Programmed death ligand-1 expression in adrenocortical carcinoma: an exploratory biomarker study

Background: Adrenocortical carcinoma (ACC) is a rare tumor in which prognostic factors are still not well established. Programmed Death Ligand-1 (PD-L1) expression in ACC and its association with clinico-pathological features and survival outcomes are unknown. Methods: Formalin-fixed paraffin-embedded (FFPE) specimens were obtained from 28 patients with ACC. PD-L1 expression was evaluated by immunohistochemistry (IHC) in both tumor cell membrane and tumor infiltrating mononuclear cells (TIMC). PD-L1 positivity on tumor cells was defined as ≥5% tumor cell membrane staining. TIMC were evaluated by IHC using a CD45 monoclonal antibody. For PD-L1 expression in TIMC, a combined score based on the extent of infiltrates and percentage of positive cells was developed. Any score greater that zero was considered PD-L1 positive. Baseline clinico-pathological characteristics and follow up data were retrospectively collected. Comparisons between PD-L1 expression and clinico-pathological features were evaluated using unpaired t-test and Fisher’s exact test. Kaplan-Meier method and log-rank test were used to assess association between PD-L1 expression and 5-year overall survival (OS). Results: Among 28 patients with surgically treated ACC, 3 (10.7%) were considered PD-L1 positive on tumor cell membrane. On the other hand, PD-L1 expression in TIMC was performed in 27 specimens and PD-L1 positive staining was observed in 19 (70.4%) patients. PD-L1 positivity in either tumor cell membrane or TIMC was not significantly associated with higher stage at diagnosis, higher tumor grade, excessive hormone secretion, or OS. Conclusions: PD-L1 expression can exist in ACC in both tumor cell membrane and TIMC with no relationship to clinico-pathologic parameters or survival. Electronic supplementary material The online version of this article (doi:10.1186/s40425-015-0047-3) contains supplementary material, which is available to authorized users

Prevention of hypertension in patients with pre-hypertension: protocol for the PREVER-prevention trial

<p>Abstract</p> <p>Background</p> <p>Blood pressure (BP) within pre-hypertensive levels confers higher cardiovascular risk and is an intermediate stage for full hypertension, which develops in an annual rate of 7 out of 100 individuals with 40 to 50 years of age. Non-drug interventions to prevent hypertension have had low effectiveness. In individuals with previous cardiovascular disease or diabetes, the use of BP-lowering agents reduces the incidence of major cardiovascular events. In the absence of higher baseline risk, the use of BP agents reduces the incidence of hypertension. The PREVER-prevention trial aims to investigate the efficacy, safety and feasibility of a population-based intervention to prevent the incidence of hypertension and the development of target-organ damage.</p> <p>Methods</p> <p>This is a randomized, double-blind, placebo-controlled clinical trial, with participants aged 30 to 70 years, with pre-hypertension. The trial arms will be chlorthalidone 12.5 mg plus amiloride 2.5 mg or identical placebo. The primary outcomes will be the incidence of hypertension, adverse events and development or worsening of microalbuminuria and of left ventricular hypertrophy in the EKG. The secondary outcomes will be fatal or non-fatal cardiovascular events: myocardial infarction, stroke, heart failure, evidence of new sub-clinical atherosclerosis, and sudden death. The study will last 18 months. The sample size was calculated on the basis of an incidence of hypertension of 14% in the control group, a size effect of 40%, power of 85% and P alpha of 5%, resulting in 625 participants per group. The project was approved by the Ethics committee of each participating institution.</p> <p>Discussion</p> <p>The early use of blood pressure-lowering drugs, particularly diuretics, which act on the main mechanism of blood pressure rising with age, may prevent cardiovascular events and the incidence of hypertension in individuals with hypertension. If this intervention shows to be effective and safe in a population-based perspective, it could be the basis for an innovative public health program to prevent hypertension in Brazil.</p> <p>Trial Registration</p> <p>Clinical Trials <a href="http://www.clinicaltrials.gov/ct2/show/NCT00970931">NCT00970931</a>.</p

Definições para a padronização da pesquisa de auto-anticorpos contra constituintes do núcleo (FAN HEp-2), nucléolo, citoplasma e aparelho mitótico e suas associações clínicas

OBJECTIVE: The Second Brazilian Consensus on Antinuclear Antibodies (ANA) in HEp-2 Cells approved and extended the decision trees developed during the First Brazilian Consensus in order to also offer information about mixed patterns of fluorescence. METHODS: Since this test elicits reactions not only to nuclear autoimmune antigens but also to different cell compartments, new denominations for the test were approved. Results and CONCLUSIONS: These new denominations encompass variations on the autoantibody testing against the nucleus (ANA HEp-2), nucleolus, cytoplasm, and mitotic apparatus issue. Furthermore, major clinical associations were described for each immunofluorescent pattern, facilitating the interpretation of laboratory results in the clinical practice.OBJETIVO: O Segundo Consenso Brasileiro de Fator Antinuclear (FAN) em Células HEp-2 ratificou os algoritmos de decisão para leitura dos padrões do FAN na imunofluorescência indireta vistos na primeira edição do Consenso Brasileiro, adicionando ainda um novo algoritmo relacionado com os padrões mistos. MÉTODOS: Tendo em vista a habilidade do teste em detectar autoantígenos nos distintos compartimentos celulares, e não apenas no núcleo, propõe-se novas denominações para este exame laboratorial. RESULTADOS E CONCLUSÕES: Como novas denominações algumas sugestões foram igualmente aceitas, dentro do tema pesquisa de auto-anticorpos contra constituintes do núcleo (FAN HEp-2), nucléolo, citoplasma e aparelho mitótico. Foram abordadas as principais relevâncias clínicas com os padrões de FAN descritos, facilitando o melhor uso do ensaio pelo médico.FMUSPUNIFESPBio-Rad Laboratório BrasilHospital Geral de GoiâniaBiomédicaUniversidade Federal de UberlândiaUFMG HCPUCRS HCNew Life Produtos HospitalaresUniversidade Católica de GoiásFMUSP HC Laboratório CentralPatologista ClínicaFMUSP HCFrischmann Aisengart Unidad InmunologíaUniversidade Católica de Goiás Laboratório de Auto-ImunidadeExame Medicina LaboratorialFMUFG HC Laboratório de Imuno-Reumatologia e HLALab. Santa LuziaMedivax/BionHSPE/SPUniversidade Católica de Goiás Laboratório da Área de SaúdeFarmacêutica-BioquímicaUniv. Fed. Mato GrossoFMUFG Serviço de ReumatologiaHospital Durand Unidad InmunologíaLaboratório ClínicoUFRGS HCPA Serviço de ReumatologiaUERJ FCMUFMG FMHospital Universitário de Brasília Laboratório de ReumatologiaUNIFESPSciEL

Assessment of canal walls after biomechanical preparation of root canals instrumented with protaper universalTM rotary system

OBJECTIVE: The aim of this study was to examine the instrumented walls of root canals prepared with the ProTaper UniversalTM rotary system. MATERIAL AND METHODS: Twenty mesiobuccal canals of human first mandibular molars were divided into 2 groups of 10 specimens each and embedded in a muffle system. The root canals were transversely sectioned 3 mm short of the apex before preparation and remounted in their molds. All root canals were prepared with ProTaper UniversalTM rotary system or with NitiflexTM files. The pre and postoperative images of the apical thirds viewed with a stereoscopic magnifier (X45) were captured digitally for further analysis. Data were analyzed statistically by Fisher's exact test and Chi-square test at 5% significance level. RESULTS: The differences observed between the instrumented and the noninstrumented walls were not statistically significant (p<0.05). CONCLUSIONS: The NitiflexTM files and the ProTaper UniversalTM rotary system failed to instrument all the root canal walls

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Imbalanced Matrix Metalloproteinases in Cardiovascular Complications of End-Stage Kidney Disease: A Potential Pharmacological Target

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)End-stage kidney disease (ESKD) is a major health problem associated with very high morbidity and mortality secondary to cardiovascular complications, especially in ESKD patients on dialysis. Therefore, exploring key mechanisms underlying cardiovascular alterations associated with ESKD may offer reasonable pharmacological targets that may benefit these patients. Imbalanced matrix metalloproteinases (MMP) activities have been implicated in many cardiovascular diseases, and growing evidence now indicates that excessive MMP activities contribute to cardiovascular complications in ESKD patients. However, there is no study on the effects of MMP inhibitors (MMPIs) in such patients. MMPIs may prevent against the vascular and cardiac changes associated with ESKD. In this MiniReview, we aimed at reviewing current evidence supporting the idea that pharmacological inhibition of imbalanced MMP activities in ESKD may decrease the morbidity and mortality associated with cardiovascular complications in ESKD patients. However, MMPs have variable effects during different phases of kidney disease, and therefore optimal timing for MMP inhibition during a disease process may vary significantly and is largely undetermined. While current research shows that MMPs play a role in the pathogenesis of the cardiovascular alterations found in ESKD patients, clinical studies are required to validate the idea of using MMPIs in ESKD.1105409415Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Imbalanced matrix metalloproteinases in cardiovascular complications of end‐stage kidney disease: a potential pharmacological target

End-stage kidney disease (ESKD) is a major health problem associated with very high morbidity and mortality secondary to cardiovascular complications, especially in ESKD patients on dialysis. Therefore, exploring key mechanisms underlying cardiovascular alterations associated with ESKD may offer reasonable pharmacological targets that may benefit these patients. Imbalanced matrix metalloproteinases (MMP) activities have been implicated in many cardiovascular diseases, and growing evidence now indicates that excessive MMP activities contribute to cardiovascular complications in ESKD patients. However, there is no study on the effects of MMP inhibitors (MMPIs) in such patients. MMPIs may prevent against the vascular and cardiac changes associated with ESKD. In this MiniReview, we aimed at reviewing current evidence supporting the idea that pharmacological inhibition of imbalanced MMP activities in ESKD may decrease the morbidity and mortality associated with cardiovascular complications in ESKD patients. However, MMPs have variable effects during different phases of kidney disease, and therefore optimal timing for MMP inhibition during a disease process may vary significantly and is largely undetermined. While current research shows that MMPs play a role in the pathogenesis of the cardiovascular alterations found in ESKD patients, clinical studies are required to validate the idea of using MMPIs in ESKD1105409415CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPES