Mercedes Sánchez-Barba

Prognostic impact of severe thrombocytopenia in low-risk myelodysplastic syndrome.

Thrombocytopenia is very common in myelodysplastic syndrome (MDS); however, its clinical impact in low‐risk patients remains controversial.

Analysis of incidence, risk factors and clinical outcome of thromboembolic and bleeding events in 431 allogeneic hematopoietic stem cell transplantation recipients

Allogeneic hematopoietic stem cell transplantation recipients have an increasing risk of both hemorrhagic and thrombotic complications. However, the competing risks of two of these life-threatening complications in these complex patients have still not been well defined. We retrospectively analyzed data from 431 allogeneic transplantation recipients to identify the incidence, risk factors and mortality due to thrombosis and bleeding. Significant clinical bleeding was more frequent than symptomatic thrombosis. The cumulative incidence of a bleeding episode was 30.2% at 14 years. The cumulative incidence of a venous or arterial thrombosis at 14 years was 11.8% and 4.1%, respectively. The analysis of competing factors for venous thrombosis revealed extensive chronic graft-versus-host disease to be the only independent prognostic risk factor. By contrast, six factors were associated with an increased risk of bleeding; advanced disease, ablative conditioning regimen, umbilical cord blood transplantation, anticoagulation, acute III-IV graft-versus-host disease, and transplant-associated microangiopathy. The development of thrombosis did not significantly affect overall survival (P=0.856). However, significant clinical bleeding was associated with inferior survival (P<0.001). In allogeneic hematopoietic stem cell transplantation, significant clinical bleeding is more common than thrombotic complications and affects survival.

Safety and efficacy of splenectomy in over 65‐yrs‐old patients with immune thrombocytopenia

Few studies specifically focus on elderly splenectomized immune thrombocytopenia (ITP) patients. Older patients with ITP and excellent health are often excluded from surgery splenectomy. We aimed to compare the safety and efficacy of splenectomy in elderly and non‐elderly ITP patients and to examine the effect of age on therapeutic response.

The degree of neutropenia has a prognostic impact in low risk myelodysplastic syndrome.

The severity of neutropenia in myelodysplastic syndrome (MDS) has not been completely studied. We analyzed the prognostic significance of severe neutropenia (neutrophils count <0.5×10(9)/L) at diagnosis in 1109 patients with de novo MDS and low/intermediate-1 IPSS included in the Spanish MDS Registry. Severe neutropenia was present at diagnosis in 48 of 1109 (4%). Patients with severe neutropenia were most strongly represented within the groups of refractory cytopenia with multilineage dysplasia (40%) and refractory anemia with excess of blast type 1 (29%). Severe neutropenia had negative effects on the low/intermediate-1 risk group. A significant difference in overall survival was observed between patients with severe neutropenia (28 months) and patients with a neutrophil count higher than 0.5×10(9)/L (66 months) (p<0.0001). Also, severe neutropenia predicted a significantly reduced on leukemia-free survival (p<0.0001). In the multivariate analysis, severe neutropenia retained its independent prognostic influence on overall survival [HR: 2.19, 95% CI (1.41-3.10), p<0.0001] and leukemia free survival [HR: 3.51, 95% CI (1.97-6.26), p<0.0001]. The degree of neutropenia should be considered as additional prognostic factor in low/intermediate-1 IPSS MDS.

Incidence and risk factors for life‐threatening bleeding after allogeneic stem cell transplant

Bleeding is a frequent complication after allogeneic haematopoietic stem cell transplantation (HSCT) and may affect survival. The purpose of this study was to determine the incidence and risk factors for life‐threatening bleeding after HSCT by retrospective evaluation of 491 allogeneic HSCT recipients. With a median follow‐up of 33 months, 126 out of 491 allogeneic HSCT recipients experienced a haemorrhagic event (25·7%) and 46 patients developed a life‐threatening bleeding episode (9·4%). Pulmonary and gastrointestinal bleeding were the most common sites for life‐threatening bleeding, followed by central nervous system. In multivariate analyses, the presence of severe thrombocytopenia after day +28 and the development of grade III–IV acute graft‐versus‐host disease (GVHD) or thrombotic microangiopathy (TMA) retained their association with life‐threatening bleeding events. The overall survival at 3 years among patients without bleeding was 67·1% for only 17·1% for patients with life‐threatening bleeding (P < 0·001). In conclusion, life‐threatening bleeding is a common complication after allogeneic HSCT. Prolonged severe thrombocytopenia, acute grade III–IV GVHD and TMA were associated with its development.

Factores pronósticos relacionados con la mortalidad del paciente con trauma grave: desde la atención prehospitalaria hasta la Unidad de Cuidados Intensivos

OBJECTIVE To identify factors related to mortality in adult trauma patients, analyzing the clinical, epidemiological and therapeutic characteristics at the pre-hospital levels, in the Emergency Care Department and in Intensive Care. DESIGN A retrospective, longitudinal descriptive study was carried out. Statistical analysis was performed using SPSS, MultBiplot and data mining methodology. SETTING Adult multiple trauma patients admitted to the Salamanca Hospital Complex (Spain) from 2006 to 2011. MAIN VARIABLES OF INTEREST Demographic variables, clinical, therapeutic and analytical data from the injury site to ICU admission. Evolution from ICU admission to hospital discharge. RESULTS A total of 497 patients with a median age of 45.5 years were included. Males predominated (76.7%). The main causes of injury were traffic accidents (56.1%), precipitation (18.4%) and falls (11%). The factors with the strongest association to increased mortality risk (P<.05) were age > 65 years (OR 3.15), head injuries (OR 3.1), pupillary abnormalities (OR 113.88), level of consciousness according to the Glasgow Coma Scale ≤ 8 (OR 12.97), and serum lactate levels > 4 mmol/L (OR 9.7). CONCLUSIONS The main risk factors identified in relation to the prognosis of trauma patients are referred to the presence of head injuries. Less widely known statistical techniques such as data mining or MultBiplot also underscore the importance of other factors such as lactate concentration. Trauma registries help assess the healthcare provided, with a view to adopting measures for improvement.

Comparative effect of two pan-class I PI3K inhibitors used as anticancer drugs on human T cell function

The phosphatidylinositol 3-kinase (PI3K) pathway is commonly deregulated in cancer and, thus, PI3K has been recognized as an attractive molecular target for novel anti-cancer therapies. However, the effect of PI3K inhibitors on T-cell function, a key component of antitumor immunity, has been scantly explored. The objective of this study was to investigate the effect on human T-cell activation of two PI3K inhibitors currently being tested in clinical trials: PX-866 and BKM120. Their activity against a leukemic T cell line was also assessed. For that purpose, Jurkat cells or anti-CD3/anti-CD28 stimulated human peripheral blood mononuclear cells were cultured in the presence of different concentrations of PX-866 or BKM120 and their effect on T-cell proliferation, apoptosis, expression of activation markers and cytokine secretion was analyzed by flow cytometry. In addition, Akt and Erk phosphorylation was analyzed by Western blotting. Both PX-866 and BKM120 decreased viability of Jurkat cells and blocked cell cycle progression. Regarding primary T cells, both compounds similarly inhibited expression of activation markers and cytokine secretion, although they did not induce apoptosis of stimulated T cells. Interestingly, we found differences in their ability to block T-cell proliferation and IL-2 secretion, exerting BKM120 a more potent inhibition. These disparate effects could be related to differences observed in PI3K/Akt and RAS/MEK/ERK signaling between PX-866 and BKM120 treated cells. Our results suggest that, when selecting a PI3K inhibitor for cancer therapy, immunosuppressive characteristics should be taken into account in order to minimize detrimental effects on immune function.

Profound blockade of T cell activation requires concomitant inhibition of different class I PI3K isoforms

PI3K inhibitors have emerged as potential therapeutic tools for a variety of diseases, and thus, a vast array of compounds with specificity for different PI3K isoforms is being developed. Gaining knowledge about the contribution of the different isoforms to PI3K function will allow selecting the most appropriate inhibitor for each pathology. In this study, we have addressed the effect of PI3K inhibitors with specificity for different class I PI3K isoforms on primary human T cell activation. In particular, we have analyzed proliferation, expression of activation and differentiation markers, apoptosis induction, cytokine secretion and Akt phosphorylation in T cells stimulated in vitro with anti-CD3 and anti-CD28 monoclonal antibodies and cultured with either one of these compounds: p110β-specific inhibitor TGX-221, p110δ-specific inhibitor IC-87114, p110γ inhibitor AS-242525 or pan-class I PI3K inhibitor BKM120. Inhibition of any of the isoforms led to an impairment of T cell activation, mainly of cytokine secretion and granzyme B expression. However, only complete blockade of class I PI3K activity with the pan-class I inhibitor effectively abrogated T cell proliferation. These results indicate that these three p110 isoforms (β, δ and γ) take part in T cell activation, but all of them are dispensable for T cell proliferation.

Association of Lysyl Oxidase-Like 1 Gene Polymorphisms in Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma in a Spanish Population

Abstract Purpose: To evaluate the association of the lysyl oxidase-like 1 (LOXL1) single nucleotide polymorphisms (SNPs) in a Spanish population with pseudoexfoliation syndrome (XFS) and pseudoexfoliation glaucoma (XFG). Materials and methods: The present case-control study included 100 Spanish patients (60 patients with XFS and 40 patients with XFG) and 90 control subjects. Genotypes of the three single nucleotide polymorphisms of LOXL1 (rs1048661, rs3825942, and rs2165241) were analyzed with direct sequencing. Results: The G allele and the GG genotype of SNP rs3825942 were detected at a statistically higher frequency in pseudoexfoliation patients than in control subjects (p = 3.36 × 10−5, OR = 5.71, 95% CI: 2.30–14.18; p = 3.38 × 10−5, OR = 6.91, 95% CI: 2.51–19.03 respectively). The T allele and the TT genotype of SNP rs2165241 presented at significantly higher frequencies in pseudoexfoliation patients than in controls (p = 2.50 × 10−4, OR = 2.18, 95% CI: 1.43–3.33; p = 1.21 × 10−2, OR = 2.13, 95% CI: 1.75–3.85 respectively). No significant association between XFS/XFG and the rs1048661 was observed. The GGT haplotype composed of all three risk alleles was determined to be significantly associated with pseudoexfoliation. The genotypic and allelic distributions of the three SNPs were similar between XFS and XFG. Conclusions: This is the first study associating two SNPs of LOXL1 (rs3825942 and rs2165241) and XFS/XFG in a Spanish population, confirming findings in patients from Europe. However rs1048661 SNP did not show an association with XFS.

Results of allogeneic stem cell transplantation in the Spanish MDS registry: Prognostic factors for low risk patients

Although new agents have been approved for the treatment of MDS, the only curative approach is allogeneic hematopoietic stem cell transplantation (HSCT) and thus, in particular circumstances this procedure has been proposed as a treatment option for low risk patients. We have retrospectively analyzed the results of HSCT in 291 patients from the Spanish MDS registry with special attention to low risk MDS (LR-MDS) in order to define the variables that could impact their clinical evolution after transplantation. At 2 years OS was 51% and EFS was 50% (95% CI 0.7-4.5 years for OS and 95% CI 0.1-3.9 years for EFS). Among 43 LR-MDS, transplant-related mortality was 28%. At 3 years, OS was 67% (95% CI 264.7-8927.2 days for OS) and EFS was 64% (95% CI 0-9697.2 days for EFS). In the multivariate analysis only cytogenetics retained statistical significant effect on both OS (p=.047) and EFS (p=.046). Conditioning regimen could improve outcome among this subset of patients (OS 86% and RFS 100% for patients receiving RIC regimen). The present study confirms that specific disease characteristic as well as transplant characteristics have a significant impact on transplant outcome. Regarding low risk patients a non-myeloablative conditioning would be preferable especially in cases without high-risk cytogenetics.