Hezova R.,Masaryk University |
Hezova R.,Comprehensive Care |
Kovarikova A.,Masaryk University |
Srovnal J.,Palacky University |
And 8 more authors.
Diagnostic Pathology | Year: 2015
Background: Esophageal cancer is the malignant tumor with very poor prognosis and increasing incidence often diagnosed at very late stage, so the prognosis of affected patients is unsatisfactory, despite the development of therapeutic option such as surgery, chemotherapy and radiotherapy. Consequently, there is a great need for biomarkers to allow a tailored multimodality approach with increased efficiency. Altered expression of microRNAs has been reported in wide range of malignancies, including esophageal cancer. The aim of this study was to examine the expression levels of candidate microRNAs in esophageal cancer and evaluate their diagnostic and prognostic potential. Findings: Using quantitative real-time PCR, expression levels of 9 candidate microRNAs were examined in 62 tissue samples, 23 esophageal adenocarcinomas, 22 esophageal squamous cell carcinomas and 17 adjacent esophageal mucosa samples. MicroRNA expression levels were further analyzed in regards to clinico-pathological features of esophageal cancer patients. We observed significantly decreased levels of miR-203 and increased levels of miR-21 in adenocarcinoma tissues when compared to normal mucosa. MiR-29c and miR-148 indicated good ability to distinguish between histological subtypes of esophageal cancer. MiR-203 and miR-148 were linked to disease-free survival and overall survival in esophageal adenocarcinoma patients, and miR-148 also in esophageal squamous cell carcinoma patients. Conclusions: Our data suggest that altered expression of miR-21, miR-29c, miR-148 and miR-203 are related to neoplastic transformation and progression of the disease and these microRNAs could serve as a potential diagnostic and prognostic biomarkers in esophageal cancer. Virtual slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/4646922201567057 © Hezova et al.
Underdiagnosis of Clostridium difficile across Europe: The European, multicentre, prospective, biannual, point-prevalence study of Clostridium difficile infection in hospitalised patients with diarrhoea (EUCLID)
Davies K.A.,University of Leeds |
Longshaw C.M.,Astellas Pharma Europe |
Davis G.L.,University of Leeds |
Bouza E.,Hospital General Universitario Gregorio Maranon |
And 18 more authors.
The Lancet Infectious Diseases | Year: 2014
Background: Variations in testing for Clostridium difficile infection can hinder patients' care, increase the risk of transmission, and skew epidemiological data. We aimed to measure the underdiagnosis of C difficile infection across Europe. Methods: We did a questionnaire-based study at 482 participating hospitals across 20 European countries. Hospitals were questioned about their methods and testing policy for C difficile infection during the periods September, 2011, to August, 2012, and September, 2012, to August, 2013. On one day in winter, 2012-13 (December, 2012, or January, 2013), and summer, 2013 (July or August), every hospital sent all diarrhoeal samples submitted to their microbiology laboratory to a national coordinating laboratory for standardised testing of C difficile infection. Our primary outcome measures were the rates of testing for and cases of C difficile infection per 10 000 patient bed-days. Results of local and national C difficile infection testing were compared with each other. If the result was positive at the national laboratory but negative at the local hospital, the result was classified as undiagnosed C difficile infection. We compared differences in proportions with the Mann-Whitney test, or McNemar's test if data were matched. Findings: During the study period, participating hospitals reported a mean of 65.8 tests (country range 4.6-223.3) for C difficile infection per 10 000 patient-bed days and a mean of 7.0 cases (country range 0.7-28.7) of C difficile infection per 10 000 patient-bed days. Only two-fifths of hospitals reported using optimum methods for testing of C difficile infection (defined by European guidelines), although the number of participating hospitals using optimum methods increased during the study period, from 152 (32%) of 468 in 2011-12 to 205 (48%) of 428 in 2012-13. Across all 482 European hospitals on the two sampling days, 148 (23%) of 641 samples positive for C difficile infection (as determined by the national laboratory) were not diagnosed by participating hospitals because of an absence of clinical suspicion, equating to about 74 missed diagnoses per day. Interpretation: A wide variety of testing strategies for C difficile infection are used across Europe. Absence of clinical suspicion and suboptimum laboratory diagnostic methods mean that an estimated 40 000 inpatients with C difficile infection are potentially undiagnosed every year in 482 European hospitals. Funding: Astellas Pharmaceuticals Europe. © 2014 Elsevier Ltd.
Baumann I.,Boeblingen Hospital |
Fuhrer M.,Boeblingen Hospital |
Behrendt S.,Ludwig Maximilians University of Munich |
Campr V.,University Hospital in Motol |
And 9 more authors.
Histopathology | Year: 2012
Aims: To evaluate the reproducibility and reliability of the histomorphological criteria differentiating severe aplastic anaemia (SAA) and hypoplastic refractory cytopenia of childhood (RCC), the most frequently acquired hypocellular bone marrow conditions of childhood. Methods and results: We performed a double-blind interobserver study of 100 different cases of SAA and RCC among seven haematopathologists of the European Working Group of MDS in Childhood (EWOG-MDS) and the German SAA study. Cases with foci of typical myelodysplastic syndrome (MDS) morphology, such as patchy erythropoiesis with defective maturation, in an otherwise highly hypocellular or adipocytic bone marrow were classified as having RCC. Bone marrow samples without a patchy distribution, few scattered myeloid cells or haematopoietic aplasia were diagnosed as SAA. In only four of 100 cases did the reference pathologists not reach agreement regarding classification as SAA or RCC. The kappa index was 0.79. Conclusions: Our results show that the vast majority of SAA and RCC cases can be reliably differentiated by morphological means alone. A clear differentiation between SAA and RCC at presentation is mandatory for optimizing therapy strategies, and might be responsible for the fact that, in the German childhood SAA study, the probability of developing clonal disease after immunosuppressive therapy has dropped to 3%. © 2012 Blackwell Publishing Ltd.
PubMed | University of Leipzig, University of Hradec Kralove, Copenhagen University, Royal Cornwall Hospital and 12 more.
Type: | Journal: BMC anesthesiology | Year: 2016
Glycaemia control (GC) remains an important therapeutic goal in critically ill patients. The enhanced Model Predictive Control (eMPC) algorithm, which models the behaviour of blood glucose (BG) and insulin sensitivity in individual ICU patients with variable blood samples, is an effective, clinically proven computer based protocol successfully tested at multiple institutions on medical and surgical patients with different nutritional protocols. eMPC has been integrated into the B.Braun Space GlucoseControl system (SGC), which allows direct data communication between pumps and microprocessor. The present study was undertaken to assess the clinical performance and safety of the SGC for glycaemia control in critically ill patients under routine conditions in different ICU settings and with various nutritional protocols.The study endpoints were the percentage of time the BG was within the target range 4.4 - 8.3 mmol.l(-1), the frequency of hypoglycaemic episodes, adherence to the advice of the SGC and BG measurement intervals. BG was monitored, and insulin was given as a continuous infusion according to the advice of the SGC. Nutritional management (enteral, parenteral or both) was carried out at the discretion of each centre.17 centres from 9 European countries included a total of 508 patients, the median study time was 2.9 (1.9-6.1) days. The median (IQR) time-in-target was 83.0 (68.7-93.1) % of time with the mean proposed measurement interval 2.0 0.5 hours. 99.6% of the SGC advices on insulin infusion rate were accepted by the user. Only 4 episodes (0.01% of all BG measurements) of severe hypoglycaemia <2.2 mmol.l(-1) in 4 patients occurred (0.8%; 95% CI 0.02-1.6%).Under routine conditions and under different nutritional protocols the Space GlucoseControl system with integrated eMPC algorithm has exhibited its suitability for glycaemia control in critically ill patients.ClinicalTrials.gov NCT01523665.
PubMed | Comprehensive Care, General University Hospital in Prague, University Hospital in Motol, Masaryk University and Palacky University
Type: Journal Article | Journal: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine | Year: 2016
Esophageal cancer is a malignant disease with poor prognosis, increasing incidence, and ineffective treatment options. MicroRNAs are post-transcriptional regulators of gene expression involved in many biological processes including carcinogenesis. We determined miR-205 expression levels in tumor/non-tumor tissues of 45 esophageal cancer patients using qPCR and found that decreased level of miR-205 in tumor tissue correlates with poor overall survival in esophageal adenocarcinoma patients. Further, we observed significantly higher levels of miR-205 in tumor tissue of esophageal squamous cell carcinoma. Ectopic overexpression of miR-205 in adenocarcinoma cell line SK-GT-4 led to decreased cell proliferation, cell cycle arrest in G1, and decreased migration ability. Conversely, in squamous cell line KYSE-150, same effects like inhibition of proliferation, migration, and colony-forming potential and cell cycle arrest in G2 were observed after silencing of miR-205. We performed global gene expression profiling and revealed that suppressive functioning of miR-205 in adenocarcinoma could be realized through regulation of epithelial-mesenchymal transition (EMT), whereas oncogenic in squamous cell carcinoma by regulation of metalloproteinase 10. Our results suggest that miR-205 could serve as biomarker in esophageal cancer and acts as a tumor suppressor in esophageal adenocarcinoma and oncogene in esophageal squamous cell carcinoma.
PubMed | Mayo Medical School, Institute of Clinical and Experimental Medicine IKEM, University Hospital in Motol, Palacky University and 2 more.
Type: | Journal: European journal of heart failure | Year: 2016
Iron replacement improves clinical status in iron-deficient patients with heart failure (HF), but the pathophysiology is poorly understood. Iron is essential not only for erythropoiesis, but also for cellular bioenergetics. The impact of myocardial iron deficiency (MID) on mitochondrial function, measured directly in the failing human heart, is unknown.Left ventricular samples were obtained from 91 consecutive HF patients undergoing transplantation and 38 HF-free organ donors (controls). Total myocardial iron content, mitochondrial respiration, citric acid cycle and respiratory chain enzyme activities, respiratory chain components (complex I-V), and protein content of reactive oxygen species (ROS)-protective enzymes were measured in tissue homogenates to quantify mitochondrial function. Myocardial iron content was lower in HF compared with controls (15641 vs. 20038ggMyocardial iron content is decreased and mitochondrial functions are impaired in advanced HF. MID in HF is associated with diminished citric acid cycle enzyme activities and decreased ROS-protecting enzymes. MID may contribute to altered myocardial substrate use and to worsening of mitochondrial dysfunction that exists in HF.
Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): A randomised, double-blind, multicentre, phase 3 trial
Zhu A.X.,Harvard University |
Park J.O.,Sungkyunkwan University |
Ryoo B.-Y.,University of Ulsan |
Yen C.-J.,National Cheng Kung University |
And 16 more authors.
The Lancet Oncology | Year: 2015
Background: VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis. Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 antagonist. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib. Methods: In this randomised, placebo-controlled, double-blind, multicentre, phase 3 trial (REACH), patients were enrolled from 154 centres in 27 countries. Eligible patients were aged 18 years or older, had hepatocellular carcinoma with Barcelona Clinic Liver Cancer stage C disease or stage B disease that was refractory or not amenable to locoregional therapy, had Child-Pugh A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, had previously received sorafenib (stopped because of progression or intolerance), and had adequate haematological and biochemical parameters. Patients were randomly assigned (1:1) to receive intravenous ramucirumab (8 mg/kg) or placebo every 2 weeks, plus best supportive care, until disease progression, unacceptable toxicity, or death. Randomisation was stratified by geographic region and cause of liver disease with a stratified permuted block method. Patients, medical staff, investigators, and the funder were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01140347. Findings: Between Nov 4, 2010, and April 18, 2013, 565 patients were enrolled, of whom 283 were assigned to ramucirumab and 282 were assigned to placebo. Median overall survival for the ramucirumab group was 9·2 months (95% CI 8·0-10·6) versus 7·6 months (6·0-9·3) for the placebo group (HR 0·87 [95% CI 0·72-1·05]; p=0·14). Grade 3 or greater adverse events occurring in 5% or more of patients in either treatment group were ascites (13 [5%] of 277 patients treated with ramucirumab vs 11 [4%] of 276 patients treated with placebo), hypertension (34 [12%] vs ten [4%]), asthenia (14 [5%] vs five [2%]), malignant neoplasm progression (18 [6%] vs 11 [4%]), increased aspartate aminotransferase concentration (15 [5%] vs 23 [8%]), thrombocytopenia (13 [5%] vs one [<1%]), hyperbilirubinaemia (three [1%] vs 13 [5%]), and increased blood bilirubin (five [2%] vs 14 [5%]). The most frequently reported (≥1%) treatment-emergent serious adverse event of any grade or grade 3 or more was malignant neoplasm progression. Interpretation: Second-line treatment with ramucirumab did not significantly improve survival over placebo in patients with advanced hepatocellular carcinoma. No new safety signals were noted in eligible patients and the safety profile is manageable. Funding: Eli Lilly and Co. © 2015 Elsevier Ltd.
PubMed | Krajska nemocnice Liberec a.s., Czech Technical University, Na Homolce Hospital, University Hospital in Motol and Charles University
Type: Journal Article | Journal: Journal of translational medicine | Year: 2016
Current research highlights the role of microcirculatory disorders in post-cardiac arrest patients. Affected microcirculation shows not only dissociation from systemic hemodynamics but also strong connection to outcome of these patients. However, only few studies evaluated microcirculation directly during cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). The aim of our experimental study in a porcine model was to describe sublingual microcirculatory changes during CA and CPR using recent videomicroscopic technology and provide a comparison to parameters of global hemodynamics.Cardiac arrest was induced in 18 female pigs (503kg). After 3min without treatment, 5min of mechanical CPR followed. Continuous hemodynamic monitoring including systemic blood pressure and carotid blood flow was performed and blood lactate was measured at the end of baseline and CPR. Sublingual microcirculation was assessed by the Sidestream Dark Field (SDF) technology during baseline, CA and CPR. Following microcirculatory parameters were assessed off-line separately for capillaries (20m) and other vessels: total and perfused vessel density (TVD, PVD), proportion of perfused vessels (PPV), microvascular flow index (MFI) and heterogeneity index (HI).In comparison to baseline the CA small vessel microcirculation was only partially preserved: TVD 15.64 (13.59-18.48) significantly decreased to 12.51 (10.57-13.98)mm/mm(2), PVD 15.57 (13.56-17.80) to 5.53 (4.17-6.60)mm/mm(2), PPV 99.64 (98.05-100.00) to 38.97 (27.60-46.29)%, MFI 3.00 (3.00-3.08) to 1.29 (1.08-1.58) and HI increased from 0.08 (0.00-0.23) to 1.5 (0.71-2.00), p=0.0003 for TVD and <0.0001 for others, respectively. Microcirculation during ongoing CPR in small vessels reached 59-85% of the baseline values: TVD 13.33 (12.11-15.11)mm/mm(2), PVD 9.34 (7.34-11.52)mm/mm(2), PPV 72.34 (54.31-87.87)%, MFI 2.04 (1.58-2.42), HI 0.65 (0.41-1.07). The correlation between microcirculation and global hemodynamic parameters as well as to lactate was only weak to moderate (i.e. Spearmans 0.02-0.51) and after adjustment for multiple correlations it was non-significant.Sublingual microcirculatory parameters did not correlate with global hemodynamic parameters during simulated porcine model of CA and CPR. SDF imaging provides additional information about tissue perfusion in the course of CPR.
Spevacek V.,Czech Technical University |
Pilarova K.,Czech Technical University |
Koncekova J.,Na Homolce Hospital |
Koncek O.,University Hospital in Motol
Physics in Medicine and Biology | Year: 2014
In order to decrease the negative influence of oxygen to the response of PAG dosimeters THPC has been added to the gel in the role of scavenger. Apart from the decreased influence of oxygen, THPC also influences other properties of gel dosimeters. This study examines these influences and their quantification. Previous studies have shown that increasing the concentration of THPC causes a decreasing response of the dosimeter (as measured in the relaxation rate R 2). Evaluation of the IR spectrum of gels irradiated by a variety of doses has shown that it is caused mostly by the changed structure of the arising polymer, not due to the decreased polymerization. THPC also changes the kinetics of the subsequent reactions in the gel after the end of irradiation. THPC has its influence also on the size of the dose response overshoot that happens in the areas of steep dose gradients. An easy model of action in the gel was suggested, which allows one to estimate the size and kinetics of the changed response of the dosimeter after the end of irradiation depending on the content of THPC, the size of the dose and the dose gradient. © 2014 Institute of Physics and Engineering in Medicine.
Pokorny J.,University Hospital in Motol |
Stanek V.,Institute for Clinical and Experimental Medicine |
Vrana M.,Institute for Clinical and Experimental Medicine
Physiological Research | Year: 2011
The most common cause of sudden cardiac death is ventricular fibrillation (VF). In addition to the status, size and location of the ventricular focus, a major pathogenic mechanism triggering VF is autonomic dysbalance (disturbance). This term refers to a wide range of reflex changes in the ratio of sympathetic to vagal ventricular activation over time, occurring immediately after coronary artery occlusion at the onset of acute myocardial infarction (AMI). Another trigger of VF is autonomic disturbance due to emotional stress. Experimental and clinical research into autonomic disturbances associated with coronary artery occlusion and emotional stress was given considerable attention as early as some 30 years ago when researchers were already searching for ways of inhibiting autonomic disturbances using predominant sympathetic and vagal activation by beta-blockers (BB) and atropine, respectively. The aim of our paper is to compare results obtained 30 years ago with current status of experimental and clinical research into SCD prevention. Another aim is to identify questions that have remained unanswered to date; answers to these outstanding questions could help further reduce the risk of SCD. © 2011 Institute of Physiology.