Phase II study of sunitinib as first-line treatment of urothelial cancer patients ineligible to receive cisplatin-based chemotherapy: Baseline interleukin-8 and tumor contrast enhancement as potential predictive factors of activity
Bellmunt J.,University of the Sea |
Gonzalez-Larriba J.L.,Hospital Clinico San Carlos |
Prior C.,University of Navarra |
Maroto P.,Hospital Of La Santa Creu I Sant Pau |
And 10 more authors.
Annals of Oncology | Year: 2011
Background: A strong rationale supports the role of antiangiogenic drugs in urothelial cancer. This trial was designed to assess the activity of sunitinib as first-line treatment in patients with metastatic urothelial cancer ineligible for cisplatin and to explore molecular and imaging variables predictive of clinical benefit. Patients and methods: This was a multicenter phase II trial with sunitinib 50 mg daily in 4/2-week schedule. Eligibility criteria were as follows: creatinine clearance 30-60 ml/min, Eastern Cooperative Oncology Group Pperformance Sstatus of one or less, and adequate hepatic and hematologic function. Twelve circulating cytokines were evaluated at baseline and sequentially using Luminex xMAP® (Austin, TX). Baseline and treatment-related changes in perfusion were evaluated in a patient subgroup using contrast-enhanced computed tomography. Results: On intention-to-treat analysis, 38 patients showed 3 (8%) partial responses (PRs) and 19 (50%) presented with stable disease (SD), 17 (45%) of them ≥3 months. Clinical benefit (PR + SD) was 58%. Median time to progression (TTP) was 4.8 months and median overall survival 8.1 months. Toxicity was consistent with previous reports for sunitinib. Low interleukin-8 (IL-8) baseline levels were significantly associated with increased TTP. Baseline tumor contrast enhancement with >40 Hounsfield units was associated with clinical benefit. Conclusions: This study highlights the potential role of the angiogenic pathway as a therapy target in urothelial cancer. Baseline IL-8 serum levels and contrast enhancement of lesions warrant further study. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.
Martinez-Rodriguez J.E.,IMIM Hospital del Mar Research Institute |
Lopez-Botet M.,Hospital del Mar Research Institute |
Lopez-Botet M.,University Pompeu Fabra |
Munteis E.,IMIM Hospital del Mar Research Institute |
And 4 more authors.
Clinical Immunology | Year: 2011
CD56 bright NK cells, which may play a role in immunoregulation, are expanded in multiple sclerosis (MS) patients treated with immunomodulatory therapies such as daclizumab and interferon-beta (IFNβ). Yet, whether this NK cell subset is directly involved in the therapeutic effect is unknown. As NK receptor (NKR) expression by subsets of NK cells and CD8+ T lymphocytes is related to MS clinical course, we addressed whether CD56 bright NK cells and NKR in IFNβ-treated MS patients differ according to the clinical response. IFNβ was associated to lower LILRB1+ and KIR+NK cells, and higher NKG2A+NK cell proportions, an immunophenotypic pattern mainly found in responders. After IFNβ treatment, a CD56 bright NK cell expansion was significantly related to a positive clinical response. Our results reveal that IFNβ may promote in responders changes in the NK cell immunophenotype, corresponding to the profile found at early maturation stages of this lymphocyte lineage. © 2011 Elsevier Inc.
Jones P.W.,St George's, University of London |
Brusselle G.,Ghent University |
Dal Negro R.W.,Orlandi General Hospital |
Ferrer M.,Hospital Del Mar Research Institute |
And 7 more authors.
Respiratory Medicine | Year: 2011
Pan-European data on health-related quality of life (HRQL) in chronic obstructive pulmonary disease (COPD) are lacking. This cross-sectional epidemiological study evaluated health status in 1817 COPD patients from an 'all-comers' primary care population in seven European countries (87% stable disease; 13% with current exacerbation) using: St George's Respiratory Questionnaire-COPD specific (SGRQ-C), the short form health survey (SF-12) and the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue scale. Mean total score for SGRQ was 44.7 ± 19.4 showing marked impairment of HRQL. Scores differed little between countries (range 39.2-50.1). Impairment was associated with the severity of airway obstruction, but within each GOLD stage the variation (SD) was wide [Stage I: 38.5 ± 19.3 (n = 223); Stage II: 40.4 ± 18.1 (n = 868); Stage III: 50.2 ± 18.6 (n = 551); Stage IV: 58.6 ± 17.7 (n = 144)]. Patients suffering an exacerbation had a worse SGRQ score (54.9 ± 19.3) than those with stable disease (43.3 ± 19.0). The presence of ≥3 co-morbidities (CM) was also associated with a significantly worse score (49.9 ± 19.1) vs. 1-2 CM (42.1 ± 19.1) or no CM (42.3 ± 18.6). Findings with the SF-12 and FACIT-F results were consistent with those from the SGRQ-C. This large observational primary care study shows that health status is significantly impaired in COPD patients of all severities, even in those with mild airway obstruction. Within each GOLD stage of severity there is considerable heterogeneity in HRQL impairment among patients. (Study number: 111749). © 2010 Elsevier Ltd. All rights reserved.
PubMed | Rovira i Virgili University, University of Barcelona, University of the Balearic Islands, University of Valencia and 8 more.
Type: Journal Article | Journal: The American journal of clinical nutrition | Year: 2016
Previous studies have suggested that metabolite profiles of elevated acylcarnitines were associated with increased risk of cardiovascular disease (CVD) in populations with established coronary disease. However, to our knowledge, this association has not been evaluated in the context of primary cardiovascular prevention.We evaluated the association between 28 plasma acylcarnitine species and risk of incident CVD and the potential modifying effect of Mediterranean diet (MedDiet) interventions.We measured plasma acylcarnitines with the use of high-throughput liquid chromatography-tandem mass spectrometry at baseline and after 1 y of follow-up, both individually and classified into short-, medium-, or long-chain scores, in a case-cohort study within the Prevencin con Dieta Mediterrnea (PREDIMED) study, which is a randomized Mediterranean dietary intervention for primary cardiovascular prevention. A randomly selected subcohort (n = 751) and all available incident CVD cases (n = 229) after 4.8 y of follow-up were included in the current study.After adjustment for age, sex, body mass index, and other CVD risk factors, participants in the highest quartile of baseline short- and medium-chain acylcarnitines had a higher risk of CVD than did participants in the lowest quartile [HRs: 1.80 (95% CI: 1.11, 2.91; P-trend 0.01) and 1.55 (95% CI: 1.01, 2.48; P-trend = 0.04), respectively]. Increased short-chain acylcarnitines after 1 y were associated with higher risks of total CVD and stroke. Participants with higher baseline concentrations of short-, medium-, and long-chain acylcarnitines who were randomly assigned to the control group had a higher risk of CVD than did subjects with lower concentrations of acylcarnitines who were assigned to the MedDiet group.Our data support the conclusion that metabolite profiles characterized by elevated concentrations of acylcarnitines are independently associated with risks of total CVD and stroke alone in participants at high risk of CVD. MedDiet interventions may mitigate the adverse associations shown between higher concentrations of acylcarnitines and CVD. This trial was registered at www.controlled-trials.com as ISRCTN35739639.
Funtikova A.N.,Hospital del Mar Research Institute |
Funtikova A.N.,CIBER ISCIII |
Funtikova A.N.,University of Barcelona |
Subirana I.,Hospital del Mar Research Institute |
And 9 more authors.
Journal of Nutrition | Year: 2015
Background: The accumulation of abdominal fat increases risk ofmetabolic disorders and premature death. There is a dearth of prospective data on the association between caloric beverage consumption and surrogatemarkers of abdominal adiposity. Objective: The aim of this study was to assess the relation between consumption of nonalcoholic caloric beverages, including soft drinks, fruit juice, whole milk, and skim and low-fat milk, and changes in waist circumference (WC) and odds of 10-y incidence of abdominal obesity. Methods: We conducted a prospective, population-based study of 2181 Spanish men and women aged 25-74 γ who were followed from 2000 to 2009. We measured weight, height, and WC, and recorded data on diet and leisure-time physical activity (LTPA) with the use of validated questionnaires. We fit multivariable linear and logistic regression models. Results: A 100 kcal increase in soft drink consumption was associated with a 1.1 cm increase in WC (P = 0.018) after 10 y of follow-up. Substitution of 100 kcal of soft drinks with 100 kcal of whole milk or 100 kcal of juice was associated with a 1.3 cm (95% CI: 0.3, 2.4) and 1.1 cm (95% CI: 0.03, 2.2) decrease in WC, respectively. Increasing consumption of soft drinks from baseline to follow-up led to WC gain compared with maintaining nonconsumption. Greater soft drink consumption was positively associated (P = 0.029) with increased odds of 10-γ incidence of abdominal obesity. Conclusion: Adults' consumption of soft drinks was associated with increasedWC and odds of 10-y incidence of abdominal obesity. This association was moderate but consistent in all statistical models. © 2015 American Society for Nutrition.
Castaner O.,Hospital del Mar Research Institute |
Castaner O.,Hospital del Mar Research Institute IMIM |
Castaner O.,Research Center Biomedica En Red Of Fisiopatologia Of La Obesidad tricion |
Corella D.,Hospital del Mar Research Institute IMIM |
And 13 more authors.
American Journal of Clinical Nutrition | Year: 2013
Background: Nutrients can exert healthy effects through nutrigenomic modulation. Data are scarce concerning the in vivo effect of a sustained traditional Mediterranean diet (TMD) pattern on the whole transcriptomic response. Objective: We explored the overall nutrigenomic effect associated with a TMD. Design: We focused on biological pathways related to cardiovascular disease (CVD) in a subsample (n = 34) of the Prevención Con Dieta Mediterránea (PREDIMED) study, which was a large, parallel-group, multicenter, randomized controlled trial that aimed to assess the effects of TMD on the primary prevention of CVD in individuals with high cardiovascular risk. Participants were randomly assigned to a low-fat diet control group or TMD intervention groups [traditional Mediterranean diet supplemented with virgin olive oil (TMD+VOO) or traditional Mediterranean diet supplemented with nuts (TMD+Nuts)] in equal proportions. Three-month changes in whole genome peripheral blood mononuclear cells were assessed by using whole transcriptome microarray analyses. Results: A functional annotation analysis was performed on 241 selected responder genes after the TMD+VOO (139 upregulated and 102 downregulated genes), 312 selected responder genes after the TMD+Nuts (165 upregulated and 147 downregulated genes), and 145 selected responder genes after the low-fat (100 upregulated and 45 downregulated genes) diets. Of 18 cardiovascular canonical pathway analyses, 12 pathways were differentially expressed, and 43% of pathways were modulated by both TMDs; the most prevalent pathways were related to atherosclerosis and hypertension. After simultaneous testing adjustment, 9 pathways were modulated by the TMD+VOO diet, and 4 pathways were modulated by the TMD+Nuts diet. Conclusion: One of the mechanisms by which TMD, particularly if supplemented with virgin olive oil, can exert health benefits is through changes in the transcriptomic response of genes related to cardiovascular risk. This trial was registered at the London-based Current Controlled Trials register as ISRCTN35739639. © 2013 American Society for Nutrition.
Morales E.,Center for Research in Environmental Epidemiology |
Morales E.,Hospital del Mar Research Institute |
Morales E.,CIBER ISCIII |
Bustamante M.,Center for Research in Environmental Epidemiology |
And 24 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2012
Rationale: Epigenetic changes may play a role in the occurrence of asthma-related phenotypes. Objectives: To identify epigenetic marks in terms ofDNAmethylation of asthma-related phenotypes in childhood, and to assess the effect of prenatal exposures and genetic variation on these epigenetic marks. Methods: Data came from two cohorts embedded in the Infancia y Medio Ambiente (INMA) Project: Menorca (n = 122) and Sabadell (n = 236). Wheezing phenotypes were defined at age 4-6 years. Cytosine-guanine (CpG) dinucleotide site DNA methylation differences associated with wheezing phenotypes were screened in children of the Menorca study using the Illumina GoldenGate Panel I. Findings were validated and replicated using pyrosequencing. Information on maternal smoking and folate supplement usewas obtained through questionnaires. Dichlorodiphenyldichloroethylene was measured in cord blood or maternal serum. Genotypes were extracted from genome-wide data. Measurement and Main Results: Screening identified lower DNA methylation at a CpG site in the arachidonate 12-lipoxygenase (ALOX12) gene in children having persistent wheezing compared with those never wheezed (P = 0.003). DNA hypomethylation at ALOX12 loci was associated with higher risk of persistent wheezing in the Menorca study (odds ratio per 1% methylation decrease, 1.13; 95% confidence interval, 0.99-1.29; P = 0.077) and in the Sabadell study (odds ratio, 1.16; 95% confidence interval, 1.03-1.37; P =0.017). Higher levels of prenatal dichlorodiphenyldichloroethylene were associated with DNA hypomethylation of ALOX12 in the Menorca study (P = 0.033), but not in the Sabadell study (P = 0.377). ALOX12 DNA methylation was strongly determined by underlying genetic polymorphisms. Conclusions: DNA methylation of ALOX12 may be an epigenetic biomarker for the risk of asthma-related phenotypes. Copyright © 2012 by the American Thoracic Society.
Montagut C.,Hospital Del Mar |
Montagut C.,Hospital Del Mar Research Institute |
Dalmases A.,Hospital Del Mar |
Dalmases A.,Hospital Del Mar Research Institute |
And 28 more authors.
Nature Medicine | Year: 2012
Antibodies against epidermal growth factor receptor (EGFR)-cetuximab and panitumumab-are widely used to treat colorectal cancer. Unfortunately, patients eventually develop resistance to these agents. We describe an acquired EGFR ectodomain mutation (S492R) that prevents cetuximab binding and confers resistance to cetuximab. Cells with this mutation, however, retain binding to and are growth inhibited by panitumumab. Two of ten subjects studied here with disease progression after cetuximab treatment acquired this mutation. A subject with cetuximab resistance harboring the S492R mutation responded to treatment with panitumumab. © 2012 Nature America, Inc. All rights reserved.
Lopez-Sola M.,University of the Sea |
Lopez-Sola M.,University of Colorado at Boulder |
Pujol J.,Hospital del Mar |
Wager T.D.,University of Colorado at Boulder |
And 9 more authors.
Arthritis and Rheumatology | Year: 2014
Objective Fibromyalgia (FM) is a disorder characterized by chronic pain and enhanced responses to acute noxious events. However, the sensory systems affected in FM may extend beyond pain itself, as FM patients show reduced tolerance to non-nociceptive sensory stimulation. Characterizing the neural substrates of multisensory hypersensitivity in FM may thus provide important clues about the underlying pathophysiology of the disorder. The aim of this study was to characterize brain responses to non-nociceptive sensory stimulation in FM patients and their relationship to subjective sensory sensitivity and clinical pain severity. Methods Functional magnetic resonance imaging (MRI) was used to assess brain response to auditory, visual, and tactile motor stimulation in 35 women with FM and 25 matched controls. Correlation and mediation analyses were performed to establish the relationship between brain responses and 3 types of outcomes: subjective hypersensitivity to daily sensory stimulation, spontaneous pain, and functional disability. Results Patients reported increased subjective sensitivity (increased unpleasantness) in response to multisensory stimulation in daily life. Functional MRI revealed that patients showed reduced task-evoked activation in primary/secondary visual and auditory areas and augmented responses in the insula and anterior lingual gyrus. Reduced responses in visual and auditory areas were correlated with subjective sensory hypersensitivity and clinical severity measures. Conclusion FM patients showed strong attenuation of brain responses to nonpainful events in early sensory cortices, accompanied by an amplified response at later stages of sensory integration in the insula. These abnormalities are associated with core FM symptoms, suggesting that they may be part of the pathophysiology of the disease. Copyright © 2014 by the American College of Rheumatology.
Pujol J.,Hospital Del Mar |
Pujol J.,Centro Investigacion Biomedica En Red Of Salud Mental |
Macia D.,Hospital Del Mar |
Garcia-Fontanals A.,Autonomous University of Barcelona |
And 12 more authors.
Pain | Year: 2014
Fibromyalgia typically presents with spontaneous body pain with no apparent cause and is considered pathophysiologically to be a functional disorder of somatosensory processing. We have investigated potential associations between the degree of self-reported clinical pain and resting-state brain functional connectivity at different levels of putative somatosensory integration. Resting-state functional magnetic resonance imaging was obtained in 40 women with fibromyalgia and 36 control subjects. A combination of functional connectivity-based measurements were used to assess (1) the basic pain signal modulation system at the level of the periaqueductal gray (PAG); (2) the sensory cortex with an emphasis on the parietal operculum/secondary somatosensory cortex (SII); and (3) the connectivity of these regions with the self-referential "default mode" network. Compared with control subjects, a reduction of functional connectivity was identified across the 3 levels of neural processing, each showing a significant and complementary correlation with the degree of clinical pain. Specifically, self-reported pain in fibromyalgia patients correlated with (1) reduced connectivity between PAG and anterior insula; (2) reduced connectivity between SII and primary somatosensory, visual, and auditory cortices; and (3) increased connectivity between SII and the default mode network. The results confirm previous research demonstrating abnormal functional connectivity in fibromyalgia and show that alterations at different levels of sensory processing may contribute to account for clinical pain. Importantly, reduced functional connectivity extended beyond the somatosensory domain and implicated visual and auditory sensory modalities. Overall, this study suggests that a general weakening of sensory integration underlies clinical pain in fibromyalgia. © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.