Peiro G.,University of Alicante |
Ortiz-Martinez F.,University of Alicante |
Gallardo A.,Clinica Girona |
Perez-Balaguer A.,University of Alicante |
And 8 more authors.
British Journal of Cancer | Year: 2014
Background:Src is a non-receptor tyrosine kinase involved in signalling and crosstalk between growth-promoting pathways. We aim to investigate the relationship of active Src in response to trastuzumab of HER2-positive breast carcinomas.Methods:We selected 278 HER2-positive breast cancer patients with (n=154) and without (n=124) trastuzumab treatment. We performed immunohistochemistry on paraffin-embedded tissue microarrays of active Src and several proteins involved in the PI3K/Akt/mTOR pathway, PIK3CA mutational analysis and in vitro studies (SKBR3 and BT474 cancer cells). The results were correlated with clinicopathological factors and patients' outcome.Results: Increased pSrc-Y416 was demonstrated in trastuzumab-resistant cells and in 37.8% of tumours that correlated positively with tumour size, necrosis, mitosis, metastasis to the central nervous system, p53 overexpression and MAPK activation but inversely with EGFR and p27. Univariate analyses showed an association of increased active Src with shorter survival in patients at early stage with HER2/hormone receptor-negative tumours treated with trastuzumab.Conclusions:Src activation participates in trastuzumab mechanisms of resistance and indicates poor prognosis, mainly in HER2/hormone receptor-negative breast cancer. Therefore, blocking this axis may be beneficial in those patients. © 2014 Cancer Research UK. All rights reserved.
Moreno M.J.,Biomedical Research Institute Sant Pau |
Moreno M.J.,University of Barcelona |
Moreno M.J.,CIBER ISCIII |
Bosch R.,University of Barcelona |
And 16 more authors.
Journal of Pathology | Year: 2015
The chemokine receptor CXCR4 has been implicated in the migration and trafficking of malignant B cells in several haematological malignancies. Over-expression of CXCR4 has been identified in haematological tumours, but data concerning the role of this receptor in diffuse large B cell lymphoma (DLBCL) are lacking. CXCR4 is a marker of poor prognosis in various neoplasms, correlating with metastatic disease and decreased survival of patients. We studied CXCR4 involvement in cell migration in vitro and dissemination in vivo. We also evaluated the prognostic significance of CXCR4 in 94 biopsies of DLBCL patients. We observed that the level of expression of CXCR4 in DLBCL cell lines correlated positively with in vitro migration. Expression of the receptor was also associated with increased engraftment and dissemination, and decreased survival time in NOD/SCID mice. Furthermore, administration of a specific CXCR4 antagonist, AMD3100, decreased dissemination of DLBCL cells in a xenograft mouse model. In addition, we found that CXCR4 expression is an independent prognostic factor for shorter overall survival and progression-free survival in DLBCL patients. These results show that CXCR4 mediates dissemination of DLBCL cells and define for the first time its value as an independent prognostic marker in DLBCL patients. © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
PubMed | Clinica Girona, Hospital Moises Broggi, Biomedical Research Institute Sant Pau, Hospital Of La Santa Creu I Sant Pau and CIBER ISCIII
Type: Journal Article | Journal: Oncotarget | Year: 2015
High SERPINE1 expression is a common event in head and neck squamous cell carcinoma (HNSCC); however, whether it plays a role in determining clinical outcome remains still unknown. We studied SERPINE1 as a prognostic marker in two HNSCC patient cohorts. In a retrospective study (n = 80), high expression of SERPINE1 was associated with poor progression-free (p = 0.022) and cancer-specific (p = 0.040) survival. In a prospective study (n = 190), high SERPINE1 expression was associated with poor local recurrence-free (p = 0.022), progression-free (p = 0.002) and cancer-specific (p = 0.006) survival. SERPINE1 expression was identified as an independent risk factor for progression-free survival in patients treated with chemo-radiotherapy or radiotherapy (p = 0.043). In both patient cohorts, high SERPINE1 expression increased the risk of metastasis spread (p = 0.045; p = 0.029). The association between SERPINE1 expression and survival was confirmed using the HNSCC cohort included in The Cancer Genome Atlas project (n = 507). Once again, patients showing high expression had a poorer survival (p < 0.001). SERPINE1 over-expression in HNSCC cells reduced cell proliferation and enhanced migration. It also protected cells from cisplatin-induced apoptosis, which was accompanied by PI3K/AKT pathway activation. Downregulation of SERPINE1 expression had the opposite effect. We propose SERPINE1 expression as a prognostic marker that could be used to stratify HNSCC patients according to their risk of recurrence.
PubMed | Rovira i Virgili University, Institute Catala Doncologia Of Girona, Autonomous University of Barcelona, University of Girona and 4 more.
Type: | Journal: World journal of surgical oncology | Year: 2015
Gastrointestinal stromal tumors are sarcomas of the digestive tract characterized by mutations mainly located in the c-KIT or in the platelet-derived growth factor receptor (PDGFR)-alpha genes. Mutations in the BRAF gene have also been described. Our purpose is to define the distribution of c-KIT, PDGFR and BRAF mutations in a population-based cohort of gastrointestinal stromal tumors (GIST) patients and correlate them with anatomical site, risk classification and survival. In addition, as most of the GIST patients have a long survival, second cancers are frequently diagnosed in them. We performed a second primary cancer risk assessment.Our analysis was based on data from Tarragona and Girona Cancer Registries. We identified all GIST diagnosed from 1996 to 2006 and performed a mutational analysis of those in which paraffin-embedded tissue was obtained. Observed (OS) and relative survival (RS) were calculated according to risk classifications and mutational status. Multivariate analysis of variables for observed survival and was also done.A total of 132 GIST cases were found and we analyzed mutations in 108 cases. We obtained 53.7% of mutations in exon 11 and 7.4% in exon 9 of c-KIT gene; 12% in exon 18 and 1.9% in exon 12 of PDGFR gene and 25% of cases were wild type GIST. Patients with mutations in exon 11 of the c-KIT gene had a 5-year OS and RS of 59.6% and 66.3%, respectively. Patients with mutations in exon 18 of the PDGFR gene had a 5-year OS and RS of 84.6% and 89.7%. In multivariate analysis, only age and risk group achieved statistical significance for observed survival. GIST patients had an increased risk of second cancer with a hazard ratio of 2.47.This population-based study shows a spectrum of mutations in the c-KIT and PDGFR genes in GIST patients similar to that previously published. The OS and RS of GIST with the exon 18 PDGFR gene mutation could indicate that this subgroup of patients may be less aggressive and have a good prognosis, although less sensitive to treatment at recurrence. In our study, GIST patients have an increased risk of developing a second neoplasm.
Bonet Saris A.,Clinica Girona
Nutrición hospitalaria : organo oficial de la Sociedad Española de Nutrición Parenteral y Enteral | Year: 2011
Energy requirements are altered in critically-ill patients and are influenced by the clinical situation, treatment, and phase of the process. Therefore, the most appropriate method to calculate calorie intake is indirect calorimetry. In the absence of this technique, fixed calorie intake (between 25 and 35 kcal/kg/day) or predictive equations such as the Penn State formula can be used to obtain a more accurate evaluation of metabolic rate. Carbohydrate administration should be limited to a maximum of 4 g/kg/day and a minimum of 2 g/kg/day. Plasma glycemia should be controlled to avoid hyperglycemia. Fat intake should be between 1 and 1.5 g/kg/day. The recommended protein intake is 1-1.5 g/kg/day but can vary according to the patient's clinical status. Particular attention should be paid to micronutrient intake. Consensus is lacking on micronutrient requirements. Some vitamins (A, B, C, E) are highly important in critically-ill patients, especially those undergoing continuous renal replacement techniques, patients with severe burns and alcoholics, although the specific requirements in each of these types of patient have not yet been established. Energy and protein intake in critically-ill patients is complex, since both clinical factors and the stage of the process must be taken into account. The first step is to calculate each patient's energy requirements and then proceed to distribute calorie intake among its three components: proteins, carbohydrates and fat. Micronutrient requirements must also be considered.
Guidelines for specialized nutritional and metabolic support in the critically-ill patient. Update. Consensus of the Spanish Society of Intensive Care Medicine and Coronary Units-Spanish Society of Parenteral and Enteral Nutrition (SEMICYUC-SENPE): Macroand micronutrient requirements [Recomendaciones para el soporte nutricional y metabólico especializado del paciente crítico. Actualización. Consenso SEMICYUC-SENPE: Requerimientos de macronutrientes y micronutrientes]
Bonet Saris A.,Clinica Girona |
Marquez Vacaro J.A.,Hospital Universitario Virgen del Rocio |
Seron Arbeloa C.,Hospital San Jorge
Medicina Intensiva | Year: 2011
Energy requirements are altered in critically-ill patients and are influenced by the clinical situation, treatment, and phase of the process. Therefore, the most appropriate method to calculate calorie intake is indirect calorimetry. In the absence of this technique, fixed calorie intake (between 25 and 35. kcal/kg/day) or predictive equations such as the Penn State formula can be used to obtain a more accurate evaluation of metabolic rate.Carbohydrate administration should be limited to a maximum of 4. g/kg/day and a minimum of 2. g/kg/day. Plasma glycemia should be controlled to avoid hyperglycemia. Fat intake should be between 1 and 1.5. g/kg/day. The recommended protein intake is 1-1.5. g/kg/day but can vary according to the patient's clinical status.Particular attention should be paid to micronutrient intake. Consensus is lacking on micronutrient requirements. Some vitamins (A, B, C, E) are highly important in critically-ill patients, especially those undergoing continuous renal replacement techniques, patients with severe burns and alcoholics, although the specific requirements in each of these types of patient have not yet been established. Energy and protein intake in critically-ill patients is complex, since both clinical factors and the stage of the process must be taken into account. The first step is to calculate each patient's energy requirements and then proceed to distribute calorie intake among its three components: proteins, carbohydrates and fat. Micronutrient requirements must also be considered. © 2011 Sociedad Española de Medicina Intensiva, Critica y Unidades Coronarias (SEMICYUC) and Elsevier España, S.L.
Vilanova J.C.,Clinica Girona |
Vilanova J.C.,University of Girona |
Vilanova J.C.,Hospital St Caterina |
Barcelo-Vidal C.,University of Girona |
And 7 more authors.
American Journal of Roentgenology | Year: 2011
OBJECTIVE. The purpose of the study was to assess the predictive value for prostate cancer of MRI using morphologic (T2-weighted imaging [T2WI]) and functional (MR spectroscopy [MRS], diffusion-weighted imaging [DWI], and dynamic contrast-enhanced [DCE] MRI) sequences and the free-to-total prostate-specific antigen (PSA) ratio, alone and combined. MATERIALS AND METHODS. This retrospective study included 70 patients (PSA level, > 4 ng/mL; free-to-total PSA ratio, < 20%) who underwent endorectal 1.5-T MRI before biopsy. We graded the likelihood of cancer on a 5-point scale. Imaging data were compared with histologic results on biopsy or prostatectomy. Accuracies were estimated from the area under receiver operating characteristic using the hemiprostate as the unit of analysis. A p value less than 0.05 denoted statistical significance. RESULTS. The model combining all variables was more accurate than each variable alone (95.2% vs 73.5% for T2WI, 76.0% for MRS, 81.8% for DWI, 75.6% for DCE-MRI, and 78.8% for free-to-total PSA ratio). The complete model had accuracy similar to that of combining two imaging variables with free-to-total PSA ratio, especially free-to-total PSA ratio, T2WI, and DWI (94.0%); and free-to-total PSA ratio, DWI, and MRS (93.8%); with negative predictive values of 91.0% and 89.5%, respectively. The best models combining two imaging variables (MRS and DWI, 85.8%; T2WI and DWI, 84.8%) had accuracy that was similar to that of the combination of all imaging variables (87.3%) and higher than that of the best individual imaging variable (DWI, 81.8%), but lower than that of the complete model. CONCLUSION. The combination of at least one functional technique with free-to-total PSA ratio is more accurate than combining only imaging variables in cancer detection. The use of more than two imaging variables does not increase the detection rate. Functional MRI has the potential to help avoid a large number of negative biopsies. © American Roentgen Ray Society.
PubMed | IIB Sant Pau, Translational Molecular Oncology, Clinica Girona, Hospital Of La Santa Creu I Sant Pau Hscsp and CIBER ISCIII
Type: | Journal: Head & neck | Year: 2016
We studied the association between the expression of a subset of previously identified genes and clinical outcome in patients with head and neck cancer.We analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) the expression of 89 genes in tumor biopsies from stage III to IVa/b chemotherapy treated patients (n=46). Two additional cohorts analyzed by RNAseq (The Cancer Genome Atlas [TCGA] project; n=371) or immunohistochemistry (IHC; n=73) were used to validate results.Thirty genes were associated with local-recurrence or progression-free survival. The best multi-gene decision-tree model to predict local recurrence included nuclear receptor coactivator 1 (NCOA1) and serum-amyloid A2 (SAA2) expression, whereas the best model to predict disease recurrence included creatine kinase mitochondrial 1 (CKMT1) and metal-regulatory transcription factor 1 (MTF1). Both models were associated with cancer-specific survival. Results were confirmed analyzing the RNAseq data included in the TCGA project. CKMT1 and NCOA1 were identified as independent risk factors for survival in an independent cohort analyzed by immunohistochemistry.CKMT1 and NCOA1 expression has prognostic significance in advanced-stage head and neck carcinoma. 2015 Wiley Periodicals, Inc. Head Neck 38: E1392-E1403, 2016.
Gallego O.,Claret Medical |
Benavides M.,Carlos Haya Hospital |
Segura P.P.,University of San Carlos |
Berrocal A.,University of Valencia |
And 8 more authors.
Journal of Neuro-Oncology | Year: 2014
Epidermal growth factor receptor gene (EGFR) alteration is a common feature in most of glioblastoma multiforme (GBM). Robust response of anti-EGFR treatments has been mostly associated with the EGFR deletion mutant variant III (EGFRvIII) and expression of PTEN. We have performed a prospective trial in order to confirm the efficacy of erlotinib treatment in patients with relapsed GBM who expressed EGFRvIII and PTEN. All patients included in the trial were required to be PTEN (+++), EGFR (+++) and EGFRvIII (+++) positives by immunohistochemistry. This new phase II trial enrolled 40 patients and was design to be stopped in case of fewer than two responses in the first 13 patients. Patient eligibility included histopathology criteria, radiological progression, more than 18 years old, Karnofsky performed status, KPS > 50, and adequate bone marrow and organ function. There was no limit to the number of prior treatments for relapses. No enzyme-inducing antiepileptic drugs were allowed. The primary endpoints were response and progression-free survival at 6 months (PFS6). Thirteen patients (6 men, 7 women) with recurrent GBM received erlotinib 150 mg/day. Median age was 53 years, median KPS was 80, and median prior treatments for relapses were 2. There was one partial response and three stable diseases (one at 18 months). PFS at 6 months was 20 %. Dose reduction for toxicity was not needed in any patient. Dermatitis was the main treatment-related toxicity, grade 1 in 8 patients and grade 2 in 5 patients. No grade 3 toxicity was observed. Median survival was 7 months (95 % IC 1.41-4.7). As conclusion, monotherapy with erlotinib in GBM relapses patients with high protein expression for PTEN (+++), EGFR (+++), and EGFRvlII (+++) showed low toxicity but minimal efficacy and the trial stopped. © 2013 The Author(s).
News Article | October 28, 2016
SALT LAKE CITY, UT (Oct. 2016) - Have you ever spotted something unexpected while walking down the street? Last December, paleontologists literally stumbled upon a new discovery of a fossil sea cow in a very unexpected place - in a limestone paving stone in Spain! Research presented this week at the Society of Vertebrate Paleontology meeting in Salt Lake City, Utah, describes this remarkable find and how it is changing our understanding of sea cow evolution. The unusual pavement was spotted in the picturesque town of Girona, northern Spain. A local geologist first noticed the fossil and submitted it to the website 'http://www. ', an online database of urban fossils worldwide. As word of the fossil spread, paleontologists Dr. Manja Voss and Dr. Oliver Hampe, from the Museum für Naturkunde, Berlin, visited Girona to take a look. Closer inspection of the paving stones by Dr. Voss and Dr. Hampe revealed that the complex array of shapes was slices of the backbone and skull of an ancient marine mammal. Based on the skull and teeth, they concluded that it was a sirenian, or sea cow, a member of a group of large, plant-eating marine mammals represented today by the living manatee and dugong. Once the significance of the fossil was understood, Dr. Voss and Dr. Hampe worked with the mayoralty of Girona and local geologists to have the 50x30cm large paving stones removed for study. Since the rock was cut into slices to form the paving stones, the paleontologists had a cross-sectional view of the sea cow's skull, revealing many details of its anatomy. However, they also wanted to see inside the stones, so they took them to a medical hospital, the Clinica Girona, where they were CT-scanned. The scientists discovered that the 'Girona Sea Cow' is most likely a representative of Prototherium, a genus of extinct sea cows from Spain and Italy. However, this find is particularly important because the rocks from which the paving slabs were quarried are 40 million years old, explains Voss. "Hence the find represents one of the oldest sea cows in Europe, making it a unique opportunity to enhance our knowledge on the evolution and diversity of this marine mammal group that arose about 50 million years ago." Next the scientists will use the CT scans to try to digitally piece together the separate skull slices of Prototherium. This can help them answer more questions, such as the animals' age when it died and its potential relationship to other fossil sea cows. The Girona Sea Cow, which is providing clues into the evolution of sea cows in the ancient oceans of Europe, shows that fossils can be found in surprising locations. Voss says "While the limestone used to build the city of Girona are enriched by fossils -- it is quite common to identify invertebrates for example--finding a marine mammal on which thousands of people walked over for the last two decades is indeed very peculiar." Image 1: Scientist Oliver Hampe examines fossil remains of Prototherium in paving stones in Girona, Spain. Image by Manja Voss and Oliver Hampe. Image 2: The skull of Prototherium exposed on the paving slab, in cross-section, showing parts of snout and tooth sockets. Image by Manja Voss and Oliver Hampe. Image 3: Paving slabs were scanned in a medical CT scanner to reveal more about the fossils anatomy. Image by Manja Voss and Oliver About the Society of Vertebrate Paleontology Founded in 1940 by thirty-four paleontologists, the Society now has more than 2,300 members representing professionals, students, artists, preparators, and others interested in VP. It is organized exclusively for educational and scientific purposes, with the object of advancing the science of vertebrate paleontology. The Journal of Vertebrate Paleontology (JVP) is the leading journal of professional vertebrate paleontology and the flagship publication of the Society. It was founded in 1980 by Dr. Jiri Zidek and publishes contributions on all aspects of vertebrate paleontology. OTHER EXPERTS NOT DIRECTLY INVOLVED WITH THE STUDY