Estudio de los Síndromes Mielodisplásicos en la población gallega: análisis descriptivo y pronóstico

Los principales objetivos de la presente tesis doctoral son tres: describir la epidemiología de los Síndromes Mielodisplásicos (SMD) en la población gallega a estudio, validar y comparar el nuevo índice pronóstico IPSS-R frente al estándar IPSS, utilizado actualmente sobre nuestra población, y analizar la capacidad de predicción de nuevos factores pronósticos (LDH, transfusiones previas, ferritina, índice de comorbilidades) incorporándolos a este nuevo IPSS-R. A partir de la base de datos de estudios citogenéticos de la Fundación Pública Galega de Medicina Xenómica seleccionamos los pacientes diagnosticados de SMD según criterios de la clasificación FAB, OMS 2001 u OMS 2008, entre enero de 2007 y diciembre de 2011 de SMD. Los pacientes procedían de todos Centros Hospitalarios de la CCAA excepto del CHUAC y POVISA por no disponer de estos datos. Cumplieron criterios de inclusión en el estudio 339 pacientes. El seguimiento se realizó a través del programa de gestión clínica del SERGAS (IANUS) o en la historia clínica física en cada centro hospitalario. El periodo de seguimiento mínimo de los pacientes vivos incluidos en el estudio fue de un año (rango 2 - 2148 días). Inicialmente describimos las variables epidemiológicas de los SMD en nuestra población a estudio. Nuestros resultados muestran una población más envejecida, con menor incidencia y misma distribución por sexo respecto a las grandes poblaciones de SMD de la literatura. Nuestra población se distribuye en subgrupos de diagnóstico según la clasificación OMS 2001 y 2008 de forma similar a las grandes series publicadas. Posteriormente describimos las variables que forman el índice pronóstico para la supervivencia y el riesgo de transformación a leucemia mieloblástica aguda más ampliamente utilizado, el IPSS, y tratamos de validar su reciente propuesta revisada, el IPSS-R en nuestra población. Comparamos dichas variables con las descritas en las grandes series de pacientes con SMD de la literatura, observando similitud con las mismas, permitiéndonos realizar la validación del IPSS-R en nuestra muestra. Con estos datos clasificamos a nuestros pacientes según los grupos de riesgo de uno y otro índice, y analizamos la capacidad de predecir la supervivencia y el riesgo de evolución a Leucemia Aguda Mieloblástica (LMA). Posteriormente observamos la redistribución de los pacientes incluídos en los subgrupos del antiguo índice en nuevo índice revisado. los resultados obtenidos de la reclasificación, aplicando el IPSS-R evidencia una mayor capacidad de predecir la supervivencia de estos pacientes que el IPSS. Cada uno de los grupos del IPSS es redistribuído con el IPSS-R en grupos de riesgo más ajustados a la supervivencia real de los pacientes. Este hecho es más evidente en el grupo intermedio-1 del IPSS. Por último, añadimos nuevas variables al índice revisado (IPSS-R), tratando de mejorar su capacidad predictiva de la supervivencia. al añadir las dos nuevas variables estadísticamente significativas por nosotros propuestas (índice de comorbilidades y transfusiones previas) al IPSS-R, observamos que la capacidad de este nuevo índice, para predecir la supervivencia, se ve notablemente mejorada. La aplicación del nuevo índice IPSS-R a nuestra población gallega a estudio, también mustra una mayor capacidad de predecir el riesgo de transformación a Leucemia Mieloblástica Aguda

A Three-Gene Expression Signature Identifies a Cluster of Patients with Short Survival in Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder characterized by its heterogeneous clinical evolution. Despite the discovery of the most frequent cytogenomic drivers of disease during the last decade, new efforts are needed in order to improve prognostication. In this study, we used gene expression data of CLL samples in order to discover novel transcriptomic patterns associated with patient survival. We observed that a 3-gene expression signature composed of SCGB2A1, KLF4, and PPP1R14B differentiate a group of circa 5% of cases with short survival. This effect was independent of the main cytogenetic markers of adverse prognosis. Finally, this finding was reproduced in an independent retrospective cohort. We believe that this small gene expression pattern will be useful for CLL prognostication and its association with CLL response to novel drugs should be explored in the future

Time to Treatment Prediction in Chronic Lymphocytic Leukemia Based on New Transcriptional Patterns

Chronic lymphocytic leukemia (CLL) is the most frequent lymphoproliferative syndrome in western countries. CLL evolution is frequently indolent, and treatment is mostly reserved for those patients with signs or symptoms of disease progression. In this work, we used RNA sequencing data from the International Cancer Genome Consortium CLL cohort to determine new gene expression patterns that correlate with clinical evolution.We determined that a 290-gene expression signature, in addition to immunoglobulin heavy chain variable region (IGHV) mutation status, stratifies patients into four groups with notably different time to first treatment. This finding was confirmed in an independent cohort. Similarly, we present a machine learning algorithm that predicts the need for treatment within the first 5 years following diagnosis using expression data from 2,198 genes. This predictor achieved 90% precision and 89% accuracy when classifying independent CLL cases. Our findings indicate that CLL progression risk largely correlates with particular transcriptomic patterns and paves the way for the identification of high-risk patients who might benefit from prompt therapy following diagnosis.S

The association of germline variants with chronic lymphocytic leukemia outcome suggests the implication of novel genes and pathways in clinical evolution

Background Chronic Lymphocytic Leukemia (CLL) is the most frequent lymphoproliferative disorder in western countries and is characterized by a remarkable clinical heterogeneity. During the last decade, multiple genomic studies have identified a myriad of somatic events driving CLL proliferation and aggressivity. Nevertheless, and despite the mounting evidence of inherited risk for CLL development, the existence of germline variants associated with clinical outcomes has not been addressed in depth. Methods Exome sequencing data from control leukocytes of CLL patients involved in the International Cancer Genome Consortium (ICGC) was used for genotyping. Cox regression was used to detect variants associated with clinical outcomes. Gene and pathways level associations were also calculated. Results Single nucleotide polymorphisms in PPP4R2 and MAP3K4 were associated with earlier treatment need. A gene-level analysis evidenced a significant association of RIPK3 with both treatment need and survival. Furthermore, germline variability in pathways such as apoptosis, cell-cycle, pentose phosphate, GNα13 and Nitric oxide was associated with overall survival. Conclusion Our results support the existence of inherited conditionants of CLL evolution and points towards genes and pathways that may results useful as biomarkers of disease outcome. More research is needed to validate these findings.S

Heart failure with recovered ejection fraction: Clinical characteristics, determinants and prognosis. CARDIOCHUS-CHOP registry

Background: The magnitude and the prognostic impact of recovering left ventricular ejection fraction (LVEF) in patients with heart failure (HF) and systolic dysfunction is unclear. The aim of this study was to evaluate the clinical characteristics and prognosis of patients with HFrecEF in an HF population. Methods: 449 consecutive patients were selected with the diagnosis of HF and an evaluation of LVEF in the 6 months prior to selection who were referred to two HF units. Patients with systolic dysfunction were only considered if a second echocardiogram was performed during the follow-up. Results: At the time of diagnosis, 207 patients had LVEF > 40% (HFpEF) and 242 had LVEF ≤ 40% (HFrEF). After 1 year, the LVEF was re-evaluated in all 242 patients with a LVEF ≤ 40%: in 126 (52%), the second LVEF was > 40% (HFrecEF), and the remaining 116 (48%) had LVEF ≤ 40% (HFrEF). After 1800 ± 900 days of follow-up patients with recovered LVEF had a significantly lower mortality rate (HFpEF vs. HFrecEF: hazard ratio [HR] = 2.286, 95% confidence interval [95% CI] 1.264–4.145, p = 0.019; HFrEF vs. HFrecEF: HR = 2.222, 95% CI 1.189–4.186, p < 0.001) and hospitalization rate (HFpEF vs. HFrecEF: HR = 1.411, 95% CI 1.046–1.903, p = 0.024; HFrEF vs. HFrecEF: HR = 1.388, 95% CI 1.002–1.924, p = 0.049). The following are predictors of LVEF recovery: younger age, lower functional class, treatment with renin–angiotensin–aldosterone system inhibitors and beta-blockers, absence of defibrillator use, and non-ischemic etiology. Conclusions: Patients with HF and reduced LVEF who were re-evaluated after 1 year, had significant improvement in their LVEF and had a more favourable prognosis than HF with preserved and reduced ejection fraction

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO

Energy Estimation of Cosmic Rays with the Engineering Radio Array of the Pierre Auger Observatory

The Auger Engineering Radio Array (AERA) is part of the Pierre Auger Observatory and is used to detect the radio emission of cosmic-ray air showers. These observations are compared to the data of the surface detector stations of the Observatory, which provide well-calibrated information on the cosmic-ray energies and arrival directions. The response of the radio stations in the 30 to 80 MHz regime has been thoroughly calibrated to enable the reconstruction of the incoming electric field. For the latter, the energy deposit per area is determined from the radio pulses at each observer position and is interpolated using a two-dimensional function that takes into account signal asymmetries due to interference between the geomagnetic and charge-excess emission components. The spatial integral over the signal distribution gives a direct measurement of the energy transferred from the primary cosmic ray into radio emission in the AERA frequency range. We measure 15.8 MeV of radiation energy for a 1 EeV air shower arriving perpendicularly to the geomagnetic field. This radiation energy -- corrected for geometrical effects -- is used as a cosmic-ray energy estimator. Performing an absolute energy calibration against the surface-detector information, we observe that this radio-energy estimator scales quadratically with the cosmic-ray energy as expected for coherent emission. We find an energy resolution of the radio reconstruction of 22% for the data set and 17% for a high-quality subset containing only events with at least five radio stations with signal.Comment: Replaced with published version. Added journal reference and DO

Measurement of the Radiation Energy in the Radio Signal of Extensive Air Showers as a Universal Estimator of Cosmic-Ray Energy

We measure the energy emitted by extensive air showers in the form of radio emission in the frequency range from 30 to 80 MHz. Exploiting the accurate energy scale of the Pierre Auger Observatory, we obtain a radiation energy of 15.8 \pm 0.7 (stat) \pm 6.7 (sys) MeV for cosmic rays with an energy of 1 EeV arriving perpendicularly to a geomagnetic field of 0.24 G, scaling quadratically with the cosmic-ray energy. A comparison with predictions from state-of-the-art first-principle calculations shows agreement with our measurement. The radiation energy provides direct access to the calorimetric energy in the electromagnetic cascade of extensive air showers. Comparison with our result thus allows the direct calibration of any cosmic-ray radio detector against the well-established energy scale of the Pierre Auger Observatory.Comment: Replaced with published version. Added journal reference and DOI. Supplemental material in the ancillary file