Ricardo Díez-Valle
University of Navarra
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Featured researches published by Ricardo Díez-Valle.
PLOS ONE | 2011
Marta M. Alonso; Ricardo Díez-Valle; Lorea Manterola; Angel Rubio; Dan Liu; Nahir Cortes-Santiago; Leire Urquiza; Patricia Jauregi; Adolfo López de Munain; Nicolás Sampron; Ander Aramburu; Sonia Tejada-Solís; Carmen Vicente; María D. Odero; Eva Bandrés; Jesús García-Foncillas; Miguel Angel Idoate; Frederick F. Lang; Juan Fueyo; Candelaria Gomez-Manzano
We undertook this study to understand how the transcription factor Sox2 contributes to the malignant phenotype of glioblastoma multiforme (GBM), the most aggressive primary brain tumor. We initially looked for unbalanced genomic rearrangements in the Sox2 locus in 42 GBM samples and found that Sox2 was amplified in 11.5% and overexpressed in all the samples. These results prompted us to further investigate the mechanisms involved in Sox2 overexpression in GBM. We analyzed the methylation status of the Sox2 promoter because high CpG density promoters are associated with key developmental genes. The Sox2 promoter presented a CpG island that was hypomethylated in all the patient samples when compared to normal cell lines. Treatment of Sox2-negative glioma cell lines with 5-azacitidine resulted in the re-expression of Sox2 and in a change in the methylation status of the Sox2 promoter. We further confirmed these results by analyzing data from GBM cases generated by The Cancer Genome Atlas project. We observed Sox2 overexpression (86%; N = 414), Sox2 gene amplification (8.5%; N = 492), and Sox 2 promoter hypomethylation (100%; N = 258), suggesting the relevance of this factor in the malignant phenotype of GBMs. To further explore the role of Sox2, we performed in vitro analysis with brain tumor stem cells (BTSCs) and established glioma cell lines. Downmodulation of Sox2 in BTSCs resulted in the loss of their self-renewal properties. Surprisingly, ectopic expression of Sox2 in established glioma cells was not sufficient to support self-renewal, suggesting that additional factors are required. Furthermore, we observed that ectopic Sox2 expression was sufficient to induce invasion and migration of glioma cells, and knockdown experiments demonstrated that Sox2 was essential for maintaining these properties. Altogether, our data underscore the importance of a pleiotropic role of Sox2 and suggest that it could be used as a therapeutic target in GBM.
Neuro-oncology | 2014
Lorea Manterola; Elizabeth Guruceaga; Jaime Gállego Pérez-Larraya; Marisol Gonzalez-Huarriz; Patricia Jauregui; Sonia Tejada; Ricardo Díez-Valle; Victor Segura; Nicolás Samprón; Cristina Barrena; Irune Ruiz; Amaia Agirre; Angel Ayuso; Javier Rodríguez; Alvaro González; Enric Xipell; Ander Matheu; Adolfo López de Munain; Teresa Tuñón; Idoya Zazpe; Jesús García-Foncillas; Sophie Paris; Jean Yves Delattre; Marta M. Alonso
BACKGROUND Glioblastoma multiforme (GBM) is the most frequent malignant brain tumor in adults, and its prognosis remains dismal despite intensive research and therapeutic advances. Diagnostic biomarkers would be clinically meaningful to allow for early detection of the tumor and for those cases in which surgery is contraindicated or biopsy results are inconclusive. Recent findings show that GBM cells release microvesicles that contain a select subset of cellular proteins and RNA. The aim of this hypothesis-generating study was to assess the diagnostic potential of miRNAs found in microvesicles isolated from the serum of GBM patients. METHODS To control disease heterogeneity, we used patients with newly diagnosed GBM. In the discovery stage, PCR-based TaqMan Low Density Arrays followed by individual quantitative reverse transcriptase polymerase chain reaction were used to test the differences in the miRNA expression levels of serum microvesicles among 25 GBM patients and healthy controls paired by age and sex. The detected noncoding RNAs were then validated in another 50 GBM patients. RESULTS We found that the expression levels of 1 small noncoding RNA (RNU6-1) and 2 microRNAs (miR-320 and miR-574-3p) were significantly associated with a GBM diagnosis. In addition, RNU6-1 was consistently an independent predictor of a GBM diagnosis. CONCLUSIONS Altogether our results uncovered a small noncoding RNA signature in microvesicles isolated from GBM patient serum that could be used as a fast and reliable differential diagnostic biomarker.
Neurosurgery | 2013
Guillermo Aldave; Sonia Tejada; Eva Pay; Miguel Marigil; Bartolomé Bejarano; Miguel Angel Idoate; Ricardo Díez-Valle
BACKGROUND There is evidence in the literature supporting that fluorescent tissue signal in fluorescence-guided surgery extends farther than tissue highlighted in gadolinium in T1 sequence magnetic resonance imaging (MRI), which is the standard to quantify the extent of resection. OBJECTIVE To study whether the presence of residual fluorescent tissue after surgery carries a different prognosis for glioblastoma (GBM) cases with complete resection confirmed by MRI. METHODS A retrospective review in our center found 118 consecutive patients with high-grade gliomas operated on with the use of fluorescence-guided surgery with 5-aminolevulinic acid. Within that series, the 52 patients with newly diagnosed GBM and complete resection of enhancing tumor (CRET) in early MRI were selected for analysis. We studied the influence of residual fluorescence in the surgical field on overall survival and neurological complication rate. Multivariate analysis included potential relevant factors: age, Karnofsky Performance Scale, O-methylguanine methyltransferase methylation promoter status, tumor eloquent location, preoperative tumor volume, and adjuvant therapy. RESULTS The median overall survival was 27.0 months (confidence interval = 22.4-31.6) in patients with nonresidual fluorescence (n = 25) and 17.5 months (confidence interval = 12.5-22.5) for the group with residual fluorescence (n = 27) (P = .015). The influence of residual fluorescence was maintained in the multivariate analysis with all covariables, hazard ratio = 2.5 (P = .041). The neurological complication rate was 18.5% in patients with nonresidual fluorescence and 8% for the group with residual fluorescence (P = .267). CONCLUSION GBM patients with CRET in early MRI and no fluorescent residual tissue had longer overall survival than patients with CRET and residual fluorescent tissue.
European Journal of Nuclear Medicine and Molecular Imaging | 2012
Javier Arbizu; Sonia Tejada; Josep M. Martí-Climent; Ricardo Díez-Valle; Elena Prieto; Gemma Quincoces; Carmen Vigil; Miguel Angel Idoate; José L. Zubieta; Iván Peñuelas; José A. Richter
PurposeThe aim of the study was to evaluate the volumetric integration patterns of standard MRI and 11C-methionine positron emission tomography (PET) images in the surgery planning of gliomas and their relationship to the histological grade.MethodsWe studied 23 patients with suspected or previously treated glioma who underwent preoperative 11C-methionine PET because MRI was imprecise in defining the surgical target contour. Images were transferred to the treatment planning system, coregistered and fused (BrainLAB). Tumour delineation was performed by 11C-methionine PET thresholding (vPET) and manual segmentation over MRI (vMRI). A 3-D volumetric study was conducted to evaluate the contribution of each modality to tumour target volume. All cases were surgically treated and histological classification was performed according to WHO grades. Additionally, several biopsy samples were taken according to the results derived either from PET or from MRI and analysed separately.ResultsFifteen patients had high-grade tumours [ten glioblastoma multiforme (GBM) and five anaplastic), whereas eight patients had low-grade tumours. Biopsies from areas with high 11C-methionine uptake without correspondence in MRI showed tumour proliferation, including infiltrative zones, distinguishing them from dysplasia and radionecrosis. Two main PET/MRI integration patterns emerged after analysis of volumetric data: pattern vMRI-in-vPET (11/23) and pattern vPET-in-vMRI (9/23). Besides, a possible third pattern with differences in both directions (vMRI-diff-vPET) could also be observed (3/23). There was a statistically significant association between the tumour classification and integration patterns described above (p < 0.001, κ = 0.72). GBM was associated with pattern vMRI-in-vPET (9/10), low-grade with pattern vPET-in-vMRI (7/8) and anaplastic with pattern vMRI-diff-vPET (3/5).ConclusionThe metabolically active tumour volume observed in 11C-methionine PET differs from the volume of MRI by showing areas of infiltrative tumour and distinguishing from non-tumour lesions. Differences in 11C-methionine PET/MRI integration patterns can be assigned to tumour grades according to the WHO classification. This finding may improve tumour delineation and therapy planning for gliomas.
PLOS ONE | 2013
Beatriz Aldaz; Ainara Sagardoy; Lorena Nogueira; Elizabeth Guruceaga; Lara Grande; Jason T. Huse; María Ángela Aznar; Ricardo Díez-Valle; Sonia Tejada-Solís; Marta M. Alonso; Jose L. Fernandez-Luna; Jose A. Martinez-Climent; Raquel Malumbres
Glioblastoma multiforme (GBM)-initiating cells (GICs) represent a tumor subpopulation with neural stem cell-like properties that is responsible for the development, progression and therapeutic resistance of human GBM. We have recently shown that blockade of NFκB pathway promotes terminal differentiation and senescence of GICs both in vitro and in vivo, indicating that induction of differentiation may be a potential therapeutic strategy for GBM. MicroRNAs have been implicated in the pathogenesis of GBM, but a high-throughput analysis of their role in GIC differentiation has not been reported. We have established human GIC cell lines that can be efficiently differentiated into cells expressing astrocytic and neuronal lineage markers. Using this in vitro system, a microarray-based high-throughput analysis to determine global expression changes of microRNAs during differentiation of GICs was performed. A number of changes in the levels of microRNAs were detected in differentiating GICs, including over-expression of hsa-miR-21, hsa-miR-29a, hsa-miR-29b, hsa-miR-221 and hsa-miR-222, and down-regulation of hsa-miR-93 and hsa-miR-106a. Functional studies showed that miR-21 over-expression in GICs induced comparable cell differentiation features and targeted SPRY1 mRNA, which encodes for a negative regulator of neural stem-cell differentiation. In addition, miR-221 and miR-222 inhibition in differentiated cells restored the expression of stem cell markers while reducing differentiation markers. Finally, miR-29a and miR-29b targeted MCL1 mRNA in GICs and increased apoptosis. Our study uncovers the microRNA dynamic expression changes occurring during differentiation of GICs, and identifies miR-21 and miR-221/222 as key regulators of this process.
The Journal of Nuclear Medicine | 2011
Elena Prieto; Josep M. Martí-Climent; Ines Dominguez-Prado; Puy Garrastachu; Ricardo Díez-Valle; Sonia Tejada; J. Aristu; Iván Peñuelas; Javier Arbizu
We have investigated dual-time-point 18F-FDG PET for the detection and delineation of high-grade brain tumors using quantitative criteria applied on a voxel basis. Methods: Twenty-five patients with suspected high-grade brain tumors and inconclusive MRI findings underwent 11C-methionine PET and dual-time-point 18F-FDG PET. Images from each subject were registered and spatially normalized. Parametric maps of standardized uptake value (SUV) and tumor–to–normal gray matter (TN) ratio for each PET image were obtained. Tumor diagnosis was evaluated according to 4 criteria comparing standard and delayed 18F-FDG PET images: any SUV increase, SUV increase greater than 10%, any TN increase, and TN increase greater than 10%. Voxel-based analysis sensitivity was assessed using 11C-methionine as a reference and compared with visual and volume-of-interest analysis for dual-time-point PET images. Additionally, volumetric assessment of the tumor extent that fulfills each criterion was compared with the volume defined for 11C-methionine PET. Results: The greatest sensitivity for tumor identification was obtained with any increase of TN ratio (100%), followed by a TN increase greater than 10% (96%), any SUV increase (80%), and an SUV increase greater than 10% (60%). These values were superior to visual analysis of standard 18F-FDG (sensitivity, 40%) and delayed 18F-FDG PET (sensitivity, 52%). Volume-of-interest analysis of dual-time-point PET reached a sensitivity of only 64% using the TN increase criterion. Regarding volumetry, voxel-based analysis with the TN ratio increase as a criterion, compared with 11C-methionine PET, detected 55.4% of the tumor volume, with the other criteria detecting volumes lower than 20%. Nevertheless, volume detection presented great variability, being better for metastasis (78%) and glioblastomas (56%) than for anaplastic tumors (12%). A positive correlation was observed between the volume detected and the time of acquisition of the delayed PET image (r = 0.66, P < 0.001), showing volumes greater than 75% when the delayed image was obtained at least 6 h after 18F-FDG injection. Conclusion: Compared with standard 18F-FDG PET studies, quantitative dual-time-point 18F-FDG PET can improve sensitivity for the identification and volume delineation of high-grade brain tumors.
Neurosurgery | 2018
Sonia Tejada; Marta M. Alonso; Ana Patiño; Juan Fueyo; Candelaria Gomez-Manzano; Ricardo Díez-Valle
BACKGROUND There are no effective treatments for diffuse intrinsic pontine gliomas (DIPGs); these tumors cannot be surgical resected, and diagnosis is based on magnetic resonance imaging. As a result, tumor tissues for molecular studies and pathologic diagnosis are infrequent. New clinical trials are investigating novel medications and therapeutic techniques in an effort to improve treatment of patients with DIPGs. OBJECTIVE To determine the safety, tolerability, and toxicity of an oncolytic adenovirus, DNX-2401, injected into the cerebellar peduncle in pediatric subjects with DIPG and to collect tumor samples of this type of tumor. METHODS Phase I, single-center, uncontrolled trial. A tumor biopsy will be performed through the cerebellar peduncle, and DNX-2401 will be injected immediately after the biopsy. Standard therapy consisting of radiotherapy and chemotherapy will follow in 2 to 6 wk. EXPECTED OUTCOMES Improvement of overall survival and quality of life in patients with DIPG and collection of tumor specimens to study the molecular profiling of these tumors. DISCUSSION The aims of this trial are to contribute to the sample collection of DIPG and to offer treatment during the tumor tissue biopsy using the virus. If this virus works as expected, it could kill the tumor cells with no damage to healthy tissue, functioning as a targeted therapy. It is important to note that edema has not been observed with this virus in all trials performed to date. The information obtained through this and other similar studies may be useful for developing or improving new therapies in the battle against DIPG.
Cancer Research | 2017
Marta M. Alonso; Marc García-Moure; Marisol González-Huarriz; Miguel Marigil; Ruben Hernandez-Alcoceba; María Buñales; Sandra Hervás; Jaime Gállego; Candelaria Gomez-Manzano; Juan Fueyo; Frederick F. Lang; Joanna Peterkin; Ricardo Díez-Valle; Sonia Tejada
DNX-2401 is a replication competent oncolytic adenovirus that has shown a potent antitumor effect in preclinical glioma models and a safe profile when administer as a single agent in glioma patients. Previously, our group showed that combination of DNX-2401 with temozolomide significantly increased the survival of mice bearing gliomas. Even though virotherapy is becoming a real therapeutic option still the precise mechanism of action, the interplay with the tumor microenvironment and biomarkers that predict response remain elusive. The main objective of this clinical trial was to investigate safety, OR, and OS following treatment with DNX-2401 and temozolomide. In addition, we aim to seek biomarkers that predict response to the virus. We included 31 glioma patients at first recurrence after prior surgery and standard treatment with radiotherapy, and temozolomide. Tumor resection or biopsy was performed to confirm recurrent disease. All patients received a single intraparenchymal injection of DNX-2401 (3x1010 vp) followed by 4 cycles of 150 mg/m2 temozolomide 2-4 weeks later. Ninety-four percent of patients completed all 4 planned cycles. The safety objective of the trial was achieved with no severe toxicities related to DNX-2401. Grade 3-4 adverse events were consistent with those associated with temozolomide (e.g., lymphopenia) or underlying disease. Several objective responses were observed with three patients alive 30, 19 and 27 months after treatment. The study is ongoing and results will be updated. Patients with higher titers of neutralizing antibodies prior to virus administration appeared to respond better to treatment. No differences were seen in the levels of serum cytokines amongst patients and treatment times. FGF2 is a growth factor that has been shown to increased cell susceptibility to virus infection and replication through inhibition of the interferon pathway. Interestingly, high expression of FGF2 in tumor samples was associated with significantly longer overall survival. FGF2 expression was inversely correlated with IFN-γ expression in the tumor and in exosomes isolated from liquid biopsies in the same patient. These data also suggest that patients with stronger innate responses did worse than those where the IFN pathway was downregulated. In summary, our data demonstrate that DNX-2401 in combination with temozolomide is well tolerated, can be safely administered and shows therapeutic activity. Moreover, FGF2 as a prognostic biomarker of DNX-2401 treatment response deserves further investigation. Citation Format: Marta M. Alonso, Marc Garcia-Moure, Marisol Gonzalez-Huarriz, Miguel Marigil, Ruben Hernandez-Alcoceba, Maria Bunales, Sandra Hervas, Jaime Gallego, Candelaria Gomez-Manzano, Juan Fueyo, Frederick Lang, Joanna Peterkin, Ricardo Diez-Valle, Sonia Tejada. Oncolytic virus DNX-2401 with a short course of temozolomide for glioblastoma at first recurrence: Clinical data and prognostic biomarkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT027. doi:10.1158/1538-7445.AM2017-CT027
Neuropathology and Applied Neurobiology | 2014
Miguel Angel Idoate; Jose Echeveste; Ricardo Díez-Valle; Maria D. Lozano; J. Aristu
Glioblastomas display marked phenotypic and molecular heterogeneity. The expression of the PTEN protein in glioblastomas also shows great intratumour heterogeneity, but the significance of this heterogeneity has so far received little attention.
Journal of Neurosurgical Anesthesiology | 2015
Cristina Honorato-Cia; Antonio Martínez-Simón; Elena Cacho-Asenjo; Francisco Guillén-Grima; Sonia Tejada-Solís; Ricardo Díez-Valle
Background: 5-Aminolevulinic acid (5-ALA) is used for brain tumor identification during surgery through fluorescence. Its use is linked to side effects such as photodermatosis, anemia, or plaquetopenia. Many institutions take very strict precautions to prevent them. Our hospital´s protocol mandates avoidance of direct sunlight during the first 24 hours only. Methods: Retrospective cohort observational study of 207 consecutive patients who underwent 5-ALA-guided brain tumor resection between 2008 and 2013, and compared with a control group of 53 patients without 5-ALA. Results: No skin reaction was reported. No difference was found in hemoglobin or platelet level comparisons at different points in time. There was no difference in trends within groups. Mean duration of surgery was longer in the 5-ALA group; the subgroup of patients undergoing their first surgery had a positive correlation with lower hemoglobin levels. In postoperative magnetic resonance imaging, patients in the 5-ALA group had a lower percentage of residual bleeding (19% of all patients; 17.9% in 5-ALA group and 22.7% in non-ALA [P=0.04]). Eight patients in the 5-ALA group required blood transfusion (3.9%), compared with 2 in the control group (3.8%). Four patients in the 5-ALA group required reintervention in the first 48 hours due to bleeding, although none had platelets <150,000/mL. Conclusions: Significant side effects appear to be uncommon. Blood count changes are likely multifactorial; surgical time may account for it partially, whereas 5-ALA role is not clear and may not be significant.