Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by Paclitaxel for early breast cancer.

BACKGROUND Taxanes are among the most active drugs for the treatment of metastatic breast cancer, and, as a consequence, they have also been studied in the adjuvant setting. METHODS After breast cancer surgery, women with lymph node-positive disease were randomly assigned to treatment with fluorouracil, epirubicin, and cyclophosphamide (FEC) or with FEC followed by weekly paclitaxel (FEC-P). The primary endpoint of study-5-year disease-free survival (DFS)-was assessed by Kaplan-Meier analysis. Secondary endpoints included overall survival and analysis of the prognostic and predictive value of clinical and molecular (hormone receptors by immunohistochemistry and HER2 by fluorescence in situ hybridization) markers. Associations and interactions were assessed with a multivariable Cox proportional hazards model for DFS for the following covariates: age, menopausal status, tumor size, lymph node status, type of chemotherapy, tumor size, positive lymph nodes, HER2 status, and hormone receptor status. All statistical tests were two-sided. RESULTS Among the 1246 eligible patients, estimated rates of DFS at 5 years were 78.5% in the FEC-P arm and 72.1% in the FEC arm (difference = 6.4%, 95% confidence interval [CI] = 1.6% to 11.2%; P = .006). FEC-P treatment was associated with a 23% reduction in the risk of relapse compared with FEC treatment (146 relapses in the 614 patients in the FEC-P arm vs 193 relapses in the 632 patients in the FEC arm, hazard ratio [HR] = 0.77, 95% CI = 0.62 to 0.95; P = .022) and a 22% reduction in the risk of death (73 and 95 deaths, respectively, HR = 0.78, 95% CI = 0.57 to 1.06; P = .110). Among the 928 patients for whom tumor samples were centrally analyzed, type of chemotherapy (FEC vs FEC-P) (P = .017), number of involved axillary lymph nodes (P < .001), tumor size (P = .020), hormone receptor status (P = .004), and HER2 status (P = .006) were all associated with DFS. We found no statistically significant interaction between HER2 status and paclitaxel treatment or between hormone receptor status and paclitaxel treatment. CONCLUSIONS Among patients with operable breast cancer, FEC-P treatment statistically significantly reduced the risk of relapse compared with FEC as adjuvant therapy.

Hepatic safety of antibiotics used in primary care

Antibiotics used by general practitioners frequently appear in adverse-event reports of drug-induced hepatotoxicity. Most cases are idiosyncratic (the adverse reaction cannot be predicted from the drug's pharmacological profile or from pre-clinical toxicology tests) and occur via an immunological reaction or in response to the presence of hepatotoxic metabolites. With the exception of trovafloxacin and telithromycin (now severely restricted), hepatotoxicity crude incidence remains globally low but variable. Thus, amoxicillin/clavulanate and co-trimoxazole, as well as flucloxacillin, cause hepatotoxic reactions at rates that make them visible in general practice (cases are often isolated, may have a delayed onset, sometimes appear only after cessation of therapy and can produce an array of hepatic lesions that mirror hepatobiliary disease, making causality often difficult to establish). Conversely, hepatotoxic reactions related to macrolides, tetracyclines and fluoroquinolones (in that order, from high to low) are much rarer, and are identifiable only through large-scale studies or worldwide pharmacovigilance reporting. For antibiotics specifically used for tuberculosis, adverse effects range from asymptomatic increases in liver enzymes to acute hepatitis and fulminant hepatic failure. Yet, it is difficult to single out individual drugs, as treatment always entails associations. Patients at risk are mainly those with previous experience of hepatotoxic reaction to antibiotics, the aged or those with impaired hepatic function in the absence of close monitoring, making it important to carefully balance potential risks with expected benefits in primary care. Pharmacogenetic testing using the new genome-wide association studies approach holds promise for better understanding the mechanism(s) underlying hepatotoxicity.

Insulin receptor substrate-1 expression is increased in circulating leukocytes of patients with acute coronary syndrome.

The mechanisms underlying the increased risk of cardiovascular disease associated with diabetes mellitus (DM) are not fully defined. Insulin resistance in human metabolic syndrome patients is associated with decreased expression of the insulin receptor substrate-2- (Irs2-) AKT2 axis in mononuclear leukocytes (MLs). Moreover, acute coronary syndrome (ACS) has been linked through genome-wide association studies to the 2q36-q37.3 locus, which contains the Irs1 gene. Here, we investigated the expression of insulin-signaling pathway genes in MLs from patients with DM, ACS, and ACS plus DM. Quantitative real-time PCR expression studies showed no differences in the mRNA levels of Irs2, Akt2, and Akt1 among all patients. However, Irs1 mRNA expression was significantly increased in patients with ACS-diabetics and nondiabetics-compared with diabetic patients without ACS (P < .02 and P < .005, resp.). The present study reveals for the first time an association between increased Irs1 mRNA levels in MLs of patients with ACS which is not related to DM.

Role of gene methylation in antitumor immune response: Implication for tumor progression

Cancer immunosurveillance theory has emphasized the role of escape mechanisms in tumor growth. In this respect, a very important factor is the molecular characterization of the mechanisms by which tumor cells evade immune recognition and destruction. Among the many escape mechanisms identified, alterations in classical and non-classical HLA (Human Leucocyte Antigens) class I and class II expression by tumor cells are of particular interest. In addition to the importance of HLA molecules, tumor-associated antigens and accessory/co-stimulatory molecules are also involved in immune recognition. The loss of HLA class I antigen expression and of co-stimulatory molecules can occur at genetic, transcriptional and post-transcriptional levels. Epigenetic defects are involved in at least some mechanisms that preclude mounting a successful host-antitumor response involving the HLA system, tumor-associated antigens, and accessory/co-stimulatory molecules. This review summarizes our current understanding of the role of methylation in the regulation of molecules involved in the tumor immune response.

Measles outbreak in Andalusia, Spain, January to August 2011.

On 7 January 2011, a six year-old child living in a Roma community near Seville, southern Spain, was hospitalised with measles. Contact tracing identified a probable index case with onset of symptoms on 20 December 2011 and several unreported cases among children under the age of 15 years in the same town. The outbreak initially spread in districts in the city of Seville with a high proportion of Roma residents, and later to other cities and towns in Andalusia. While some towns experienced wide spread of the disease with significant clusters of cases, most of the affected locations saw non-clustered cases or very few secondary cases. The outbreak resulted in 1,759 confirmed or probable cases of which 393 (19%) required hospitalisation. Measles virus of genotype D4 was diagnosed in more than half of the cases. Significant differences (p<0.0001) by age group were found between clustered and non-clustered cases. The highest proportion of clustered cases occurred in the age group of 5-14 yearolds, while the highest proportion of non-clustered cases was seen in those older than 29 years. The last confirmed case related to this outbreak was reported on 20 August 2011.

Community cluster of meningococcal disease by Neisseria meningitidis serogroup C in Andalusia, Spain, March to May 2011.

Between March and May of 2011, a cluster of three fatal cases of meningococcal sepsis occurred in Andalusia, Spain, in a municipality with a population of around 20,000 inhabitants. The cases were in their mid-teens to early thirties and were notified to the epidemiological surveillance system of Andalusia (Sistema de Vigilancia Epidemiológica de Andalucía, SVEA) during a 68-day period from March through May 2011. All three were infected with the same strain of Neisseria meningitidis serogroup C genosubtype VR1:5-1;VR2:10-8. None of the cases had been previously vaccinated against N. meningitidis serogroup C. Antibiotic post-exposure chemoprophylaxis was administered to close contacts of every diagnosed case. Once the cluster was confirmed, the local population was informed through the media about the control measures taken by the health authorities. The vaccination history against N. meningitidis serogroup C of the population under 25 years-old in the municipality was checked. Vaccination was offered to unimmunised individuals younger than 25 years of age and an additional dose of vaccine was offered to those who had been vaccinated between 2000 and 2006 with a vaccination schedule of three doses before the first year of age. No further cases occurred since the beginning of these actions.

Early estimates of the effectiveness of the 2011/12 influenza vaccine in the population targeted for vaccination in Spain, 25 December 2011 to 19 February 2012.

We present early estimates of influenza vaccine effectiveness (VE) in the population targeted for vaccination, during 25 December 2011 to 19 February 2012. The adjusted VE was 55% (95% CI: 3 to 79) against any type of influenza virus and 54% (95% CI: 1 to 79) against influenza A(H3N2) virus. This suggests a moderate protective effect of the vaccine in the targeted population in a late influenza epidemic with limited match between vaccine and circulating strains.

Rabid puppy-dog imported into the Netherlands from Morocco via Spain, February 2012.

To the editor: We read with interest the article by van Rijckevorsel et al. on a rabid puppy-dog imported into the Netherlands from Morocco via Spain, recently published in Eurosurveillance [1]. We would like to complete the information on this event with actions taken by the Spanish health authorities and lessons learnt.

Análisis de la Morfología del Raquis Torácico y Lumbar en Mujeres Trabajadoras de una Cooperativa Hortofrutícola

The aim of this study was to analyze the sagittal spinal morphology of thoracic and lumbar spine in standing and sitting in women workers from a cooperative in the production, handling and marketing business of vegetable and fruit products. A total of 50 women (mean age: 43.62±8.43 years old) were evaluated. The Spinal Mouse system was used to mesasure the sagittal thoracic and lumbar curvatures in standing and relaxed sitting. The values for thoracic and lumbar curvatures were 32.74±8.76 and -21.66±19.12 in standing and 36.32±10.55 and -1.08±18.14 in sitting. A high frequency (86.0% and 68.3%) of normal thoracic kyphosis and lumbar lordosis were found in standing posture. While sitting the 74.0% and 20.0% presented thoracic hyperkyphosis and lumbar kyphosis. In conclusion, a high percentaje of women workers presented normality values in standing posture, although a high percentage of women were found with thoracic hyperkyphosis and lumbar flexed while sitting relaxed. It is recommended that these women carry out a program to improve their actitudinal postures in their work place.

Sociodemographic factors and clinical conditions associated to hospitalization in influenza A (H1N1) 2009 virus infected patients in Spain, 2009-2010.

The emergence and pandemic spread of a new strain of influenza A (H1N1) virus in 2009 resulted in a serious alarm in clinical and public health services all over the world. One distinguishing feature of this new influenza pandemic was the different profile of hospitalized patients compared to those from traditional seasonal influenza infections. Our goal was to analyze sociodemographic and clinical factors associated to hospitalization following infection by influenza A(H1N1) virus. We report the results of a Spanish nationwide study with laboratory confirmed infection by the new pandemic virus in a case-control design based on hospitalized patients. The main risk factors for hospitalization of influenza A (H1N1) 2009 were determined to be obesity (BMI≥40, with an odds-ratio [OR] 14.27), hematological neoplasia (OR 10.71), chronic heart disease, COPD (OR 5.16) and neurological disease, among the clinical conditions, whereas low education level and some ethnic backgrounds (Gypsies and Amerinds) were the sociodemographic variables found associated to hospitalization. The presence of any clinical condition of moderate risk almost triples the risk of hospitalization (OR 2.88) and high risk conditions raise this value markedly (OR 6.43). The risk of hospitalization increased proportionally when for two (OR 2.08) or for three or more (OR 4.86) risk factors were simultaneously present in the same patient. These findings should be considered when a new influenza virus appears in the human population.

Análisis de las principales variables determinantes de la evolución de la mortalidad por demencias en Andalucía.

BACKGROUND The dementias are a cause of mortality have increased over the last years. Therefore is important to analyze the variables more related to its development in Andalusia between 1999 and 2010. METHODS With the deaths of 60 and over by dementia from Andalusia Statistical Institute and the populations from corresponding years, are estimated crude mortality rates, standardized and age-specific; by joinpoint regression was calculated percentages annual change; and also, with the population estimates by marital status and deaths was calculated crude rates and standardized for age, sex and marital status. RESULTS The standardized mortality rates increased from 124.8 to 161.0 deaths per 100,000 in women and 110.3 to 147.7 in men, the annual increase was 4.2% and 3.8% in women and men. The women died more than men with a standardized rate ratio between 1.08 and 1.29. Age was the variable that determined mortality. CONCLUSIONS Mortality from dementia in Andalusia has increased over the past 12 years and will continue to increase with the consequent social and health impacts posed by these diseases, configured as a major health problem.

Role of the paclitaxel-eluting stent and tirofiban in patients with ST-elevation myocardial infarction undergoing postfibrinolysis angioplasty: the GRACIA-3 randomized clinical trial.

BACKGROUND A catheter-based approach after fibrinolysis is recommended if fibrinolysis is likely to be successful in patients with acute ST-elevation myocardial infarction. We designed a 2x2 randomized, open-label, multicenter trial to evaluate the efficacy and safety of the paclitaxel-eluting stent and tirofiban administered after fibrinolysis but before catheterization to optimize the results of this reperfusion strategy. METHODS AND RESULTS We randomly assigned 436 patients with acute ST-elevation myocardial infarction to (1) bare-metal stent without tirofiban, (2) bare-metal stent with tirofiban, (3) paclitaxel-eluting stent without tirofiban, and (4) paclitaxel-eluting stent with tirofiban. All patients were initially treated with tenecteplase and enoxaparin. Tirofiban was started 120 minutes after tenecteplase in those patients randomly assigned to tirofiban. Cardiac catheterization was performed within the first 3 to 12 hours after inclusion, and stenting (randomized paclitaxel or bare stent) was applied to the culprit artery. The primary objectives were the rate of in-segment binary restenosis of paclitaxel-eluting stent compared with that of bare-metal stent and the effect of tirofiban on epicardial and myocardial flow before and after mechanical revascularization. At 12 months, in-segment binary restenosis was similar between paclitaxel-eluting stent and bare-metal stent (10.1% versus 11.3%; relative risk, 1.06; 95% confidence interval, 0.74 to 1.52; P=0.89). However, late lumen loss (0.04+/-0.055 mm versus 0.27+/-0.057 mm, P=0.003) was reduced in the paclitaxel-eluting stent group. No evidence was found of any association between the use of tirofiban and any improvement in the epicardial and myocardial perfusion. Major bleeding was observed in 6.1% of patients receiving tirofiban and in 2.7% of patients not receiving it (relative risk, 2.22; 95% confidence interval, 0.86 to 5.73; P=0.14). CONCLUSIONS This trial does not provide evidence to support the use of tirofiban after fibrinolysis to improve epicardial and myocardial perfusion. Compared with bare-metal stent, paclitaxel-eluting stent significantly reduced late loss but appeared not to reduce in-segment binary restenosis. CLINICAL TRIAL REGISTRATION URL: http://clinicaltrials.gov. Unique identifier: NCT00306228.

Influence of IL28B polymorphisms on response to a lower-than-standard dose peg-IFN-α 2a for genotype 3 chronic hepatitis C in HIV-coinfected patients.

BACKGROUND Data on which to base definitive recommendations on the doses and duration of therapy for genotype 3 HCV/HIV-coinfected patients are scarce. We evaluated the efficacy of a lower peginterferon-α 2a dose and a shorter duration of therapy than the current standard of care in genotype 3 HCV/HIV-coinfected patients. METHODS AND FINDINGS Pilot, open-label, single arm clinical trial which involved 58 Caucasian HCV/HIV-coinfected patients who received weekly 135 µg peginterferon-α 2a plus ribavirin 400 mg twice daily during 20 weeks after attaining undetectable viremia. The relationships between baseline patient-related variables, including IL28B genotype, plasma HCV-RNA, ribavirin dose/kg, peginterferon-α 2a and ribavirin levels with virological responses were analyzed. Only 4 patients showed lack of response and 5 patients dropped out due to adverse events related to the study medication. Overall, sustained virologic response (SVR) rates were 58.3% by intention-to-treat and 71.4% by per protocol analysis, respectively. Among patients with rapid virologic response (RVR), SVR and relapses rates were 92.6% and 7.4%, respectively. No relationships were observed between viral responses and ribavirin dose/kg, peginterferon-α 2a concentrations, ribavirin levels or rs129679860 genotype. CONCLUSIONS Weekly 135 µg pegIFN-α 2a could be as effective as the standard 180 µg dose, with a very low incidence of severe adverse events. A 24-week treatment duration appears to be appropriate in patients achieving RVR, but extending treatment up to just 20 weeks beyond negativization of viremia is associated with a high relapse rate in those patients not achieving RVR. There was no influence of IL28B genotype on the virological responses.

Comunicación paciente-médico y toma de decisiones en salud en Andalucía. Expectativas de pacientes crónicos del Sistema Sanitario Público Andaluz

The purpose of the study was to know about the expectations had by chronic patients within th e Public Healthcare System in Andalusi a, concerning commu nication and making deci sions with the med ical professionals who take care of them duri ng the entire treatment process. A qualitative study was carried out in Andalusia, based on 19 i n-depth interviews and 17 focus groups with 15 4 chronic patients and their relatives, suffering from seven different types of illness, of which the content was later analyzed based on the type of disease (pathologies), and the level of care (Primary, Sp eci aliz ed or Em ergen cy Ser vices). The study shows that patients i ncl uded in all healthcare processes want information about their illness. In Primary Care, they value continued attention, closeness and trust as well as being referred to a proper specialist. In Specialized Care, they expect to receive trustworthy information, proper tests and a correct diagnosis, friendly treatment and to be listened to. In the Emergency Room, lack of tim e and overcrowding d i sru pt proper communic ation. The type of chronic illne ss i nfluenc es patients’ expectations in terms of communication and decisionmaking. Communic ation between patients and medical personnel and the decision-making process related to chronic illness are crucial for the improvement of the qualit y o f healthcare. The type of chr onic disease marks diffe rent expectation s about the communication and decision-making. The communication and the decision making in the chronic assistance is a priority to improve the quality of the assistance