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Background: Night-shift work (NSW) has been suggested as a possible cause of breast cancer, and its association with mammographic density (MD), one of the strongest risk factors for breast cancer, has been scarcely addressed. This study examined NSW and MD in Spanish women.Methods: The study covered 2,752 women aged 45–68 years recruited in 2007–2008 in 7 population-based public breast cancer screening centers, which included 243 women who had performed NSW for at least one year. Occupational data and information on potential confounders were collected by personal interview. Two trained radiologist estimated the percentage of MD assisted by a validated semiautomatic computer tool (DM-scan). Multivariable mixed linear regression models with random screening center–specific intercepts were fitted using log-transformed percentage of MD as the dependent variable and adjusting by known confounding variables.Results: Having ever worked in NSW was not associated with MD [{e^\beta }$:0.96; 95% confidence interval (CI), 0.86–1.06]. However, the adjusted geometric mean of the percentage of MD in women with NSW for more than 15 years was 25% higher than that of those without NSW history (MD>15 years:20.7% vs. MDnever:16.5%;{e^\beta }$:1.25; 95% CI,1.01–1.54). This association was mainly observed in postmenopausal participants ({e^\beta }$:1.28; 95% CI, 1.00–1.64). Among NSW-exposed women, those with ≤2 night-shifts per week had higher MD than those with 5 to 7 nightshifts per week ({e^\beta }$:1.42; 95% CI, 1.10–1.84).Conclusions: Performing NSW was associated with higher MD only in women with more than 15 years of cumulated exposure. These findings warrant replication in futures studies.Impact: Our findings suggest that MD could play a role in the pathway between long-term NSW and breast cancer. Cancer Epidemiol Biomarkers Prev; 26(6); 905–13. ©2017 AACR.

Supplementary table S1. Association of current or recent (stopped NSW

Supplementary Figure 1. Graphic esqueme summarizing the proposed pathways of the association between night-shift work and mammographic density.

[EN] Background and Objective: Breast density assessed from digital mammograms is a biomarker for higher risk of developing breast cancer. Experienced radiologists assess breast density using the Breast Image and Data System (BI-RADS) categories. Supervised learning algorithms have been developed with this objective in mind, however, the performance of these algorithms depends on the quality of the ground truth information which is usually labeled by expert readers. These labels are noisy approximations of the ground truth, as there is often intra-and inter-reader variability among labels. Thus, it is crucial to provide a reliable method to obtain digital mammograms matching BI-RADS categories. This paper presents RegL (Labels Regularizer), a methodology that includes different image pre-processes to allow both a correct breast segmentation and the enhancement of image quality through an intensity adjustment, thus allowing the use of deep learning to classify the mammograms into BI-RADS categories. The Confusion Matrix (CM) CNN network used implements an architecture that models each radiologist's noisy label. The final methodology pipeline was determined after comparing the performance of image pre-processes combined with different DL architectures.Methods: A multi-center study composed of 1395 women whose mammograms were classified into the four BI-RADS categories by three experienced radiologists is presented. A total of 892 mammograms were used as the training corpus, 224 formed the validation corpus, and 279 the test corpus.Results: The combination of five networks implementing the RegL methodology achieved the best results among all the models in the test set. The ensemble model obtained an accuracy of (0.85) and a kappa index of 0.71. Conclusions: The proposed methodology has a similar performance to the experienced radiologists in the classification of digital mammograms into BI-RADS categories. This suggests that the pre-processing steps and modelling of each radiologist's label allows for a better estimation of the unknown ground truth labels., This work was partially funded by Generalitat Valenciana through IVACE (Valencian Institute of Business Competitiveness) distributed nominatively to Valencian technological innovation centres under project expedient IMAMCN/2021/1.

Current health promotion and early cancer detection programmes yield different results depending on the social group and have a different impact among individuals. Thus, they may generate social inequalities in health. The Contest of Best Practices tackling social inequalities in cancer prevention is an initiative that emerged in the framework of the Innovative Partnership for Action Against Cancer Joint Action. This contest identifies interventions that have proven to be effective in reducing social inequalities in cancer prevention in European countries, with the aim of sharing lessons learned and inspiring solutions, as well as facilitating replication in other health systems and similar social settings.

The population-based Program for the Prevention of Colorectal Cancer (PPCRC) was implemented in 2005 in the Valencian Community, following the guidelines of the European Union. To achieve the desired effectiveness in these programs, it is necessary to achieve a series of requirements, assessable through the program indicators. The objective of this study was to analyze the evolution of the program indicators from 2006 to 2016.The accumulated indicators for the period were calculated. The Poisson regression model was used to compare the indicators by age groups and sex, by type of screening, by type of fecal occult blood test (FOBT) and by year.The number of people invited to participate was 1,934,266. The participation rate was 44.4%, being 87.6% in the subsequent screening and 33.7% in the initial one, with men over 60 having the lowest participation figures. Except for the positive predictive value (PPV) for low risk adenomas, which was higher in a group of men aged 50 to 59 years of successive screening, the detection rates and PPV for the different types of lesions were higher in the initial screening, with immunological test and in the group of men over 60 years old. Throughout the period, there was a decrease in the test positivity rates and in the advanced adenomas and cancers detection rates.The PPCCR reaches levels of quality for which the effectiveness of the program is demonstrated. However, the insufficient participation of some population groups highlights the need to carry out studies to achieve the desired objectives in all population groups and thus result in greater effectiveness of the program.El Programa Poblacional de Preven-ción de Cáncer Colorrectal (PPCCR) se implantó en 2005 en la Comunitat Valenciana, siguiendo las directrices de la Unión Europea. Para alcanzar la efectividad deseada en estos programas es necesario conseguir una serie de requisitos, valorables mediante los indicadores del programa. El objetivo del presente estudio fue analizar la evolución de los indicadores del programa de 2006 a 2016.Se calcularon los indicadores acumulados para el periodo. Se empleó el modelo de regresión de Poisson para comparar los indicadores por grupos de edad y sexo, por tipología de cribado, por tipo de test de sangre oculta en heces (TSOH) y por año.El número de personas invitadas a participar fue de 1.934.266. La tasa de participación fue del 44,4%, siendo del 87,6% en el cribado sucesivo y del 33,7% en el inicial, teniendo los hombres mayores de 60 años las menores cifras de participación. Excepto el valor predictivo positivo (VPP) para adenomas de bajo riesgo, que fue superior en grupo de hombres de 50 a 59 años en cribado sucesivo, las tasas de detección y VPP para los diferentes tipos de lesiones fueron mayores en el cribado inicial, con el tipo de test inmunológico y en el grupo de hombres mayores de 60 años. A lo largo del periodo se produjo un descenso en las tasas de positividad para el test y las tasas de detección de adenomas avanzados y cánceres.El PPCCR alcanza niveles de calidad para los que se demuestra la eficacia del programa. Sin embargo, la participación insuficiente de algunos grupos poblacionales remarca la necesidad de realizar estudios para conseguir los objetivos deseados en todos los grupos poblacionales y así redundar en una mayor eficacia del programa.

[EN] Introduction: Mammographic density (MD), the proportion of radiologically dense breast tissue, is a strong risk factor for breast cancer. Our objective is to investigate the influence of occupations and occupational exposure to physical, chemical, and microbiological agents on MD in Spanish premenopausal women. Methods: This is a cross-sectional study based on 1362 premenopausal workers, aged 39-50, who attended a gynecological screening in a breast radiodiagnosis unit of Madrid City Council. The work history was compiled through a personal interview. Exposure to occupational agents was evaluated using the Spanish job-exposure matrix MatEmESp. MD percentage was assessed using the validated semi-automated computer tool DM-Scan. The association between occupation, occupational exposures, and MD was quantified using multiple linear regression models, adjusted for age, educational level, body mass index, parity, previous breast biopsies, family history of breast cancer, energy intake, use of oral contraceptives, smoking, and alcohol consumption. Results: Although no occupation was statistically significantly associated with MD, a borderline significant inverse association was mainly observed in orchard, greenhouse, nursery, and garden workers (beta = -6.60; 95% confidence interval (95%CI) = -14.27; 1.07) and information and communication technology technicians (beta = -7.27; 95%CI = -15.37; 0.84). On the contrary, a positive association was found among technicians in art galleries, museums, and libraries (beta = 8.47; 95%CI = -0.65; 17.60). Women occupationally exposed to fungicides, herbicides, and insecticides tended to have lower MD. The percentage of density decreased by almost 2% for every 5 years spent in occupations exposed to the mentioned agents. Conclusions: Although our findings point to a lack of association with the occupations and exposures analyzed, this study supports a deeper exploration of the role of certain occupational agents in MD, such as pesticides., This work was supported by the Carlos III Institute of Health (AESI PI15CIII/00029 and AESI PI15CIII/00013). The article presents independent research. The views expressed are those of the authors and not necessarily those of the Carlos III Institute of Health.

The aim was to assess the effect of adherence to the Mediterranean Diet, measured with five different indexes, on the risk of gastric cancer. Data come from the multicase-control study MCC—Spain, which included 354 gastric cancer cases and 3040 controls with data on diet. We used five indexes to evaluate adherence to the Mediterranean diet and assess the association between each pattern with the risk of gastric cancer, using multivariate logistic regression. The analyses were performed for the whole set of gastric cancer cases, by anatomical location (cardia and non-cardia) and by histological type (intestinal and diffuse). According to the used index, a high adherence protects one from gastric cancer (between 48% (aOR = 0.52, CI 95% = 0.28–0.94) and 75% (aOR = 0.25, CI 95% = 0.12–0.52)), from non-cardia (between 48% (aOR = 0.52, CI 95% = 0.36–0.75) and 65% (aOR = 0.35, CI 95% = 0.23–0.52)), and from the intestinal type (between 41% (aOR = 0.59, CI 95% = 0.36–0.95) and 72% (aOR = 0.28, CI 95% = 0.16–0.50)), but not from the diffuse type. In conclusion, high adherence to a Mediterranean diet pattern is a protective factor for the risk of gastric cancer, with greater adherence leading to greater protection.

The use of new devices such as the self-sampling for the determination of the Human Papilloma Virus (HPV), could facilitate the implementation of population screening programs and increase the participation of women. The objective of the study was to find out the women´s knowledge and attitudes towards cervical cancer screening as well as the acceptability of self-sampling.Analytical cross-sectional study by telephone survey carried out on a random sample of 389 women from 35 to 65 years of age. The women were asked about their attitudes and knowledge of the screening and preference for HPV determination by self-sampling or by a healthcare professional.86.9% of the women preferred self-sampling as a screening method and 93.3% had undergone a previous cervical cytology. 51.4% of the women had a high level of knowledge about cervical cancer screening. Younger women (POR 9.26; 95% CI 1.04-24.38), higher level of education (POR 4.6; 95% CI: 1.92-11.00), and higher level of knowledge (POR 2.78; 95% CI: 1.69-9.29), presented higher preferences for the determination of HPV by self-sampling. The trend in age, educational level and knowledge was the same for the prevalence of previous cervical cytology.The acceptance of self-testing as a method of cervical cancer screening is high among women. Efforts should be made to raise awareness among women to reduce possible inequalities in access and to encourage informed participation.El uso de la auto-toma para determinación del Virus del Papiloma Humano (VPH), podría facilitar la implantación de los programas de cribado poblacional y aumentar la participación de las mujeres. El objetivo de estudio fue conocer los conocimientos y actitudes de las mujeres frente al cribado del cáncer de cérvix y la aceptación de la auto-toma como método de cribado para la detección del VPH.Estudio transversal analítico mediante encuesta telefónica realizada a una muestra aleatoria de 389 mujeres entre 35 y 65 años de la Comunitat Valenciana. Se preguntó a las mujeres sobre prácticas preventivas previas, actitudes y conocimientos del cribado, y la preferencia por la determinación de VPH mediante auto-toma o por un profesional sanitario.El 86,9% de las mujeres encuestadas prefirieron la auto-toma como método de cribado y el 93,3% se habían realizado una citología cervical previa. El 51,4% de las mujeres tenían un nivel de conocimiento alto sobre el cribado del cáncer de cérvix. Las mujeres de menor edad (POR 9,26; IC95%1,04-24,38), mayor nivel de estudios (POR 4,6; IC95%:1,92-11,00), y mayor nivel de conocimientos (POR 2,78; IC95%:1,69-9,29), presentaron preferencias mayores por la determinación de VPH mediante auto-toma. La tendencia en la edad, nivel de estudios y conocimientos fue la misma para la prevalencia de realización de la citología cervical previa.La aceptación de la auto-toma como método de cribado del cáncer de cérvix es elevada entre las mujeres. Se deben dedicar esfuerzos para aumentar el conocimiento en las mujeres para reducir posibles desigualdades de acceso y fomentar una participación informada.

The European Commission recommends ensuring equity in cancer screening. The aim of this study was to find out if there were inequalities in access to cancer screening programmes in Spain.A transversal study was carried out by means of a survey addressed to the people responsible for breast, colorectal (CRC) and cervical cancer screening programmes in the 19 Autonomous Communities (AC) of Spain in 2013 and 2020. Information was collected on organizational characteristics, inequalities in access and interventions to reduce them. A descriptive analysis was made by AC and time period, by calculating frequencies and percentages, depending on the type of programme (breast, CRC and cervix).In 2013, 14 ACs participated for the breast programme, 8 for the CRC and 7 for the cervical programme; and in 2020, 14, 13 and 11 ACs respectively. All breast programmes were population-based in both periods (14/14 in 2013 and 14/14 in 2020), as well as CRC ones (8/8 in 2013 and 13/13 in 2020), with an increase in cervical cancer programmes (0/7 en 2013 y 6/11 en 2020). In both periods, social groups not included in the target population and groups that were less involved were identified, with differences according to the type of programme. A total of 53 interventions were carried out to reduce inequalities in access (27 in breast, 22 in RCC and 4 in cervical), 66% of them aimed at specific social groups (35/53).Inequalities in access to cancer screening programmes in Spain are identified, as well as interventions to reduce them.La Comisión Europea recomienda asegurar la equidad en el cribado del cáncer. El objetivo de este estudio fue conocer si existían desigualdades en el acceso a los programas de cribado del cáncer en España.Se realizó un estudio transversal mediante encuesta dirigida a las personas responsables de los programas de cribado del cáncer de mama, colorrectal (CCR) y cérvix de las diecinueve Comunidades Autónomas (CCAA) del Estado Español en 2013 y 2020. Se recogió información sobre características organizativas, desigualdades de acceso e intervenciones para reducirlas. Se hizo un análisis descriptivo por CCAA y periodo temporal, mediante el cálculo de frecuencias y porcentajes, en función del tipo de programa (mama, CCR y cérvix).En 2013 participaron catorce CCAA para el programa de mama, ocho para el de CCR y siete para el de cérvix, y en 2020, catorce, trece y once CCAA, respectivamente. Todos los programas de mama eran poblacionales en ambos periodos (14/14 en 2013 y 14/14 en 2020), así como los de CCR (8/8 en 2013 y 13/13 en 2020), con un aumento en el caso de los programas de cribado del cáncer de cérvix (0/7 en 2013 y 6/11 en 2020). Se identificaron en ambos periodos grupos sociales no incluidos en la población diana y grupos que, estando incluidos, participaban menos, con diferencias según el tipo de programa. Se realizaron un total de cincuenta y tres intervenciones para reducir desigualdades en el acceso (veintisiete en mama, veintidós en CCR y cuatro en cérvix), el 66% de ellas dirigidas a grupos sociales específicos (35/53).Se identifican desigualdades de acceso a los programas de cribado del cáncer en España, así como intervenciones para reducirlas.

[EN] Background: The role of fatty acids (FAs) on mammographic density (MD) is unclear, and available studies are based on self-reported dietary intake. Objectives: This study assessed the association between specific serum phospholipid fatty acids (PLFAs) and MD in premenopausal women. Methods: The cross-sectional study DDM-Madrid recruited 1392 Spanish premenopausal women, aged 39-50 y, who attended a screening in a breast radiodiagnosis unit of Madrid City Council. Women completed lifestyle questionnaires and FFQs. Percentage MD was estimated using a validated computer tool (DM-Scan), and serum PLFA percentages were measured by GC-MS. Multivariable linear regression models were used to quantify the association of FA tertiles with MD. Models were adjusted for age, education, BMI, waist circumference, parity, oral contraceptive use, previous breast biopsies, and energy intake, and they were corrected for multiple testing. Results: Women in the third tertile of SFAs showed significantly higher MD compared with those in the first tertile (beta(T3vsT1) = 7.53; 95% CI: 5.44, 9.61). Elevated relative concentrations of palmitoleic (beta(T3vsT1) = 3.12; 95% CI: 0.99, 5.25) and gondoic (beta(T3vsT1) = 2.67; 95% CI: 0.57, 4.77) MUFAs, as well as high relative concentrations of palmitelaidic (beta(T3vsT1) = 5.22; 95% CI: 3.15, 7.29) and elaidic (beta(T3vsT1) = 2.69; 95% CI: 0.59, 4.79) trans FAs, were also associated with higher MD. On the contrary, women with elevated relative concentrations of n-6 (omega-6) linoleic (beta(T3vsT1) = -5.49; 95% CI; -7.62, -3.35) and arachidonic (beta(T3vsT1) = -4.68; 95% CI: -6.79, -2.58) PUFAs showed lower MD. Regarding desaturation indices, an elevated palmitoleic to palmitic ratio and a low ratio of oleic to steric and arachidonic to dihomo. gamma-linolenic acids were associated with higher MD. Conclusions: Spanish premenopausal women with high relative concentrations of most SFAs and some MUFAs and trans FAs showed an increased MD, whereas those with high relative concentrations of some n-6 PUFAs presented lower density. These results, which should be confirmed in further studies, underscore the importance of analyzing serum FAs individually., This study was funded by the Carlos III Institute of Health (AESI PI15CIII/0029). The article presents independent research. The views expressed are those of the authors and not necessarily those of the Carlos III Institute of Health.

[EN] Background and Objective: Breast cancer is the most frequent cancer in women. The Spanish healthcare network established population-based screening programs in all Autonomous Communities, where mammograms of asymptomatic women are taken with early diagnosis purposes. Breast density assessed from digital mammograms is a biomarker known to be related to a higher risk to develop breast cancer. It is thus crucial to provide a reliable method to measure breast density from mammograms. Furthermore the complete automation of this segmentation process is becoming fundamental as the amount of mammograms increases every day. Important challenges are related with the differences in images from different devices and the lack of an objective gold standard. This paper presents a fully automated framework based on deep learning to estimate the breast density. The framework covers breast detection, pectoral muscle exclusion, and fibroglandular tissue segmentation. Methods: A multi-center study, composed of 1785 women whose "for presentation" mammograms were segmented by two experienced radiologists. A total of 4992 of the 6680 mammograms were used as training corpus and the remaining (1688) formed the test corpus. This paper presents a histogram normalization step that smoothed the difference between acquisition, a regression architecture that learned segmentation parameters as intrinsic image features and a loss function based on the DICE score. Results: The results obtained indicate that the level of concordance (DICE score) reached by the two radiologists (0.77) was also achieved by the automated framework when it was compared to the closest breast segmentation from the radiologists. For the acquired with the highest quality device, the DICE score per acquisition device reached 0.84, while the concordance between radiologists was 0.76. Conclusions: An automatic breast density estimator based on deep learning exhibits similar performance when compared with two experienced radiologists. It suggests that this system could be used to support radiologists to ease its work., This work was partially funded by Generalitat Valenciana through I+D IVACE (Valencian Institute of Business Competitiviness) and GVA (European Regional Development Fund) supports under the project IMAMCN/2019/1, and by Carlos III Institute of Health under the project DTS15/00080.

[EN] Objectives: Mammographic density (MD) is a strong risk factor for breast cancer. The present study evaluates the association between relative caloric intake and MD in Spanish women. Study design: We conducted a cross-sectional study in which 3517 women were recruited from seven breast cancer screening centers. MD was measured by an experienced radiologist using craniocaudal mammography and Boyd's semi-quantitative scale. Information was collected through an epidemiological survey. Predicted calories were calculated using linear regression models, including the basal metabolic rate and physical activity as explanatory variables. Overeating and caloric restriction were defined taking into account the 99% confidence interval of the predicted value. Odds ratios (OR) and 95% confidence intervals (95%CI) were estimated using center-specific mixed ordinal logistic regression models, adjusted for age, menopausal status, body mass index, parity, tobacco use, family history of breast cancer, previous biopsies, age at menarche and adherence to a Western diet. Main outcome measure: Mammographic density. Results: Those women with an excessive caloric intake ( > 40% above predicted) presented higher MD (OR = 1.41, 95%CI = 0.97-2.03; p = 0.070). For every 20% increase in relative caloric consumption the probability of having higher MD increased by 5% (OR = 1.05, 95%CI = 0.98-1.14; p = 0.178), not observing differences between the categories of explanatory variables. Caloric restriction was not associated with MD in our study. Conclusions: This is the first study exploring the association between MD and the effect of caloric deficit or excessive caloric consumption according to the energy requirements of each woman. Although caloric restriction does not seem to affect breast density, a caloric intake above predicted levels seems to increase this phenotype, This study was supported by the Research Grant FIS PI060386 from Spanish Public Health Research Fund (Fondo de Investigacion Sanitaria); the Carlos III Institute of Health (Institute de Salud Carlos III)PI15CIII/0029 and PI15CIII/00013; the EPY 1306/06Collaboration Agreement between Astra-Zeneca and the Carlos III Institute of Health; and a grant from the Spanish Federation of Breast Cancer Patients (FECMA EPY 1169/10).

Resumen Objetivo Identificar y caracterizar las complicaciones graves de las colonoscopias de confirmacion diagnostica del Programa de Prevencion de Cancer Colorrectal de la Comunitat Valenciana (PPCCR-CV). Metodo Estudio observacional retrospectivo (2005-2012). Para identificar las complicaciones se utilizo el sistema de informacion del PPCCR-CV, las altas hospitalarias del conjunto minimo basico de datos (CMBD) y la historia clinica. Se estimaron tasas de incidencia acumulada para el total de complicaciones, para inmediatas (mismo dia de la colonoscopia) y tardias (1-30 dias desde la colonoscopia) por 1.000 colonoscopias. Analisis bivariado con la prueba Chi cuadrado para la aparicion de complicacion segun sexo, edad y tipo de test (guayaco/inmunologico) y para el tiempo de aparicion de la complicacion (inmediata/tardia) segun el tipo de colonoscopia (diagnostica/terapeutica) y el tipo de complicacion (hemorragia/perforacion). Resultados De las 8.831 colonoscopias del estudio se detectaron 23 complicaciones graves de las cuales 13 fueron perforaciones (56,5%) y 10 hemorragias (43,5%) y ningun sindrome vagal grave, peritonitis o fallecimiento. La tasa de incidencia acumulada fue del 2,60‰, para el test de guayaco del 2,85‰ y del 2,56‰ para el inmunologico. La tasa de incidencia fue mayor en hombres (2,93‰) que en mujeres (2,16‰) y en grupos de mayor edad (3,02‰ vs. 1,98‰). El 61% (n = 14) de las complicaciones fueron inmediatas. Conclusiones Las tasas de complicaciones de las colonoscopias de cribado graves son un indicador de calidad de los programas poblacionales de cribado de cancer colorrectal y requieren una investigacion exhaustiva para mantener el balance adecuado de beneficios y efectos adversos de estos programas.

[EN] Objectives: The association between breast cancer (BC) and thyroid disorders has been widely explored with unclear results. Mammographic density (MD) is one of the strongest risk factor for BC. This study explores the relationship between thyroid diseases and MD in Spanish women. Materials & methods: This cross-sectional study covered 2883 women aged 47-71 years participating in 7 BC screening programs in 2010. They allowed access to their mammograms, had anthropometrical-measures taken, and answered a telephonic epidemiological interview which included specific questions on thyroid diseases. Percentage of MD was assessed with a semiautomatic-computer tool (DM-scan) by two trained radiologists. We calculated the geometric mean of MD percentages (mean MD). Multivariable mixed linear regression models with random screening-center-specific intercepts were fitted, using log-transformed percentage of MD as dependent variable and adjusting for age, body mass index, menopausal status and other confounders. e(beta) represents the relative increase of mean MD. Results: 13.9% of the participants reported personal history of thyroid disease. MD was not associated to hyperthyroidism (e(beta): 1.05, 95%CI: 0.82-1.36), hypothyroidism (e(beta):1.02, 95%CI: 0.75-1.38), thyroid nodules (e(beta):1.01, 95%CI: 0.85-1.19) or thyroid cancer (e(beta):1.03, 95%CI: 0.56-1.92). However, women with goiter had lower MD (mean MDno-goiter: 13.4% vs mean MDgoiter: 10.6%; e(beta):0.79, 95%CI: 0.64-0.98) and those with Hashimoto thyroiditis had higher MD (mean MDno-thyroiditis: 13.3% vs mean MDthyroidits: 25.8%; e(beta) 95%CI: 1.00-3.77). Conclusion: Functional thyroid disorders were not related to MD. However, MD was lower in women with goiter and higher in those reporting Hashimoto's thyroiditis. These relationships should be confirmed in future studies. (C) 2017 Elsevier Ltd. All rights reserved., This work was supported by the Spanish Ministry of Economy and Competitiveness - Carlos III Institute of Health (ISCIII) (FI14CIII/00013, FIS PI060386 & PS09/0790); the Spanish Federation of Breast Cancer Patients (FECMA 485 EPY 1170-10); the Gent per Gent Fund (EDEMAC Project); and the EPY1306/06 collaboration agreement between Astra-Zeneca and the ISCIII and partially funded by the European Regional Development Fund. None of these funding sources had any role in the study design, in the collection, analysis or interpretation of data. Other members of DDM-Spain/Var-DDM: María Casals, Inmaculada Martínez, María Ederra and Jesús Vioque.

En este estudio se presentan los resultados de seis programas poblacionales de cribado de cáncer colorrectal desde 2005 a 2012 (Cataluña, Valencia, Murcia, Cantabria, País Vasco y Canarias) que utilizan diferentes tipos de test de cribado de sangre oculta en heces (SOH) bienal. El objetivo fue describir y comparar los resultados en cuanto a lesiones detectadas tanto por programa, participación, sexo, edad, tipo de test y comunidad autónoma. Metodos: Estudio de cohorte retrospectivo de las personas participantes en al menos una ronda completa cuya edad estaba comprendida entre los 50 y los 74 años. Lesiones consideradas: adenomas avanzados (AA), cáncer aolorrectal invasivo (CCR) y la suma de ambos, neoplasia avanzada (NA). Se realizó un nálisis de regresión logística y estudio de tendencias temporales. Resultados: Se obtuvieron 1.995.719 participaciones, lo que supuso el 46,7% de las invitaciones a participar. Se detectaron 21.228 neoplasias avanzadas (2.813 CCR y 18.415 AA). Se observaron diferencias en la detección de neoplasia avanzada (NA) entre los programas variando entre 15,1‰ y 35,8‰ participantes. La participación se relacionó con las tasas de detección (OR: 1,25 en 40-60% de participación). El test inmunoquímico cualitativo obtuvo una OR de 4,79 y el cuantitativo de 7,30 sobre guayaco. Los hombres tuvieron una OR de 2,73 sobre las mujeres, observándose en el 2012 una tasa de detección de neoplasia avanzada en hombres y mujeres de 33,1 y 14,2 x 1.000 respectivamente. Conclusiones: El tipo de test resultó el factor más determinante en la detección de lesiones. Las tendencias temporales mostraron un aumento de la tasa de detección por el cambio de test a partir del 2010.

[EN] Background The breast dense tissue percentage on digital mammograms is one of the most commonly used markers for breast cancer risk estimation. Geometric features of dense tissue over the breast and the presence of texture structures contained in sliding windows that scan the mammograms may improve the predictive ability when combined with the breast dense tissue percentage. Methods A case/control study nested within a screening program covering 1563 women with craniocaudal and mediolateral-oblique mammograms (755 controls and the contralateral breast mammograms at the closest screening visit before cancer diagnostic for 808 cases) aging 45 to 70 from Comunitat Valenciana (Spain) was used to extract geometric and texture features. The dense tissue segmentation was performed using DMScan and validated by two experienced radiologists. A model based on Random Forests was trained several times varying the set of variables. A training dataset of 1172 patients was evaluated with a 10-stratified-fold cross-validation scheme. The area under the Receiver Operating Characteristic curve (AUC) was the metric for the predictive ability. The results were assessed by only considering the output after applying the model to the test set, which was composed of the remaining 391 patients. Results The AUC score obtained by the dense tissue percentage (0.55) was compared to a machine learning-based classifier results. The classifier, apart from the percentage of dense tissue of both views, firstly included global geometric features such as the distance of dense tissue to the pectoral muscle, dense tissue eccentricity or the dense tissue perimeter, obtaining an accuracy of 0.56. By the inclusion of a global feature based on local histograms of oriented gradients, the accuracy of the classifier was significantly improved (0.61). The number of well-classified patients was improved up to 236 when it was 208. Conclusion Relative geometric features of dense tissue over the breast and histograms of standardized local texture features based on sliding windows scanning the whole breast improve risk prediction beyond the dense tissue percentage adjusted by geometrical variables. Other classifiers could improve the results obtained by the conventional Random Forests used in this study., This work was partially funded by Generalitat Valenciana through I+D IVACE (Valencian Institute of Business Competitiviness) and GVA (European Regional Development Fund) supports under the project IMAMCN/2018/1, and by Carlos III Institute of Health under the project DTS15/00080

OBJECTIVE: To examine the association between two dietary patterns (Western and Mediterranean), previously linked to breast cancer risk, and mammographic density. METHODS: This cross-sectional study included 3,584 women attending population-based breast cancer screening programs and recruited between October 7, 2007, and July 14, 2008 (participation rate 74.5%). Collected data included anthropometric measurements; demographic, obstetric, and gynecologic characteristics; family and personal health history; and diet in the preceding year. Mammographic density was blindly assessed by a single radiologist and classified into four categories: less than 10%, 10-25%, 25-50%, and greater than 50%. The association between adherence to either a Western or a Mediterranean dietary pattern and mammographic density was explored using multivariable ordinal logistic regression models with random center-specific intercepts. Models were adjusted for age, body mass index, parity, menopause, smoking, family history, hormonal treatment, and calorie and alcohol intake. Differences according to women's characteristics were tested including interaction terms. RESULTS: Women with a higher adherence to the Western dietary pattern were more likely to have high mammographic density (n=242 [27%]) than women with low adherence (n=169 [19%]) with a fully adjusted odds ratio (ORQ4vsQ1) of 1.25 (95% confidence interval [CI] 1.03-1.52). This association was confined to overweight-obese women (adjusted ORQ4vsQ1 [95% CI] 1.41 [1.13-1.76]). No association between Mediterranean dietary pattern and mammographic density was observed. CONCLUSION: The Western dietary pattern was associated with increased mammographic density among overweight-obese women. Our results might inform specific dietary recommendations for women with high mammographic density. Sí

[EN] Objectives The association between occupational exposures and mammographic density (MD), a marker of breast cancer risk, has not been previously explored. Our objective was to investigate the influence of occupational exposure to chemical, physical and microbiological agents on MD in adult women. Methods This is a population-based cross-sectional study based on 1476 female workers aged 45-65 years from seven Spanish breast cancer screening programmes. Occupational history was surveyed by trained staff. Exposure to occupational agents was assessed using the Spanish job-exposure matrix MatEmESp. Percentage of MD was measured by two radiologists using a semiautomatic computer tool. The association was estimated using mixed log-linear regression models adjusting for age, education, body mass index, menopausal status, parity, smoking, alcohol intake, type of mammography, family history of breast cancer and hormonal therapy use, and including screening centre and professional reader as random effects terms. Results Although no association was found with most of the agents, women occupationally exposed to perchloroethylene (e(beta)=1.51; 95% CI 1.04 to 2.19), ionising radiation (e(beta)=1.23; 95% CI 0.99 to 1.52) and mould spores (e(beta)=1.44; 95% CI 1.01 to 2.04) tended to have higher MD. The percentage of density increased 12% for every 5 years exposure to perchloroethylene or mould spores, 11% for every 5 years exposure to aliphatic/alicyclic hydrocarbon solvents and 3% for each 5 years exposure to ionising radiation. Conclusions Exposure to perchloroethylene, ionising radiation, mould spores or aliphatic/alicyclic hydrocarbon solvents in occupational settings could be associated with higher MD. Further studies are needed to clarify the accuracy and the reasons for these findings., This study was funded by the Spanish Ministry of Economy and Competitiveness - Carlos II Institute of Health (ISCI) (AESI PI15CI/00013); the Scientific Foundation of the Spanish Association Against Cancer (Fundacion Cientifica de la Asociacion Espanola Contra el Cancer (AEC) - EVP-1178/14); the Spanish Public Health Research Fund (FIS PI060386 & PS09/0790); the collaboration agreement between Astra-Zeneca and the ISCI (EPY1306/06) and a grant from the Spanish Federation of Breast Cancer Patients (FECMA 485 EPY 1170-10).

[EN] We explored the relationship between sleep patterns and sleep disorders and mammographic density (MD), a marker of breast cancer risk. Participants in the DDM-Spain/var-DDM study, which included 2878 middle-aged Spanish women, were interviewed via telephone and asked questions on sleep characteristics. Two radiologists assessed MD in their left craneo-caudal mammogram, assisted by a validated semiautomatic-computer tool (DM-scan). We used log-transformed percentage MD as the dependent variable and fitted mixed linear regression models, including known confounding variables. Our results showed that neither sleeping patterns nor sleep disorders were associated with MD. However, women with frequent changes in their bedtime due to anxiety or depression had higher MD (e¿:1.53;95%CI:1.04¿2.26)., This work was supported by grants from the Spanish Ministry of Economy and Competitiveness - Carlos III Institute of Health (ISCIII) (FI14CIII/00013, FIS PI060386 & PS09/0790), from the Spanish Federation of Breast Cancer Patients (FECMA 485 EPY 1170-10), Gent per Gent Fund (EDEMAC Project), the EPY1306/06 collaboration agreement between Astra-Zeneca and the ISCIII and partially funded by the European Regional Development Fund (FEDER)

Mammographic density (MD) is an intermediate phenotype for breast cancer. Previous studies have identified genetic variants associated with MD; however, much of the genetic contribution to MD is unexplained. We conducted a two-stage genome-wide association analysis among the participants in the "Determinants of Density in Mammographies in Spain" study, together with a replication analysis in women from the Australian MD Twins and Sisters Study. Our discovery set covered a total of 3,351 Caucasian women aged 45 to 68 years, recruited from Spanish breast cancer screening centres. MD was blindly assessed by a single reader using Boyd's scale. A two-stage approach was employed, including a feature selection phase exploring 575,374 SNPs in 239 pairs of women with extreme phenotypes and a verification stage for the 183 selected SNPs in the remaining sample (2,873 women). Replication was conducted in 1,786 women aged 40 to 70 years old recruited via the Australian Twin Registry, where MD were measured using Cumulus-3.0, assessing 14 SNPs with a p value

In this study, the results of six Colorectal Cancer Screening Population Programmes are shown (Catalonia, Valence, Murcia, Cantabria, the Basque Country and the Canary Islands collected between 2005 and 2012. These programmes use the faeces occult blood test (FOBt) biennial. Objective: To determine and compare the results of lesions detected by the programmes, participation, sex, age and test used.Retrospective cohort study based on people invited, aged between 50-74 years, in at least a complete round. Lesions considered: Advanced Adenomas (AA), Colorectal Invasive Cancer (CRC) and both of them, known as Advanced Neoplasia (AN). Logistic Regression and time trends are used.1,995,719 of invitations registered, with an average participation-rate of 46.7%. 21,228 Advanced Neoplasias (2,813 CRC and 18,415 AA). Differences in detection rates observed between programmes (varying from 15.1‰ to 35.8‰ between participants). Participation rates were related to lesions' detection rates (OR 1.25 in 40-60% of participation). . Inmunochemical qualitative test showed an OR of 4.79 and quantitative test an OR of 7.30 over the guaiac test. Men showed an OR of 2.73 with respect to women. In 2012 the Advanced Neoplasia rate for women and men was 33.1 and 14.2 by 1,000 participants.The test used was the most important factor for detecting lesions. Time trends showed an increase in detected lesions caused by the change of the type of test in 2010.En este estudio se presentan los resultados de seis programas poblacionales de cribado de cáncer colorrectal desde 2005 a 2012 (Cataluña, Valencia, Murcia, Cantabria, País Vasco y Canarias) que utilizan diferentes tipos de test de cribado de sangre oculta en heces (SOH) bienal. El objetivo fue describir y comparar los resultados en cuanto a lesiones detectadas tanto por programa, participación, sexo, edad, tipo de test y comunidad autónoma.Estudio de cohorte retrospectivo de las personas participantes en al menos una ronda completa cuya edad estaba comprendida entre los 50 y los 74 años. Lesiones consideradas: adenomas avanzados (AA), cáncer aolorrectal invasivo (CCR) y la suma de ambos, neoplasia avanzada (NA). Se realizó un nálisis de regresión logística y estudio de tendencias temporales.Se obtuvieron 1.995.719 participaciones, lo que supuso el 46,7% de las invitaciones a participar. Se detectaron 21.228 neoplasias avanzadas (2.813 CCR y 18.415 AA). Se observaron diferencias en la detección de neoplasia avanzada (NA) entre los programas variando entre 15,1‰ y 35,8‰ participantes. La participación se relacionó con las tasas de detección (OR: 1,25 en 40-60% de participación). El test inmunoquímico cualitativo obtuvo una OR de 4,79 y el cuantitativo de 7,30 sobre guayaco. Los hombres tuvieron una OR de 2,73 sobre las mujeres, observándose en el 2012 una tasa de detección de neoplasia avanzada en hombres y mujeres de 33,1 y 14,2 x 1.000 respectivamente.El tipo de test resultó el factor más determinante en la detección de lesiones. Las tendencias temporales mostraron un aumento de la tasa de detección por el cambio de test a partir del 2010.

To evaluate the cancer genetic counselling programme in Valencian Community using intermediate indicators. Descriptive analysis of organisational and effectiveness indicators from the start in 2005 until December 2010: correct referral of patients according to the area from where they were referred (primary or hospital-based care) and syndrome; families identified as having each syndrome; suitability of the genetic testing for individuals with a cancer diagnosis (index cases, IC) and relatives of ICs with mutations; family size; and results of genetic testing on genes, ICs and relatives. 9,942 individuals attended, 87.7 % were referred by hospital-based care and 8.4 % by primary care. 7,516 patients (79 %) fulfilled cancer genetic counselling criteria (82 % from hospital-based care and 46 % from primary care). Amongst those who fulfilled the criteria, 59 % of referrals were related to hereditary breast ovarian cancer syndrome and 32 % to hereditary non-polyposis colorectal cancer. ICs were found in 3,082 families (78.7 %) and genetic testing was carried out on 91.3 % of them. Pathogenic mutations were detected in 21.8 % of the ICs and the testing was then offered to their relatives (an average of 3 per IC). Pathogenic mutations were found in 54 % of the assessed relatives. Results in 5 years confirm the appropriateness of these facilities, as part of an integrated health service, to identify families and individuals with genetic risk to offer them personalized counselling. Improvements have to be made with regard to the information given to both health professionals and patients about the risk criteria for various syndromes.

During the first 6 years of the Program of Genetic Counselling in Cancer of Valencia (eastern Spain), 310 mutations (155 in BRCA1 and 155 in BRCA2) in 1,763 hereditary breast (BC) and ovarian cancer (OC) families were identified. Of the mutations found 105 were distinct (53 in BRCA1 and 52 in BRCA2), eight new and 37 recurrent. Two of the novel mutations were frame-shift placed in exons 2 and 11 of BRCA1 and the remaining six were placed in BRCA2; four frame-shift (three in exon 11 and one in exon 23), one deletion of the entire exon 19 and one in the intervening sequence of exon 22. The BRCA1 mutations with higher recurrence were c.66_68delAG, c.5123C > A, c.1961delA, c.3770_3771delAG and c.5152+5G > A that covered 45.2% of mutations of this gene. The age of onset of BCs of c.68_69delAG mutation carriers occurs later than for the other recurrent mutations of this gene (45 vs. 37 years; p = 0.008). The BRCA2 mutations with higher recurrence were c.9026_9030delATCAT, c.3264insT and c.8978_8991del14 which represented 43.2% of all mutations in this gene, being the most recurrent mutation by far c.9026_9030delATCAT that represents 21.3% of BRCA2 mutations and 10.6% of all mutations. Probands with family histories of BC and OC, or OC and/or BC in at least two first degree relatives, were the more likely to have BRCA1/BRCA2 mutations (35.2% of the total mutations). And that most BRCA1mutations (73.19% mutations) occurred in probands with early-onset BC or with family history of OC.

The objective of the present study was to assess the reproducibility of data-driven dietary patterns in different samples extracted from similar populations. Dietary patterns were extracted by applying principal component analyses to the dietary information collected from a sample of 3550 women recruited from seven screening centres belonging to the Spanish breast cancer (BC) screening network (Determinants of Mammographic Density in Spain (DDM-Spain) study). The resulting patterns were compared with three dietary patterns obtained from a previous Spanish case-control study on female BC (Epidemiological study of the Spanish group for breast cancer research (GEICAM: grupo Español de investigación en cáncer de mama)) using the dietary intake data of 973 healthy participants. The level of agreement between patterns was determined using both the congruence coefficient (CC) between the pattern loadings (considering patterns with a CC≥0·85 as fairly similar) and the linear correlation between patterns scores (considering as fairly similar those patterns with a statistically significant correlation). The conclusions reached with both methods were compared. This is the first study exploring the reproducibility of data-driven patterns from two studies and the first using the CC to determine pattern similarity. We were able to reproduce the EpiGEICAM Western pattern in the DDM-Spain sample (CC=0·90). However, the reproducibility of the Prudent (CC=0·76) and Mediterranean (CC=0·77) patterns was not as good. The linear correlation between pattern scores was statistically significant in all cases, highlighting its arbitrariness for determining pattern similarity. We conclude that the reproducibility of widely prevalent dietary patterns is better than the reproducibility of more population-specific patterns. More methodological studies are needed to establish an objective measurement and threshold to determine pattern similarity. This study was supported by Carlos III Institute of Health FIS(Spanish Public Health Research Fund: PI060386 FIS; PS09/00790 and PI15CIII/0029 research grants), the Spanish Ministryof Health (EC11-273), the Spanish Ministry of Economyand Competitiveness (IJCI-2014-20900), the Spanish Federationof Breast Cancer Patients (FECMA: EPY 1169-10) and theAssociation of Women with Breast Cancer from Elche (AMAC-MEC: EPY 1394/15). None of the funders had any role in thedesign, analysis or writing of this article.V.L.,N.A.,B.P.-G.andM.P.designedthestudy;A.C.,J.V.,C.S.,C.P.-P.,S.A.,M.E.,D.S.-T.,C.V.andC.S.-C.collectedthedataand/or prepared the database. A. C. performed statistical analysisand wrote the initial version of the manuscript that M. P. revised andcorrected in its different versions. All the authors have read andapproved thefinal version of the manuscript.The authors declare that there are no conflicts of interest. Sí

The Spanish Cancer Screening Network involves the participation of all regional programmes and has been working for over 20 years to co-ordinate strategies and implement quality assurance in current and new regional programmes. In colorectal cancer, the target population is the group aged 50-69 years, who are offered biennial testing using the faecal occult blood test in all programmes, with follow-up colonoscopy if the faecal occult blood test is positive. This article presents the main trends, indicators and differences by sex. The main indicators from 2006 to 2011 were analysed: coverage, participation rate, positivity rate, colonoscopy uptake and lesions detected. Annual trends were adjusted by sex and region. In 2011, coverage was 9.74% of the Spanish target population. A total of 1 001 669 first invitations were registered from 2006 to 2011 and 596 649 individuals participated in the programmes (43.83% participation rate). Results were positive in 30 544 individuals (5.47%), with the lowest positivity rate occurring in 2007 (3.06%) and the highest in 2011 (6.30%) (P

OBJECTIVE The use of some forms of hormone therapy (HT) is associated with an increase in mammographic density-a major risk factor for breast cancer. The role of isoflavones, however, is unclear. Here, we quantify the prevalence of HT and isoflavone use among postmenopausal Spanish women, determine associated risk factors, and explore the relationship between these therapies and mammographic density. METHODS This cross-sectional study included 2,754 postmenopausal women who underwent breast cancer screening in seven geographical areas. Mammographic density was evaluated using Boyd's semiquantitative scale. Multinomial logistic regression models were adjusted to assess risk factors associated with both therapies. Ordinal regression models were fitted to study the association between HT and isoflavone consumption with mammographic density. RESULTS The prevalence of ever-use of HT was 12%, whereas that of the current use was 2.3%. Isoflavone lifetime prevalence was 3.7%, and current use was 1.7%. The most common HT types were tibolone and estrogens. Surgical menopause, oral contraceptive use, educational level, population density, and years since menopause were positively associated with HT, whereas body mass index and parity were inversely associated. Mammographic density was not associated with current or past HT use. However, women who reported having consumed isoflavones in the past and those who started their use after menopause had a higher mammographic density when compared with never-users (odds ratio 1.98, 95% CI 1.21-3.25, P = 0.007; and odds ratio 1.60, 95% CI 1.01-2.53, P = 0.045 respectively). CONCLUSIONS Our results show a low prevalence of HT and isoflavone use in postmenopausal Spanish women. In this population, HT use was not associated with mammographic density, whereas some categories of isoflavone users had higher density.

BACKGROUND: Accumulated exposure to hormones and growth factors during early life may influence the future risk of breast cancer (BC). This study examines the influence of childhood-related, socio-demographic and anthropometric variables on BC risk, overall and by specific pathologic subtypes. METHODS: This is a case-control study where 1539 histologically-confirmed BC cases (23-85 years) and 1621 population controls, frequency matched by age, were recruited in 10 Spanish provinces. Perinatal and childhood-related characteristics were directly surveyed by trained staff. The association with BC risk, globally and according to menopausal status and pathologic subtypes, was evaluated using logistic and multinomial regression models, adjusting for tumor specific risk factors. RESULTS: Birth characteristics were not related with BC risk. However, women with high socioeconomic level at birth presented a decreased BC risk (OR=0.45; 95% CI=0.29-0.70), while those whose mothers were aged over 39 years at their birth showed an almost significant excess risk of hormone receptor positive tumors (HR+) (OR=1.35; 95% CI=0.99-1.84). Women who were taller than their girl mates before puberty showed increased postmenopausal BC risk (OR=1.26; 95% CI=1.03-1.54) and increased HR+ BC risk (OR=1.26; 95% CI=1.04-1.52). Regarding prepubertal weight, while those women who were thinner than average showed higher postmenopausal BC risk (OR=1.46; 95% CI=1.20-1.78), associated with HR+ tumors (OR=1.34; 95% CI=1.12-1.61) and with triple negative tumors (OR=1.56; 95% CI=1.03-2.35), those who were heavier than average presented lower premenopausal BC risk (OR=0.64; 95% CI=0.46-0.90) and lower risk of epidermal growth factor receptor positive tumors (OR=0.61; 95% CI=0.40-0.93). CONCLUSION: These data reflect the importance of hormones and growth factors in the early stages of life, when the mammary gland is in development and therefore more vulnerable to proliferative stimuli. The authors acknowledge funds provided by the Spanish Ministry of Economy and Competitiveness (Carlos III Institute of Health; PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI08/1770, PI08/0533, PI08/1359, PS09/00773, PS09/01286, PS09/01903, PS09/02078, PS09/01662, PI11/01403, PI11/01889, PI11/00226, PI11/01810, PI11/02213, PI14/01219 and Rio Hortega CM13/00232), the Catalan Government 2009SGR1489 & 2014SGR756-F, and, by the Fundación Marqués de Valdecilla (API 10/09), by the ICGC International Cancer Genome Consortium CLL, by the Junta de Castilla y León (LE22A10-2), by the Consejería de Salud of the Junta de Andalucía (PI-0571), by the Conselleria de Sanitat of the Generalitat Valenciana (AP 061/10), by the Recercaixa (2010ACUP 310), by the Regional Government of the Basque Country by European Commission grants FOOD-CT-2006-036224-HIWATE, and by the Spanish Association Against Cancer (AECC) Scientific Foundation.

Objetivos: Conocer los factores asociados a la satisfacción con la duración del proceso de valoración adicional en el cribado mamográfico. Métodos: Estudio transversal descriptivo y multivariado mediante encuesta telefónica a una muestra representativa de mujeres (N=316) participantes en el Programa de Prevención del Cáncer de Mama de la Comunidad Valenciana, que requirieron valoración adicional mediante pruebas complementarias para confirmar el diagnóstico. Análisis descriptivo mediante tablas de contingencia (pObjectives: To determine the factors associated with satisfaction with waiting times for further investigation in breast cancer screening. Methods: We carried out a cross-sectional study by telephone survey of a representative sample of women (N=316) participating in the breast cancer screening program of the autonomous region of Valencia (Spain) who required additional tests to confirm the diagnosis. Descriptive analysis was performed by contingency tables (p

Growth and development factors could contribute to the development of breast cancer associated with an increase in mammographic density. This study examines the influence of certain childhood-related, socio-demographic and anthropometric variables on mammographic density in adult woman. The study covered 3574 women aged 45-68 years, participating in breast cancer-screening programmes in seven Spanish cities. Based on a craniocaudal mammogram, blind, anonymous measurement of mammographic density was made by a single radiologist, using Boyd's semiquantitative scale. Data associated with the early stages of life were obtained from a direct survey. Ordinal logistic regression and generalised linear models were employed to estimate the association between mammographic density and the variables covered by the questionnaire. Screening programme was introduced as a random effects term. Age, number of children, body mass index (BMI) and other childhood-related variables were used as adjustment variables, and stratified by menopausal status. A total of 811 women (23%) presented mammographic density of over 50%, and 5% of densities exceeded 75%. Our results show a greater prevalence of high mammographic density in women with low prepubertal weight (OR: 1.18; 95% CI: 1.02-1.36); marked prepubertal height (OR: 1.25; 95% CI: 0.97-1.60) and advanced age of their mothers at their birth (>39 years: OR: 1.28; 95% CI: 1.03-1.60); and a lower prevalence of high mammographic density in women with higher prepubertal weight, low birth weight and earlier menarche. The influence of these early-life factors may be explained by greater exposure to hormones and growth factors during the development of the breast gland, when breast tissue would be particularly susceptible to proliferative and carcinogenic stimulus.

To evaluate the effect of radiologist experience on the risk of false-positive results in population-based breast cancer screening programmes.We evaluated 1,440,384 single-read screening mammograms, corresponding to 471,112 women aged 45-69 years participating in four Spanish programmes between 1990 and 2006. The mammograms were interpreted by 72 radiologists.The overall percentage of false-positive results was 5.85% and that for false-positives resulting in an invasive procedure was 0.38%. Both the risk of false-positives overall and of false-positives leading to an invasive procedure significantly decreased (p 0.001) with greater reading volume in the previous year: OR 0.77 and OR 0.78, respectively, for a reading volume 500-1,999 mammograms and OR 0.59 and OR 0.60 for a reading volume of14,999 mammograms with respect to the reference category (500). The risk of both categories of false-positives was also significantly reduced (p 0.001) as radiologists' years of experience increased: OR 0.96 and OR 0.84, respectively, for 1 year's experience and OR 0.72 and OR 0.73, respectively, for more than 4 years' experience with regard to the category of1 year's experience.Radiologist experience is a determining factor in the risk of a false-positive result in breast cancer screening.

Background: Mutation screening of BRCA1 and BRCA2 (BRCAs) genes is a time-consuming and costly procedure that demands faster and cheaper alternative methods for routine diagnostics. The present study is aimed at comparing the results obtained with screening mutations methods, conformation sensitive gel electrophoresis (CSGE) and high-resolution melting analysis (HRMA), for BRCAs attending to their specificity, sensitivity, reliability and cost-efficiency. Methods: We included 52 DNA samples of index patients from high-risk families. The mutational screening was performed by CSGE according to the Ganguly (1993) method and HRMA according to a modified De Leeneer (2008) method. The assays were performed in 384 well plates in the LightCycler 480 (Roche). All PCR products showing altered patterns were confirmed by sequencing. Results: The results obtained with the mutational study of BRCAs genes showed that HRMA exhibited higher sensitivity than CSGE as it was able to detect a wide mutational spectra of genetic variants in a larger number of samples. Aditionally, the combination of HRMA with hybiridization probes in a second step of the assay allows the specific confirmation of mutations. Furthermore, HRMA use less time, allowing the reduction of analysis time. Conclusions: HRMA offers clear advantages over CSGE for the mutation screening of BRCAs genes as it has greater sensitivity and higher efficiency and it is less time-consuming. (C) 2010 Elsevier B.V. All rights reserved.

The aim of the present study is to analyze the relationship of the incidence of mutations in the two major genes BRCA1 and BRCA2 conferring risk of breast cancer (BC) and ovarian cancer (OC) with the cancer burden in families and with the presence and age of onset of BC/OC. We included 704 index patients (IP) and 668 family members of the IP who tested positive for BRCA1/BRCA2 who were studied in the Program of Genetic Counselling in Cancer of the Valencia Community (Spain). We found 129 IPs with deleterious mutations (18.3%), 59 in BRCA1 and 70 in BRCA2, detecting 396 mutations in this kindred. The incidence of mutations and their distribution between BRCA1 and BRCA2 showed a significantly uneven incidence among the family groups (P < 0.001). We found 179 tumors in the 396 mutation carriers (45%) and detected only 11 cancers among the 272 non-mutation carriers (P < 0.001). No differences in the tumor prevalence or the age of onset of cancer between the genes among the mutation carriers were found. The mutation carriers showed a 50% probability of having BC/OC at a median age of 49 years (95% CI 46-52 years) and 78% at the age of 70 years (95% CI: 71-85%). In conclusion the family burden of BC and OC is strongly associated with the incidence of BRCAs mutations and could foretell which of the two BRCAs genes is more likely to have mutations. Mutation carriers have a 50% risk of having BC/OC by the age of 50 years.

Fundamento: Diferentes estudios de cribado de cáncer colorrectal (CCR) mediante test de sangre oculta en heces (TSOH) han mostrado reducciones significativas en la mortalidad por este tumor. El objetivo del trabajo es describir los resultados de la primera ronda del programa de cribado de CCR en población de riesgo medio de la Comunidad Valenciana y valorar su factibilidad y aceptabilidad. Métodos: Estudio piloto de cribado de cáncer colorrectal mediante la realización de TSOH bienal. Población diana: 106.000 personas de edades comprendidas entre 50-69 años (un subgrupo de 70-74 años), de 3 Departamentos de Salud que mediante correo postal fueron invitadas a participar. Alas que tuvieron TSOH positivo se les remitió al hospital para la realización de una colonoscopia. Se calcularon: las tasas de participación, de positividad del test, de aceptación de la colonoscopia, porcentaje colonoscopias realizadas y porcentaje y tasa de lesiones precursoras y cánceres invasores, así como el valor predicitivo positivo del TSOH como indicador de calidad del programa. Resultados: La participación alcanzada fue de 35.231 personas (35,70% de las invitadas). El número de test positivos del TSOH fue de 579 (1,64% del total de test analizados). Aceptaron hacerse colonoscopia 548 personas (tasa de aceptación: 94,69%). Se detectaron 61 CCR, 61 adenomas de alto riesgo y 153 adenomas de bajo riesgo (tasas del 1,77, 1,77 y 4,46% por 1.000 participantes). Los valores predictivos positivos para cáncer, adenomas de bajo riesgo y adenomas de alto riesgo fueron de 10,95%, 10,95% y 27,46% respectivamente. Conclusiones: Los indicadores del programa sugieren que un programa poblacional de cáncer colorrectal es factible en nuestro contesto ya que los indicadores de proceso obtenidos son similares a los que se dan en otros programas realizados en España y Europa.

BACKGROUND AND OBJECTIVE: The objective of the present study was to investigate the mutational spectrum of BRCA1 and BRCA2 in the Valencian Community, comparing this spectrum with that reported in Spain. We also analyze the association of the mutations with the family history of the selected families. PATIENTS AND METHOD: We analyzed the mutations in the BRCA1 and BRCA2 in 147 families with history of breast and/or ovarian cancer. The detection was based on the amplification of in frame and flanking regions of BRCA1 and BRCA2 genes by polymerase chain reaction, detection of the heteroduplex formed by conformation-sensitive gel electrophoresis and their characterization by sequencing. RESULTS: We identified 24 different pathogenic mutations in 50 out of the 147 families (34.0%; 23 in BRCA1 and 27 in BRCA2). The higher incidence of pathogenic mutations was observed in families with breast and ovarian cancer or with more than 3 cases of breast cancer. The most frequent mutations in BRCA1 were the c.187_188delAG, c.2080delA and the c.3889_3890delAG, whereas for BRCA2 the mutations with higher prevalence was observed for c.9254_9258delATCAT and the c.9204delCATCAGATTTATAT. We detected 5 pathogenic mutations (p.Y1429X in BRCA1 and c.1835insT, c.5025delT, c.6722delT and p.Q3156X in BRCA2) not reported in the Breast Cancer Information Core Database. Among them, the BRCA2 mutations c.1835insT and c.5025delT were recurrent and seemed to be characteristic of the population the Valencian Community. CONCLUSIONS: We detected pathogenic mutations in BRCA1 and BRCA2 genes in 34.0% of the families studied. The mutations c.1835insT and c.5025delT were 2 new recurrent pathogenic mutations in BRCA2 that seemed to be characteristic of the population of the Valencian Community. The study reports 5 new pathogenic mutations to the world spectrum of BRCA1 and BRCA2 mutations and other 5 mutations to the Spanish spectrum.

INTRODUCTION: Mammographic density (MD) is one of the strongest determinants of sporadic breast cancer (BC). In this study, we compared MD in BRCA1/2 mutation carriers and non-carriers from BRCA1/2 mutation-positive families and investigated the association between MD and BC among BRCA1/2 mutation carriers per type of mutation and tumor subtype. METHODS: The study was carried out in 1039 female members of BRCA1 and BRCA2 mutation-positive families followed at 16 Spanish Genetic Counseling Units. Participants' density was scored retrospectively from available mammograms by a single blinded radiologist using a 5-category scale (75 %). In BC cases, we selected mammograms taken prior to diagnosis or from the contralateral breast, whereas, in non-cases, the last screening mammogram was evaluated. MD distribution in carriers and non-carriers was compared using ordinal logistic models, and the association between MD and BC in BRCA1/2 mutation carriers was studied using logistic regression. Huber-White robust estimators of variance were used to take into account correlations between family members. A similar multinomial model was used to explore this association by BC subtype. RESULTS: We identified and scored mammograms from 341 BRCA1, 350 BRCA2 mutation carriers and 229 non-carriers. Compared to non-carriers, MD was significantly lower among BRCA2 mutation carriers (odds ratio (OR) =0.71; P-value=0.04), but not among BRCA1 carriers (OR=0.84; P-value=0.33). MD was associated with subsequent development BC (OR per category of MD=1.45; 95 % confidence interval=1.18-1.78, P-value

Mammographic density (MD) is an intermediate phenotype for breast cancer. Previous studies have identified genetic variants associated with MD; however, much of the genetic contribution to MD is unexplained. We conducted a two-stage genome-wide association analysis among the participants in the "Determinants of Density in Mammographies in Spain" study, together with a replication analysis in women from the Australian MD Twins and Sisters Study. Our discovery set covered a total of 3,351 Caucasian women aged 45 to 68 years, recruited from Spanish breast cancer screening centres. MD was blindly assessed by a single reader using Boyd's scale. A two-stage approach was employed, including a feature selection phase exploring 575,374 SNPs in 239 pairs of women with extreme phenotypes and a verification stage for the 183 selected SNPs in the remaining sample (2,873 women). Replication was conducted in 1,786 women aged 40 to 70 years old recruited via the Australian Twin Registry, where MD were measured using Cumulus-3.0, assessing 14 SNPs with a p value0.10 in stage 2. Finally, two genetic variants in high linkage disequilibrium with our best hit were studied using the whole Spanish sample. Evidence of association with MD was found for variant rs11205277 (OR = 0.74; 95% CI = 0.67-0.81; p = 1.33 × 10(-10) ). In replication analysis, only a marginal association between this SNP and absolute dense area was found. There were also evidence of association between MD and SNPs in high linkage disequilibrium with rs11205277, rs11205303 in gene MTMR11 (OR = 0.73; 95% CI = 0.66-0.80; p = 2.64 × 10(-11) ) and rs67807996 in gene OTUD7B (OR = 0.72; 95% CI = 0.66-0.80; p = 2.03 × 10(-11)). Our findings provide additional evidence on common genetic variations that may contribute to MD.

The task of breast density quantification is becoming increasingly relevant due to its association with breast cancer risk. In this work, a semi-automated and a fully automated tools to assess breast density from full-field digitized mammograms are presented. The first tool is based on a supervised interactive thresholding procedure for segmenting dense from fatty tissue and is used with a twofold goal: for assessing mammographic density(MD) in a more objective and accurate way than via visual-based methods and for labeling the mammograms that are later employed to train the fully automated tool. Although most automated methods rely on supervised approaches based on a global labeling of the mammogram, the proposed method relies on pixel-level labeling, allowing better tissue classification and density measurement on a continuous scale. The fully automated method presented combines a classification scheme based on local features and thresholding operations that improve the performance of the classifier. A dataset of 655 mammograms was used to test the concordance of both approaches in measuring MD. Three expert radiologists measured MD in each of the mammograms using the semi-automated tool (DM-Scan). It was then measured by the fully automated system and the correlation between both methods was computed. The relation between MD and breast cancer was then analyzed using a case-control dataset consisting of 230 mammograms. The Intraclass Correlation Coefficient (ICC) was used to compute reliability among raters and between techniques. The results obtained showed an average ICC = 0.922 among raters when using the semi-automated tool, whilst the average correlation between the semi-automated and automated measures was ICC = 0.838. In the case-control study, the results obtained showed Odds Ratios (OR) of 1.38 and 1.50 per 10% increase in MD when using the semi-automated and fully automated approaches respectively. It can therefore be concluded that the automated and semi-automated MD assessments present a good correlation. Both the methods also found an association between MD and breast cancer risk, which warrants the proposed tools for breast cancer risk prediction and clinical decision making. A full version of the DM-Scan is freely available. (C) 2014 Elsevier Ireland Ltd. All rights reserved., This work was supported by research grants from Gent per Gent Fund (EDEMAC Project); Spain's Health Research Fund (Fondo de Investigacion Santiaria) (PI060386 & FIS PS09/00790); Spanish MICINN grants TIN2009-14205-C04-02 and Consolider-Ingenio 2010: MIPRCV (CSD2007-00018); Spanish Federation of Breast Cancer Patients (Federacion Espanola de Cancer de Mama) (FECMA 485 EPY 1170-10). The English revision of this paper was funded by the Universitat Politecnica de Valencia, Spain.

We developed a semi-automated tool to assess mammographic density (MD), a phenotype risk marker for breast cancer (BC), in full-field digital images and evaluated its performance testing its reproducibility, comparing our MD estimates with those obtained by visual inspection and using Cumulus, verifying their association with factors that influence MD, and studying the association between MD measures and subsequent BC risk. Three radiologists assessed MD using DM-Scan, the new tool, on 655 processed images (craniocaudal view) obtained in two screening centers. Reproducibility was explored computing pair-wise concordance correlation coefficients (CCC). The agreement between DM-Scan estimates and visual assessment (semi- uantitative scale, 6 categories) was quantified computing weighted kappa statistics (quadratic weights). DM-Scan and Cumulus readings were compared using CCC. Variation of DM-Scan measures by age, body mass index (BMI) and other MD modifiers was tested in regression mixed models with mammographic device as a random-effect term. The association between DM-Scan measures and subsequent BC was estimated in a case control study. All BC cases in screening attendants (2007 2010) at a center with full-field digital mammography were matched by age and screening year with healthy controls (127 pairs). DM-Scan was used to blindly assess MD in available mammograms (112 cases/119 controls). Unconditional logistic models were fitted, including age, menopausal status and BMI as confounders. DM-Scan estimates were very reliable (pairwise CCC: 0.921, 0.928 and 0.916). They showed a reasonable agreement with visual MD assessment (weighted kappa ranging 0.79-0.81). DM-Scan and Cumulus measures were highly concordant (CCC ranging 0.80-0.84), but ours tended to be higher (4%-5% on average). As expected, DM-Scan estimates varied with age, BMI, parity and family history of BC. Finally, DM-Scan measures were significantly associated with BC (p-trend=0.005). Taking MD=29%=3.10 (95% CI=1.35-7.14). Our results confirm that DM-Scan is a reliable tool to assess MD in full-field digital mammograms., This work was supported by research grants from Spain's Health Research Fund (Fondo de INvestigacion Santiaria) (PI060386 & PI09/1230); Gent per Gent Fund (EDEMAC Project) and the Spanish Federation of Breast Cancer Patients (Federacion Espanola de Cancer de Mama) (FECMA 485 EPY 1170-10).

High mammographic density (MD) is used as a phenotype risk marker for developing breast cancer. During pregnancy and lactation the breast attains full development, with a cellular-proliferation followed by a lobular-differentiation stage. This study investigates the influence of obstetric factors on MD among pre- and post-menopausal women. We enrolled 3,574 women aged 45-68 years who were participating in breast cancer screening programmes in seven screening centers. To measure MD, blind anonymous readings were taken by an experienced radiologist, using craniocaudal mammography and Boyd's semiquantitative scale. Demographic and reproductive data were directly surveyed by purpose-trained staff at the date of screening. The association between MD and obstetric variables was quantified by ordinal logistic regression, with screening centre introduced as a random effect term. We adjusted for age, number of children and body mass index, and stratified by menopausal status. Parity was inversely associated with density, the probability of having high MD decreased by 16% for each new birth (P value < 0.001). Among parous women, a positive association was detected with duration of lactation [>9 months: odds ratio (OR) = 1.33; 95% confidence interval (CI) = 1.02-1.72] and weight of first child (>3,500 g: OR = 1.32; 95% CI = 1.12-1.54). Age at first birth showed a different effect in pre- and post-menopausal women (P value for interaction = 0.030). No association was found among pre-menopausal women. However, in post-menopausal women the probability of having high MD increased in women who had their first child after the age of 30 (OR = 1.53; 95% CI = 1.17-2.00). A higher risk associated with birth of twins was also mainly observed in post-menopausal women (OR = 2.02; 95% CI = 1.18-3.46). Our study shows a greater prevalence of high MD in mothers of advanced age at first birth, those who had twins, those who have breastfed for longer periods, and mothers whose first child had an elevated birth weight. These results suggest the influence of hormones and growth factors over the proliferative activity of the mammary gland. This study was supported by the Research Grant FIS PI060386 from Spain’s Health Research Fund (Fondo de Investigación Sanitaria); the EPY 1306/06 Collaboration Agreement between Astra-Zeneca and the Carlos III Institute of Health (Instituto de Salud Carlos III); and a grant from the Spanish Federation of Breast Cancer patients (FECMA 485 EPY 1170-10). Sí

Several studies evaluating colorectal cancer (CRC) screening with fecal occult blood testing (FOBT) have reported a significant reduction in mortality from this tumor. The study aims to describe the results of the first round of the CRC screening program in medium-risk population of Valencia and assessing their feasibility and acceptability.Colorectal cancer screening pilot study using biennial FOBT. All residents (106,000 Inhabitants) between 50 and 69 years old (a subgroup of 70-74 years), from 3 selected health departments (04, 07 and 13) were invited by mail to participate. The individuals with FOBT positive were referred to hospital for colonoscopy. The following rates were calculated as indicators of program quality: the participation rate, positive FOBT rate, acceptance rate of colonoscopy, and detection rate of low and high-risk adenomas and invasive cancers, and positive predictive value of FOBT.The participation was 35,231 individuals (35.70%). The number of FOBT positive was 579 (1.64% of total analyzed test), 548 people agreed colonoscopy (acceptance rate: 94.69%). 61 CRC were detected, 61 and 153 High-Risk and Low-Risk Adenomas (rates of 1.77, 1.77 and 4.46% per 1,000 participants). The positive predictive values for cancer, low-risk and high risk adenomas were 10.95%, 10.95%, and 27.46% respectively.The program indicators suggest that a population program of colorectal cancer is feasible in our community as the process indicators obtained are similar to those given in other programs in Spain and Europe.

To determine the factors associated with satisfaction with waiting times for further investigation in breast cancer screening.We carried out a cross-sectional study by telephone survey of a representative sample of women (N=316) participating in the breast cancer screening program of the autonomous region of Valencia (Spain) who required additional tests to confirm the diagnosis. Descriptive analysis was performed by contingency tables (p0.05) and multivariate association by odds ratios (OR) of logistic regression models (95%CI).Satisfaction with the waiting time was 78.6%. A higher risk of dissatisfaction was found in women from a "high" social class (OR=3.17; 95% CI: 1.10-9.14), those who perceived that the waiting time was "more than 2 weeks", both "since the notification of the need for further investigation until completion of the first test" (OR=15,54; 95%CI: 5,87-41,12) and "since the completion of the last test until notification of the final result" (OR=11.57; 95% CI: 2.96-45.19), and in women who experienced the attention as "worse than expected" (OR=15.40; 95% CI: 1.41-168.64). The maximum waiting time acceptable to the highest percentage of women was "up to 1 week" for each waiting period (n=47, 73.5%; n=14, 45.2%).Waiting times of no more than 1 week and never more than 2 weeks for each waiting period are recommended. Women should be given an approximate waiting time, paying special attention to women aged 45 to 54 years attending their initial screening.

High mammographic density (MD) is a phenotype risk marker for breast cancer. Body mass index (BMI) is inversely associated with MD, with the breast being a fat storage site. We investigated the influence of abdominal fat distribution and adult weight gain on MD, taking age, BMI and other confounders into account. Because visceral adiposity and BMI are associated with breast cancer only after menopause, differences in pre- and post-menopausal women were also explored. We recruited 3,584 women aged 45–68 years within the Spanish breast cancer screening network. Demographic, reproductive, family and personal history data were collected by purpose-trained staff, who measured current weight, height, waist and hip circumferences under the same protocol and with the same tools. MD was assessed in the left craniocaudal view using Boyd’s Semiquantitative Scale. Association between waist-to-hip ratio, adult weight gain (difference between current weight and self-reported weight at 18 years) and MD was quantified by ordinal logistic regression, with random center-specific intercepts. Models were adjusted for age, BMI, breast size, time since menopause, parity, family history of breast cancer and hormonal replacement therapy use. Natural splines were used to describe the shape of the relationship between these two variables and MD. Waist-to-hip ratio was inversely associated with MD, and the effect was more pronounced in pre-menopausal (OR = 0.53 per 0.1 units; 95 % CI = 0.42–0.66) than in post-menopausal women (OR = 0.73; 95 % CI = 0.65–0.82) (P of heterogeneity = 0.010). In contrast, adult weight gain displayed a positive association with MD, which was similar in both groups (OR = 1.17 per 6 kg; 95 % CI = 1.11–1.23). Women who had gained more than 24 kg displayed higher MD (OR = 2.05; 95 % CI = 1.53–2.73). MD was also evaluated using Wolfe’s and Tabar’s classifications, with similar results being obtained. Once BMI, fat distribution and other confounders were considered, our results showed a clear dose–response gradient between the number of kg gained during adulthood and the proportion of dense tissue in the breast.

ResumenObjetivosConocer los factores asociados a la satisfacción con la duración del proceso de valoración adicional en el cribado mamográfico.MétodosEstudio transversal descriptivo y multivariado mediante encuesta telefónica a una muestra representativa de mujeres (N=316) participantes en el Programa de Prevención del Cáncer de Mama de la Comunidad Valenciana, que requirieron valoración adicional mediante pruebas complementarias para confirmar el diagnóstico. Análisis descriptivo mediante tablas de contingencia (p

Epidemiologic evidence on the association between vitamin D and breast cancer is still inconclusive. This study analyzes the association between serum 25-hydroxyvitamin D (25(OH)D) and breast cancer risk by pathologic subtype, stage at diagnosis and specific breast cancer risk factors. We conducted a population-based multicase-control study where 546 histologically-confirmed breast cancer cases and 558 population controls, frequently matched by geographic area, age and body mass index, were recruited in 12 Spanish provinces (MCC-Spain). Information was collected by a questionnaire and plasma 25(OH)D was measured by solid-phase extraction on-line coupled to liquid chromatography-tandem mass spectrometry (SPE-LC-MS/MS). Odds ratios and 95% confidence intervals were calculated using logistic and multinomial mixed regression models. We found a clear protective effect between 25(OH)D levels and breast cancer risk, with a significant dose-response trend (OR per 10?nmol/L?=?0.88; 95%CI?=?0.82-0.94). While no differences were observed between pre and postmenopausal women, stage at diagnosis, or across strata of the main breast cancer risk factors, the protection was more pronounced for triple negative tumors (OR per 10?nmol/L?=?0.64; p-heterogeneity?=?0.038). Similar results were observed when only cases sampled in the first month after diagnosis were considered. The protective effect of vitamin D on breast cancer risk may be subtype specific, being stronger for more aggressive tumors, which provides a new approach to prevent this disease. The study was funded by Carlos III Institute of Health grants (PI12/00488, PI12/00265, PI12/00715, PI12/01270, PI09/00773 and PI08/1770), by the Spanish Ministry of Health (EC11-273), by the Spanish Ministry of Economy and Competitiveness (IJCI-2014-20900) and by Consejería de Salud de la Junta de Andalucía (PI-0571-2009) competitive calls including peer review for scientific quality. Additional funding was provided by the Spanish Federation of Breast Cancer Patients (FECMA: EPY 1169-10), the Association of Women with Breast Cancer from Elche (AMACMEC: EPY 1394/15), the Marqués de Valdecilla foundation (grant API 10/09), and by Acción Transversal del Cancer, approved by the Spanish Ministry Council on October 11, 2007. None of the funders played any role in conducting research or writing the paper. This article presents independent research. The views expressed are those of the authors and not necessarily those of the Carlos III Institute of Health.