Revistas
Autores:
Maggioni, G.; Bersanelli, M.; Travaglino, E.; et al.
Revista:
THE LANCET. HAEMATOLOGY
ISSN:
2352-3026
Año:
2023
Vol.:
10
N°:
2
Págs.:
e117 - e128
Background Sex is a major source of diversity among patients and a sex-informed approach is becoming a new paradigm in precision medicine. We aimed to describe sex diversity in myelodysplastic syndromes in terms of disease genotype, phenotype, and clinical outcome. Moreover, we sought to incorporate sex information into the clinical decision-making process as a fundamental component of patient individuality. Methods In this multicentre, observational cohort study, we retrospectively analysed 13 284 patients aged 18 years or older with a diagnosis of myelodysplastic syndrome according to 2016 WHO criteria included in the EuroMDS network (n=2025), International Working Group for Prognosis in MDS (IWG-PM; n=2387), the Spanish Group of Myelodysplastic Syndromes registry (GESMD; n=7687), or the Dusseldorf MDS registry (n=1185). Recruitment periods for these cohorts were between 1990 and 2016. The correlation between sex and genomic features was analysed in the EuroMDS cohort and validated in the IWG-PM cohort. The effect of sex on clinical outcome, with overall survival as the main endpoint, was analysed in the EuroMDS population and validated in the other three cohorts. Finally, novel prognostic models incorporating sex and genomic information were built and validated, and compared to the widely used revised International Prognostic Scoring System (IPSS-R). This study is registered with ClinicalTrials.gov, NCT04889729. Findings The study included 7792 (58middot7%) men and 5492 (41middot3%) women. 10 906 (82middot1%) patients were White, and race was not reported for 2378 (17middot9%) patients. Sex biases were observed at the single-gene level with mutations in seven genes enriched in men (ASXL1, SRSF2, and ZRSR2 p<0middot0001 in both cohorts; DDX41 not available in the EuroMDS cohort vs p=0middot0062 in the IWG-PM cohort; IDH2 p<0middot0001 in EuroMDS vs p=0middot042 in IWG-PM; TET2 p=0middot031 vs p=0middot035; U2AF1 p=0middot033 vs p<0middot0001) and mutations in two genes were enriched in women (DNMT3A p<0middot0001 in EuroMDS vs p=0middot011 in IWG-PM; TP53 p=0middot030 vs p=0middot037). Additionally, sex biases were observed in co-mutational pathways of founding genomic lesions (splicing-related genes, predominantly in men, p<0middot0001 in both the EuroMDS and IWG-PM cohorts), in DNA methylation (predominantly in men, p=0middot046 in EuroMDS vs p<0middot0001 in IWG-PM), and TP53 mutational pathways (predominantly in women, p=0middot0073 in EuroMDS vs p<0middot0001 in IWG-PM). In the retrospective EuroMDS cohort, men had worse median overall survival (81middot3 months, 95% CI 70middot4-95middot0 in men vs 123middot5 months, 104middot5-127middot5 in women; hazard ratio [HR] 1middot40, 95% CI 1middot26-1middot52; p<0middot0001). This result was confirmed in the prospective validation cohorts (median overall survival was 54middot7 months, 95% CI 52middot4-59middot1 in men vs 74middot4 months, 69middot3-81middot2 in women; HR 1middot30, 95% CI 1middot23-1middot35; p<0middot0001 in the GEMSD MDS registry; 40middot0 months, 95% CI 33middot4-43middot7 in men vs 54middot2 months, 38middot6-63middot8 in women; HR 1middot23, 95% CI 1middot08-1middot36; p<0middot0001 in the Dusseldorf MDS registry). We developed new personalised prognostic tools that included sex information (the sex-informed prognostic scoring system and the sex-informed genomic scoring system). Sex maintained independent prognostic power in all prognostic systems; the highest performance was observed in the model that included both sex and genomic information.
A five-to-five mapping between the IPSS-R and new score categories resulted in the re-stratification of 871 (43middot0%) of 2025 patients from the EuroMDS cohort and 1003 (42middot0%) of 2387 patients from the IWG-PM cohort by using the sex-informed prognostic scoring system, and of 1134 (56middot0%) patients from the EuroMDS cohort and 1265 (53middot0%) patients from the IWG-PM cohort by using the sex-informed genomic scoring system. We created a web portal that enables outcome predictions based on a sex-informed personalised approach. Interpretation Our results suggest that a sex-informed approach can improve the personalised decision making process in patients with myelodysplastic syndromes and should be considered in the design of clinical trials including low-risk patients.
Revista:
CLINICAL CASE REPORTS
ISSN:
2050-0904
Año:
2023
Vol.:
11
N°:
6
Págs.:
e7281
This case aims to report an unusual clinical situation with uncommon and severe side effects, which can even be life threatening for the patient. The ENT and Hematology specialist should be aware of diagnosing and treating adequately.
Revista:
BRITISH JOURNAL OF HAEMATOLOGY
ISSN:
0007-1048
Año:
2023
Vol.:
201
N°:
6
Págs.:
1239 - 1244
Revista:
ELIFE
ISSN:
2050-084X
Año:
2023
Vol.:
12
Págs.:
e79363
Early hematopoiesis is a continuous process in which hematopoietic stem and progenitor cells (HSPCs) gradually differentiate toward specific lineages. Aging and myeloid malignant transformation are characterized by changes in the composition and regulation of HSPCs. In this study, we used single-cell RNA sequencing (scRNA-seq) to characterize an enriched population of human HSPCs obtained from young and elderly healthy individuals.
Based on their transcriptional profile, we identified changes in the proportions of progenitor compartments during aging, and differences in their functionality, as evidenced by gene set enrichment analysis. Trajectory inference revealed that altered gene expression dynamics accompanied cell differentiation, which could explain aging-associated changes in hematopoiesis. Next, we focused on key regulators of transcription by constructing gene regulatory networks (GRNs) and detected regulons that were specifically active in elderly individuals. Using previous findings in healthy cells as a reference, we analyzed scRNA-seq data obtained from patients with myelodysplastic syndrome (MDS) and detected specific alterations of the expression dynamics of genes involved in erythroid differentiation in all patients with MDS such as TRIB2. In addition, the comparison between transcriptional programs and GRNs regulating normal HSPCs and MDS HSPCs allowed identification of regulons that were specifically active in MDS cases such as SMAD1, HOXA6, POU2F2, and RUNX1 suggesting a role of these transcription factors (TFs) in the pathogenesis of the disease.
In summary, we demonstrate that the combination of single-cell technologies with computational analysis tools enable the study of a variety of cellular mechanisms involved in complex biological systems such as early hematopoiesis and can be used to dissect perturbed differentiation trajectories associated with perturbations such as aging and malignant transformation. Furthermore, the identification of abnormal regulatory mechanisms associated with myeloid malignancies could be exploited for personalized therapeutic approaches in individual patients.
Revista:
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN:
1422-0067
Año:
2022
Vol.:
23
N°:
17
Págs.:
9895
Multiple myeloma (MM) is the second most common haematological malignancy and remains incurable despite therapeutic advances. 18F-FDG (FDG) PET/CT is a relevant tool MM for staging and it is the reference imaging technique for treatment evaluation. However, it has limitations, and investigation of other PET tracers is required. Preliminary results with L-methyl-[11C]- methionine (MET), suggest higher sensitivity than 18F-FDG. This study aimed to compare the diagnostic accuracy and prognostic value of 1FDG and MET in MM patients. We prospectively compared FDG and MET PET/CT for assessment of bone disease and extramedullary disease (EMD) in a series of 52 consecutive patients (8 smoldering MM, 18 newly diagnosed MM and 26 relapsed MM patients). Bone marrow (BM) uptake patterns and the detection of focal lesions (FLs) and EMD were compared. Furthermore, FDG PET parameters with known MM prognostic value were explored for both tracers, as well as total lesion MET uptake (TLMU). Median patient age was 61 years (range, 37-83 years), 54% were male, 13% of them were in stage ISS (International Staging System) III, and 31% had high-risk cytogenetics. FDG PET/CT did not detect active disease in 6 patients, while they were shown to be positive by MET PET/CT. Additionally, MET PET/CT identified a higher number of FLs than FDG in more than half of the patients (63%). For prognostication we focussed on the relapsed cohort, due to the low number of progressions in the two other cohorts. Upon using FDG PET/CT in relapsed patients, the presence of more than 3 FLs (HR 4.61, p = 0.056), more than 10 FLs (HR 5.65, p = 0.013), total metabolic tumor volume (TMTV) p50 (HR 4.91, p = 0.049) or TMTV p75 (HR 5.32, p = 0.016) were associated with adverse prognosis. In MET PET/CT analysis, TMTV p50 (HR 4.71, p = 0.056), TMTV p75 (HR 6.27, p = 0.007), TLMU p50 (HR 8.8, p = 0.04) and TLMU p75 (HR 6.3, p = 0.007) adversely affected PFS. This study confirmed the diagnostic and prognostic value of FDG in MM. In addition, it highlights that MET has higher sensitivity than FDG PET/CT for detection of myeloma lesions, including FLs. Moreover, we show, for the first time, the prognostic value of TMTV and TLMU MET PET/CT in the imaging evaluation of MM patients.
Revista:
SCIENCE ADVANCES
ISSN:
2375-2548
Año:
2022
Vol.:
8
N°:
39
Págs.:
eabo0514
Identification of new markers associated with long-term efficacy in patients treated with CAR T cells is a current medical need, particularly in diseases such as multiple myeloma. In this study, we address the impact of CAR density on the functionality of BCMA CAR T cells. Functional and transcriptional studies demonstrate that CAR T cells with high expression of the CAR construct show an increased tonic signaling with up-regulation of exhaustion markers and increased in vitro cytotoxicity but a decrease in in vivo BM infiltration. Characterization of gene regulatory networks using scRNA-seq identified regulons associated to activation and exhaustion up-regulated in CARHigh T cells, providing mechanistic insights behind differential functionality of these cells. Last, we demonstrate that patients treated with CAR T cell products enriched in CARHigh T cells show a significantly worse clinical response in several hematological malignancies. In summary, our work demonstrates that CAR density plays an important role in CAR T activity with notable impact on clinical response.
Autores:
Saumell, S.; Fernández-Serrano, M.; Mesa, A.; et al.
Revista:
LEUKEMIA AND LYMPHOMA
ISSN:
1042-8194
Año:
2022
Vol.:
63
N°:
5
Págs.:
1227 - 1235
Micromegakaryocytes (microMKs) are considered a myelodysplastic feature of myeloid neoplasms in adults, with an adverse prognosis connotation. However, this notion in MDS has not been well proved. In our cohort of 287 MDS, patients with microMKs showed lower overall survival (OS) (HR, 2.12; 95% CI, 1.47-3.06; p = 0.000036) and higher risk of acute myeloid leukemia (AML) evolution (HR, 4.8; 95% CI, 2.9-11.01; p = 0.00021). Results were validated with an independent cohort. In multivariate analysis, the presence of microMKs maintained its independent association with OS (HR, 1.54, 95% CI, 1.13-2.1, p = 0.0059) and AML transformation (HR, 2.28, 95% CI, 1.2-4.4, p = 0.014). Moreover, by adding 1 point to the IPSS-R score in patients with microMKs, we improved the IPSS-R accuracy. Interestingly, adding that 1-point, 29% of intermediate IPSS-R risk group patients were upgraded to the high-risk group. In summary, we confirmed that the presence of microMKs implies worse outcomes in MDS and suggested a modification improving IPSS-R.
Revista:
NATURE COMMUNICATIONS
ISSN:
2041-1723
Año:
2022
Vol.:
13
N°:
1
Págs.:
7619
Myelodysplastic syndromes (MDS) are hematopoietic stem cell (HSC) malignancies characterized by ineffective hematopoiesis, with increased incidence in older individuals. Here we analyze the transcriptome of human HSCs purified from young and older healthy adults, as well as MDS patients, identifying transcriptional alterations following different patterns of expression. While aging-associated lesions seem to predispose HSCs to myeloid transformation, disease-specific alterations may trigger MDS development. Among MDS-specific lesions, we detect the upregulation of the transcription factor DNA Damage Inducible Transcript 3 (DDIT3). Overexpression of DDIT3 in human healthy HSCs induces an MDS-like transcriptional state, and dyserythropoiesis, an effect associated with a failure in the activation of transcriptional programs required for normal erythroid differentiation. Moreover, DDIT3 knockdown in CD34+ cells from MDS patients with anemia is able to restore erythropoiesis. These results identify DDIT3 as a driver of dyserythropoiesis, and a potential therapeutic target to restore the inefficient erythroid differentiation characterizing MDS patients. © 2022, The Author(s).
Revista:
FRONTIERS IN ONCOLOGY
ISSN:
2234-943X
Año:
2022
Vol.:
12
Págs.:
1054458
Acute myeloid leukemia (AML) in the elderly remains a clinical challenge, with a five-year overall survival rate below 10%. The current ELN 2017 genetic risk classification considers cytogenetic and mutational characteristics to stratify fit AML patients into different prognostic groups. However, this classification is not validated for elderly patients treated with a non-intensive approach, and its performance may be suboptimal in this context. Indeed, the transcriptomic landscape of AML in the elderly has been less explored and it might help stratify this group of patients. In the current study, we analyzed the transcriptome of 224 AML patients > 65 years-old at diagnosis treated in the Spanish PETHEMA-FLUGAZA clinical trial in order to identify new prognostic biomarkers in this population. We identified a specific transcriptomic signature for high-risk patients with mutated TP53 or complex karyotype, revealing that low expression of B7H3 gene with high expression of BANP gene identifies a subset of high-risk AML patients surviving more than 12 months. This result was further validated in the BEAT AML cohort. This unique signature highlights the potential of transcriptomics to identify prognostic biomarkers in in elderly AML.
Autores:
Steensma, D. P.; Wermke, M.; Klimek, V. M.; et al.
Revista:
LEUKEMIA
ISSN:
0887-6924
Año:
2021
Vol.:
35
N°:
12
Págs.:
3542 - 3550
We conducted a phase I clinical trial of H3B-8800, an oral small molecule that binds Splicing Factor 3B1 (SF3B1), in patients with MDS, CMML, or AML. Among 84 enrolled patients (42 MDS, 4 CMML and 38 AML), 62 were red blood cell (RBC) transfusion dependent at study entry. Dose escalation cohorts examined two once-daily dosing regimens: schedule I (5 days on/9 days off, range of doses studied 1-40 mg, n = 65) and schedule II (21 days on/7 days off, 7-20 mg, n = 19); 27 patients received treatment for >= 180 days. The most common treatment-related, treatment-emergent adverse events included diarrhea, nausea, fatigue, and vomiting. No complete or partial responses meeting IWG criteria were observed; however, RBC transfusion free intervals >56 days were observed in nine patients who were transfusion dependent at study entry (15%). Of 15 MDS patients with missense SF3B1 mutations, five experienced RBC transfusion independence (TI). Elevated pre-treatment expression of aberrant transcripts of Transmembrane Protein 14C (TMEM14C), an SF3B1 splicing target encoding a mitochondrial porphyrin transporter, was observed in MDS patients experiencing RBC TI. In summary, H3B-8800 treatment was associated with mostly low-grade TAEs and induced RBC TI in a biomarker-defined subset of MDS.
Revista:
PLOS ONE
ISSN:
1932-6203
Año:
2020
Vol.:
15
N°:
1
Págs.:
e0227986
The diagnosis of myeloid neoplasms (MN) has significantly evolved through the last few decades. Next Generation Sequencing (NGS) is gradually becoming an essential tool to help clinicians with disease management. To this end, most specialized genetic laboratories have implemented NGS panels targeting a number of different genes relevant to MN. The aim of the present study is to evaluate the performance of four different targeted NGS gene panels based on their technical features and clinical utility. A total of 32 patient bone marrow samples were accrued and sequenced with 3 commercially available panels and 1 custom panel. Variants were classified by two geneticists based on their clinical relevance in MN. There was a difference in panel¿s depth of coverage. We found 11 discordant clinically relevant variants between panels, with a trend to miss long insertions. Our data show that there is a high risk of finding different mutations depending on the panel of choice, due both to the panel design and the data analysis method. Of note, CEBPA, CALR and FLT3 genes, remains challenging the use of NGS for diagnosis of MN in compliance with current guidelines. Therefore, conventional molecular testing might need to be kept in place for the correct diagnosis of MN for now.
Revista:
JCO GLOBAL ONCOLOGY
ISSN:
2687-8941
Año:
2020
Vol.:
6
Págs.:
904 - 905
Revista:
LEUKEMIA RESEARCH
ISSN:
0145-2126
Myeloid neoplasms (MN) are usually sporadic late-onset cancers; nevertheless, growing evidence suggests that similar to 5% of the cases could emerge as a consequence of inherited predisposition. Distinguishing somatic from germline variants is of vital importance, in order to establish an appropriate individualized management and counsel the patients and their relatives. Since many of the genes associated with myeloid neoplasm germline predisposition (MNGP) are also affected in sporadic MN, we intended to design a strategy to identify potentially inherited variants in a tumor only NGS panel in a cohort of 299 patients with a variety of MN. We considered as indicative of potential inherited origin, variants detected in BM sample at a similar to 50% VAF classified as pathogenic, likely pathogenic or of unknown significance detected in MNGP-related genes. A total of 104 suspicious variants from 90 patients were filtered-in in tumor samples. Mutational patterns, follow-up data, and sequencing of a range of non-myeloid tissues were used for narrowing down the list of suspicious variants, and ultimately discriminate their nature. Our data supports the importance of considering variants found upon tumor-only sequencing as potentially of germline origin, and we offer a pipeline to define the nature of the variants.
Autores:
Naqvi, K.; Sasaki, K.; Montalban-Bravo, G.; et al.
Revista:
CANCER
ISSN:
0008-543X
Año:
2019
Vol.:
125
N°:
13
Págs.:
2233 - 2241
Background: Clonal hematopoiesis of indeterminate potential (CHIP)-associated mutations increase the risk of atherosclerotic heart disease. Comorbidities significantly impact the prognosis of patients with myelodysplastic syndromes (MDS). The objective of this study was to determine the association and impact of CHIP mutations with comorbidities in patients with MDS.
Methods: This retrospective analysis of 566 consecutive patients with MDS was conducted at The University of Texas MD Anderson Cancer Center from August 2013 to December 2016. The 27-item Adult Comorbidity Evaluation (ACE-27) scale was used to assess the severity of comorbid conditions. Next-generation sequencing was used to detect the presence of CHIP mutations in bone marrow aspirates. Spearman correlations and logistic regression analyses were used to determine the association between mutations and comorbidities.
Results: Mutations in the genes tet methylcytosine dioxygenase 2 (TET2), ASXL transcriptional regulator 1 (ASXL1), DNA methyltransferase 3¿ (DNMT3A), Janus kinase 2 (JAK2), and tumor protein 53 (TP53) were noted in 20%, 18%, 9%, 2%, and 21% of patients, respectively. Patients with DNMT3A and JAK2 mutations had higher likelihoods of a prior history of myocardial infarction (odds ratio, 2.62; P = .03) and veno-occlusive disease (odds ratio, 6.48; P = .02), respectively. TP53 mutation was associated with a prior history of malignancy. Patients with TET2 mutation had no association with any comorbidity. A prognostic model including the revised International Prognostic Scoring System classification, the ACE-27 score, and TP53 mutation status (the I-RAT model) predicted median overall survival.
Conclusions: In patients with MDS, the presence of CHIP-associated mutations is associated with comorbidities. DNMT3A and JAK2 mutations were associated with higher likelihoods of prior myocardial infarction and thrombotic events. There was no association between comorbidity and TET2 mutation. Incorporating the revised International Prognostic Scoring System classification with the ACE-27 and TP53 mutation status improved outcome prediction in patients with MDS.
Revista:
TH OPEN
ISSN:
2512-9465
Año:
2019
Vol.:
3
N°:
2
Págs.:
e153 - e156
Revista:
CLINICAL AND TRANSLATIONAL ONCOLOGY
ISSN:
1699-048X
Año:
2019
Vol.:
21
N°:
6
Págs.:
805 - 809
PURPOSE:
Thromboprophylaxis use among medical inpatients, including cancer patients, is suboptimal. We aimed to evaluate the impact of a novel multiscreen version (v2.0) of an e-alert system for VTE prevention in hospitalised cancer medical patients compared to the original software.
METHODS:
Prospective study including 989 consecutive adult cancer patients with high-risk of VTE. Patients were followed-up 30 days post-discharge. Two periods were defined, according to the operative software.
RESULTS:
E-alert v2.0 was associated with an increase in the use of LMWH prophylaxis (65.5% vs. 72.0%); risk difference (95% CI) 0.064 (0.0043-0.12). Only 16% of patients in whom LMWH prophylaxis was not prescribed lacked a contraindication. No significant differences in the rates of VTE (2.9% vs. 3.2%) and major bleeding (2.7% vs. 4.0%) were observed.
CONCLUSIONS:
E-alert v2.0 further increased the use of appropriate thromboprophylaxis in hospitalised cancer patients, although was not associated with a reduction in VTE incidence.
Autores:
Montalbán-Bravo, G. (Autor de correspondencia); Takahashi, K.; Patel, K.; et al.
Revista:
ONCOTARGET
ISSN:
1949-2553
Año:
2018
Vol.:
9
N°:
11
Págs.:
9714 - 9727
The prognostic and predictive value of sequencing analysis in myelodysplastic syndromes (MDS) has not been fully integrated into clinical practice. We performed whole exome sequencing (WES) of bone marrow samples from 83 patients with MDS and 31 with MDS/MPN identifying 218 driver mutations in 31 genes in 98 (86%) patients. A total of 65 (57%) patients received therapy with hypomethylating agents. By univariate analysis, mutations in BCOR, STAG2, TP53 and SF3B1 significantly influenced survival. Increased number of mutations (¿ 3), but not clonal heterogeneity, predicted for shorter survival and LFS. Presence of 3 or more mutations also predicted for lower likelihood of response (26 vs 50%, p = 0.055), and shorter response duration (3.6 vs 26.5 months, p = 0.022). By multivariate analysis, TP53 mutations (HR 3.1, CI 1.3-7.5, p = 0.011) and number of mutations (¿ 3) (HR 2.5, CI 1.3-4.8, p = 0.005) predicted for shorter survival. A novel prognostic model integrating this mutation data with IPSS-R separated patients into three categories with median survival of not reached, 29 months and 12 months respectively (p < 0.001) and increased stratification potential, compared to IPSS-R, in patients with high/very-high IPSS-R. This model was validated in a separate cohort of 413 patients with untreated MDS. Although the use of WES did not provide significant more information than that obtained with targeted sequencing, our findings indicate that increased number of mutations is an inde
Revista:
PLOS ONE
ISSN:
1932-6203
Año:
2018
Vol.:
13
N°:
8
Págs.:
e0200220
Hospitalized cancer patients are at high risk of venous thromboembolism (VTE). Despite current recommendations in clinical guidelines, thromboprophylaxis with low molecular weight heparin (LMWH) is underused. We performed an observational prospective study to analyse factors influencing prophylaxis use, VTE events and mortality in cancer-hospitalized patients. 1072 consecutive adult cancer patients were included in an University Hospital from April 2014 to February 2017, and followed-up for 30 days after discharge. The rate of LMWH prophylaxis was 67.6% (95% confidence interval [CI]64.7% to 70.4%), with a 2.8% rate of VTE events (95% CI 1.9% to 3.9%) and 3.5% rate of major bleeding events (95% CI 2.5% to 4.8%). 80% of VTE events occurred despite appropriate thromboprophylaxis. Overall, 30-day mortality rate was 13.2% (95% C111.2% to 15.3%). Active chemotherapy treatment, hospital stay >= 4 days, and metastatic disease were associated with a higher use of LMWH. On the contrary, patients with hematologic malignancies,anemia or thrombocytopenia were less prone to receive thromboprophylaxis. The main reasons for not prescribing LMWH prophylaxis were thrombocytopenia (23.9%) and active/recent bleeding (21.8%). The PRETEMED score, used for VTE risk stratification, correlated with 30-day mortality. There is room for improvement in thromboprophylaxis use among hospitalized-cancer patients, especially among those with hematologic malignancies. A relevant number of VTE events occurred despite prophylaxis with LMWH. Therefore, identification of risk factors for thromboprophylaxis failure is needed.
Revista:
EUROPEAN JOURNAL OF HAEMATOLOGY
ISSN:
0902-4441
Año:
2017
Vol.:
98
N°:
1
Págs.:
38 - 43
This retrospective study evaluates the impact of rituximab on PTLD response and survival in a single-centre cohort. PTLD cases between 1984 and 2009, including heart, kidney, liver and lung transplant recipients, were included. Survival was analysed taking into account the type of PTLD (monomorphic vs. polymorphic), EBV infection status, IPI score, Ann Arbor stage and use of rituximab. Among 1335 transplanted patients, 24 developed PTLD. Median age was 54 yr (range 29-69), median time to diagnosis 50 months (range 0-100). PTLD type was predominantly late/monomorphic (79% and 75%), mostly diffuse large B-cell type. Overall response rate (ORR) was 62% (66% rituximab vs. 50% non-rituximab; P = 0.5). R-CHOP-like regimens were used most frequently (72% of patients treated with rituximab). Median overall survival was 64 months (CI 95% 31-96). OS was significantly increased in patients treated with rituximab (P = 0.01; CI 95% rituximab 58-79 months; non-rituximab 1-30 months). Post-transplant immunosuppression regimen had no effect on survival or time to PTLD, except for cyclosporine A (CyA), which associated with increased time to PTLD (P = 0.02). Rituximab was associated with increased survival in our single-centre series, and it should be considered as first-line therapy for PTLD patients. The possible protective effect of CyA for development of PTLD should be prospectively evaluated.
Revista:
LANCET ONCOLOGY
ISSN:
1470-2045
Año:
2016
Vol.:
17
N°:
2
Págs.:
128 - 129
Revista:
MEDICINA INTENSIVA
ISSN:
0210-5691
Año:
2016
Vol.:
40
N°:
9
Págs.:
550 - 559
Objective: To audit the impact upon mortality of a massive bleeding management protocol (MBP) implemented in our center since 2007. Design: A retrospective, single-center study was carried out. Patients transfused after MBP implementation (2007-2012, Group 2) were compared with a historical cohort (2005-2006, Group 1). Background: Massive bleeding is associated to high mortality rates. Available MBPs are designed for trauma patients, whereas specific recommendations in the medical/surgical settings are scarce. Patients: After excluding patients who died shortly (<6 h) after MBP activation (n=20), a total of 304 were included in the data analysis (68% males, 87% surgical). Interventions: Our MBP featured goal-directed transfusion with early use of adjuvant hemostatic medications. Variables of interest: Primary endpoints were 24-h and 30-day mortality. Fresh frozen plasma to-red blood cells (FFP:RBC) and platelet-to-RBC (PLT:RBC) transfusion ratios, time to first FFP unit and the proactive MBP triggering rate were secondary endpoints. Results: After MBP implementation (Group 2; n=222), RBC use remained stable, whereas FFP and hemostatic agents increased, when compared with Group 1 (n=82). Increased FFP:RBC ratio (p = 0.053) and earlier administration of FFP (p = 0.001) were also observed, especially with proactive MBP triggering. Group 2 patients presented lower rates of 24-h (0.5% vs. 7.3%; p = 0.002) and 30-day mortality (15.9% vs. 30.2%; p = 0.018) - the greatest reduction corresponding to non-surgical patients. Logistic regression showed an independent protective effect of MBP implementation upon 30-day mortality (OR = 0.3; 95% CI 0.15-0.61). Conclusions: These data suggest that the implementation of a goal-directed MBP for prompt and aggressive management of non-trauma, massive bleeding patients is associated to reduced 24-h and 30-day mortality rates. (C) 2016 Elsevier Espana, S.L.U. y SEMICYUC. All rights reserved.
Revista:
REVISTA ESPAÑOLA DE CARDIOLOGIA
ISSN:
0300-8932
Año:
2015
Vol.:
68
N°:
7
Págs.:
638-640
Nuestra experiencia indica que, para los pacientes con asistencia ventricular que sufran TIH sin trombosis asociada, en ausencia de test de activación plaquetaria disponible, la reexposición precoz a HNF exclusivamente durante el trasplante cardiaco podría ser una alternativa al uso de inhibidores directos de la trombina durante la CEC, siempre y cuando el recuento plaquetario se haya recuperado previamente y tras la intervención se reinicie un tratamiento anticoagulante alternativo a la heparina.
Revista:
THROMBOSIS RESEARCH
ISSN:
0049-3848
Año:
2015
Vol.:
136
N°:
6
Págs.:
1145-1148
Although the type of malignancy appears as the most relevant variable for decision-making, additional efforts are required to identify patients at particular high thrombosis risk.
Revista:
ANALES DEL SISTEMA SANITARIO DE NAVARRA
ISSN:
1137-6627
Año:
2014
Vol.:
37
N°:
3
Págs.:
363 - 369
Fundamento: Los concentrados de factores del complejo protrombínico (CCP) están indicados para reversión del efecto de antagonistas de vitamina K (AVK). Recientemente se han utilizado en el manejo de la coagulopatía de la hemorragia masiva. El objetivo del presente trabajo es evaluar la seguridad y eficacia del CCP en dos situaciones clínicas, para reversión de AVK y manejo integral de la hemorragia masiva.
Material y métodos: Revisión retrospectiva de los casos tratados con CCP entre enero de 2010 y febrero de 2013 en un único centro universitario. El objetivo primario fue la seguridad de administración del CCP en cuanto a reacciones inmediatas y episodios trombóticos. El objetivo secundario fue la eficacia, en 2 grupos: 1) Reversión de AVK y 2) Corrección de coagulopatía en hemorragia masiva.
Resultados: El análisis de seguridad incluyó 31 pacientes (22 varones), edad mediana 61 años (rango 30-86). No se registraron reacciones adversas durante la infusión y solo se observó un evento trombótico.
La eficacia en la reversión de AVK fue del 100% (6/6 pacientes), alcanzando normalización del INR en todos los pacientes. En hemorragia masiva, la supervivencia a las 24 horas fue 64% (16/25). Se requirieron procedimientos invasivos adicionales en 28% de los pacientes (7/25). El uso de CCP se asoció a cese de hemorragia en 44% de los pacientes (11/25), que correlacionó positivamente con la supervivencia (p=0,01).
Conclusión: El uso de CCP es una alternativa segura y eficaz, para la reversión urgente del efecto de AVK, así como para el control de sangrado en situación de hemorragia masiva.
Revista:
THROMBOSIS AND HAEMOSTASIS
ISSN:
0340-6245
Año:
2013
Vol.:
110
N°:
4
Págs.:
834 - 843
In patients with venous thromboembolism (VTE), assessment of the risk of fatal recurrent VTE and fatal bleeding during anticoagulation may help to guide intensity and duration of therapy. We aimed to provide estimates of the case-fatality rate (CFR) of recurrent VTE and major bleeding during anticoagulation in a 'real life' population, and to assess these outcomes according to the initial presentation of VTE and its etiology. The study included 41,826 patients with confirmed VTE from the RIETE registry who received different durations of anticoagulation (mean 7.8 +/- 0.6 months). During 27,110 patient-years, the CFR was 12.1% (95% Cl, 10.2-14.2) for recurrent VTE, and 19.7% (95% Cl, 17.4-22.1) for major bleeding. During the first three months of anticoagulant therapy, the CFR of recurrent VTE was 16.1% (95% Cl, 13.6-18.9), compared to 2.0% (95% Cl, 0-4.2) beyond this period. The CFR of bleeding was 20.2% (95% Cl, 17.5-23.1) during the first three months, compared to 18.2% (95% Cl, 14.0-23.2) beyond this period. The CFR of recurrent VTE was higher in patients initially presenting with PE (18.5%; 95% Cl, 15.3-22.1) than in those with DVT (6.3%; 95% Cl, 4.5-8.6), and in patients with provoked VTE (16.3%; 95% Cl, 13.6-19.4) than in those with unprovoked VTE (5.5%; 95% Cl, 3.5-8.0). In conclusion, the CFR of recurrent VTE decreased over time during anticoagulation, while the CFR of major bleeding remained stable. The CFR of recurrent VTE was higher in patients initially presenting with PE and in those with provoked VTE.
Revista:
THROMBOSIS AND HAEMOSTASIS
ISSN:
0340-6245
Año:
2013
Vol.:
110
N°:
1
Págs.:
184-190
Many cancer patients are at high risk of venous thromboembolism (VTE) during hospitalisation; nevertheless, thromboprophylaxis is frequently underused. Electronic alerts (e-alerts) have been associated with improvement in thromboprophylaxis use and a reduction of the incidence of VTE, both during hospitalisation and after discharge, particularly in the medical setting. However, there are no data regarding the benefit of this tool in cancer patients. Our aim was to evaluate the impact of a computer-alert system for VTE prevention in patients with cancer, particularly in those admitted to the Oncology/Haematology ward, comparing the results with the rest of inpatients at a university teaching hospital. The study included 32,167 adult patients hospitalised during the first semesters of years 2006 to 2010, 9,265 (28.8%) with an active malignancy. Appropriate prophylaxis in medical patients, significantly increased over time (from 40% in 2006 to 57% in 2010) and was maintained over 80% in surgical patients. However, while e-alerts were associated with a reduction of the incidence of VTE during hospitalisation in patients without cancer (odds ratio [OR] 0.31; 95% confidence interval [CI], 0.15-0.64), the impact was modest in cancer patients (OR 0.89; 95% CI, 0.42-1.86) and no benefit was observed in patients admitted to the Oncology/Haematology Departments (OR 1.11; 95% CI, 0.45-2.73). Interestingly, 60% of VTE episodes in cancer patients during recent years developed despite appro
Revista:
INTERNATIONAL JOURNAL OF CANCER
ISSN:
0020-7136
Año:
2013
Vol.:
133
N°:
9
Págs.:
2157 - 2164
Extensive screening strategies to detect occult cancer in patients with unprovoked venous thromboembolism (VTE) are complex and no benefit in terms of survival has been reported. FDG-PET/CT (2-[F-18] fluoro-2-deoxy-D-glucose positron emission tomography combined with computed tomography), a noninvasive technique for the diagnosis and staging of malignancies, could be useful in this setting. Consecutive patients ¿ 50 years with a first unprovoked VTE episode were prospectively included. Screening with FDG-PET/CT was performed 3¿4 weeks after the index event. If positive, appropriate diagnostic work-up was programmed. Clinical follow-up continued for 2 years. Blood samples were collected to assess coagulation biomarkers. FDG-PET/CT was negative in 68/99 patients (68.7%), while suspicious FDG uptake was detected in 31/99 patients (31.3%). Additional diagnostic work-up confirmed a malignancy in 7/31 patients (22.6%), with six of them at early stage. During follow-up, two patients with negative FDG-PET/CT were diagnosed with cancer. Sensitivity (S), positive (PPV) and negative predictive values (NPV) of FDG-PET/CT as single tool for the detection of occult malignancy were 77.8% (95% CI: 0.51¿1), 22.6% (95% CI: 0.08¿0.37) and 97.1% (95% CI: 0.93¿1), respectively. Median tissue factor (TF) activity in patients with occult cancer was 5.38 pM vs. 2.40 pM in those without cancer (p = 0.03). ...
Revista:
MEDICINE (ELSEVIER)
ISSN:
0304-5412
Año:
2012
Vol.:
11
N°:
22
Págs.:
1337-44
Las púrpuras representan la patología genuina de los trastornos de la hemostasia primaria y se dividen en: a) púrpuras vasculares, con alteración en el componente vascular, con número y función plaquetaria normal y hemorragias cutáneas superficiales; b) púrpuras trombopénicas, causadas por un fallo cuantitativo en el componente plaquetario, de ellas, el cuadro más importante es la trombocitopenia inmune primaria (PTI) causada por autoanticuerpos antiplaquetarios, con una forma infantil autolimitada y otra crónica presente en adultos y cuadro hemorrágico cutaneomucoso; el tratamiento de primera línea de la PTI son los corticoides e inmunoglobulinas, y de segunda línea la esplenectomía y los nuevos agentes trombopoyéticos como romiplostin y eltrombopag y c) púrpuras trombopáticas, causadas por un fallo cualitativo, que pueden ser congénitas, como síndrome de Bernard-Soulier y trombastenia de Glanzmann, o adquiridas (por ejemplo, hepatopatía, enfermedad renal, ingesta de antiplaquetarios, etc.). El tratamiento se basa en la administración de antifibrinolíticos y desmopresina en las formas moderadas y concentrado de plaquetas y factor VII activado recombinante en las formas graves.
Revista:
MEDICINE (ELSEVIER)
ISSN:
0304-5412
Año:
2012
Vol.:
11
N°:
22
Págs.:
1359-65
Las coagulopatías adquiridas son procesos muy frecuentes en la práctica clínica. En general, son el resultado del consumo de factores de coagulación, como en la coagulación intravascular diseminada (CID), defecto de síntesis de factores, como en las hepatopatías y déficits de vitamina K, o como resultado de la presencia de anticoagulantes circulantes o de fármacos que alteran la coagulación (antivitaminas K, acenocumarol o warfarina). La intensidad de la hemorragia es muy variable, existiendo una pobre correlación con las alteraciones hemostáticas detectadas en los estudios rutinarios de coagulación (tiempo de protrombina y tromboplastina parcial activado, fibrinógeno, dímero D y recuento de plaquetas). El tratamiento debe ser individualizado y requiere el uso apropiado de hemoderivados, plasma, plaquetas y crioprecipitado, en combinación con agentes farmacológicos, tales como concentrado de factores del complejo protrombínico y antifibrinolíticos. La administración de vitamina K será esencial para corregir el déficit secundario al tratamiento con acenocumarol o warfarina.
Revista:
MEDICINE (ELSEVIER)
ISSN:
0304-5412
Año:
2012
Vol.:
11
N°:
22
Págs.:
1366-70
El tromboembolismo venoso (TEV) es la tercera causa de mortalidad cardiovascular, tras el infarto agudo de miocardio y el ictus. Las secuelas del TEV a largo plazo son el síndrome postrombótico y la hipertensión pulmonar crónica. El diagnóstico se basa en modelos de probabilidad clínica, el dímero D y pruebas de imagen no invasivas, como ecografía para trombosis venosa profunda y angiotomografía computadorizada (TC) para embolismo pulmonar. La base del tratamiento la constituye la anticoagulación, generalmente con heparina no fraccionada o de bajo peso molecular por vía parenteral, seguida por antivitaminas K por vía oral (acenocumarol o warfarina) durante 3¿6 meses, requiriendo una estrecha monitorización del INR (índice normalizado internacional). Se han desarrollado nuevos anticoagulantes orales (dabigatran, rivaroxaban, apixaban) que pueden a corto plazo reemplazar a las heparinas y acenocumarol, con la ventaja de tener una administración oral y sin necesidad de monitorización.