Grupos Investigadores

Miembros del Grupo

Investigadores
Marta María
Alonso Roldán (Co-coordinadora)
Iker
Ausejo Mauleón
Laasya
Dhandapani
Marta
Zalacain Díez
Colaboradores
Daniel
De la Nava Martin
Reyes
Hérnandez Osuna
Andrea
Lacalle Carrasco
Lucía
Marrodán Fernández

Líneas de Investigación

  • Biomarcadores de diagnóstico y pronóstico en tumores cerebrales
  • Comprensión del microambiente tumoral en tumores sólidos pediátricos y tumores cerebrales del adultos
  • Mejora de la radioterapia para tumores cerebrales
  • Protección de la cognición tras radioterapia y otros tratamientos en pacientes pediátricos
  • Terapias avanzadas en tumores sólidos pediátricos y tumores cerebrales del adulto

Palabras Clave

  • Biomarcador
  • Car-t cells
  • Cognición
  • Mejora
  • Microambiente tumoral
  • Neuroprotección
  • Radiorresistencia
  • Radioterapia
  • RNA
  • Sangre periférica
  • Terapia génica
  • Toxicidad
  • Virus oncolíticos

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: Antoñanzas Pérez, Javier; Querol Cisneros, Elena; Alkorta Aranburu, Gorka; et al.
    Revista: INTERNATIONAL JOURNAL OF DERMATOLOGY
    ISSN: 0011-9059 Vol.62 N° 3 2023 págs. e176 - e178
  • Autores: Fonseca, E.; Cabrera-Maqueda, J. M.; Ruiz-Garcia, R.; et al.
    Revista: LANCET NEUROLOGY
    ISSN: 1474-4422 Vol.22 N° 12 2023 págs. 1150 - 1159
    Resumen
    Background Neurological immune-related adverse events associated with immune checkpoint inhibitors can have several clinical manifestations, but the syndromes and prognostic factors are still not well known. We aimed to characterise and group the clinical features, with a special focus in patients presenting with encephalopathy, and to identify predictors of response to therapy and survival.Methods This retrospective observational study included patients with neurological immune-related adverse events from 20 hospitals in Spain whose clinical information, serum samples, and CSF samples were studied at Hospital Clinic de Barcelona, Barcelona, Spain. Patients with pre-existing paraneoplastic syndromes or evidence of alternative causes for their neurological symptoms were excluded. We reviewed the clinical information, classified their clinical features, and determined the presence of neural antibodies. Neurological status was assessed by the treating physician one month after adverse event onset (as improvement vs no improvement) and at the last evaluation (complete recovery or modified Rankin Scale score decrease of at least 2 points, indicating good outcome, vs all other modified Rankin Scale scores, indicating poor outcome); if the participant had died, the date and cause of death were recorded. We used Fisher's exact tests and Mann-Whitney U tests to analyse clinical features, and multivariable logistic regression to analyse prognostic factors.Findings From Jan 1, 2018, until Feb 1, 2023, 83 patients with suspected neurological immune-related adverse events after use of immune checkpoint inhibitors were identified, of whom 64 patients were included. These patients had a median age of 67 years (IQR 59-74); 42 (66%) were male and 22 (34%) were female. The predominant tumours were lung cancer (30 [47%] patients), melanoma (13 [21%] patients), and renal cell carcinoma (seven [11%] patients). Neural antibodies were detected in 14 (22%) patients; 52 (81%) patients had CNS involvement and 12 (19%) had peripheral nervous system involvement. Encephalopathy occurred in 45 (70%) patients, 12 (27%) of whom had antibodies or well defined syndromes consistent with definite paraneoplastic or autoimmune encephalitis, 24 (53%) of whom had encephalitis without antibodies or clinical features characteristic of a defined syndrome, and nine (20%) of whom had encephalopathy without antibodies or inflammatory changes in CSF or brain MRI. Nine (14%) of 64 patients had combined myasthenia and myositis, five of them with myocarditis. Even though 58 (91%) of 64 patients received steroids and 31 (48%) of 64 received additional therapies, 18 (28%) did not improve during the first month after adverse event onset, and 11 of these 18 people died. At the last follow-up for the 53 remaining patients (median 6 months, IQR 3-13), 20 (38%) had a poor outcome (16 deaths, one related to a neurological immune-related adverse event). Mortality risk was increased in patients with lung cancer (vs those with other cancers: HR 2 center dot 5, 95% CI 1 center dot 1-6 center dot 0) and in patients with encephalopathy without evidence of CNS inflammation or combined myocarditis, myasthenia, and myositis (vs those with the remaining syndromes: HR 5 center dot 0, 1 center dot 4-17 center dot 8 and HR 6 center dot 6, 1 center dot 4-31 center dot 0, respectively).Interpretation Most neurological immune-related adverse events involved the CNS and were antibody negative. The presence of myocarditis, myasthenia, and myositis, of encephalopathy without inflammatory changes, or of lung cancer were independent predictors of death. Most deaths occurred during the first month of symptom onset. If our findings are replicated in additional cohorts, they could confirm that these patients need early and intensive treatment.
  • Autores: Gómez-Vecino, A.; Corchado-Cobos, R.; Blanco-Gómez, A.; et al.
    Revista: CELLS
    ISSN: 2073-4409 Vol.12 N° 15 2023 págs. 1956
    Resumen
    Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.
  • Autores: Imizcoz Fabra, Teresa (Autor de correspondencia); Prieto Matos, Carlos; Manrique Huarte, Raquel; et al.
    Revista: FRONTIERS IN GENETICS
    ISSN: 1664-8021 Vol.14 2023 págs. 1264899
    Resumen
    Background: An early etiological diagnosis of hearing loss positively impacts children's quality of life including language and cognitive development. Even though hearing loss associates with extremely high genetic and allelic heterogeneity, several studies have proven that Next-Generation Sequencing (NGS)-based gene panel testing significantly reduces the time between onset and diagnosis. Methods: In order to assess the clinical utility of our custom NGS GHELP panel, the prevalence of pathogenic single nucleotide variants, indels or copy number variants was assessed by sequencing 171 nuclear and 8 mitochondrial genes in 155 Spanish individuals with hearing loss. Results: A genetic diagnosis of hearing loss was achieved in 34% (52/155) of the individuals (5 out of 52 were syndromic). Among the diagnosed cases, 87% (45/52) and 12% (6/52) associated with autosomal recessive and dominant inheritance patterns respectively; remarkably, 2% (1/52) associated with mitochondrial inheritance pattern. Although the most frequently mutated genes in this cohort were consistent with those described in the literature (GJB2, OTOF or MYO7A), causative variants in less frequent genes such as TMC1, FGF3 or mitCOX1 were also identified. Moreover, 5% of the diagnosed cases (3/52) were associated with pathogenic copy number variants. Conclusion: The clinical utility of NGS panels that allows identification of different types of pathogenic variants-not only single nucleotide variants/indels in both nuclear and mitochondrial genes but also copy number variants-has been demonstrated to reduce the clinical diagnostic odyssey in hearing loss. Thus, clinical implementation of genomic strategies within the regular clinical practice, and, more significantly, within the newborn screening protocols, is warranted.
  • Autores: García-Peláez, J.; Barbosa-Matos, R.; Lobo, S.; et al.
    Revista: LANCET ONCOLOGY
    ISSN: 1470-2045 Vol.24 N° 1 2023 págs. 91 - 106
    Resumen
    Background Truncating pathogenic or likely pathogenic variants of CDH1 cause hereditary diffuse gastric cancer (HDGC), a tumour risk syndrome that predisposes carrier individuals to diffuse gastric and lobular breast cancer. Rare CDH1 missense variants are often classified as variants of unknown significance. We conducted a genotypephenotype analysis in families carrying rare CDH1 variants, comparing cancer spectrum in carriers of pathogenic or likely pathogenic variants (PV/LPV; analysed jointly) or missense variants of unknown significance, assessing the frequency of families with lobular breast cancer among PV/LPV carrier families, and testing the performance of lobular breast cancer-expanded criteria for CDH1 testing. Methods This genotype-first study used retrospective diagnostic and clinical data from 854 carriers of 398 rare CDH1 variants and 1021 relatives, irrespective of HDGC clinical criteria, from 29 institutions in ten member-countries of the European Reference Network on Tumour Risk Syndromes (ERN GENTURIS). Data were collected from Oct 1, 2018, to Sept 20, 2022. Variants were classified by molecular type and clinical actionability with the American College of Medical Genetics and Association for Molecular Pathology CDH1 guidelines (version 2). Families were categorised by whether they fulfilled the 2015 and 2020 HDGC clinical criteria. Genotype-phenotype associations were analysed by Student's t test, Kruskal-Wallis, chi (2), and multivariable logistic regression models. Performance of HDGC clinical criteria sets were assessed with an equivalence test and Youden index, and the areas under the receiver operating characteristic curves were compared by Z test. Findings From 1971 phenotypes (contributed by 854 probands and 1021 relatives aged 1-93 years), 460 had gastric and breast cancer histology available. CDH1 truncating PV/LPVs occurred in 176 (21%) of 854 families and missense variants of unknown significance in 169 (20%) families. Multivariable logistic regression comparing phenotypes occurring in families carrying PV/LPVs or missense variants of unknown significance showed that lobular breast cancer had the greatest positive association with the presence of PV/LPVs (odds ratio 12.39 [95% CI 2.66-57.74], p=0.0014), followed by diffuse gastric cancer (8.00 [2.18-29.39], p=0.0017) and gastric cancer (7.81 [2.03-29.96], p=0.0027). 136 (77%) of 176 families carrying PV/LPVs fulfilled the 2015 HDGC criteria. Of the remaining 40 (23%) families, who did not fulfil the 2015 criteria, 11 fulfilled the 2020 HDGC criteria, and 18 had lobular breast cancer only or lobular breast cancer and gastric cancer, but did not meet the 2020 criteria. No specific CDH1 variant was found to predispose individuals specifically to lobular breast cancer, although 12 (7%) of 176 PV/LPV carrier families had lobular breast cancer only. Addition of three new lobular breast cancer-centred criteria improved testing sensitivity while retaining high specificity. The probability of finding CDH1 PV/LPVs in patients fulfilling the lobular breast cancer-expanded criteria, compared with the 2020 criteria, increased significantly (AUC 0.92 vs 0.88; Z score 3.54; p=0.0004). Interpretation CDH1 PV/ LPVs were positively associated with HDGC-related phenotypes (lobular breast cancer, diffuse gastric cancer, and gastric cancer), and no evidence for a positive association with these phenotypes was found for CDH1 missense variants of unknown significance. CDH1 PV/LPVs occurred often in families with lobular breast cancer who did not fulfil the 2020 HDGC criteria, supporting the expansion of lobular breast cancer-centred criteria.
  • Autores: Melero Bermejo, Ignacio (Autor de correspondencia); Ochoa Nieto, Maria del Carmen; Molina Samper, Carmen; et al.
    Revista: EMBO MOLECULAR MEDICINE
    ISSN: 1757-4676 Vol.15 N° 11 2023 págs. e17804
    Resumen
    NK-cell reactivity against cancer is conceivably suppressed in the tumor microenvironment by the interaction of the inhibitory receptor NKG2A with the non-classical MHC-I molecules HLA-E in humans or Qa-1(b) in mice. We found that intratumoral delivery of NK cells attains significant therapeutic effects only if co-injected with anti-NKG2A and anti-Qa-1(b) blocking monoclonal antibodies against solid mouse tumor models. Such therapeutic activity was contingent on endogenous CD8 T cells and type-1 conventional dendritic cells (cDC1). Moreover, the anti-tumor effects were enhanced upon combination with systemic anti-PD-1 mAb treatment and achieved partial abscopal efficacy against distant non-injected tumors. In xenografted mice bearing HLA-E-expressing human cancer cells, intratumoral co-injection of activated allogeneic human NK cells and clinical-grade anti-NKG2A mAb (monalizumab) synergistically achieved therapeutic effects. In conclusion, these studies provide evidence for the clinical potential of intratumoral NK cell-based immunotherapies that exert their anti-tumor efficacy as a result of eliciting endogenous T-cell responses.
  • Autores: Hervás Corpión, Irati; Navarro-Calvo, J.; Martín-Climent, P.; et al.
    Revista: CELLS
    ISSN: 2073-4409 Vol.12 N° 3 2023 págs. 374
    Resumen
    Glioblastoma (GB) is the most prevalent primary brain cancer and the most aggressive form of glioma because of its poor prognosis and high recurrence. To confirm the importance of epigenetics in glioma, we explored The Cancer Gene Atlas (TCGA) database and we found that several histone/DNA modifications and chromatin remodeling factors were affected at transcriptional and genetic levels in GB compared to lower-grade gliomas. We associated these alterations in our own cohort of study with a significant reduction in the bulk levels of acetylated lysines 9 and 14 of histone H3 in high-grade compared to low-grade tumors. Within GB, we performed an RNA-seq analysis between samples exhibiting the lowest and highest levels of acetylated H3 in the cohort; these results are in general concordance with the transcriptional changes obtained after histone deacetylase (HDAC) inhibition of GB-derived cultures that affected relevant genes in glioma biology and treatment (e.g., A2ML1, CD83, SLC17A7, TNFSF18). Overall, we identified a transcriptional signature linked to histone acetylation that was potentially associated with good prognosis, i.e., high overall survival and low rate of somatic mutations in epigenetically related genes in GB. Our study identifies lysine acetylation as a key defective histone modification in adult high-grade glioma, and offers novel insights regarding the use of HDAC inhibitors in therapy.
  • 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: Gállego Pérez de Larraya, Jaime; García Moure, Marc; González Huarriz, María Soledad; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.25 N° Supl. 2 2023 págs. ii120
  • 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: 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: Villino Rodríguez, Rafael Angel; Esparragosa Vázquez, Inés; Valentí Azcárate, Rafael; et al.
    Revista: EUROPEAN JOURNAL OF NEUROLOGY
    ISSN: 1351-5101 Vol.30 N° Supl. 1 2023 págs. 377
  • Autores: Alba Pavon, P.; Alaña, L.; Gutiérrez Jimeno, Miriam; et al.
    Revista: SCIENTIFIC REPORTS
    ISSN: 2045-2322 Vol.13 N° 1 2023 págs. 2959
    Resumen
    Genetic predisposition is an important risk factor for cancer in children and adolescents but detailed associations of individual genetic mutations to childhood cancer are still under intense investigation. Among pediatric cancers, sarcomas can arise in the setting of cancer predisposition syndromes. The association of sarcomas with these syndromes is often missed, due to the rarity and heterogeneity of sarcomas and the limited search of cancer genetic syndromes. This study included 43 pediatric and young adult patients with different sarcoma subtypes. Tumor profiling was undertaken using the Oncomine Childhood Cancer Research Assay (Thermo Fisher Scientific). Sequencing results were reviewed for potential germline alterations in clinically relevant genes associated with cancer predisposition syndromes. Jongmans¿ criteria were taken into consideration for the patient selection. Fifteen patients were selected as having potential pathogenic germline variants due to tumor sequencing that identified variants in the following genes: CDKN2A, NF1, NF2, RB1, SMARCA4, SMARCB1 and TP53. The variants found in NF1 and CDKN2A in two different patients were detected in the germline, confirming the diagnosis of a cancer predisposition syndrome. We have shown that the results of somatic testing can be used to identify those at risk of an underlying cancer predisposition syndrome.
  • Autores: Gállego Pérez de Larraya, Jaime; De la Nava Martin, Daniel; González Huarriz, María Soledad; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.25 N° Supl. 2 2023 págs. ii120
  • 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: Sánchez Lorenzo, María Luisa; Salas Benito, Diego; Villamayor Sánchez, Julia; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.14 N° 5 2022 págs. 1235
    Resumen
    Epithelial ovarian cancer (EOC) is still the most lethal gynecological cancer. Germline alterations in breast cancer 1 (gBRCA1) and breast cancer 2 (gBRCA2) genes have been identified in up to 18% of women diagnosed with EOC, and somatic mutations are found in an additional 7%. Testing of BRCA at the primary diagnosis of patients with EOC is recommended due to the implications in the genomic counseling of the patients and their families, as well as for the therapeutic implications. Indeed, the introduction of poly-(ADP ribose) polymerase inhibitors (PARPis) has changed the natural history of patients harboring a mutation in BRCA, and has resulted in a new era in the treatment of patients with ovarian cancer harboring a BRCA mutation.
  • Autores: De la Nava Martin, Daniel; Mert Selvi, K.; Alonso Roldán, Marta María (Autor de correspondencia)
    Revista: FRONTIERS IN IMMUNOLOGY
    ISSN: 1664-3224 Vol.13 2022 págs. 866892
    Resumen
    Immunotherapy has seen tremendous strides in the last decade, acquiring a prominent position at the forefront of cancer treatment since it has been proven to be efficacious for a wide variety of tumors. Nevertheless, while immunotherapy has changed the paradigm of adult tumor treatment, this progress has not yet been translated to the pediatric solid tumor population. For this reason, alternative curative therapies are urgently needed for the most aggressive pediatric tumors. In recent years, oncolytic virotherapy has consolidated as a feasible strategy for cancer treatment, not only for its tumor-specific effects and safety profile but also for its capacity to trigger an antitumor immune response. This review will summarize the current status of immunovirotherapy to treat cancer, focusing on pediatric solid malignancies. We will revisit previous basic, translational, and clinical research and discuss advances in overcoming the existing barriers and limitations to translate this promising therapeutic as an every-day cancer treatment for the pediatric and young adult populations.
  • Autores: Martínez Velez, Naiara; Laspidea Ustés, Virginia; Zalacain Díez, Marta; et al.
    Revista: MOLECULAR CANCER THERAPEUTICS
    ISSN: 1535-7163 Vol.21 N° 3 2022 págs. 471 - 480
    Resumen
    Osteosarcoma is an aggressive bone tumor occurring primarily in pediatric patients. Despite years of intensive research, the outcomes of patients with metastatic disease or those who do not respond to therapy have remained poor and have not changed in the last 30 years. Oncolytic virotherapy is becoming a reality to treat local and metastatic tumors while maintaining a favorable safety profile. Delta-24-ACT is a replicative oncolytic adenovirus engineered to selectively target cancer cells and to potentiate immune responses through expression of the immune costimulatory ligand 4-1BB. This work aimed to assess the antisarcoma effect of Delta-24-ACr. MIS and replication assays were used to quantify the antitumor effects of Delta-24-ACT in vitro in osteosarcoma human and murine cell lines. Evaluation of the in vivo antitumor effect and immune response to Delta-24-ACI was performed in immunocompetent mice bearing the orthotopic K7M2 cell line. Immunophenotyping of the tumor microenvironment was characterized by immunohistochemistry and flow cytomcny. In vitro, Delta-24-ACT killed osteosarcoma cells and triggered the production of danger signals. In vivo, local treatment with Delta-24-ACT led to antitumor effects against both the primary tumor and spontaneous metastases in a murine osteosarcoma model. Viral treatment was safe, with no noted toxicity. Delta-24-ACT significantly increased the median survival time of treated mice. Collectively, our data identify Delta24-ACT administration as an effective and safe therapeutic strategy for patients with local and metastatic osteosarcoma. These results support clinical translation of this viral immunothcrapy approach.
  • Autores: Gállego Pérez de Larraya, Jaime; García Moure, Marc; Labiano Almiñana, Sara; et al.
    Revista: NEW ENGLAND JOURNAL OF MEDICINE
    ISSN: 0028-4793 Vol.386 N° 26 2022 págs. 2471 - 2481
    Resumen
    Background: Pediatric patients with diffuse intrinsic pontine glioma (DIPG) have a poor prognosis, with a median survival of less than 1 year. Oncolytic viral therapy has been evaluated in patients with pediatric gliomas elsewhere in the brain, but data regarding oncolytic viral therapy in patients with DIPG are lacking. Methods: We conducted a single-center, dose-escalation study of DNX-2401, an oncolytic adenovirus that selectively replicates in tumor cells, in patients with newly diagnosed DIPG. The patients received a single virus infusion through a catheter placed in the cerebellar peduncle, followed by radiotherapy. The primary objective was to assess the safety and adverse-event profile of DNX-2401. The secondary objectives were to evaluate the effect of DNX-2401 on overall survival and quality of life, to determine the percentage of patients who have an objective response, and to collect tumor-biopsy and peripheral-blood samples for correlative studies of the molecular features of DIPG and antitumor immune responses. Results: A total of 12 patients, 3 to 18 years of age, with newly diagnosed DIPG received 1×1010 (the first 4 patients) or 5×1010 (the subsequent 8 patients) viral particles of DNX-2401, and 11 received subsequent radiotherapy. Adverse events among the patients included headache, nausea, vomiting, and fatigue. Hemiparesis and tetraparesis developed in 1 patient each. Over a median follow-up of 17.8 months (range, 5.9 to 33.5), a reduction in tumor size, as assessed on magnetic resonance imaging, was reported in 9 patients, a partial response in 3 patients, and stable disease in 8 patients. The median survival was 17.8 months. Two patients were alive at the time of preparation of the current report, 1 of whom was free of tumor progression at 38 months. Examination of a tumor sample obtained during autopsy from 1 patient and peripheral-blood studies revealed alteration of the tumor microenvironment and T-cell repertoire. Conclusions: Intratumoral infusion of oncolytic virus DNX-2401 followed by radiotherapy in pediatric patients with DIPG resulted in changes in T-cell activity and a reduction in or stabilization of tumor size in some patients but was associated with adverse events. (Funded by the European Research Council under the European Union's Horizon 2020 Research and Innovation Program and others; EudraCT number, 2016-001577-33; ClinicalTrials.gov number, NCT03178032.).
  • 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: Gargallo, P. (Autor de correspondencia); Bautista, F.; Juan-Ribelles, A.; et al.
    Revista: CLINICAL AND TRANSLATIONAL ONCOLOGY
    ISSN: 1699-048X Vol.24 N° 5 2022 págs. 809 - 815
    Resumen
    The study analyzes the current status of personalized medicine in pediatric oncology in Spain. It gathers national data on the tumor molecular studies and genomic sequencing carried out at diagnosis and at relapse, the centers that perform these studies, the technology used and the interpretation and clinical applicability of the results. Current challenges and future directions to achieve a coordinated national personalized medicine strategy in pediatric oncology are also discussed. Next generation sequencing-based (NGS) gene panels are the technology used in the majority of centers and financial limitations are the main reason for not incorporating these studies into routine care. Nowadays, the application of precision medicine in pediatric oncology is a reality in a great number of Spanish centers. However, its implementation is uneven and lacks standardization of protocols; therefore, national coordination to overcome the inequalities is required. Collaborative work within the Personalized Medicine Group of SEHOP is an adequate framework for encouraging a step forward in the effort to move precision medicine into the national healthcare system.
  • 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: 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: 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: Gutiérrez Jimeno, Miriam; Panizo Morgado, Elena; Calvo Imirizaldu, Marta; et al.
    Revista: FRONTIERS IN PEDIATRICS
    ISSN: 2296-2360 Vol.10 2022 págs. 875510
    Resumen
    We report the case of a 7-month-old female patient who developed acute megakaryoblastic leukemia 6 months after the appearance of skull bone lesions. Initial evaluation and diagnosis of this patient were challenging and only achieved thanks to genomic analysis by NGS (next generation sequencing). It is unusual for the initial manifestation of acute megakaryoblastic leukemia to be a skull bone lesion. Extramedullary acute myeloid leukemia (eAML), also known as myeloid sarcoma (MS), often occurs simultaneously with acute myeloid leukemia (AML), although it may precede AML. Genomic analysis based on a NGS panel (Oncomine Childhood Cancer Research Assay) detected a RBM15::MKL1 fusion, a consequence of a t (1;22)(p13;q13) translocation, establishing the diagnosis of acute megakaryoblastic leukemia and enabling disease follow-up by qPCR. A diagnosis of eAML is built up from various findings in radiological, histological, immunophenotypic and genomic studies; when the tumor appears de novo, diagnosis is more complicated. We emphasize the importance of a multidisciplinary team in the initial approach to rare tumors and the use of genomic studies to contribute to the knowledge of these neoplasms, risk stratification and treatment planning.
  • Autores: Hurkmans, E. G. E.; Koenderink, J. B.; an den Heuvel, J. J. M. W.; et al.
    Revista: FRONTIERS IN PHARMACOLOGY
    ISSN: 1663-9812 Vol.13 2022 págs. 1042989
    Resumen
    Background: Despite (neo) adjuvant chemotherapy with cisplatin, doxorubicin and methotrexate, some patients with primary osteosarcoma progress during first-line systemic treatment and have a poor prognosis. In this study, we investigated whether patients with early disease progression (EDP), are characterized by a distinctive pharmacogenetic profile. Methods and Findings: Germline DNA from 287 Dutch high-grade osteosarcoma patients was genotyped using the DMET Plus array (containing 1,936 genetic markers in 231 drug metabolism and transporter genes). Associations between genetic variants and EDP were assessed using logistic regression models and associated variants (p < 0.05) were validated in independent cohorts of 146 (Spain and United Kingdom) and 28 patients (Australia). In the association analyses, EDP was significantly associated with an SLC7A8 locus and was independently validated (meta-analysis validation cohorts: OR 0.19 [0.06-0.55], p = 0.002). The functional relevance of the top hits was explored by immunohistochemistry staining and an in vitro transport models. SLC7A8 encodes for the L-type amino acid transporter 2 (LAT2). Transport assays in HEK293 cells overexpressing LAT2 showed that doxorubicin, but not cisplatin and methotrexate, is a substrate for LAT2 (p < 0.0001). Finally, SLC7A8 mRNA expression analysis and LAT2 immunohistochemistry of osteosarcoma tissue showed that the lack of LAT2 expression is a prognostic factor of poor prognosis and reduced overall survival in patients without metastases (p = 0.0099 and p = 0.14, resp.). Conclusion: This study identified a novel locus in SLC7A8 to be associated with EDP in osteosarcoma. Functional studies indicate LAT2-mediates uptake of doxorubicin, which could give new opportunities to personalize treatment of osteosarcoma patients.
  • Autores: Herrador Cañete, Guillermo; Zalacain Díez, Marta; Labiano Almiñana, Sara; et al.
    Revista: MOLECULAR THERAPY ONCOLYTICS
    ISSN: 2372-7705 Vol.26 2022 págs. 246 - 264
    Resumen
    The outcomes of metastatic and nonresponder pediatric osteosarcoma patients are very poor and have not improved in the last 30 years. These tumors harbor a highly immunosuppressive environment, making existing immunotherapies ineffective. Here, we evaluated the use of Semliki Forest virus (SFV) vectors expressing galectin-3 (Gal3) inhibitors as therapeutic tools, since both the inhibition of Gal3, which is involved in immunosuppression and metastasis, and virotherapy based on SFV have been demonstrated to reduce tumor progression in different tumor models. In vitro, inhibitors based on the Gal3 amino-terminal domain alone (Gal3-N) or fused to a Gal3 peptide inhibitor (Gal3-N-C12) were able to block the binding of Gal3 to the surface of activated T cells. In vivo, SFV expressing Gal3-N-C12 induced strong antitumor responses in orthotopic K7M2 and MOS-J osteosarcoma tumors, leading to complete regressions in 47% and 30% of mice, respectively. Pulmonary metastases were also reduced in K7M2 tumor-bearing mice after treatment with SFV-Gal3-N-C12. Both the antitumor and antimetastatic responses were dependent on modulation of the immune system, primarily including an increase in tumor-infiltrating lymphocytes and a reduction in the immunosuppressive environment inside tumors. Our results demonstrated that SFV-Gal3-N-C12 could constitute a potential therapeutic agent for osteosarcoma patients expressing Gal3.
  • Autores: Laspidea Ustés, Virginia; Labiano Almiñana, Sara; Gupta, S.; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.82 N° 12 Supl. 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: 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: 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: 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: Hurkmans, E. G. E.; Groothuismink, J. M. G.; Vos, H. I.; et al.
    Revista: EUROPEAN JOURNAL OF HUMAN GENETICS
    ISSN: 1018-4813 Vol.30 N° Supl. 1 2022 págs. 515
  • 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: Alba-Pavón, P.; Alana, L.; Gutiérrez Jimeno, Miriam; et al.
    Revista: PEDIATRIC BLOOD AND CANCER
    ISSN: 1545-5009 Vol.69 N° Supl. 5 2022 págs. S237 - S238
  • Autores: Manrique Rodríguez, Manuel Jesús; Patiño García, Ana; Prieto Matos, Carlos (Autor de correspondencia); et al.
    Revista: JOURNAL OF PEDIATRICS RESEARCH REVIEWS & REPORTS
    ISSN: 2755-0281 Vol.3 N° 1 2021 págs. 1 - 7
    Resumen
    Current early hearing detection and intervention (EHDI) programs for children indicate that the diagnosis and treatment must be carried out within the first six months of life. Genetic testing can identify the causal variant of the hereditary hearing loss and is very useful for that. Implementing this testing would enable personalized medicine, avoiding other more costly and time consuming tests, and the negative effect of treating a child outside of the period of greatest hearing sensitivity. Genetic tools are not part of EHDI programs. These programs are based on testing hearing. If genetic tools are used, the most likely gene is selected and analyzed via Sanger sequencing. The latest next-generation sequencing (NGS) can be applied to EHDI programs. From 100 to 200 genes associated to hearing loss can be analyzed through NGS in one blood sample or saliva set, bringing down the cost of analysis and enabling the causal diagnosis of hearing loss in a short time span. This paper reviews the current state of early hearing detection and intervention programs in children, discusses the next generation gene sequencing tools applied to hearing loss in children, presents potential approaches to the EHDI programs and analyzes the key issues to personalize the treatment of hearing loss.
  • Autores: Agullo Pérez, A. D. (Autor de correspondencia); Resano Abarzuza, M. A.; Córdoba Iturriagagoitia, A.; et al.
    Revista: ANALES DEL SISTEMA SANITARIO DE NAVARRA
    ISSN: 1137-6627 Vol.44 N° 2 2021 págs. 163 - 176
    Resumen
    Background. Cutaneous, superficial and or suprafascial leiomyoma are divided into three variants: piloleiomyomas (PL), angioleiomyomas (AL) and genital leiomyomas (GL) that include the vulvar, scrotal and areolar forms. This study set out to establish the clinical and histological characteristics and incidence of each variant, and any likely associations with internal neoplasms. Methods. A review was carried out of 255 cases of cutaneous leiomyomas diagnosed between 1982 and 2018 at the Pathology departments of three hospitals (Navarra and Alicante). Demographic, clinical, histological and immunohistochemical variables were described and compared. Results. The incidence of PL in Navarra was 4.3 cases per million inhabitants a year, with another 20 cases of AL and 1.4 cases of GL. Cutaneous forms make up approximately 3.5% of the total leiomyomas. The population with PL suffered more frequently from breast cancer (OR = 4.8; CI 95%: 1.3-17.4; p = 0.006). Nipple leiomyomas are small, accompanied by localised pain, and are predominantly fascicular or solid, with very infrequent effect on the subcutaneous cellular tissue and scarce atypia. This makes for a contrast with the other GLs, which are medium sized and infrequently painful, predominantly nodular, and frequent effect on the subcutaneous tissue and atypia. Conclusions. The information provided here about the clinical and histological characteristics of the different varieties of leiomyomas indicate that there is a need to reconsider the classification of nipple leiomyomas outside the group of GLs. An association between PL and breast carcinoma was detected, which needs to be confirmed in future studies so as to determine if this leiomyoma is a risk marker for breast cancer.
  • Autores: Pan, C. ; Humbatova, A.; Zheng, L.; et al.
    Revista: BRITISH JOURNAL OF DERMATOLOGY
    ISSN: 0007-0963 Vol.185 N° 2 2021 págs. 439 - 441
  • Autores: Zalacain Díez, Marta; Buñuales Aramendía, María; Marrodán Fernández, Lucía; et al.
    Revista: MOLECULAR THERAPY ONCOLYTICS
    ISSN: 2372-7705 Vol.20 2021 págs. 23 - 33
    Resumen
    Osteosarcoma is the most frequent and aggressive bone tumor in children and adolescents, with a long-term survival rate of 30%. Interleukin-12 (IL-12) is a potent cytokine that bridges innate and adaptive immunity, triggers antiangiogenic responses, and achieves potent antitumor effects. In this work, we evaluated the antisarcoma effect of a high-capacity adenoviral vector encoding mouse IL-12. This vector harbored a mifepristone-inducible system for controlled expression of IL-12 (High-Capacity adenoviral vector enconding the EF1alpha promoter [HCA-EFZP]-IL-12). We found that local administration of the vector resulted in a reduction in the tumor burden, extended overall survival, and tumor eradication. Moreover, long-term survivors exhibited immunological memory when rechallenged with the same tumor cells. Treatment with HCA-EFZP-IL-12 also resulted in a significant decrease in lung metastasis. Immunohistochemical analyses showed profound remodeling of the osteosarcoma microenvironment with decreases in angiogenesis and macrophage and myeloid cell numbers. In summary, our data underscore the potential therapeutic value of IL-12 in the context of a drug-inducible system that allows controlled expression of this cytokine, which can trigger a potent antitumor immune response in primary and metastatic pediatric osteosarcoma.
  • Autores: Gutiérrez Jimeno, Miriam; Alba-Pavón, P.; Astigarraga, I.; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.13 N° 21 2021 págs. 5436
    Resumen
    Simple Summary: Clinical management of sarcomas is complex because they are rare and heterogeneous tumors. Management requires a coordinated multidisciplinary approach, especially in children. Genomic characterization of this complex group of tumors contributes to the identification of prognostic biomarkers and to the continued expansion of therapeutic options. In this article, we present the positive experience of two Spanish hospitals in the use of genomic analysis in the overall clinical management of sarcomas in children and young adults. We describe on a case-by-case basis how genomic analysis has contributed to both diagnosis and treatment.Genomic techniques enable diagnosis and management of children and young adults with sarcomas by identifying high-risk patients and those who may benefit from targeted therapy or participation in clinical trials. Objective: to analyze the performance of an NGS gene panel for the clinical management of pediatric sarcoma patients. We studied 53 pediatric and young adult patients diagnosed with sarcoma, from two Spanish centers. Genomic data were obtained using the Oncomine Childhood Cancer Research Assay, and categorized according to their diagnostic, predictive, or prognostic value. In 44 (83%) of the 53 patients, at least one genetic alteration was identified. In 80% of these patients, the diagnosis was obtained (n = 11) or changed (n = 9), and thus genomic data affected therapy. The most frequent initial misdiagnosis was Ewing's sarcoma, instead of myxoid liposarcoma (FUS-DDDIT3), rhabdoid soft tissue tumor (SMARCB1), or angiomatoid fibrous histiocytoma (EWSR1-CREB1). In our series, two patients had a genetic alteration with an FDA-approved targeted therapy, and 30% had at least one potentially actionable alteration. NGS-based genomic studies are useful and feasible in diagnosis and clinical management of pediatric sarcomas. Genomic characterization of these rare and heterogeneous tumors also helps in the search for prognostic biomarkers and therapeutic opportunities.
  • 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: Henarejos-Castillo, I.; Aleman, A.; Martínez-Montoro, B.; et al.
    Revista: JOURNAL OF PERSONALIZED MEDICINE
    ISSN: 2075-4426 Vol.11 N° 7 2021 págs. 609
    Resumen
    Ovarian failure (OF) is a common cause of infertility usually diagnosed as idiopathic, with genetic causes accounting for 10-25% of cases. Whole-exome sequencing (WES) may enable identifying contributing genes and variant profiles to stratify the population into subtypes of OF. This study sought to identify a blood-based gene variant profile using accumulation of rare variants to promote precision medicine in fertility preservation programs. A case-control (n = 118, n = 32, respectively) WES study was performed in which only non-synonymous rare variants <5% minor allele frequency (MAF; in the IGSR) and coverage >= 100x were considered. A profile of 66 variants of uncertain significance was used for training an unsupervised machine learning model to separate cases from controls (97.2% sensitivity, 99.2% specificity) and stratify the population into two subtypes of OF (A and B) (93.31% sensitivity, 96.67% specificity). Model testing within the IGSR female population predicted 0.5% of women as subtype A and 2.4% as subtype B. This is the first study linking OF to the accumulation of rare variants and generates a new potential taxonomy supporting application of this approach for precision medicine in fertility preservation.
  • Autores: Rubio-San Simón, A.; Hladun Alvaro, R.; Juan Ribelles, A.; et al.
    Revista: CLINICAL AND TRANSLATIONAL ONCOLOGY
    ISSN: 1699-048X Vol.23 2021 págs. 2489 - 2496
    Resumen
    Purpose Early phase trials are crucial in developing innovative effective agents for childhood malignancies. We report the activity in early phase paediatric oncology trials in Spain from its beginning to the present time and incorporate longitudinal data to evaluate the trends in trial characteristics and recruitment rates. Methods Members of SEHOP were contacted to obtain information about the open trials at their institutions. The study period was split into two equal periods for analysis: 2007-2013 and 2014-2020. Results Eighty-one trials and two molecular platforms have been initiated. The number of trials has increased over the time of the study for all tumour types, with a predominance of trials available for solid tumours (66%). The number of trials addressed to tumours harbouring specific molecular alterations has doubled during the second period. The proportion of industry-sponsored compared to academic trials has increased over the same years. A total of 565 children and adolescents were included, with an increasing trend over the study period. For international trials, the median time between the first country study approval and the Spanish competent authority approval was 2 months (IQR 0-6.5). Fourteen out of 81 trials were sponsored by Spanish academic institutions. Conclusions The number of available trials, and the number of participating patients, has increased in Spain from 2007. Studies focused on molecular-specific targets are now being implemented. Barrie
  • 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: Gambera, S.; Patiño García, Ana; Alfranca, A.; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.13 N° 9 2021 págs. 2003
    Resumen
    Osteosarcoma (OS) is a highly aggressive tumor characterized by malignant cells producing pathologic bone; the disease presents a natural tendency to metastasize. Genetic studies indicate that the OS genome is extremely complex, presenting signs of macro-evolution, and linear and branched patterns of clonal development. However, those studies were based on the phylogenetic reconstruction of next-generation sequencing (NGS) data, which present important limitations. Thus, testing clonal evolution in experimental models could be useful for validating this hypothesis. In the present study, lentiviral LeGO-vectors were employed to generate colorimetric red, green, blue (RGB)-marking in murine, canine, and human OS. With this strategy, we studied tumor heterogeneity and the clonal dynamics occurring in vivo in immunodeficient NOD.Cg-Prkdcscid-Il2rgtm1Wjl/SzJ (NSG) mice. Based on colorimetric label, tumor clonal composition was analyzed by confocal microscopy, flow cytometry, and different types of supervised and unsupervised clonal analyses. With this approach, we observed a consistent reduction in the clonal composition of RGB-marked tumors and identified evident clonal selection at the first passage in immunodeficient mice. Furthermore, we also demonstrated that OS could follow a neutral model of growth, where the disease is defined by the coexistence of different tumor sub-clones. Our study demonstrates the importance of rigorous testing of the selective forces in commonly used experimental models.
  • Autores: Herrador Cañete, Guillermo; Zalacain Díez, Marta; De la Nava Martin, Daniel; et al.
    Revista: HUMAN GENE THERAPY
    ISSN: 1043-0342 Vol.32 N° 19-20 2021 págs. A127
  • Autores: Puigdelloses Vallcorba, Montserrat; Laspidea Ustés, Virginia; Hambardzumyan, D.; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.23 2021 págs. 28 - 29
  • 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: 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. S.; Madduri, D.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.39 N° 15 2021
  • Autores: Ausejo Mauleón, Iker; Labiano Almiñana, Sara; Laspidea Ustés, Virginia; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.23 N° Supl. 1 2021 págs. 28
  • 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: Alana-Rodrigo, L.; Alba-Pavon, P.; Villate-Bejarano, O.; et al.
    Revista: PEDIATRIC BLOOD AND CANCER
    ISSN: 1545-5009 Vol.68 N° Supl. 5 2021 págs. S288
  • 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: Pelaez, J.; Monteiro, R.; Lobo, S.; et al.
    Revista: MEDICINE (BALTIMORE)
    ISSN: 0025-7974 Vol.100 N° 4 2021 págs. OP4
  • 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: 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: Zuazo, M.; Arasanz, H.; Chocarro, L.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.32 N° Supl. 5 2021 págs. S1028 - S1028
  • Autores: García Moure, Marc; Gállego Pérez de Larraya, Jaime; Patiño García, Ana; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.23 N° Supl. 1 2021 págs. 47
  • Autores: Martín Pastor, Santiago Mariano; Calvo Manuel, Felipe; García-Consuegra López-Picazo, Alejandro; et al.
    Revista: RADIOTHERAPY AND ONCOLOGY
    ISSN: 0167-8140 Vol.161 N° Supl. 1 2021 págs. S874 - S875
  • 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: 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: Mirones, I.; Moreno, L.; Patiño García, Ana; et al.
    Revista: ANALES DE PEDIATRIA
    ISSN: 1695-4033 Vol.93 N° 1 2020 págs. 59.e1 - 59.e10
    Resumen
    Despite being a rare disease, cancer is the first cause of mortality due to disease during the paediatric age in the developed countries. The current, great increase in new treatments, such as immunotherapy, constitutes a new clinical and regulatory paradigm. Cellular immunotherapy is one of these types of immunotherapy. In particular, the advanced therapy drugs with chimeric antigen receptors in the T-lymphocytes (CAR-T), and particularly the CAR-T19 cells, has opened up a new scenario in the approach to haematology tumours like acute lymphoblastic leukaemia and the B-Cell lymphomas. The approval of tisagenlecleucel and axicabtagene ciloleucel by the regulatory authorities has led to the setting up of the National Plan for Advanced Therapies-CAR-T drugs in Spain. There is evidence of, not only the advantage of identifying the centres most suitable for their administration, but also the need for these to undergo a profound change in order that their healthcare activity is extended, in some cases, to the ability for the in-house manufacture of these types of therapies. The hospitals specialised in paediatric haematology-oncology thus have the challenge of progressing towards a healthcare model that integrates cellular immunotherapy, having the appropriate capacity to manage all aspects relative to their use, manufacture, and administration of these new treatments.
  • Autores: Mirabello, L.; Zhu, B.; koster, R.; et al.
    Revista: JAMA ONCOLOGY
    ISSN: 2374-2437 Vol.6 N° 5 2020 págs. 724 - 734
    Resumen
    This next-generation exome sequencing study investigates the frequency of pathogenic or likely pathogenic germline genetic variants in known cancer-susceptibility genes among patients with osteosarcoma. Importance Osteosarcoma, the most common malignant bone tumor in children and adolescents, occurs in a high number of cancer predisposition syndromes that are defined by highly penetrant germline mutations. The germline genetic susceptibility to osteosarcoma outside of familial cancer syndromes remains unclear. Objective To investigate the germline genetic architecture of 1244 patients with osteosarcoma. Design, Setting, and Participants Whole-exome sequencing (n = 1104) or targeted sequencing (n = 140) of the DNA of 1244 patients with osteosarcoma from 10 participating international centers or studies was conducted from April 21, 2014, to September 1, 2017. The results were compared with the DNA of 1062 individuals without cancer assembled internally from 4 participating studies who underwent comparable whole-exome sequencing and 27 & x202f;173 individuals of non-Finnish European ancestry who were identified through the Exome Aggregation Consortium (ExAC) database. In the analysis, 238 high-interest cancer-susceptibility genes were assessed followed by testing of the mutational burden across 736 additional candidate genes. Principal component analyses were used to identify 732 European patients with osteosarcoma and 994 European individuals without cancer, with outliers removed for patient-control group comparisons. Patients were subsequently compared with individuals in the ExAC group. All data were analyzed from June 1, 2017, to July 1, 2019. Main Outcomes and Measures The frequency of rare pathogenic or likely pathogenic genetic variants. Results Among 1244 patients with osteosarcoma (mean [SD] age at diagnosis, 16 [8.9] years [range, 2-80 years]; 684 patients [55.0%] were male), an analysis restricted to individuals with European ancestry indicated a significantly higher pathogenic or likely pathogenic variant burden in 238 high-interest cancer-susceptibility genes among patients with osteosarcoma compared with the control group (732 vs 994, respectively; P = 1.3 x 10(-18)). A pathogenic or likely pathogenic cancer-susceptibility gene variant was identified in 281 of 1004 patients with osteosarcoma (28.0%), of which nearly three-quarters had a variant that mapped to an autosomal-dominant gene or a known osteosarcoma-associated cancer predisposition syndrome gene. The frequency of a pathogenic or likely pathogenic cancer-susceptibility gene variant was 128 of 1062 individuals (12.1%) in the control group and 2527 of 27 & x202f;173 individuals (9.3%) in the ExAC group. A higher than expected frequency of pathogenic or likely pathogenic variants was observed in genes not previously linked to osteosarcoma (eg, CDKN2A, MEN1, VHL, POT1, APC, MSH2, and ATRX) and in the Li-Fraumeni syndrome-associated gene, TP53. Conclusions and Relevance In this study, approximately one-fourth of patients with osteosarcoma unselected for family history had a highly penetrant germline mutation requiring additional follow-up analysis and possible genetic counseling with cascade testing. Question What is the frequency of pathogenic or likely pathogenic germline genetic variants in known cancer-susceptibility genes in a large population of patients with osteosarcoma who were unselected for family history? Findings In this next-generation exome sequencing study of 1244 patients with osteosarcoma, 28.0% of patients in the discovery set carried a rare pathogenic or likely pathogenic germline variant in a cancer-susceptibility gene compared with 12.1% of individuals without cancer who were comparably sequenced and 9.3% of individuals of non-Finnish European ancestry identified through the Exome Aggregation Consortium database. Meaning A higher than expected frequency of patients with osteosarcoma carrying a pathogenic or likely pathogenic germline variant suggests germline genetic testing may be warranted for individuals with osteosarcoma.
  • Autores: Lin, S. H. ; Sampson, J. N. ; Grunewald, T. G. P. ; et al.
    Revista: PLOS ONE
    ISSN: 1932-6203 Vol.15 N° 9 2020 págs. e0237792
    Resumen
    Background Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor. Methods We investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry). Results We identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively; P-value < 5x10(-8)) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84x10(-8)). Conclusions These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk. Impact Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci.
  • 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: 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: Gutiérrez-Jimeno, M.; Panizo-Morgado, E.; Tamayo Uria, Ibon; et al.
    Revista: NPJ GENOMIC MEDICINE
    ISSN: 2056-7944 Vol.5 N° 1 2020 págs. 51
    Resumen
    Rothmund-Thomson syndrome (RTS) is characterized by a rash that begins in the first few months of life and eventually develops into poikiloderma. Associated symptoms are alterations in the teeth, sparse hair, thin eyebrows, lack of eyelashes, low stature, bone abnormalities, hematological illnesses, gastrointestinal disease, malnutrition, cataracts, and predisposition to cancer, principally to bone tumors and skin cancer. Diagnostic certitude is provided by a genetic study involving detection of pathogenic variants of the RECQL4 gene. We hereby present a familiar case of RTS in two siblings from a Portuguese family, both diagnosed with osteosarcoma. Genomic analysis (203 genes) of both tumors as well as germline analysis of the RECQL4 gene, thus confirming the syndrome in the family, have been performed. The relevance of clinical recognition of the hallmarks of the disease and thus early diagnosis with early intervention is highlighted.
  • 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: García Moure, Marc; González Huarriz, María Soledad; Laspidea Ustés, Virginia; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.22 N° Suppl. 2 2020 págs. 100 - 100
  • 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: Castillo, I. H.; Aleman, A.; Martinez-Montoro, B.; et al.
    Revista: HUMAN REPRODUCTION
    ISSN: 0268-1161 Vol.35 N° Supl. 1 2020 págs. I364
  • 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: García-Peláez, J.; Monteiro, R.; Sousa, L.; et al.
    Revista: EUROPEAN JOURNAL OF HUMAN GENETICS
    ISSN: 1018-4813 Vol.28 N° Suppl. 1 2020 págs. 61 - 63
  • 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; Martínez Velez, Naiara; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.22 2020 págs. 107 - 107
  • 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: García Moure, Marc; Martínez Velez, Naiara; González Huarriz, María Soledad; et al.
    Revista: SCIENTIFIC REPORTS
    ISSN: 2045-2322 Vol.9 N° 1 2019 págs. 14368
    Resumen
    Last advances in the treatment of pediatric tumors has led to an increase of survival rates of children affected by primitive neuroectodermal tumors, however, still a significant amount of the patients do not overcome the disease. In addition, the survivors might suffer from severe side effects caused by the current standard treatments. Oncolytic virotherapy has emerged in the last years as a promising alternative for the treatment of solid tumors. In this work, we study the anti-tumor effect mediated by the oncolytic adenovirus VCN-01 in CNS-PNET models. VCN-01 is able to infect and replicate in PNET cell cultures, leading to a cytotoxicity and immunogenic cell death. In vivo, VCN-01 increased significantly the median survival of mice and led to long-term survivors in two orthotopic models of PNETs. In summary, these results underscore the therapeutic effect ofVCN-01 for rare pediatric cancers such as PNETs, and warrants further exploration on the use of this virus to treat them.
  • 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: Martínez Velez, Naiara; Marigil Sánchez, Miguel; García Moure, Marc; et al.
    Revista: ACTA NEUROPATHOLOGICA
    ISSN: 1432-0533 Vol.7 2019 págs. 64
    Resumen
    Pediatric high grade gliomas (pHGG), including diffuse intrinsic pontine gliomas (DIPGs), are aggressive tumors with a dismal outcome. Radiotherapy (RT) is part of the standard of care of these tumors; however, radiotherapy only leads to a transient clinical improvement. Delta-24-RGD is a genetically engineered tumor-selective adenovirus that has shown safety and clinical efficacy in adults with recurrent gliomas. In this work, we evaluated the feasibility, safety and therapeutic efficacy of Delta-24-RGD in combination with radiotherapy in pHGGs and DIPGs models. Our results showed that the combination of Delta-24-RGD with radiotherapy was feasible and resulted in a synergistic anti-glioma effect in vitro and in vivo in pHGG and DIPG models. Interestingly, Delta-24-RGD treatment led to the downregulation of relevant DNA damage repair proteins, further sensitizing tumors cells to the effect of radiotherapy. Additionally, Delta-24-RGD/radiotherapy treatment significantly increased the trafficking of immune cells (CD3, CD4+ and CD8+) to the tumor niche compared with single treatments. In summary, administration of the Delta-24-RGD/radiotherapy combination to pHGG and DIPG models is safe and significantly increases the overall survival of mice bearing these tumors. Our data offer a rationale for the combination Delta-24-RGD/radiotherapy as a therapeutic option for children with these tumors. SIGNIFICANCE: Delta-24-RGD/radiotherapy administration is safe and significantly increases the survival of treated mice. These positive data underscore the urge to translate this approach to the clinical treatment of children with pHGG and DIPGs.
  • Autores: Martínez Velez, Naiara; García Moure, Marc; Marigil Sánchez, Miguel; et al.
    Revista: NATURE COMMUNICATIONS
    ISSN: 2041-1723 Vol.10 N° 1 2019 págs. 2235
    Resumen
    Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors in desperate need of a curative treatment. Oncolytic virotherapy is emerging as a solid therapeutic approach. Delta-24-RGD is a replication competent adenovirus engineered to replicate in tumor cells with an aberrant RB pathway. This virus has proven to be safe and effective in adult gliomas. Here we report that the administration of Delta-24-RGD is safe in mice and results in a significant increase in survival in immunodeficient and immunocompetent models of pHGG and DIPGs. Our results show that the Delta-24-RGD antiglioma effect is mediated by the oncolytic effect and the immune response elicited against the tumor. Altogether, our data highlight the potential of this virus as treatment for patients with these tumors. Of clinical significance, these data have led to the start of a phase I/II clinical trial at our institution for newly diagnosed DIPG (NCT03178032).
  • Autores: Elgendy, M.; Fusco Morales, Juan Pablo; Segura Ruiz, Victor; et al.
    Revista: INTERNATIONAL JOURNAL OF CANCER
    ISSN: 0020-7136 Vol.145 N° 7 2019 págs. 1991 - 2001
    Resumen
    Sunitinib is one of the most widely used targeted therapeutics for renal cell carcinoma (RCC), but acquired resistance against targeted therapies remains a major clinical challenge. To dissect mechanisms of acquired resistance and unravel reliable predictive biomarkers for sunitinib in RCC, we sequenced the exons of 409 tumor-suppressor genes and oncogenes in paired tumor samples from an RCC patient, obtained at baseline and after development of acquired resistance to sunitinib. From newly arising mutations, we selected, using in silico prediction models, six predicted to be deleterious, located in G6PD, LRP1B, SETD2, TET2, SYNE1, and DCC. Consistently, immunoblotting analysis of lysates derived from sunitinib-desensitized RCC cells and their parental counterparts showed marked differences in the levels and expression pattern of the proteins encoded by these genes. Our further analysis demonstrates essential roles for these proteins in mediating sunitinib cytotoxicity and shows that their loss of function renders tumor cells resistant to sunitinib in vitro and in vivo. Finally, sunitinib resistance induced by continuous exposure or by inhibition of the six proteins was overcome by treatment with cabozantinib or a low-dose combination of lenvatinib and everolimus. Collectively, our results unravel novel markers of acquired resistance to sunitinib and clinically relevant approaches for overcoming this resistance in RCC.
  • Autores: Habel, N.; Stefanovska, B.; Carene, D. ; et al.
    Revista: BMC CANCER
    ISSN: 1471-2407 Vol.19 2019 págs. 62
    Resumen
    BACKGROUND: Osteosarcoma is the most prevalent primary bone malignancy in children and young adults. These tumors are highly metastatic, leading to poor outcome. We previously demonstrated that Cysteine-rich protein 61 (CYR61/CCN1) expression level is correlated to osteosarcoma aggressiveness in preclinical model and in patient tumor samples. The aim of the present study was to investigate the CYR61-induced intracellular mechanisms leading to the acquisition of an invasive phenotype by osteosarcoma cells. METHODS: Modified murine and human osteosarcoma cell lines were evaluated for cell adhesion, aggregation (spheroid), motility (wound healing assay), phenotypic markers expression (RT-qPCR, western blot). Cell-derived xenograft FFPE samples and patients samples (TMA) were assessed by IHC. RESULTS: CYR61 levels controlled the expression of markers related to an Epithelial-mesenchymal transition (EMT)-like process, allowing tumor cells to migrate acquiring a competent morphology, and to be able to invade the surrounding stroma. This phenotypic shift indeed correlated with tumor grade and aggressiveness in patient samples and with the metastatic dissemination potential in cell-derived xenograft models. Unlike EGFR or PDGFR, IGF1Rß levels correlated with CYR61 and N-cadherin levels, and with the aggressiveness of osteosarcoma and overall survival. The expression levels of IGF1Rß/IGF1 axis were controlled by CYR61, and anti-IGF1 neutralizing antibody prevented the CYR61-induced phenotypic shift, aggregation, and motility abilities. CONCLUSIONS: Taken together, our study provides new evidence that CYR61 acts as a key inducing factor in the metastatic progression of osteosarcoma by playing a critical role in primary tumor dissemination, with a process associated with IGF1/IGFR stimulation. This suggests that CYR61 may represent a potential pivotal target for therapeutic management of metastases spreading in osteosarcoma, in correlation with IGF1/IGFR pathway.
  • 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: Laspidea Ustés, Virginia; Puigdelloses Vallcorba, Montserrat; García Moure, Marc; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.21 2019 págs. 36 - 36
  • 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: Puigdelloses Vallcorba, Montserrat; Martínez Velez, Naiara; García Moure, Marc; et al.
    Revista: NEURO-ONCOLOGY
    ISSN: 1522-8517 Vol.21 2019 págs. 56 - 56
  • 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: 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: 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: Martínez Velez, Naiara; García Moure, Marc; Laspidea Ustés, Virginia; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.79 N° Supl. 13 2019
  • 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: Zalacain Díez, Marta; Laspidea Ustés, Virginia; Martínez Velez, Naiara; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.79 N° 13 2019
  • 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: Alba-Pavon, P.; Astigarraga, I. ; Garcia-Obregon, S.; et al.
    Revista: PEDIATRIC BLOOD AND CANCER
    ISSN: 1545-5009 Vol.66 2019 págs. S347 - S348
  • Autores: Pelaez, J. G. ; Monteiro, A.; Sousa, L. ; et al.
    Revista: EUROPEAN JOURNAL OF HUMAN GENETICS
    ISSN: 1018-4813 Vol.27 N° Supl. 2 2019 págs. 1126 - 1128
  • 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: 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: 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: 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: Varela Guruceaga, Maider; Tejada Solís, Sonia; García Moure, Marc; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.10 N° 7 2018 págs. E226.
  • Autores: Koster, R.; Panagiotou, O.A.; Wheeler, W.A.; et al.
    Revista: INTERNATIONAL JOURNAL OF CANCER
    ISSN: 0020-7136 Vol.142 N° 8 2018 págs. 1594 - 1601
    Resumen
    Survival rates for osteosarcoma, the most common primary bone cancer, have changed little over the past three decades and are particularly low for patients with metastatic disease. We conducted a multi-institutional genome-wide association study (GWAS) to identify germline genetic variants associated with overall survival in 632 patients with osteosarcoma, including 523 patients of European ancestry and 109 from Brazil. We conducted a time-to-event analysis and estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards models, with and without adjustment for metastatic disease. The results were combined across the European and Brazilian case sets using a random-effects meta-analysis. The strongest association after meta-analysis was for rs3765555 at 9p24.1, which was inversely associated with overall survival (HR¿=¿1.76; 95% CI 1.41-2.18, p¿=¿4.84 × 10-7 ). After imputation across this region, the combined analysis identified two SNPs that reached genome-wide significance. The strongest single association was with rs55933544 (HR¿=¿1.9; 95% CI 1.5-2.4; p¿=¿1.3 × 10-8 ), which localizes to the GLDC gene, adjacent to the IL33 gene and was consistent across both the European and Brazilian case sets. Using publicly available data, the risk allele was associated with lower expression of IL33 and low expression of IL33 was associated with poor survival in an independent set of patients with osteosarcoma. In conclusion, we have identified the GLDC/IL33 locus on chromosome 9p24.1 as associated with overall survival in patients with osteosarcoma. Further studies are needed to confirm this association and shed light on the biological underpinnings of this susceptibility locus.
  • Autores: Ruiz-Pinto, S.; Pita, G.; Martín, M.; et al.
    Revista: BREAST CANCER RESEARCH AND TREATMENT
    ISSN: 0167-6806 Vol.167 N° 1 2018 págs. 249 - 256
    Resumen
    PURPOSE: Anthracyclines are widely used chemotherapeutic drugs that can cause progressive and irreversible cardiac damage and fatal heart failure. Several genetic variants associated with anthracycline-induced cardiotoxicity (AIC) have been identified, but they explain only a small proportion of the interindividual differences in AIC susceptibility. METHODS: In this study, we evaluated the association of low-frequency variants with risk of chronic AIC using the Illumina HumanExome BeadChip array in a discovery cohort of 61 anthracycline-treated breast cancer patients with replication in a second independent cohort of 83 anthracycline-treated pediatric cancer patients, using gene-based tests (SKAT-O). RESULTS: The most significant associated gene in the discovery cohort was ETFB (electron transfer flavoprotein beta subunit) involved in mitochondrial ß-oxidation and ATP production (P = 4.16 × 10-4) and this association was replicated in an independent set of anthracycline-treated cancer patients (P = 2.81 × 10-3). Within ETFB, we found that the missense variant rs79338777 (p.Pro52Leu; c.155C > T) made the greatest contribution to the observed gene association and it was associated with increased risk of chronic AIC in the two cohorts separately and when combined (OR 9.00, P = 1.95 × 10-4, 95% CI 2.83-28.6). CONCLUSIONS: We identified and replicated a novel gene, ETFB, strongly associated with chronic AIC independently of age at tumor onset and related to anthracycline-mediated mitochondrial dysfunction. Although experimental verification and further studies in larger patient cohorts are required to confirm our finding, we demonstrated that exome array data analysis represents a valuable strategy to identify novel genes contributing to the susceptibility to chronic AIC.
  • 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: Collantes Martínez, María; Martínez Velez, Naiara; Zalacain Díez, Marta; et al.
    Revista: BMC CANCER
    ISSN: 1471-2407 Vol.18 N° 1 2018 págs. 1193
    Resumen
    BACKGROUND: Osteosarcoma is the most common malignant bone tumor in children and young adults that produces aberrant osteoid. The aim of this study was to assess the utility of 2-deoxy-2-[18F-] fluoro-D-glucose ([18F] FDG) and sodium [18F] Fluoride (Na [18F] F) PET scans in orthotopic murine models of osteosarcoma to describe the metabolic pattern of the tumors, to detect and diagnose tumors and to evaluate the efficacy of a new treatment based in oncolytic adenoviruses. METHODS: Orthotopic osteosarcoma murine models were created by the injection of 143B and 531MII cell lines. [18F]FDG and Na [18F] F PET scans were performed 30 days (143B) and 90 days (531MII) post-injection. The antitumor effect of two doses (107 and 108 pfu) of the oncolytic adenovirus VCN-01 was evaluated in 531 MII model by [18F] FDG PET studies. [18F] FDG uptake was quantified by SUVmax and Total Lesion Glycolysis (TLG) indexes. For Na [18F] F, the ratio tumor SUVmax/hip SUVmax was calculated. PET findings were confirmed by histopathological techniques. RESULTS: The metabolic pattern of tumors was different between both orthotopic models. All tumors showed [18F] FDG uptake, with a sensitivity and specificity of 100%. The [18F] FDG uptake was significantly higher for the 143B model (p < 0.001). Sensitivity for Na [18F] F was around 70% in both models, with a specificity of 100%. 531MII tumors showed a heterogeneous Na [18F] F uptake, significantly higher than 143B tumors (p < 0.01).
  • 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: 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: Machiela, MJ.; Grünewald, TGP.; Surdez, D.; et al.
    Revista: NATURE COMMUNICATIONS
    ISSN: 2041-1723 Vol.9 N° 1 2018 págs. 3184
    Resumen
    Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk.
  • Autores: Martín-Guerrero, I.; Bilbao-Aldaiturriaga, N.; Gutiérrez-Camino, A.; et al.
    Revista: SCIENTIFIC REPORTS
    ISSN: 2045-2322 Vol.8 N° 1 2018 págs. 15414
    Resumen
    Association studies in osteosarcoma risk found significant results in intergenic regions, suggesting that regions which do not codify for proteins could play an important role. The deregulation of microRNAs (miRNAs) has been already associated with osteosarcoma. Consequently, genetic variants affecting miRNA function could be associated with risk. This study aimed to evaluate the involvement of all genetic variants in pre-miRNAs described so far in relationship to the risk of osteosarcoma. We analyzed a total of 213 genetic variants in 206 pre-miRNAs in two cohorts of osteosarcoma patients (n¿=¿100) and their corresponding controls (n¿=¿256) from Spanish and Slovenian populations, using Goldengate Veracode technology (Illumina). Four polymorphisms in pre-miRNAs at 14q32 miRNA cluster were associated with osteosarcoma risk in the Spanish population (rs12894467, rs61992671, rs58834075 and rs12879262). Pathway enrichment analysis including target genes of these miRNAs pointed out the WNT signaling pathways overrepresented. Moreover, different single nucleotide polymorphism (SNP) effects between the two populations included were observed, suggesting the existence of population differences. In conclusion, 14q32 miRNA cluster seems to be a hotspot for osteosarcoma susceptibility in the Spanish population, but not in the Slovenian, which supports the idea of the existence of population differences in developing this disease.
  • Autores: Machiela, M. J.; Grunewald, T. G.; Surdez, D.; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.78 N° 13 2018
  • 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
  • Autores: Machiela, M. J. ; Grunewald, T. G. P.; Surdez, D.; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.78 N° 19 2018
  • Autores: Koster, R.; Panagiotou, O. A.; Wheeler, W. A. ; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.78 N° 13 Supl. 2018
  • 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: 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: Patiño García, Ana; Lecanda Cordero, Fernando
    Libro: Bone cancer: bone sarcomas and bone metastases - from bench to bedside
    ISSN: 978-012821666-8 2022 págs. 591 - 604
    Resumen
    Osteosarcoma (OS) is characterized by its complex ontology. Nevertheless, an array of molecular tools for the global analysis at the genomic or postgenomic level has brought to light a wealth of data illuminating some of the molecular intricacies of this tumor. Systematic molecular profiling driven by the emergence of novel technological platforms is shaping our understanding of OS. This review gathers all the information into a comprehensive and systematic summary, underlining the contribution of each gene, protein, or signaling pathway to OS tumorigenesis. We place special emphasis on their functional relevance in chemoresistance and metastasis, together with their potential clinical impact. This chapter should inspire researchers to explore new avenues with potential clinical impact.

Proyectos desde 2018

  • Título: Modelo de Arquitectura Genómica Avanzada (MARGA). (Esta empresa/entidad ha recibido una ayuda cofinanciada al 100% con recursos REACT UE, a través del Programa Operativo FEDER 2014-2020 de Navarra, del Objetivo Específico ¿OE REACT UE 2. Apoyo a las inversiones que contribuyan a la transición hacia una economía digital¿ como parte de la respuesta de la Unión a la pandemia de COVID-19)
    Código de expediente: 0011-4218-2022-000032
    Investigador principal: ALBERTO GARCIA MOURIZ.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2022 GN Ayudas para la realización de alianzas digitales
    Fecha de inicio: 13-09-2022
    Fecha fin: 14-08-2023
    Importe concedido: 29.880,00€
    Otros fondos: Fondos FEDER
  • Título: MEdicina PERsonalizada para el TRatamiento de la OBEsidad: Integración de datos ómicos, dietéticos y de estilo de vida para la optimización de la nutrición personalizada del paciente con obesidad
    Código de expediente: 0011-1383-2022-000015 (PC098 MEPERTROBE)
    Investigador principal: JAVIER GOMEZ AMBROSI, JAVIER GOMEZ AMBROSI.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2022 GN Proyectos Colaborativos
    Fecha de inicio: 01-09-2022
    Fecha fin: 30-11-2024
    Importe concedido: 280.995,26€
    Otros fondos: -
  • 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, INNOVACIÓN Y UNIVERSIDADES
    Convocatoria: 2021 AEI Proyectos de Colaboración Internacional - 2
    Fecha de inicio: 01-02-2022
    Fecha fin: 23-05-2024
    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: SEHOP-PENCIL study- Personalised Medicine for Cancer in Children in Spain Estrategia nacional para la implementación de la medicina personalizada en niños y adolescentes con cáncer A Spanish nation-wide strategy to implement personalised medicine in child
    Código de expediente: PMP21/00087
    Investigador principal: ANA PATIÑO GARCIA.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2021 AES Medicina Personalizada
    Fecha de inicio: 01-01-2022
    Fecha fin: 31-12-2025
    Importe concedido: 200.420,00€
    Otros fondos: -
  • 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: 31-12-2024
    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, INNOVACIÓN Y UNIVERSIDADES
    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: 30-06-2024
    Importe concedido: 96.800,00€
    Otros fondos: Fondos FEDER
  • Título: Inmunoviroterapia contra el osteosarcoma infantil.
    Código de expediente: PI18/00614
    Investigador principal: ANA PATIÑO GARCIA.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: AES2018 PI
    Fecha de inicio: 01-01-2019
    Fecha fin: 31-12-2021
    Importe concedido: 93.170,00€
    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: Desarrollo y validación de paneles génicos en niños y adolescentes con cáncer: herramientas clínicas de diagnóstico, predicción y asesoramiento genético.
    Código de expediente: 54/2018
    Investigador principal: ANA PATIÑO GARCIA.
    Financiador: GOBIERNO DE NAVARRA. DEPARTAMENTO DE SALUD
    Convocatoria: 2018 PROYECTOS DE I+D EN SALUD
    Fecha de inicio: 01-01-2019
    Fecha fin: 31-12-2020
    Importe concedido: 49.352,25€
    Otros fondos: Fondos FEDER
  • Título: Implantación del diagnóstico de la epilepsia y la migraña en Navarra (Geneurona)
    Código de expediente: 0011-1411-2018-000053
    Investigador principal: MARIA CRUZ RODRIGUEZ OROZ.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2018 GN PROYECTOS ESTRATEGICOS DE I+D 2018-2020
    Fecha de inicio: 01-04-2018
    Fecha fin: 30-11-2020
    Importe concedido: 18.481,69€
    Otros fondos: -
  • Título: Personalización genómica de la población navarra para la prevención del fallo ovárico precoz
    Código de expediente: 0011-1365-2017-000215
    Investigador principal: GORKA ALKORTA ARANBURU.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2017 GN I+D
    Fecha de inicio: 01-06-2017
    Fecha fin: 30-04-2019
    Importe concedido: 153.704,12€
    Otros fondos: -
  • Título: Tecnología de secuenciación de nueva generación (NGS) para optimizar la eficacia del diagnóstico y tratamiento en pacientes con tumores de alta mortalidad (DIANA: Diagnostico biomédico e Innovación Abierta en Navarra)
    Código de expediente: 0011-1411-2017-000030
    Investigador principal: FELIPE LUIS PROSPER CARDOSO.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2017 GN ESTRATEGICOS
    Fecha de inicio: 01-04-2017
    Fecha fin: 30-11-2019
    Importe concedido: 37.315,72€
    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: Inmunomodulación del microambiente tumoral para el tratamiento del glioma difuso de línea media
    Investigador principal: SARA LABIANO ALMIÑANA, JAIME GALLEGO PEREZ DE LARRAYA
    Financiador: FUNDACIÓN BLANCA MORELL
    Convocatoria: 2021 FD BLANCA MORELL - Proyectos de Investigación en Gliomas
    Fecha de inicio: 10-02-2022
    Fecha fin: 09-02-2025
    Importe concedido: 194.352,00€
  • 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: 08-03-2027
    Importe concedido: 360.000,00€
  • 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: 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: Optimización de la quimioterapia en sarcomas óseos pediátricos mediante el uso de nanopartículas lipídicas
    Investigador principal: MARIA JOSE BLANCO PRIETO
    Financiador: ASOCIACION ESPAÑOLA CONTRA EL CANCER
    Convocatoria: 2014 AECC Cancer Infantil
    Fecha de inicio: 01-10-2014
    Fecha fin: 30-09-2019
    Importe concedido: 150.000,00€