukaemia (AML) patients and 3477 controls ascertained through the NuCLEAR consortium to evaluate the effect of 27 immune-related single nucleotide polymorphisms (SNPs) on AML risk. In a pooled analysis of cohort studies, we found that carriers of the IL13rs1295686A/A genotype had an increased risk of AML (PCorr = 0.0144) whereas carriers of the VEGFArs25648T allele had a decreased risk of developing the disease (PCorr = 0.00086). In addition, we found an association of the IL8rs2227307 SNP with a decreased risk of developing AML that remained marginally significant after multiple testing (PCorr = 0.072). Functional experiments suggested that the effect of the IL13rs1295686 SNP on AML risk might be explained by its role in regulating IL1Ra secretion that modulates AML blast proliferation. Likewise, the protective effect of the IL8rs2227307 SNP might be mediated by TLR2-mediated immune responses that affect AML blast viability, proliferation and chemorresistance. Despite the potential interest of these results, additional functional studies are still warranted to unravel the mechanisms by which these variants modulate the risk of AML. These findings suggested that IL13, VEGFA and IL8 SNPs play a role in modulating AML risk.

Invasive aspergillosis (IA) is a life-threatening infection that affects an increasing number of patients undergoing chemotherapy or allo-transplantation, and recent studies have shown that genetic factors contribute to disease susceptibility. In this two-stage, population-based, case-control study, we evaluated whether 7 potentially functional single nucleotide polymorphisms (SNPs) within the ARNT2 and CX3CR1 genes influence the risk of IA in high-risk hematological patients.

espanolIntroduccion. La enfermedad fungica invasora (EFI) es una importante causa de morbimortalidad en pacientes hematologicos. La profilaxis antifungica (PAF) esta indicada en muchos episodios de este grupo de pacientes. El objetivo de este trabajo fue alcanzar un consenso sobre el abordaje profilactico de las EFI en el paciente hematologico con el fin de optimizar su manejo. Metodos. Un comite de expertos en hematologia y enfermedades infecciosas planteo un cuestionario de 79 items con aspectos controvertidos sobre la profilaxis antifungica en el paciente hematologico. El cuestionario fue evaluado en dos rondas por un panel de expertos siguiendo una metodologia Delphi modificada. Resultados. El cuestionario fue respondido por 44 expertos en hematologia y enfermedades infecciosas. Tras dos rondas de evaluacion se consensuaron 48 items en el acuerdo (60,7%) y 19 en el desacuerdo (24%) por lo que hubo consenso en 67 de los 79 items planteados (84,8%). Se consensuaron los perfiles de pacientes candidatos a profilaxis y se dilucidaron cuestiones relacionadas con indicaciones, mecanismos de accion, espectro de actividad, toxicidad e interacciones de los antifungicos. Se analizo particularmente la utilidad de micafungina como profilaxis de EFI. Se consensuo que micafungina es un antifungico a considerar en este contexto. Puede presentar ventajas sobre otros antifungicos por su seguridad y menor potencial de interacciones. Conclusiones. Se encontro un alto nivel de consenso en el manejo de la profilaxis de la EFI en el paciente hematologico. Este consenso ofrece indicaciones practicas sobre su manejo optimo y puede ayudar a determinar el perfil de los pacientes idoneos a recibir este tipo de intervencion. EnglishIntroduction. Invasive fungal disease (IFD) is an important cause of morbidity and mortality in haematological patients. Antifungal prophylaxis (AFP) is indicated for a number of clinical scenarios in this group of patients. The aim of this study was to reach a consensus on IFD prophylaxis in haematological patients in order to optimize their management. Methods. A committee of experts in haematology and infectious diseases compiled a survey of 79 items with controversial aspects about antifungal prophylaxis in haematological patients. The survey was evaluated in two rounds by a panel of experts following a modified Delphi methodology. Results. Forty-four experts in haematology and infectious diseases answered the survey. After two evaluation rounds, consensus was reached in 67 of the 79 items (84.8%), specifically 48 items were consensually agreed on (60.7%) and 19 were disagreed on (24.0%). Consensus was reached on prophylaxis candidates profiles and questions related to indications, mechanisms of action, spectrum of activity, toxicity and interactions of antifungal were elucidated. The usefulness of micafungin in IFD prophylaxis was particularly analysed. The consensus reached was that micafungin is an antifungal to be considered in this context as its safety profile and lower interaction potential may be advantageous. Conclusions. A broad consensus was found in the management of IFD prophylaxis in the haematological patient. This consensus provides practical indications about its optimal management and can help determine the profile of patients eligible for this type of intervention.

The widespread use of novel agents along with a more frequent application of intensive therapy, have induced better outcomes in multiple myeloma (MM). The true impact of this improvement in the context of real-life patients should be ideally assessed through population-based registry (PBR) data.

Recent studies suggest that immune-modulating single-nucleotide polymorphisms (SNPs) influence the risk of developing cancer-related infections. Here, we evaluated whether 36 SNPs within 14 immune-related genes are associated with the risk of invasive aspergillosis (IA) and whether genotyping of these variants might improve disease risk prediction. We conducted a case-control association study of 781 immunocompromised patients, 149 of whom were diagnosed with IA. Association analysis showed that the IL4Rrs2107356 and IL8rs2227307 SNPs (using dbSNP numbering) were associated with an increased risk of IA (IL4Rrs2107356 odds ratio [OR], 1.92; 95% confidence interval [CI], 1.20 to 3.09; IL8rs2227307 OR, 1.73; 95% CI, 1.06 to 2.81), whereas the IL12Brs3212227 and IFNγrs2069705 variants were significantly associated with a decreased risk of developing the infection (IL12Brs3212227 OR, 0.60; 95% CI, 0.38 to 0.96; IFNγrs2069705 OR, 0.63; 95% CI, 0.41 to 0.97). An allogeneic hematopoietic stem cell transplantation (allo-HSCT)-stratified analysis revealed that the effect observed for the IL4Rrs2107356 and IFNγrs2069705 SNPs was stronger in allo-HSCT (IL4Rrs2107356 OR, 5.63; 95% CI, 1.20 to 3.09; IFNγrs2069705 OR, 0.24; 95% CI, 0.10 to 0.59) than in non-HSCT patients, suggesting that the presence of these SNPs renders patients more vulnerable to infection, especially under severe and prolonged immunosuppressive conditions. Importantly, in vitro studies revealed that carriers of the IFNγrs2069705C allele showed a significantly increased macrophage-mediated neutralization of fungal conidia (P = 0.0003) and, under stimulation conditions, produced higher levels of gamma interferon (IFNγ) mRNA (P = 0.049) and IFNγ and tumor necrosis factor alpha (TNF-α) cytokines (P value for 96 h of treatment with lipopolysaccharide [PLPS-96 h], 0.057; P value for 96 h of treatment with phytohemagglutinin [PPHA-96 h], 0.036; PLPS+PHA-96 h = 0.030; PPHA-72 h = 0.045; PLPS+PHA-72 h = 0.018; PLPS-96 h = 0.058; PLPS+PHA-96 h = 0.0058). Finally, we also observed that the addition of SNPs significantly associated with IA to a model including clinical variables led to a substantial improvement in the discriminatory ability to predict disease (area under the concentration-time curve [AUC] of 0.659 versus AUC of 0.564; P-2 log likehood ratio test = 5.2 · 10(-4) and P50.000 permutation test = 9.34 · 10(-5)). These findings suggest that the IFNγrs2069705 SNP influences the risk of IA and that predictive models built with IFNγ, IL8, IL12p70, and VEGFA variants can used to predict disease risk and to implement risk-adapted prophylaxis or diagnostic strategies.

Introduction:The combination of a myeloablative dose of intravenous (iv) busulfan with cyclophosphamide (BuCy2) is the standard conditioning regimen for allogeneic hematopoietic stem cell transplantation in AML.In patients older than 40 years, it can be associated to high non relapse mortality (NRM).The same myeloablative dose of busulfan combined to fludarabine (BuFlu) may be associated to a lower NRM.Materials (or patients) and methods: The standard conditioning with iv busulfan at a dose of 0.8 mg/kg/6 h for 4 consecutive days for a total dose of 12.8 mg/kg, in combination with cyclophosphamide at the dose of 60 mg/kg/day for 2 consecutive days for a total dose of 120 mg/kg (BUCY2 arm) was randomly compared to the same dose of busulfan combined with fludarabine at the dose of 40 mg/m 2 /day for 4 consecutive days, for a total dose of 160 mg/m2(BUFLU arm).Eligible were patients with a diagnosis of AML in 1st or 2nd complete remission (CR) with an age Z40 andr65 years, and the availability of an HLA compatible sibling or unrelated donor.The GvHD prophylaxis was based on conventional Cyclosporine A and Methotrexate.In case of unrelated donors, ATG was given at a total dose of 5 mg/kg.The primary study end-point was the one-year NRM using an intent-to-treat analysis.Results: 252 patients were assessed for eligibility: 125 were randomized to BuCy2 (121 received the allocated intervention, 3 withdrew consent and 1 relapsed before conditioning) while 127 were randomized to BuFlu (124 received the allocated intervention and 3 relapsed before conditioning).Patients were stratified according to donor type and remission (1st vs. 2nd or more).The main clinical and transplant characteristics were well balanced between the randomization arms.The median age was 51 years, 85% of patients was in 1st remission and the ELN risk subgroups were good (11%), intermediate-1 (49%), intermediate-2 (16%) and adverse (25%).The donor was a sibling related (45%) or matched unrelated (55%) while the stem cell graft was the peripheral blood in the majority of cases.On an intent to treat basis, at 1 year, the NRM in the BUCY2 arm was 17.2% vs. 7.9% in the BUFLU (Gray Test P ¼ 0.03).At 2 years and throughout the study, the same significantly different NRM was observed between study arms being respectively 18.2% vs. 8.9% and 19% vs. 9.7% (Gray Test P ¼ 0.05) (Figure 1).By forest plots analysis the experimental treatment was better in all strata and particularly in patients in CR1.A non-significant lower incidence of relapse was documented in the BUCY2 vs. the BUFLU arm being 22.1% vs. 25.2% at 1 year, respectively (Gray test 0.47) and no difference could be detected by forest plot analysis in any strata.At 4 year, in the BuFlu and the BuCy2 arm respectively, the leukemia free survival was 51% vs. 42% and the overall survival 55% vs. 54%.The overall (grade II-IV) cumulative incidence of acute GVHD was slightly higher in the BuCy2 arm and this difference was significant (P ¼ 0.0083) when only grade III and IV were considered. Conclusion:The conditioning regimen based on Busulfan and Fludarabine was associated with a lower non-relapse mortality and less acute GvHD (grade III-IV), with a similar incidence of relapse and comparable LFS and OS.This myeloablative, albeit reduced toxicity program is a valid alternative for older AML patients.

Objective: To analyze the impact of the type of hospital in overall survival of multiple myeloma patients.Patients and method: A survival analysis was performed of all patients (n = 431) diagnosed in 5 public hospitals (4 community hospitals and one university hospital) during the period 1993-2006.Results: Patients attended to in community hospitals differ significantly from those seen in the university hospital in the following variables: mean age (70 years [31-92] versus 67.9 (35-91), P=.038); percentage of stage III patients (62.6% versus 69.1%, P=.033), and percentage of patients who had autologous stem cell transplant (8.2% versus 18.2%, P=.026). The variables associated with mortality in the multivariate analysis were age (P<.001), stage (III versus I; P=.03) and renal failure (P=.04). The type of hospital did not reach statistical significance (hazard ratio of 0.72 (95% confidence interval 0.48-1.07), P=.1].Conclusions: The type of hospital is not significantly associated with mortality in multiple myeloma patients. These data support our current model of health care, in which the community hospitals are responsible for the primary care of these patients, in a coordinated work with the university hospital. (C) 2012 Elsevier Espana, S.L. All rights reserved.