Multiple myeloma and SARS-CoV-2 infection : clinical characteristics and prognostic factors of inpatient mortality

There is limited information on the characteristics, prognostic factors, and outcomes of patients with multiple myeloma (MM) hospitalized with COVID-19. This retrospective case series investigated 167 patients reported from 73 hospitals within the Spanish Myeloma Collaborative Group network in March and April, 2020. Outcomes were compared with 167 randomly selected, contemporary, age-/sex-matched noncancer patients with COVID-19 admitted at six participating hospitals. Among MM and noncancer patients, median age was 71 years, and 57% of patients were male; 75 and 77% of patients, respectively, had at least one comorbidity. COVID-19 clinical severity was moderate-severe in 77 and 89% of patients and critical in 8 and 4%, respectively. Supplemental oxygen was required by 47 and 55% of MM and noncancer patients, respectively, and 21%/9% vs 8%/6% required noninvasive/invasive ventilation. Inpatient mortality was 34 and 23% in MM and noncancer patients, respectively. Among MM patients, inpatient mortality was 41% in males, 42% in patients aged >65 years, 49% in patients with active/progressive MM at hospitalization, and 59% in patients with comorbid renal disease at hospitalization, which were independent prognostic factors on adjusted multivariate analysis. This case series demonstrates the increased risk and identifies predictors of inpatient mortality among MM patients hospitalized with COVID-19

Results of an early access treatment protocol of daratumumab monotherapy in spanish patients with relapsed or refractory multiple myeloma

Daratumumab is a human CD38-targeted monoclonal antibody approved as monotherapy for heavily pretreated relapsed and refractory multiple myeloma. We report findings for the Spanish cohort of an open-label treatment protocol that provided early access to daratumumab monotherapy and collected safety and patient-reported outcomes data for patients with relapsed or refractory multiple myeloma. At 15 centers across Spain, intravenous daratumumab (16mg/kg) was administered to 73 patients who had ≥3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or who were double refractory to both. The median duration of daratumumab treatment was 3.3 (range: 0.03–13.17) months, with a median number of 12 (range: 1–25) infusions. Grade 3/4 treatment-emergent adverse events were reported in 74% of patients and included lymphopenia (28.8%), thrombocytopenia (27.4%), neutropenia (21.9%), leukopenia (19.2%), and anemia (15.1%). Common (>5%) serious treatmentemergent adverse events included respiratory tract infection (9.6%), general physical health deterioration (6.8%), and back pain (5.5%). Infusion-related reactions occurred in 45% of patients. The median change from baseline in all domains of the EQ-5D-5L and EORTC QLQ-C30 was mostly 0. A total of 18 (24.7%) patients achieved a partial response or better, with 10 (13.7%) patients achieving a very good partial response or better. Median progression-free survival was 3.98 months. The results of this early access treatment protocol are consistent with previously reported trials of daratumumab monotherapy and confirm its safety and antitumoral efficacy in Spanish patients with heavily treated relapsed or refractory multiple myeloma

Predicting long-term disease control in transplant-ineligible patients with multiple myeloma: impact of an MGUS-like signature

Disease control at 5 years would be a desirable endpoint for elderly multiple myeloma (MM) patients, but biomarkers predicting this are not defined. Therefore, to gain further insights in this endpoint, a population of 498 newly diagnosed transplant-ineligible patients enrolled in two Spanish trials (GEM2005MAS65 and GEM2010MAS65), has been analyzed. Among the 435 patients included in this post-hoc study, 18.6% remained alive and progression free after 5 years of treatment initiation. In these patients, overall survival (OS) rate at 10 years was 60.8% as compared with 11.8% for those progressing within the first 5 years. Hemoglobin (Hb) >= 12 g/dl (OR 2.74, p = 0.001) and MGUS-like profile (OR 4.18, p = 0.005) were the two baseline variables associated with long-term disease-free survival. Upon including depth of response (and MRD), Hb >= 12 g/dl (OR 2.27) and MGUS-like signature (OR 7.48) retained their predictive value along with MRD negativity (OR 5.18). This study shows that despite the use of novel agents, the probability of disease control at 5 years is still restricted to a small fraction (18.6%) of elderly MM patients. Since this endpoint is associated with higher rates of OS, this study provides important information about diagnostic and post-treatment biomarkers helpful in predicting the likelihood of disease control at 5 years

Multiple myeloma and SARS-CoV-2 infection: clinical characteristics and prognostic factors of inpatient mortality

There is limited information on the characteristics, prognostic factors, and outcomes of patients with multiple myeloma (MM) hospitalized with COVID-19. This retrospective case series investigated 167 patients reported from 73 hospitals within the Spanish Myeloma Collaborative Group network in March and April, 2020. Outcomes were compared with 167 randomly selected, contemporary, age-/sex-matched noncancer patients with COVID-19 admitted at six participating hospitals. Among MM and noncancer patients, median age was 71 years, and 57% of patients were male; 75 and 77% of patients, respectively, had at least one comorbidity. COVID-19 clinical severity was moderate–severe in 77 and 89% of patients and critical in 8 and 4%, respectively. Supplemental oxygen was required by 47 and 55% of MM and noncancer patients, respectively, and 21%/9% vs 8%/6% required noninvasive/invasive ventilation. Inpatient mortality was 34 and 23% in MM and noncancer patients, respectively. Among MM patients, inpatient mortality was 41% in males, 42% in patients aged >65 years, 49% in patients with active/progressive MM at hospitalization, and 59% in patients with comorbid renal disease at hospitalization, which were independent prognostic factors on adjusted multivariate analysis. This case series demonstrates the increased risk and identifies predictors of inpatient mortality among MM patients hospitalized with COVID-19

Minimal residual disease monitoring and immune profiling using second generation flow cytometry in elderly multiple myeloma

The value of minimal residual disease (MRD) in multiple myeloma (MM) has been more frequently investigated in transplant-eligible than elderly patients. Since an optimal balance between treatment efficacy and toxicity is of utmost importance in elderly MM, sensitive MRD monitoring might be particularly valuable in this patient population. Here, we used 2nd generation 8-color multiparameter-flow-cytometry (MFC) to monitor MRD in 162 transplant-ineligible MM patients enrolled in the PETHEMA/GEM2010MAS65 study, The transition from 1st to 2nd generation MFC resulted in increased sensitivity, and allowed to identify three patient groups according to MRD levels: MRD-negative (75-years (HR:4.8; P<.001), and those with high-risk cytogenetics (HR:12.6; P=.01). Using 2nd generation MFC, immune profiling concomitant to MRD monitoring also contributed to identify patients with poor, intermediate and favorable outcome (25%, 61% and 100% OS at 3-years; P=.01); the later patients being characterized by an increased compartment of mature B-cells. Our results show that similarly to transplant-candidates, MRD monitoring is one of the most relevant prognostic factors in elderly MM, irrespectively of patients’ age and cytogenetic risk

Nucleotide specificity of Saccharomyces cerevisiae phosphoenolpyruvate carboxykinase Kinetics, fluorescence spectroscopy, and molecular simulation studies

Gonzalez-Nilo,F. Centro de Bioinformática, Universidad de Talca, 2 Norte 685, Casilla 721, Talca, ChilePhosphoenolpyruvate carboxykinases, depending on the enzyme origin, preferentially use adenine or guanine nucleotides as substrates. In this work, analyses of the substrate specificity of the Saccharomyces cerevisiae ATP-dependent enzyme have been carried out. Kinetics studies gave relative values of kcat/Km for the nucleoside triphosphate complexes in the order ATP GTP > ITP > UTP > CTP. For the nucleoside diphosphate complexes the order is ADP GDP > IDP UDP > CDP. This shows that the enzyme has a strong preference for ADP (or ATP) over other nucleotides, being this preference about an order of magnitude higher for the diphosphorylated than for the triphosphorylated nucleosides. The calculated binding free energies (kcal mol−1) at 25 °C are 7.39 and 6.51 for ATP and ADP, respectively. These values decrease with the nucleotide structure in the same order than the kinetic specificity. The binding energy for any triphosphorylated nucleoside is more favourable than for the corresponding diphosphorylated compound, showing the relevance of the Pγ for nucleotide binding. Homology models of the adenine and guanine nucleotides in complex with the enzyme show that the base adopts a similar conformation in the diphosphorylated nucleosides while in the triphosphorylated nucleosides the sugar-base torsion angle is 61° for ATP and −53° for GTP. Differences are also noted in the distance between Pβ and Mn2+ at site 1. This distance is almost the same in the ATP, GTP, and UTP complexes, however in the ADP, GDP and UDP complexes it is 2.9, 5.1, and 7 Å, respectively. Experimental data obtained with a Thr463Ala mutant enzyme agree with molecular simulation predictions. The results here presented are discussed in terms of the proposed interactions of the nucleotides with the protein

On the Preparation of Thin Films of Stearyl Methacrylate Directly Photo-polymerized at the Air–Water Interface

Characterization of bidimensional polymeric films at the air–water interface in the Langmuir trough, despite being a recurrent topic, usually refers to films of already formed polymeric materials, with very scarce reports on direct polymerization at the air–water interface. In the present work, we studied the photo-polymerization of stearyl methacrylate directly at the air–water interface under a nitrogen atmosphere, with the radical initiator solubilized in the aqueous phase. Two-dimensional (2D) polymerization was monitored by measuring the pressure–area isotherm at different irradiation times. The polymerization leads to a film with an isotherm different from that observed for the monomer, where the surface pressure is directly related to the irradiation time. The shape of this isotherm confirms the presence of a compressed liquid phase, where a higher order can be attained as a consequence of stronger packing forces involving polymer chains. The presence of inter-chain interactions allows rearrangements on the surface of the subphase, and even before the collapse a dense 2D ordering (with a solid phase-like behavior) can be observed. We present a new one-step, solvent-free procedure to obtain a photo-polymeric film directly at the air–water interface, which can be transferred to a solid surface by the Langmuir–Blodgett method, allowing film preparation of controlled thickness. Films were characterized by measuring properties such as thickness, roughness, and hydrophobicity and comparing them with films obtained from a conventional polymer. We report the differences between the interfacial behavior of amphiphilic molecules and nanomaterials such as films obtained by photo-polymerization, PSMA, directly on the air–water interface

Enseñanza del ordenamiento constitucional

Demostrar, experimentalmente, cómo un programa diseñado para la enseñanza del ordenamiento constitucional en tercero de BUP, logra crearles hábitos democráticos, desarrollar su identidad en el descubrimiento de la identidad de su pueblo y fomentar su integración en la comunidad como forma de provocar la adquisición de modos concretos de actuación ciudadana, políticos y profesionales. Según el diseño de la investigación, la muestra debía estar formada por los 240 alumnos de tercero de BUP del Instituto de Bachillerato Padre Isla de León. No representativa. Finalmente sólo pudo experimentarse sobre un grupo de 40 alumnos, aunque el resto participó en algunas de las actividades programadas. Se experimentan estos recursos didácticos (variables independientes): a) contenidos, el ciudadano y su entorno, cauces participativos, Ayuntamiento, Comunidad Autónoma, Estado, orden constitucional, problemática mundial, papel de España; b) instrumentos: materiales (seminario sobre Constitución, libros, prensa, vídeo, mapas) y formales (clases, entrevistas, visitas a organismos oficiales, debates, dinámicas de grupo con los padres). c) actividades, investigaciones en grupos, recogida, elaboración, discusión de información; d) programación horaria de las variables dependientes, sobre las que se espera incidan las independientes, y que son: adquisición de conocimientos (Constitución, Estado Autonómico, la transición, partidos políticos, Castilla-León), actitudes (tolerancia, valoración de la democracia, defensa de las libertades) y conductas (solidaridad, participación) por parte de los alumnos. La programación se reestructuró por retrasos inevitables, fijándose máximos y mínimos a realizar. La metodología es óptima en la coordinación entre profesores y en la participación grupal, no sólo individual, de los alumnos. En cuanto a los medios materiales, son positivos en el vídeo, aunque su poca flexibilidad y la falta de experiencia impidieron aprovecharlo mejor. Óptimos en el material bibliográfico, por adquisiciones y uso. Los trabajos de investigación son óptimos como medios de abordar la realidad y fomentar su estudio. En cuanto al cumplimiento de objetivos, los de conducta aún no son evaluables, aunque el alumno ha aprendido a discutir argumentando; sobre los cognoscitivos, del análisis del pre y posttest, se desprende el inicial bajo nivel de los alumnos y su radical mejoría tras el experimento, han adquirido conocimientos sobre temas. Tratados en mesas redondas, entrevistas y visitas; relativo a los actitudinales, es difícil evaluarlos aunque los alumnos rinden lo deseado respeto a la constitución. Objetivos no alcanzados, no se han realizado dinámicas de grupo ni tantas visitas como las deseadas y no se ha manejado la prensa con profusión. Los investigadores se sienten satisfechos con la aceptación y el cambio de actitud operado en los alumnos hacia la Constitución. En este marco incluso los intereses profesionales del alumnado se han concretado, lo que demuestra como el orden natural del aprendizaje debe empezar por la integración en la sociedad, o por una fuerte motivación para alcanzar dicha integración, donde el alumno descubrirá el modo, laboral o profesional, concreto de realizarla.Castilla y LeónBiblioteca de Educación del Ministerio de Educación, Cultura y Deporte; Calle San Agustín, 5 - 3 Planta; 28014 Madrid; Tel. +34917748000; Fax +34917748026; [email protected]

Proyecto de enseñanza del ordenamiento constitucional

Que el individuo (alumno) se integre o se sienta movido a integrarse en la comunidad social y política. Que de esta integración, surja en el el modo concreto (laboral y político) de ser ciudadano, al que le corresponderá el aprendizaje adecuado en el centro de enseñanza adecuado. 240 alumnos masculinos de tercero de BUP de régimen diurno del Instituto de Bachillerato Padre Isla (León). Este proyecto trata de convertir el texto constitucional en modos de vivir y sentir. Ello, implica sacarlo del aula y cotejarlo con la realidad. La actividad constitucional se extenderá a lo largo de todo el curso, se le dedicarán 3 horas lectivas semanales y tendrá las siguientes fases: Primera fase: recogida de información. Los datos serán recogidos mediante la visita y la entrevista. Se acompañará de la prensa diaria. Segunda fase: elaboración de la información. Se constituirá un archivo de prensa y documentos. Tercera fase: transmisión y puesta en común de la información, mediante exposiciones orales, cuestiones polémicas, sesiones videotelevisadas, mesas redondas y dinámica grupal. Las fases no se realizarán cronológicamente una tras otra. El contenido de las mismas se ha pormenorizado. Sin embargo, se le propondrá al alumno un conjunto de unidades didácticas en los que ir enmarcando sus resultados. El conjunto temático, será el marco teórico para la localización y ubicación de la experiencia práctica. La evaluación del proyecto será grupal mediante ítems que se pasaran a todos los participantes. En la puesta en marcha del proyecto: A. De 3 horas semanales de dedicación se pasó a 2 horas. B. No se inició en octubre sino prácticamente en enero. C. Fue necesaria la reordenación de actividades. D. No se consiguió introducir a los padres de los alumnos en discusiones o debates conjuntos. E. No se hicieron tantas visitas. F. No se manejó la prensa con tanta profusión. Y en general no se hizo todo lo proyectado, pero sí más de lo programado. A pesar de ello: F. La participación e interés de los alumnos han sido muy altos. G. Ahora tienen una visión realista de la Constitución.Castilla y LeónBiblioteca de Educación del Ministerio de Educación, Cultura y Deporte; Calle San Agustín, 5 - 3 Planta; 28014 Madrid; Tel. +34917748000; Fax +34917748026; [email protected]