ESR1 gene promoter region methylation in free circulating DNA and its correlation with estrogen receptor protein expression in tumor tissue in breast cancer patients.

BACKGROUND Tumor expression of estrogen receptor (ER) is an important marker of prognosis, and is predictive of response to endocrine therapy in breast cancer. Several studies have observed that epigenetic events, such methylation of cytosines and deacetylation of histones, are involved in the complex mechanisms that regulate promoter transcription. However, the exact interplay of these factors in transcription activity is not well understood. In this study, we explored the relationship between ER expression status in tumor tissue samples and the methylation of the 5' CpG promoter region of the estrogen receptor gene (ESR1) isolated from free circulating DNA (fcDNA) in plasma samples from breast cancer patients. METHODS Patients (n = 110) with non-metastatic breast cancer had analyses performed of ER expression (luminal phenotype in tumor tissue, by immunohistochemistry method), and the ESR1-DNA methylation status (fcDNA in plasma, by quantitative methylation specific PCR technique). RESULTS Our results showed a significant association between presence of methylated ESR1 in patients with breast cancer and ER negative status in the tumor tissue (p = 0.0179). There was a trend towards a higher probability of ESR1-methylation in those phenotypes with poor prognosis i.e. 80% of triple negative patients, 60% of HER2 patients, compared to 28% and 5.9% of patients with better prognosis such as luminal A and luminal B, respectively. CONCLUSION Silencing, by methylation, of the promoter region of the ESR1 affects the expression of the estrogen receptor protein in tumors of breast cancer patients; high methylation of ESR1-DNA is associated with estrogen receptor negative status which, in turn, may be implicated in the patient's resistance to hormonal treatment in breast cancer. As such, epigenetic markers in plasma may be of interest as new targets for anticancer therapy, especially with respect to endocrine treatment.

Prognostic impact of MGMT promoter methylation and MGMT and CD133 expression in colorectal adenocarcinoma.

BACKGROUND New biomarkers are needed for the prognosis of advanced colorectal cancer, which remains incurable by conventional treatments. O6-methylguanine DNA methyltransferase (MGMT) methylation and protein expression have been related to colorectal cancer treatment failure and tumor progression. Moreover, the presence in these tumors of cancer stem cells, which are characterized by CD133 expression, has been associated with chemoresistance, radioresistance, metastasis, and local recurrence. The objective of this study was to determine the prognostic value of CD133 and MGMT and their possible interaction in colorectal cancer patients. METHODS MGMT and CD133 expression was analyzed by immunohistochemistry in 123 paraffin-embedded colorectal adenocarcinoma samples, obtaining the percentage staining and intensity. MGMT promoter methylation status was obtained by using bisulfite modification and methylation-specific PCR (MSP). These values were correlated with clinical data, including overall survival (OS), disease-free survival (DFS), tumor stage, and differentiation grade. RESULTS Low MGMT expression intensity was significantly correlated with shorter OS and was a prognostic factor independently of treatment and histopathological variables. High percentage of CD133 expression was significantly correlated with shorter DFS but was not an independent factor. Patients with low-intensity MGMT expression and ≥50% CD133 expression had the poorest DFS and OS outcomes. CONCLUSIONS Our results support the hypothesis that MGMT expression may be an OS biomarker as useful as tumor stage or differentiation grade and that CD133 expression may be a predictive biomarker of DFS. Thus, MGMT and CD133 may both be useful for determining the prognosis of colorectal cancer patients and to identify those requiring more aggressive adjuvant therapies. Future studies will be necessary to determine its clinical utility.

All-cause mortality in the cohorts of the Spanish AIDS Research Network (RIS) compared with the general population: 1997-2010.

BACKGROUND Combination antiretroviral therapy (cART) has produced significant changes in mortality of HIV-infected persons. Our objective was to estimate mortality rates, standardized mortality ratios and excess mortality rates of cohorts of the AIDS Research Network (RIS) (CoRIS-MD and CoRIS) compared to the general population. METHODS We analysed data of CoRIS-MD and CoRIS cohorts from 1997 to 2010. We calculated: (i) all-cause mortality rates, (ii) standardized mortality ratio (SMR) and (iii) excess mortality rates for both cohort for 100 person-years (py) of follow-up, comparing all-cause mortality with that of the general population of similar age and gender. RESULTS Between 1997 and 2010, 8,214 HIV positive subjects were included, 2,453 (29.9%) in CoRIS-MD and 5,761 (70.1%) in CoRIS and 294 deaths were registered. All-cause mortality rate was 1.02 (95% CI 0.91-1.15) per 100 py, SMR was 6.8 (95% CI 5.9-7.9) and excess mortality rate was 0.8 (95% CI 0.7-0.9) per 100 py. Mortality was higher in patients with AIDS, hepatitis C virus (HCV) co-infection, and those from CoRIS-MD cohort (1997-2003). CONCLUSION Mortality among HIV-positive persons remains higher than that of the general population of similar age and sex, with significant differences depending on the history of AIDS or HCV coinfection.

Evaluation of the IL2/IL21, IL2RA and IL2RB genetic variants influence on the endogenous non-anterior uveitis genetic predisposition.

BACKGROUND Recently, different genetic variants located within the IL2/IL21 genetic region as well as within both IL2RA and IL2RB loci have been associated to multiple autoimmune disorders. We aimed to investigate for the first time the potential influence of the IL2/IL21, IL2RA and IL2RB most associated polymorphisms with autoimmunity on the endogenous non-anterior uveitis genetic predisposition. METHODS A total of 196 patients with endogenous non-anterior uveitis and 760 healthy controls, all of them from Caucasian population, were included in the current study. The IL2/IL21 (rs2069762, rs6822844 and rs907715), IL2RA (2104286, rs11594656 and rs12722495) and IL2RB (rs743777) genetic variants were genotyped using TaqMan® allelic discrimination assays. RESULTS A statistically significant difference was found for the rs6822844 (IL2/IL21 region) minor allele frequency in the group of uveitis patients compared with controls (P(-value)=0.02, OR=0.64 CI 95%=0.43-0.94) although the significance was lost after multiple testing correction. Furthermore, no evidence of association with uveitis was detected for the analyzed genetic variants of the IL2RA or IL2RB loci. CONCLUSION Our results indicate that analyzed IL2/IL21, IL2RA and IL2RB polymorphisms do not seem to play a significant role on the non-anterior uveitis genetic predisposition although further studies are needed in order to clear up the influence of these loci on the non-anterior uveitis susceptibility.

Identification of factors associated with diagnostic error in primary care.

BACKGROUND Missed, delayed or incorrect diagnoses are considered to be diagnostic errors. The aim of this paper is to describe the methodology of a study to analyse cognitive aspects of the process by which primary care (PC) physicians diagnose dyspnoea. It examines the possible links between the use of heuristics, suboptimal cognitive acts and diagnostic errors, using Reason's taxonomy of human error (slips, lapses, mistakes and violations). The influence of situational factors (professional experience, perceived overwork and fatigue) is also analysed. METHODS Cohort study of new episodes of dyspnoea in patients receiving care from family physicians and residents at PC centres in Granada (Spain). With an initial expected diagnostic error rate of 20%, and a sampling error of 3%, 384 episodes of dyspnoea are calculated to be required. In addition to filling out the electronic medical record of the patients attended, each physician fills out 2 specially designed questionnaires about the diagnostic process performed in each case of dyspnoea. The first questionnaire includes questions on the physician's initial diagnostic impression, the 3 most likely diagnoses (in order of likelihood), and the diagnosis reached after the initial medical history and physical examination. It also includes items on the physicians' perceived overwork and fatigue during patient care. The second questionnaire records the confirmed diagnosis once it is reached. The complete diagnostic process is peer-reviewed to identify and classify the diagnostic errors. The possible use of heuristics of representativeness, availability, and anchoring and adjustment in each diagnostic process is also analysed. Each audit is reviewed with the physician responsible for the diagnostic process. Finally, logistic regression models are used to determine if there are differences in the diagnostic error variables based on the heuristics identified. DISCUSSION This work sets out a new approach to studying the diagnostic decision-making process in PC, taking advantage of new technologies which allow immediate recording of the decision-making process.

Factors associated with chronic pain in patients with bipolar depression: a cross-sectional study.

BACKGROUND While pain is frequently associated with unipolar depression, few studies have investigated the link between pain and bipolar depression. In the present study we estimated the prevalence and characteristics of pain among patients with bipolar depression treated by psychiatrists in their regular clinical practice. The study was designed to identify factors associated with the manifestation of pain in these patients. METHODS Patients diagnosed with bipolar disorder (n=121) were selected to participate in a cross-sectional study in which DSM-IV-TR criteria were employed to identify depressive episodes. The patients were asked to describe any pain experienced during the study, and in the 6 weeks beforehand, by means of a Visual Analogical Scale (VAS). RESULTS Over half of the bipolar depressed patients (51.2%, 95% CI: 41.9%-60.6%), and 2/3 of the female experienced concomitant pain. The pain was of moderate to severe intensity and prolonged duration, and it occurred at multiple sites, significantly limiting the patient's everyday activities. The most important factors associated with the presence of pain were older age, sleep disorders and delayed diagnosis of bipolar disorder. CONCLUSIONS Chronic pain is common in bipolar depressed patients, and it is related to sleep disorders and delayed diagnosis of their disorder. More attention should be paid to study the presence of pain in bipolar depressed patients, in order to achieve more accurate diagnoses and to provide better treatment options.

Pattern of use of radiotherapy for lung cancer: a descriptive study.

BACKGROUND Lung cancer remains one of the most prevalent forms of cancer. Radiotherapy, with or without other therapeutic modalities, is an effective treatment. Our objective was to report on the use of radiotherapy for lung cancer, its variability in our region, and to compare our results with the previous study done in 2004 (VARA-I) in our region and with other published data. METHODS We reviewed the clinical records and radiotherapy treatment sheets of all patients undergoing radiotherapy for lung cancer during 2007 in the 12 public hospitals in Andalusia, an autonomous region of Spain. Data were gathered on hospital, patient type and histological type, radiotherapy treatment characteristics, and tumor stage. RESULTS 610 patients underwent initial radiotherapy. 37% of cases had stage III squamous cell lung cancer and were treated with radical therapy. 81% of patients with non-small and small cell lung cancer were treated with concomitant chemo-radiotherapy and the administered total dose was ≥60 Gy and ≥45 Gy respectively. The most common regimen for patients treated with palliative intent (44.6%) was 30 Gy. The total irradiation rate was 19.6% with significant differences among provinces (range, 8.5-25.6%; p<0.001). These differences were significantly correlated with the geographical distribution of radiation oncologists (r=0.78; p=0.02). Our results were similar to other published data and previous study VARA-I. CONCLUSIONS Our results shows no differences according to the other published data and data gathered in the study VARA-I. There is still wide variability in the application of radiotherapy for lung cancer in our setting that significantly correlates with the geographical distribution of radiation oncologists.

Unanswered clinical questions in the management of cardiometabolic risk in the elderly: a statement of the Spanish society of internal medicine.

BACKGROUND Despite the progressive increase in life expectancy and the relationship between aging with multi-morbidities and the increased use of healthcare resources, current clinical practice guidelines (CPG) on cardiometabolic risk cannot be adequately applied to elderly subjects with multiple chronic conditions. Its management frequently becomes complicated by both, an excessive use of medications that may lead to overtreatment, drug interactions and increased toxicity, and errors in dosage and non-compliance. Concerned by this gap, the Spanish Society of Internal Medicine created a group of independent experts on cardiometabolic risk who discussed what they considered to be unanswered questions in the management of elderly patients. DISCUSSION Current guidelines do not specifically address the problem of elderly with multiple chronic conditions. For this reason, the combined use of the limited available evidence, clinical experience and common sense, could all help us to address this unmet need. In very old people, life expectancy and functionality are the most important factors for guiding potential treatments. Their higher propensity to develop serious adverse events and their shorter lifespan could prevent them from obtaining the potential benefits of the interventions administered. SUMMARY In this document, experts on cardiometabolic risk factors have established a number of consensual recommendations that have taken into account international guidelines and clinical experience, and have also considered the more effective use of healthcare resources. This document is intended to provide general recommendations for clinicians and to promote the effective use of procedures and medications.

Use of Hy's law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury.

BACKGROUND & AIMS Hy's Law, which states that hepatocellular drug-induced liver injury (DILI) with jaundice indicates a serious reaction, is used widely to determine risk for acute liver failure (ALF). We aimed to optimize the definition of Hy's Law and to develop a model for predicting ALF in patients with DILI. METHODS We collected data from 771 patients with DILI (805 episodes) from the Spanish DILI registry, from April 1994 through August 2012. We analyzed data collected at DILI recognition and at the time of peak levels of alanine aminotransferase (ALT) and total bilirubin (TBL). RESULTS Of the 771 patients with DILI, 32 developed ALF. Hepatocellular injury, female sex, high levels of TBL, and a high ratio of aspartate aminotransferase (AST):ALT were independent risk factors for ALF. We compared 3 ways to use Hy's Law to predict which patients would develop ALF; all included TBL greater than 2-fold the upper limit of normal (×ULN) and either ALT level greater than 3 × ULN, a ratio (R) value (ALT × ULN/alkaline phosphatase × ULN) of 5 or greater, or a new ratio (nR) value (ALT or AST, whichever produced the highest ×ULN/ alkaline phosphatase × ULN value) of 5 or greater. At recognition of DILI, the R- and nR-based models identified patients who developed ALF with 67% and 63% specificity, respectively, whereas use of only ALT level identified them with 44% specificity. However, the level of ALT and the nR model each identified patients who developed ALF with 90% sensitivity, whereas the R criteria identified them with 83% sensitivity. An equal number of patients who did and did not develop ALF had alkaline phosphatase levels greater than 2 × ULN. An algorithm based on AST level greater than 17.3 × ULN, TBL greater than 6.6 × ULN, and AST:ALT greater than 1.5 identified patients who developed ALF with 82% specificity and 80% sensitivity. CONCLUSIONS When applied at DILI recognition, the nR criteria for Hy's Law provides the best balance of sensitivity and specificity whereas our new composite algorithm provides additional specificity in predicting the ultimate development of ALF.

Cost-effectiveness of an exercise intervention program in perimenopausal women: the Fitness League Against MENopause COst (FLAMENCO) randomized controlled trial.

BACKGROUND The high prevalence of women that do not reach the recommended level of physical activity is worrisome. A sedentary lifestyle has negative consequences on health status and increases health care costs. The main objective of this project is to assess the cost-effectiveness of a primary care-based exercise intervention in perimenopausal women. METHODS/DESIGN The present study is a Randomized Controlled Trial. A total of 150 eligible women will be recruited and randomly assigned to either a 16-week exercise intervention (3 sessions/week), or to usual care (control) group. The primary outcome measure is the incremental cost-effectiveness ratio. The secondary outcome measures are: i) socio-demographic and clinical information; ii) body composition; iii) dietary patterns; iv) glycaemic and lipid profile; v) physical fitness; vi) physical activity and sedentary behaviour; vii) sleep quality; viii) quality of life, mental health and positive health; ix) menopause symptoms. All outcomes will be assessed at baseline and post intervention. The data will be analysed on an intention-to-treat basis and per protocol. In addition, we will conduct a cost effectiveness analysis from a health system perspective. DISCUSSION The intervention designed is feasible and if it proves to be clinically and cost effective, it can be easily transferred to other similar contexts. Consequently, the findings of this project might help the Health Systems to identify strategies for primary prevention and health promotion as well as to reduce health care requirements and costs. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02358109 . Date of registration: 05/02/2015.

Are the health messages in schoolbooks based on scientific evidence? A descriptive study.

BACKGROUND Most textbooks contains messages relating to health. This profuse information requires analysis with regards to the quality of such information. The objective was to identify the scientific evidence on which the health messages in textbooks are based. METHODS The degree of evidence on which such messages are based was identified and the messages were subsequently classified into three categories: Messages with high, medium or low levels of evidence; Messages with an unknown level of evidence; and Messages with no known evidence. RESULTS 844 messages were studied. Of this total, 61% were classified as messages with an unknown level of evidence. Less than 15% fell into the category where the level of evidence was known and less than 6% were classified as possessing high levels of evidence. More than 70% of the messages relating to "Balanced Diets and Malnutrition", "Food Hygiene", "Tobacco", "Sexual behaviour and AIDS" and "Rest and ergonomics" are based on an unknown level of evidence. "Oral health" registered the highest percentage of messages based on a high level of evidence (37.5%), followed by "Pregnancy and newly born infants" (35%). Of the total, 24.6% are not based on any known evidence. Two of the messages appeared to contravene known evidence. CONCLUSION Many of the messages included in school textbooks are not based on scientific evidence. Standards must be established to facilitate the production of texts that include messages that are based on the best available evidence and which can improve children's health more effectively.

Clinical intervals and diagnostic characteristics in a cohort of prostate cancer patients in Spain: a multicentre observational study.

BACKGROUND Little is known about the healthcare process for patients with prostate cancer, mainly because hospital-based data are not routinely published. The main objective of this study was to determine the clinical characteristics of prostate cancer patients, the, diagnostic process and the factors that might influence intervals from consultation to diagnosis and from diagnosis to treatment. METHODS We conducted a multicentre, cohort study in seven hospitals in Spain. Patients' characteristics and diagnostic and therapeutic variables were obtained from hospital records and patients' structured interviews from October 2010 to September 2011. We used a multilevel logistic regression model to examine the association between patient care intervals and various variables influencing these intervals (age, BMI, educational level, ECOG, first specialist consultation, tumour stage, PSA, Gleason score, and presence of symptoms) and calculated the odds ratio (OR) and the interquartile range (IQR). To estimate the random inter-hospital variability, we used the median odds ratio (MOR). RESULTS 470 patients with prostate cancer were included. Mean age was 67.8 (SD: 7.6) years and 75.4 % were physically active. Tumour size was classified as T1 in 41.0 % and as T2 in 40 % of patients, their median Gleason score was 6.0 (IQR:1.0), and 36.1 % had low risk cancer according to the D'Amico classification. The median interval between first consultation and diagnosis was 89 days (IQR:123.5) with no statistically significant variability between centres. Presence of symptoms was associated with a significantly longer interval between first consultation and diagnosis than no symptoms (OR:1.93, 95%CI 1.29-2.89). The median time between diagnosis and first treatment (therapeutic interval) was 75.0 days (IQR:78.0) and significant variability between centres was found (MOR:2.16, 95%CI 1.45-4.87). This interval was shorter in patients with a high PSA value (p = 0.012) and a high Gleason score (p = 0.026). CONCLUSIONS Most incident prostate cancer patients in Spain are diagnosed at an early stage of an adenocarcinoma. The period to complete the diagnostic process is approximately three months whereas the therapeutic intervals vary among centres and are shorter for patients with a worse prognosis. The presence of prostatic symptoms, PSA level, and Gleason score influence all the clinical intervals differently.

International trends in health science librarianship: part 4--four Southern European countries.

This is the fourth in a series of articles exploring international trends in health science librarianship in four Southern European countries in the first decade of the 21st century. The invited authors are from Greece, Italy, Spain and Portugal. Future issues will track trends in Latin America and Central Europe.

Evaluation of the efficacy and safety of lanreotide in combination with targeted therapies in patients with neuroendocrine tumours in clinical practice: a retrospective cross-sectional analysis.

BACKGROUND Based on the mechanism of action, combining somatostatin analogues (SSAs) with mTOR inhibitors or antiangiogenic agents may provide synergistic effects for the treatment of patients with neuroendocrine tumours (NETs). Herein, we investigate the use of these treatment combinations in clinical practice. METHODS This retrospective cross-sectional analysis of patients with NETs treated with the SSA lanreotide and targeted therapies at 35 Spanish hospitals evaluated the efficacy and safety of lanreotide treatment combinations in clinical practice. The data of 159 treatment combinations with lanreotide in 133 patients was retrospectively collected. RESULTS Of the 133 patients, with a median age of 59.4 (16-83) years, 70 (52.6 %) patients were male, 64 (48.1 %) had pancreatic NET, 23 (17.3 %) had ECOG PS ≥2, 41 (30.8 %) had functioning tumours, 63 (47.7 %) underwent surgery of the primary tumour, 45 (33.8 %) had received prior chemotherapy, and 115 (86.5 %) had received prior SSAs. 115 patients received 1 lanreotide treatment combination and 18 patients received between 2 and 5 combinations. Lanreotide was mainly administered in combination with everolimus (73 combinations) or sunitinib (61 combinations). The probability of being progression-free was 78.5 % (6 months), 68.6 % (12 months) and 57.0 % (18 months) for patients who only received everolimus plus lanreotide (n = 57) and 89.3 % (6 months), 73.0 % (12 months), and 67.4 % (18 months) for patients who only received sunitinib and lanreotide (n = 50). In patients who only received everolimus plus lanreotide the median time-to-progression from the initiation of lanreotide combination treatment was 25.8 months (95 % CI, 11.3, 40.3) and it had not yet been reached among the subgroup of patients only receiving sunitinib plus lanreotide. The safety profile of the combination treatment was comparable to that of the targeted agent alone. CONCLUSIONS The combination of lanreotide and targeted therapies, mainly everolimus and sunitinib, is widely used in clinical practice without unexpected toxicities and suggests efficacy that should be explored in randomized prospective clinical trials.

Regression of cardiac growth in kidney transplant recipients using anti-m-TOR drugs plus RAS blockers: a controlled longitudinal study.

BACKGROUND Left ventricular hypertrophy (LVH) is common in kidney transplant (KT) recipients. LVH is associated with a worse outcome, though m-TOR therapy may help to revert this complication. We therefore conducted a longitudinal study to assess morphological and functional echocardiographic changes after conversion from CNI to m-TOR inhibitor drugs in nondiabetic KT patients who had previously received RAS blockers during the follow-up. METHODS We undertook a 1-year nonrandomized controlled study in 30 non-diabetic KT patients who were converted from calcineurin inhibitor (CNI) to m-TOR therapy. A control group received immunosuppressive therapy based on CNIs. Two echocardiograms were done during the follow-up. RESULTS Nineteen patients were switched to SRL and 11 to EVL. The m-TOR group showed a significant reduction in LVMi after 1 year (from 62 ± 22 to 55 ± 20 g/m2.7; P=0.003, paired t-test). A higher proportion of patients showing LVMi reduction was observed in the m-TOR group (53.3 versus 29.3%, P=0.048) at the study end. In addition, only 56% of the m-TOR patients had LVH at the study end compared to 77% of the control group (P=0.047). A significant change from baseline in deceleration time in early diastole was observed in the m-TOR group compared with the control group (P=0.019). CONCLUSIONS Switching from CNI to m-TOR therapy in non-diabetic KT patients may regress LVH, independently of blood pressure changes and follow-up time. This suggests a direct non-hemodynamic effect of m-TOR drugs on cardiac mass.