Evaluación del grado de conversión de los receptores HER2, RE y RPg entre el cáncer de mama primario y sus respectivas metástasis

Introducción: Tradicionalmente, las decisiones terapéuticas tanto del cáncer de mama precoz como de los estadios avanzados se han basado en los marcadores predictivos del tumor primario, tales como el receptor de estrógeno (RE), el receptor de progesterona (RPg) y el receptor 2 del factor de crecimiento epidérmico humano (HER2), asumiendo que éstos permanecían inmutables a nivel de la recaída metastásica. Objetivos: El objetivo general de esta tesis era investigar si el estado de los receptores HER2, RE y RPg realmente puede cambiar durante la progresión del cáncer de mama y profundizar en las causas y en el impacto clínico de dichos cambios. El objetivo principal era determinar la tasa de conversión de los receptores HER2, RE y RPg entre los tumores primarios de mama y sus respectivas lesiones metastásicas analizados en un laboratorio central. Pacientes y Método: Diseñamos un estudio observacional, prospectivo y multicéntrico coordinado por GEICAM (Grupo Español de Investigación en Cáncer de Mama) en el que se incluyeron pacientes con cáncer de mama localmente recidivante o metastásico de 31 hospitales españoles. Las pacientes podían encontrarse bien en primera recaída o tras sucesivas progresiones de la enfermedad, debían disponer de una muestra apropiadamente conservada de su tumor primario y tener programada la realización de una biopsia de una lesión supuestamente recidivante o metastásica. Se determinó el estado de los receptores hormonales y HER2 mediante inmunohistoquímica e hibridación in situ fluorescente en muestras pareadas (tumor primario – metástasis) de forma ciega y utilizando la misma metodología en un laboratorio central de referencia para minimizar la variabilidad inherente a las técnicas de análisis. Estos resultados se compararon con las determinaciones realizadas en las instituciones locales. Resultados: En total se incluyeron 196 pacientes, excluyéndose a 12 pacientes de la población evaluable por imposibilidad para realizarse la biopsia (n=4) o bien porque los resultados de la biopsia correspondieron a tejido sano (n=3), enfermedad benigna (n=3) o una segunda neoplasia maligna (n=2). Las tasas de conversión de los receptores determinados en el laboratorio central, aun siendo menores que las determinadas en los laboratorios locales, eran clínicamente relevantes: HER2: 3% (vs 16% según las evaluaciones de los laboratorios locales); RE: 13% (vs 21%) y RPg: 28% (vs 35%). Al comparar los resultados de los laboratorios locales y el central, hubo una buena concordancia en la determinación de HER2 tanto en el tumor primario como en las metástasis, y en la expresión del RE en las metástasis, mientras que el RE en el tumor primario y el RPg mostraron una modesta concordancia. El subtipo tumoral se modificó en un 14,5% de las pacientes según las determinaciones del laboratorio central (y en un 26% según las determinaciones de los laboratorios locales). Los oncólogos tras la realización de la biopsia modificaron sus planes terapéuticos en un 8% de todas las pacientes incluidas en el estudio, y en el 31% de las pacientes cuyo subtipo tumoral había cambiado en la metástasis. Conclusiones: Estos resultados refuerzan la recomendación de realizar biopsias confirmatorias de las metástasis de cáncer de mama, no sólo para evitar un diagnóstico erróneo de recaída, sino también para identificar cambios en los biomarcadores con la posibilidad de optimizar el tratamiento adaptándolo al perfil biológico de la enfermedad metastásica. Finalmente, la mayor tasa de discordancias en los receptores y en el subtipo tumoral observada en los laboratorios locales sugiere la necesidad de implantar medidas destinadas a mejorar la calidad de las determinaciones de biomarcadores con repercusión directa en las decisiones terapéuticas. Agradecimientos: GEICAM, CIBERONC, ROCHE y a todas las pacientes que han participado en el estudio CONVERTHER.Introduction: Traditionally, therapeutic decisions for both early and advanced breast cancer have been based on predictive markers of the primary tumor, such as estrogen receptor (ER), progesterone receptor (PR) and receptor of human epidermal growth factor-2 (HER2), assuming that they remained immutable at the level of metastatic relapse. Objectives: The overall aim of this thesis was to investigate whether the status of HER2, ER and PR receptors can actually change during breast cancer progression and to delve into the causes and clinical impact of these changes. The main objective was to determine the rate of conversion of HER2, ER and PR receptors between primary breast tumors and their respective metastatic lesions analyzed in a central laboratory. PATIENTS AND METHODS: We designed an observational, prospective and multicenter study coordinated by GEICAM (Spanish Breast Cancer Group), which included patients with locally recurrent or metastatic breast cancer in 31 Spanish hospitals. Patients could be included on their first relapse or after successive disease progressions, they should have an appropriately conserved sample of their primary tumor and have a biopsy of a suspected relapsing or metastatic lesion scheduled. The status of the hormone receptors and HER2 were determined by immunohistochemistry and fluorescence in situ hybridization in paired samples (primary tumor - metastasis) in a blind fashion and using the same methodology in a central reference laboratory to minimize the variability inherent in the analysis techniques. These results were compared with the determinations made in the local institutions. RESULTS: A total of 196 patients were included, 12 patients were excluded from the evaluable population due to the impossibility of performing the biopsy (n = 4) or because the biopsy results corresponded to healthy tissue (n = 3), benign disease (n = 3) or a second malignant neoplasm (n = 2). Conversion rates of the receptors determined in the central laboratory, although lower than those determined in the local laboratories, were clinically relevant: HER2: 3% (vs 16% according to local laboratory evaluations); RE: 13% (vs 21%) and RPg: 28% (vs. 35%). When comparing the results of the local and central laboratories, there was a good concordance in the determination of HER2 in both the primary tumor and in the metastases, and in the expression of the ER in the metastases, while the ER in the primary tumor and The PR showed a modest agreement. The tumor subtype was modified in 14,5% of the patients according to the central laboratory determinations (and in 26% according to the determinations of the local laboratories). Oncologists after the biopsy modified their therapeutic plans in 8% of all the patients included in the study, and in 31% of the patients whose tumor subtype had changed in the metastasis. CONCLUSIONS: These results reinforce the recommendation to perform confirmatory biopsies of breast cancer metastases, not only to avoid a misdiagnosis of relapse, but also to identify changes in biomarkers with the possibility of optimizing the treatment, adapting it to the biological profile of the metastatic disease. Finally, the higher rate of receptor and tumor subtype discordances observed in local laboratories suggests the need to implement measures aimed at improving the quality of biomarkers determinations with a direct impact on therapeutic decisions

NESS®, una alternativa al doble ramal de retorno que ahorra agua y energía

El objetivo de este trabajo es establecer las principales diferencias entre dos sistemas de ahorro de agua: el doble ramal de agua caliente y una solución alternativa capaz de recircular toda el agua que normalmente se desperdicia hasta que sale caliente, pero empleando la instalación convencional de cualquier edificio. Este sistema alternativo consigue ahorrar la misma cantidad de agua que el doble ramal o ramal de retorno, es decir, toda el agua fría que queda almacenada en la tubería de agua caliente después de un tiempo sin utilizar el agua caliente. Este ahorro suma aproximadamente un 27% del uso de agua doméstico. La principal diferencia con respecto al doble ramal es el consumo energético derivado de cada sistema: mientras NESS® funciona a demanda del usuario, el doble ramal funciona continua o periódicamente para mantener el agua por encima de una temperatura alrededor de 50ºC, sin considerar si existe demanda o no. NESS® genera un ahorro energético significativo con respecto al doble ramal o red de retorno, empleando un 35% de la energía que usa el doble ramal. Además, NESS presenta otras ventajas tanto para profesionales como para personas interesadas en la sostenibilidad, como un coste de implementación de la mitad del doble ramal o un tercio del tiempo de instalación

NESS. Sistema de recirculación de agua caliente sin ramal adicional de retorno. Ahorro de agua y energía

El objetivo del presente estudio es identificar las diferencias existentes entre el sistema de aprovechamiento de agua basado en el doble ramal de agua caliente y una innovadora alternativa que realiza la recirculación sin la necesidad de un ramal de retorno adicional, empleando la instalación convencional de cualquier vivienda. Para ello, se realizará un detallado análisis del consumo de energía y económico proporcionado por la ya conocida red de retorno con doble ramal de agua caliente, para posteriormente compararlo con el sistema de recirculación sin ramal adicional de retorno. Atendiendo a los datos arrojados por esta comparación, se presentan las ventajas e inconvenientes de un sistema respecto al otro, y por tanto, cuál es considerado óptimo en cada caso.Consejo General de la Arquitectura Técnica de Españ

New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49)

Spinocerebellar ataxias consist of a highly heterogeneous group of inherited movement disorders clinically characterized by progressive cerebellar ataxia variably associated with additional distinctive clinical signs. The genetic heterogeneity is evidenced by the myriad of associated genes and underlying genetic defects identified. In this study, we describe a new spinocerebellar ataxia subtype in nine members of a Spanish five-generation family from Menorca with affected individuals variably presenting with ataxia, nystagmus, dysarthria, polyneuropathy, pyramidal signs, cerebellar atrophy and distinctive cerebral demyelination. Affected individuals presented with horizontal and vertical gaze-evoked nystagmus and hyperreflexia as initial clinical signs, and a variable age of onset ranging from 12 to 60 years. Neurophysiological studies showed moderate axonal sensory polyneuropathy with altered sympathetic skin response predominantly in the lower limbs. We identified the c.1877C > T (p.Ser626Leu) pathogenic variant within the SAMD9L gene as the disease causative genetic defect with a significant log-odds score (Z(max) = 3.43; theta = 0.00; P < 3.53 x 10(-5)). We demonstrate the mitochondrial location of human SAMD9L protein, and its decreased levels in patients' fibroblasts in addition to mitochondrial perturbations. Furthermore, mutant SAMD9L in zebrafish impaired mobility and vestibular/sensory functions. This study describes a novel spinocerebellar ataxia subtype caused by SAMD9L mutation, SCA49, which triggers mitochondrial alterations pointing to a role of SAMD9L in neurological motor and sensory functions. Corral-Juan et al. describe a novel dominantly inherited spinocerebellar ataxia subtype, SCA49, caused by SAMD9L mutation characterized by polyneuropathy, distinctive cerebral demyelination with gaze-evoked nystagmus and hyperreflexia as initial clinical signs. The study demonstrates the mitochondrial location of human SAMD9L protein triggering mitochondrial and lysosomal alterations

HGF, IL-1α, and IL-27 Are Robust Biomarkers in Early Severity Stratification of COVID-19 Patients

Producción CientíficaPneumonia is the leading cause of hospital admission and mortality in coronavirus disease 2019 (COVID-19). We aimed to identify the cytokines responsible for lung damage and mortality. We prospectively recruited 108 COVID-19 patients between March and April 2020 and divided them into four groups according to the severity of respiratory symptoms. Twenty-eight healthy volunteers were used for normalization of the results. Multiple cytokines showed statistically significant differences between mild and critical patients. High HGF levels were associated with the critical group (OR = 3.51; p < 0.001; 95%CI = 1.95–6.33). Moreover, high IL-1α (OR = 1.36; p = 0.01; 95%CI = 1.07–1.73) and low IL-27 (OR = 0.58; p < 0.005; 95%CI = 0.39–0.85) greatly increased the risk of ending up in the severe group. This model was especially sensitive in order to predict critical status (AUC = 0.794; specificity = 69.74%; sensitivity = 81.25%). Furthermore, high levels of HGF and IL-1α showed significant results in the survival analysis (p = 0.033 and p = 0.011, respectively). HGF, IL-1α, and IL 27 at hospital admission were strongly associated with severe/critical COVID-19 patients and therefore are excellent predictors of bad prognosis. HGF and IL-1α were also mortality biomarkers.Instituto de Salud Carlos III (grant COV20/00491

HGF, IL-1α, and IL-27 are robust biomarkers in early severity stratification of COVID-19 patients

© 2021 by the authors.Pneumonia is the leading cause of hospital admission and mortality in coronavirus disease 2019 (COVID-19). We aimed to identify the cytokines responsible for lung damage and mortality. We prospectively recruited 108 COVID-19 patients between March and April 2020 and divided them into four groups according to the severity of respiratory symptoms. Twenty-eight healthy volunteers were used for normalization of the results. Multiple cytokines showed statistically significant differences between mild and critical patients. High HGF levels were associated with the critical group (OR = 3.51; p < 0.001; 95%CI = 1.95–6.33). Moreover, high IL-1α (OR = 1.36; p = 0.01; 95%CI = 1.07–1.73) and low IL-27 (OR = 0.58; p < 0.005; 95%CI = 0.39–0.85) greatly increased the risk of ending up in the severe group. This model was especially sensitive in order to predict critical status (AUC = 0.794; specificity = 69.74%; sensitivity = 81.25%). Furthermore, high levels of HGF and IL-1α showed significant results in the survival analysis (p = 0.033 and p = 0.011, respectively). HGF, IL-1α, and IL 27 at hospital admission were strongly associated with severe/critical COVID-19 patients and therefore are excellent predictors of bad prognosis. HGF and IL-1α were also mortality biomarkers.This work was supported by the Carlos III Health Institute (Grant COV20/00491)

Evaluation of cytokines as robust diagnostic biomarkers for COVID-19 detection

Producción CientíficaAntigen tests or polymerase chain reaction (PCR) amplification are currently COVID-19 diagnostic tools. However, developing complementary diagnosis tools is mandatory. Thus, we performed a plasma cytokine array in COVID-19 patients to identify novel diagnostic biomarkers. A discovery–validation study in two independent prospective cohorts was performed. The discovery cohort included 136 COVID-19 and non-COVID-19 patients recruited consecutively from 24 March to 11 April 2020. Forty-five cytokines’ quantification by the MAGPIX system (Luminex Corp., Austin, TX, USA) was performed in plasma samples. The validation cohort included 117 patients recruited consecutively from 15 to 25 April 2020 for validating results by ELISA. COVID-19 patients showed different levels of multiple cytokines compared to non-COVID-19 patients. A single chemokine, IP-10, accurately identified COVID-19 patients who required hospital admission (AUC: 0.962; 95%CI (0.933–0.992); p < 0.001)). The results were validated in an independent cohort by multivariable analysis (OR: 25.573; 95%CI (8.127–80.469); p < 0.001) and AUROC (AUC: 0.900; 95%CI (0.846–0.954); p < 0.001). Moreover, showing IP-10 plasma levels over 173.35 pg/mL identified COVID-19 with higher sensitivity (86.20%) than the first SARS-CoV-2 PCR. Our discover–validation study identified IP-10 as a robust biomarker in clinical practice for COVID-19 diagnosis at hospital. Therefore, IP-10 could be used as a complementary tool in clinical practice, especially in emergency departments.Instituto de Salud Carlos III (grant COV20/00491)Consejo Superior de Investigaciones científicas (grant CSIC-COV19-016/202020E155)Junta de Castilla y León (project COVID 07.04.467B04.74011.0)IBGM excellence programme (grant CLU-2029-02

Can the Cytokine Profile According to ABO Blood Groups Be Related to Worse Outcome in COVID-19 Patients? Yes, They Can

Producción CientíficaSevere status of coronavirus disease 2019 (COVID-19) is extremely associated to cytokine release. Moreover, it has been suggested that blood group is also associated with the prevalence and severity of this disease. However, the relationship between the cytokine profile and blood group remains unclear in COVID-19 patients. In this sense, we prospectively recruited 108 COVID-19 patients between March and April 2020 and divided according to ABO blood group. For the analysis of 45 cytokines, plasma samples were collected in the time of admission to hospital ward or intensive care unit and at the sixth day after hospital admission. The results show that there was a risk of more than two times lower of mechanical ventilation or death in patients with blood group O (log rank: p = 0.042). At first time, all statistically significant cytokine levels, except from hepatocyte growth factor, were higher in O blood group patients meanwhile the second time showed a significant drop, between 20% and 40%. In contrast, A/B/AB group presented a maintenance of cytokine levels during time. Hepatocyte growth factor showed a significant association with intubation or mortality risk in non-O blood group patients (OR: 4.229, 95% CI (2.064–8.665), p < 0.001) and also was the only one bad prognosis biomarker in O blood group patients (OR: 8.852, 95% CI (1.540–50.878), p = 0.015). Therefore, higher cytokine levels in O blood group are associated with a better outcome than A/B/AB group in COVID-19 patients.Instituto de Salud Carlos III (grant COV20/00491)Junta de Castilla y León (grant 18IGOF

Intrinsic Subtypes and Gene Expression Profiles in Primary and Metastatic Breast Cancer

Biological changes that occur during metastatic progression of breast cancer are still incompletely characterized. In this study, we compared intrinsic molecular subtypes and gene expression in 123 paired primary and metastatic tissues from breast cancer patients. Intrinsic subtype was identified using a PAM50 classifier and χ 2 tests determined the differences in variable distribution. The rate of subtype conversion was 0% in basal-like tumors, 23.1% in HER2-enriched (HER2-E) tumors, 30.0% in luminal B tumors, and 55.3% in luminal A tumors. In 40.2% of cases, luminal A tumors converted to luminal B tumors, whereas in 14.3% of cases luminal A and B tumors converted to HER2-E tumors. We identified 47 genes that were expressed differentially in metastatic versus primary disease. Metastatic tumors were enriched for proliferation-related and migration-related genes and diminished for luminal-related genes. Expression of proliferation-related genes were better at predicting overall survival in metastatic disease (OSmet) when analyzed in metastatic tissue rather than primary tissue. In contrast, a basal-like gene expression signature was better at predicting OSmet in primary disease compared with metastatic tissue. We observed correlations between time to tumor relapse and the magnitude of changes of proliferation, luminal B, or HER2-E signatures in metastatic versus primary disease. Although the intrinsic subtype was largely maintained during metastatic progression, luminal/HER2-negative tumors acquired a luminal B or HER2-E profile during metastatic progression, likely reflecting tumor evolution or acquisition of estrogen independence. Overall, our analysis revealed the value of stratifying gene expression by both cancer subtype and tissue type, providing clinicians more refined tools to evaluate prognosis and treatment. Cancer Res; 77(9); 1-9. ©2017 AACR

Phase III Trial of Adjuvant Capecitabine After Standard Neo-/Adjuvant Chemotherapy in Patients With Early Triple-Negative Breast Cancer (GEICAM/2003-11_CIBOMA/2004-01)

Altres ajuts: Agustí Barnadas: Honoraria: Pfizer. Consulting or Advisory Role: Pfizer, Novartis, Eli Lilly. Speakers'Bureau: Roche, Pfizer, Novartis, Genomic Health International. Travel, Accommodations, Expenses: Roche, Pfizer; Miguel A. Seguí: Consulting or Advisory Role: Roche, Pfizer, Novartis, Amgen, Eisai, Eli Lilly. Speakers' Bureau: Roche, Pfizer, Amgen. Research Funding: Roche (Inst), Novartis (Inst). Travel, Accommodations, Expenses: Roche, Pfizer, Novartis, Amgen.Operable triple-negative breast cancers (TNBCs) have a higher risk of relapse than non-TNBCs with standard therapy. The GEICAM/2003-11_CIBOMA/2004-01 trial explored extended adjuvant capecitabine after completion of standard chemotherapy in patients with early TNBC. Eligible patients were those with operable, node-positive-or node negative with tumor 1 cm or greater-TNBC, with prior anthracycline- and/or taxane-containing chemotherapy. After central confirmation of TNBC status by immunohistochemistry, patients were randomly assigned to either capecitabine or observation. Stratification factors included institution, prior taxane-based therapy, involved axillary lymph nodes, and centrally determined phenotype (basal v nonbasal, according to cytokeratins 5/6 and/or epidermal growth factor receptor positivity by immunohistochemistry). The primary objective was to compare disease-free survival (DFS) between both arms. Eight hundred seventy-six patients were randomly assigned to capecitabine (n = 448) or observation (n = 428). Median age was 49 years, 55.9% were lymph node negative, 73.9% had a basal phenotype, and 67.5% received previous anthracyclines plus taxanes. Median length of follow-up was 7.3 years. DFS was not significantly prolonged with capecitabine versus observation [hazard ratio (HR), 0.82; 95% CI, 0.63 to 1.06; P =.136]. In a preplanned subgroup analysis, nonbasal patients seemed to derive benefit from the addition of capecitabine with a DFS HR of 0.53 versus 0.94 in those with basal phenotype (interaction test P =.0694) and an HR for overall survival of 0.42 versus 1.23 in basal phenotype (interaction test P =.0052). Tolerance of capecitabine was as expected, with 75.2% of patients completing the planned 8 cycles. This study failed to show a statistically significant increase in DFS by adding extended capecitabine to standard chemotherapy in patients with early TNBC. In a preplanned subset analysis, patients with nonbasal phenotype seemed to obtain benefit with capecitabine, although this will require additional validation