Expert consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology on the determination of biomarkers in pancreatic and biliary tract cancer

Biliary tract cancer; Predictive value; Targeted therapiesCáncer de vías biliares; Valor predictivo; Terapias dirigidasCàncer de vies biliars; Valor predictiu; Teràpies dirigidesPancreatic cancer and biliary tract cancer have a poor prognosis. In recent years, the development of new diagnostic techniques has enabled the identification of the main genetic alterations involved in the development of these tumours. Multiple studies have assessed the ability of certain biomarkers, such as BRCA in pancreatic cancer, IDH1 or FGFR2 in biliary tract cancer and microsatellite instability or NTRK fusions in an agnostic tumour fashion, to predict response to treatment. In this consensus, a group of experts selected by the Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Pathology (SEAP) reviewed the role played by these mutations in the process of carcinogenesis and their clinical implications. As a result, this article proposes a series of recommendations to optimize the determination of these biomarkers to help standardize the diagnosis and treatment of these tumours.SEOM and SEAP acknowledge the financial support for this project in the form of unrestricted collaboration in the logistics from AstraZeneca

Sporadic, Non‐Functional , Gastrin‐Producing Duodenal Neuroendocrine Tumors: A Retrospective Study of an Infrequent Disease

Objective non-functioning gastrin-producing Neuroendocrine Neoplasms (NEN) of the duodenum are rare tumors of the gastrointestinal tract without a clinical syndrome due to gastrin-production. Their incidence has significantly increased in the last few years especially as an incidental finding during endoscopic studies. The aim of this study is to describe the characteristics of this emergent neoplasm, to provide more information on this rare pathology and its possible prognostic factors. Methods we performed a retrospective observational study based on the duodenal-NENs samples with positive staining for gastrin, registered in the Pathology Department of University Hospital 12-de-Octubre (Madrid, Spain) between 2000 and 2017. We excluded all those clinically functional [(Zollinger-Ellison-Syndrome) and/or gastrinemia >1000pg/ml], with a previous diagnosis of multiple endocrine neoplasia(MEN-syndrome) or a synchronous neoplasia. Clinicopathological and therapeutic variables, follow-up time, recurrence and mortality data were collected. Results 21 patients were included. Most of the tumors were diagnosed incidentally as a single small polypoid lesion, they were limited to mucosa/submucosa and had a low histological-grade. 4 patients (19%) presented metastatic involvement at diagnosis (lymphatic and/or hepatic). These 4 patients also had a high or intermediate mitotic grade and infiltration further than submucosa. Local resection was used in most cases as curative treatment. The median follow-up was 25 months. There were 2 relapses and 2 deaths attributed to the tumor with a 5-year disease-free-survival of 81%. Conclusions The majority of these tumors were diagnosed at a local stage and had a good prognosis with local treatment. Nevertheless, given the potential metastatic risk, a close follow-up and extensive study is necessary, especially in those with aggressive pathological factors such as deep infiltration or high-histological-grade

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Regulación de la mielinización por la hormona tiroidea

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 03-07-1996Resumen La hormona tiroidea es fundamental para el desarrollo del sistema nervioso central de los venebrados. Entre los efectos más dramáticos del hipotiroidismo se encuentra la disminución en la cantidad de mielina del cerebro una vez terminado su desarrollo. La mielinización sigue un patrón espacial que comienza en las regiones caudales y termina en las frontales. Este proceso se debe a la diferenciación y maduración de una célula muy especializada, el oligodendrocito. En la presente tesis hemos estudiado las bases mnleculares de la acción de la hormona tiroidea en la mielinización. Hemos demostrado que la expresión de los genes de las proteínas de la mielina, MAG, MBP, PLP y CNP, está alterada en el hipotiroidismo. Este no afecta al patr6n espacial de expresión de dichos genes sino que disminuye los niveles de sus ARNm. Los niveles de expresión de los genes de las proteínas de mielina se recuperaban antes del primer mes postnatal en la mayoría de las regiones excepto en la corteza y el estriado, regiones cuyos niveles se hayan disminuídos más alla de esta edad. Hemos demostrado que el mecanismo común de regulación no es a nivel transcripcional sino que se debe al control que la hormona tiroidea ejerce sobre la diferenciación del oligodendrocito. Los animales hipotiroideos presentan una dramática reducción en el número de dichas células en su nervio óptico. El análisis clonal de la diferenciación de los oligodendrocitos en cultivos puros ha demostrado que la hormona tiroidea promueve de forma directa la diferenciación de los precursores 0-2A a oligodendrocitos. Además el análisis de la acción de la hormona tiroidea en los cultivos de células disociadas de cerebro embrionario nos ha permitido demostrar que la generación inicial de oligodendrocitos en cultivo se produce por diferenciación asimémca.Summary Thyroid hormone plays a fundamental role on the development of vertebnte central nervous system. Amongst the most dramatic effects of hypothyroidism, there is a decrease myelin deposition when brain development is already finished. Myelination follows a spatial and temporal pattem, starting from the caudal regions towards the most rostral ones. This pmess is due to the differentiation and maturation of the oligodendrocyte, a very specialized cell. In this thesis, we have studied the molecular basis of thyroid hormone action on myelination. We have shown that hypothyroidism affects the expression of the myelin protein genes: MAG, MBP, PLP and CNP. Hypothyroidism does not affect the spatial pattem of expression of these genes but decreases their mRNA levels and therefore their protein levels in a transient and coordinated way. In most brain regions myelin protein gene expression levels recovers before the-first postnatal month wiih the exception of conex and smatum in which the impairment remains beyond that age. We have demonstrated that the common mechanism of regulation is not at the transcriptional level, but thyroid hormone controls of oligodendrocyte differentiation. Thus and accordingly, thyroid hormone increases the oligodendrocyte numbers in mixed cultures from optic nerve of P1 and P7 animals. Hypothyroid animals show a smking decrease on oligodendrocyte cell number in the optic nerve. Furthermore, clonal analysis of oligodendrocyte differentiation in pure cultures of 0-2A precursor cells has shown that thyroid hormone promotes directly 0-2A progenitor cell differentiation "in vitro". Finally, our clonal studies on cuihires of embryonic cells have demonstrated that initial generation of oligodendrocytes follow an asymmetric differentiation. ADN

Les savoirs productifs

Suite à une série d’entretiens réalisés en profondeur auprès de 17 micro-entrepreneurs issus du secteur informel de l’industrie de la confection localisée en milieu urbain marginal dans deux métropoles latino-américaines, notre article développe les propositions suivantes : a) les micro-entreprises informelles se forment sur la base d’une structure spécifique composée par des éléments de production et de travail et présentent une source de travail et de revenus à la portée de nombreux secteurs de la population en Amérique latine ; b) les micro-entrepreneurs qui les dirigent, mettent en œuvre une quantité importante de savoirs techniques mais aussi de gestion de la production et des réseaux sociaux qui composent le marché ; c) chaque micro-entrepreneur structure ces savoirs et les associe en combinatoires diverses et uniques qui forment la ressource fondamentale dont il dispose, en fin de compte, pour donner un sens à son activité productive, et sur la base desquels les circuits économiques personnels s’articulent et se soutiennent.Based on in-depth interviews of 17 informal micro entrepreneurs of the garment industry in urban marginal areas of two Mexican cities, this paper argues the following proposals: a) The informal microenterprises are structured in a specific configuration of elements of production and labour that set up a work and income option available to the poor population in Latin America; b) The entrepreneurs who lead them put into play different kinds of “knowledge” (formal and informal) not only of technical nature but also of management production and the management of social networks that make up the market in which they are involved; c) Every small informal micro entrepreneur uses this knowledge in diverse and unique arrays as his/her major and most available resource, this particular knowledge makes sense of their productive activities and is the base in which to build and sustain their own business systems.Con base en una serie de entrevistas en profundidad con 17 microempresarios del sector informal de la industria de la confección, localizados en zonas urbano marginales de dos metrópolis latinoamericanas, el artículo desarrolla las siguientes propuestas : a) Las microempresas informales se forman como tales sobre la base de una estructura específica de producción y de trabajo y constituyen una alternativa de trabajo y una fuente de ingresos accesibles para numerosos sectores de población pobre de américa latina ; b) los microempresarios que las dirigen ponen en juego una importante cantidad de saberes productivos, ciertamente técnicos pero también de gestión de la producción y de las redes sociales que conforman el mercado en el que se sitúan ; c) cada microempresarios estructura estos saberes y los asocia en combinaciones muy diversas y únicas que consituyen el recurso fundamental del que dispone para darle sentido a su actividad productiva y sobre el cual se articulan y se sostienen los circuitos económicos personales

Esteatohepatitis no alcohólica y adenomatosis hepática: ¿asociación casual o causal?

RESUMEN La adenomatosis hepática es una enfermedad benigna definida por la aparición de múltiples adenomas en un hígado normal. Se trata de una entidad poco frecuente y de causa no conocida, de la que existen menos de un centenar de casos publicados en la literatura médica y que se ha relacionado con la toma de anticonceptivos orales o esteroides anabolizantes, con enfermedades por depósito y con mutaciones genéticas asociadas a la diabetes mellitus tipo MODY (maturity onset diabetes of the young). En los últimos años se ha comunicado la coexistencia de adenomatosis hepática con lesiones de esteatohepatitis no alcohólica en dos pacientes con síndrome metabólico, una asociación de interés por la creciente prevalencia de la enfermedad hepática grasa no alcohólica en los países desarrollados y por la posibilidad de que compartan un mecanismo causal. Comunicamos el caso de una mujer joven con fructosemia familiar y esteatosis hepática durante cuyo seguimiento aparecieron múltiples adenomas hepáticos asociados a lesiones de esteatohepatitis y discutimos el posible significado de dicha asociación

Advanced interatrial block and P-wave duration are associated with atrial fibrillation and stroke in older adults with heart disease: The BAYES registry

Aims Advanced interatrial block (IAB), is an unrecognized surrogate of atrial dysfunction and a trigger of atrial dysrhythmias, mainly atrial fibrillation (AF). Our aim was to prospectively assess whether advanced IAB in sinus rhythm is associated with AF and stroke in elderly outpatients with structural heart disease, a group not previously studied. Methods and results Prospective observational registry that included outpatients aged ≥70 years with structural heart disease and no previous diagnosis of AF. Patients were divided into three groups: normal P-wave duration (<120 ms), partial IAB (P-wave duration ≥120 ms, positive in the inferior leads), and advanced IAB [P-wave duration ≥120 ms, biphasic (plus/minus) morphology in the inferior leads]. Among 556 individuals, 223 had normal P-wave (40.1%), 196 partial IAB (35.3%), and 137 advanced IAB (24.6%). After a median follow-up of 694 days, 93 patients (16.7%) developed AF, 30 stroke (5.4%), and 34 died (6.1%). Advanced IAB was independently associated with AF –[hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.7–5.1; P < 0.001], stroke [HR 3.8, 95% CI 1.4–10.7; P = 0.010), and AF/stroke (HR 2.6, 95% CI 1.5–4.4; P = 0.001). P-wave duration (ms) was independently associated with AF (HR 1.05, 95% CI 1.03–1.07; P < 0.001), AF/stroke (HR 1.04, 95% CI 1.02–1.06; P < 0.001), and mortality (HR 1.04, 95% CI 1.00–1.08; P = 0.021). Conclusions The presence of advanced IAB in sinus rhythm is independently associated with AF and stroke in an elderly population with structural heart disease and no previous diagnosis of AF. P-wave duration was also associated with all-cause mortality.Sin financiación5.214 JCR (2020) Q2, 40/142 Cardiac & Cardiovascular Systems2.119 SJR (2020) Q1, 36/349 Cardiology and Cardiovascular MedicineNo data IDR 2020UE

Age-related differences in hepatic ischemia/reperfusion: gene activation, liver injury, and protective effect of melatonin

Abstract Background Ischemia/reperfusion (I/R) causes functional and structural damage to liver cells, this being more pronounced with increasing age of the tissue. Melatonin is a pineal indole that has been shown to play an important role as a free radical scavenger and anti-inflammatory molecule. Material and methods The age-dependent responses to I/R were compared in 2-mo-old and 14-mo-old male Wistar rats. After 35 min of hepatic ischemia followed by 36 h of reperfusion, rats were sacrificed. Sham-operated control rats underwent the same protocol without real vascular occlusion. Animals were intraperitoneally injected with 10 mg/kg melatonin 24 h before the operation, at the time of surgery, and 12 and 24 h after it. The tissues were submitted to histopathologic evaluation. The levels of ALT and AST were analyzed in plasma. The expression of TNF-α, IL-1β, IL-10, MCP-1, IFN-γ, iNOS, eNOS, Bad, Bax, Bcl2, AIF, PCNA, and NFKB1 genes were detected by RT-PCR in hepatic tissue. Results I/R was associated with significant increases in the expression of pro-inflammatory and pro-apoptotic genes in liver. Older rats submitted to I/R were found to respond with increased liver damage as compared with young rats, with serum ALT and AST levels significantly higher than in young animals. Mature rats also showed more evident increases in expression of pro-inflammatory cytokines (IL-1β, MCP-1, and IFN-γ) as well as a decrease in the mRNA expression of IL-10 as compared with young animals. Pro-apoptotic genes (Bax, Bad, and AIF) were significantly enhanced in liver after I/R, without differences between young and mature animals. However, the expression of Bcl2 gene did not show any change. Melatonin treatment was able to lower the expression of pro-inflammatory cytokines and pro-apoptotic genes and to improve liver function, as indicated by normalization of plasma AST and ALT levels and by reduction of necrosis and microsteatosis areas. Conclusions Melatonin treatment was able to reduce the I/R-stimulated pro-inflammatory and pro-apoptotic genes in the rat liver. Since older animals showed a more marked increase in inflammation and in liver injury, the treatment was more effective in those subjects.Fundación Mutua Madrileña Investigación MédicaDepto. de FisiologíaFac. de MedicinaTRUEpu