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Introduction: Candida albicans is a ubiquitous commensal organism that commonly colonizes the oral mucosa. In fact, up to 80% of the general population are carriers. Objective: To analyze the literature about C. albicans, its epidemiology, diagnosis, clinical manifestations, antimicrobial resistance and treatment in relation to endodontics. Methodology: Using the keywords Candida albicans in conjunction with epidemiology, diagnosis, clinical manifestations, antimicrobial resistance and treatment, the main public databases were searched, with emphasis on the last 5 years. It was evaluated with the PRISMA and AMSTAR-2 guidelines. Results: C. albicans is the fungus most frequently isolated in root canal infections, it binds to the dentin to form biofilms within the dentin tubules. C. albicans can be detected by different diagnostic methods, the most used is cultivation. This microorganism is increasingly found in the oral cavity, it is responsible for endodontic failure, its biofilms are inherently resistant to antifungal drugs, the host's immune system, environmental stresses and biomechanical treatment. The most favourable method to eliminate is using QmiX irritant and EndoVac as a suction system, together with chemo mechanical debridement. Conclusions: C. albicans is a pathogen which has been presenting itself more frequently in the oral cavity, in the endodontic area, it is the fungus that is most frequently found in the root canals, either due to primary or secondary infection.

Introduction: Orthodontic appliances may be associated with a worsening of preexisting periodontal diseases caused by Aggregatibacter actinomycetemcomitans. Objective: To analyze the literature on the characteristics of A. actinomycetemcomitans and its relationship with orthodontics, particularly epidemiology, oral manifestations, diagnostic methods and treatments. Methodology: Using the keywords “A. actinomycetemcomitans”, “orthodontics”, “oral manifestations”, “treatment” and “epidemiology”, the main public databases were searched, with emphasis on the last 5 years. It was evaluated with the PRISMA and AMSTAR-2 guidelines. Results: Orthodontic treatment increase the prevalence of A. actinomycetemcomitans. Preexisting aggressive periodontitis is a great challenge to clinicians when providing orthodontic treatment due to A. actinomycetemcomitans. PCR is the technique of choice as a diagnostic method that is currently used most frequently in research centers. The removal of orthodontic appliances has shown a significant reduction in dentobacterial plaque, as well as proper oral hygiene and, if necessary, the use of alternative treatments such as moxifloxacin and antimicrobial photodynamic therapy. Conclusions: Correct oral hygiene during orthodontic treatment is essential to reduce the presence of A. actinomycetemcomitans, thus diminishing cariogenic risk as well as a worsening of periodontal diseases.

Introduction: Tannerella forsythia, is an anaerobic, Gram-negative microorganism closely related to periodontal disease. Factors such as poor dental hygiene, fixed orthodontic appliances, etc. can cause dysbiosis in the bacterial community. Objective: To analyze the literature about the epidemiology, diagnostic methods, oral manifestations, relationship with systemic diseases and treatment of Tannerella forsythia in orthodontic patients. Methodology: Using the keywords “T. forsythia”, “orthodontics”, “oral manifestations”, “diagnostics”, “treatment” and “epidemiology”, the main public databases were searched, with emphasis on the last 5 years. It was evaluated with the PRISMA and AMSTAR-2 guidelines. Results: At the national level, in 2019, cases of gingivitis and periodontal disease ranked fifth among the twenty main causes of diseases. As a diagnostic method, most of the studies used molecular biology (PCR) for the identification of bacterial DNA. Very few studies performed cultures for identification. T. forsythia is capable of inducing characteristic signs of gingivitis and periodontal disease. Non-surgical mechanical therapy remains the gold standard in its treatment. There are multiple diseases that can be related to the presence of T. forsythia, so its medical importance becomes more relevant and its control, essential. Conclusion: T. forsythia is closely related to periodontal disease. Its presence is mainly found in the easily accumulated plaque in patients with fixed appliances. It is essential to diagnose it for a treatment that can avoid harm to the patient.

Introduction: Atypical odontalgia (AO) is one of the most complicated challenges that a dentist can face for an adequate diagnosis and treatment plan. It can cause prolonged visits and costly overtreatments for the patient, increasing the time of resolution of the condition.Objective: To analyze the literature about AO, as well as its epidemiology, pathophysiology, predisposing factors, associated pathologies and treatment.Methodology: Information was searched in PubMed, SCOPUS and Google Scholar. Key words were used to search for information such as: atypical odontology, epidemiology, pathophysiology, related disease, treatment, among other relevant articles.Results: AO occurs in women (85%) and men (20%) between 50 - 60 years old, hormonal or psychiatric disorders, related to local neuropathies due to problems in electrical conduction, and present or largely confused with trigeminal neuralgia and burning mouth syndrome mainly, sometimes it is possible to identify duct treatment or a history of aggressive therapy in the area, and can be treated with Amitriptyline, Imipramine, Aripiprazole, and locally with Botulinum Toxin A with favorable results found at 4 weeks.Conclusion: AO does not have specific characteristic criteria for its diagnosis, leaving a wide spectrum of possibilities that represent a complex pathology that needs further study.

Background: Neurologic impairment persisting months after acute severe SARS-CoV-2 infection has been described because of several pathogenic mechanisms, including persistent systemic inflammation. The objective of this study is to analyze the selective involvement of the different cognitive domains, it impacts on quality of life and the possible existence of related biomarkers.Methods: Cross-sectional study of patients who survived severe infection with SARS-CoV-2 consecutively recruited from 13 neurology services in Spain between 90 and 120 days after hospital discharge. All patients underwent an exhaustive study of cognitive functions as well as plasma determination of pro-inflammatory factors (chemokines), and neurotrophic factors and light-chain neurofilaments. A Principal Component Analysis extracted the main independent characteristics of the syndrome.Results: 152 patients were recruited. The results of our study show a pattern of cognitive impairment with preferential involvement of episodic and working memory, executive functions, and attention and relatively less affectation of information processing speed, denomination, verbal fluency, and other cortical functions. In addition, psychiatric affectation such as anxiety and depression pictures are constant in our cohort. Several plasma chemokines concentrations were elevated compared with both, a non-SARS-Cov2 infected cohort of neurological outpatients or a control healthy general population, suggesting a pro-inflammatory chronic state derived of viral infection.Conclusion: The neurologic Subacute Impairment in severe Covid-19 consist in an amnesic and dysexecutive syndrome with neuropsychiatric manifestations. We do not know if the deficits detected can persist in the long term and, in this case, if this can trigger or accelerate the onset of neurodegenerative diseases.

Background and Aims There is a high prevalence of malnutrition (PEW) in patients on dialysis (HD-PD). There is no single tool to diagnose it, varying the percentage according to the one used. Aim To assess prevalence of malnutrition-inflammation by MIS scale (malnutrition-inflammation-score) in HD or PD patients of Spanish dialysis units. Method We evaluated 2937 patients on dialysis (HD+PD) in Spain were evaluated on the MIS scale strata (Kalantar-Zadeh 1999) also analyzing: Common data Age, sex, dialysis time, Charlson-I., RRF, albumin,prealbumin,Kt/V transferrin, CRP, DM , Specific-HD HD type, AVF or Catheter , Specific-PD PD-type, transport type. Statistical analysis with SPSS.23 software, using parametric and non-parametric test. Results We evaluate 2748 HD patients, median age 71 (RIC20), 65.90% male, median MIS 6 (RIC4), DM 36.91%, T in HD 36m (RIC54), FRR 35.44% , Charlson Index 7 (RIC4) and 186 in PD (62.96% men), median -age 62 (RIC 24), median-MIS 4 (RIC 2), T in PD of 18.5 m (RIC 23.5),DM 30.77%, FRR 79.89%, I Charlson 5 (RIC 4), In PDA 99pac-52.38%. Prevalence of global malnutrition (MIS>2) was 89% considering HD+DP and 50% when MIS>5 (table 1) In PD the higher normonutrides greater Kt/V in manual vs automatic not the malnourished ones. FRR significantly in greater % in normonutrides. No differences in malnutrition depending on carrier type. CRP sig major in MIS>2 and >5 In HD, Normo versus malnourished and with MIS>5 significant difference: HD type, CRP, HD Type, AVF vs catheter, age,sex. The prescription for Oral supplement was low and higher in HD 12.4% vs DP 6.3%. Conclusions 1.- There is a high prevalence of malnutrition on dialysis being higher in HD. 2.- In PD, FRR major and CRP minor in well-nourished versus malnourished. 3.- In HD: Normo versus malnourished and with MIS>5 significant difference: HD type, CRP,Charlson I. AVF vs catheter, age,sex. 4.- There is a percentage of malnourished patients with very low percentage of oral supplement.

Summary Background Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. Interpretation This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. Funding Sanofi and Regeneron Pharmaceuticals.

Background and Aims Vascular calcification as cause of vascular stiffness is a major contributor to the high cardiac burden among stage 5 chronic kidney disease dialysis (CKD5HD) patients. Early identification of patients with high calcification propensity is crucial for proper risk stratification and management of these patients. Recently, a novel in vitro test (T50-test) was developed which determines calcification propensity of human serum and predicts mortality among ND-CKD (non-dialysis chronic kidney disease) patients, kidney transplant recipients and CKD5HD patients suffering from secondary hyperparathyroidism. We now evaluated whether these results can be confirmed in an unselected cohort of CKD5HD patients and can be used in the future for improving care of these patients. Method This prospective clinical study included 776 incident and prevalent hemodialysis patients from 8 Fresenius Medical Care NephroCare centers in Cataluña (Spain). T50 was determined at Calciscon AG, all other clinical data were retrieved from the European Clinical Database (EuCliD®). After their baseline T50 measurement, patients were followed for two years for the occurrence of the primary endpoint all-cause mortality. The association between T50 and all-cause mortality was examined by using proportional subdistribution hazards regression modelling accounting for kidney transplantation as competing event. In sensitivity analyses we adjusted for age, sex, vascular access (fistula/graft, catheter), treatment modality (HD, HDF), Charlson comorbidity index and dialysis vintage. Results Mean age of the study population was 72.2 years and 63.8% were male. 42.5% had diabetes and 55.0% past history of cardiovascular disease. Mean T50 was 283.4 min among the total cohort. During follow-up, 185 (23.8%) patients died. Patients who reached the endpoint had a significantly lower T50 at baseline as compared to those who survived during follow-up (269.6 vs 287.7 min, p = 0.001). A cross-validated model (mean c statistic: 0.5767) identified T50 as a linear predictor of all-cause-mortality (subdistribution hazard ratio (per min): 0.9957, 95% CI [0.9933;0.9981]). T50 remained a significant predictor of all-cause mortality after adjusting for relevant confounding in sensitivity analyses. Conclusion In this prospective study, we confirmed that T50 is an independent predictor of all-cause mortality among a large unselected cohort of hemodialysis patients. T50 may be used to identify patients with high vascular calcification propensity and mortality risks and may help physicians to implement a personalized and more precise renal replacement therapy option.

Background and Aims Anemia management is still challenging in a large share of dialysis patients. ESA resistance show wide variations across patients as well as fluctuations along time within the same patient. The Anemia Control Model (ACM) is a software application which can be integrated in electronic health record systems. ACM is based on an artificial neural network system trained on 1 million health records which simulates patient’s personalized dose-response relationship to ESA and Iron. Based on patients’ response forecast, ACM suggests the optimal drug dose recommendations to reach or maintain the hemoglobin level within target and to minimize the drug consumption. The ACM has earned medical device certification and it is currently used in 13 countries within the EMEA FMC network. Effectiveness and safety of ACM has been demonstrated in previous real-world evidence studies. We report ACM use and its clinical outcomes among hemodialysis patients registered in the Spanish FME Network Method We recorded all medical prescriptions and their clinical outcome for which an ACM recommendation was computed (ACM prescription). prescription occurred in 9 clinics located in Catalunya (Spain) from September 2017 to September 2018. We report dynamics of ACM suggestion acceptance rate, ESA consumption and Hb target achievement in the study period. Results There were 1189 active patients per month during the study period on average. ACM suggestion acceptance rate was 73,3%. ESA monthly consumption ranged from 234:7±281:9 – 310.2 ± 310:8 UI/Kg; 86% of patients receiving ESA doses according to ACM recommendations achieved or remained within Hb target range; on the contrary, when physicians rejected ACM recommendations and prescribed a different dosage, only 77% of patients reached or maintained the Hb level on target (p Conclusion Our study demonstrated that ACM suggestions were frequently accepted by physicians. Acceptance of ACM suggestion was associated with higher Hb target achievement.

Background and Aims This retrospective analysis of data from the European Clinical Database (EuCliD®) evaluated changes in iron-related parameters and use of concomitant anti-anaemic therapies in European haemodialysis (HD) patients treated with sucroferric oxyhydroxide (SFOH). Previous Phase 3 clinical studies and non-clinical studies have indicated that there is minimal iron absorption from SFOH. This study aimed to evaluate the changes in iron-related parameters among patients treated with SFOH in the real-world setting. Method De-identified patient data were extracted from a clinical database (EuCliD®) for adult HD patients newly prescribed SFOH routinely for up to 1 year (1 Jan 2015–1 Jan 2019). Levels of serum ferritin, transferrin saturation (TSAT) and haemoglobin were compared between baseline (BL; 3-month period before starting SFOH) and each quarterly period in the year after starting SFOH treatment (Q1–Q4). Proportions of patients receiving intravenous (IV) iron and erythropoiesis-stimulating agent (ESA) therapies, in addition to their mean weekly doses, during each quarter were recorded. Results The cohort included 1,096 patients with recorded SFOH prescriptions (mean age: 60.6 years; 65.8% male). There were small, but significant increases in ferritin from BL to Q1–Q4 (P Conclusion This real-world study showed that SFOH treatment in routine clinical practice for up to 1 year was associated with small increases in iron-related parameters and decreases in the use and mean dose of concomitant anti-anaemic therapies in European HD patients. The results from this study indicate that SFOH treatment may be associated with the reduction in concomitant IV iron and ESA use in HD patients, in line with previous findings from the Phase 3 study.

Background: Genetic risk factors for dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) and dengue fever (DF) are limited, in particular there are sparse data on genetic risk across diverse populations. Methods: We conducted a genome-wide association study (GWAS) in a derivation and validation sample of 7, 460 participants of Latin American, South Asian, and South East Asian ancestries. We then developed a weighted polygenic risk score (PRS) for each participant in each of the validation cohorts of the three ancestries to predict the risk of DHF/DSS compared to DF, DHF/DSS compared to controls, and, DF compared to controls. Findings: The risk of DHF/DSS was significantly increased, odds ratio [OR] 1.84 (95%CI 1.47 to 2.31) (195 SNPs), compared to DF, fourth PRS quartile versus first quartile, in the validation cohort. The risk of DHF/DSS compared to controls was increased (OR=3.94; 95% CI 2.84 to 5.45) (278 SNPs), as was the risk of DF compared to controls (OR=1.97; 95%CI 1.63 to 2.39) (251 SNPs). Risk increased in a dose-dependent manner with increase in quartiles of PRS across comparisons. Significant associations persisted for PRS built within ancestries and applied to the same or different ancestries as well as for PRS built for one outcome (DHF/DSS or DF) and applied to the other. Interpretation: There is a strong genetic effect that predisposes to risk of DHF/DSS and DF. The genetic risk for DHF/DSS is higher than that for DF when compared to controls, and this effect persists across multiple ancestries. Keywords: Dengue, Genetics, Risk, GWAS, Ancestry

Doravirine is a novel, potent, nonnucleoside reverse-transcriptase inhibitor currently in development for HIV-1 infection treatment. As a substrate for CYP3A-mediated metabolism, doravirine could potentially be affected by liver-function changes. As a portion of the HIV-1-infected population has varying degrees of liver impairment, we investigated the effect of moderate hepatic impairment on the pharmacokinetic profile and tolerability of single-dose doravirine 100 mg in otherwise healthy subjects. A total of 16 subjects aged 44-64 years took part in the open-label, single-dose trial: 8 with moderate hepatic impairment (Child-Pugh score, 7-9; 6 men, 2 women) and 8 healthy individuals (mean age and height matched with the impairment group; 6 men, 2 women). Subjects with hepatic impairment were required to have chronic, stable hepatic impairment with features of cirrhosis of any etiology. Blood sampling revealed that doravirine exposure was similar in both groups. The observed geometric least-squares mean ratio (90% confidence interval; moderately impaired/healthy subjects) was 0.99 (0.72-1.35) for AUC0-∞ , 0.93 (0.74-1.18) for AUC0-24 h , 0.90 (0.66-1.24) for Cmax , and 0.99 (0.74-1.33) for C24 h . Geometric mean apparent terminal t½ was ∼18 hours for both groups, whereas median Tmax was 2 hours (range, 1-6 hours) and 2.5 hours (range, 1-3 hours) for impaired and healthy individuals, respectively. In addition, doravirine was generally well tolerated. The results demonstrate that moderate hepatic impairment does not have a clinically meaningful effect on doravirine pharmacokinetics. Therefore, dose adjustment should not be necessary in patients with both HIV-1 and moderate hepatic impairment.

Background: Benefits of tracheostomy have been well established. Most of the literature, refers these benefits to general intensive care population, excluding cardiac surgery or including only small number of these patients. On the other hand, there is no clear definition describing the proper time to perform the procedure and defining what are potential benefits of early compared to late tracheostomy. This retrospective cohort aims to assess the potential benefits of early tracheostomy on post-operative outcomes, length of stay and post-tracheostomy complications within cardiac surgical population. Methods: After obtaining REB approval, we conducted a retrospective chart review in a single, tertiary care institution, identifying patients who underwent tracheostomy after cardiac surgery from 1999 to 2006. Time-to-tracheostomy was defined as “early” if < 7 days or “late” if ≥ 7 days post-cardiac surgery). Results: 14,101 patients underwent cardiac surgery over the 7-year study period; from those, 147 (1.36%) received tracheostomy. 32 (22%) patients underwent early tracheostomy and 115 (78%) late tracheostomy. Incidence of atrial fibrillation (31.2% vs 61.7%; P = 0.003), kidney dysfunction (6.3% vs 27.2%; P =0.015) and kidney failure 18.8% vs 43.5%; P = 0.013) were lower in the early tracheostomy group. There were no differences on post tracheostomy infection or presence of acute respiratory distress syndrome. Both the ICU and hospital length of stay were significantly shorter in early tracheostomy group, 21.5 (ET) vs 36.9 (LT) days and 37.5 (ET) vs 57.6 (LT) days respectively. There were no differences in mortality between groups. Conclusions: There are significant benefits in reduction of postoperative morbidities with overall shorter ICU and hospital stay. These benefits may promote faster patient rehabilitation with reduced healthcare costs.

Management of unstable thoracolumbar fractures remains controversial. Furthermore, when these are accompanied by related neurological injury, the choice of approach, decompression technique and timing of the intervention could have a neuroprotective effect. In terms of site, the lumbar spine represents only 1.2% of cases, yet fractures with severe instability and neurological injury call for attainment of the same goals, i.e., neurological stability and decompression. After suffering high-energy trauma as a result of an accidental fall, a young male patient presenting with unstable injury of the lumbar spine and neurological impairment compatible with incomplete cauda equina syndrome was treated with emergency stabilisation and decompression through single-stage posterior transpedicular approach. At one year of the intervention, the patient is making good progress, with absence of lumbar pain, isolated deficit in left ankle dorsiflexion with no need of orthosis or cane, adequate sphincter control and return to his previous activity. Patients who present with unstable injury of the lumbar spine and incomplete neurological involvement can benefit from emergency stabilisation and decompression treatment by posterior transpedicular approach, with improvement in neurological status and functional recovery.

Background and objectives: Few studies have investigated the role psychological inflexibility (PI) could have in the context of chronic renal failure. The primary objective of this study was to analyse the psychometric features, the reliability and the validity of the Spanish version of the Acceptance and Action Questionnaire-II (AAQ-II) adapted to the context of patients undergoing haemodialysis (HD). The secondary objective was to assess the relationship between PI and parameters related to the adherence to treatment and quality of life in these types of patients. Materials and methods: Prospective cross-sectional study with patients on haemodialysis (N = 186). Results: The fat tissue index (15.56 ± 5.72 vs. 18.99 ± 8.91, P = 0.033), phosphorus levels (3.92 ± 1.24 vs. 4.66 ± 1.38; P = 0.001) and interdialytic weight gain (1.56 ± 0.69 vs. 1.89 ± 0.93, P = 0.016) were higher in patients with a higher PI score. Phosphorus levels (P = 0.013) significantly explained the variability of PI levels. PI was also shown as a significant predictor (P = 0.026) of the variability of phosphorus levels. Conclusions: The adaptation of the AAQ-II questionnaire to the HD context led to a valid and reliable measurement of PI in these types of patients and our results also seem to support the relationship between PI and health and quality of life parameters in patients with chronic conditions. Resumen: Antecedentes y objetivos: Apenas existen estudios que hayan investigado el papel que la inflexibilidad psicológica (IP) pudiera tener en el contexto de la IRC. El objetivo primario de este estudio fue analizar las propiedades psicométricas, la fiabilidad y la validez de la versión española del Acceptance and Action Questionnaire – II (AAQ-II) adaptada al contexto de pacientes en tratamiento de hemodiálisis (HD). El objetivo secundario fue analizar la relación entre IP y parámetros relacionados con la adhesión al tratamiento y calidad de vida en este tipo de pacientes. Materiales y métodos: Estudio transversal prospectivo con pacientes en hemodiálisis (N = 186). Resultados: El índice de tejido graso (15,56 ± 5,72 vs. 18,99 ± 8,91; p = 0,033), los niveles de fósforo (3,92 ± 1,24 vs. 4,66 ± 1,38; p = 0,001) y la ganancia de peso interdiálisis (1,56 ± 0,69 vs. 1,89 ± 0,93; p = 0,016) fueron mayores en los pacientes con más puntuación en IP. Los niveles de fósforo (p = 0,013) explicaron de forma significativa la variabilidad de los niveles de IP, la cual también se mostró como un predictor significativo (p = 0,026) de la variabilidad de los niveles de fósforo. Conclusiones: La adaptación del cuestionario AAQ-II al contexto de HD da lugar a una medida válida y fiable de la IP para este tipo de pacientes y los resultados de este estudio parecen apoyar el papel de la IP con relación a parámetros de salud y calidad de vida en el ámbito de las patologías crónicas.

Doravirine is a novel nonnucleoside reverse transcriptase inhibitor in development for use with other antiretroviral therapies to treat human immunodeficiency virus type 1 (HIV-1) infection. Doravirine metabolism predominantly occurs via cytochrome P450 3A with

Previous functional magnetic resonance imaging (fMRI) studies have demonstrated digit somatotopy in primary somatosensory cortex (SI), and even shown that at high spatial resolution it is possible to resolve within-digit somatotopy. However, fMRI studies have failed to resolve the spatial organisation of digit representations in secondary somatosensory cortex (SII). One of the major limitations of high spatial resolution fMRI studies of the somatosensory system has been the long acquisition time needed to acquire slices spanning both SI and SII. Here, we exploit the increased blood oxygenation level dependent contrast of ultra-high-field (7 Tesla) fMRI and the use of multiband imaging to study the topographic organisation in SI and SII with high spatial resolution at the individual subject level. A total of n = 6 subjects underwent vibrotactile stimulation of their face, hand digits and foot (body imaging) and their individual hand digits (digit mapping) for each left and right sides of the body. In addition, n = 2 subjects participated only in the body imaging experiment on both their left and right sides. We show an orderly representation of the face, hand digits and foot in contralateral primary cortex in each individual subject. In SII, there is clear separation of the body areas of the face, hand and foot but the spatial organisation varies across individual subjects. However, separate representation of the individual digits of the hand in SII could not be resolved, even at the spatial resolution of 1.5 mm due to largely overlapping representations.

Cardiopulmonary bypass (CPB) during cardiac surgery can involve deliberate hypothermia of the systemic (22-36 °C) and coronary circulations (as low as 8-12 °C). Adverse sequelae of cold-active antibodies have been feared and reported under such conditions, and some centers thus elect to screen for cold agglutinins before CPB. We reviewed the literature on cold agglutinins in cardiac surgery and described the yields and effects of cold agglutinin screening (CAS) in 14,900 cardiac surgery patients undergoing CPB over 8 years at a single institution. Cold agglutinin screening was positive in 47 cases (0.3%), at an annual testing cost of $17,000 CAD. The response of the surgical team to the preoperative discovery of a cold agglutinin was variable, with CPB modified to avoid hypothermia in approximately one-third of cases. In patients discovered to have a positive CAS, postoperative intensive care unit and hospital length of stay were marginally increased (54.6 vs. 42.8 hours, P = .02; 7 [6-14] vs. 7 [5-9] days, P = .04). However, the composite of mortality or severe morbidity (stroke, myocardial infarction, dialysis, low output syndrome, sepsis, and deep vein thrombosis) was not significantly different (14.9% vs. 9.2%, P = .2). Antibody verification found that only 43% of positive CAS patients had true cold agglutinins (20 patients). Furthermore, the rate of adverse events was low in both CAS-positive and true-positive cold agglutinin patients undergoing CPB and cardiac surgery. Finally, modification of CPB to attenuate hypothermia did not decrease adverse events. Based upon historical and local data, preclinical CAS is cost-substantial and nonspecific. Cold agglutinin screening does not promote an algorithm of care that meaningfully improves patient CPB outcomes.

Secondary dengue virus infections are a major risk for developing dengue hemorrhagic fever. Recent exposure to infectious bites of Aedes aegypti (L.) females in previously diagnosed dengue cases fulfills the epidemiological model of dengue hemorrhagic fever. A study was comprised of 357 (89.2%) dengue and 43 (10.8%) dengue hemorrhagic fever cases confirmed by laboratory tests and clinical manifestations. An entomological survey was done in homes and backyards. Concurrently, a questionnaire was used to assess the impact of healthpromotion campaigns through knowledge of the vector and its epidemiological role. Seventy-six (28.4%) of the 268 (67.0%) total wet or dry oviposition sites were positive for the presence of larvae or pupae, while adult Ae. aegypti were found in 32 (8.0%). One hundred thirty-two (33%) householders who formerly had dengue fever or dengue hemorrhagic fever had knowledge of either larval or adult dengue vector stages. According to gender distribution, 145 (36.2%) and 14 (3.5%...

There are several treatment options for hyperplastic gingival lesions. Among these, diode lasers have the advantages of less bleeding, which is an important characteristic in mucosal lesions, a shorter procedure time, better healing, and less complications. We present the case of a 48-year-old male patient with a history of cerebral palsy and a presumptive diagnosis of traumatic fibroma. The entire lesion was removed in one session with no complications. No recurrence was observed at 3 months follow up. This procedure can be considered a good modality especially for physically challenged patients.

Background: Current clinical guidelines recommend nutritional evaluation in respiratory patients. Thanks to bioimpedance it is possible to obtain an estimation of body composition in both normal and disease states, identifying protein and fat reserves. Aim: To compare, in a population of respiratory patients, the two most common methods of analysis of body composition by bioelectrical impedance: Single Frequency Bioimpedance Analysis (SFBIA), and Bioimpedance Spectroscopy (BIS). Methods: Pilot study. Group I (COPD patients included in a Pulmonary Rehabilitation program, 6 volunteers); Group II (hospitalized patients in a Unit of Pneumology, 10 volunteers); Group III (healthy subjects, 5 volunteers). Two measurements were performed in each case: a body composition estimation with a SFBIA device (Bodystat, Bodystat Limited) and another estimation with a BIS device (BCM, Fresenius Medical Care). For comparative analysis variables fat percentage and Fat-Free Mass Index (FFMI) were used. Results: Bland-Altman analysis of fat percentage revealed a mean bias of -3.5% of (SFBIA versus BIS, 95% limits of agreement from -18.8% to 11.7%, 100% of the measurements within the range). Bland-Altman analysis of FFMI revealed a mean bias of 0.8 kg/m 2 (95% limits of agreement from -3.5 kg/m 2 to 5.1 kg/m 2 , 94% of the measurements within the range). The correlation between measurements for fat percentage was r=0.73 (p=0.0009) and in the case of FFMI was r=0.86 (p=0.00001). Conclusions: Bland Altman approach revealed a good agreement between a SFBIA device and a BIS device to estimate body composition. The largest discrepancies between the two methods were observed in extreme values of body composition.

Several investigators have suggested that certain hydroxylated metabolites of 17β-estradiol (E2) are the proximate carcinogens that induce mammary carcinomas in estrogen-sensitive rodent models. The studies reported here were designed to examine the carcinogenic potential of different levels of E2 and the effects of genotoxic metabolites of E2 in an in vivo model sensitive to E2-induced mammary cancer. The potential induction of mammary tumors was determined in female ACI rats subcutaneously implanted with cholesterol pellets containing E2 (1, 2, or 3 mg), or 2-hydroxyestradiol (2-OH E2), 4-hydroxyestradiol (4-OH E2), 16α-hydroxyestradiol (16α-OH E2), or 4-hydoxyestrone (4-OH E1) (equimolar to 2 mg E2). Treatment with 1, 2, or 3 mg E2 resulted in the first appearance of a mammary tumor between 12 and 17 weeks, and a 50% incidence of mammary tumors was observed at 36, 19, and 18 weeks respectively. The final cumulative mammary tumor incidence in rats treated with 1, 2, or 3 mg E2 for 36 weeks was 50%, 73%, and 100% respectively. Treatment of rats with pellets containing 2-OH E2, 4-OH E2, 16α-OH E2, or 4-OH E1 did not induce any detectable mammary tumors. The serum levels of E2 in rats treated with a 1 or 3 mg E2 pellet for 12 weeks was increased 2- to 6-fold above control values (~30 pg/ml). Treatment of rats with E2 enhanced the hepatic microsomal metabolism of E2 to E1, but did not influence the 2- or 4-hydroxylation of E2. In summary, we observed a dose-dependent induction of mammary tumors in female ACI rats treated continuously with E2; however, under these conditions 2-OH E2, 4-OH E2, 16α-OH E2, and 4-OH E1 were inactive in inducing mammary tumors.

The contribution of human cytochrome P450 (P450) isoforms to the metabolism of aprepitant in humans was investigated using recombinant P450s and inhibition studies. In addition, aprepitant was evaluated as an inhibitor of human P450s. Metabolism of aprepitant by microsomes prepared from baculovirus-expressed human P450s was observed only when CYP1A2, CYP2C19, or CYP3A4 was present in the expression system. Incubation with CYP1A2 and CYP2C19 yielded only products of O-dealkylation, whereas CYP3A4 catalyzed both N- and O-dealkylation reactions. The metabolism of aprepitant by human liver microsomes was inhibited completely by ketoconazole or troleandomycin. No inhibition was observed with other P450 isoform-selective inhibitors. Aprepitant was evaluated also as a P450 inhibitor in human liver microsomes. No significant inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2D6, and CYP2E1 was observed in experiments with isoform-specific substrates (IC50 > 70 microM). Aprepitant was a moderate inhibitor of CYP3A4, with Ki values of approximately 10 microM for the 1'- and 4-hydroxylation of midazolam, and the N-demethylation of diltiazem, respectively. Aprepitant was a very weak inhibitor of CYP2C9 and CYP2C19, with Ki values of 108 and 66 microM for the 7-hydroxylation of warfarin and the 4'-hydroxylation of S-mephenytoin, respectively. Collectively, these results indicated that aprepitant is both a substrate and a moderate inhibitor of CYP3A4.

Excess production of H2O2 has been implicated in oncogenesis. The object of the present study was twofold: first, to determine the influence of chronic estradiol (E2) on the activities of selected hepatic antioxidant enzymes in female ACI rats, a strain that is highly sensitive to the induction of estrogen dependent mammary tumors; secondly, to evaluate the actions of dietary clofibrate, a peroxisome proliferator, on activities of these enzymes in control and E2-treated ACI rats. Enzymes selected for study were: NAD(P)H quinone oxidoreductase (NQO1), glutathione S-transferase (GST) and glutathione peroxidase (GPx). Cytosolic catalase (CAT) was also measured as an index of peroxisome proferation in control and E2- treated animals. E2 was administered chronically over 6 and 12 week periods from cholesterol pellet implants containing either 1 or 3 mg E2. Animals were fed AIN-76A diets with or without 0.4% clofibrate over the experimental period. NQO1 and GST but not GPx were induced to varying degrees (NQO1 about 300%, and GST about 45-97%) by chronic E2-treatment. E2-induced increases in these activities were completely prevented in rats exposed to dietary clofibrate. Dietary clofibrate also caused slight but significant reductions in baseline activities of NQO1, GST and GPx in control animals. Serum E2 levels, increased approximately 540% in a dose-dependent manner, and were not altered by dietary clofibrate. It is concluded that chronic E2 treatment markedly induces several important hepatic antioxidant enzymes in female ACI rats, and induction of these activities by E2 is inhibited completely by dietary clofibrate. Both of these actions have the potential to markedly influence the profile of E2 metabolites exported from the liver to E2 sensitive extrahepatic tissues and influence the initiation and progression of hormone-dependent tumors.

Administration of 0.4% clofibrate in the diet stimulated estradiol (E(2))-induced mammary carcinogenesis in the August-Copenhagen Irish (ACI) rat without having an effect on serum levels of E(2). This treatment stimulated by several-fold the NAD(P)H-dependent oxidative metabolism of E(2) and oleyl-CoA-dependent esterification of E(2) to 17beta-oleyl-estradiol by liver microsomes. Glucuronidation of E(2) by microsomal glucuronosyltransferase was increased moderately. In contrast, the activity of NAD(P)H quinone reductase 1 (NQO1), a representative monofunctional phase 2 enzyme, was significantly decreased in liver cytosol of rats fed clofibrate. Decreases in hepatic NQO1 in livers of animals fed clofibrate were noted before the appearance of mammary tumors. E(2) was delivered in cholesterol pellets implanted in 7-8-week-old female ACI rats. The animals received AIN-76A diet containing 0.4% clofibrate for 6, 12 or 28 weeks. Control animals received AIN-76A diet. Dietary clofibrate increased the number and size of palpable mammary tumors but did not alter the histopathology of the E(2)-induced mammary adenocarcinomas. Collectively, these results suggest that the stimulatory effect of clofibrate on hepatic esterification of E(2) with fatty acids coupled with the inhibition of protective phase 2 enzymes, may in part, enhance E(2)-dependent mammary carcinogenesis in the ACI rat model.

A comparative study of the effects of chronic 17β-estradiol (E2) treatment on microsomal oxidation and conjugation of E2 via Phase I and II enzymes in the ACI rat mammary gland (MG) and liver was performed. NADPH-dependent oxidation of E2 was not detected in the MG, but was readily measured in the liver. Oxidation was not altered by chronic E2 treatment. Ascorbic acid stimulated E2 oxidation (non-enzymatically) in MG microsomes, but had no effect in the liver. Hepatic but not MG NADP(H):quinone oxidoreductase and glutathione S-transferase activities increased 4.0- and 2.0-fold, respectively, after 6 weeks (w) of treatment. MG catalase activity was decreased 64% after 28 w of E2 treatment, when the rats had developed 100% incidence of MG adenocarcinomas. Moreover, the activities of phenolsulfotransferase SULT1A1 and fatty acyl-CoA:E2-acyltransferase ACO:E2 decreased by 95 and 80%, respectively, in the MG but not in liver. Decreases in these enzymes were maximal after 6 w and preceded induction of MG tumors. Collectively, these data indicate that E2 regulates the expression of antioxidant and E2-metabolizing enzymes differentially in the ACI rat liver and MG. The decreased activities of SULT1A1 and ACO:E2 may favor accumulation of E2 available for receptor binding and conversion to catechol estrogens, both of which are implicated in E2-induced mammary oncogenesis.

Exposure of female August-Copenhagen Irish (ACI) rats for 28 weeks to 3 mg of estradiol (E(2)) contained in cholesterol pellets elevated blood E(2) levels and caused palpable mammary tumors in all animals. Coadministration of phenobarbital (PB) in their drinking water reduced the incidence, number, and size of mammary tumors (MTs) but did not reduce blood E(2) levels. Inhibition of MTs by PB was accompanied by significant changes in total hepatic metabolism of E(2) measured in vitro. PB treatment caused approximately a 4-fold increase in hepatic metabolism of E(2) in control and E(2)-treated rats. The major NAD(P)H-dependent metabolites of E(2) were 2-OH-E(2) and estrone (E(1)). PB, either alone or together with E(2), increased microsomal 2-hydroxylation of E(2); formation of E(1) was either unaffected or decreased slightly. PB also increased microsomal metabolism of E(2) to minor metabolites (4-OH-E(2), 6alpha-OH-E(2), 6beta-OH-E(2), 14alpha-OH-E(2), 6-keto E(1), and 2-OH-E(1)) and reduced the formation of the E(2)-17beta-oleoyl ester and the E(2) 3- and 17-glucuronides. In contrast, when given in combination with E(2), PB increased the formation of both glucuronides. Cotreatment of animals with PB and E(2) increased activities of NAD(P)H:quinone oxidoreductase and glutathione S-transferase to a greater extent than either compound alone. Collectively, these results show that the multiple actions of PB on hepatic metabolism of E(2), including induction of E(2) hydroxylation, glucuronidation, and antioxidant defense enzymes along with inhibition of E(2) esterification in livers of female ACI rats, accompany a marked reduction of E(2)-dependent mammary tumors in this model.

Estradiol (E2) has been linked to both, protection against damage associated with chronic diseases or exposure to chemicals, and to the incidence of cancer. In its protective role, E2 appears to attenuate oxidative stress while as a carcinogen, E2 damages macromolecules via formation of reactive catechol metabolites. Alterations in the expression of antioxidant and xenobiotic metabolizing enzymes upon administration of pharmacological doses of E2 have been previously identified, but the effect of chronic exposure to low concentrations of E2 on activities of those enzymes in liver is unclear. The August-Copenhagen Irish (ACI) rat is more sensitive to estrogen-induced carcinogenesis than the Sprague–Dawley rat. Accordingly, the effect of treatment of female ACI and Sprague–Dawley rats for 6 weeks with E2 on activities of NAD(P)H quinone oxidoreductase 1 (NQO1), glutathione peroxidase, glutathione S-transferase (GST), phenol sulfotransferase (SULT1A1), cytochrome P450 (CYP450) and UDP-glucuronosyltransferase (UGT) was studied. Basal expression of these enzymes was similar in livers from both strains prior to exposure to E2. However, only NQO1 and GST activity was increased (3- and 2.5-fold, respectively) in liver cytosol of ACI rats treated with E2. In contrast, only NQO1 activity was increased modestly in livers of Sprague–Dawley rats. Other enzymes were not significantly affected in the livers of ACI or Sprague–Dawley rats following chronic treatment with E2. The selective induction of NQO1 and GST activity suggests that under physiological conditions, E2 may protect against oxidative stress via elevation of these antioxidant enzymes. The marked induction of NQO1 and GST in the ACI rat indicates a potential for this strain to be used as a model to study the E2-mediated modulation of these enzymes in tissues that are either sensitive to E2 carcinogenesis or to its protective effects.

The pharmacokinetics, metabolism, and brain penetration of the neurokinin 1 (NK1) receptor antagonist (substance P receptor antagonist), aprepitant (MK-0869), were examined in ferrets. This species exhibits human-type NK1receptor pharmacology and is of proven value in the identification of clinically useful drugs for the treatment of chemotherapy-induced nausea and vomiting in humans. After a single p.o. dose of aprepitant at 1 or 2 mg/kg, plasma levels of the compound were between approximately 200 and 270 ng/ml, 24 h after dosing. In the brain cortex, concentrations of aprepitant reached between approximately 80 and 150 ng/g of tissue 24 h after dosing. The predominant radioactive component present in the plasma and the brain of ferrets at 24 or 48 h after a single oral dose of [14C]aprepitant at 3 mg/kg was the parent compound itself. The slow plasma clearance of aprepitant ( approximately 1.5 ml/min/kg) and its abundance in ferret brain were in accord with its efficacy in blocking the retching and vomiting at 24 and 48 h postdose when ferrets were challenged with the emetic anticancer drug, cisplatin. When aprepitant and some of its metabolites were assessed for their in vitro binding affinity to the human NK1receptor, aprepitant demonstrated the highest affinity. Collectively, these data suggested that aprepitant, rather than its metabolites, was responsible, primarily, for the antiemetic activity of this compound in the male ferret.

was suggested that the formation of a greater amount of hepatic 4-OH-E2 relative to that of 2-OH-E2 is related to the higher susceptibility of the ACI rat to E2-induced mammary tumors as 4-OH-E2 but not 2-OH-E2 is carcinogenic in the Syrian hamster kidney (7–9), and 4-OH-E2 is more carcinogenic towards the uterus of CD-1 mice than is 2-OH-E2 (10). Elevated 4-hydroxylation of E2 is observed in the Syrian hamster kidney (11,12) and in the CD-1 mouse uterus (13) and pituitary (14), all of which organs are susceptible to E2 carcinogenesis. Moreover, when compared with normal biopsies of breast tissues, elevated ratios of 4-OH-E2 to 2OH-E2 formation have been reported in human breast tumor samples (15,16). In the present report, we describe and compare the patterns of E2 hydroxylation in liver microsomes from the highly estrogen-sensitive female ACI rat with patterns in microsomes from the less estrogen-sensitive female Sprague–Dawley rat strain. Because of the potential importance of the high 4hydroxylation of E2 in a rat strain that is highly sensitive to E2-induced mammary carcinogenesis, we have made an attempt to confirm and extend the studies of Wilson and Reed (4). The data presented herein, however, indicate that liver microsomal preparations from female ACI rats hydroxylate E2 predominantly in the 2-position, and only a very small amount of 4-OH-E2 is formed. Materials and methods

10529 Background: Pathogenesis in GIST could be related to cancer stem cell hypothesis (highly chemo resistant, very uncommon complete responses, kit is stem cell marker) even though no stem cell component in GIST has been yet demonstrated. Wnt signaling regulates proliferation in some normal and cancer stem cells as it occurs with intestinal epithelium. We have explored the prognostic significance of several Wnt signaling pathway and related molecules. To investigate the prognostic significance of β-Catenin, CDC25A, ROR2, p53, CUL4A, AKT-p and VEGFR-3 by immunohistochemical (IHC) analysis in TMA specimens of 101 non-gastric GIST. Methods: Data of diagnostic, therapeutic and follow-up procedures stem from the GIST Registry of GEIS. Cytoplasmic and/or membrane staining was deemed positive for ROR-2, VEGFR-3 and p-AKT antibodies whereas nuclear staining was positive for β-Catenin, CDC25A, CUL4A and p53 antibodies. IHC positive cases were considered if they displayed staining in at least 10% of cells. Statistical analyses for correlation of protein expression with known prognostic variables (mitoses, size) were performed with Mann-Whitney U test. Results: A subset of 101 non-gastric localized GIST patients was selected (90 intestinal, 15 others: mainly rectum and omentum). The median age was 62 y with gender distribution of 59M/42F and the median of follow-up was 36 months. The positivity for each protein was distributed as follows: ROR-2 63%, p-AKT 55%, β-Catenin 53%, VEGFR-3 22%, CDC25A 20%, p53 8% and CUL4A 7%. A statistically significant correlation was found between mitoses and β-Catenin (median 5 if negative/ 10 if positive, p=0.028); VEGFR-3 (median 5 if negative/21 if positive, p=0.002); CUL4A (median 6 if negative/60 if positive, p= 0.027). Additionally, tumor size was statistically correlated with VEGFR-3 (median 7 if negative/11 if positive, p=0.007). Conclusions: VEGFR-3, β-Catenin and CUL4A are correlated with the highest proliferative non-gastric GIST. These findings deserve further analysis and lead to potential new molecular therapeutic targets in GIST. This study was partially granted by Buesa Grant of GEIS.

10595 Background: To evaluate potential biomarkers of pathological response to bevacizumab-based neoadjuvant therapy in untreated breast cancers (BC) patients recruited in a phase II, multicenter clinical trial. Methods: Patients received a single infusion of bevacizumab (15 mg/ kg) (C1) 3 weeks prior to the beginning of neoadjuvant chemotherapy (NAC) consisting in 4 cycles of docetaxel (60 mg/mq), doxorubicin (50 mg/mq) and bevacizumab (15 mg/ kg) every 21 days (C2-C5) following by surgery. Biomarker expression was assessed by immunohistochemistry (Ki67, CD31, CD31/Ki67, VEGFR2, pVEGFR2 [Y951]) before and after bevacizumab infusion (C1). Gene expression was analyzed using Affimetrix Human Gene ST 1.0. Results: This analysis was performed on 73 patients (49 yr, range 29-70). Twenty (27%) patients obtained best response (G4-G5) whether 50 (68%) were considered as no responder (G1-G2-G3). Response was associated with negative estrogen receptors expression (p=0.02) and high Ki67 basal and after C1 expression (p=0.009 and p=0.01). Six (54%) of the triple negative tumors were responders (p=0.05). Interestingly, change in pVEGFR2 [Y951] staining induced by bevacizumab administration was found significantly associated with response (p=0.0). Decrease in the phosphorilation status of VEGFR2 (Y951) >70% yielded a receiver operating characteristic (ROC) curve area of 0.681 (95% CI: 0.536 - 0.825) with 84% sensitivity and 95% specificity. The positive and negative predictive values for this marker were 60% and 64%, respectively. The change in phosphorilation status of VEGFR2p remains a significant predictor biomarker of response in multivariate analysis (OR=0.9, IC%95 0.96-0.99, p=0.04) after adjusting for clinical-pathological characteristics. Conclusions: These findings suggest the role of the phosphorilation status of VEGFR2 as predictive biomarkers of pathological response to bevacizumab in neoadjuvant setting in breast cancer.

10512 Background: To investigate the role of DCE-MRI versus 18F-Misonidazole (FMISO) positron emission tomography (PET/CT) in the prediction of pathological response to bevacizumab-based neodajuvant therapy. Methods: 73 chemotherapy naïve, stage II and III breast cancer (BC) patients (pts) were enrolled in a phase II, single-arm, multicenter, open-label and prospective clinical trial. Pts received single infusion of bevacizumab (15 mg/ kg) (C1) 3 weeks prior to the beginning of neoadjuvant chemotherapy (NAC) consisting of 4 cycles of docetaxel (60 mg/mq), doxorubicin (50 mg/mq) and bevacizumab (15 mg/ kg) every 21 days (C2-C5), followed by surgery. Tumor proliferation, hypoxia and perfusion were evaluated respectively using 18F-Fluorothymidine (FLT) and 18F-Misonidazole (FMISO) positron emission tomography (PET/CT) and dynamic contrast enhancement magnetic resonance (DCE-MR). Serial imaging studies were performed in parallel at several time points including baseline (BL) and 14-21 days after bevacizumab alone (C1). Results: After only one administration of bev, tumor proliferation and perfusion assessed using FLT-PET and DCE-MRI significantly decrease (-26% and -46%, p10% yielded a ROC curve area of 0.7 (95% CI: 0.56 - 0.85) with high specificity (94%). Conclusions: Our findings suggest a significant value of early changes in tumor hypoxia assessed by FMISO-PET as a biomarker of pathological response in bevacizumab-based neoadjuvant therapy in breast cancer.

TPS153 Background: Despite several investigations, currently there are no proven biomarkers of bevacizumab efficacy. These studies are in advanced cancers and types of biomarkers and/or time points investigated are often limited. To determine the mechanisms of response and identify pathological characteristics of breast cancer (BC) patients (pts) most likely to be benefited of bevacizumab therapy, we choose a neoadjuvant setting where response could be examined as pathological response and where likely mechanisms of resistance are not yet developed. Multiple dynamic biomarkers are analyzed to best characterize tumors and combined to make robust predictions. Methods: This is a multicenter, phase II, non randomized study. Ethical approval was obtained in June 2009. Enrolment of 72 pts in the training set and 160 in the validation set is expected. Eligibility criteria are: women with age ≥18 years, performance status 0-1, histologically proven, previously untreated and stage II-III BC, adequate bone marrow, ...

2529 Background: PET offers a non invasive tool to assess cancer biology, staging tumors and potentially monitoring treatment response, anti-angiogenic therapy included. The aim of this study was t...

Background Medically unexplained symptoms are an important mental health problem in primary care and generate a high cost in health services. Cognitive behavioral therapy and psychodynamic therapy have proven effective in these patients. However, there are few studies on the effectiveness of psychosocial interventions by primary health care. The project aims to determine whether a cognitive-behavioral group intervention in patients with medically unexplained symptoms, is more effective than routine clinical practice to improve the quality of life measured by the SF-12 questionary at 12 month. Methods/design This study involves a community based cluster randomized trial in primary healthcare centres in Madrid (Spain). The number of patients required is 242 (121 in each arm), all between 18 and 65 of age with medically unexplained symptoms that had seeked medical attention in primary care at least 10 times during the previous year. The main outcome variable is the quality of life measured by the SF-12 questionnaire on Mental Healthcare. Secondary outcome variables include number of consultations, number of drug (prescriptions) and number of days of sick leave together with other prognosis and descriptive variables. Main effectiveness will be analyzed by comparing the percentage of patients that improve at least 4 points on the SF-12 questionnaire between intervention and control groups at 12 months. All statistical tests will be performed with intention to treat. Logistic regression with random effects will be used to adjust for prognostic factors. Confounding factors or factors that might alter the effect recorded will be taken into account in this analysis. Discussion This study aims to provide more insight to address medically unexplained symptoms, highly prevalent in primary care, from a quantitative methodology. It involves intervention group conducted by previously trained nursing staff to diminish the progression to the chronicity of the symptoms, improve quality of life, and reduce frequency of medical consultations. Trial registration The trial was registered with ClinicalTrials.gov, number NCT01484223 [http://ClinicalTrials.gov].