Morancho B.,Vall dHebron Institute of Oncology VHIO |
Parra-Palau J.L.,Vall dHebron Institute of Oncology VHIO |
Ibrahim Y.H.,Vall dHebron Institute of Oncology VHIO |
Bernado Morales C.,Vall dHebron Institute of Oncology VHIO |
And 11 more authors.
Oncogene | Year: 2013
The transmembrane tyrosine kinase HER2 (ErbB2, neu) is a prototypical biomarker for breast cancers and a therapeutic target. Although anti-HER2 therapies are remarkably effective, HER2-positive tumors are heterogeneous and some subtypes do not respond or develop resistance to these therapies. Here we show that H2NTF, a novel N-terminal fragment of HER2, is expressed at variable levels in 60% of the breast cancer samples analyzed. Characterization of H2NTF shows that it is devoid of the tyrosine kinase domain but it readily interacts with full-length HER2 and other HER receptors. As a consequence, H2NTF acts as a dominant-negative, attenuating the signaling triggered by full-length HER receptors. Expression of H2NTF results in resistance to the treatment with low concentrations of trastuzumab in vitro. However, cells expressing H2NTF and non-expressing cells have similar sensitivity to trastuzumab in vivo, indicating that H2NTF/trastuzumab complexes trigger antibody-dependent cell-mediated cytotoxicity. © 2013 Macmillan Publishers Limited. All rights reserved.
Roberts J.A.,University of Queensland |
Ulldemolins M.,University of Queensland |
Ulldemolins M.,Vall Dhebron University Hospital |
Roberts M.S.,University of Queensland |
And 6 more authors.
International Journal of Antimicrobial Agents | Year: 2010
The extreme pharmacokinetic behaviour of drugs sometimes observed in critically ill patients poses a significant threat to the achievement of optimal antibiotic treatment outcomes. Scant information on β-lactam antibiotic therapeutic drug monitoring (TDM) is available. The objective of this prospective study was to evaluate the practicality and utility of a β-lactam TDM programme in critically ill patients. TDM was performed twice weekly on all eligible patients at a 30-bed tertiary referral critical care unit. Blood concentrations were determined by fast-throughput high-performance liquid chromatography (HPLC) assays and were available within 12. h of sampling. Dose adjustment was instituted if the trough or steady-state blood concentration was below 4-5× the minimum inhibitory concentration (MIC) or above 10× MIC. A total of 236 patients were subject to TDM over an 11-month period. The mean ± standard deviation age was 53.5 ± 18.3 years. Dose adjustment was required in 175 (74.2%) of the patients, with 119 of these patients (50.4%) requiring dose increases after the first TDM. For outcome of therapy, 206 (87.3%) courses resulted in a positive treatment outcome and there were 30 (12.7%) treatment failures observed including 14 deaths and 15 courses requiring escalation to broader-spectrum agents; 1 course was ceased due to an adverse drug reaction. Using binomial logistic regression, only an elevated Acute Physiology and Chronic Health Evaluation (APACHE) II score (P<0.01) and elevated plasma creatinine concentration (P=0.05) were found to be predictive of mortality. In conclusion, further research is required to determine definitively whether achievement of optimal β-lactam pharmacodynamic targets improves clinical outcomes. © 2010 Elsevier B.V. and the International Society of Chemotherapy.
Miller D.H.,University College London |
Fazekas F.,Medical University of Graz |
Montalban X.,Vall Dhebron University Hospital |
Reingold S.C.,Scientific and Clinical Review Associates |
Trojano M.,University of Bari
Multiple Sclerosis Journal | Year: 2014
Background: Multiple sclerosis (MS) is influenced by pregnancy, sex and hormonal factors.Objectives: A comprehensive understanding of the role of pregnancy, sex and hormonal factors can provide insights into disease mechanisms, and new therapeutic developments and can provide improved patient care and treatment. Methods: Based on an international conference of experts and a comprehensive PubMed search for publications on these areas in MS, we provide a review of what is known about the impact of these factors on disease demographics, etiology, pathophysiology and clinical course and outcomes. Results and conclusions: Recommendations are provided for counseling and management of people with MS before conception, during pregnancy and after delivery. The use of disease-modifying and symptomatic therapies in pregnancy is problematic and such treatments are normally discontinued. Available knowledge about the impact of treatment on the mother, fetus and newborn is discussed. Recommendations for future research to fill knowledge gaps and clarify inconsistencies in available data are made. © The Author(s) 2013.
Ramirez-Estrada S.,Vall Dhebron University Hospital |
Borgatta B.,Vall Dhebron University Hospital |
Borgatta B.,Vall Dhebron Institute Of Research Vhir |
Rello J.,Autonomous University of Barcelona |
Rello J.,Research Center Biomedica en Red enfermedad Respiratoria eReS
Infection and Drug Resistance | Year: 2016
Ventilator-associated pneumonia is the most common infection in intensive care unit patients associated with high morbidity rates and elevated economic costs; Pseudomonas aeruginosa is one of the most frequent bacteria linked with this entity, with a high attributable mortality despite adequate treatment that is increased in the presence of multiresistant strains, a situation that is becoming more common in intensive care units. In this manuscript, we review the current management of ventilator-associated pneumonia due to P. aeruginosa, the most recent antipseudomonal agents, and new adjunctive therapies that are shifting the way we treat these infections. We support early initiation of broad-spectrum antipseudomonal antibiotics in present, followed by culture-guided monotherapy de-escalation when susceptibilities are available. Future management should be directed at blocking virulence; the role of alternative strategies such as new antibiotics, nebulized treatments, and vaccines is promising. © 2016 Ramírez-Estrada et al.
Walden A.P.,Intensive Care Unit |
Clarke G.M.,University of Oxford |
McKechnie S.,Intensive Care Unit |
Hutton P.,Intensive Care Unit |
And 6 more authors.
Critical Care | Year: 2014
Introduction: Community acquired pneumonia (CAP) is the most common infectious reason for admission to the Intensive Care Unit (ICU). The GenOSept study was designed to determine genetic influences on sepsis outcome. Phenotypic data was recorded using a robust clinical database allowing a contemporary analysis of the clinical characteristics, microbiology, outcomes and independent risk factors in patients with severe CAP admitted to ICUs across Europe.Methods: Kaplan-Meier analysis was used to determine mortality rates. A Cox Proportional Hazards (PH) model was used to identify variables independently associated with 28-day and six-month mortality.Results: Data from 1166 patients admitted to 102 centres across 17 countries was extracted. Median age was 64 years, 62% were male. Mortality rate at 28 days was 17%, rising to 27% at six months. Streptococcus pneumoniae was the commonest organism isolated (28% of cases) with no organism identified in 36%. Independent risk factors associated with an increased risk of death at six months included APACHE II score (hazard ratio, HR, 1.03; confidence interval, CI, 1.01-1.05), bilateral pulmonary infiltrates (HR1.44; CI 1.11-1.87) and ventilator support (HR 3.04; CI 1.64-5.62). Haematocrit, pH and urine volume on day one were all associated with a worse outcome.Conclusions: The mortality rate in patients with severe CAP admitted to European ICUs was 27% at six months. Streptococcus pneumoniae was the commonest organism isolated. In many cases the infecting organism was not identified. Ventilator support, the presence of diffuse pulmonary infiltrates, lower haematocrit, urine volume and pH on admission were independent predictors of a worse outcome. © 2014 Walden et al.; licensee BioMed Central Ltd.