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PurposeProgression-free survival (PFS) has previously been established as a surrogate for overall survival (OS) for first-line metastatic colorectal cancer (mCRC). Because mCRC treatment has advanced in the last decade with extended OS, this surrogacy requires re-examination.MethodsIndividual patient data from 16,762 patients were available from 22 first-line mCRC studies conducted from 1997 to 2006; 12 of those studies tested antiangiogenic and/or anti-epidermal growth factor receptor agents. The relationship between PFS (first event of progression or death) and OS was evaluated by using R(2) statistics (the closer the value is to 1, the stronger the correlation) from weighted least squares regression of trial-specific hazard ratios estimated by using Cox and Copula models.ResultsForty-four percent of patients received a regimen that included biologic agents. Median first-line PFS was 8.3 months, and median OS was 18.2 months. The correlation between PFS and OS was modest (R(2), 0.45 to 0.69). Analyses limited to trials that tested treatments with biologic agents, nonstrategy trials, or superiority trials did not improve surrogacy.ConclusionIn modern mCRC trials, in which survival after the first progression exceeds time to first progression, a positive but modest correlation was observed between OS and PFS at both the patient and trial levels. This finding demonstrates the substantial variability in OS introduced by the number of lines of therapy and types of effective subsequent treatments and the associated challenge to the use of OS as an end point to assess the benefit attributable to a single line of therapy. PFS remains an appropriate primary end point for first-line mCRC trials to detect the direct treatment effect of new agents.

Carlos Camps Herrero,1 Antonio Antón Torres,2 Juan Jesús Cruz-Hernández,3 Alfredo Carrato,4 Manuel Constenla,5 Eduardo Díaz-Rubio,6 Margarita Feyjoo Saus,7 Jesus Garcia-Foncillas,8 Pere Gascón,9 Vicente Guillem101Jefe de Servicio de Oncología Médica, Consorcio Hospital General Universitario, Valencia, Spain; 2Jefe del Servicio de Oncología Médica, Hospital Universitario Miguel Servet, Zaragoza, Spain; 3Jefe del Servicio de Oncología Médica, Hospital Universitario De Salamanca-IBSAL, Salamanca, Spain; 4Jefe del Servicio de Oncología Médica, Hospital Universitario Ramón y Cajal, Madrid, Spain; 5Jefe de Servicio de Oncología, Complejo Hospitalario Universitario de Pontevedra, Pontevedra, Spain; 6Jefe del Servicio de Oncología Médica, Hospital Universitario Clínico San Carlos, Madrid, Spain; 7Jefe del Servicio de Oncología Médica, Hospital La Moraleja, Madrid, Spain; 8Jefe de Servicio de Oncología Médica, Hospital Universitario “Fundación Jiménez Díaz”, Madrid, Spain; 9Jefe del Servicio de Oncología Médica, Hospital Clínic, IDIBAPS, Universidad de Barcelona, Barcelona, Spain; 10Jefe del Servicio de Oncología Médica, Instituto Valenciano de Oncología, Valencia, SpainPurpose: There is a lack of standards for the diagnosis, assessment and management of breakthrough cancer pain (BTcP). La Fundación ECO (the Foundation for Excellence and Quality in Oncology) commissioned a study to establish a consensus and lay the foundations for the appropriate management of BTcP in oncology patients.Patients and methods: A modified Delphi survey comprising two rounds was used to gather and analyze data, which was conducted over the Internet. Each statement that reached a consensus with the respondents was defined as a median consensus score (MED) of ≥7, and agreement among panelists as an interquartile range (IQR) of ≤3.Results: In total, 69 medical oncologists responded, with a broad consensus that BTcP implied exacerbations of high-intensity pain, as opposed to moderate pain. Furthermore, they concurred that appropriate diagnostic equipment is needed, and that rapid-onset fentanyl formulations should be the preferred treatment for BTcP management. The panelists agreed that a lack of appropriate information and training to attend to patients, as well as limited patient visitation rights, were barriers to effective BTcP management. Regarding gaps in detected knowledge, the panelists were unsure of the measures necessary to assess the burden of the disease on the patient’s quality of life and associated medication costs. Alongside this, there was a lack of awareness of the technical specifics of the different formulations of rapid-onset fentanyl.Conclusion: These results represent the current status of BTcP management. They may inform recommendations and provide a framework for future research.Keywords: breakthrough pain, rapid-onset opioids, fentanyl, medical oncology, pain management

Objetivos: describir las características clínicas y epidemiológicas de niños admitidos por bronquiolitis en 13 unidades de cuidados intensivos pediátricos (UCIP) del Uruguay y comparar los resultados asistenciales finales entre UCIP de Montevideo (UM) y del interior del país (UI). Material y método: estudio observacional retrospectivo multicéntrico de los registros ingresados a base de datos prospectiva de LARed Network. Se incluyeron niños mayores de 1 mes y menores de 2 años admitidos en el período 1 de mayo de 2017 y 30 de abril de 2019 con diagnóstico de bronquiolitis comunitaria. Se analizaron datos demográficos, clínicos, así como intervenciones y desenlaces al alta. Resultados: se analizaron 666 casos. No se detectaron diferencias significativas de comorbilidades ni en el soporte respiratorio al ingreso. En UI los pacientes fueron derivados con más frecuencia desde otro hospital. La distancia y tiempo medio, así como el porcentaje de traslados mayor de 50 km, fue también mayor. En UI los pacientes tuvieron mayor gravedad clínica y gasométrica al ingreso. El perfil radiológico y etiológico fue similar. Virus respiratorio sincicial (VRS) aislado > 50%. La indicación global de corticoides superó el 25% y el de broncodilatadores el 85%. La prescripción de antibióticos y adrenalina nebulizada fue mayor en UI. La cánula nasal de alto flujo (CNAF) fue globalmente el método de soporte respiratorio más utilizado, aunque se observó un mayor uso de ventilación mecánica invasiva (VMI) y CPAP en UI (47% vs 28% en UM). No hubo diferencias en el número de complicaciones por VMI o ventilación no invasiva, ni en el uso de terapias de rescate. Tampoco se notaron diferencias significativas en la duración de la estadía en UCIP, ni en la mortalidad absoluta y ajustada, y hubo un solo caso de nueva morbilidad. Conclusiones: los niños admitidos en UI tuvieron mayor gravedad al ingreso y más factores de riesgo relacionados con mal pronóstico en el traslado, recibiendo más antibióticos y soporte invasivo que aquellos ingresados en UM. El CNAF fue el tipo de soporte respiratorio más utilizado en el país. Se detectó alto porcentaje de prescripción de terapias no recomendadas, como broncodilatadores y corticoides. La mortalidad y complicaciones fueron bajas, así como la generación de morbilidad residual.

Background Tumor-infiltrating lymphocytes (TILs), mainly CD8+ cytotoxic T lymphocytes (CTL), are linked to immune-mediated control of human cancers and response to immunotherapy. Tumors have nonetheless developed specific mechanisms that selectively restrict T cell entry into the tumor microenvironment. The extracellular superoxide dismutase (SOD3) is an anti-oxidant enzyme usually downregulated in tumors. We hypothesize that upregulation of SOD3 in the tumor microenvironment might be a mechanism to boost T cell infiltration by normalizing the tumor-associated endothelium.Results Here we show that SOD3 overexpression in endothelial cells increased in vitro transmigration of naïve and activated CD4+ and CD8+ T cells, but not of myeloid cells. Perivascular expression of SOD3 also specifically increased CD4+ and CD8+ effector T cell infiltration into tumors and improved the effectiveness of adoptively transferred tumor-specific CD8+ T cells. SOD3-induced enhanced transmigration in vitro and tumor infiltration in vivo were not associated to upregulation of T cell chemokines such as CXCL9 or CXCL10, nor to changes in the levels of endothelial adhesion receptors such as intercellular adhesion molecule-1 (ICAM-1) or vascular cell adhesion molecule-1 (VCAM-1). Instead, SOD3 enhanced T cell infiltration via HIF-2α-dependent induction of specific WNT ligands in endothelial cells; this led to WNT signaling pathway activation in the endothelium, FOXM1 stabilization, and transcriptional induction of laminin-α4 (LAMA4), an endothelial basement membrane component permissive for T cell infiltration. In patients with stage II colorectal cancer, SOD3 was associated with increased CD8+ TIL density and disease-free survival. SOD3 expression was also linked to a T cell–inflamed gene signature using the COAD cohort from The Cancer Genome Atlas program.Conclusion Our findings suggest that SOD3-induced upregulation of LAMA4 in endothelial cells boosts selective tumor infiltration by T lymphocytes, thus transforming immunologically “cold” into “hot” tumors. High SOD3 levels are associated with human colon cancer infiltration by CD8+ T cells, with potential consequences for the clinical outcome of these patients. Our results also uncover a cell type–specific, distinct activity of the WNT pathway for the regulation of T cell infiltration into tumors.

The acoustic evaluation of indoor environments is common in the application of virtual acoustics. In addition, in the study of cultural heritage buildings, it is a useful tool, but it is not so common when describing the acoustic environment in intangible cultural heritage events and even in outdoor environments. In this paper, the acoustic environment of the Water Tribunal of the Plain of Valencia (Spain) is studied. It is analyzed from a soundscape perspective, characterizing the sound source and evaluating it within relation to the environment and evaluating its subjective response. With the research carried out, it has been obtained, on the one hand, a complete study of the acoustics of the environment of the Water Tribunal and, on the other, an enhancement of the Valencian tangible and intangible heritage.

La recuperación de ayudas de Estado que afecten al ámbito tributario es el objeto de análisis del presente trabajo. Para ello, en primer lugar, se estudia el Derecho de la Unión Europea que regula la materia. Y, en segundo lugar, se analiza el Título VII de la Ley 58/2003, de 17 de diciembre, General Tributaria regulador, entre otros aspectos, de los procedimientos a seguir para la ejecución de las decisiones de recuperación de la Comisión Europea sobre ayudas de Estado de carácter fiscal.

Metasurfaces as optically thin composite layers can be modeled as electric and magnetic surface current sheets flowing in the layer volume in the metasurface plane. In the most general linear metasurface, the electric surface current can be induced by both incident electric and magnetic fields. Likewise, magnetic polarization and magnetic current can be induced also by external electric field. Metasurfaces which exhibit magnetoelectric coupling are called bianisotropic metasurfaces. In this review, we explain the role of bianisotropic properties in realizing various metasurface devices and overview the state-of-the-art of research in this field. Interestingly, engineered bianisotropic response is seen to be required for realization of many key field transformations, such as anomalous refraction, asymmetric reflection, polarization transformation, isolation, and more. Moreover, we summarize previously reported findings on uniform and gradient bianisotropic metasurfaces and envision novel and prospective research directions in this field.

Tumour vasculature influences drug delivery. Here, the authors show that SOD3 re-expression enhances doxorubicin delivery and effects through normalization of tumour vasculature via the HIF-2a/VE-cadherin pathway.