Análisis de factores pronósticos clásicos y emergentes en linfomas no Hodgkin de estirpe B. Utilidad pronóstica del mRNA aislado en exosomas de sangre periférica

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. Fecha de lectura: 28-06-2017Los linfomas no Hodgkin de estirpe B son neoplasias malignas de origen linfoide, el linfoma difuso de célula grande y el linfoma folicular son las variantes más frecuentes. Ambas entidades han visto modificado su evolución natural tras la introducción del rituximab, anticuerpo monoclonal anti CD 20. Los factores pronósticos clásicos en la era prerituximab se han visto modificados tras la introducción del anticuerpo y algunos de ellos han perdido su valor. El tratamiento con inmunoquimioterapia ha conseguido aumentar la supervivencia libre de progresión , la supervivencia global y las tasas de respuestas tanto en los linfomas difusos de célula grande como en los linfomas foliculares. La adición del anticuerpo ha conseguido disminuir el porcentaje de recaídas precoces, entendidas como las que ocurren en los dos primeros años y hemos podido demostrar que las recaídas precoces son las que confieren peor pronóstico en ambas entidades histológicas. A pesar de las mejoras en los tratamientos siguen existiendo un porcentaje nada desdeñable de pacientes que recaen en los primeros años tras el diagnóstico, las recaídas en linfomas difusos pueden variar según las series entre un 20 y un 40% de los casos , y de estas solo una pequeña minoría serán rescatables con los tratamientos posteriores. En el caso de los linfomas foliculares las tasas de recaídas han disminuido considerablemente tras la introducción del rituximab pero en nuestra serie hasta un 30% de los pacientes tratados con inmunoterapia recaen. Existe una evidente necesidad de búsqueda de nuevos factores pronóstico que nos seleccionen a los pacientes de una forma más adecuada. Sabemos que las características biológicas moleculares pueden marcar diferencias en el comportamiento tumoral y es por ello que decidimos ahondar en el estudio molecular de los linfomas a través de una fuente de material genético fácilmente accesible como son los exosomas. En el avance de la ciencia hemos detectado material genético tumoral en la sangre de nuestro pacientes y los exosomas emergen como una fuente de material genético accesible y estable, haciéndolo idóneo para su estudio. Hemos aislado en el plasma de pacientes, exosomas que contienen mRNA de genes que en la literatura se han relacionado con el pronóstico de los linfomas ( bcl-­‐6, bcl-­‐xl, c-­‐myc, pten, AKT y NF-­‐kB) pre y post tratamiento con inmunoquimioterapia y hemos observado su valor pronóstico en nuestra serie de pacientes. Se observan diferencias en la expresión de mRNA en los exosomas de los pacientes tras el tratamiento con inmunoquimioterapia, la presencia de mRNA de bcl-­‐6 y la pérdida de expresión de pTEN tras los tratamientos parece asociarse con peor pronóstico y la presencia de c-­‐myc pre tratamiento se asocia con una respuesta parcial de la enfermedad. Existen diferencias en la expresión de bcl-­‐6 y pten entre individuos sanos y pacientes afectos de linfoma. Es necesario continuar esta línea de investigación para una correcta caracterización de los linfomas y poder diseñar estrategias más precisas de tratamiento acorde a las características moleculares de los linfomas

Knowledge and Opinions of Healthcare Professionals about Thirdhand Smoke: A Multi-National, Cross-Sectional Study

There is scarce evidence on the knowledge and opinions about third-hand smoke (THS) of health care professionals. The main aim of this study was to explore the knowledge and opinions of health care professionals about THS and, secondarily, to explore the factors that are associated with this knowledge. Cross-sectional study using a snowball sample of multi-national health care professionals (n = 233). Data were obtained from an exploratory, online questionnaire. The health care professionals’ knowledge and opinions on THS were described with absolute frequency and percentage. Chi-square and Fisher-Freeman-Halton exact tests, and simple logistic regression models, were used to explore the bivariate association between the knowledge of the concept THS and sex, continent of birth, educational level, occupation, years of experience, and attitude towards smoking. Finally, a multivariable logistic regression model incorporating all the above variables was fitted. A total of 65.2% of the participants were unaware of the term THS before the study began. In the bivariate analysis, an association was found between prior knowledge of the term THS and continent of birth (p-value = 0.030) and occupation (p-value = 0.014). In the multivariable logistic regression model, a significant association was observed between prior knowledge of the concept THS and sex (p-value = 0.005), continent of birth (p-value = 0.012), and occupation (p-value = 0.001). Almost two out of three health care professionals who participated in our study did not know what THS was. Educational activities on this topic should be implemented

mRNA in exosomas as a liquid biopsy in non-Hodgkin Lymphoma: a multicentric study by the Spanish Lymphoma Oncology Group

Purpose: To determine the feasibility of mRNAs (C-MYC, BCL-XL, BCL-6, NF-κβ, PTEN and AKT) in exosomes of plasma as a liquid biopsy method for monitoring and prognostic evolution in B-cell lymphomas. Patients and Methods: Exosomes were isolated from 98 patients with B-cell Lymphoma and 68 healthy controls. mRNAs were analyzed by quantitative PCR. An additional 31 post-treatment samples were also studied. Results: In the general and follicular lymphoma series, the presence of AKT mRNA was associated with poor response to rituximab-based treatment. Patients with first relapse or disease progression showed a lower percentage of PTEN and BCL-XL mRNA. The presence of BCL-6 mRNA was associated with a high death rate. The absence of PTEN mRNA in the general series, and presence of C-MYC mRNA in follicular lymphomas, were associated with short progression-free survival. BCL-6 and C-MYC mRNA were independent prognostic variables of overall survival. C-MYC mRNA may provide prognostic information with respect to overall survival. BCL-XL mRNA and increase of BCL-6 mRNA in post-treatment samples could serve as molecular monitoring markers. Conclusions: This is the first large study to evaluate the prognostic and predictive values of pretreatment tumor-associated mRNA in exosomes. BCL-6 and C-MYC mRNA positivity in pretreatment samples were predictors of worse PFS compared to patients with mRNA negativity. C-MYC mRNA positivity was also a statistically significant predictor of inability to obtain complete response with first-line therapyThis study was supported by grants FIS-PI08/0862, and SAF2010-20750. During this study, V. García received Fundación AECC and RTICC-RD2012/0036/0006 fellowship

Chronodisruption and Ambulatory Circadian Monitoring in Cancer Patients: Beyond the Body Clock

Purpose of Review: Circadian rhythms impose daily rhythms a remarkable variety of metabolic and physiological functions, such as cell proliferation, inflammation, and DNA damage response. Accumulating epidemiological and genetic evidence indicates that circadian rhythms’ disruption may be linked to cancer. The integration of circadian biology into cancer research may offer new options for increasing cancer treatment effectiveness and would encompass the prevention, diagnosis, and treatment of this disease. Recent Findings: In recent years, there has been a significant development and use of multi-modal sensors to monitor physical activity, sleep, and circadian rhythms, allowing, for the very first time, scaling accurate sleep monitoring to epidemiological research linking sleep patterns to disease, and wellness applications providing new potential applications. Summary: This review highlights the role of circadian clock in tumorigenesis, cancer hallmarks and introduces the state-of-the-art in sleep-monitoring technologies, discussing the eventual application of insights in clinical settings and cancer research.publishersversionpublishe

Chronodisruption and Ambulatory Circadian Monitoring in Cancer Patients: Beyond the Body Clock.

Purpose of Review Circadian rhythms impose daily rhythms a remarkable variety of metabolic and physiological functions, such as cell proliferation, infammation, and DNA damage response. Accumulating epidemiological and genetic evidence indicates that circadian rhythms’ disruption may be linked to cancer. The integration of circadian biology into cancer research may ofer new options for increasing cancer treatment efectiveness and would encompass the prevention, diagnosis, and treatment of this disease. Recent Findings In recent years, there has been a signifcant development and use of multi-modal sensors to monitor physical activity, sleep, and circadian rhythms, allowing, for the very frst time, scaling accurate sleep monitoring to epidemiological research linking sleep patterns to disease, and wellness applications providing new potential applications. Summary This review highlights the role of circadian clock in tumorigenesis, cancer hallmarks and introduces the stateof-the-art in sleep-monitoring technologies, discussing the eventual application of insights in clinical settings and cancer research.post-print1077 K

Assessing the risk of cardiovascular events in patients receiving immune checkpoint inhibitors

Funding Information: This article is part of the CLARIFY project, supported by the European Union Horizon 2020 Research and Innovation Program under grant agreement number 875160. Publisher Copyright: Copyright © 2022 Torrente, Blanco, Franco, Garitaonaindia, Calvo, Collazo-Lorduy, Gutiérrez, Sánchez, González-del-Alba, Hernández, Méndez, Cantos, Núñez, Sousa and Provencio.Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. However, despite their excellent therapeutic effect, these medications typically result in a broad spectrum of toxicity reactions. Immune-related cardiotoxicity is uncommon but can be potentially fatal, and its true incidence is underestimated in clinical trials. The aim of this study is to assess the incidence and identify risk factors for developing a cardiac event in patients treated with ICIs. Methods: We conducted a single-institution retrospective study, including patients treated with ICIs in our center. The main outcomes were cardiac events (CE) and cardiovascular death. Results: A total of 378 patients were analyzed. The incidence of CE was 16.7%, during a median follow-up of 50.5 months. The multivariable analysis showed that age, a history of arrhythmia or ischemic heart disease, and prior immune-related adverse events were significantly associated with CE. Conclusion: CE during ICI treatment are more common than currently appreciated. A complete initial cardiovascular evaluation is recommended, especially in high-risk patients, being necessary a multidisciplinary approach of a specialized cardio-oncology team.publishersversionpublishe

Chronodisruption and Ambulatory Circadian Monitoring in Cancer Patients: Beyond the Body Clock

Purpose of Review: Circadian rhythms impose daily rhythms a remarkable variety of metabolic and physiological functions, such as cell proliferation, inflammation, and DNA damage response. Accumulating epidemiological and genetic evidence indicates that circadian rhythms’ disruption may be linked to cancer. The integration of circadian biology into cancer research may offer new options for increasing cancer treatment effectiveness and would encompass the prevention, diagnosis, and treatment of this disease. Recent Findings: In recent years, there has been a significant development and use of multi-modal sensors to monitor physical activity, sleep, and circadian rhythms, allowing, for the very first time, scaling accurate sleep monitoring to epidemiological research linking sleep patterns to disease, and wellness applications providing new potential applications. Summary: This review highlights the role of circadian clock in tumorigenesis, cancer hallmarks and introduces the state-of-the-art in sleep-monitoring technologies, discussing the eventual application of insights in clinical settings and cancer researchThis work was supported in part by CLARIFY project, within European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 875160, Instituto de Fomento de la Región de Murcia (INFO) and the European Regional Development Fund (FEDER

Safety and efficacy of ribociclib plus letrozole in patients with HR+, HER2– advanced breast cancer: Results from the Spanish sub-population of the phase 3b CompLEEment-1 trial

Background: Breast cancer is the most common malignancy and the second leading cause of cancer-related mortality in Spanish women. Ribociclib in combination with endocrine therapy (ET) has shown superiority in prolonging survival in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) vs. ET alone.Methods: CompLEEment-1 is a single-arm, open-label phase 3b trial evaluating ribociclib plus letrozole in a broad population of patients with HR+, HER2- ABC. The primary endpoints were safety and tolerability. Here we report data for Spanish patients enrolled in CompLEEment-1.Results: A total of 526 patients were evaluated (median follow-up: 26.97 months). Baseline characteristics showed a diverse population with a median age of 54 years. At study entry, 56.5% of patients had visceral metastases and 8.7% had received prior chemotherapy for advanced disease. Rates of all-grade and Grade >= 3 adverse events (AEs) were 99.0% and 76.2%, respectively; 21.3% of patients experienced a serious AE, and 15.8% of AEs led to treatment discontinuation. AEs of special interest of neutropenia, increased alanine aminotransferase, increased aspartate aminotransferase and QTcF prolongation occurred in 77.8%, 14.8%, 11.4% and 4.0% of patients, respectively. Patients aged >70 years experienced increased rates of all-grade and Grade >= 3 neutropenia and anemia. Efficacy results were consistent with the global study.Conclusions: Results from Spanish patients enrolled in CompLEEment-1 are consistent with global data showing efficacy and a manageable safety profile for ribociclib plus letrozole treatment in patients with HR+, HER2-ABC, including populations of interest (NCT02941926).Trial registration: ClinicalTrials.gov NCT0294192