Utility of CYP2D6 copy number variants as prognostic biomarker in localized anal squamous cell carcinoma

CYP2D6; Anal squamous cell carcinoma; Cell cycleCYP2D6; Carcinoma de células escamosas anales; Ciclo celularCYP2D6; Carcinoma anal de cèl·lules escamoses; Cicle cel·lularBackground: Anal squamous cell carcinoma (ASCC) is an infrequent tumor whose treatment has not changed since the 1970s. The aim of this study is the identification of biomarkers allowing personalized treatments and improvement of therapeutic outcomes. Methods: Forty-six paraffin tumor samples from ASCC patients were analyzed by whole-exome sequencing. Copy number variants (CNVs) were identified and their relation to disease-free survival (DFS) was studied and validated in an independent retrospective cohort of 101 ASCC patients from the Multidisciplinary Spanish Digestive Cancer Group (GEMCAD). GEMCAD cohort proteomics allowed assessing the biological features of these tumors. Results: On the discovery cohort, the median age was 61 years old, 50% were males, stages I/II/III: 3 (7%)/16 (35%)/27 (58%), respectively, median DFS was 33 months, and overall survival was 45 months. Twenty-nine genes whose duplication was related to DFS were identified. The most representative was duplications of the CYP2D locus, including CYP2D6, CYP2D7P, and CYP2D8P genes. Patients with CYP2D6 CNV had worse DFS at 5 years than those with two CYP2D6 copies (21% vs. 84%; p < .0002, hazard ratio [HR], 5.8; 95% confidence interval [CI], 2.7-24.9). In the GEMCAD validation cohort, patients with CYP2D6 CNV also had worse DFS at 5 years (56% vs. 87%; p = .02, HR = 3.6; 95% CI, 1.1-5.7). Mitochondria and mitochondrial cell-cycle proteins were overexpressed in patients with CYP2D6 CNV. Conclusions: Tumor CYP2D6 CNV identified patients with a significantly worse DFS at 5 years among localized ASCC patients treated with 5-fluorouracil, mitomycin C, and radiotherapy. Proteomics pointed out mitochondria and mitochondrial cell-cycle genes as possible therapeutic targets for these high-risk patients. Plain language summary: Anal squamous cell carcinoma is an infrequent tumor whose treatment has not been changed since the 1970s. However, disease-free survival in late staged tumors is between 40% and 70%. The presence of an alteration in the number of copies of CYP2D6 gene is a biomarker of worse disease-free survival. The analysis of the proteins in these high-risk patients pointed out mitochondria and mitochondrial cell-cycle genes as possible therapeutic targets. Therefore, the determination of the number of copies of CYP2D6 allows the identification of anal squamous carcinoma patients with a high-risk of relapse that could be redirected to a clinical trial. Additionally, this study may be useful to suggest new treatment strategies to increase current therapy efficacy

Indicadores de observación y competencias en el Prácticum Grados Infantil y Primaria: centro y aula

El trabajo que se presenta está enmarcado en la RED Diseño y desarrollo de una Guía observacional para la implementación del Prácticum de los Grados de Infantil y Primaria, dentro del Programa de REDES de investigación en docencia universitaria del ICE/ Universidad de Alicante. Tomando como referencia las competencias de la asignatura Prácticum que se desarrolla a lo largo de varios periodos, se han establecido una serie de indicadores de observación a nivel de centro y de aula, que nos permitan configurar una Guía observacional como instrumento de observación y análisis de la realidad escolar durante el desarrollo del Prácticum. La metodología utilizada se ha centrado en el trabajo colaborativo de los integrantes de la RED, desde sus diversas experiencias y aportaciones en sus campos profesionales. Los primeros resultados han determinado los seis grandes bloques de indicadores de esta Guía: la organización y gestión del centro; la organización y gestión del aula; el clima del aula y el alumnado; el planteamiento metodológico y la evaluación; la atención a las n.e.e.; y la participación de las familias

Un estudio en RED: Guía observacional en el Prácticum Grados Infantil y Primaria

El trabajo que se presenta está enmarcado en la RED Diseño y desarrollo de una Guía observacional para la implementación del Prácticum de los Grados de Infantil y Primaria, dentro del Programa de REDES de investigación en docencia universitaria del ICE/ Universidad de Alicante. Tomando como referencia las competencias de la asignatura Prácticum que se desarrolla a lo largo de varios periodos, se han establecido una serie de indicadores de observación a nivel de centro y de aula, que nos permitan configurar una Guía observacional como instrumento de observación y análisis de la realidad escolar durante el desarrollo del Prácticum. La metodología utilizada se ha centrado en el trabajo colaborativo de los integrantes de la RED, desde sus diversas experiencias y aportaciones en sus campos profesionales. Los primeros resultados han determinado los seis grandes bloques de indicadores de esta Guía: la organización y gestión del centro; la organización y gestión del aula; el clima del aula y el alumnado; el planteamiento metodológico y la evaluación; la atención a las n.e.e.; y la participación de las familias

Utility of CYP2D6 copy number variants as prognostic biomarker in localized anal squamous cell carcinoma

Background: Anal squamous cell carcinoma (ASCC) is an infrequent tumor whose treatment has not changed since the 1970s. The aim of this study is the identification of biomarkers allowing personalized treatments and improvement of therapeutic outcomes. Methods: Forty-six paraffin tumor samples from ASCC patients were analyzed by whole-exome sequencing. Copy number variants (CNVs) were identified and their relation to disease-free survival (DFS) was studied and validated in an independent retrospective cohort of 101 ASCC patients from the Multidisciplinary Spanish Digestive Cancer Group (GEMCAD). GEMCAD cohort proteomics allowed assessing the biological features of these tumors. Results: On the discovery cohort, the median age was 61 years old, 50% were males, stages I/II/III: 3 (7%)/16 (35%)/27 (58%), respectively, median DFS was 33 months, and overall survival was 45 months. Twenty-nine genes whose duplication was related to DFS were identified. The most representative was duplications of the CYP2D locus, including CYP2D6, CYP2D7P, and CYP2D8P genes. Patients with CYP2D6 CNV had worse DFS at 5 years than those with two CYP2D6 copies (21% vs. 84%; p <.0002, hazard ratio [HR], 5.8; 95% confidence interval [CI], 2.7–24.9). In the GEMCAD validation cohort, patients with CYP2D6 CNV also had worse DFS at 5 years (56% vs. 87%; p =.02, HR = 3.6; 95% CI, 1.1–5.7). Mitochondria and mitochondrial cell-cycle proteins were overexpressed in patients with CYP2D6 CNV. Conclusions: Tumor CYP2D6 CNV identified patients with a significantly worse DFS at 5 years among localized ASCC patients treated with 5-fluorouracil, mitomycin C, and radiotherapy. Proteomics pointed out mitochondria and mitochondrial cell-cycle genes as possible therapeutic targets for these high-risk patients. Plain Language Summary: Anal squamous cell carcinoma is an infrequent tumor whose treatment has not been changed since the 1970s. However, disease-free survival in late staged tumors is between 40% and 70%. The presence of an alteration in the number of copies of CYP2D6 gene is a biomarker of worse disease-free survival. The analysis of the proteins in these high-risk patients pointed out mitochondria and mitochondrial cell-cycle genes as possible therapeutic targets. Therefore, the determination of the number of copies of CYP2D6 allows the identification of anal squamous carcinoma patients with a high-risk of relapse that could be redirected to a clinical trial. Additionally, this study may be useful to suggest new treatment strategies to increase current therapy efficacyIdiPAZ, Grant/Award Number: Jesús Antolín Garciarena Fellowship; European Proteomics Infrastructure Consortium, Grant/Award Number: 823839, Horizon 2020 Programm

Evolution of <i>RAS</i> Mutations in Cell-Free DNA of Patients with Tissue <i>RAS</i> Wild-Type Metastatic Colorectal Cancer Receiving First-Line Treatment: The PERSEIDA Study

The serial analysis of cell-free DNA (cfDNA) enables minimally invasive monitoring of tumor evolution, providing continuous genetic information. PERSEIDA was an observational, prospective study assessing the cfDNA RAS (KRAS/NRAS) mutational status evolution in first-line, metastatic CRC, RAS wild-type (according to baseline tumor tissue biopsy) patients. Plasma samples were collected before first-line treatment, after 20 ± 2 weeks, and at disease progression. One hundred and nineteen patients were included (102 received panitumumab and chemotherapy as first-line treatment—panitumumab subpopulation). Fifteen (12.6%) patients presented baseline cfDNA RAS mutations (n = 14 [13.7%], panitumumab subpopulation) (mutant allele fraction ≥0.02 for all results). No patients presented emergent mutations (cfDNA RAS mutations not present at baseline) at 20 weeks. At disease progression, 11 patients (n = 9; panitumumab subpopulation) presented emergent mutations (RAS conversion rate: 19.0% [11/58]; 17.7% [9/51], panitumumab subpopulation). In contrast, three (5.2%) patients presenting baseline cfDNA RAS mutations were RAS wild-type at disease progression. No significant associations were observed between overall response rate or progression-free survival and cfDNA RAS mutational status in the total panitumumab subpopulation. Although, in patients with left-sided tumors, a significantly longer progression-free survival was observed in cfDNA RAS wild-type patients compared to those presenting cfDNA RAS mutations at any time. Continuous evaluation of RAS mutations may provide valuable insights on tumor molecular dynamics that can help clinical practice

I Congreso Pizarra Digital

Resumen basado en el de la publicaciónSe recogen algunas de las comunicaciones presentadas en el I Congresos Pizarra Digital. Con la llegada de nuevos métodos, modelos didácticos, herramientas, recursos y contenidos digitales a las aulas, se hace necesario un punto de encuentro, referencia y reflexión sobre la digitalización de los entornos educativos. Se pretende asimismo reconocer el esfuerzo de los profesores en su labor docente para integrar en las aulas la tecnología y los formatos y contenidos digitales. Se realiza una presentación de novedades, y una reflexión y puesta en común de proyectos referidos a la Pizarra Digital, la creatividad, los contenidos digitales y otras herramientas multimedia e interactivas y su aporte como ayuda para el profesor, desde la Educación Infantil hasta la Universidad.MadridBiblioteca de Educación del Ministerio de Educación, Cultura y Deporte; Calle San Agustín, 5 - 3 planta; 28014 Madrid; Tel. +34917748000; [email protected]