Grupos Investigadores

Miembros del Grupo

Coordinador
Alonso Roldán, Marta María
(mmalonso@unav.es)
Investigadores
José Javier
Aristu Mendioroz
Ricardo
Diez Valle
Marc
García Moure
Jaime
Gállego Pérez de Larraya
Miguel Ángel
Idoate Gastearena
Marta
Moreno Jiménez
Sonia
Tejada Solís
Ignacio
Íñigo Marco
Colaboradores
Iker
Ausejo Mauleón
Montserrat
Puigdelloses Vallcorba

Líneas de Investigación

  • Búsquedas de marcadores diagnósticos, pronósticos de respuesta a terapias en exosomas de sangre periférica.
  • Ensayos clínicos de nuevas terapias.
  • Mejora de nuestro conocimiento de la respuesta a radioterapia.
  • Nuevas terapias biológicas solas o en combinación con radioterapia.

Palabras Clave

  • Biomarcadores
  • Exosomas
  • Genética molecular
  • Inmunoterapia
  • Metástasis cerebrales
  • Radioterapia
  • Terapias biológicas
  • Tumores cerebrales
  • Viroterapia

Publicaciones Científicas desde 2018

  • Autores: Gállego Pérez de Larraya, Jaime (Autor de correspondencia); García Moure, Marc; Alonso Roldán, Marta María
    Revista: REVUE NEUROLOGIQUE
    ISSN: 0035-3787 Vol.179 N° 5 2023 págs. 475 - 480
    Resumen
    Diffuse intrinsic pontine glioma (DIPG) is the most frequent brainstem glioma and the most lethal brain tumor in childhood. Despite transient benefit with radiotherapy, the prognosis of children with this disease remains dismal with severe neurological morbidity and median survival less than 12 months. Oncolytic immunovirotherapy is emerging as a potential therapeutic approach in neuro-oncology. The oncolytic adenovirus Delta-24-RGD has shown efficacy in adult patients with recurrent GBM. Our group has demonstrated that Delta-24-RGD has oncolytic activity and triggers immune response in preclinical models of DIPG, and has a synergistic effect with radiotherapy in animal models of this disease. In this scenario, we conducted a first-in-human phase 1 clinical trial to evaluate the safety and efficacy of intratumoral injection of Delta-24-RGD in pediatric patients with newly diagnosed DIPG prior to standard radiotherapy. The study confirmed the feasibility of this treatment with an acceptable safety profile and encouraging efficacy results. Correlative analyses showed a biological activity from Delta-24-RGD in DIPG. Further advanced trials are needed to validate these results. Meanwhile, plenty of opportunities to increase the potential contribution of oncolytic viruses in the management of devastating tumors with no current effective treatment such as DIPG need to be explored and exploited.
  • Autores: Foster, J. B. (Autor de correspondencia); Alonso Roldán, Marta María; Sayour, E.; et al.
    Revista: NEOPLASIA
    ISSN: 1476-5586 Vol.42 2023 págs. 100909
    Resumen
    While immunotherapy for pediatric cancer has made great strides in recent decades, including the FDA approval of agents such as dinutuximab and tisgenlecleucel, these successes have rarely impacted children with pediatric central nervous system (CNS) tumors. As our understanding of the biological underpinnings of these tumors evolves, new immunotherapeutics are undergoing rapid clinical translation specifically designed for children with CNS tumors. Most recently, there have been notable clinical successes with oncolytic viruses, vaccines, adoptive cellular therapy, and immune checkpoint inhibition. In this article, the immunotherapy working group of the Pacific Pediatric Neuro-Oncology Consortium (PNOC) reviews the current and future state of immunotherapeutic CNS clinical trials with a focus on clinical trial development. Based on recent therapeutic trials, we discuss unique immunotherapy clinical trial challenges, including toxicity considerations, disease assessment, and correlative studies. Combinatorial strategies and future directions will be addressed. Through internationally collaborative efforts and consortia, we aim to direct this promising field of immuno-oncology to the next frontier of successful application against pediatric CNS tumors.
  • Autores: Jablonska, Paola Anna (Autor de correspondencia); Galán Gallego, Nuria; Barranco, J.; et al.
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN: 1661-6596 Vol.24 N° 18 2023 págs. 14219
    Resumen
    Brain radiation necrosis (RN) is a subacute or late adverse event following radiotherapy, involving an exacerbated inflammatory response of the brain tissue. The risk of symptomatic RN associated with stereotactic radiosurgery (SRS) as part of the treatment of brain metastases (BMs) has been a subject of recent investigation. The activation of the signal transducer and activator of transcription 3 (STAT3) was shown in reactive astrocytes (RA) associated with BMs. Given that the pathophysiological mechanisms behind RN are not fully understood, we sought to investigate the role of STAT3 among other inflammatory markers in RN development. A mouse model of RN using clinical LINAC-based SRS was designed to induce brain necrosis with the administration of 50 Gy in a single fraction to the left hemisphere using a circular collimator of 5 mm diameter. Immunohistochemistry and multiplex staining for CD4, CD8, CD68, GFAP, and STAT3 were performed. For validation, eleven patients with BMs treated with SRS who developed symptomatic RN and required surgery were identified to perform staining for CD68, GFAP, and STAT3. In the mouse model, the RN and perinecrotic areas showed significantly higher staining for F4/80+ and GFAP+ cells, with a high infiltration of CD4 and CD8 T-lymphocytes, when compared to the non-irradiated cerebral hemisphere. A high number of GFAP+pSTAT3+ and F4/80+pSTAT3+ cells was found in the RN areas and the rest of the irradiated hemisphere. The analysis of human brain specimens showed that astrocytes and microglia were actively phosphorylating STAT3 in the areas of RN and gliosis. Phosphorylated STAT3 is highly expressed in the microglia and RA pertaining to the areas of brain RN. Targeting STAT3 via inhibition represents a promising strategy to ameliorate symptomatic RN in BM patients undergoing SRS.
  • Autores: Vicente Ruiz, Miriam; Aristu Mendioroz, José Javier; Hontanilla Calatayud, Bernardo Carlos (Autor de correspondencia)
    Revista: JOURNAL OF RADIOTHERAPY IN PRACTICE
    ISSN: 1460-3969 Vol.22 2023 págs. e47
    Resumen
    Introduction: The management of extracranial arterio-venous malformations (AVMs) is complex and often requires a multidisciplinary approach. Currently, treatment includes surgical resection and embolotherapy. Methods: We present the case of a foot AVM that was managed with adjuvant radiotherapy after previous surgery and embolotherapy had been attempted, and we discuss the role of radiotherapy in the management of extracranial AVMs. Results: The malformation was successfully eradicated with complete obliteration of the nidus and no recurrence. Conclusions: The addition of radiotherapy in the management of extracranial arterio-venous malformations offers promising results using similar doses to those used in brain AVMs.
  • Autores: Nassiri, F.; Patil, V.; Yefet, L. S.; et al.
    Revista: NATURE MEDICINE
    ISSN: 1078-8956 Vol.29 N° 6 2023 págs. 1370 - 1378
    Resumen
    Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2-20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1-69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7-13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05-0.87). A total of 56.2% (95% CI 41.1-70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406).
  • Autores: Hoang-Xuan, K. (Autor de correspondencia); Deckert, M.; Ferreri, A. J. M.; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.25 N° 1 2023 págs. 37 - 53
    Resumen
    The management of primary central nervous system (PCNSL) is one of the most controversial topics in neuro-oncology because of the complexity of the disease and the limited number of controlled studies available. In 2021, given recent advances and the publication of practice-changing randomized trials, the European Association of Neuro-Oncology (EANO) created a multidisciplinary task force to update the previously published evidence-based guidelines for immunocompetent adult patients with PCNSL and added a section on immunosuppressed patients. The guideline provides consensus considerations and recommendations for the treatment of PCNSL, including intraocular manifestations and specific management of the elderly. The main changes from the previous guideline include strengthened evidence for the consolidation with ASCT in first-line treatment, prospectively assessed chemotherapy combinations for both young and elderly patients, clarification of the role of rituximab even though the data remain inconclusive, of the role of new agents, and the incorporation of immunosuppressed patients and primary ocular lymphoma. The guideline should aid the clinicians in everyday practice and decision making and serve as a basis for future research in the field.
  • Autores: Nussbaumer, G.; Benesch, M.; Grabovska, Y.; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.25 N° Supl. 1 2023
  • Autores: Ausejo Mauleón, Iker; Laspidea Ustés, Virginia; De la Nava Martin, Daniel; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.25 N° Supl. 1 2023 págs. NOAD073.051
  • Autores: Ciani, L.; Laternser, S.; Kritzer, B.; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.25 N° Supl. 1 2023 págs. NOAD073.069
  • Autores: Laspidea Ustés, Virginia; Ausejo Mauleón, Iker; De la Nava Martin, Daniel; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.25 N° Supl. 1 2023 págs. NOAD073.057
  • Autores: García Moure, Marc (Autor de correspondencia); Tallón-Cobos, A. C.; Alonso Roldán, Marta María (Autor de correspondencia)
    Revista: MOLECULAR THERAPY ONCOLYTICS
    ISSN: 2372-7705 Vol.27 2022 págs. 124 - 125
  • Autores: Idoate Gastearena, Miguel Ángel (Autor de correspondencia); Aquerreta Beola, Jesús Dámaso; Lamo de Espinosa Vázquez de Sola, José María; et al.
    Revista: DIAGNOSTICS
    ISSN: 2075-4418 Vol.12 N° 2 2022 págs. 450
    Resumen
    Osteosarcoma is a primary malignant bone tumor usually arising at the metaphysis of long bones, particularly around the knee. The physis has been regarded as a barrier capable of blocking tumor extension, thus allowing it to preserve their epiphysis and therefore improve functional results. With the objective of clarifying how effective the physis is as a barrier to tumor spread, a large series of skeletally immature patients with osteosarcoma were reviewed. From 452 metaphyseal osteosarcomas a selection of 282 cases in which the tumor was close or crossing the physis were carried out. This sub-sample was split into two groups according to the surgical treatment (epiphyseal preservation or not). The specimens obtained by resection were studied, and the physeal and metaphyseal areas were studied by multiple sections. Immunostaining against VEGF of physis was obtained in selected cases. In about half of the patients affected by metaphyseal malignant bone tumors, the growth plate and epiphysis were not compromised by the tumor. Three sequential invasive growth patterns of an osteosarcoma in its relationship with the physis could be distinguished. An intense angiogenesis and osteoclastic reaction could be observed in the growth plate in the free zone between the tumor and the physis. The local recurrence incidence was lower in the epiphyseal preservation treated patients than it was in the conventional treatment (8% vs. 12%). Most local recurrences appeared in the first 2 years. The overall survival of patients treated with epiphyseal preservation was better than that of the patients treated without preserving the epiphysis (73% vs. 59%; p = 0.03) at a mean follow-up of 18 years. We have described an angiogenic and osteoclastic reaction in the base of the growth plate in the proximity of the advance front of the tumor, which could facilitate the osteosarcoma invasion. It is also shown that the preoperative imaging method for examination is a valid approach for the decision to carry out epiphyseal preservation. Finally, we concluded that epiphyseal preservation combined with protective chemotherapy is an excellent clinical approach for selected patients with metaphyseal osteosarcoma.
  • Autores: Cohen, A. D.; Parekh, S.; Santomasso, B. D.; et al.
    Revista: BLOOD CANCER JOURNAL
    ISSN: 2044-5385 Vol.12 N° 2 2022 págs. 32
    Resumen
    Chimeric antigen receptor (CAR) T-cell therapies are highly effective for multiple myeloma (MM) but their impressive efficacy is associated with treatment-related neurotoxicities in some patients. In CARTITUDE-1, 5% of patients with MM reported movement and neurocognitive treatment-emergent adverse events (MNTs) with ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen-targeted CAR T-cell therapy. We assessed the associated factors for MNTs in CARTITUDE-1. Based on common features, patients who experienced MNTs were characterized by the presence of a combination of at least two variables: high tumor burden, grade >= 2 cytokine release syndrome (CRS) or any grade immune effector cell-associated neurotoxicity syndrome (ICANS) after cilta-cel infusion, and high CAR T-cell expansion/persistence. Strategies were implemented across the cilta-cel development program to monitor and manage patients with MNTs, including enhanced bridging therapy to reduce baseline tumor burden, early aggressive treatment of CRS and ICANS, handwriting assessments for early symptom detection, and extended monitoring/reporting time for neurotoxicity beyond 100 days post-infusion. After successful implementation of these strategies, the incidence of MNTs was reduced from 5% to <1% across the cilta-cel program, supporting its favorable benefit-risk profile for treatment of MM.
  • Autores: Laspidea Ustés, Virginia; Puigdelloses Vallcorba, Montserrat; Labiano Almiñana, Sara; et al.
    Revista: JCI INSIGHT
    ISSN: 2379-3708 Vol.7 N° 7 2022 págs. e154812
    Resumen
    Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors, and patient survival has not changed despite many therapeutic efforts, emphasizing the urgent need for effective treatments. Here, we evaluated the anti-DIPG effect of the oncolytic adenovirus Delta-24-ACT, which was engineered to express the costimulatory ligand 4-1BBL to potentiate the antitumor immune response of the virus. Delta-24-ACT induced the expression of functional 4-1BBL on the membranes of infected DIPG cells, which enhanced the costimulation of CD8(+) T lymphocytes. In vivo, Delta-24-ACT treatment of murine DIPG orthotopic tumors significantly improved the survival of treated mice, leading to long-term survivors that developed immunological memory against these tumors. In addition, Delta-24-ACT was safe and caused no local or systemic toxicity. Mechanistic studies showed that Delta-24-ACT modulated the tumor-immune content, not only increasing the number, but also improving the functionality of immune cells. All of these data highlight the safety and potential therapeutic benefit of Delta-24-ACT the treatment of patients with DIPG.
  • Autores: Damanskiene, E. (Autor de correspondencia); Balnyte, I.; Valanciute, A.; et al.
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN: 1422-0067 Vol.23 N° 4 2022 págs. 2001
    Resumen
    It is necessary to elucidate the individual effects of temozolomide (TMZ) on carcinogenesis and tumor resistance to chemotherapy mechanisms. The study aimed to investigate the TMZ 50 and 100 mu M dose effect difference between PBT24 and SF8628 cell line high-grade pediatric glioblastoma (phGBM) xenografts in a chicken chorioallantoic membrane (CAM) model, on PCNA and EZH2 immunohistochemical expression in the tumor and on the expression of NKCC1, KCC2, E- and N-cadherin genes in TMZ-treated and control cell groups in vitro. TMZ at a 100 mu g dose reduced the incidence of PBT24 xenograft invasion into the CAM, CAM thickening and the number of blood vessels in the CAM (p < 0.05), but did not affect the SF8628 tumor in the CAM model. The TMZ impact on PBT24 and SF8628 tumor PCNA expression was similarly significantly effective but did not alter EZH2 expression in the studied tumors. The TMZ at 50 mu M caused significantly increased RNA expression of the NKCC1 gene in both studied cell types compared with controls (p < 0.05). The expression of the KCC2 gene was increased in PBT24 TMZ-treated cells (p < 0.05), and no TMZ effect was found in SF8628-treated cells. The study supports the suggestion that individual sensitivity to TMZ should be assessed when starting treatment.
  • Autores: Paricio Martínez, José Joaquín (Autor de correspondencia); Panadero Meseguer, Pablo; Baptista Jardín, Peter Michael; et al.
    Revista: REVISTA ESPAÑOLA DE PATOLOGIA
    ISSN: 1988-561X Vol.55 N° 3 2022 págs. 192 - 196
    Resumen
    A 54-year-old female patient presented with a left nasal obstruction. On physical examination a pink delimited mass in the left nostril was observed. A cranial computed tomography scan revealed an expansive mass in the upper anterior third of the left nasal fossa, partially obstructing it. Endoscopic resection of the mass was performed. Histopathology revealed an atypical mesenchymal proliferation formed by cells disposed in disorganized and interconnected long bundles. Tumor cells had abundant eosinophilic cytoplasm and an oval, vesicular and hyperchromatic nucleus. Frequent mitotic figures were observed, many of them atypical. Necrosis was not observed. Immunohistochemistry showed tumor cells to be positive for calponin, muscle specific actin, caldesmon and smooth muscle specific myosin. Ki-67 index proliferation was 30%. A diagnosis of leiomyosarcoma of the nasal fossa was established.
  • Autores: Arbizu Lostao, Javier; Gállego Pérez de Larraya, Jaime; Hilario, A.; et al.
    Revista: REVISTA ESPAÑOLA DE MEDICINA NUCLEAR E IMAGEN MOLECULAR
    ISSN: 2253-654X Vol.41 N° 4 2022 págs. 247 - 257
    Resumen
    Autoimmune encephalitis are brain inflammatory processes that are classified into two main groups according to the underlying pathogenic mechanism: antibodies to intracellular antigens (paraneoplastic) and antibodies to extracellular or neuronal surface antigens. The clinical manifestations of autoimmune encephalitis are very varied and non-specific. Complementary tests included in its clinical diagnosis include determination of antibodies in serum or cerebrospinal fluid and magnetic resonance imaging (MRI). MRI may show characteristic patterns such as mesial temporal involvement, although in some cases it may be normal or non-specific. 18F-Fluorodeoxyglucose PET/CT (18F-FDG PET/CT) imaging may be helpful in cases of paraneoplastic autoimmune encephalitis to find the primary tumor. In autoimmune encephalitis mediated by antibodies to extracellular antigens, 18F-FDG PET/CT shows distinctive patterns that can aid clinical diagnosis. This continuing education aims to present in a clear and easy-to-understand way, the clinical features of autoimmune encephalitis, the difficulties in clinical diagnosis and the patterns seen on MRI and 18F-FDG PET/CT.
  • Autores: Nguyen, T. T.; Shin, D. H.; Sohoni, S.; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.10 N° 7 2022 págs. e004935
    Resumen
    Background Oncolytic viruses are considered part of immunotherapy and have shown promise in preclinical experiments and clinical trials. Results from these studies have suggested that tumor microenvironment remodeling is required to achieve an effective response in solid tumors. Here, we assess the extent to which targeting specific mechanisms underlying the immunosuppressive tumor microenvironment optimizes viroimmunotherapy. Methods We used RNA-seq analyses to analyze the transcriptome, and validated the results using Q-PCR, flow cytometry, and immunofluorescence. Viral activity was analyzed by replication assays and viral titration. Kyn and Trp metabolite levels were quantified using liquid chromatography-mass spectrometry. Aryl hydrocarbon receptor (AhR) activation was analyzed by examination of promoter activity. Therapeutic efficacy was assessed by tumor histopathology and survival in syngeneic murine models of gliomas, including Indoleamine 2,3-dioxygenase (IDO)-/- mice. Flow cytometry was used for immunophenotyping and quantification of cell populations. Immune activation was examined in co-cultures of immune and cancer cells. T-cell depletion was used to identify the role played by specific cell populations. Rechallenge experiments were performed to identify the development of anti-tumor memory. Results Bulk RNA-seq analyses showed the activation of the immunosuppressive IDO-kynurenine-AhR circuitry in response to Delta-24-RGDOX infection of tumors. To overcome the effect of this pivotal pathway, we combined Delta-24-RGDOX with clinically relevant IDO inhibitors. The combination therapy increased the frequency of CD8(+) T cells and decreased the rate of myeloid-derived suppressor cell and immunosupressive Treg tumor populations in animal models of solid tumors. Functional studies demonstrated that IDO-blockade-dependent activation of immune cells against tumor antigens could be reversed by the oncometabolite kynurenine. The concurrent targeting of the effectors and suppressors of the tumor immune landscape significantly prolonged the survival in animal models of orthotopic gliomas. Conclusions Our data identified for the first time the in vivo role of IDO-dependent immunosuppressive pathways in the resistance of solid tumors to oncolytic adenoviruses. Specifically, the IDO-Kyn-AhR activity was responsible for the resurface of local immunosuppression and resistance to therapy, which was ablated through IDO inhibition. Our data indicate that combined molecular and immune therapy may improve outcomes in human gliomas and other cancers treated with virotherapy.
  • Autores: Persson, M. L.; Douglas, A. M.; Alvaro, F.; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.24 N° 9 2022 págs. 1408 - 1422
    Resumen
    Diffuse midline glioma (DMG), including those of the brainstem (diffuse intrinsic pontine glioma), are pediatric tumors of the central nervous system (CNS). Recognized as the most lethal of all childhood cancers, palliative radiotherapy remains the only proven treatment option, however, even for those that respond, survival is only temporarily extended. DMG harbor an immunologically cold tumor microenvironment (TME) with few infiltrating immune cells. The mechanisms underpinning the cold TME are not well understood. Low expression levels of immune checkpoint proteins, including PD-1, PD-L1, and CTLA-4, are recurring features of DMG and likely contribute to the lack of response to immune checkpoint inhibitors (ICIs). The unique epigenetic signatures (including stem cell-like methylation patterns), a low tumor mutational burden, and recurring somatic mutations (H3K27M, TP53, ACVR1, MYC, and PIK3CA), possibly play a role in the reduced efficacy of traditional immunotherapies. Therefore, to circumvent the lack of efficacy thus far seen for the use of ICIs, adoptive cell transfer (including chimeric antigen receptor T cells) and the use of oncolytic viruses, are currently being evaluated for the treatment of DMG. It remains an absolute imperative that we improve our understanding of DMG's intrinsic and TME features if patients are to realize the potential benefits offered by these sophisticated treatments. Herein, we summarize the limitations of immunotherapeutic approaches, highlight the emerging safety and clinical efficacy shown for sophisticated cell-based therapies, as well as the evolving knowledge underpinning the DMG-immune axis, to guide the development of immunotherapies that we hope will improve outcomes.
  • Autores: Idoate Gastearena, Miguel Ángel (Autor de correspondencia); López Janeiro, Álvaro; Lecumberri Aznarez, A.; et al.
    Revista: BIOMEDICINES
    ISSN: 2227-9059 Vol.10 N° 7 2022 págs. 1753
    Resumen
    Objectives: Immunostimulatory therapies using immune checkpoint blockers show clinical activity in a subset of glioblastoma (GBM) patients. Several inhibitory mechanisms play a relevant role in the immune response to GBM. With the objective of analyzing the tumor immune microenvironment and its clinical significance, we quantified several relevant immune biomarkers. Design: We studied 76 primary (non-recurrent) GBMs with sufficient clinical follow-up, including a subgroup of patients treated with a dendritic cell vaccine. The IDH-mutation, EGFR-amplification, and MGMT methylation statuses were determined. Several relevant immune biomarkers, including CD163, CD8, PD1, and PDL1, were quantified in representative selected areas by digital image analysis and semiquantitative evaluation. The percentage of each immune expression was calculated with respect to the total number of tumor cells. Results: All GBMs were wild-type IDH, with a subgroup of classical GBMs according to the EGFR amplification (44%). Morphologically, CD163 immunostained microglia and intratumor clusters of macrophages were observed. A significant direct correlation was found between the expression of CD8 and the mechanisms of lymphocyte immunosuppression, in such a way that higher values of CD8 were directly associated with higher values of CD163 (p < 0.001), PDL1 (0.026), and PD1 (0.007). In a multivariate analysis, high expressions of CD8+ (HR = 2.05, 95%CI (1.02-4.13), p = 0.034) and CD163+ cells (HR 2.50, 95%CI (1.29-4.85), p = 0.007), were associated with shorter survival durations. The expression of immune biomarkers was higher in the non-classical (non-EGFR amplified tumors) GBMs. Other relevant prognostic factors were age, receipt of the dendritic cell vaccine, and MGMT methylation status. Conclusions: In accordance with the inverse correlation between CD8 and survival and the direct correlation between effector cells and CD163 macrophages and immune-checkpoint expression, we postulate that CD8 infiltration could be placed in a state of anergy or lymphocytic inefficient activity. Furthermore, the significant inverse correlation between CD163 tissue concentration and survival explains the relevance of this type of immune cell when creating a strong immunosuppressive environment. This information may potentially be used to support the selection of patients for immunotherapy.
  • Autores: Le Rhun, E. (Autor de correspondencia); Devos, P.; Winklhofer, S.; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.24 N° 10 2022 págs. 1726 - 1735
    Resumen
    Background Validation of the 2016 RANO MRI scorecard for leptomeningeal metastasis failed for multiple reasons. Accordingly, this joint EORTC Brain Tumor Group and RANO effort sought to prospectively validate a revised MRI scorecard for response assessment in leptomeningeal metastasis. Methods Coded paired cerebrospinal MRI of 20 patients with leptomeningeal metastases from solid cancers at baseline and follow-up after treatment and instructions for assessment were provided via the EORTC imaging platform. The Kappa coefficient was used to evaluate the interobserver pairwise agreement. Results Thirty-five raters participated, including 9 neuroradiologists, 17 neurologists, 4 radiation oncologists, 3 neurosurgeons, and 2 medical oncologists. Among single leptomeningeal metastases-related imaging findings at baseline, the best median concordance was noted for hydrocephalus (Kappa = 0.63), and the worst median concordance for spinal linear enhancing disease (Kappa = 0.46). The median concordance of raters for the overall response assessment was moderate (Kappa = 0.44). Notably, the interobserver agreement for the presence of parenchymal brain metastases at baseline was fair (Kappa = 0.29) and virtually absent for their response to treatment. 394 of 700 ratings (20 patients x 35 raters, 56%) were fully completed. In 308 of 394 fully completed ratings (78%), the overall response assessment perfectly matched the summary interpretation of the single ratings as proposed in the scorecard instructions. Conclusion This study confirms the principle utility of the new scorecard, but also indicates the need for training of MRI assessment with a dedicated reviewer panel in clinical trials. Electronic case report forms with "blocking options" may be required to enforce completeness and quality of scoring.
  • Autores: Persson, M.; Jackson, E.; Duchatel, R.; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.24 2022 págs. 272 - 272
  • Autores: Ausejo Mauleón, Iker; Labiano Almiñana, Sara; De la Nava Martin, Daniel; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.24 N° Supl. 1 2022 págs. 22 - 23
  • Autores: Shin, D. H.; Jiang, H.; Gillard, A.; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.24 N° SUPPL 7 2022 págs. 139 - 140
  • Autores: Jiang, H.; Shin, D. H.; Yi, Y. H.; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.82 N° 12 2022
  • Autores: De la Nava Martin, Daniel; Marco Sanz, Javier; Laspidea Ustés, Virginia; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.82 N° 12 Supl. 2022 págs. 2000
  • Autores: Ausejo Mauleón, Iker; Labiano Almiñana, Sara; Laspidea Ustés, Virginia; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.24 N° Supl. 7 2022 págs. 222
  • Autores: Illade, L.; Garrido, C.; Cruz, O.; et al.
    Revista: PEDIATRIC BLOOD AND CANCER
    ISSN: 1545-5009 Vol.69 N° SUPPL 5 2022 págs. S295 - S296
  • Autores: Jiang, H.; Shin, D. H.; Yi, Y. H.; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.24 N° SUPPL 7 2022 págs. 231 - 231
  • Autores: Van Wieren, A. C.; Sahoni, S.; Nguyen, T.; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.82 N° 12 2022
  • Autores: Shin, D. H.; Jiang, H.; Kim, D.; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.82 N° 12 2022
  • Autores: Lohmann, P.; Smits, M.; Razis, E.; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.24 N° Supl. 7 2022 págs. 168
  • Autores: Nguyen, T.; Shin, D. H.; Kim, D.; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.24 N° SUPPL 7 2022 págs. 223 - 223
  • Autores: Gillard, A.; Shin, D. H.; Laspidea Ustés, Virginia; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.24 N° SUPPL 7 2022 págs. 133 - 133
  • Autores: Nguyen, T. T.; Shin, D. H.; Sohoni, S.; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.82 N° 12 2022
  • Autores: Labiano Almiñana, Sara; Marco Sanz, Javier; Laspidea Ustés, Virginia; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.24 N° Supl. 1 2022 págs. i85
  • Autores: Laspidea Ustés, Virginia; Labiano Almiñana, Sara; Gupta, S.; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.82 N° 12 Supl. 2022
  • Autores: Herrador Cañete, Guillermo; Zalacain Díez, Marta; Labiano Almiñana, Sara; et al.
    Revista: MOLECULAR THERAPY
    ISSN: 1525-0016 Vol.30 N° 4 2022 págs. 416 - 417
  • Autores: Luna, J. (Autor de correspondencia); Bobo, A.; Cabrera-Rodríguez, J. J. ; et al.
    Revista: WORLD JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 2218-4333 Vol.12 N° 8 2021 págs. 581 - 608
    Resumen
    Malignant pleural mesothelioma (MPM) is a rare tumor with poor prognosis and rising incidence. Palliative care is common in MPM as radical treatment with curative intent is often not possible due to metastasis or extensive locoregional involvement. Numerous therapeutic advances have been made in recent years, including the use of less aggressive surgical techniques associated with lower morbidity and mortality (e.g., pleurectomy/decortication), technological advancements in the field of radiotherapy (intensity-modulated radiotherapy, image-guided radiotherapy, stereotactic body radiotherapy, proton therapy), and developments in systemic therapies (chemotherapy and immunotherapy). These improvements have had as yet only a modest effect on local control and survival. Advances in the management of MPM and standardization of care are hampered by the evidence to date, limited by high heterogeneity among studies and small sample sizes. In this clinical guideline prepared by the oncological group for the study of lung cancer of the Spanish Society of Radiation Oncology, we review clinical, histologic, and therapeutic aspects of MPM, with a particular focus on all aspects relating to radiotherapy, including the current evidence base, associations with chemotherapy and surgery, treatment volumes and planning, technological advances, and reradiation.
  • Autores: Shin, D. H.; Nguyen, T.; Ozpolat, B.; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.9 N° 4 2021 págs. e002086
    Resumen
    Cancer virotherapy is a paradigm-shifting treatment modality based on virus-mediated oncolysis and subsequent antitumor immune responses. Clinical trials of currently available virotherapies showed that robust antitumor immunity characterizes the remarkable and long-term responses observed in a subset of patients. These data suggest that future therapies should incorporate strategies to maximize the immunotherapeutic potential of oncolytic viruses. In this review, we highlight the recent evidence that the antiviral immunity of the patients may limit the immunotherapeutic potential of oncolytic viruses and summarize the most relevant approaches to strategically redirect the immune response away from the viruses and toward tumors to heighten the clinical impact of viro-immunotherapy platforms.
  • Autores: Fueyo, J.; Gómez-Manzano, C.; Lang, F. F.; et al.
    Revista: LANCET ONCOLOGY
    ISSN: 1470-2045 Vol.22 N° 8 2021 págs. 1049 - 1051
  • Autores: Ross, J. L.; Chen, Z.; Herting, C. J.; et al.
    Revista: BRAIN
    ISSN: 0006-8950 Vol.144 2021 págs. 53 - 69
    Resumen
    Paediatric high-grade gliomas (HGGs) account for the most brain tumour-related deaths in children and have a median survival of 12-15 months. One promising avenue of research is the development of novel therapies targeting the properties of non-neoplastic cell-types within the tumour such as tumour associated macrophages (TAMs). TAMs are immunosuppressive and promote tumour malignancy in adult HGG; however, in paediatric medulloblastoma, TAMs exhibit anti-tumour properties. Much is known about TAMs in adult HGG, yet little is known about them in the paediatric setting. This raises the question of whether paediatric HGGs possess a distinct constituency of TAMs because of their unique genetic landscapes. Using human paediatric HGG tissue samples and murine models of paediatric HGG, we demonstrate diffuse midline gliomas possess a greater inflammatory gene expression profile compared to hemispheric paediatric HGGs. We also show despite possessing sparse T-cell infiltration, human paediatric HGGs possess high infiltration of IBA1+ TAMs. CD31, PDGFR beta, and PDGFB all strongly correlate with IBA1+ TAM infiltration. To investigate the TAM population, we used the RCAS/tv-a system to recapitulate paediatric HGG in newborn immunocompetent mice. Tumours are induced in Nestin-positive brain cells by PDGFA or PDGFB overexpression with Cdkn2a or Tp53 co-mutations. Tumours driven by PDGFB have a significantly lower median survival compared to PDGFA-driven tumours and have increased TAM infiltration. NanoString and quantitative PCR analysis indicates PDGFB-driven tumours have a highly inflammatory microenvironment characterized by high chemokine expression. In vitro bone marrow-derived monocyte and microglial cultures demonstrate bone marrow-derived monocytes are most responsible for the production of inflammatory signals in the tumour microenvironment in response to PDGFB stimulation. Lastly, using knockout mice deficient for individual chemokines, we demonstrate the feasibility of reducing TAM infiltration and prolonging survival in both PDGFA and PDGFB-driven tumours. We identify CCL3 as a potential key chemokine in these processes in both humans and mice. Together, these studies provide evidence for the potent inflammatory effects PDGFB has in paediatric HGGs.
  • Autores: Urdiciain Ezpeleta, Alejandro; Erausquin, E.; Zelaya, M. V.; et al.
    Revista: BIOLOGY
    ISSN: 2079-7737 Vol.10 N° 6 2021 págs. 467
    Resumen
    Simple Summary Glioblastoma multiforme (GBM) is the most common as well as the most aggressive malignant brain tumor, with an overall survival of almost 15 months. Histone deacetylase 6 (HDAC6), an enzyme related to the deacetylation of alpha-tubulin, is overexpressed in GBM. The aim of our research was to study the effects of HDAC6 silencing in GBM cells. We first confirmed the overexpression of HDAC6 in GBM tissue (n = 40) against control brain (n = 10). Treatment with siHDAC6 diminished viability, clonogenic potential, and migration ability in GBM-derived cell lines. HDAC6 inhibition also reverted the mesenchymal phenotype, inhibited the Sonic Hedgehog pathway, restored primary cilium structure, and decreased autophagy. Thus, we confirm that HDAC6 is a good therapeutic target for GBM treatment. Glioblastoma multiforme, the most common type of malignant brain tumor as well as the most aggressive one, lacks an effective therapy. Glioblastoma presents overexpression of mesenchymal markers Snail, Slug, and N-Cadherin and of the autophagic marker p62. Glioblastoma cell lines also present increased autophagy, overexpression of mesenchymal markers, Shh pathway activation, and lack of primary cilia. In this study, we aimed to evaluate the role of HDAC6 in the pathogenesis of glioblastoma, as HDAC6 is the most overexpressed of all HDACs isoforms in this tumor.
  • Autores: Urdiciain Ezpeleta, Alejandro; Bermúdez-Lekerika, P.; Meléndez, B.; et al.
    Revista: GLIOMA
    ISSN: 2589-6113 Vol.4 N° 2 2021 págs. 27 - 33
    Resumen
    Background and Aim: Glioblastoma is the most lethal brain tumor. No effective curative treatment is available yet, and it is treated by surgery, temozolomide (TMZ), and radiotherapy, with an average overall survival of around 15 months. Inhibitors of histone deacetylases (HDACs) are being explored against a variety of tumors, including glioblastoma. Specific inhibitors of HDAC6, such as tubastatin A (Tub A), may potentially be beneficial as HDAC6 has been demonstrated to be the most expressed HDACs in glioblastoma. Our aim was to test whether Tub A could reverse the malignant phenotype of U87MG cells via the inhibition of HDAC6. Materials and Methods: U87MG cells were treated with cyclopamine (Cyp), TMZ, and Tub A. Two double treatments were performed as well (Cyp + Tub A and TMZ + Tub A). Colony formation, wound healing, Caspase¿Glo 3/7, quantitative reverse transcription¿polymerase chain reaction, luciferase assay, and Western blot assays were conducted to determine clonogenic and migration capacity, apoptosis, activation of the Sonic Hedgehog pathway, acetylation of ¿¿tubulin and epithelial-to-mesenchymal transition, and autophagic flux of U87MG glioblastoma cells, respectively. Results: Tub A treatment caused a reversal of the U87MG malignant phenotype by reducing its clonogenic and migratory cellular potential, and inducing apoptosis.
  • Autores: de la Rosa Fernández-Pacheco, Francisco Javier; Urdiciain Ezpeleta, Alejandro; Zelaya, M. V.; et al.
    Revista: INTERNATIONAL JOURNAL OF ONCOLOGY
    ISSN: 1019-6439 Vol.58 N° 3 2021 págs. 312 - 330
    Resumen
    Glioblastoma is the most malignant brain tumor and presents high resistance to chemotherapy and radiotherapy. Surgery, radiotherapy and chemotherapy with temozolomide are the only treatments against this tumor. New targeted therapies, including epigenetic modulators such as 3-deazane-planocin A (DZ-Nep; an EZH2 inhibitor) and panobinostat (a histone deacetylase inhibitor) are being tested in vitro, together with temozolomide. The present study combined APR-246 with DZ-Nep, panobinostat and teomozolomide in order to explore the possibility of restoring p53 function in mutated cases of glioblastoma. Following the Chou-Talalay method it was demonstrated that APR-246 acts in an additive manner together with the other compounds, reducing clonogenicity and inducing apoptosis in glioblastoma cells independently of p53 status.
  • Autores: Puigdelloses Vallcorba, Montserrat; García Moure, Marc; Labiano Almiñana, Sara; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.9 N° 7 2021 págs. e002644
    Resumen
    Background Glioblastoma (GBM) is a devastating primary brain tumor with a highly immunosuppressive tumor microenvironment, and treatment with oncolytic viruses (OVs) has emerged as a promising strategy for these tumors. Our group constructed a new OV named Delta-24-ACT, which was based on the Delta-24-RGD platform armed with 4-1BB ligand (4-1BBL). In this study, we evaluated the antitumor effect of Delta-24-ACT alone or in combination with an immune checkpoint inhibitor (ICI) in preclinical models of glioma. Methods The in vitro effect of Delta-24-ACT was characterized through analyses of its infectivity, replication and cytotoxicity by flow cytometry, immunofluorescence (IF) and MTS assays, respectively. The antitumor effect and therapeutic mechanism were evaluated in vivo using several immunocompetent murine glioma models. The tumor microenvironment was studied by flow cytometry, immunohistochemistry and IF. Results Delta-24-ACT was able to infect and exert a cytotoxic effect on murine and human glioma cell lines. Moreover, Delta-24-ACT expressed functional 4-1BBL that was able to costimulate T lymphocytes in vitro and in vivo. Delta-24-ACT elicited a more potent antitumor effect in GBM murine models than Delta-24-RGD, as demonstrated by significant increases in median survival and the percentage of long-term survivors. Furthermore, Delta-24-ACT modulated the tumor microenvironment, which led to lymphocyte infiltration and alteration of their immune phenotype, as ...
  • Autores: García Moure, Marc (Autor de correspondencia); Gonzalez-Huarriz, M.; Labiano Almiñana, Sara; et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN: 1078-0432 Vol.27 N° 6 2021 págs. 1807 - 1820
    Resumen
    Purpose: Atypical teratoid/rhabdoid tumors (AT/RT) and central nervous system primitive neuroectodermal tumors (CNS-PNET) are pediatric brain tumors with poor survival and life-long negative side effects. Here, the aim was to characterize the efficacy and safety of the oncolytic adenovirus, Delta-24-RGD, which selectively replicates in and kills tumor cells. Experimental Design: Delta-24-RGD determinants for infection and replication were evaluated in patient expression datasets. Viral replication and cytotoxicity were assessed in vitro in a battery of CNS-PNET and AT/RT cell lines. In vivo, efficacy was determined in different orthotopic mouse models, including early and established tumor models, a disseminated AT/RT lesion model, and immunocompetent humanized mouse models (hCD34(+)-NSG-SGM3). Results: Delta-24-RGD infected and replicated efficiently in all the cell lines tested. In addition, the virus induced dose-dependent cytotoxicity [IC50 value below 1 plaque-forming unit (PFU)/cell] and the release of immunogenic markers. In vivo, a single intratumoral Delta-24-RGD injection (10(7) or 10(8) PFU) significantly increased survival and led to long-term survival in AT/RT and PNET models. Delta-24-RGD hindered the dissemination of AT/RTs and increased survival, leading to 70% of long-term survivors. Of relevance, viral administration to established tumor masses (30 days after engraftment) showed therapeutic benefit. In humanized immunocompetent models, Delta-24-RGD significantly extended the survival of mice bearing AT/RTs or PNETs (ranging from 11 to 27 days) and did not display any toxicity associated with inflammation. Immunophenotyping of Delta-24-RGD-treated tumors revealed increased CD8(+) T-cell infiltration. Conclusions: Delta-24-RGD is a feasible therapeutic option for AT/RTs and CNS-PNETs. This work constitutes the basis for potential translation to the clinical setting.
  • Autores: Rodríguez Garijo, Nuria; Bielsa, I.; Mascaro, J. M.; et al.
    Revista: JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY
    ISSN: 0926-9959 Vol.35 N° 4 2021 págs. 988 - 994
    Resumen
    Background Confusion exists regarding interstitial granulomatous dermatitis (IGD) and palisaded neutrophilic and granulomatous dermatitis (PNGD). Objective To determine whether IGD and PNGD are two different entities, or whether they must be considered as two subtypes of the same reactive pattern, and thus whether the unification of the nomenclature is necessary. Methods Observational retrospective multicentre study of patients with IGD and PNGD evaluated between 1999 and 2019 and review of their clinical and histological features. Results We identified 52 patients (38 women and 14 men). Clinical and histological findings of IGD were observed in 88.4% of cases. The most common cutaneous lesions were plaques/macules (IGD) or annular plaques and papules/nodules (PNGD), located mostly on the limbs and trunk. The rope sign was developed in two patients with IGD that associated autoimmune disorders. Similar associated comorbidities (75%) were found in both entities, mainly autoimmune diseases (53.8%). In IGD, the infiltrate was predominantly lympho-histiocytic. Neutrophilic infiltrates, karyorrhexis and skin lesions with limited clinical course were mainly associated with PNGD biopsies. In biopsies with a limited recurrent course, a predominant lymphocytic inflammatory infiltrate was found. Collagen degeneration was present in 75.9% of cases. The floating sign was observed only in IGD type patients (63%). Overlapping histological findings were found in one fourth of cases, especia
  • Autores: Stakisaitis, D. (Autor de correspondencia); Damanskiene, E.; Curkunaviciute, R.; et al.
    Revista: DOSE-RESPONSE
    ISSN: 1559-3258 Vol.19 N° 1 2021 págs. 1559325821990166
    Resumen
    The study's aim was to investigate the effectiveness of sodium dichloroacetate (NaDCA) or magnesium dichloroacetate (MgDCA) on adult U87 MG and pediatric PBT24 cell lines glioblastoma (GB) xenografts in a chicken chorioallantoic membrane (CAM) model. The study groups were: treated with 10 mM, 5 mM of NaDCA, and 5 mM, 2.5 mM of MgDCA, and controls. The U87 MG and PBT24 xenografts growth, frequency of tumor invasion into CAM, CAM thickening, and the number of blood vessels in CAM differed depending on the dichloroacetate salt treatment. NaDCA impact on U87 MG and PBT24 tumor on proliferating cell nunclear antigen (PCNA) and enhancer of zeste homolog 2 (EZH2) expression in the tumor was different, depending on the NaDCA dose. The 5 mM MgDCA impact was more potent and had similar effects on U87 MG and PBT24 tumors, and its impact was also reflected in changes in PCNA and EZH2 expression in tumor cells. The U87 MG and PBT24 tumor response variations to treatment with different NaDCA concentration on tumor growth or a contrast between NaDCA and MgDCA effectiveness may reflect some differences in U87 MG and PBT24 cell biology.
  • Autores: Laspidea Ustés, Virginia; Gupta, S.; Puigdelloses Vallcorba, Montserrat; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.23 N° Supl. 1 2021 págs. 28
  • Autores: Einsele, H.; Parekh, S. S.; Madduri, D.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.39 N° 15 2021
  • Autores: Puigdelloses Vallcorba, Montserrat; Laspidea Ustés, Virginia; Hambardzumyan, D.; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.23 2021 págs. 28 - 29
  • Autores: Shashikant-Sohoni, S.; Nguyen, T.; Shin, D. H.; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.81 N° 13 Supl. S 2021
  • Autores: Laspidea Ustés, Virginia; Labiano Almiñana, Sara; Ausejo Mauleón, Iker; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.9 N° Supl. 2 2021 págs. A776
  • Autores: Jakubowiak, A.; Parekh, S.; Madduri, D. ; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN: 2152-2650 Vol.21 N° Supl. 1 2021 págs. S421 - S422
  • Autores: Einsele, H.; Parekh, S.; Madduri, D.; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN: 2152-2650 Vol.21 N° Supl. 2 2021 págs. S120 - S121
  • Autores: Labiano Almiñana, Sara; Laspidea Ustés, Virginia; García Moure, Marc; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.23 N° Supl. 1 2021 págs. i26 - i27
    Resumen
    With a 2-year survival less than 20%, Diffuse Intrinsic Pontine Glioma (DIPG) is the principal cause of pediatric death. Despite recent advances in the current treatments, the outcome for children with DIPGs remains dismal. Since the approval of T-VEC for melanoma by the FDA, oncolytic adenoviruses have emerged as a promising therapeutic strategy for brain tumors. Thus, our group launched the first world clinical trial phase I with the oncolytic adenovirus Delta-24-RGD (DNX-2401 in the clinic) for newly diagnosed DIPG (NCT03178032), which has shown safety and feasibility. Despite DNX-2401 increases the recruitment of T cells into the tumor, they usually become inactive due to the suppressive tumor microenvironment evidencing the urgent need to improve this strategy focusing on the generation of effective long-term immune responses. Therefore, we decided to combine the Delta-24-RGD with the targeting of the costimulatory molecule CD40 in two unique orthotopic immunocompetent mouse models of DIPG. The activation of the CD40 receptor, which is expressed by antigen presenting cells (APC) such as microglia, macrophages and dendritic cells, is known to increase antigen presentation and enable T-cell priming and activation. Here, we have observed that in addition to Delta-24-RGD anti-tumor effects, the stimulation of CD40 on the tumor APCs results in a remodeling of the tumor immune compartment with a more efficient T-cell tumor infiltration. Of importance, there is an increase of the survival of mice treated with the combination as compared to single treatments or non-treated mice. In addition, the combination therapy induced a complete regression of tumors in 25% of treated mice indicating the development of long-term anti-tumor immunity. We believe that these results provide a translational breakthrough in the treatment of these lethal tumors and open the door for a future innovative clinical trial.
  • Autores: De la Nava Martin, Daniel; Ausejo Mauleón, Iker; Laspidea Ustés, Virginia; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.23 N° Supl. 1 2021 págs. 20
  • Autores: Gallego Pérez-Larraya, J.; García Moure, Marc; Patiño García, Ana; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.23 2021 págs. 50 - 51
  • Autores: Eguren Santamaría, Iñaki; Fernández de Sanmamed Gutiérrez, Miguel; Goldberg, S. B.; et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN: 1078-0432 Vol.26 N° 16 2020 págs. 4186 - 4197
    Resumen
    Immune checkpoint inhibitors (ICI) have revolutionized the management of advanced non-small cell lung cancer (NSCLC). However, most pivotal phase III trials systematically excluded patients with active brain metastases, precluding the generalization of the results. Although theoretically restricted from crossing the blood-brain barrier, the novel pharmacokinetic/pharmacodynamic profiles of anti-PD-1/PD-L1 drugs have prompted studies to evaluate their activity in patients with NSCLC with active central nervous system (CNS) involvement. Encouraging results have suggested that ICI could be active in the CNS in selected patients with driver-negative advanced NSCLC with high PD-L1 expression and low CNS disease burden. Single-agent CNS response rates around 30% have been reported. Beyond this particular setting, anti-PD-1/PD-L1 antibodies have been evaluated in patients receiving local therapy for brain metastases (BM), addressing concerns about potential neurologic toxicity risks associated with radiotherapy, more specifically, radionecrosis (RN). Accordingly, a variety of clinical and imaging strategies are being appropriately developed to evaluate tumor response and to rule out pseudoprogression or radionecrosis. Our purpose is to critically summarize the advances regarding the role of systemic anti-PD-1/PD-L1 antibodies for the treatment of NSCLC BM. Data were collected from the PubMed database, reference lists, and abstracts from the latest scientific meetings. Recent reports suggest anti-PD-1/PD-L1 agents are active in a subset of patients with NSCLC with BM showing acceptable toxicity. These advances are expected to change soon the management of these patients but additional research is required to address concerns regarding radionecrosis and the appropriate sequencing of local and systemic therapy combinations.
  • Autores: Grünewald, T. G. P. (Autor de correspondencia); Alonso Roldán, Marta María; Avnet, S.; et al.
    Revista: EMBO MOLECULAR MEDICINE
    ISSN: 1757-4676 Vol.12 N° 11 2020 págs. e11131
    Resumen
    Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult-to-treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma.
  • Autores: Jablonska, P. A. (Autor de correspondencia); Serrano Tejero, Diego; Calvo González, Alfonso; et al.
    Revista: CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY
    ISSN: 1040-8428 Vol.153 2020
    Resumen
    Due to improvements in systemic therapies and longer survivals, cancer patients frequently present with recurrent brain metastases (BM). The optimal therapeutic strategies for limited brain relapse remain undefined. We analyzed tumor control and survival in patients treated with salvage focal radiotherapy in our center. Thirty-three patients with 112 BM received salvage stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) for local or regional recurrences. Local progression was observed in 11 BM (9.8 %). After 1 year, 72 % of patients were free of distant brain failure, and the 2-year overall survival (OS) was 37.7 %. No increase in toxicity or neurologically related deaths were observed. The 2- and 3-year whole brain radiation therapy free survival (WFS) rates were 92.9 % and 77.4 %, respectively. Hence, focal radiotherapy is a feasible salvage of recurrent BM in selected group of patients with limited brain disease, achieving a maintained intracranial control and less neurological toxicity.
  • Autores: de la Rosa Fernández-Pacheco, Francisco Javier; Urdiciain Ezpeleta, Alejandro; Zazpe, I.; et al.
    Revista: INTERNATIONAL JOURNAL OF ONCOLOGY
    ISSN: 1019-6439 Vol.56 N° 1 2020 págs. 283 - 300
    Resumen
    Current treatment against glioblastoma consists of surgical resection followed by temozolomide, with or without combined radiotherapy. Glioblastoma frequently acquires resistance to chemotherapy and/or radiotherapy. Novel therapeutic approaches are thus required. The inhibition of enhancer of zeste homolog 2 (EZH2; a histone methylase) and histone deacetylases (HDACs) are possible epigenetic treatments. Temozolomide, 3-deazaneplanocin A (DZ-Nep; an EZH2 inhibitor) and panobinostat (an HDAC inhibitor) were tested in regular and temozolomide-resistant glioblastoma cells to confirm whether the compounds could behave in a synergistic, additive or antagonistic manner. A total of six commercial cell lines, two temozolomide-induced resistant cell lines and two primary cultures derived from glioblastoma samples were used. Cell lines were exposed to single treatments of the drugs in addition to all possible two-and three-drug combinations. Colony formation assays, synergistic assays and reverse transcription-quantitative PCR analysis of apoptosis-associated genes were performed. The highest synergistic combination was DZ-Nep + panobinostat. Triple treatment was also synergistic. Reduced clonogenicity and increased apoptosis were both induced. It was concluded that the therapeutic potential of the combination of these three drugs in glioblastoma was evident and should be further explored.
  • Autores: Velasco, R. (Autor de correspondencia); Mercadal, S. ; Vidal, N.; et al.
    Revista: JOURNAL OF NEURO-ONCOLOGY
    ISSN: 0167-594X Vol.148 N° 3 2020 págs. 545 - 554
    Resumen
    Introduction To assess the management of immunocompetent patients with primary central nervous system lymphomas (PCNSL) in Spain. Methods Retrospective analysis of 327 immunocompetent patients with histologically confirmed PCNSL diagnosed between 2005 and 2014 in 27 Spanish hospitals. Results Median age was 64 years (range: 19-84; 33% >= 70 years), 54% were men, and 59% had a performance status (PS) >= 2 at diagnosis. Median delay to diagnosis was 47 days (IQR 24-81). Diagnostic delay > 47 days was associated with PS >= 2 (OR 1.99; 95% CI 1.13-3.50; p = 0.016) and treatment with corticosteroids (OR 2.47; 95% CI 1.14-5.40; p = 0.023), and it did not improve over the years. Patients treated with corticosteroids (62%) had a higher risk of additional biopsies (11.7% vs 4.0%, p = 0.04) but corticosteroids withdrawal before surgery did not reduce this risk and increased the diagnostic delay (64 vs 40 days, p = 0.04). Median overall survival (OS) was 8.9 months [95% CI 5.9-11.7] for the whole series, including 52 (16%) patients that were not treated, and 14.1 months (95%CI 7.7-20.5) for the 240 (73.4%) patients that received high-dose methotrexate (HD-MTX)-based chemotherapy. Median OS was shorter in patients >= 70 years (4.1 vs. 13.4 months; p < 0.0001). Multivariate analysis identified age >= 65 years, PS >= 2, no treatment, and cognitive/psychiatric symptoms at diagnosis as independent predictors of short survival. Conclusions Corticosteroids withdrawal before surgery does not decrease the risk of a negative biopsy but delays diagnosis. In this community-based study, only 73.4% of patients could receive HD-MTX-based chemotherapy and OS remains poor, particularly in elderly patients >= 70 years.
  • Autores: Rodríguez Garijo, Nuria; Tomás Velázquez, Alejandra; Estenaga Pérez de Albéniz, Ángela; et al.
    Revista: PEDIATRIC DERMATOLOGY
    ISSN: 0736-8046 Vol.37 2020 págs. 750 - 751
  • Autores: Tomás Velázquez, Alejandra; Idoate Gastearena, Miguel Ángel; Rodríguez Garijo, Nuria; et al.
    Revista: JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT
    ISSN: 1610-0379 Vol.18 N° 10 2020 págs. 1192 - 1196
  • Autores: Valentí Azcárate, Rafael (Autor de correspondencia); Esparragosa Vázquez, Inés; Toledano Illán, Carlos; et al.
    Revista: NEUROMUSCULAR DISORDERS
    ISSN: 0960-8966 Vol.30 N° 1 2020 págs. 67 - 69
    Resumen
    The rapidly growing field of cancer immunotherapy has led to the development of new treatments such as immune checkpoint inhibitors. These agents are monoclonal antibodies that enable tumor-reactive T cells to overcome regulatory mechanisms and produce effective antitumor responses. The use of immune checkpoint inhibitors is expected to progressively increase because they have shown promising therapeutic outcomes in multiple types of cancer and clinicians should be aware of their possible side-effects. We report a case of a man diagnosed with a non-microcytic lung carcinoma who started treatment with a combination of immune checkpoint inhibitors (Nivolumab and Ipilimumab). He subsequently developed binocular diplopia, fatigue, mild dyspnea and upper back pain resembling a myasthenia gravis presentation. Finally, a diagnosis of immune checkpoint inhibitor-related myositis and myocarditis was made. The detection of GFAP antibodies in CSF has unclear clinical and pathogenic significance and they may rather represent an epiphenomenon of the immune inflammation process.
  • Autores: Puigdelloses Vallcorba, Montserrat; González Huarriz, María Soledad; García Moure, Marc; et al.
    Revista: NEURO-ONCOLOGY ADVANCES
    ISSN: 2632-2498 Vol.2 N° 1 2020 págs. vdaa010
    Resumen
    Background: Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Circulating biomarkers may assist in the processes of differential diagnosis and response assessment. GBM cells release extracellular vesicles containing a subset of proteins and nucleic acids. We previously demonstrated that exosomes isolated from the serum of GBM patients had an increased expression of RNU6-1 compared to healthy subjects. In this exploratory study, we investigated the role of this small noncoding RNA as a diagnostic biomarker for GBM versus other brain lesions with some potential radiological similarities. Methods: We analyzed the expression of RNU6-1 in circulating exosomes of GBM patients (n = 18), healthy controls (n = 30), and patients with subacute stroke (n = 30), acute/subacute hemorrhage (n = 30), acute demyelinating lesions (n = 18), brain metastases (n = 21), and primary central nervous system lymphoma (PCNSL; n = 12) using digital droplet PCR. Results: Expression of RNU6-1 was significantly higher in GBM patients than in healthy controls (P = .002). RNU6-1 levels were also significantly higher in exosomes from GBM patients than from patients with non-neoplastic lesions (stroke [P = .05], hemorrhage [P = .01], demyelinating lesions [P = .019]) and PCNSL (P = .004). In contrast, no significant differences were found between patients with GBM and brain metastases (P = .573). Receiver operator characteristic curve analyses supported the role of this biomarker in differentiating GBM from subacute stroke, acute/subacute hemorrhage, acute demyelinating lesions, and PCNSL (P < .05), but again not from brain metastases (P = .575). Conclusions: Our data suggest that the expression of RNU6-1 in circulating exosomes could be useful for the differentiation of GBM from non-neoplastic brain lesions and PCNSL, but not from brain metastases.
  • Autores: Martínez Velez, Naiara; García Moure, Marc; Puigdelloses Vallcorba, Montserrat; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.22 N° Suppl. 2 2020 págs. 113 - 113
  • Autores: García Moure, Marc; González Huarriz, María Soledad; De la Nava Martin, Daniel; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.22 2020 págs. 471 - 471
  • Autores: Laspidea Ustés, Virginia; Puigdelloses Vallcorba, Montserrat; Ausejo Mauleón, Iker; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.22 2020 págs. 471 - 471
  • Autores: Puigdelloses Vallcorba, Montserrat; Laspidea Ustés, Virginia; García Moure, Marc; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.22 N° Suppl. 2 2020 págs. 109 - 109
  • Autores: Shin, D. H.; Nguyen, T.; Jiang, H.; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.22 N° Supl. 2 2020 págs. 95
  • Autores: Nguyen, T. ; Shin, D. H. ; Jiang, H.; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.22 N° Suppl. 2 2020 págs. 97 - 97
  • Autores: Alonso Roldán, Marta María; Íñigo Marco, Ignacio; García Moure, Marc; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.22 2020 págs. 38 - 38
  • Autores: Stakisaitis, D. (Autor de correspondencia); Jukneviciene, M.; Damanskiene, E. ; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.11 N° 8 2019 págs. 1210
    Resumen
    Sodium dichloroacetate (DCA) is an investigational medicinal product which has a potential anticancer preparation as a metabolic regulator in cancer cells' mitochondria. Inhibition of pyruvate dehydrogenase kinases by DCA keeps the pyruvate dehydrogenase complex in the active form, resulting in decreased lactic acid in the tumor microenvironment. This literature review displays the preclinical research data on DCA's effects on the cell pyruvate dehydrogenase deficiency, pyruvate mitochondrial oxidative phosphorylation, reactive oxygen species generation, and the Na+-K+-2Cl(-) cotransporter expression regulation in relation to gender. It presents DCA pharmacokinetics and the hepatocarcinogenic effect, and the safety data covers the DCA monotherapy efficacy for various human cancer xenografts in vivo in male and female animals. Preclinical cancer researchers report the synergistic effects of DCA combined with different drugs on cancer by reversing resistance to chemotherapy and promoting cell apoptosis. Researchers note that female and male animals differ in the mechanisms of cancerogenesis but often ignore studying DCA's effects in relation to gender. Preclinical gender-related differences in DCA pharmacology, pharmacological mechanisms, and the elucidation of treatment efficacy in gonad hormone dependency could be relevant for individualized therapy approaches so that gender-related differences in treatment response and safety can be proposed.
  • Autores: Stummer, W. (Autor de correspondencia); Koch, R.; Diez Valle, Ricardo; et al.
    Revista: ACTA NEUROCHIRURGICA
    ISSN: 0001-6268 Vol.161 N° 10 2019 págs. 2083 - 2098
    Resumen
    Background Surgery for gliomas is often confounded by difficulties in distinguishing tumor from surrounding normal brain. For better discrimination, intraoperative optical imaging methods using fluorescent dyes are currently being explored. Understandably, such methods require the demonstration of a high degree of diagnostic accuracy and clinical benefit. Currently, clinical utility is determined by tissue biopsies which are correlated to optical signals, and quantified using measures such as sensitivity, specificity, positive predictive values, and negative predictive values. In addition, surgical outcomes, such as extent of resection rates and/or survival (progression-free survival (PFS) and overall survival (OS)) have been measured. These assessments, however, potentially involve multiple biases and confounders, which have to be minimized to ensure reproducibility, generalizability and comparability of test results. Test should aim at having a high internal and external validity. The objective of this article is to analyze how diagnostic accuracy and outcomes are utilized in available studies describing intraoperative imaging and furthermore, to derive recommendations for reliable and reproducible evaluations. Methods A review of the literature was performed for assessing the use of measures of diagnostic accuracy and outcomes of intraoperative optical imaging methods. From these data, we derive recommendations for designing and reporting future studies. Results Available literature indicates that potential confounders and biases for reporting the diagnostic accuracy and usefulness of intraoperative optical imaging methods are seldom accounted for. Furthermore, methods for bias reduction are rarely used nor reported. Conclusions Detailed, transparent, and uniform reporting on diagnostic accuracy of intraoperative imaging methods is necessary. In the absence of such reporting, studies will not be comparable or reproducible. Future studies should consider some of the recommendations given here.
  • Autores: Diez Valle, Ricardo (Autor de correspondencia); Hadjipanayis, C. G.; Stummer, W.
    Revista: JOURNAL OF NEURO-ONCOLOGY
    ISSN: 0167-594X Vol.141 N° 3 2019 págs. 487 - 494
    Resumen
    Introduction5-aminolevulinic acid (5-ALA) was approved by the FDA in June 2017 as an intra-operative optical imaging agent for patients with gliomas (suspected World Health Organization Grades III or IV on preoperative imaging) as an adjunct for the visualization of malignant tissue during surgery. 5-ALA fluorescence-guided surgery (FGS) has been in widespread use in Europe and other continents since 2007.MethodsWe reviewed the data available and summarize the most important known uses of 5-ALA FGS and its potential future applications.Results/conclusionsThe technique has been extensively studied, and more than 300 papers have been published on this topic. Visualization of high-grade glioma tissue is robust and reproducible, and can impact the extent of tumor resection and patient outcomes. 5-ALA FGS for other kind of tumors needs further development
  • Autores: Íñigo Marco, Ignacio; Alonso Roldán, Marta María (Autor de correspondencia)
    Revista: JOURNAL OF CLINICAL INVESTIGATION
    ISSN: 0021-9738 Vol.129 N° 12 2019 págs. 5086 - 5088
    Resumen
    Tumor-induced immunosuppression is a common obstacle for cancer treatment. Adrenergic signaling triggered by chronic stress participates in the creation of an immunosuppressive microenvironment by promoting myeloid-derived suppressor cell (MDSC) proliferation and activation. In this issue of the JCI, Mohammadpour et al. elegantly delve into the mechanisms underlying MDSC contribution to tumor development. They used in vitro and in vivo mouse models to demonstrate that chronic stress results in MDSC accumulation, survival, and immune-inhibitory activity. Of therapeutic relevance, the authors showed that propranolol, a commonly prescribed beta-blocker, can reduce MDSC immunosuppression and enhance the effect of other cancer therapies.
  • Autores: Urdiciain Ezpeleta, Alejandro; Erausquin, E.; Meléndez, B.; et al.
    Revista: INTERNATIONAL JOURNAL OF ONCOLOGY
    ISSN: 1019-6439 Vol.54 N° 5 2019 págs. 1797 - 1808
    Resumen
    Glioblastoma or grade IV astrocytoma is the most common and lethal form of glioma. Current glioblastoma treatment strategies use surgery followed by chemotherapy with temozolomide. Despite this, numerous glioblastoma cases develop resistance to temozolomide treatments, resulting in a poor prognosis for the patients. Novel approaches are being investigated, including the inhibition of histone deacetylase 6 (HDAC6), an enzyme that deacetylates a-tubulin, and whose overexpression in glioblastoma is associated with the loss of primary cilia. The aim of the present study was to treat glioblastoma cells with a selective HDAC6 inhibitor, tubastatin A, to determine if the malignant phenotype may be reverted. The results demonstrated a notable increase in acetylated a-tubulin levels in treated cells, which associated with downregulation of the sonic hedgehog pathway, and may hypothetically promote ciliogenesis in those cells. Treatment with tubastatin A also reduced glioblastoma clonogenicity and migration capacities, and accelerated temozolomide-induced apoptosis. Finally, HDAC6 inhibition decreased the expression of mesenchymal markers, contributing to reverse epithelial-mesenchymal transition in glioblastoma cells.
  • Autores: Jiang, H. (Autor de correspondencia); Shin, D. H.; Nguyen, T. T.; et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN: 1078-0432 Vol.25 N° 22 2019 págs. 6801 - 6814
    Resumen
    Purpose: Intratumoral injection of oncolytic adenovirus Delta-24-RGDOX induces efficacious antiglioma immunity in syngeneic glioma mouse models. We hypothesized that localized treatment with the virus is effective against disseminated melanomas. Experimental Design: We tested the therapeutic effect of injecting Delta-24-RGDOX into primary subcutaneous (s. c.) B16-Red-FLuc tumors in s.c./s.c. and s.c./intracranial (i.c.) melanoma models in C57BL/6 mice. Tumor growth and in vivo luciferase-expressing ovalbumin-specific (OT-I/Luc) T cells were monitored with bioluminescence imaging. Cells were profiled for surface markers with flow cytometry. Results: In both s.c./s.c. and s.c./i. c. models, 3 injections of Delta-24- RGDOX significantly inhibited the growth of both the virus-injected s.c. tumor and untreated distant s.c. and i.c. tumors, thereby prolonging survival. The surviving mice were protected from rechallenging with the same tumor cells. The virus treatment increased the presence of T cells and the frequency of effector T cells in the virus-injected tumor and mediated the same changes in T cells from peripheral blood, spleen, and brain hemispheres with untreated tumor. Moreover, Delta-24- RGDOX decreased the numbers of exhausted T cells and regulatory T cells in the virus-injected and untreated tumors. Consequently, the virus promoted the in situ expansion of tumor-specific T cells and their migration to tumors expressing the target antigen. Conclusions: Localized intratumoral injection of Delta24-RGDOX induces an in situ antovaccination of the treated melanoma, the effect of which changes the immune landscape of the treated mice, resulting in systemic immunity against disseminated s.c. and i.c. tumors.
  • Autores: Jablonska, Paola Anna (Autor de correspondencia); Diez Valle, Ricardo; Gállego Pérez de Larraya, Jaime; et al.
    Revista: PLOS ONE
    ISSN: 1932-6203 Vol.14 N° 6 2019 págs. e0217881
    Resumen
    Background Hypofractionated radiation therapy is a feasible and safe treatment option in elderly and frail patients with glioblastoma. The aim of this study was to evaluate the effectiveness of hypofractionated radiation therapy with concurrent temozolomide in terms of feasibility and disease control in primary glioblastoma patients with poor prognostic factors other than advanced age, such as post-surgical neurological complications, high tumor burden, unresectable or multifocal lesions, and potential low treatment compliance due to social factors or rapidly progressive disease. Material and methods GTV included the surgical cavity plus disease visible in T1WI-MRI, FLAIR-MRI and in the MET-uptake. The CTV was defined as the GTV plus 1.5-2 cm margin; the PTV was the CTV+0.3 cm margin. Forty, fourty-five, and fifty grays in 15 fractions were prescribed to 95% of PTV, CTV, and GTV, respectively. Treatment was delivered using IMRT or the VMAT technique. Simultaneously, 75 mg/m(2)/day of temozolomide were administered. Results Between January 2010 and November 2017, we treated a total of 17 patients. The median age at diagnosis was 68-years; median KPS was 50-70%. MGMT-methylation status was negative in 5 patients, and 8 patients were IDH-wildtype. Eight of 18 patients were younger than 65-years. Median tumor volume was 26.95cc; median PTV volume was 322cc. Four lesions were unresectable; 6 patients underwent complete surgical resection. Median residual volume was 1.14cc. Progression-free survival was 60% at 6 months, 33% at 1-year and 13% at 2-years (median OS = 7 months). No acute grade 3-5 toxicities were documented. Symptomatic grade 3 radiation necrosis was observed in one patient. Conclusions Patients with poor clinical factors other than advanced age can be selected for hypofractionated radiotherapy. The OS and PFS rates obtained in our series are similar to those in patients treated with standard fractionation, assuring good treatment adherence, low rates of toxicity and probable improved cost-effectiveness.
  • Autores: Gonzalez-Morales, A.; Zabaleta Azpiroz, Aintzane; García Moure, Marc; et al.
    Revista: JOURNAL OF PROTEOMICS
    ISSN: 1874-3919 Vol.194 2019 págs. 168 - 178
    Resumen
    Adenovirus Delta-24-RGD has shown a remarkable efficacy in a phase I clinical trial for glioblastoma. Delta-24-RGD induces autophagy in glioma cells, however, the molecular derangements associated with Delta-24-RGD infection remains poorly understood. Here, proteomics was applied to characterize the glioma metabolic disturbances soon after Delta-24-RGD internalization and late in infection. Minutes post-infection, a rapid survival reprogramming of glioma cells was evidenced by an early c-Jun activation and a time-dependent dephosphorylation of multiple survival kinases. At 48 h post-infection (hpi), a severe intracellular proteostasis impairment was characterized, detecting differentially expressed proteins related to mRNA splicing, cytoskeletal organization, oxidative response, and inflammation. Specific kinase-regulated protein interactomes for Delta-24-RGD-modulated proteome revealed interferences with the activation dynamics of protein kinases C and A (PKC, PKA), tyrosine-protein kinase Src (c-Src), glycogen synthase kinase-3 (GSK-3) as well as serine/threonine-protein phosphatases 1 and 2A (PP1, PP2A) at 48hpi, in parallel with adenoviral protein overproduction. Moreover, the late activation of the nuclear factor kappa B (NF-kappa B) correlates with the extracellular increment of specific cytokines involved in migration, and activation of different inflammatory cells. Taken together, our integrative analysis provides further insights into the effects triggered by Delta-24-RGD in the modulation of tumor suppression and immune response against glioma. Significance: The current study provides new insights regarding the molecular mechanisms governing the glioma metabolism during Delta-24-RGD oncolytic adenoviral therapy. The compilation and analysis of intracellular and extracellular proteomics have led us to characterize: i) the cell survival reprogramming during Delta-24-RGD internalization, ii) the proteostatic disarrangement induced by Delta-24-RGD during the autophagic stage, iii) the protein interactomes for Delta-24-RGD-modulated proteome, iv) the regulatory effects on kinase dynamics induced by Delta-24-RGD late in infection, and v) the overproduction of multitasking cytokines upon Delta-24-RGD treatment. We consider that the quantitative molecular maps generated in this study may establish the foundations for the development of complementary adenoviral based-vectors to increase the potency against glioma.
  • Autores: Rodríguez Garijo, Nuria; Querol Cisneros, Elena; Tomás Velázquez, Alejandra; et al.
    Revista: PEDIATRIC DERMATOLOGY
    ISSN: 0736-8046 2019
  • Autores: García Moure, Marc; González Huarriz, María Soledad; Laspidea Ustés, Virginia; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.21 N° Supl. 6 2019 págs. 192 - 192
  • Autores: Gállego Pérez de Larraya, Jaime; Esparragosa Vázquez, Inés; Puigdelloses Vallcorba, Montserrat; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.21 2019 págs. 37 - 38
  • Autores: Íñigo Marco, Ignacio; Diez Valle, Ricardo; García Moure, Marc; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.21 N° Supl. 6 2019 págs. 283 - 284
  • Autores: García Moure, Marc; González Huarriz, María Soledad; Marrodán Fernández, Lucía; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.21 N° Supl. 2 2019 págs. 63
  • Autores: Puigdelloses Vallcorba, Montserrat; Martínez Velez, Naiara; García Moure, Marc; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.21 2019 págs. 56 - 56
  • Autores: Jiang, H.; Shin, D. H. ; Nguyen, T.; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.21 N° Supl. 6 2019 págs. 84 - 84
  • Autores: Alonso Roldán, Marta María; Íñigo Marco, Ignacio; González Huarriz, María Soledad; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.21 N° S3 2019 págs. 11 - 11
  • Autores: García Moure, Marc; González Huarriz, María Soledad; Marrodán Fernández, Lucía; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.21 N° Supl. 3 2019 págs. 47
  • Autores: Laspidea Ustés, Virginia; Puigdelloses Vallcorba, Montserrat; Íñigo Marco, Ignacio; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.21 N° Supl. 6 2019 págs. 122
  • Autores: Idoate Gastearena, Miguel Ángel; Roca, P. G.; Benitez, E.; et al.
    Revista: VIRCHOWS ARCHIV
    ISSN: 0945-6317 Vol.475 2019 págs. S32 - S32
  • Autores: Martínez Velez, Naiara; García Moure, Marc; Laspidea Ustés, Virginia; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.21 2019 págs. 68 - 69
  • Autores: Laspidea Ustés, Virginia; Puigdelloses Vallcorba, Montserrat; García Moure, Marc; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.21 2019 págs. 36 - 36
  • Autores: Rivera-Molina, Y.; Fueyo, J.; Jiang, H.; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.21 N° Supl. 6 2019 págs. 87
  • Autores: Laspidea Ustés, Virginia; Varela Guruceaga, Maider; García Moure, Marc; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.21 N° Supl. 2 2019 págs. 119
  • Autores: Martínez Velez, Naiara; García Moure, Marc; Laspidea Ustés, Virginia; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.79 N° Supl. 13 2019
  • Autores: Garriz Luis, Maite (Autor de correspondencia); Sánchez-Carpintero Abad, Rocío; Alegre Esteban, Manuel; et al.
    Revista: REVISTA DE NEUROLOGIA
    ISSN: 0210-0010 Vol.66 N° 11 2018 págs. 387 - 394
    Resumen
    Introduction. Infantile cerebral palsy is a well-known condition, the prevalence of which has varied only slightly over the years. The most common subtype is spastic diplegia, and spasticity is the most disabling symptom. Its treatment involves a multidisciplinary intervention that includes rehabilitation, the use of drugs, and orthopaedic and nervous system surgery, where selective dorsal rhizotomy is a prominent procedure. Aim. To present a thorough review of the use, indication and long-term consequences of selective dorsal rhizotomy. Development. It is a minimally invasive procedure aimed at reducing spasticity in the lower extremities in order to improve the ability to walk, lessen pain, facilitate care in everyday life and diminish the need for orthopaedic surgery. The literature contains a wide range of criteria for its use, and the main indication is spastic diplegia with the absence of dystonia. It is routinely performed in several countries, while we have no evidence of its application in ours. Conclusions. Following the literature review, we believe there is enough experience to state that selective dorsal rhizotomy is a safe and simple technique from which many patients with spasticity of the lower limbs secondary to infantile cerebral palsy can benefit in both the short and the long term.
  • Autores: Moreno Artero, Ester; Querol Cisneros, Elena; Rodríguez Garijo, Nuria; et al.
    Revista: ANNALS OF HEMATOLOGY
    ISSN: 0939-5555 Vol.97 N° 3 2018 págs. 543 - 544
  • Autores: Sievers, P.; Stichel, D.; Hielscher, T.; et al.
    Revista: ACTA NEUROPATHOLOGICA
    ISSN: 0001-6322 Vol.136 N° 6 2018 págs. 975 - 978
  • Autores: Lara, P. C. (Autor de correspondencia); Rodriguez, A.; Ferrer, C.; et al.
    Revista: INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS
    ISSN: 0360-3016 Vol.100 N° 2 2018 págs. 292 - 296
  • Autores: Ezponda Casajús, Ana; González de la Huebra Rodríguez, Ignacio Javier; Calvo Imirizaldu, Marta; et al.
    Revista: ONCOLOGY LETTERS
    ISSN: 1792-1074 Vol.16 N° 3 2018 págs. 4043 - 4048
    Resumen
    Pazopanib is the first multitargeted tyrosine¿kinase inhibitor approved for the treatment of patients with advanced non¿adipocytic soft tissue sarcoma (STS). It has been demonstrated to improve progression¿free survival without impairing health¿associated quality of life. However, Pazopanib is associated with several adverse side effects associated with inhibition of the vascular endothelial growth factor receptor. These include hepatotoxicity, as manifested by abnormal liver function tests. To the best of our knowledge, the current study presents the first case of a patient with recurrent STS who developed biopsy proven Pazopanib¿induced chronic active hepatitis and whose previous computed tomography examination demonstrated multiple hypervascular liver lesions. These lesions were indistinguishable from metastases and to the best of our knowledge, have not been described previously. These lesions therefore appear to be a novel finding of Pazopanib¿induced chronic active hepatitis. It is crucial to be aware of this unusual finding within a clinical setting, to avoid overstaging and early discontinuation of effective treatment.
  • Autores: Lang, F. F. (Autor de correspondencia); Conrad, C.; Gomez-Manzano, C.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.36 N° 14 2018 págs. 1419 - 27
    Resumen
    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: de la Rosa Fernández-Pacheco, Francisco Javier; Urdiciain Ezpeleta, Alejandro; Meléndez, B.; et al.
    Revista: GLIOMA
    ISSN: 2589-6113 Vol.1 N° 1 2018 págs. 22 - 26
    Resumen
    Background: Glioblastoma multiforme (GBM) is the most malignant primary brain tumor. Current treatment against this tumor consists of maximal surgical resection without threatening the patient's life, followed by a treatment with temozolomide, with or without combined radiotherapy. GBM is resistant to the conventional antitumor therapies, so in this research, we tried to inhibit tumor growth with the combination of three drugs: (1) panobinostat, an inhibitor of histone deacetylases, (2) 3-Dezaneplanocin-A (DZNep), an inhibitor of EZH2, a protein which belongs to the polycomb repressor complex 2, acting as a histone methylase, and (3) temozolomide, an alkylating agent. Methods: The T98G GBM commercial cell line was used. Cells were exposed to single treatments of the drugs and to the three possible combinations among them. Soon after, two-dimensional (2D) and 3D clonogenic assays were assessed for in vitro tumorigenicity testing. Real-time quantitative polymerase chain reaction of 2 proapoptotic genes (BAX and NOXA) and 2 antiapoptotic genes (BCL2 and BCL-XL) was also assessed. Results: The panobinostat and temozolomide combination produced a positive effect against T98G glioblastoma cells by reducing soft agar colony formation, by inducing high expression levels of NOXA, and by reducing BCL-XL expression.
  • Autores: Tejada Solís, Sonia (Autor de correspondencia); Avula, S.; Pettorini, B.; et al.
    Revista: CHILDS NERVOUS SYSTEM
    ISSN: 0256-7040 Vol.34 N° 4 2018 págs. 617 - 626
    Resumen
    The intraoperative magnetic resonance scanner (ioMR) was introduced in our unit in 2009, and has been used routinely since then. This study aims to describe indications, radiological features, and clinical outcomes of the patients operated on with ioMRI and analyze our experience. A retrospective analysis of a prospective surgical database has been performed, including surgical procedure, intent, radiological reports, need for second-look surgery, and complications, supplemented by further review of the clinical notes and the scans. From 2009 to 2015, 255 surgical procedures with ioMR were performed: 175 were craniotomies for tumor excision, 65 were epilepsy related, and 15 were biopsies or cyst drainages. The mean age was 9.4 years. One ioMR was performed in 79.5% patients; the mean duration of the MR was 41 min. In 172 cases (67.4%), no actions followed the ioMR. When the aim of the surgery was debulking of the tumor, the percentage of patients in which the ioMR was followed by resection was higher than when complete resection was the aim (56 vs 27.5%). The complication rate was not increased when compared with our previous results (infection 1%, neurological deficits 12%). This is the largest published series of ioMRI-aided pediatric neurosurgery to date. We have demonstrated that it can be used safely and routinely in pediatric neurosurgical procedures at any age, assisting the surgeon in achieving the best extent of resection and aiding in intra-operative decision-making for tumor- and non-tumor-related intracranial pathology.
  • Autores: De la Rosa, J; Urdiciain Ezpeleta, Alejandro; Aznar-Morales, J. J.; et al.
    Revista: CANCER TRANSLATIONAL MEDICINE
    ISSN: 2395-3012 Vol.4 N° 5 2018 págs. 39 - 47
  • Autores: Diez Valle, Ricardo (Autor de correspondencia); Becerra Castro, María Victoria; Marigil Sánchez, Miguel; et al.
    Revista: WORLD NEUROSURGERY
    ISSN: 1878-8750 Vol.109 2018 págs. e845 - e852
    Resumen
    BACKGROUND: Corticosteroids are routinely used to treat brain tumors. Although steroids have an immediate clinical benefit, their use can lead to a number of relevant complications, and a negative association with overall survival has been shown in glioblastoma (GBM) patients. There is no evidence in the literature regarding the ideal dose. We assessed the use of steroids in patients with GBM after resection surgery. METHODS: This is a cohort study of 131 newly diagnosed GBM patients that underwent tumor resection surgery. Dose of steroids was as low as possible, without a formal guideline. Fifteen patients were lost at baseline (retention rate, 88.5%). Our population for analysis included 114 patients that were still at risk of death at a landmark time point 2 months after surgery. RESULTS: Within 1 month of surgery, 93.9% of patients came off steroids, and 84.7% came off steroids before 2 weeks. One month after radiotherapy, 86 (75.4%) patients remained steroid-free and 28 (24.6%) were steroid-dependent. During 2235 person-months of follow-up, we documented 101 incident deaths. After adjusting for age, sex, Karnofsky Performance Scale score, MGMT promoter methylation, and extent of tumor resection, and time to surgery, the hazard ratio for the steroid-free group of patients was 0.46 (95% confidence interval, 0.28-0.77) compared with steroid-dependent patients. CONCLUSIONS: This study provides evidence for an inverse association between the lack of steroid dependency and mortality risk in patients whose steroid dosage was rapidly tapered after surgery. After resection, most patients can stop steroids within 2 weeks and finish radiotherapy without steroids.
  • Autores: Tejada Solís, Sonia; Diez Valle, Ricardo; Domínguez Echávarri, Pablo Daniel; et al.
    Revista: FRONTIERS IN ONCOLOGY
    ISSN: 2234-943X Vol.12 N° 8 2018 págs. 61
    Resumen
    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: Cayuela, N.; Simo, M. ; Majos, C.; et al.
    Revista: EUROPEAN JOURNAL OF NEUROLOGY
    ISSN: 1351-5101 Vol.25 N° 2 2018 págs. 387 - 394
    Resumen
    Background and purposeThe main aim of this study was to identify which patients with glioblastoma multiforme (GBM) have a higher risk of presenting seizures during follow-up. MethodsPatients with newly diagnosed GBM were reviewed (n = 306) and classified as patients with (Group 1) and without (Group 2) seizures at onset. Group 2 was split into patients with seizures during follow-up (Group 2A) and patients who never had seizures (Group 2B). The anatomical location of GBM was identified and compared by voxel-based lesion symptom mapping (discovery set). Seizure-susceptible brain regions obtained were assessed visually and automatically in external GBM validation series (n = 85). ResultsIn patients with GBM who had no seizures at onset, an increased risk of presenting seizures during follow-up was identified in the superior frontal and inferior occipital lobe, as well as in inferoposterior regions of the temporal lobe. Conversely, those patients with GBM located in medial and inferoanterior temporal areas had a significantly lower risk of suffering from seizures during follow-up. Additionally, the seizure-susceptible brain region maps obtained classified patients in the validation set with high positive and negative predictive values. ConclusionsTumor location is a useful marker to identify patients with GBM who are at risk of suffering from seizures during follow-up. These results may help to support the use of antiepileptic prophylaxis in a selected GBM population and to improve stratification in antiepileptic clinical trials.
  • Autores: Aldave, G.; González Huarriz, María Soledad; Rubio Díaz-Cordoves, Ángel; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.20 N° 7 2018 págs. 930 - 941
    Resumen
    Background: Glioblastoma, the most aggressive primary brain tumor, is genetically heterogeneous. Alternative splicing (AS) plays a key role in numerous pathologies, including cancer. The objectives of our study were to determine whether aberrant AS could play a role in the malignant phenotype of glioma and to understand the mechanism underlying its aberrant regulation. Methods: We obtained surgical samples from patients with glioblastoma who underwent 5-aminolevulinic fluorescence-guided surgery. Biopsies were taken from the tumor center as well as from adjacent normal-appearing tissue. We used a global splicing array to identify candidate genes aberrantly spliced in these glioblastoma samples. Mechanistic and functional studies were performed to elucidate the role of our top candidate splice variant, BAF45d, in glioblastoma. Results: BAF45d is part of the switch/sucrose nonfermentable complex and plays a key role in the development of the CNS. The BAF45d/6A isoform is present in 85% of over 200 glioma samples that have been analyzed and contributes to the malignant glioma phenotype through the maintenance of an undifferentiated cellular state. We demonstrate that BAF45d splicing is mediated by polypyrimidine tract-binding protein 1 (PTBP1) and that BAF45d regulates PTBP1, uncovering a reciprocal interplay between RNA splicing regulation and transcription. Conclusions: Our data indicate that AS is a mechanism that contributes to the malignant phenotype of glioblastoma. Understanding the consequences of this biological process will uncover new therapeutic targets for this devastating disease.
  • Autores: García Baizán, Alejandra (Autor de correspondencia); Tomás-Biosca Martín, Ana; Bartolomé Leal, Pablo; et al.
    Revista: RADIOLOGIA
    ISSN: 0033-8338 Vol.60 N° 2 2018 págs. 136 - 142
    Resumen
    Objective: To report our experience in the use of 3 testa intraoperative magnetic resonance imaging (MRI) in neurosurgical procedures for tumors, and to evaluate the criteria for increasing the extension of resection. Material and methods: This retrospective study included all consecutive intraoperative MRI studies done for neuro-oncologic disease in the first 13 months after the implementation of the technique. We registered possible immediate complications, the presence of tumor remnants, and whether the results of the intraoperative MRI study changed the surgical management. We recorded the duration of surgery in all cases. Results: The most common tumor was recurrent glioblastoma, followed by primary glioblastoma and metastases. Complete resection was achieved in 28%, and tumor remnants remained in 72%. Intraoperative MRI enabled neurosurgeons to improve the extent of the resection in 85% of cases. The mean duration of surgery was 390 +/- 122 minutes. Conclusion: Intraoperative MRI using a strong magnetic field (3 teslas) is a valid new technique that enables precise study of the tumor resection to determine whether the resection can be extended without damaging eloquent zones. Although the use of MRI increases the duration of surgery, the time required decreases as the team becomes more familiar with the technique. (C) 2018 SERAM. Published by Elsevier Espana, S.L.U. All rights reserved.
  • Autores: Prieto de Frías, César (Autor de correspondencia); Muñoz Navas, Miguel Ángel; Idoate Gastearena, Miguel Ángel
    Revista: CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
    ISSN: 1542-3565 Vol.16 N° 2 2018 págs. A29 - A30
  • Autores: Moreno Ajona, David; Yuste Ara, José Ramón; Martín Moreno, Paloma Leticia; et al.
    Revista: JOURNAL OF NEUROVIROLOGY
    ISSN: 1355-0284 Vol.24 N° 4 2018 págs. 523 - 525
    Resumen
    The human T-lymphotropic virus type 1 (HTLV-1) is a RNA retrovirus that infects a minimum of 5-10 million people worldwide. Transmission by cell-containing blood products and solid organ transplantation has been reported. Clinical disease occurs in about 5-10% of infected individuals and consists mainly in adult T cell leukemia and HTLV-1-associated myelopathy (HAM). We present a 54-year-old woman who underwent kidney transplant from cadaveric donor in March 2015. Donor also underwent cornea extraction for another recipient (corneal transplant protocol includes HTLV-1/2 serology). Twenty-four hours after completion of kidney transplant donor, HTLV-1 serology was revealed positive. Following experts' recommendations, once donor seropositivity was demonstrated, antiviral prophylaxis including zidovudine and raltegravir was initially given to our patient, in spite of which the patient developed HAM. Once the diagnosis of HAM was established, antiretroviral therapy was restarted, and intravenous pulses of methylprednisolone were periodically administered with transient initial improvement. Later on, the patient experienced neurological deterioration becoming wheelchair dependent. Since the occurrence of this case, HTLV-1 screening has become mandatory for solid organ transplantation in the Spanish province of Navarra, and the same should happen worldwide.
  • Autores: Urdiciain Ezpeleta, Alejandro; Melendez, B.; Rey, J. A.; et al.
    Revista: EPIGENOMES
    ISSN: 2075-4655 Vol.2 N° 1 2018
    Resumen
    Glioblastoma is the most common form of glioma, as well as the most aggressive. Patients suffering from this disease have a very poor prognosis. Surgery, radiotherapy, and temozolomide are the only approved treatments nowadays. Panobinostat is a pan-inhibitor of histone deacetylases (HDACs) that has been shown to break some pathways which play an important role in cancer development. A global intention of using panobinostat as a therapeutic agent against glioblastoma is beginning to be a reality. We have treated the LN405 glioblastoma cell line with temozolomide, panobinostat, and combined treatment, in order to test apoptosis, colony formation, and a possible molecular reversion of the mesenchymal phenotype of the cells to an epithelial one. Our results show that panobinostat decreased N-cadherin levels in the LN405 glioblastoma cell line while it increased the expression of E-cadherin, which might be associated with a mesenchymal-epithelial transition in glioblastoma cells. Colony formation was reduced, and apoptosis was increased with treatments. Our research highlights the importance of panobinostat as a potential adjuvant therapy to be used with temozolomide to treat glioblastoma and the advantages of the combined treatment versus temozolomide alone, which is currently the first-line treatment used to treat this tumor.
  • Autores: Tejada Solís, Sonia; Avula, S.; Pettorini, B.; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.20 N° Supl.2 2018 págs. S147 -S148
  • Autores: Esparragosa Vázquez, Inés; Inoges Sancho, Susana Inmaculada; López Díaz de Cerio, Ascensión; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.20 N° Supl. 3 2018 págs. 243 - 243
  • Autores: Martínez Velez, Naiara; Marigil, M. ; Aristu Mendioroz, José Javier; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.78 N° 13 Supl. 2018
  • Autores: Tejada Solís, Sonia; Martínez Velez, Naiara; Varela Guruceaga, Maider; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.20 N° Supl.2 2018 págs. S52
  • Autores: Puigdelloses Vallcorba, Montserrat; González Huarriz, María Soledad; Zandio, B. ; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.20 N° Supl. 3 2018 págs. 216 - 217
  • Autores: Puigdelloses Vallcorba, Montserrat; Varela Guruceaga, Maider; González Huarriz, María Soledad; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.20 N° Supl. 6 2018 págs. 36 - 36
Mostrar más resultados
  • Autores: Diez Valle, Ricardo; Stummer, W.
    Libro: Fluorescence-guided neurosurgery. Neuro-oncology and cerebrovascular applications
    ISSN: 978-1626237148 2018 págs. 13 - 20

Proyectos desde 2018

  • Título: GRANATE - GRUPO DE RADIOTERAPIA AVANZADA DE NAVARRA ¿ TERAPIA Y EFICACIA
    Código de expediente: 0011-1411-2022-000066
    Investigador principal: ANA PATIÑO GARCIA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2022 GN PROYECTOS ESTRATEGICOS DE I+D 2022-2025
    Fecha de inicio: 01-06-2022
    Fecha fin: 31-12-2024
    Importe concedido: 536.739,00€
    Otros fondos: -
  • Título: Tumor Immune Microenvironment (TIME) targeted therapy in pediatric brain cancer
    Código de expediente: PCI2021-122084-2B
    Investigador principal: MARTA MARIA ALONSO ROLDAN.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: 2021 AEI Proyectos de Colaboración Internacional - 2
    Fecha de inicio: 01-02-2022
    Fecha fin: 31-01-2024
    Importe concedido: 160.932,00€
    Otros fondos: -
  • Título: Inmunoviroterapia contra el osteosarcoma pediátrico: análisis preclínico de las estrategias basadas en el virus Delta-24-RGDOX.
    Código de expediente: PI21/00940
    Investigador principal: ANA PATIÑO GARCIA.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2021 AES Proyectos de investigación
    Fecha de inicio: 01-01-2022
    Fecha fin: 31-12-2024
    Importe concedido: 171.820,00€
    Otros fondos: Fondos FEDER
  • Título: Identificación de biomarcadores para la detección de radionecrosis en pacientes tratados con radioterapia estereopática y desarrollo experimental de nuevas terapias para su prevención.
    Código de expediente: PI20/01531
    Investigador principal: JOSE JAVIER ARISTU MENDIOROZ.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2020 AES Proyectos de investigación
    Fecha de inicio: 01-01-2021
    Fecha fin: 31-12-2023
    Importe concedido: 123.420,00€
    Otros fondos: Fondos FEDER
  • Título: Plasma extracellular vesicles (EVs): the key for precision medicine in Glioblastoma
    Código de expediente: AC20/00094
    Investigador principal: JAIME GALLEGO PEREZ DE LARRAYA.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2020 AES Programación Conjunta Internacional
    Fecha de inicio: 01-01-2021
    Fecha fin: 31-12-2023
    Importe concedido: 38.720,00€
    Otros fondos: -
  • Título: Ayuda para contratación Juan de la Cierva Formación 2018
    Código de expediente: FJC2018-037394-I
    Investigador principal: MARTA MARIA ALONSO ROLDAN.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: 2018 AEI - MCIU JUAN DE LA CIERVA FORMACIÓN
    Fecha de inicio: 01-04-2020
    Fecha fin: 31-03-2022
    Importe concedido: 50.000,00€
    Otros fondos: Fondos FEDER
  • Título: Ensayo clínico fase I con el adenovirus oncolítico DNX-2440 para el tratamiento de tumores cerebrales pediátricos recurrentes.
    Código de expediente: PI19/01896
    Investigador principal: MARTA MARIA ALONSO ROLDAN.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2019 AES Proyectos de investigación
    Fecha de inicio: 01-01-2020
    Fecha fin: 30-06-2024
    Importe concedido: 189.970,00€
    Otros fondos: Fondos FEDER
  • Título: Papel del RNU6 aislado de exosomas circulantes como marcador diagnóstico y de seguimiento en pacientes con glioblastoma
    Código de expediente: PI19/01440
    Investigador principal: JAIME GALLEGO PEREZ DE LARRAYA.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2019 AES Proyectos de investigación
    Fecha de inicio: 01-01-2020
    Fecha fin: 31-12-2023
    Importe concedido: 96.800,00€
    Otros fondos: Fondos FEDER
  • Título: Desarrollo de técnicas de mapeado de la reactividad cerebrovascular. Aplicaciones en la cirugía de tumores cerebrales.
    Código de expediente: PI18/00084
    Investigador principal: MARIA ASUNCION FERNANDEZ SEARA.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: AES2018 PI
    Fecha de inicio: 01-01-2019
    Fecha fin: 30-06-2023
    Importe concedido: 62.920,00€
    Otros fondos: Fondos FEDER
  • Título: Implantes Crónicos con aplicación en Neurociencias
    Código de expediente: 0011-1383-2018-000011
    Investigador principal: MIGUEL VALENCIA USTARROZ.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2018 - GN INDUSTRIA PROYECTOS CENTROS TECNOLOGICOS Y ORGANISMOS DE INVESTIGACION
    Fecha de inicio: 01-02-2018
    Fecha fin: 30-11-2018
    Importe concedido: 151.269,06€
    Otros fondos: -
  • Título: Modulando el sistema inmune con adenovirus oncolíticos como estrategia para los tumores difusos de tronco (DIPGs).
    Código de expediente: PI16/00066
    Investigador principal: MARTA MARIA ALONSO ROLDAN.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2016 AES PROYECTOS DE INVESTIGACIÓN
    Fecha de inicio: 01-01-2017
    Fecha fin: 31-12-2019
    Importe concedido: 86.515,00€
    Otros fondos: Fondos FEDER
  • Título: Utilidad de un perfil de ARN pequeño no codificante aislado en exosomas circulantes como marcador diagnóstico y de seguimiento en pacientes con glioblastoma multiforme
    Código de expediente: 42/2015
    Investigador principal: JAIME GALLEGO PEREZ DE LARRAYA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2015 GN SALUD
    Fecha de inicio: 06-12-2015
    Fecha fin: 05-12-2018
    Importe concedido: 50.682,00€
    Otros fondos: -
  • Título: Oncolytic Immunotherapy for Diffuse Intrinsic Pontine Gliomas
    Código de expediente:
    Investigador principal: MARTA MARIA ALONSO ROLDAN
    Financiador: National Institute of Health
    Convocatoria: DOD -USA-DEFENCE-2017
    Fecha de inicio: 01-08-2017
    Fecha fin: 31-07-2020
    Importe concedido: 544.625,00€
    Otros fondos: -
  • Título: Combinatorial biotherapies for the treatment of pediatric diffuse midline glioma
    Investigador principal: MARTA MARIA ALONSO ROLDAN
    Financiador: ASOCIACION ESPAÑOLA CONTRA EL CANCER
    Convocatoria: 2021 AECC Proyectos Generales
    Fecha de inicio: 01-12-2021
    Fecha fin: 30-11-2024
    Importe concedido: 300.000,00€
  • Título: Estudio de los mecanismos implicados en el déficit neurocognitivo en supervivientes de un tumor cerebral infantil y desarrollo de estrategias terapéuticas que minimicen las secuelas neurológicas a largo plazo.
    Investigador principal: SARA LABIANO ALMIÑANA
    Financiador: FUNDACION ALICIA KOPLOWITZ
    Convocatoria: 2021 FD Alicia Koplowitz - Proyectos de investigación
    Fecha de inicio: 01-11-2021
    Fecha fin: 31-10-2023
    Importe concedido: 45.000,00€
  • Título: Niños Contra el Cáncer (3 Convenio FDBLC)
    Investigador principal: MARTA MARIA ALONSO ROLDAN, ANA PATIÑO GARCIA
    Financiador: FUNDACIÓN BANCARIA LA CAIXA
    Convocatoria: 2021 FD La Caixa Niños contra el cáncer
    Fecha de inicio: 28-09-2021
    Fecha fin: 31-12-2022
    Importe concedido: 100.000,00€
  • Título: Terapias avanzadas para tumores sólidos pediátricos
    Investigador principal: MARTA MARIA ALONSO ROLDAN, ANA PATIÑO GARCIA, JAIME GALLEGO PEREZ DE LARRAYA
    Financiador: FUNDACIÓN ADEY
    Convocatoria: 2021 FD ADEY Proyectos
    Fecha de inicio: 01-04-2021
    Fecha fin: 03-04-2024
    Importe concedido: 120.000,00€
  • Título: Plasma extracellular vesicles (EVs): the key for precision medicine in Glioblastoma
    Investigador principal: JAIME GALLEGO PEREZ DE LARRAYA
    Financiador: ASOCIACION ESPAÑOLA CONTRA EL CANCER
    Convocatoria: 2020 AECC ERA Permed
    Fecha de inicio: 01-12-2020
    Fecha fin: 30-11-2023
    Importe concedido: 41.295,00€
  • Título: Targeting calcium channels against primary and resistant glioblastoma
    Investigador principal: MARTA MARIA ALONSO ROLDAN
    Financiador: FUNDACIO "LA MARATO DE TV3"
    Convocatoria: 2019 FD LA MARATÓ PROYECTOS DE INVESTIGACIÓN
    Fecha de inicio: 31-07-2020
    Fecha fin: 30-07-2023
    Importe concedido: 117.500,00€
  • Título: Moduladores epigenéticos y promotores del cilio primario como nuevos agentes terapéuticos contra el glioblastoma
    Investigador principal: FRANCISCO JAVIER SAEZ CASTRESANA
    Financiador: UNIVERSIDAD DE NAVARRA
    Convocatoria: 2020 Convocatoria PIUNA, 2019 Convocatoria PIUNA, 2018 Convocatoria PIUNA
    Fecha de inicio: 01-09-2018
    Fecha fin: 31-08-2021
    Importe concedido: 35.000,00€
  • Título: Inmunovirus para el tratamiento del Osteosarcoma.
    Investigador principal: MARTA MARIA ALONSO ROLDAN
    Financiador: Asociación Pablo Ugarte
    Convocatoria: 2018 APU PI
    Fecha de inicio: 05-02-2018
    Fecha fin: 31-12-2024
    Importe concedido: 112.300,00€
  • Título: Niños contra el cáncer - Inmunoterapia basada en el uso de células dendríticas en tumores sólidos avanzados de niños y adolescentes
    Investigador principal: MARTA MARIA ALONSO ROLDAN, ANA PATIÑO GARCIA
    Financiador: FUNDACIÓN BANCARIA LA CAIXA
    Convocatoria: 2017 CAIXA NCC
    Fecha de inicio: 26-09-2017
    Fecha fin: 27-09-2021
    Importe concedido: 400.000,00€
  • Título: Estudio de moduladores de toxicidad de la proteína alfa-sinucleína: modificaciones post-traduccionales y respuesta al malplegamiento de proteínas
    Investigador principal: MONTSERRAT ARRASATE IRAGUI
    Financiador: FUNDACION TATIANA PEREZ DE GUZMAN EL BUENO
    Convocatoria: 2014 - FUND. TATIANA PROYECTOS I+D
    Fecha de inicio: 15-12-2014
    Fecha fin: 14-04-2018
    Importe concedido: 82.500,00€