Nuestros investigadores

Ricardo Diez Valle

Publicaciones científicas más recientes (desde 2010)

Autores: Tejada, Sonia; Diez Valle, Ricardo; Domínguez, Pablo Daniel; et al.
Revista: FRONTIERS IN ONCOLOGY
ISSN 2234-943X  Vol. 12  Nº 8  2018  págs. 61
Diffuse intrinsic pontine gliomas (DIPGs) are aggressive glial brain tumors that primarily affect children, for which there is no curative treatment. Median overall survival is only one year. Currently, the scientific focus is on expanding the knowledge base of the molecular biology of DIPG, and identifying effective therapies. Oncolytic adenovirus DNX-2401 is a replication-competent, genetically modified virus capable of infecting and killing glioma cells, and stimulating an anti-tumor immune response. Clinical trials evaluating intratumoral DNX-2401 in adults with recurrent glioblastoma have demonstrated that the virus has a favorable safety profile and can prolong survival. Subsequently, these results have encouraged the transition of this biologically active therapy from adults into the pediatric population. To this aim, we have designed a clinical Phase I trial for newly diagnosed pediatric DIPG to investigate the feasibility, safety, and preliminary efficacy of delivering DNX-2401 into tumors within the pons following biopsy. This case report presents a pediatric patient enrolled in this ongoing Phase I trial for children and adolescents with newly diagnosed DIPG. The case involves an 8-year-old female patient with radiologically diagnosed DIPG who underwent stereotactic tumor biopsy immediately followed by intratumoral DNX-2401 in the same biopsy track. Because there were no safety concerns or new neurological deficits, the patient was discharged 3¿days after the procedures. To our knowledge, this is the first report of intratumoral DNX-2401 for a patient with DIPG in a clinical trial. We plan to demonstrate that intratumoral delivery of an oncolytic virus following tumor biopsy for pediatric patients with DIPG is a novel and feasible approach and that DNX-2401 represents an innovative treatment for the disease.
Autores: Lang, F. F., (Autor de correspondencia); Conrad, C.; Gomez-Manzano, C.; et al.
Revista: JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X  Vol. 36  Nº 14  2018  págs. 1419 - 27
PurposeDNX-2401 (Delta-24-RGD; tasadenoturev) is a tumor-selective, replication-competent oncolytic adenovirus. Preclinical studies demonstrated antiglioma efficacy, but the effects and mechanisms of action have not been evaluated in patients.MethodsA phase I, dose-escalation, biologic-end-point clinical trial of DNX-2401 was conducted in 37 patients with recurrent malignant glioma. Patients received a single intratumoral injection of DNX-2401 into biopsy-confirmed recurrent tumor to evaluate safety and response across eight dose levels (group A). To investigate the mechanism of action, a second group of patients (group B) underwent intratumoral injection through a permanently implanted catheter, followed 14 days later by en bloc resection to acquire post-treatment specimens.ResultsIn group A (n = 25), 20% of patients survived > 3 years from treatment, and three patients had a 95% reduction in the enhancing tumor (12%), with all three of these dramatic responses resulting in > 3 years of progression-free survival from the time of treatment. Analyses of post-treatment surgical specimens (group B, n = 12) showed that DNX-2401 replicates and spreads within the tumor, documenting direct virus-induced oncolysis in patients. In addition to radiographic signs of inflammation, histopathologic examination of immune markers in post-treatment specimens showed tumor infiltration by CD8(+) and T-bet(+) cells, and transmembrane immunoglobulin mucin-3 downregulation after treatment. Analyses of patient-derived cell lines for damage-associated molecular patterns revealed induction of immunogenic cell death in tumor cells after DNX-2401 administration.ConclusionTreatment with DNX-2401 resulted in dramatic responses with long-term survival in recurrent high-grade gliomas that are probably due to direct oncolytic effects of the virus followed by elicitation of an immune-mediated antiglioma response.
Autores: Martinez-Velez, N.; Domínguez, Pablo Daniel; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 12  Nº 1  2017  págs. e0170501
Objective In this work we set to develop and to validate a new in vivo frameless orthotopic Diffuse Intrinsic Pontine Glioma (DIPG) model based in the implantation of a guide-screw system. Methods It consisted of a guide-screw also called bolt, a Hamilton syringe with a 26-gauge needle and an insulin-like 15-gauge needle. The guide screw is 2.6 mm in length and harbors a 0.5 mm central hole which accepts the needle of the Hamilton syringe avoiding a theoretical displacement during insertion. The guide-screw is fixed on the mouse skull according to the coordinates: 1 mm right to and 0.8 mm posterior to lambda. To reach the pons the Hamilton syringe is adjusted to a 6.5 mm depth using a cuff that serves as a stopper. This system allows delivering not only cells but also any kind of intratumoral chemotherapy, antibodies or gene/viral therapies. Results The guide-screw was successfully implanted in 10 immunodeficient mice and the animals were inoculated with DIPG human cell lines during the same anesthetic period. All the mice developed severe neurologic symptoms and had a median overall survival of 95 days ranging the time of death from 81 to 116 days. Histopathological analysis confirmed tumor into the pons in all animals confirming the validity of this model. Conclusion Here we presented a reproducible and frameless DIPG model that allows for rapid evaluation of tumorigenicity and efficacy of chemotherapeutic or gene therapy products delivered intratumorally to the pons.
Autores: Inoges S; Tejada, Sonia; López, A; et al.
Revista: JOURNAL OF TRANSLATIONAL MEDICINE
ISSN 1479-5876  Vol. 15  Nº 1  2017  págs. 104-116
Our results suggest that the addition of tumor lysate-pulsed autologous DCs vaccination to tumor resection and combined radio-chemotherapy is feasible and safe. A multicenter randomized clinical trial is warranted to evaluate the potential survival benefit of this therapeutic approach. Trial registration This phase-II trial was registered as EudraCT: 2009-009879-35 and ClinicalTrials.gov Identifier: NCT01006044 retrospectively registered.
Autores: Idoate, Miguel Ángel; Lopez Janeiro, A.; Lecumberri, A.; et al.
Revista: LABORATORY INVESTIGATION
ISSN 0023-6837  Vol. 97  Nº Supl. 1  2017  págs. 434A
Autores: Martínez-Vélez, N.; Aristu, José Javier; et al.
Revista: NEURO-ONCOLOGY
ISSN 1522-8517  Vol. 19  2017  págs. 28 - 28
Autores: García, Marc; et al.
Revista: NEURO-ONCOLOGY
ISSN 1522-8517  Vol. 19  Nº Supl 6  2017  págs. 34
Autores: Idoate, Miguel Ángel; Janeiro, A. L.; Lecumberri, A.; et al.
Revista: MODERN PATHOLOGY
ISSN 0893-3952  Vol. 30  Nº Supl. 2  2017  págs. 434A
Autores: García, Marc; Martinez-Velez, N.; Gonzalez-Huarriz, M.; et al.
Revista: NEURO-ONCOLOGY
ISSN 1522-8517  Vol. 19  Nº Supl. 4  2017  págs. 42
Primitive Neuroectodermal Tumors (PNETs) are very rare aggressive pediatric tumors characterized by the presence of poorly differentiated tumor cells. Despite formidable advances in targeted therapies and in the knowledge of the molecular make-up of these tumors, the development of curative therapies is still lagging. Therefore, the outcome for children affected with PNETs still remains dismal. Thus, it is critical to propel alternative therapeutic approaches to improve the survival and quality of life of these children. Delta-24-RGD is an oncolytic adenovirus engineered to have a tumor restricted replication and an expanded tropism to cancer cells. Altogether, these modifications result in a potent antitumor and lack of toxicity as shown by preclinical and clinical studies. In this work we describe the antitumor effect mediated by Delta-24-RGD in PNETs (PFSK-1 and SK-PN-DW cells), as well as a in a new unpublished cell line (PBT-25) that we have generated from a tumor biopsy. First, we demonstrated in vitro that Delta-24-RGD transduces efficiently PNET cells leading to an effective replication yielding high titers of new infectious particles when compared with other type of brain tumors such as glioma. Treatment with the virus in vitro resulted in an effective cell killing effect, obtaining IC50 values ranging from 7 to 18 MOIs. In vivo, Delta-24-RGD showed a safety profile since no signs of toxicity were observed upon its administration. Finally, the antitumor effect of Delta-24-RGD was assessed in vivo in two orthotopic models of sPNET. Delta-24-RGD treatment resulted in a significant increase in overall survival of the animals (19 and 21 days for PFSK-1 and SK-PN-DW, respectively) compared to vehicle treated animals (14 days) and led to long-term survivors free of disease. In vivo antitumor effect in PBT-25 is on-going. In summary, these results demonstrate the potential therapeutic benefit of Delta-24-RGD for the treatment of PNETs.
Autores: Martinez Velez, N.; Domínguez, Pablo Daniel; et al.
Revista: NEURO-ONCOLOGY
ISSN 1522-8517  Vol. 18  Nº Supl.6  2016  págs. 61
Autores: Tejada, Sonia; Diez Valle, Ricardo; Gállego, Jaime; et al.
Revista: NEURO-ONCOLOGY
ISSN 1522-8517  Vol. 18  Nº Supl.6  2016  págs. 4
Autores: Landeira Freire, M.A.; Sánchez, Emilio; Tejada, Sonia; et al.
Revista: REVISTA IBEROAMERICANA DE AUTOMATICA E INFORMATICA INDUSTRIAL
ISSN 1697-7912  Vol. 12  Nº 1  2015  págs. 80 - 91
In this research work, a new prototype of collaborative robot-assisted surgical platform for transpedicular fixation surgeries is presented. The usage of assistive robotic systems during conventional surgical procedures improves surgical outcomes, as they ensure high levels of precision and safety. Hence, robustness and dexterity of the mechatronic devices must be guaranteed, even in the neighborhood of unstable configurations during their performance. Bearing this in mind, a singularity management strategy has been implemented in the robotic platform, based on the Damped Least Squares method using an adaptive damping factor together with a methodology for optimization of joint redundancy of the platform manipulator, Mitsubishi PA10-7C.
Autores: Idoate, Miguel Ángel; Echeveste, José Ignacio; Diez Valle, Ricardo; et al.
Revista: NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
ISSN 0305-1846  Vol. 40  Nº 6  2014  págs. 736 - 746
AIMS: 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. METHODS: We conducted a comparative study on paraffin and frozen samples from 60 glioblastomas. Based on PTEN immunostaining, paraffin glioblastomas were divided into positive (homogeneous staining) and both positive and negative (heterogeneous staining) tumours. DNA was extracted from manually microdissected samples from representative areas, and from frozen samples taken randomly from the same tumours. Loss of heterozygosity (LOH) of 10q23 and hypermethylation status of the PTEN promoter were studied, and the molecular findings were correlated with overall survival. RESULTS: PTEN protein was present heterogeneously in 42 cases and homogeneously in 18 cases. In homogeneous glioblastomas, no correlation was found between PTEN protein expression and the LOH of the gene. Surprisingly, in the heterogeneous glioblastomas, LOH was found significantly more frequently (P < 0.001) in PTEN-positive areas (81%) than in PTEN-negative ones (35.7%). In general, molecular results of frozen tissue were representative of the tumour. Only two cases of methylation of the PTEN promoter were identified. A significant difference was found for overall survival for LOH10q23 status (P = 0.005) and for homogeneous vs. heterogeneous tumours (P = 0.014). CONCLUSION: The expression of PTEN protein does not correlate with the abnormalities of the LOH of the gene. Interestingly, patients with glioblastomas presenting either LOH of 10q23 or heterogeneous PTEN expression have a poorer prognosis.
Autores: Tejada, Sonia; et al.
Revista: JOURNAL OF NEURO-ONCOLOGY
ISSN 0167-594X  Vol. 116  Nº 1  2014  págs. 169-175
Our purpose was to analyze the pattern of failure in glioblastoma (GBM) patients at first recurrence after radiotherapy and temozolomide and its relationship with different factors. From 77 consecutive GBM patients treated at our institution with fluorescence guided surgery and standard radiochemotherapy, 58 first recurrences were identified and included in a retrospective review. Clinical data including age, Karnofsky performance score, preoperative tumor volume and location, extend of resection, MGMT promoter methylation status, time to progression (PFS), overall survival (OS) and adjuvant therapies were reviewed for every patient. Recurrent tumor location respect the original lesion was the end point of the study. The recurrence pattern was local only in 65.5% of patients and non-local in 34.5%. The univariate and multivariate analysis showed that greater preoperative tumor volume in T1 gadolinium enhanced sequences, was the only variable with statistical signification (p < 0.001) for increased rate of non-local recurrences, although patients with MGMT methylation and complete resection of enhancing tumor presented non-local recurrences more frequently. PFS was longer in patients with non-local recurrences (13.8 vs. 6.4 months; p = 0.019, log-rank). However, OS was not significantly different in both groups (24.0 non-local vs. 19.3 local; p = 0.9). Rate of non-local recurrences in our series of patients treated with fluorescence guided surgery and standard radiochemotherap
Autores: Tejada, Sonia; Pay, Eva María; et al.
Revista: NEUROSURGERY
ISSN 0148-396X  Vol. 72  Nº 6  2013  págs. 915 - 921
There is evidence that fluorescent tissue signal extends farther than tissue highlighted in Gad T1 sequence MRI. To study whether the presence of residual fluorescent tissue after surgery carries a different prognosis for glioblastoma (GBM) with complete resection confirmed by MRI. A retrospective review in our center found 118 consecutive patients with high-grade GBMs operated on with 5-aminolevulinic acid. 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 (OS) 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. The median OS was 27.0 months in patients with nonresidual fluorescence (n = 25) and 17.5 months for the group with residual fluorescence (n = 27) (P = .015). The influence of residual fluorescence was maintained in 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). GBM patients with CRET in early MRI and no fluorescent residual tissue had longer overall survival than patients with CRET and residual fluorescent tissue.
Autores: Arbizu, Javier Ignacio; Tejada, Sonia; Marti-Climent, JM; et al.
Revista: EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
ISSN 1619-7070  Vol. 39  Nº 5  2012  págs. 771 - 781
PURPOSE: The aim of the study was to evaluate the volumetric integration patterns of standard MRI and (11)C-methionine positron emission tomography (PET) images in the surgery planning of gliomas and their relationship to the histological grade. METHODS: We studied 23 patients with suspected or previously treated glioma who underwent preoperative (11)C-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 (11)C-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. RESULTS: Fifteen patients had high-grade tumours [ten glioblastoma multiforme (GBM) and five anaplastic), whereas eight patients had low-grade tumours. Biopsies from areas with high (11)C-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, ¿¿=¿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). CONCLUSION: The metabolically active tumour volume observed in (11)C-methionine PET differs from the volume of MRI by showing areas of infiltrative tumour and distinguishing from non-tumour lesions. Differences in (11)C-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.
Autores: Diez Valle, Ricardo; López, A; Inoges S; et al.
Revista: WORLD JOURNAL OF CLINICAL ONCOLOGY
ISSN 2218-4333  Vol. 3  Nº 11  2012  págs. 142-149
Active immunotherapy with tumor lysate-pulsed, autologous dendritic cells is feasible, safe, well tolerated and biologically efficacious. A phase-II study is ongoing to possibly improve further on our very encouraging clinical results.
Autores: Prieto, Elena; Marti-Climent, JM; et al.
Revista: JOURNAL OF NUCLEAR MEDICINE
ISSN 0161-5505  Vol. 52  Nº 6  2011  págs. 865-72
Compared with standard (18)F-FDG PET studies, quantitative dual-time-point (18)F-FDG PET can improve sensitivity for the identification and volume delineation of high-grade brain tumors.
Autores: Arbizu, Javier Ignacio; Domínguez, Pablo Daniel; Diez Valle, Ricardo; et al.
Revista: REVISTA ESPAÑOLA DE MEDICINA NUCLEAR
ISSN 0212-6982  Vol. 30  Nº 1  2011  págs. 47-65
Autores: Alonso, Marta María, (Autor de correspondencia); Diez Valle, Ricardo; Rubio, A; et al.
Revista: PLoS One
ISSN 1932-6203  Vol. 6  Nº 11  2011  págs.  -
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 esta
Autores: Idoate, Miguel Ángel; Diez Valle, Ricardo; Echeveste, José Ignacio; et al.
Revista: NEUROPATHOLOGY
ISSN 0919-6544  Vol. 31  Nº 6  2011  págs. 575 - 582
Thirty consecutive surgical patients with glioblastoma, were operated upon using fluorescence induced by 5-aminolevulinic acid as guidance. The fluorescent quality of the tissue was used to take biopsies from the tumor center, from the invasive area around it and from adjacent normal-looking tissue. These samples were analyzed with HE, Ki-67 and nestin. Nestin expression in tissue surrounding glioblastoma cases was compared to tissue surrounding vascular lesions, metastasis and hippocampal sclerosis. The rate of gross total resection assessed by volumetric MRI was 83%. Using HE examination as the gold standard, fluorescence identified solid tumor with 100% positive predictive value, invasive areas with 97%, and normal tissue with 67% negative predictive value. Ki67 stained some cells in 69% of the non-fluorescent samples around the tumor. There was always strong nestin expression around the tumor but it was similar to control cases in non-glioma lesions with subacute expansion. 5-aminolevulinic acid fluorescence guidance is very reliable and can help to study the tumor-brain interface. Nestin expression is strong and constant in the tissue around the tumor, but is mostly an acute glial reaction, not specific of the neoplasm. Nestin staining is not recommended as a tumor stem cell marker.
Autores: Diez Valle, Ricardo; Tejada, Sonia; Idoate, Miguel Ángel; et al.
Revista: JOURNAL OF NEURO-ONCOLOGY
ISSN 0167-594X  Vol. 102  Nº 1  2010  págs. 105 - 113
We analyzed the efficacy and applicability of surgery guided by 5-aminolevulinic acid (ALA) fluorescence in consecutive patients with glioblastoma multiforme (GBM). Thirty-six patients with GBM were operated on using ALA fluorescence. Resections were performed using the fluorescent light to assess the right plane of dissection. In each case, biopsies with different fluorescent quality were taken from the tumor center, from the edges, and from the surrounding tissue. These samples were analyzed separately with hematoxylin¿eosin examination and immunostaining against Ki67. Tumor volume was quantified with pre- and postoperative volumetric magnetic resonance imaging. Strong fluorescence identified solid tumor with 100% positive predictive value. Invaded tissue beyond the solid tumor mass was identified by vague fluorescence with 97% positive predictive value and 66% negative predictive value, measured against hematoxylin¿eosin examination. All the contrast-enhancing volume was resected in 83.3% of the patients, all patients had resection over 98% of the volume and mean volume resected was 99.8%. One month after surgery there was no mortality, and new or increased neurological morbidity was 8.2%. The fluorescence induced by 5-aminolevulinic can help to achieve near total resection of enhancing tumor volume in most surgical cases of GBM. It is possible during surgery to obtain separate samples of the infiltrating cells from the tumor border.
Autores: Irimia, Pablo; González, Roberto; Domínguez, Pablo Daniel; et al.
Revista: Cephalalgia
ISSN 0333-1024  Vol. 30  Nº 5  2010  págs. 626 - 630