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Background: The ETOP 10-16 BOOSTER trial failed to demonstrate a progression-free survival (PFS) benefit for adding bevacizumab to osimertinib in second line. An exploratory subgroup analysis, however, suggested a PFS benefit of the combination in patients with a smoking history and prompted us to do this study.Methods: A systematic review and meta-analysis to evaluate the differential effect of smoking status on the benefit of adding an angiogenesis inhibitor to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor therapy was carried out. All relevant randomized controlled trials appearing in main oncology congresses or in PubMed as of 1 November 2021 were used according to the Preferred Reporting Items for Systematic Review and Meta-Analyses statement. Primarily PFS according to smoking status, and secondarily overall survival (OS) were of interest. Pooled and interaction hazard ratios (HRs) were estimated by fixed or random effects models, depending on the detected degree of heterogeneity. Bias was assessed using the revised Cochrane tool for randomized controlled trials (RoB 2).Results: Information by smoking was available for 1291 patients for PFS (seven studies) and 678 patients for OS (four studies). The risk of bias was low for all studies. Combination treatment significantly prolonged PFS for smokers [n =502, HR = 0.55, 95% confidence interval (CI): 0.44-0.69] but not for nonsmokers (n = 789, HR = 0.92, 95% CI: 0.66-1.27; treatment-by-smoking interaction P= 0.02). Similarly, a significant OS benefit was found for smokers (n =271, HR 0.66, 95% CI: 0.47-0.93) but not for nonsmokers (n = 407, HR = 1.07, 95% CI: 0.82-1.42; treatment-by-smoking interaction P= 0.03).Conclusion: In advanced EGFR-non-small-cell lung cancer patients, the addition of an angiogenesis inhibitor to EGFR-tyrosine kinase inhibitor therapy provides a statistically significant PFS and OS benefit in smokers, but not in nonsmokers. The biological basis for this observation should be pursued and could determine whether this might be due to a specific co-mutational pattern produced by tobacco exposure.

BACKGROUND The ETOP 10-16 BOOSTER trial failed to demonstrate a progression-free survival (PFS) benefit for adding bevacizumab to osimertinib in second line. An exploratory subgroup analysis, however, suggested a PFS benefit of the combination in patients with a smoking history and prompted us to do this study. METHODS A systematic review and meta-analysis to evaluate the differential effect of smoking status on the benefit of adding an angiogenesis inhibitor to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor therapy was carried out. All relevant randomized controlled trials appearing in main oncology congresses or in PubMed as of 1 November 2021 were used according to the Preferred Reporting Items for Systematic Review and Meta-Analyses statement. Primarily PFS according to smoking status, and secondarily overall survival (OS) were of interest. Pooled and interaction hazard ratios (HRs) were estimated by fixed or random effects models, depending on the detected degree of heterogeneity. Bias was assessed using the revised Cochrane tool for randomized controlled trials (RoB 2). RESULTS Information by smoking was available for 1291 patients for PFS (seven studies) and 678 patients for OS (four studies). The risk of bias was low for all studies. Combination treatment significantly prolonged PFS for smokers [n = 502, HR = 0.55, 95% confidence interval (CI): 0.44-0.69] but not for nonsmokers (n = 789, HR = 0.92, 95% CI: 0.66-1.27; treatment-by-smoking interaction P = 0.02). Similarly, a significant OS benefit was found for smokers (n = 271, HR = 0.66, 95% CI: 0.47-0.93) but not for nonsmokers (n = 407, HR = 1.07, 95% CI: 0.82-1.42; treatment-by-smoking interaction P = 0.03). CONCLUSION In advanced EGFR-non-small-cell lung cancer patients, the addition of an angiogenesis inhibitor to EGFR-tyrosine kinase inhibitor therapy provides a statistically significant PFS and OS benefit in smokers, but not in non-smokers. The biological basis for this observation should be pursued and could determine whether this might be due to a specific co-mutational pattern produced by tobacco exposure.

Workshop MicSeaOnMed (EEA GRANT) Blue Biotechnology: from the academy to the entrepreneur sector, Guimarães, Portugal, 24 May 2022

Background: While osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is the standard treatment in patients with advanced non-small-cell lung cancer (NSCLC) with sensitising EGFR and acquired T790M mutations, progression inevitably occurs. The angiogenic pathway is implicated in EGFR TKI resistance. Patients and methods: BOOSTER is an open-label randomised phase II trial investigating the efficacy and safety of combined osimertinib 80 mg daily and bevacizumab 15 mg/kg every 3 weeks, versus osimertinib alone, in patients with EGFR-mutant advanced NSCLC and acquired T790M mutations after failure on previous EGFR TKI therapy. Primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR) and adverse events (AEs). Results: Between May 2017 and February 2019, 155 patients were randomised (combination: 78; osimertinib: 77). At data cut-off of 22 February 2021, median follow-up was 33.8 months [interquartile range (IQR): 26.5-37.6 months] and 129 (83.2%) PFS events were reported in the intention-to-treat population. There was no difference in median PFS between the combination [15.4 months; 95% confidence interval (CI) 9.2-18.0 months] and osimertinib arm (12.3 months; 95% CI 6.2-17.2 months; stratified log-rank P = 0.83), [hazard ratio (HR) = 0.96; 95% CI 0.68-1.37]. Median OS was 24.0 months (95% CI 17.8- 32.1 months) in the combination arm and 24.3 months (95% CI 16.9-37.0 months) in the osimertinib arm (stratified log-rank P = 0.91), (HR = 1.03; 95% CI 0.67-1.56). Exploratory analysis revealed a significant interaction of smoking history with treatment for PFS (adjusted P = 0.0052) with a HR of 0.52 (95% CI 0.30-0.90) for smokers, and 1.47 (95% CI 0.92-2.33) for never smokers. ORR was 55% in both arms and the median time to treatment failure was significantly shorter in the combination than in the osimertinib arm, 8.2 months versus 10.8 months, respectively (P = 0.0074). Safety of osimertinib and bevacizumab was consistent with previous reports with grade >= 3 treatment-related AEs (TRAEs) reported in 47% and 18% of patients on combination and osimertinib alone, respectively. Conclusions: No difference in PFS was observed between osimertinib plus bevacizumab and osimertinib alone. Grade >= 3 TRAEs were more common in patients on combination.

A scientific report based on solid scientific data has been published by AESAN Identifying the most relevant dietary sources of microplastics, knowing the occurrence of the different molecules and polymers and their relevance in terms of exposure will contribute to focus future research projects, regulatory initiatives and monitoring programs. It is the interest of AESAN to promote research on MP and NP in the food supply and contribute to fill the identified knowledge gaps. Toxicokinetic; biomarkers of exposure; toxicity in experimental animals/models like acute toxicity, repeat dose and chronic toxicity; mode of action of the different MP and the observations in humans (Acute and Chronic effects); health based guidance values (dose response models and selection of critical reference points) Assessing the Spanish population dietary exposure to MP should be a challenge for our Food Safety experts and networking among the research groups should be promoted through our national food agencies and EFSA.

[EN] Finding angiogenic prognostic markers in advanced non-small-cell lung cancer is still an unmet medical need. We explored a set of genetic variants in the VEGF-pathway as potential biomarkers to predict clinical outcomes of patients with non-small-cell lung cancer treated with chemotherapy plus bevacizumab. We prospectively analyzed the relationship between VEGF-pathway components with both pathological and prognostic variables in response to chemotherapy plus bevacizumab in 168 patients with non-squamous non-small-cell lung cancer. Circulating levels of VEGF and VEGFR2 and expression of specific endothelial surface markers and single-nucleotide polymorphisms in VEGF-pathway genes were analyzed. The primary clinical endpoint was progression-free survival. Secondary endpoints included overall survival and objective tumor response. VEGFR-1 rs9582036 variants AA/AC were associated with increased progression-free survival (p = 0.012 and p = 0.035, respectively), and with improved overall survival (p = 0.019) with respect to CC allele. Patients with VEGF-A rs3025039 harboring allele TT had also reduced mortality risk (p = 0.049) compared with the CC allele. The VEGF-A rs833061 variant was found to be related with response to treatment, with 61.1% of patients harboring the CC allele achieving partial treatment response. High pre-treatment circulating levels of VEGF-A were associated with shorter progression-free survival (p = 0.036). In conclusion, in this prospective study, genetic variants in VEGFR-1 and VEGF-A and plasma levels of VEGF-A were associated with clinical benefit, progression-free survival, or overall survival in a cohort of advanced non-squamous non-small-cell lung cancer patients receiving chemotherapy plus antiangiogenic therapy., The authors thank Drs. Blanca Piedrafita and Vanessa Marfil at Medical Statistics Consulting for medial writing services. RR also wish to acknowledge the support by the Asociacion Espanola Contra el Cancer (AECC).

Objectives: Multiple reasons for suboptimal treatment of breakthrough cancer pain (BTcP) have been reported in the literature. We aimed to ascertain the perception of physicians on the potential inappropriate use and prescription of rapid-onset opioids (ROOs) for breakthrough cancer pain (BTcP) and the causes thereof.Methods: Observational study based on an online survey addressed to doctors from different specialties (radiation oncology, medical oncology, anesthesia, palliative care and general practitioners) with experience in the management of BTcP in the Spanish public health setting.Results: A total of 114 eligible specialists mainly from radiation oncology (37.7%), medical oncology (24.6%) and pain units (18.4%) participated in the study. Most agreed on important aspects of BTcP management, such as their preference for ROOs or the need for early follow-up after treatment initiation. However, their answers revealed a lack of standardization of BTcP diagnosis. Half of respondents believed that their BTcP patients might misuse ROOs. Physicians polled believed that lack of training in pain management (71.9%) and inadequate BTcP diagnosis and evaluation (66.7%) were the greatest obstacles for prescribing opioids. Specialists also thought that they do not provide the necessary information to patients (51.8%) and caregivers (57.9%) to guarantee the correct use of these drugs.Conclusions: These results are of utmost importance as they highlight the need to increase physicians' awareness of BTcP and its management and the need to improve communication with patients and their caregivers. Our findings also indicate the need for future research on the possible misuse of opioids in BTcP patients and its causes.

International audience

International audience

Population genomic studies of ancient human remains have shown how modern-day European population structure has been shaped by a number of prehistoric migrations. The Neolithization of Europe has been associated with large-scale migrations from Anatolia, which was followed by migrations of herders from the Pontic steppe at the onset of the Bronze Age. Southwestern Europe was one of the last parts of the continent reached by these migrations, and modern-day populations from this region show intriguing similarities to the initial Neolithic migrants. Partly due to climatic conditions that are unfavorable for DNA preservation, regional studies on the Mediterranean remain challenging. Here, we present genome-wide sequence data from 13 individuals combined with stable isotope analysis from the north and south of Iberia covering a four-millennial temporal transect (7, 500–3, 500 BP). Early Iberian farmers and Early Central European farmers exhibit significant genetic differences, suggesting two independent fronts of the Neolithic expansion. The first Neolithic migrants that arrived in Iberia had low levels of genetic diversity, potentially reflecting a small number of individuals; this diversity gradually increased over time from mixing with local hunter-gatherers and potential population expansion. The impact of post-Neolithic migrations on Iberia was much smaller than for the rest of the continent, showing little external influence from the Neolithic to the Bronze Age. Paleodietary reconstruction shows that these populations have a remarkable degree of dietary homogeneity across space and time, suggesting a strong reliance on terrestrial food resources despite changing culture and genetic make-up.

The so-called “Gran Dolina site” (Atapuerca mountain range, N Spain) is a karstic cavity filled by sediments during the Pleistocene, some of which contain a rich ensemble of archaeological and paleontological records. These sediments have contributed significantly to our understanding of early human dispersal in Europe but, in contrast, older, interior facies deposits have received much less of attention. The stratigraphy of Gran Dolina reveals an abrupt sedimentary change of interior to entrance facies from bottom to top, reflecting a significant paleoenvironmental change that promoted the accumulation of sediments transported from the vicinity of the cave by water or “en masse”. Since the major magnetic polarity reversal known as the Matuyama-Brunhes boundary (0.78 Ma) was detected within the TD7 unit in the middle of the stratigraphic section, we carried out a new combined paleomagnetic, radiometric (U-Pb), and electron spin resonance (ESR) dating study of the lower part of the sequence in order to constrain the chronology of the interior facies at Gran Dolina. U-Pb analysis of speleothems did not produce age information as the samples proved to be extremely unradiogenic. The magnetic stratigraphy of the cave interior sediments reveals a dominant reverse magnetic polarity, coherent with a Matuyama age, and interrupted by a normal polarity magnetozone interpreted as the Jaramillo Subchron (1.0–1.1 Ma). ESR ages on quartz grains from the upper part of the interior facies sediments are coherent with such an interpretation. We conclude that the fluvial deposits (interior facies) that constitute the cave floor began accumulating before 1.2 Ma. The development of large cave entrances at Gran Dolina occurred shortly after the Jaramillo Subchron but before ca 900 ka ago.

© 2019 24th European Meeting of Environmental and Engineering Geophysics. All rights reserved. This work evaluates the potential of magnetometry to detect the inaccessible sediment-filled caves of the Sierra de Atapuerca karstic system. This karst consists of numerous caves filled with sediments that bear outstanding archaeo-paleontological remains from the Early and Middle Pleistocene. In order to find the continuity of the caves, the Sierra de Atapuerca sites have already been the target of ERT and GPR surveys, which have revealed their suitability for detecting different karstic features. Although our expectations were to find positive anomalies when crossing these filled conduits, the results showed a negative anomaly of the magnetic field where these sediments were expected. So far, the only explanation for this phenomenon is that these sediments were deposited in a reversed magnetic polarity period. This theory is supported by the fact that the Matuyama-Brunhes boundary is present in many of the studied caves.

© 2019 24th European Meeting of Environmental and Engineering Geophysics. All rights reserved. This work evaluates the potential of magnetometry to detect the inaccessible sediment-filled caves of the Sierra de Atapuerca karstic system. This karst consists of numerous caves filled with sediments that bear outstanding archaeo-paleontological remains from the Early and Middle Pleistocene. In order to find the continuity of the caves, the Sierra de Atapuerca sites have already been the target of ERT and GPR surveys, which have revealed their suitability for detecting different karstic features. Although our expectations were to find positive anomalies when crossing these filled conduits, the results showed a negative anomaly of the magnetic field where these sediments were expected. So far, the only explanation for this phenomenon is that these sediments were deposited in a reversed magnetic polarity period. This theory is supported by the fact that the Matuyama-Brunhes boundary is present in many of the studied caves.

Lung cancer is the most common cancer globally and has the highest mortality. Although this disease is not associated with a particular gender, its incidence is rising among women, who are diagnosed at an increasingly younger age compared with men. One of the main reasons for this rise is women taking up smoking. However, many non-smoking women also develop this disease. Other risk factors implicated in the differential development of lung cancer in women are genetic predisposition, tumour histology and molecular profile. Proportionally more women than men with lung cancer have a mutation in the EGFR gene. This consensus statement reviews the available evidence about the epidemiological, biological, diagnostic, therapeutic, social and psychological aspects of lung cancer in women.

This work is part of the study of the dissemination of Greek and Latin classics through translations published in Spanish collections in the nineteenth and twentieth centuries. It focuses on the Biblioteca Universal, a collection created by Joaquín Pi y Margall, and describes the collection’s main characteristics and those of the classic authors’ volumes contained in that collection. The Biblioteca Universal has peculiar characteristics that make it a representative example of a certain type of dissemination, directed at the general public by maintaining a very affordable price. The volumes published in it therefore achieved a wide circulation, not only among the general public but also among the intellectuals of the time. Having presented in the first part of the paper the general characteristics of the collection and the translations published by Angel Lasso de la Vega, it will be studied now the rest of translators and versions and some conclusions on the relevance of this collection as a vehicle for disseminating the classics will be drawn. Este trabajo se enmarca en el estudio de la divulgación de los clásicos grecolatinos por medio de traducciones publicadas en colecciones españolas a lo largo de los siglos XIX y XX. Se centra en la Biblioteca Universal de Joaquín Pi y Margall, describiendo las características principales de la colección y las de los volúmenes de autores clásicos en ella publicados. La Biblioteca Universal tiene características peculiares que la convierten en un ejemplo representativo de un tipo determinado de divulgación, la dirigida a un público generalista gracias al mantenimiento de un precio muy económico. Los volúmenes en ella publicados lograron, por ello, una notable difusión, pero no sólo entre el público general, sino también entre los intelectuales de la época. Tras haber presentado en la primera parte del trabajo las características generales de la colección y las traducciones que en ella publicó Ángel Lasso de la Vega, abordamos ahora el resto de traductores y versiones y ofrecemos unas conclusiones sobre la relevancia de esta colección como vehículo de difusión de los clásicos.

Introduction: Hemangiomas are benign lesions of the blood vessels or vascular elements, in the nose, they are a rarity, when intraosseous, even more so. When intraosseous hemangioma, characteristic imaging may suggest this diagnosis. Keywords: Nasal hemangioma; Cavernous; Intraosseous imaging Case Presentation: We describe the case of a 48-year-old woman manifesting a solid mass in the lateral aspect of the nose. Computer tomography (CT) of the Para nasal sinuses revealed an expansive lesion of the left lateral aspect of the nose, originating from the left nasal bone (Figure 1). This lesion appeared heterogeneous with calcifications in its interior, not disturbing adjacent tissues (Figure 2). Excised in an open nasal Para lateral approach (Figure 3), pathology analysis revealed an intraosseous hemangioma. Discussion: Imaging characteristics that may contribute to the diagnosis of intraosseous hemangiomas include: a rounded unilocular with radial trabeculation lesion, with a honeycomb or soap balls pattern. Recommended treatment is surgical excision, for cure and posterior definitive histopathological diagnosis.

This work is part of the study of the dissemination of Greek and Latin classics through translations published in Spanish collections in the nineteenth and twentieth centuries. It focuses on the Biblioteca Universal, a collection created by Joaquín Pi y Margall, and describes the collection’s main characteristics and those of the classic authors’ volumes contained in that collection. The Biblioteca Universal has peculiar characteristics that make it a representative example of a certain type of dissemination, directed at the general public by maintaining a very affordable price. The volumes published in it therefore achieved a wide circulation, not only among the general public but also among the intellectuals of the time. In the first part of the paper we describe the general characteristics of the collection and the translations published by Ángel Lasso de la Vega. Este trabajo se enmarca en el estudio de la divulgación de los clásicos grecolatinos por medio de traducciones publicadas en colecciones españolas a lo largo de los siglos XIX y XX. Se centra en la Biblioteca Universal de Joaquín Pi y Margall, describiendo las características principales de la colección y las de los volúmenes de autores clásicos en ella publicados. La Biblioteca Universal tiene características peculiares que la convierten en un ejemplo representativo de un tipo determinado de divulgación, la dirigida a un público generalista gracias al mantenimiento de un precio muy económico. Los volúmenes en ella publicados lograron, por ello, una notable difusión, pero no sólo entre el público general, sino también entre los intelectuales de la época. En la primera parte del trabajo presentamos las características generales de la colección y las traducciones que en ella publicó Ángel Lasso de la Vega.

A Diabetes Mellitus tipo 2 é um flagelo individual, social e económico, em particular nas sociedades ocidentais. A metformina surge como fármaco de primeira linha na terapêutica farmacológica desta patologia, mas na impossibilidade de controlo metabólico adequado sob esta em monoterapia, as recomendações colocam as restantes classes de fármacos ao mesmo nível, reflectindo uma mudança de paradigma para a individualização da terapêutica. A partir de 2007 foram disponibilizadas três novas classes de fármacos antidiabéticos: inibidores da dipeptidil peptidase 4, agonistas dos receptores do glucagon-like peptide-1, e inibidores do co-transportador 2 de sódio e glicose. Destas três, os agonistas dos receptores do glucagon-like peptide-1 são a classe considerada mais eficaz no controlo glicémico. Este artigo debruça-se sobre as mais recentes evidências científicas sobre os agonistas dos receptores do glucagon-like peptide-1, concluindo que, para além da eficácia no controlo glicémico, são bem tolerados, com a vantagem de reduzirem o peso e apresentarem benefícios cardiovasculares. No entanto, devido às actuais condições económicas e à impossibilidade de prescrever estes fármacos indiscriminadamente, propomos as características dos doentes que mais poderão beneficiar da terapêutica com esta classe, bem como um sistema de controlo de reembolso que permita que esta seja utilizada nos doentes que mais beneficiam. info:eu-repo/semantics/publishedVersion

Therapy with bone marrow-derived cells has been used in ischemic patients with reported success. The aim of this study was to determine the therapeutic efficacy of fresh and frozen human umbilical cord blood cells (hUCB) in Wistar rats submitted to permanent occlusion of the left coronary artery. Three hours after myocardial infarction, 2 x 10(7) hUCB cells or vehicle were administered by intramyocardial injection. The animals were divided into five groups: control (N = 10), sham operated (N = 10), infarcted that received vehicle (N = 9), infarcted treated with cryopreserved hUCB (N = 7), and infarcted treated with fresh hUCB (N = 5). Cardiac function was evaluated by electrocardiogram (ECG) and echocardiogram (ECHO) before cell therapy, and by ECG, ECHO, cardiopulmonary test, and left ventricular pressure measurements 3 weeks later. After 3 weeks, both groups treated with hUCB still had Q wave present in L1, âQRS >90° and reduced shortening fraction (less than 50%). In addition, cardiac indexes of left ventricular contractility and relaxation were 5484 ± 875 and -4032 ± 643 mmHg (cryopreserved hUCB) and 4585 ± 955 and -2862 ± 590 mmHg (fresh hUCB), respectively. These values were not statistically different from those of saline-treated animals. Cardiopulmonary exercise test profile was typical of infarcted hearts; exercise time was about 14 min and maximal VO2 was 24.77 ± 5.00 mL·kg-1·min-1. These data show that hUCB therapy did not improve the cardiac function of infarcted animals or prevent cardiac remodeling.

Approximately up to 40% of patients with lung cancer develop bone metastasis, with 22% to 59% of them experiencing skeletal-related events (SREs), which result in an important quality of life deterioration and economic burden. Denosumab, a fully human antibody that targets the receptor activator of nuclear factor-kappa B (RANK) ligand (RANKL), is indicated for prevention of SREs in patients with solid tumors and has demonstrated superiority in breast and prostate cancer, and in other solid tumors, in reducing the risk of first SRE by 17% versus zoledronic acid. In the subset of patients with nonesmall-cell lung carcinoma (NSCLC), denosumab has also shown a positive trend to SRE risk reduction. Denosumab might have direct or indirect antitumor effects. Cancer cells produce factors that stimulate increased bone resorption by osteoclasts, which in turn release tumor growth factors into the bone microenvironment, initiating a tumor/bone vicious cycle. An increasing body of evidence suggests RANK/RANKL signaling plays a role in this tumorigenesis. Both proteins are overexpressed in different tumor types including lung cancer cells. RANK/RANKL signaling activates nuclear factor-kappa B pathways related to lung carcinogenesis and increases intercellular adhesion molecule 1 expression and MEK/extracellular signal-regulated kinase phosphorylation, which in turn enhances tumor cell migration. In animal NSCLC models, denosumab delayed bone metastases and reduced skeletal tumor growth. In patients with lung cancer (post hoc analysis), denosumab prolonged overall survival by 1.2 months versus zoledronic acid (P = .01). This hypothesis-generating outcome warrants further investigation and 2 studies in lung cancer are ongoing to elucidate the therapeutic potential of denosumab beyond SRE prevention.

A floating liquid bridge configuration that operates in a pulsed relaxation mode in which charge (cations) and fluid injection alternatively assume forward and opposite directions in the bridge structure is reported. Cations formed at the high voltage anode are surrounded by clusters of dimethylsulphoxide (DMSO) molecules that migrate to the cathode resulting in forward fluid transport with a period of ~200 s until an equilibrium point is attained. The fluid motion then assumes the opposite direction of the current for~60 s. Charged clusters travel to the bridge surface modifying its structural properties forming a plastic layer with an ~85 KPa stiffness.

The Aurora Stratum of the TD6 level of the Pleistocene site of Gran Dolina (Trinchera del Ferrocarril, Sierra de Atapuerca, Burgos, Spain) have yielded more than one hundred human fossil remains, of the species Homo antecessor and belonging to a minimum (MNI) of nine individuals. In this paper we made the MNI determination and the age at death of the individuals, using data observed in the mandibular, maxillary, and dental remains. The previous taphonomic analysis concluded that the origin of the hominin accumulation was due to a punctual or recurrent episode of «gastronomic» cannibalism. Our analysis revealed that most individuals (N = 7) are immature between three and thirteen, whereas two are young adults between fifteen and eighteen. Considering this peculiar mortality distribution, alternative hypotheses on the possible scenarios in which hominins were apprehended, as well as the implications for the human behaviour in the Pleistocene are discussed.En el Estrato Aurora del nivel TD6 del yacimiento pleistoceno de Gran Dolina (Trinchera del Ferrocarril, Sierra de Atapuerca, Burgos) se han obtenido más de cien restos fósiles de homininos de la especie Homo antecessor, que pertenecen a un mínimo (NMI) de nueve individuos. En este trabajo realizamos la determinación del NMI y de la edad de muerte de los individuos, empleando datos observados en los restos de mandíbula, maxilar y dientes. El análisis tafonómico previo concluyó que el origen de la acumulación de los restos de homininos fue un acto puntual o recurrente de canibalismo de tipo «gastronómico ». Nuestro análisis revela que la mayor parte de los individuos (n = 7) son inmaduros, de entre tres y trece años, mientras que dos son adultos jóvenes, de entre quince y dieciocho años. En función de esta peculiar distribución de mortalidad se discuten hipótesis alternativas sobre los escenarios en los que los homininos fueron aprehendidos y las implicaciones que ello conlleva para el comportamiento de las poblaciones del Pleistoceno inferior.

The Aurora Stratum of the TD6 level of the Pleistocene site of Gran Dolina (Trinchera del Ferrocarril, Sierra de Atapuerca, Burgos, Spain) have yielded more than one hundred human fossil remains, of the species Homo antecessor and belonging to a minimum (MNI) of nine individuals. In this paper we made the MNI determination and the age at death of the individuals, using data observed in the mandibular, maxillary, and dental remains. The previous taphonomic analysis concluded that the origin of the hominin accumulation was due to a punctual or recurrent episode of «gastronomic» cannibalism. Our analysis revealed that most individuals (N = 7) are immature between three and thirteen, whereas two are young adults between fifteen and eighteen. Considering this peculiar mortality distribution, alternative hypotheses on the possible scenarios in which hominins were apprehended, as well as the implications for the human behaviour in the Pleistocene are discussed. En el Estrato Aurora del nivel TD6 del yacimiento pleistoceno de Gran Dolina (Trinchera del Ferrocarril, Sierra de Atapuerca, Burgos) se han obtenido más de cien restos fósiles de homininos de la especie Homo antecessor, que pertenecen a un mínimo (NMI) de nueve individuos. En este trabajo realizamos la determinación del NMI y de la edad de muerte de los individuos, empleando datos observados en los restos de mandíbula, maxilar y dientes. El análisis tafonómico previo concluyó que el origen de la acumulación de los restos de homininos fue un acto puntual o recurrente de canibalismo de tipo «gastronómico ». Nuestro análisis revela que la mayor parte de los individuos (n = 7) son inmaduros, de entre tres y trece años, mientras que dos son adultos jóvenes, de entre quince y dieciocho años. En función de esta peculiar distribución de mortalidad se discuten hipótesis alternativas sobre los escenarios en los que los homininos fueron aprehendidos y las implicaciones que ello conlleva para el comportamiento de las poblaciones del Pleistoceno inferior.

We designed a study to assess the prevalence of type 1 diabetes mellitus among the Portuguese population. The study was based on a cohort of young Portuguese men inspected at the different recruitment Centres of the Portuguese Armed Forces in 1995 and 1999. We found a prevalence of 1.28 and 1.58 cases per 1,000 young men aged 20 (median), in 1995 and 1999, respectively. As far as the geographical distribution of this population was concerned, the recruitment centres (RC) with highest prevalence of diabetes in 1995 were that of Oporto, Évora and Lisboa. In 1999, highest prevalence was in Évora, Faro and Lisbon. The greatest increase was found at the RCs in Faro, Évora and Vila Real. Although the regional asymmetries are not very significant, they point to a higher prevalence in the southern region and in the urban areas of Lisbon and Oporto.

Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations. We aimed to assess the safety and efficacy of erlotinib compared with standard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC.We undertook the open-label, randomised phase 3 EURTAC trial at 42 hospitals in France, Italy, and Spain. Eligible participants were adults (18 years) with NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease (neoadjuvant or adjuvant chemotherapy ending ≥ 6 months before study entry was allowed). We randomly allocated participants (1:1) according to a computer-generated allocation schedule to receive oral erlotinib 150 mg per day or 3 week cycles of standard intravenous chemotherapy of cisplatin 75 mg/m(2) on day 1 plus docetaxel (75 mg/m(2) on day 1) or gemcitabine (1250 mg/m(2) on days 1 and 8). Carboplatin (AUC 6 with docetaxel 75 mg/m(2) or AUC 5 with gemcitabine 1000 mg/m(2)) was allowed in patients unable to have cisplatin. Patients were stratified by EGFR mutation type and Eastern Cooperative Oncology Group performance status (0 vs 1 vs 2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed safety in all patients who received study drug (≥ 1 dose). This study is registered with ClinicalTrials.gov, number NCT00446225.Between Feb 15, 2007, and Jan 4, 2011, 174 patients with EGFR mutations were enrolled. One patient received treatment before randomisation and was thus withdrawn from the study; of the remaining patients, 86 were randomly assigned to receive erlotinib and 87 to receive standard chemotherapy. The preplanned interim analysis showed that the study met its primary endpoint; enrolment was halted, and full evaluation of the results was recommended. At data cutoff (Jan 26, 2011), median PFS was 9·7 months (95% CI 8·4-12·3) in the erlotinib group, compared with 5·2 months (4·5-5·8) in the standard chemotherapy group (hazard ratio 0·37, 95% CI 0·25-0·54; p0·0001). Main grade 3 or 4 toxicities were rash (11 [13%] of 84 patients given erlotinib vs none of 82 patients in the chemotherapy group), neutropenia (none vs 18 [22%]), anaemia (one [1%] vs three [4%]), and increased amino-transferase concentrations (two [2%] vs 0). Five (6%) patients on erlotinib had treatment-related severe adverse events compared with 16 patients (20%) on chemotherapy. One patient in the erlotinib group and two in the standard chemotherapy group died from treatment-related causes.Our findings strengthen the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors.Spanish Lung Cancer Group, Roche Farma, Hoffmann-La Roche, and Red Temática de Investigacion Cooperativa en Cancer.

10.1002/ajpa.22020

The aim of our study was to create, from the French method IDEA (Indicateurs de Durabilité des Exploitations Agricoles; Indicators of farming system sustainability; Vilain, 2003), a tool for assessing farming system sustainability in São Pedro Valley (State of São Paulo, Brazil). Evaluation criteria appropriate to the actual agro-ecological, economic and social conditions of the region were constructed in a participatory manner with the help of experts and farmers. The new method SEASP (Sustentabilidade dos Estabelecimentos Agropecuarios São Pedro) is based on three pillars of sustainability (agroecological, socio-territorial and economic), taking into account twenty composite indicators each. For each indicator, the farm system studied was given a certain number of points according to criteria that are easily assessed in the field. A macro made with Microsoft Excel software enabled the score entry and generated graphics that enabled explicit comparison of farm systems. The method was tested on a dozen farms to verify its functionality and relevance and the main factors favourable or unfavourable to the sustainability of production systems were identified. All of this raises the broader question of the universality of family farming sustainability and the genericity of assessment methods.; L’objectif de notre étude était de créer, à partir de la méthode française IDEA (indicateurs de durabilité des exploitations agricoles, Vilain, 2003), un outil d'évaluation de la durabilité des exploitations agricoles de la Vallée de São Pedro (État de São Paulo, Brésil). Des critères d’évaluation adaptés à la réalité agroécologique, économique et sociale de la région ont été construits de manière participative avec l’aide d’experts et d’agriculteurs. La nouvelle méthode SEASP (Sustentabilidade dos Estabelecimentos Agropecuarios de São Pedro) ainsi élaborée repose sur trois axes de durabilité (agroécologique, socioterritorial et économique), prenant en compte chacun une vingtaine d’indicateurs composites. Pour chaque indicateur, l’exploitation étudiée se voit attribuer un nombre de points selon des critères facilement mesurables sur le terrain. Une macro réalisée avec le logiciel Microsoft Excel permet la saisie des scores et génère des représentations graphiques explicites qui permettent une comparaison des systèmes agricoles. La méthode a été testée sur une dizaine d’exploitations afin de vérifier sa fonctionnalité et sa pertinence et les principaux facteurs favorables ou non à la durabilité des systèmes de production ont ainsi été identifiés. L’ensemble de ce travail soulève plus largement la question de l’universalité de la notion de durabilité de l’agriculture familiale et de la généricité des méthodes d’évaluation.

The Atapuerca Quaternarian sites are of worldwide interest due to the presence of human remains belonging to the last million years. The oribatid mites (Acari, Oribatida) found in several archaeological samples extracted from the Atapuerca Quaternarian deposits, have been analyzed during the 2003 excavation campaign to study the Palaeoentomology of the site. The oribatid mite fauna consists of 7 individuals, 6 of which were obtained from Gran Dolina site (about 300.000 years old) and belong to families Cosmochthoniidae, Scheloribatidae, Oribatulidae and Hemileiidae. Most of the taxa were identified to species level. The results obtained were used as a basis to reconstruct the paleo-environments of the site in correspondence with the biological and ecological preferences of the taxa. Los yacimientos cuaternarios de la Sierra de Atapuerca ofrecen interés mundial por haber hospedado varias especies de homínidos que vivieron en el último millón de años. En este contexto, durante la campaña de excavaciones de 2003 se realizó un muestreo puntual en algunos de sus yacimientos para obtener los primeros datos de restos de artrópodos que pudieran conservarse en los mismos. En este trabajo se presentan los resultados obtenidos de ácaros subfósiles pertenecientes al suborden de los oribátidos (Acari, Oribatida). Después de procesar los sedimentos, se obtuvieron un total de 7 individuos en el conjunto de los yacimientos muestreados, de los cuales 6 aparecieron en Gran Dolina en un nivel con datación en torno a los 300.000 años. Los ejemplares, identificados en su mayoría a nivel taxonómico de especie, pertenecen a las familias Cosmochthoniidae, Scheloribatidae, Oribatulidae y Hemileiidae. Dado el conocimiento que se dispone de la biología de los taxones encontrados, que pertenecen a géneros y especies presentes en la actualidad, se han realizado inferencias sobre los ambientes pretéritos en que los animales vivieron.

European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium Furio Pacini, Martin Schlumberger, Henning Dralle, Rossella Elisei, Johannes W A Smit, Wilmar Wiersinga and the European Thyroid Cancer Taskforce Section of Endocrinology and Metabolism, University of Siena, Via Bracci, 53100 Siena, Italy, Service de Medicine Nucleaire, Institut Gustave Roussy, Villejuif, France, Department of General, Visceral and Vascular Surgery, University of Halle, Germany, Department of Endocrinology, University of Pisa, Italy, Department of Endocrinology and Metabolic Disease, Leiden University Medical Center, The Netherlands and Department of Endocrinology and Metabolism, University of Amsterdam, The Netherlands

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El dolor neuropático es una forma de dolor crónico con gran repercusión sobre los pacientes. La diabetes mellitus es una de las prinicipales causas de de dolor neuropático. Es uno de los síndromes dolorosos más complejos, con diversos síntomas y signos que fluctúan con el tiempo tanto en su número como en intensidad. Suele asociar clínica acompañante repercutiendo sobre la actividad social y laboral, con la consiguiente disminución de la calidad de vida. Su tratamiento es difícil y, en general, poco satisfactorio, debido a la falta de conocimiento de los mecanismos fisiopatológicos. Los antidepresivos han sido, hasta ahora, los fármacos de primera elección, pero dada su limitada eficacia y efectos secundarios, se han tenido que buscar alternativas terapéuticas. Mediante una búsqueda en la base de datos del Medline, hemos analizado los estudios controlados que estudian la eficacia de la amitriptilina y de la gabapentina en el tratamiento del dolor neuropático del diabético. Los antidepresivos se han considerado, durante años, tratamiento de primera elección en el dolor neuropático del diabético, siendo la amitriptilina el más empleado. Es creciente la importancia de los anticomiciales para el tratamiento de este tipo de dolor, y se apunta a la gabapentina como el más efectivo. Los efectos secundarios anticolinérgicos de la amitriptilina limitan su uso, sobre todo en los pacientes de mayor edad. La gabapentina parece ser un fármaco bien tolerado, siendo los efectos secundarios más frecuentes el mareo y la somonolencia, por lo parece una buena alternativa como tratamiento de primera elección del dolor neuropático en pacientes añosos. Únicamente se han publicado dos estudios controlados y aleatorizados que comparan ambos tratamientos. No obstante, estos estudios no pueden considerarse concluyentes debido al pequeño tamaño muestral. La gabapentina puede considerarse de primera elección en el tratamiento del dolor neuropático del diabético. La elección de uno u otro fármaco debe hacerse de forma individualizada, basándose en la relación riesgo/beneficio. Neuropathic pain is a form of chronic pain that has a great impact on the patients. Diabetes mellitus is one of the major causes of neuropathic pain. It is one of the most complex painful syndromes, with different symptoms and signs that vary over time both in their number and severity. The accompanying clinical signs affect the social and occupational activity of the patient, with the resulting decrease in the quality of life. Its treatment is difficult and, in general, unsatisfactory due to the lack of knowledge regarding its pathophysiological mechanisms. Antidepressants have been, up to now, the first-line drugs, but given its limited effectiveness and side effects, other therapeutic alternatives have been looked for. Through a search in the Medline database, we reviewed controlled trials that study the effectiveness of amitriptyline and gabapentin for the management of painful diabetic neuropathy. Antidepressants have been considered for years the first-line treatment for neuropathic pain in the diabetic patient, amitriptyline being the most widely used. Antiepileptics are increasingly important the management of this type of pain and they are believed to be the most effective ones. The anticolinergic side effects of amitriptyline restrict its use, the most common side effects being dizziness and somnolence, so it seems to be a good alternative as first-line treatment for neuropathic pain in aged patients. Just two controlled and randomized studies have been published that compare both treatments. However, these studies cannot be considered conclusive due to their small sample size. Gabapentin can also be considered a first-line treatment for neuropathic pain in the diabetic. The election of one or the other drug must be made in each individual case based on the risk-benefit relation.