CD200 genotype is associated with clinical outcome of patients with multiple myeloma.

Immune dysfunction in patients with MM affects both the innate and adaptive immune system. Molecules involved in the immune response pathways are essential to determine the ability of cancer cells to escape from the immune system surveillance. However, few data are available concerning the role of immune checkpoint molecules in predicting the myeloma control and immunological scape as mechanism of disease progression. We retrospectively analyzed the clinical impact of the CD200 genotype (rs1131199 and rs2272022) in 291 patients with newly diagnosed MM. Patients with a CD200 rs1131199 GG genotype showed a median overall survival (OS) significantly lower than those with CC+CG genotype (67.8 months versus 94.4 months respectively; p: 0.022) maintaining significance in the multivariate analysis. This effect was specially detected in patients not receiving an autologous stem cell transplant (auto-SCT) (p < 0.001). In these patients the rs1131199 GG genotype negatively influenced in the mortality not related with the progression of MM (p: 0.02) mainly due to infections events.

Genetic variants of CTLA4 are associated with clinical outcome of patients with multiple myeloma.

Immune dysfunction in patients with multiple myeloma (MM) affects both the innate and adaptive immune system. Molecules involved in the immune checkpoint pathways are essential to determine the ability of cancer cells to escape from the immune system surveillance. However, few data are available concerning the role of these molecules in predicting the kinetics of progression of MM. We retrospectively analysed polymorphisms of CTLA4 (rs231775 and rs733618), BTLA (rs9288953), CD28 (rs3116496), PD-1 (rs36084323 and rs11568821) and LAG-3 (rs870849) genes in 239 patients with newly diagnosed MM. Patients with a CTLA4 rs231775 AA/AG genotype showed a median progression-free survival (PFS) significantly lower than those with GG genotype (32.3 months versus 96.8 months respectively; p: 0.008). The 5-year PFS rate was 25% for patients with grouped AA and AG genotype vs 55.4% for patients with GG genotype. Multivariate analysis confirmed the CTLA4 rs231775 genotype as an independent risk factor for PFS (Hazard Ratio (HR): 2.05; 95% CI: 1.0-6.2; p: 0.047). Our results suggest that the CTLA4 genotype may identify patients with earlier progression of MM. This polymorphism could potentially be used as a prognostic biomarker.

LAG3 genotype of the donor and clinical outcome after allogeneic transplantation from HLA-identical sibling donors.

Introduction: The association of polymorphisms in molecules involved in the immune response (checkpoint inhibitors) with the clinical outcome after allogeneic transplantation (alloHSCT) has been described. Lymphocyte Activation 3 (LAG3) is a surface protein that plays a regulatory role in immunity as an inhibitory immune checkpoint molecule. Methods: To determine its role in the alloHSCT setting, we analyzed 797 patients transplanted from HLA-identical sibling donors. The LAG3 rs870849 C>T polymorphism was genotyped in donors. Results: We detected a higher incidence of severe acute GVHD in patients transplanted from donors with TT genotype (p: 0.047, HR 1.64; 95% CI 1.01 - 2.67). Overall survival (OS) was worse for patients transplanted from donors with the rs870849 CT/TT genotype (0.020; HR, 1.44; 95% CI 1.06 - 1.96), as well as disease-free survival (DFS) (p: 0.002; HR 1.58, 95%CI: 1.18 - 2.14) and transplant-related mortality (TRM) (p< 0.001; HR: 1.88, 95% CI 1.29 - 2.74). When combining the LAG3 rs870849 and the PDCD1 rs36084323 genotypes of the donor, three genetic groups were well defined, allowing a good stratification of the risk of acute GVHD, TRM, OS and DFS. Discussion: We conclude that the LAG3 genotype of the donor may be considered in donors' selection. As this selection may be limited in the HLA-identical sibling donor scenario, further studies exploring the impact of LAG3 genotype of the donor in unrelated transplantation are warranted.

5'-nucleotidase, cytosolic II genotype, and clinical outcome in patients with acute myeloid leukemia with intermediate-risk cytogenetics.

Acute myeloid leukemia (AML) is a complex disease, and its treatment needs to be adjusted to the risk, which is conferred by cytogenetics and molecular markers. Cytarabine is the main drug to treat AML, and it has been suggested that the genotype of cytarabine metabolizing enzymes may have a prognostic relevance in AML. Here we report the association between the 5'-nucleotidase, cytosolic II (NT5C2) rs10883841, cytidine deaminase (CDA) rs2072671 and rs532545 genotypes and the clinical outcome of 477 intermediate-risk cytogenetic AML patients receiving cytarabine-based chemotherapy. Patients younger than 50 years old with the NT5C2 rs10883841 AA genotype had lower overall survival (OS) (p: .003; HR 2.16, 95% CI 1.29-3.61) and lower disease-free survival (DFS) (p: .002; HR 2.45, 95% CI 1.41-4.27), associated to a higher relapse incidence (p: .010; HR 2.23, 95% CI 1.21-4.12). Interestingly, subgroup analysis showed that the negative effect of the NT5C2 rs10883841 AA genotype was detected in all subgroups except in patients with nucleophosmin mutation without high ratio FLT-3 internal tandem duplication. CDA polymorphisms were associated with the complete remission rate after induction chemotherapy, without influencing OS. Further studies are warranted to determine whether this pharmacogenomic approach may be helpful to individualize AML treatment.

UGT1A1 genotype influences clinical outcome in patients with intermediate-risk acute myeloid leukemia treated with cytarabine-based chemotherapy.

The treatment of acute myeloid leukemia (AML) is adjusted according to cytogenetic risk factors and molecular markers. Cytarabine remains the main drug to treat AML, and several studies have explored the prognostic relevance of the genotype of cytarabine metabolizing enzymes in AML. Glucuronidation has been identified to be relevant in the cytarabine clearance, but there are still few data concerning the clinical impact of genetic polymorphisms known to condition the activity of UDP-glucuronosyl transferases in AML patients. Here we report the association between the UGT1A1 rs8175347 genotype and the clinical outcome of 455 intermediate-risk cytogenetic AML patients receiving cytarabine-based chemotherapy. Patients with the UGT1A1*28 homozygous variant (associated to a lower UGT1A1 activity) had a lower overall survival (OS) (25.8% vs. 45.5%; p: 0.004). Multivariate analysis confirmed this association (p: 0.008; HR: 1.79; 95% CI: 1.16-2.76). Subgroup analysis showed the negative effect of the UGT1A1*28 homozygous genotype on OS in women (14.8% vs. 52.7%; p: 0.001) but not in men. This lower OS was associated with longer neutropenia after consolidation chemotherapy and with higher mortality without previous relapse, suggesting an association between a low glucuronidation activity and mortal toxic events.

Is survival in myeloid malignancies really improving? A retrospective 15-year population-based study.

Myeloid malignancies (MMs) are heterogeneous groups of diseases which present different prognoses. Using data from the population-based Girona Cancer Registry, we estimated the relative survival (RS) rates and relative excess risk of death among patients with MMs in the province of Girona between 1994 and 2008. The 5-year RS rate was 49.7%, ranging from 20.2% for acute myeloid leukemia (AML) to 75.3% for myeloproliferative neoplasms (MPN). Marked differences in RS were observed when the age of patients was considered: an increase in RS was mainly found in younger patients with myelodysplastic syndromes and MPN. Furthermore, cases of chronic myeloid leukemia treated with imatinib had a significantly better outcome compared with those that were untreated. Despite the slight improvement in the survival rate of younger patients with AML, RS remained stable for 15 years, as no significant improvements were made in the management of the disease during that period.

Kinetics of the CTLA-4 isoforms expression after T-lymphocyte activation and role of the promoter polymorphisms on CTLA-4 gene transcription.

Cytotoxic T lymphocyte antigen 4 (CTLA-4) plays a key inhibitory role during T lymphocyte activation. The CTLA4 gene is translated into two proteic isoforms: a full-length protein (flCTLA-4) and a soluble counterpart. We explored the expression of both isoforms on healthy subjects. Whereas in non-stimulated cells the flCTLA-4 isoform is predominant, after stimulation the expression of the soluble form rapidly increases, reaching its maximum 24h after and falling again to the basal levels 72 h after stimulation. In contrast, the flCTLA-4 mRNA levels increase is slower, reaching the maximum level 72 h after stimulation. The presence of the T allele in the promoter positions -1722 and -318 is associated with an increased transcriptional activity and this effect seems to be synergic. We conclude that the kinetics of CTLA-4 isoform expression are sequential, and that the promoter polymorphisms -1722(C/T) and -318(C/T) are involved in the control of the CTLA4 transcription.

Donor CTLA-4 genotype influences clinical outcome after T cell-depleted allogeneic hematopoietic stem cell transplantation from HLA-identical sibling donors.

CTLA-4 (cytotoxic T-lymphocyte antigen-4) plays a pivotal role in inhibiting T cell activation through competitive interaction with B7 molecules and interruption of costimulatory signals mediated by CD28. Polymorphisms on the CTLA-4 gene have been previously associated with autoimmune diseases, predisposition to leukemic relapse, and with graft-versus-host disease (GVHD) or relapse after allogeneic transplant. As CTLA-4 is expressed on T-lymphocytes, the aim of this study was to determine whether the donor CTLA-4 CT60 genotype also influences clinical outcome even after T cell depletion with CD34-positive selection. We studied 136 patient-donor pairs. Overall survival (OS) was worse for those patients who received grafts from a donor with the CT60 AA genotype rather than from a donor with the AG or GG genotype (35.6% vs 49.4%; P = .043). This association was confirmed through multivariate analysis, which identified the donor CT60 genotype as an independent risk factor for OS (P = .008; hazard ratio [HR]: 2.24, 95% confidence interval [CI]: 1.23-4.08). The donor CT60 AA genotype was also associated with lower disease-free survival, this being related to an increased risk of relapse (P = .001; HR: 3.41, 95% CI: 1.67-6.96) and a trend toward higher transplant-related mortality. These associations were stronger when considering only patients in the early stage of disease. Our results suggest that graft-versus-leukemia (GVL) activity after T cell depletion is conditioned by the donor CTLA-4 genotype.

Visceral leishmaniasis and macrophagic activation syndrome in a patient with rheumatoid arthritis under treatment with adalimumab.

BACKGROUND: Visceral leishmaniasis is a protozoan infection usually asymptomatic, but can progress to fatal disease in immunocompromised hosts, especially in HIV patients. Visceral leishmaniasis is rare among patients under immunosuppressive therapies, and even more among patients under anti-TNF-alpha treatment, where only four cases have been described. OBJECTIVE: 1) To describe a patient with rheumatoid arthritis receiving adalimumab who developed fever, pancytopenia, splenomegaly, and extreme hyperferritinemia. 2) To perform a review of the published cases of visceral leishmaniasis and anti-TNF-alpha therapy, and cases of coexisting leishmaniasis and macrophagic activation syndrome by search in PubMed (period 1991-2008). RESULTS: Visceral leishmaniasis was established by bone marrow aspiration, and although there was no histological confirmation, according to HLH-2004 criteria, a secondary macrophagic activation syndrome was established. The patient had a favourable outcome. CONCLUSION: We report herein the fifth case of visceral leishmaniasis in a patient under TNF-alpha therapy, and the first one, to our knowledge, presenting a consequent secondary macrophagic activation syndrome.

Advanced stage is the most important prognostic factor for survival in patients with systemic acquired immunodeficiency syndrome-related non-Hodgkin's Lymphoma treated with CHOP and highly active antiretroviral therapy.

In the era of highly active antiretroviral therapy (HAART), the prognosis for acquired immunodeficiency syndrome-related lymphomas (ARL) seems to be similar to that for aggressive B-cell lymphomas in human immunodeficiency virus (HIV)-negative patients. This improvement in prognosis might lead to a modification of the classic prognostic factors for ARL. We evaluated the prognostic factors for response and survival in a series of HIV-infected patients with systemic non-Hodgkin's lymphoma (NHL) in the HAART era. Forty patients with systemic NHL treated with a CHOP-based chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone) and HAART were studied. The main clinicopathologic and laboratory parameters were recorded in each case. Patients were scheduled to receive cycles of CHOP therapy, and all received granulocyte colony-stimulating factor. In addition, 9 patients received rituximab (375 mg/m2). The complete remission (CR) rate was 62.5% (n = 25). No prognostic factors influencing CR attainment were found. The 5-year disease-free survival (DFS) probability (95% confidence interval [CI]) was 73% (54%-92%). The median overall survival (OS) time was 69.17 months, and the 5-year OS rate (95% CI) was 51% (35%-67%). A disease stage of III to IV was the only parameter with prognostic influence on DFS. The factors influencing OS were an International Prognostic Index >2, an Eastern Cooperative Ecology Group (ECOG) score >2, and a disease stage of III to IV. Patients with an advanced stage had a lower OS probability in a multivariate analysis (odds ratio, 4.24; 95% CI, 1.24- 14.57). Advanced stage was the main prognostic factor predicting survival in ARL treated with CHOP and HAART.

Outcome and prognostic factors in patients with hematologic malignancies admitted to the intensive care unit: a single-center experience.

Patients who are admitted to the intensive care unit (ICU) with hematologic malignancies have a poor prognosis, although outcomes have improved in recent years. This study analyzed ICU mortality, short- and long-term survival, and prognostic factors for 100 consecutive critically ill patients with a hematologic malignancy who were admitted to our polyvalent ICU from January 2000 to May 2006. The median age was 55 years (range, 15-75 years; male-female ratio, 60:40). The main acute life-threatening diseases precipitating ICU transfer were respiratory failure (45 patients, 45%) and septic shock (33 patients, 33%). Forty-two patients (42%) were discharged from the ICU. The ICU mortality rate from 2004 to 2006 was lower than from 2000 to 2003 (49% versus 69%, P < .047). The 1- and 2-year probabilities of survival for patients discharged from the ICU were 67% (95% confidence interval [CI], 51%-84%) and 54% (95% CI, 34%-73%), respectively. A multivariate analysis revealed hemodynamic instability (odds ratio, 2.11; 95% CI, 1.17-3.83; P = .014) and mechanical ventilation (odds ratio, 4.27; 95% CI, 1.70-10.74; P = .002) to be the main predictors of a poor survival prognosis. Almost half of patients with hematologic malignancy and life-threatening complications can be discharged from the ICU. Age and underlying disease characteristics do not influence ICU outcome, which is mainly determined by hemodynamic and ventilatory status.

Manejo del paciente con neutropenia de bajo riesgo y fiebre / Management of low-risk febrile patients with neutropenia

La conducta clásica ante un episodio febril en un paciente neutropénico por quimioterapia ha consistido, durante años, en el ingreso hospitalario y la administración de antibioterapia empírica de amplio espectro por vía intravenosa. Sin embargo, desde finales de la década de los ochenta, se ha establecido que no todos los episodios de neutropenia comportan el mismo riesgo de complicaciones. Estos pacientes con fiebre y neutropenia de bajo riesgo, es decir, sin foco infeccioso claro, sin criterios de sepsis grave y con una duración esperada de la neutropenia inferior a 7-10 días, podrían beneficiarse de un tratamiento antibiótico ambulatorio por vía oral o, en su defecto, por vía intravenosa mediante bombas de perfusión en el propio domicilio del paciente. En este trabajo se analiza la situación actual de estas nuevas modalidades de tratamiento, que tienen como objetivos mejorar la calidad de vida de los pacientes y optimizar los recursos y costes sanitarios

For years the classical approach to febrile episodes in patients with chemotherapy-induced neutropenia consisted of hospital admission and intravenous administration of broad-spectrum antibiotics. However, since the end of the 1980s, it has been known that not all episodes of neutropenia carry the same risk of developing complications. These low risk febrile patients with neutropenia, that is, those without a clear focus of infection, without criteria for severe sepsis, and with an expected duration of neutropenia of less than 7-10 days, could benefit from outpatient oral antibiotic therapy or, failing this, from intravenous administration through a perfusion pump in the home. The present study analyzes the current situation of the new treatment modalities that aim to improve patients' quality of life and to optimize healthcare resources and costs

The prognosis of HIV-infected patients with diffuse large B-cell lymphoma treated with chemotherapy and highly active antiretroviral therapy is similar to that of HIV-negative patients receiving chemotherapy.

In the era of highly active antiretroviral treatment (HAART), the prognosis of AIDS-related lymphomas might be similar to that of aggressive B-cell lymphomas in human immunodeficiency (HIV)-negative patients. In this study we found that HIV-infected patients with diffuse large B-cell lymphoma treated with cyclophosphamide, hydroxydoxorubicin, vincristine and prednisone (CHOP) and HAART showed a similar response rate to chemotherapy, disease-free survival and overall survival as those of HIV-negative patients receiving CHOP.

¿Se ha sobrevalorado la razón normalizada internacional (INR)? / Has the international normalized ratio (INR) been overestimated?

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[Management of low-risk febrile patients with neutropenia]. / Manejo del paciente con neutropenia de bajo riesgo y fiebre.

For years the classical approach to febrile episodes in patients with chemotherapy-induced neutropenia consisted of hospital admission and intravenous administration of broad-spectrum antibiotics. However, since the end of the 1980s, it has been known that not all episodes of neutropenia carry the same risk of developing complications. These low risk febrile patients with neutropenia, that is, those without a clear focus of infection, without criteria for severe sepsis, and with an expected duration of neutropenia of less than 7-10 days, could benefit from outpatient oral antibiotic therapy or, failing this, from intravenous administration through a perfusion pump in the home. The present study analyzes the current situation of the new treatment modalities that aim to improve patients' quality of life and to optimize healthcare resources and costs.