Prediction of progression-free survival in patients with advanced, well-differentiated, neuroendocrine tumors being treated with a somatostatin analog: the GETNE-TRASGU study

Artículo escrito por un elevado número de autores, sólo se referencian el que aparece en primer lugar, y los autores pertenecientes a la UAMSomatostatin analogs (SSAs) are recommended for the first-line treatment of most patients with well-differentiated, gastroenteropancreatic (GEP) neuroendocrine tumors; however, benefit from treatment is heterogeneous. The aim of the current study was to develop and validate a progression-free survival (PFS) prediction model in SSA-treated patients. PATIENTS AND METHODS We extracted data from the Spanish Group of Neuroendocrine and Endocrine Tumors Registry (R-GETNE). Patient eligibility criteria included GEP primary, Ki-67 of 20% or less, and first-line SSA monotherapy for advanced disease. An accelerated failure time model was developed to predict PFS, which was represented as a nomogram and an online calculator. The nomogram was externally validated in an independent series of consecutive eligible patients (The Christie NHS Foundation Trust, Manchester, United Kingdom). RESULTS We recruited 535 patients (R-GETNE, n = 438; Manchester, n = 97). Median PFS and overall survival in the derivation cohort were 28.7 (95% CI, 23.8 to 31.1) and 85.9 months (95% CI, 71.5 to 96.7 months), respectively. Nine covariates significantly associated with PFS were primary tumor location, Ki-67 percentage, neutrophil-to-lymphocyte ratio, alkaline phosphatase, extent of liver involvement, presence of bone and peritoneal metastases, documented progression status, and the presence of symptoms when initiating SSA. The GETNE-TRASGU (Treated With Analog of Somatostatin in Gastroenteropancreatic and Unknown Primary NETs) model demonstrated suitable calibration, as well as fair discrimination ability with a C-index value of 0.714 (95% CI, 0.680 to 0.747) and 0.732 (95% CI, 0.658 to 0.806) in the derivation and validation series, respectively. CONCLUSION The GETNE-TRASGU evidence-based prognostic tool stratifies patients with GEP neuroendocrine tumors receiving SSA treatment according to their estimated PFS. This nomogram may be useful when stratifying patients with neuroendocrine tumors in future trials. Furthermore, it could be a valuable tool for making treatment decisions in daily clinical practiceFunded by a restricted grant from Novartis Farmacéutic

Modified gravity : from theoretical aspects to observational constraints

IDPAS

Modified gravity : from theoretical aspects to observational constraints

IDPAS

Hydrogeology of salt flats : the Salar de Atacama example

Aplicat embargament des de la data de defensa fins al 31 de desembre de 2021Premi extraordinari doctorat UPC curs 2019-2020, àmbit d’Enginyeria Civil i AmbientalThis thesis aims to advance the knowledge of the hydrogeological functioning of salt flats in order to achieve a sustainable management of their mineral resources and ecosystems. Salt flats are a major source of Li, B, I, K, Mg and NaCl, and they host some of the most outstanding ecosystems on earth. Around 25 % of Li world reserves are located in the Salar de Atacama (NE of Chile). The exploitation of this raw material, highly valued in the technological and pharmaceutical industries, is carried out by brine pumping. Brine pumping can affect the natural hydrogeological regime of salt flats and, in many cases, the possible impact on their ecosystems is unknown. This thesis contributes to (1) explain the geometry and groundwater flow of the mixing zone (saline interface) located around salt flats, (2) define the water balance and hydrodynamics of the Salar de Atacama under the natural regime, (3) analyse and quantify the impacts caused by brine pumping, (4) improve the design of the brine exploitations in salt flats and (5) question the traditional ideas on the origin of the Li-enrichment in the Salar de Atacama. The groundwater recharged in the mountains is forced to flow upward when it reaches the mixing zone around the salt flat due to its lower density, feeding the lake and wetland ecosystems. The first 3D mapping of a salt flat mixing zone has been carried out in the Salar de Atacama and it has shown a slope of the mixing zone much lower than previous assumptions. The 2D modelling of the mixing zone demonstrated as the permeability of the upper aquifer increases, the slope of the mixing zone decreases, resulting in a shallower mixing zone. Thus, the permeability of the upper aquifer, mostly constituted of very permeable karstified evaporites and alluvial deposits, is critical to the geometry of the mixing zone. The hydrogeological conceptual model of the Salar de Atacama, prior to brine pumping (natural regime), has been defined and validated using a 3D steady-state groundwater flow model. The asymmetric distribution of the recharge by infiltration of rainwater and, above all, the evaporation discharge results in a water table whose minimum hydraulic head is located in the easternmost nucleus, close to the eastern mixing zone. The 3D transient-state modelling of the Salar de Atacama basin from 1986 to 2018 has allowed to explain the hydrodynamics and water balance impacts caused by brine exploitation. From 1994 to 2015, under the mining regime, the brine pumping caused an additional drawdown of the water table that triggered a decrease of the phreatic evaporation. This effect has been defined as "damping capacity" and it allows to counteract the disturbances occasioned by natural or anthropogenic events on the water table and balance of salt flat basins. The damping capacity compensated, at least in part, the decrease of the evaporation discharge, but nowadays it is already amortized in the nucleus and the mixing zone begins to be impacted. The 3D modelling of a hypothetical salt flat under brine exploitation has contributed to optimize the spatial distribution of the pumping wells in terms of impact on the water balance. Brine exploitations should consider to distribute the pumping outflow in the greatest extent possible to take full advantage of the damping capacity. The results of the hydro-thermo-haline modelling of the Salar de Atacama basin has suggested the Salar Fault System as the main contributor for the extreme Li-enrichment, either through the rise of Li-rich brines from a deep hydrothermal reservoir or remobilization of ancient layers of Li-enriched salts and/or clays by non-evaporated recharge waters coming from the W. The persistence of the mixing zones in depth also dismissed previous ideas of (1) leaking of brines from the present salt flats or (2) leaching of hypothetical salt flats buried by volcanic eruptions in the Altiplano-Puna as sources for the extreme Li-enrichment of the Salar de Atacama brines.Esta tesis contribuye a avanzar en el conocimiento del funcionamiento hidrogeológico de los salares con el fin de mejorar la gestión de sus recursos minerales y ecosistemas. Los salares son una fuente principal de Li, B, I, K, Mg y NaCl, y albergan algunos de los ecosistemas más excepcionales de la tierra. Alrededor del 25 % de las reservas mundiales de Li se localizan en el Salar de Atacama (NE de Chile). La explotación de esta materia prima, altamente valorada en las industrias tecnológica y farmacéutica, se realiza mediante bombeo de salmuera. El bombeo de salmuera puede afectar al régimen hídrico natural de los salares y, en muchos casos, se desconoce el posible impacto sobre sus ecosistemas. Esta tesis ayuda a (1) explicar la geometría y el flujo subterráneo de la zona de mezcla (interfaz salina) ubicada alrededor de los salares, (2) definir el balance hídrico y la hidrodinámica del Salar de Atacama en su régimen natural, (3) analizar y cuantificar los impactos causados por el bombeo de salmuera, (4) mejorar el diseño de las explotaciones de salmuera en salares y (5) cuestionar las ideas tradicionales que explican el origen del enriquecimiento en Li del Salar de Atacama. El agua subterránea recargada en las montañas es forzada a fluir hacia la superficie cuando alcanza la zona de mezcla que rodea al salar debido a su menor densidad, alimentando los ecosistemas lagunares y humedales. La primera cartografía 3D de la zona de mezcla de un salar se ha llevado a cabo en el Salar de Atacama, evidenciando una pendiente mucho menor que las predicciones anteriores. El modelado 2D de la zona de mezcla ha demostrado que cuanto mayor es la permeabilidad del acuífero superior, más baja es la pendiente y más superficial se vuelve la zona de mezcla. Por lo tanto, la permeabilidad del acuífero superior, principalmente constituido por evaporitas karstificadas y depósitos aluviales muy permeables, es crítica para la geometría de la zona de mezcla. El modelo hidrogeológico conceptual del Salar de Atacama, previo al bombeo de salmuera (régimen natural), se ha definido y validado utilizando un modelo estacionario 3D del flujo subterráneo. La distribución asimétrica de la recarga por infiltración del agua de lluvia y, sobre todo, de la descarga por evaporación da como resultado una superficie freática cuyo mínimo nivel hidráulico se localiza en el sector más oriental del núcleo, cerca de la zona de mezcla oriental. El modelado transitorio 3D de la cuenca del Salar de Atacama desde 1986 hasta 2018 ha permitido explicar los impactos causados por la explotación de salmuera sobre la hidrodinámica y el balance hídrico. Desde 1994 hasta 2015, el bombeo de salmuera causó una profundización de la superficie freática que desencadenó una reducción de la evaporación freática. Este efecto ha sido definido como la "capacidad de autorregulación" y permite a los salares contrarrestar las perturbaciones ocasionadas por eventos naturales o antropogénicos sobre la superficie freática y el balance hídrico. La capacidad de autorregulación compensó, al menos en parte, la disminución de la descarga por evaporación, pero hoy en día ya está amortizada en el núcleo y la zona de mezcla comienza a verse afectada. El modelado 3D de un hipotético salar bajo explotación de salmuera ha contribuido a optimizar la distribución espacial de los pozos de bombeo en términos de impacto sobre el balance hídrico. Para aprovechar al máximo la capacidad de autorregulación, las explotaciones de salmuera deben considerar distribuir el caudal bombeado en la mayor área posible. Los resultados del modelado hidro-termo-halino de una sección vertical Este-Oeste de la cuenca del Salar de Atacama han señalado al Sistema de Fallas Salar (SFS), localizado en el sector central del núcleo, como el principal contribuyente para explicar el enriquecimiento extremo en Li, ya sea por el ascenso de salmueras ricas en Li desde un reservorio hidrotermal profundo o por removilización de antiguas capas de sales y/o arcillas ricas en Li por aguas de recarga no evaporadas provenientes del Oeste. La localización del mínimo nivel hidráulico regional en el lado oriental del núcleo descarta considerar la evaporación avanzada como un mecanismo actual para alcanzar el alto contenido de Li de las salmueras ubicadas sobre el SFS. Además, la persistencia de las zonas de mezcla en profundidad también permite descartar las hipótesis previas de 1) infiltración de salmueras desde los salares actuales del Altiplano-Puna y 2) lixiviado de hipotéticos salares enterrados por erupciones volcánicas en el Altiplano-Puna como origen del enriquecimiento excepcional en Li de las salmueras de Salar de Atacama.Award-winningPostprint (published version

MicroRNAs in autoimmune thyroid diseases and their role as biomarkers

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the posttranscriptional level. They are emerging as potential biomarkers and as therapeutic targets for several diseases including autoimmune thyroid diseases (AITD). They control a wide range of biological phenomena, including immune activation, apoptosis, differentiation and development, proliferation and metabolism. This function makes miRNAs attractive as disease biomarker candidates or even as therapeutic agents. Because of their stability and reproducibility circulating miRNAs have been an interesting area of research in many diseases, and studies describing their role in the immune response and in autoimmune diseases have progressively developed. The mechanisms underlying AITD remain elusive. AITD pathogenesis is characterized by a multifactorial interplay based on the synergy between susceptibility genes and environmental stimulation, together with epigenetic modulation. Understanding the regulatory role of miRNAs could lead to identify potential susceptibility pathways, diagnostic biomarkers and therapeutic targets for this disease. Herein we update our present knowledge on the role of microRNAs in AITD and discuss on their importance as possible diagnostic and prognostic biomarkers in the most prevalent AITDs: Hashimoto's thyroiditis (HT), Graves' disease (GD) and Graves’ Ophthalmopathy (GO). This review provides an overview of the state of the art in the pathological roles of microRNAs as well as in possible novel miRNA-based therapeutic approaches in AITDThis work was funding by Proyectos de Investigacion en Salud (PI) PI19-00584, PI22/01404 and PMP22-00021 (funded by Instituto de Salud Carlos III) and P2022/BMD7379 (funded by la Comunidad de Madrid) and cofinanced by FEDER funds to Mónica Marazuela and Rebeca Martínez-Hernánde

COVID-19 and endocrine diseases. A statement from the European Society of Endocrinology

ESE has issued a statement about the role and responsibilities of endocrinologists worldwide during the current COVID-19 outbreak, prepared by Manuel Puig-Domingo, Mónica Marazuela and Andrea Giustina also includes a ‘decalogue’ for endocrinologists in midst of the COVID-19 pandemic. This statement is the "draft" document for the Springer articl

A geological model for the management of subsurface data in the urban environment of Barcelona and surrounding area

The overdevelopment of cities since the industrial revolution has shown the need to incorporate a sound geological knowledge in the management of required subsurface infrastructures and in the assessment of increasingly needed groundwater resources. Additionally, the scarcity of outcrops and the technical difficulty to conduct underground exploration in urban areas highlights the importance of implementing efficient management plans that deal with the legacy of heterogeneous subsurface information. To deal with these difficulties, a methodology has been proposed to integrate all the available spatio-temporal data into a comprehensive spatial database and a set of tools that facilitates the analysis and processing of the existing and newly added data for the city of Barcelona (NE Spain). Here we present the resulting actual subsurface 3-D geological model that incorporates and articulates all the information stored in the database. The methodology applied to Barcelona benefited from a good collaboration between administrative bodies and researchers that enabled the realization of a comprehensive geological database despite logistic difficulties. Currently, the public administration and also private sectors both benefit from the geological understanding acquired in the city of Barcelona, for example, when preparing the hydrogeological models used in groundwater assessment plans. The methodology further facilitates the continuous incorporation of new data in the implementation and sustainable management of urban groundwater, and also contributes to significantly reducing the costs of new infrastructures.Peer ReviewedPostprint (published version