An Active Isodicentric X Chromosome in a Case of Refractory Anaemia with Ring Sideroblasts Associated with Marked Thrombocytosis

Refractory anaemia with ring sideroblasts and marked thrombocytosis (RARS-T) is a provisional entity in the World Health Organization (WHO) classification. It displays features characteristic of both myelodysplastic syndrome and myeloproliferative neoplasia plus ring sideroblasts ≥15% and marked thrombocytosis. Most patients with RARS-T show a normal karyotype. We report a 76-year-old woman diagnosed with RARS-T (76% of ring sideroblasts) with JAK2 (V617F) mutation and a load of 30-40%. Classical and molecular cytogenetic (FISH) studies of a bone marrow sample revealed the presence of isodicentric X chromosome [(idic(X)(q13)]. Moreover, HUMARA assay showed the idic(X)(q13) as the active X chromosome. This finding was correlated with the cytochemical finding of ring sideroblasts. To our knowledge, this is the first reported case of an active isodicentric X in a woman with RARS-T

SF3B1, RUNX1 and TP53 Mutations Significantly Impact the Outcome of Patients With Lower-Risk Myelodysplastic Syndrome

[Introduction] Prognosis of patients with myelodysplastic syndrome (MDS), particularly the group with lower-risk disease (LR-MDS) is very heterogeneous. Several studies have described the prognostic value of recurrent somatic mutations in MDS including all risk categories. Recently, the incorporation of genomic data to clinical parameters defined the new Molecular International Prognostic Scoring System (IPSS-M).[Materials and Methods] In this study, we evaluated the impact of molecular profile in a series of 181 patients with LR-MDS and non-proliferative chronic myelomonocytic leukemia.[Results] Epigenetic regulators (TET2, ASXL1) and splicing (SF3B1) were the most recurrent mutated pathways. In univariate analysis, RUNX1 or TP53 mutations correlated with lower median overall survival (OS). In contrast, SF3B1 mutation was associated with prolonged median OS [95 months (95% IC, 32-157) vs. 33 months (95% CI, 19-46) in unmutated patients (P < 0.01)]. In a multivariate Cox regression model, RUNX1 mutations independently associated with shorter OS, while SF3B1 mutation retained its favorable impact on outcome (HR: 0.24, 95% CI, 0.1-0.5; P = 0.001). In addition, TP53 or RUNX1 mutations were identified as predictive covariates for the probability of leukemic progression (P < 0.001).[Conclusion] Incorporation of molecular testing in LR-MDS identified a subset of patients with expected poorer outcome, either due to lower survival or probability of leukemic progression.Peer reviewe

The Mutational Landscape of Acute Myeloid Leukaemia Predicts Responses and Outcomes in Elderly Patients from the PETHEMA-FLUGAZA Phase 3 Clinical Trial

This article belongs to the Collection The Biomarkers for the Diagnosis and Prognosis in Cancer.[Simple Summary] Mutational profiling using a custom 43-gene next-generation sequencing panel revealed that patients with mutated DNMT3A or EZH2, or an increase in TET2 VAF and lower TP53 VAF showed a higher overall response. NRAS and TP53 variants were associated with shorter overall survival (OS), whereas only mutated BCOR was associated with a shorter relapse-free survival (RFS). Subgroup analyses of OS according to biological and genomic characteristics showed that patients with low–intermediate cytogenetic risk and mutated NRAS benefited from azacytidine therapy and patients with mutated TP53 showed a better RFS in the azacytidine arm. In conclusion, differential mutational profiling might anticipate the outcomes of first-line treatment choices (AZA or FLUGA) in older patients with AML.[Abstract] We sought to predict treatment responses and outcomes in older patients with newly diagnosed acute myeloid leukemia (AML) from our FLUGAZA phase III clinical trial (PETHEMA group) based on mutational status, comparing azacytidine (AZA) with fludarabine plus low-dose cytarabine (FLUGA). Mutational profiling using a custom 43-gene next-generation sequencing panel revealed differences in profiles between older and younger patients, and several prognostic markers that were useful in young patients were ineffective in older patients. We examined the associations between variables and overall responses at the end of the third cycle. Patients with mutated DNMT3A or EZH2 were shown to benefit from azacytidine in the treatment-adjusted subgroup analysis. An analysis of the associations with tumor burden using variant allele frequency (VAF) quantification showed that a higher overall response was associated with an increase in TET2 VAF (odds ratio (OR), 1.014; p = 0.030) and lower TP53 VAF (OR, 0.981; p = 0.003). In the treatment-adjusted multivariate survival analyses, only the NRAS (hazard ratio (HR), 1.9, p = 0.005) and TP53 (HR, 2.6, p = 9.8 × 10−7) variants were associated with shorter overall survival (OS), whereas only mutated BCOR (HR, 3.6, p = 0.0003) was associated with a shorter relapse-free survival (RFS). Subgroup analyses of OS according to biological and genomic characteristics showed that patients with low–intermediate cytogenetic risk (HR, 1.51, p = 0.045) and mutated NRAS (HR, 3.66, p = 0.047) benefited from azacytidine therapy. In the subgroup analyses, patients with mutated TP53 (HR, 4.71, p = 0.009) showed a better RFS in the azacytidine arm. In conclusion, differential mutational profiling might anticipate the outcomes of first-line treatment choices (AZA or FLUGA) in older patients with AML. The study is registered at ClinicalTrials.gov as NCT02319135.This study was supported by the Centro de Investigación Biomédica en Red—Área de Oncología–del Instituto de Salud Carlos III (CIBERONC; CB16/12/00369) and the Subdirección General de Investigación Sanitaria (Instituto de Salud Carlos III, Spain) grants PI16/01530, PI16/01661, PI19/01518, and PI19/00730, the CRIS against Cancer foundation, grant 2018/001, and by the Instituto de Investigación Hospital 12 de Octubre (IMAS12) (co-financed by FEDER funds). The study was supported internationally by Cancer Research UK, FCAECC and AIRC under the Accelerator Award Program

The Mutational Landscape of Acute Myeloid Leukaemia Predicts Responses and Outcomes in Elderly Patients from the PETHEMA-FLUGAZA Phase 3 Clinical Trial

Mutational profiling using a custom 43-gene next-generation sequencing panel revealed that patients with mutated DNMT3A or EZH2, or an increase in TET2 VAF and lower TP53 VAF showed a higher overall response. NRAS and TP53 variants were associated with shorter overall survival (OS), whereas only mutated BCOR was associated with a shorter relapse-free survival (RFS). Subgroup analyses of OS according to biological and genomic characteristics showed that patients with low-intermediate cytogenetic risk and mutated NRAS benefited from azacytidine therapy and patients with mutated TP53 showed a better RFS in the azacytidine arm. In conclusion, differential mutational profiling might anticipate the outcomes of first-line treatment choices (AZA or FLUGA) in older patients with AML. We sought to predict treatment responses and outcomes in older patients with newly diagnosed acute myeloid leukemia (AML) from our FLUGAZA phase III clinical trial (PETHEMA group) based on mutational status, comparing azacytidine (AZA) with fludarabine plus low-dose cytarabine (FLUGA). Mutational profiling using a custom 43-gene next-generation sequencing panel revealed differences in profiles between older and younger patients, and several prognostic markers that were useful in young patients were ineffective in older patients. We examined the associations between variables and overall responses at the end of the third cycle. Patients with mutated DNMT3A or EZH2 were shown to benefit from azacytidine in the treatment-adjusted subgroup analysis. An analysis of the associations with tumor burden using variant allele frequency (VAF) quantification showed that a higher overall response was associated with an increase in TET2 VAF (odds ratio (OR), 1.014; p = 0.030) and lower TP53 VAF (OR, 0.981; p = 0.003). In the treatment-adjusted multivariate survival analyses, only the NRAS (hazard ratio (HR), 1.9, p = 0.005) and TP53 (HR, 2.6, p = 9.8 × 10 −7) variants were associated with shorter overall survival (OS), whereas only mutated BCOR (HR, 3.6, p = 0.0003) was associated with a shorter relapse-free survival (RFS). Subgroup analyses of OS according to biological and genomic characteristics showed that patients with low-intermediate cytogenetic risk (HR, 1.51, p = 0.045) and mutated NRAS (HR, 3.66, p = 0.047) benefited from azacytidine therapy. In the subgroup analyses, patients with mutated TP53 (HR, 4.71, p = 0.009) showed a better RFS in the azacytidine arm. In conclusion, differential mutational profiling might anticipate the outcomes of first-line treatment choices (AZA or FLUGA) in older patients with AML. The study is registered at ClinicalTrials.gov as NCT0231913

A phase 3 trial of azacitidine versus a semi-intensive fludarabine and cytarabine schedule in older patients with untreated acute myeloid leukemia

PETHEMA Group.[Background] Options to treat elderly patients (≥65 years old) newly diagnosed with acute myeloid leukemia (AML) include intensive and attenuated chemotherapy, hypomethylating agents with or without venetoclax, and supportive care. This multicenter, randomized, open-label, phase 3 trial was designed to assess the efficacy and safety of a fludarabine, cytarabine, and filgrastim (FLUGA) regimen in comparison with azacitidine (AZA).[Methods] Patients (n = 283) were randomized 1:1 to FLUGA (n = 141) or AZA (n = 142). Response was evaluated after cycles 1, 3, 6, and 9. Measurable residual disease (MRD) was assessed after cycle 9. When MRD was ≥0.01%, patients continued with the treatment until relapse or progressive disease. Patients with MRD < 0.01% suspended treatment to enter the follow-up phase. [Results] The complete remission (CR) rate after 3 cycles was significantly better in the FLUGA arm (18% vs 9%; P = .04), but the CR/CR with incomplete recovery rate at 9 months was similar (33% vs 29%; P = .41). There were no significant differences between arms in early mortality at 30 or 60 days. Hematologic toxicities were more frequent with FLUGA, especially during induction. The 1-year overall survival (OS) rate and the median OS were superior with AZA versus FLUGA: 47% versus 27% and 9.8 months (95% confidence interval [CI], 5.6-14 months) versus 4.1 months (95% CI, 2.7-5.5 months; P = .005), respectively. The median event-free survival was 4.9 months (95% CI, 2.8-7 months) with AZA and 3 months (95% CI, 2.5-3.5 months) with FLUGA (P = .001). [Conclusions] FLUGA achieved more remissions after 3 cycles, but the 1-year OS rate was superior with AZA. However, long-term outcomes were disappointing in both arms (3-year OS rate, 10% vs 5%). This study supports the use of an AZA backbone for future combinations in elderly patients with AML.This study was supported by the Spanish Biomedical Research Centre in Cancer of the Carlos III Health Institute (CB16/12/00369) and by the Carlos III Health Institute/Subdirectorate General for Health Research (FIS No. PI16/01661). Celgene provided the azacitidine and financial support for this study

Investigación en la escuela

Resumen tomado de la revistaEl sistema educativo ha prestado muy poca atención a la educación de los riesgos, ya sean ambientales o de otro tipo. En este artículo se exponen las estrategias de enseñanza y líneas maestras de una unidad didáctica centrada en la educación de los riesgos ambientales tomando como punto de partida la percepción de alumnos y alumnas de secundaria del desastre ambiental ocurrido en Doñana en 1998. Se trata de una unidad didáctica transdisciplinar que parte de la idea de que la educación para el ambiente debe contemplar de forma global aspectos naturales, sociales, culturales, sanitarios e ideológicos.AndalucíaES

Alambique : didáctica de las ciencias experimentales

Resumen literal de la revista. Incluye cuestionario anexo sobre la catástrofe de Doñana el 25 de abril de 1998Este artículo se centra en el análisis de la percepción del riesgo ambiental de los desastres tecnológicos, de sus causas, prevención, soluciones y efectos sistémicos en el medio natural de tres grupos de alumnos de secundaria, tomando como ejemplo el desastre ecológico de Doñana. Asimismo, se discute la importancia del estudio de casos en ecoaccidentes en la educación ambiental por su incidencia en tres factores de gran importancia: el medio ambiente, la sociedad y la salud humana.CataluñaES

Long-Term Impact of an Educational Antimicrobial Stewardship Program on Management of Patients with Hematological Diseases.

Antimicrobial stewardship programs (ASPs) in hematological patients are especially relevant. However, information about ASPs in this population is scarce. For 11 years, we quarterly assessed antimicrobial consumption and incidence and death rates of multidrug-resistant (MDR) bloodstream infections (BSI) in the hematology Department. Healthcare activity indicators were also monitored yearly. We performed an interrupted time-series analysis. Antimicrobials showed a sustained reduction with a relative effect of -62.3% (95% CI -84.5 to -40.1) nine years after the inception of the ASP, being especially relevant for antifungals (relative effect -80.4%, -90.9 to -69.9), quinolones (relative effect -85.0%, -102.0 to -68.1), and carbapenems (relative effect -68.8%, -126.0 to -10.6). Incidence density of MDR BSI remained low and stable (mean 1.10 vs. 0.82 episodes per 1000 occupied bed days for the pre-intervention and the ASP period, respectively) with a quarterly percentage of change of -0.3% (95% CI -2.0 to 1.4). Early and late mortality of MDR BSI presented a steady trend (quarterly percentage of change -0.7%, 95% CI -1.7 to 0.3 and -0.6%, 95% CI -1.5 to 0.3, respectively). Volume and complexity of healthcare activity increased over the years. The ASP effectively achieved long-term reductions in antimicrobial consumption and improvements in the prescription profile, without increasing the mortality of MDR BSI