First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study.

BACKGROUND Phase-IV, open-label, single-arm study (NCT01203917) to assess efficacy and safety/tolerability of first-line gefitinib in Caucasian patients with stage IIIA/B/IV, epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). METHODS Treatment: gefitinib 250 mg day(-1) until progression. Primary endpoint: objective response rate (ORR). Secondary endpoints: disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety/tolerability. Pre-planned exploratory objective: EGFR mutation analysis in matched tumour and plasma samples. RESULTS Of 1060 screened patients with NSCLC (859 known mutation status; 118 positive, mutation frequency 14%), 106 with EGFR sensitising mutations were enrolled (female 70.8%; adenocarcinoma 97.2%; never-smoker 64.2%). At data cutoff: ORR 69.8% (95% confidence interval (CI) 60.5-77.7), DCR 90.6% (95% CI 83.5-94.8), median PFS 9.7 months (95% CI 8.5-11.0), median OS 19.2 months (95% CI 17.0-NC; 27% maturity). Most common adverse events (AEs; any grade): rash (44.9%), diarrhoea (30.8%); CTC (Common Toxicity Criteria) grade 3/4 AEs: 15%; SAEs: 19%. Baseline plasma 1 samples were available in 803 patients (784 known mutation status; 82 positive; mutation frequency 10%). Plasma 1 EGFR mutation test sensitivity: 65.7% (95% CI 55.8-74.7). CONCLUSION First-line gefitinib was effective and well tolerated in Caucasian patients with EGFR mutation-positive NSCLC. Plasma samples could be considered for mutation analysis if tumour tissue is unavailable.

Selection of Reference Genes for Quantitative Real Time PCR (qPCR) Assays in Tissue from Human Ascending Aorta.

Dilatation of the ascending aorta (AAD) is a prevalent aortopathy that occurs frequently associated with bicuspid aortic valve (BAV), the most common human congenital cardiac malformation. The molecular mechanisms leading to AAD associated with BAV are still poorly understood. The search for differentially expressed genes in diseased tissue by quantitative real-time PCR (qPCR) is an invaluable tool to fill this gap. However, studies dedicated to identify reference genes necessary for normalization of mRNA expression in aortic tissue are scarce. In this report, we evaluate the qPCR expression of six candidate reference genes in tissue from the ascending aorta of 52 patients with a variety of clinical and demographic characteristics, normal and dilated aortas, and different morphologies of the aortic valve (normal aorta and normal valve n = 30; dilated aorta and normal valve n = 10; normal aorta and BAV n = 4; dilated aorta and BAV n = 8). The expression stability of the candidate reference genes was determined with three statistical algorithms, GeNorm, NormFinder and Bestkeeper. The expression analyses showed that the most stable genes for the three algorithms employed were CDKN1β, POLR2A and CASC3, independently of the structure of the aorta and the valve morphology. In conclusion, we propose the use of these three genes as reference genes for mRNA expression analysis in human ascending aorta. However, we suggest searching for specific reference genes when conducting qPCR experiments with new cohort of samples.

Efectividad de una estrategia de intervención preventiva, basada en entrevistas telefónicas estructuradas, en una población laboral con riesgo cardiovascular moderado/alto.

OBJECTIVE This study assesses the effectiveness of a structured telephone survey on cardiovascular prevention, in modifying lifestyle, on cardiovascular risk parameters, percentage of smoking cessation and overall cardiovascular risk (CVR). DESIGN Quasi-experimental study of preventive intervention. SETTING Ibermutuamur (Spanish Accident and Health Insurance Company). Centres established throughout Spain. PARTICIPANTS A total of 4,792 workers with moderate/high cardiovascular risk who had agreed to be contacted by phone. Subjects with a previous diagnosis of cardiovascular disease and those receiving treatment for hypertension, hypercholesterolemia or diabetes were excluded. INTERVENTION A final total of 3,085 workers were contacted and were followed up by telephone surveys on the first, fourth and eighth month after the initial check up (CU) in order to emphasise cardiovascular health advice (Group A); we failed to contact 1,707 workers, who only attended the baseline and one year CUs (Group B). PRINCIPAL OUTCOMES: CUs included medical records and physical examination, with two blood pressure measurements, Body Mass Index (BMI), and biochemical parameters. Cardiovascular risk was stratified following the European cardiovascular SCORE. Individuals with a relative risk higher than 4 were also considered as high-risk. All workers were informed about their cardiovascular risk profile (CVRF) and healthy cardiovascular lifestyle measures. They were also given a letter for their General Practitioner (GP) to inform them on the worker's cardiovascular risk level. RESULTS A total of 71.5% of the workers were over 45 years, 95.0% males, 76.6% manual workers ("Blue Collar") and 69.7% smokers. Both groups showed improvement in lipid parameters, blood pressure, smoking cessation and overall cardiovascular risk in the second CU. There were significant differences in favour of Group A as regards blood pressure, lipids (except HDL cholesterol), BMI, glycaemia, smoking cessation (A: 23.5%/B: 19.44%, P=0.001) and CVR stratum improvement (A: 46.6%/B: 37.7%, P=0.0001). The large majority (85%) of workers read preventive recommendations; 33% knew their risk level and 73% knew their CVRF. 52.9% gave the letter to the GP, which led them to start therapies on diet (47%), hypertension (19.5%), dyslipidaemia (16.7%), diabetes (4.4%) and smoking (2.9%) and no changes were made in 36.5% of cases. CONCLUSIONS The results of this study suggests that cardiovascular prevention strategy based on structured telephone surveys on high/moderate CVR subjects to promote lifestyle changes could be effective at reducing CVR. A clinical trial is required for confirmation. Sending information on CVRF following routine medial CUs and Primary Care involvement, could contribute to the positive changes observed.

Structural and functional brain changes in middle-aged type 2 diabetic patients: a cross-sectional study.

BACKGROUND Type 2 diabetes mellitus (T2DM) is an emerging risk factor for cognitive impairment. Whether this impairment is a direct effect of this metabolic disorder on brain function, a consequence of vascular disease, or both, remains unknown. Structural and functional neuroimaging studies in patients with T2DM could help to elucidate this question. OBJECTIVE We designed a cross-sectional study comparing 25 T2DM patients with 25 age- and gender-matched healthy control participants. Clinical information, APOE genotype, lipid and glucose analysis, structural cerebral magnetic resonance imaging including voxel-based morphometry, and F-18 fluorodeoxyglucose positron emission tomography were obtained in all subjects. METHODS Gray matter densities and metabolic differences between groups were analyzed using statistical parametric mapping. In addition to comparing the neuroimaging profiles of both groups, we correlated neuroimaging findings with HbA1c levels, duration of T2DM, and insulin resistance measurement (HOMA-IR) in the diabetic patients group. Results: Patients with T2DM presented reduced gray matter densities and reduced cerebral glucose metabolism in several fronto-temporal brain regions after controlling for various vascular risk factors. Furthermore, within the T2DM group, longer disease duration, and higher HbA1c levels and HOMA-IR were associated with lower gray matter density and reduced cerebral glucose metabolism in fronto-temporal regions. CONCLUSION In agreement with previous reports, our findings indicate that T2DM leads to structural and metabolic abnormalities in fronto-temporal areas. Furthermore, they suggest that these abnormalities are not entirely explained by the role of T2DM as a cardiovascular risk factor.

Drug-induced autoimmune liver disease: A diagnostic dilemma of an increasingly reported disease.

The aetiology of autoimmune hepatitis (AIH) is uncertain but the disease can be triggered in susceptible patients by external factors such as viruses or drugs. AIH usually develops in individuals with a genetic background mainly consisting of some risk alleles of the major histocompatibility complex (HLA). Many drugs have been linked to AIH phenotypes, which sometimes persist after drug discontinuation, suggesting that they awaken latent autoimmunity. At least three clinical scenarios have been proposed that refers to drug- induced autoimmune liver disease (DIAILD): AIH with drug-induced liver injury (DILI); drug induced-AIH (DI-AIH); and immune mediated DILI (IM-DILI). In addition, there are instances showing mixed features of DI-AIH and IM-DILI, as well as DILI cases with positive autoantibodies. Histologically distinguishing DILI from AIH remains a challenge. Even more challenging is the differentiation of AIH from DI-AIH mainly relying in histological features; however, a detailed standardised histologic evaluation of large cohorts of AIH and DI-AIH patients would probably render more subtle features that could be of help in the differential diagnosis between both entities. Growing information on the relationship of drugs and AIH is being available, being drugs like statins and biologic agents more frequently involved in cases of DIAILD. In addition, there is some evidence on the fact that patients diagnosed with DIAILD may have had a previous episode of hepatotoxicity. Further collaborative studies in DIAILD will strengthen the knowledge and understanding of this intriguing and complex disorder which might represent different phenotypes across the spectrum of disease.

Trends in self-reported past alcoholic beverage consumption and ethanol intake from 1950 to 1995 observed in eight European countries participating in the European Investigation into Cancer and Nutrition (EPIC).

OBJECTIVE To describe the trends of self-reported past consumption of alcoholic beverages and ethanol intake from 1950 to 1995 within the European Prospective Investigation into Cancer and Nutrition (EPIC). DESIGN Data on consumption of beer/cider, wine and liqueur/spirits were obtained retrospectively at age 20, 30 and 40 years to calculate average consumption and ethanol intake for the time periods 1950-1975 (at age 20), 1960-1985 (at age 30) and 1970-1995 (at age 40). Regression analysis was conducted with the time period data to assess trends in past alcoholic beverage consumption and ethanol intake with time. SETTING The EPIC project. SUBJECTS In total, 392 064 EPIC participants (275 249 women and 116 815 men) from 21 study centres in eight European countries. RESULTS Generally, increases in beer/cider consumption were observed for most EPIC centres for 1950-1975, 1960-1985 and 1970-1995. Trends in wine consumption differed according to geographical location: downward trends with time were observed for men in southern European EPIC centres, upward trends for those in middle/northern European study centres. For women, similar but less pronounced trends were observed. Because wine consumption was the major contributor to ethanol intake for both men and women in most study centres, time trends for ethanol intake showed a similar geographical pattern to that of wine consumption. CONCLUSION The different trends in alcoholic beverage consumption and ethanol intake suggest that information depicting lifetime history of ethanol intake should be included in analyses of the relationship between ethanol and chronic diseases, particularly in multi-centre studies such as EPIC.

Nuevos datos sobre fibrilación auricular, observaciones al estudio OFRECE. Respuesta

We appreciate the interest shown by Vidal-Pérez et al. in our article published recently in Revista Española de Cardiología,1 which provides us with an opportunity to present some interesting additional information not included in the article itself. We agree on the importance of knowing the thromboembolic risk of the population included in the OFRECE study, both for patients with a diagnosis of atrial fibrillation and for the general population. In our study, the mean (standard deviation) CHADS2 and CHAD2DS2-VASc of patients with atrial fibrillation was 2.3 (1.3) and 3.8 (1.6), respectively. In the general population, the mean (standard deviation) CHADS2 and CHAD2DS2-VASc of patients with atrial fibrillation was 0.8 (1) and 1.8 (1.5), respectively. The distribution of both scales is in agreement with that of the Val-FAAP and AFABE studies,2, 3 although the similarity is greater in the 2 population-based studies (Figure). These data are, we believe, relevant because they show that the level of risk in the population with atrial fibrillation is very similar to that of the populations included in clinical trials with new oral anticoagulants. In addition, an increasing body of evidence suggests that thromboembolic risk, as measured with these scales in the population without a diagnosis of atrial fibrillation, is associated with the onset of events.

La violencia contra la mujer en la pareja como factor asociado a una mala salud física y psíquica.

OBJECTIVE: To study the impact of intimate partner violence (IPV) on women's physical and psychological health. DESIGN: Cross-sectional study. SETTING:Primary care centers in 3 Andalusian provinces. PATIENTS: A total of 425 women, aged 18 to 65 years, were recruited following the same randomisation process in 6 primary care centers. MEASUREMENTS: A self-administered structured questionnaire for this study was used to gather the information. As well as sociodemographic variables, the instrument included questions about IPV, physical health indicators (chronic disease and type, lifetime surgeries, days in bed), psychological health (psychological morbidity, use of tranquilizers, antidepressants, pain killers, alcohol and recreational drugs), self-perceived health and social support. RESULTS: Of 425 women, 31.5% ever experienced any type of partner violence. Women experiencing IPV were more likely to suffer a chronic disease. IPV was significantly associated with a number of adverse health outcomes, including spending more than 7 days in bed in the last three months (ORa=2.96; CI 95%, 1.00-8.76), psychological morbidity (ORa=2.68; CI 95%, 1.60-4.49) and worse self-perceived health (ORa=1.89; CI 95%, 1.04-3.43), after controlling for potential confounding variables. CONCLUSION: This study shows that ever experiencing IPV is associated with a worse psychological and self-perceived health. Physical injuries are not the only "evidence" of the presence of IPV. Primary health care professionals are in a privileged position to help women who are abused by their partners.

Prospective registry of symptomatic severe aortic stenosis in octogenarians: a need for intervention.

OBJECTIVE To study the factors associated with choice of therapy and prognosis in octogenarians with severe symptomatic aortic stenosis (AS). STUDY DESIGN Prospective, observational, multicenter registry. Centralized follow-up included survival status and, if possible, mode of death and Katz index. SETTING Transnational registry in Spain. SUBJECTS We included 928 patients aged ≥80 years with severe symptomatic AS. INTERVENTIONS Aortic-valve replacement (AVR), transcatheter aortic-valve implantation (TAVI) or conservative therapy. MAIN OUTCOME MEASURES All-cause death. RESULTS Mean age was 84.2 ± 3.5 years, and only 49.0% were independent (Katz index A). The most frequent planned management was conservative therapy in 423 (46%) patients, followed by TAVI in 261 (28%) and AVR in 244 (26%). The main reason against recommending AVR in 684 patients was high surgical risk [322 (47.1%)], other medical motives [193 (28.2%)], patient refusal [134 (19.6%)] and family refusal in the case of incompetent patients [35 (5.1%)]. The mean time from treatment decision to AVR was 4.8 ± 4.6 months and to TAVI 2.1 ± 3.2 months, P < 0.001. During follow-up (11.2-38.9 months), 357 patients (38.5%) died. Survival rates at 6, 12, 18 and 24 months were 81.8%, 72.6%, 64.1% and 57.3%, respectively. Planned intervention, adjusted for multiple propensity score, was associated with lower mortality when compared with planned conservative treatment: TAVI Hazard ratio (HR) 0.68 (95% confidence interval [CI] 0.49-0.93; P = 0.016) and AVR HR 0.56 (95% CI 0.39-0.8; P = 0.002). CONCLUSION Octogenarians with symptomatic severe AS are frequently managed conservatively. Planned conservative management is associated with a poor prognosis.

Salvage radiosurgery for selected patients with recurrent malignant gliomas.

Purpose. To analyse the survival after salvage radiosurgery and to identify prognostic factors. Methods. We retrospectively reviewed 87 consecutive patients, with recurrent high-grade glioma, that underwent stereotactic radiosurgery between 1997 and 2010. We evaluated the survival after initial diagnosis and after reirradiation. The prognostic factors were analysed by bivariate and multivariate Cox regression model. Results. The median age was 48 years old. The primary histology included anaplastic astrocytoma (47%) and glioblastoma (53%). A margin dose of 18 Gy was administered in the majority of cases (74%). The median survival after initial diagnosis was 21 months (39 months for anaplastic astrocytoma and 18.5 months for glioblastoma) and after reirradiation it was 10 months (17 months for anaplastic astrocytoma and 7.5 months for glioblastoma). In the bivariate analyses, the prognostic factors significantly associated with survival after reirradiation were age, tumour and treatment volume at recurrence, recursive partitioning analyses classification, Karnofsky performance score, histology, and margin to the planning target volume. Only the last four showed significant association in the multivariate analyses. Conclusion. stereotactic radiosurgery is a safe and may be an effective treatment option for selected patients diagnosed with recurrent high-grade glioma. The identified prognostic factors could help individualise the treatment.

Plasmapheresis as treatment for hyperlipidemic pancreatitis.

BACKGROUND Severe hypertriglyceridemia with an accumulation of chylomicrons and triglyceride figures >1000 mg/dL can cause acute pancreatitis, a potentially fatal complication. The option of rapid reduction in triglyceride concentrations is attractive and possible with plasmapheresis. METHODS We present the results of an analysis of 11 patients admitted to the intensive care unit with severe hypertriglyceridemic pancreatitis and treated with plasmapheresis. The procedure was repeated until serum triglycerides were below 1000 mg/dL. We recorded anthropometric, clinical data as well as final outcome. RESULTS In eight patients a single plasma exchange was sufficient to reduce triglyceride figures <1000 mg/dL. Only three patients died, all with the worst severity indexes and who experienced the longest delay before the procedure. CONCLUSIONS Our results, together with a review of the literature, confirm the need for a randomized clinical trial to compare conventional treatment vs. plasmapheresis in patients with severe hypertriglyceridemic pancreatitis.

Protocolo de tratamiento de la deficiencia de vitamina D.

Vitamin D deficiency is highly prevalent worldwide and in our country estimated un 60% in the adult population and closer to 80% in the elderly population and the fractured hip.

Association of 25-hydroxyvitamin D with metabolic syndrome in patients with psoriasis: a case-control study.

Vitamin D deficiency is associated with higher cardiovascular risk and metabolic syndrome (MeS) criteria. The main objective of this study was to analyse the association of 25-hydroxyvitamin D (25-OHD) serum levels with MeS (National Cholesterol Education Program-Adult Treatment Panel-III criteria) in 46 Spanish patients with psoriasis, but without arthritis and systemic treatment, and 46 control subjects, matched by sex and age. The patients with psoriasis showed significantly lower level of 25-OHD than controls (30.5 vs. 38.3 ng/ml; p = 0.0001). Patients with MeS had significantly lower serum levels of 25-OHD than those without MeS (24.1 ± 7.5 vs. 32.8 ± 8.9, p = 0.007), and a negative correlation was found between 25-OHD and waist circumference, diastolic blood pressure, fasting glucose, and triglyceridaemia. In the control group no significant correlation between 25-OHD and MeS was found. Al-though the sample was small, our results suggest a potential protective role for 25-OHD in the metabolic profile of patients with psoriasis without arthritis.

Experiencias y cambios en los padres de niños con parálisis cerebral infantil: estudio cualitativo.

BACKGROUND The diagnosis of infant cerebral palsy (ICP) is a traumatic event that can provoke multiple effects and changes in the family. The aim of the study is to discover the difficulties that parents face in the process of parenting, especially in the initial period following diagnosis. METHODS A qualitative study was carried out through semi-structured interviews. Sixteen mothers and fathers whose children were diagnosed with cerebral palsy participated in the study. Data analysis was performed with Atlas.ti 6.2 software following a strategy of open coding. RESULTS The reception of the diagnosis is perceived as an unexpected event that makes parents change expectations and hopes related to their children. The mode of relation with the child with ICP is different from that with other children as parents are more focused on the possibility of improvement and the future evolution of their child. Changes in different aspects of the lives of these parents are shown, such as demands on time, their economic and labour situation, as well as the relationship of the couple. CONCLUSIONS In providing care for children with cerebral palsy it is necessary to take the problems of the parents into account, especially in the initial period after diagnosis. The process of parenting a child with cerebral palsy entails many changes in the family so a global perspective is needed to organize interventions.

Tuberculosis in migrant populations. A systematic review of the qualitative literature.

BACKGROUND The re-emergence of tuberculosis (TB) in low-incidence countries and its disproportionate burden on immigrants is a public health concern posing specific social and ethical challenges. This review explores perceptions, knowledge, attitudes and treatment adherence behaviour relating to TB and their social implications as reported in the qualitative literature. METHODS Systematic review in four electronic databases. Findings from thirty selected studies extracted, tabulated, compared and synthesized. FINDINGS TB was attributed to many non-exclusive causes including air-born transmission of bacteria, genetics, malnutrition, excessive work, irresponsible lifestyles, casual contact with infected persons or objects; and exposure to low temperatures, dirt, stress and witchcraft. Perceived as curable but potentially lethal and highly contagious, there was confusion around a condition surrounded by fears. A range of economic, legislative, cultural, social and health system barriers could delay treatment seeking. Fears of deportation and having contacts traced could prevent individuals from seeking medical assistance. Once on treatment, family support and "the personal touch" of health providers emerged as key factors facilitating adherence. The concept of latent infection was difficult to comprehend and while TB screening was often seen as a socially responsible act, it could be perceived as discriminatory. Immigration and the infectiousness of TB mutually reinforced each another exacerbating stigma. This was further aggravated by indirect costs such as losing a job, being evicted by a landlord or not being able to attend school. CONCLUSIONS Understanding immigrants' views of TB and the obstacles that they face when accessing the health system and adhering to a treatment programme-taking into consideration their previous experiences at countries of origin as well as the social, economic and legislative context in which they live at host countries- has an important role and should be considered in the design, evaluation and adaptation of programmes.