Tejada-Solis, S. (Sonia)
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- Hypofractionated radiation therapy and temozolomide in patients with glioblastoma and poor prognostic factors. A prospective, single-institution experience(Public Library of Science (PLoS), 2019) Arbizu, J. (Javier); Garcia-de-Eulate, R. (Reyes); Aristu-Mendioroz, J.J. (José Javier); Domínguez-Echávarri, P.D. (Pablo Daniel); Arbea-Moreno, L. (Leire); Tejada-Solis, S. (Sonia); Jablonska, P.A. (Paola Anna); Diez-Valle, R. (Ricardo); Idoate, M.A. (Miguel Ángel); Ramos, L. (Luis); Gallego-Perez-Larraya, J. (Jaime); Moreno-Jimenez, M. (Marta)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/m2/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.
- Infratentorial hygroma secondary to decompressive craniectomy after cerebellar infarction(Sociedad Española de Neurocirugía, 2009) Gomez-Ibañez, A. (Asier); Garcia-de-Eulate, R. (Reyes); Domínguez-Echávarri, P.D. (Pablo Daniel); Tejada-Solis, S. (Sonia); Diez-Valle, R. (Ricardo)We present a case of expansive CSF collection in the cerebellar convexity. The patient was a 74 years old lady who one month before had suffered a cerebellar infarct complicated with acute hydrocephalus. She had good evolution after decompressive craniectomy without shunting. Fifteen days after surgery, the patient started with new positional vertigo, nausea and vomiting and a wound CSF fistula that needed ventriculoperitoneal shunt (medium pressure) because conservative treatment failed. After shunting, the fistula closed, but the patient symptoms worsened. The MRI showed normal ventricular size with a cerebellar hygroma, extending to the posterior interhemispheric fissure. The collection had no blood signal and expanded during observation. A catheter was implanted in the collection and connected to the shunt. The patient became asymptomatic after surgery, and the hygromas had disappeared in control CT at one month. This case shows an infrequent problem of CSF circulation at posterior fossa that resulted in vertigo of central origin. A higroma-ventricle-peritoneal shunt solved the symptoms of the patient.
- RNU6-1 in circulating exosomes differentiates GBM from non-neoplastic brain lesions and PCNSL but not from brain metastases.(Society for NeuroOncology (SNO), 2020) Patiño-García, A. (Ana); Alonso-Roldán, M.M. (Marta María); Martinez-Velez, N. (Naiara); Marigil, M. (Miguel); Zandio, B. (Beatriz); Bruna, J. (Jordi); Gonzalez-Huarriz, M. (Marisol); Tejada-Solis, S. (Sonia); Esparragosa-Vázquez, I. (I.); Diez-Valle, R. (Ricardo); Garcia-Moure, M. (Marc); Gállego-Culleré, J. (Jaime); Agirre, A. (Amaia); Puigdelloses-Vallcorba, M. (Montserrat); Martinez-Vila, E. (Eduardo); Gallego-Perez-Larraya, J. (Jaime); Petrirena, G. (Gregorio); Nuñez-Cordoba, J.M. (Jorge M.)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 nonneoplastic 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).
- Oncolytic viruses as therapeutic tools for pediatric brain tumors(MDPI AG, 2018) Patiño-García, A. (Ana); Alonso-Roldán, M.M. (Marta María); Gomez-Manzano, C. (Candelaria); Tejada-Solis, S. (Sonia); Garcia-Moure, M. (Marc); Varela-Guruceaga, M. (Maider); Fueyo, J. (Juan)In recent years, we have seen an important progress in our comprehension of the molecular basis of pediatric brain tumors (PBTs). However, they still represent the main cause of death by disease in children. Due to the poor prognosis of some types of PBTs and the long-term adverse effects associated with the traditional treatments, oncolytic viruses (OVs) have emerged as an interesting therapeutic option since they displayed safety and high tolerability in pre-clinical and clinical levels. In this review, we summarize the OVs evaluated in different types of PBTs, mostly in pre-clinical studies, and we discuss the possible future direction of research in this field. In this sense, one important aspect of OVs antitumoral effect is the stimulation of an immune response against the tumor which is necessary for a complete response in preclinical immunocompetent models and in the clinic. The role of the immune system in the response of OVs needs to be evaluated in PBTs and represents an experimental challenge due to the limited immunocompetent models of these diseases available for pre-clinical research.
- Involvement of miRNAs in the differentiation of human glioblastoma multiforme stem-like cells(Public Library of Science, 2013) Grande, L. (Lara); Huse, J.T. (Jason T.); Alonso-Roldán, M.M. (Marta María); Nogueira, L. (Lorena); Martinez-Climent, J.A. (José Ángel); Tejada-Solis, S. (Sonia); Aznar, M.A. (María Ángela); Aldaz-Arrieta, B. (Beatriz); Diez-Valle, R. (Ricardo); Fernandez-Luna, J.L. (J.L.); Raquel; Sagardoy, A. (Ainara); Guruceaga, E. (Elizabeth)Glioblastoma multiforme (GBM)-initiating cells (GICs) represent a tumor subpopulation with neural stem cell-like properties that is responsible for the development, progression and therapeutic resistance of human GBM. We have recently shown that blockade of NFκB pathway promotes terminal differentiation and senescence of GICs both in vitro and in vivo, indicating that induction of differentiation may be a potential therapeutic strategy for GBM. MicroRNAs have been implicated in the pathogenesis of GBM, but a high-throughput analysis of their role in GIC differentiation has not been reported. We have established human GIC cell lines that can be efficiently differentiated into cells expressing astrocytic and neuronal lineage markers. Using this in vitro system, a microarray-based high-throughput analysis to determine global expression changes of microRNAs during differentiation of GICs was performed. A number of changes in the levels of microRNAs were detected in differentiating GICs, including over-expression of hsa-miR-21, hsa-miR-29a, hsa-miR-29b, hsa-miR-221 and hsa-miR-222, and down-regulation of hsa-miR-93 and hsa-miR-106a. Functional studies showed that miR-21 over-expression in GICs induced comparable cell differentiation features and targeted SPRY1 mRNA, which encodes for a negative regulator of neural stem-cell differentiation. In addition, miR-221 and miR-222 inhibition in differentiated cells restored the expression of stem cell markers while reducing differentiation markers. Finally, miR-29a and miR-29b targeted MCL1 mRNA in GICs and increased apoptosis. Our study uncovers the microRNA dynamic expression changes occurring during differentiation of GICs, and identifies miR-21 and miR-221/222 as key regulators of this process.
- The oncolytic virus Delta-24-RGD elicits an antitumor effect in pediatric glioma and DIPG mouse models(Springer Science and Business Media LLC, 2019) Mackay, A. (Alan); Patiño-García, A. (Ana); Aldave, G. (Guillermo); Alonso-Roldán, M.M. (Marta María); El-Habr, E. (Elías); Gomez-Manzano, C. (Candelaria); Chneiweiss, H. (Hervé); Zalacain, M. (Marta); Martinez-Velez, N. (Naiara); Marigil, M. (Miguel); Raabe, E. (Eric); Aristu-Mendioroz, J.J. (José Javier); García-Barchino, M.J. (María José); Martinez-Climent, J.A. (José Ángel); Gonzalez-Huarriz, M. (Marisol); Tejada-Solis, S. (Sonia); Monje, M. (Michelle); Marrodán, L. (Lucía); Ramos, L.I. (Luis Isaac); Diez-Valle, R. (Ricardo); Garcia-Moure, M. (Marc); Junier, M.P. (Marie Pierre); Varela-Guruceaga, M. (Maider); Puigdelloses-Vallcorba, M. (Montserrat); Laspidea, V. (Virginia); Fueyo, J. (Juan); Gallego-Perez-Larraya, J. (Jaime); Becher, O.J. (Oren J.); Jiang, H. (Hong); Jones, C. (Chris)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).
- Factors associated with a higher rate of distant failure after primary treatment for glioblastoma(Springer, 2014) Aldave, G. (Guillermo); Marigil, M. (Miguel); Domínguez-Echávarri, P.D. (Pablo Daniel); Tejada-Solis, S. (Sonia); Diez-Valle, R. (Ricardo); Gallego-Perez-Larraya, J. (Jaime)Our purpose was to analyze the pattern of failure in glioblastoma (GBM) patients at first recurrence after radiotherapy and temozolomide and its relationship with different factors. From 77 consecutive GBM patients treated at our institution with fluorescence guided surgery and standard radiochemotherapy, 58 first recurrences were identified and included in a retrospective review. Clinical data including age, Karnofsky performance score, preoperative tumor volume and location, extend of resection, MGMT promoter methylation status, time to progression (PFS), overall survival (OS) and adjuvant therapies were reviewed for every patient. Recurrent tumor location respect the original lesion was the end point of the study. The recurrence pattern was local only in 65.5% of patients and non-local in 34.5%. The univariate and multivariate analysis showed that greater preoperative tumor volume in T1 gadolinium enhanced sequences, was the only variable with statistical signification (p < 0.001) for increased rate of non-local recurrences, although patients with MGMT methylation and complete resection of enhancing tumor presented non-local recurrences more frequently. PFS was longer in patients with non-local recurrences (13.8 vs. 6.4 months; p = 0.019, log-rank). However, OS was not significantly different in both groups (24.0 non-local vs. 19.3 local; p = 0.9). Rate of non-local recurrences in our series of patients treated with fluorescence guided surgery and standard radiochemotherapy was higher than previously published in GBM, especially in patients with longer PFS. Greater preoperative enhancing tumor volume was associated with increased rate of non-local recurrences.
- DNX-2401, an oncolytic virus, for the treatment of newly diagnosed diffuse intrinsic pontine gliomas: a case report(Frontiers, 2018) Patiño-García, A. (Ana); Alonso-Roldán, M.M. (Marta María); Gomez-Manzano, C. (Candelaria); Domínguez-Echávarri, P.D. (Pablo Daniel); Gonzalez-Huarriz, M. (Marisol); Tejada-Solis, S. (Sonia); Diez-Valle, R. (Ricardo); Idoate, M.A. (Miguel Ángel); Peterkin, J. (Joanna); Fueyo, J. (Juan)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.
- 3D printing in neurosurgery: A specific model for patients with craniosynostosis(Elsevier, 2017) Unamuno, X. (Xabier); Tejada-Solis, S. (Sonia); Zaratiegui-Fernández, J.I. (Javier Ignacio); Diez-Valle, R. (Ricardo); Jiménez-Ormabera, B. (Borja); Llorente-Ortega, M. (Marcos)Introduction: Craniosynostosis is a rare condition and requires a personalised surgical approach, which is why we consider the use of 3D printed models beneficial in the surgical planning of this procedure. Material and methods: Acrylonitrile butadiene styrene plastic skull models were designed and printed from CT images of patients between 3 and 6 months of age with craniosynostosis of different sutures. The models were used to simulate surgical procedures. Results: Four models of four patients with craniosynostosis were produced: two with closure of the metopic suture and two with sagittal suture closure. The mean age of the patients was 5 months (3-6m) and the mean duration of the surgery was 286min (127-380min). The acrylonitrile butadiene styrene plastic models printed for the project proved to be optimal for the simulation of craniosynostosis surgeries, both anatomically and in terms of mechanical properties and reaction to surgical instruments. Conclusions: 3D printers have a wide range of medical applications and they offer an easy and affordable way to produce skull models. The acrylonitrile butadiene styrene material is suitable for the production of operable bone models as it faithfully reproduces the mechanical characteristics of bone tissue.
- Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma(Nature Publishing Group, 2019) Berraondo, P. (Pedro); Perez-Gracia, J.L. (Jose Luis); Rodriguez-Ruiz, M.E. (María Esperanza); Lopez-Diaz-de-Cerio, A. (Ascensión); Tejada-Solis, S. (Sonia); Diez-Valle, R. (Ricardo); Goicoechea, I. (Iosune); Inoges, S. (Susana); Gurpide, A. (Alfonso); Melero, I. (Ignacio); Choi, J. (Jungmin); Porciuncula, A. (Angelo); Idoate, M.A. (Miguel Ángel); Andrea, C.E. (Carlos Eduardo) de; López-Janeiro, Á. (Álvaro); Gallego-Perez-Larraya, J. (Jaime); Villarroel-Espindola, F. (Franz); Schalper, K.A. (Kurt A.); Giraldez, M. (Miriam); Fernandez-Sanmamed, M. (Miguel)Glioblastoma is the most common primary central nervous system malignancy and has a poor prognosis. Standard first-line treatment, which includes surgery followed by adjuvant radio-chemotherapy, produces only modest benefits to survival1,2. Here, to explore the feasibility, safety and immunobiological effects of PD-1 blockade in patients undergoing surgery for glioblastoma, we conducted a single-arm phase II clinical trial (NCT02550249) in which we tested a presurgical dose of nivolumab followed by postsurgical nivolumab until disease progression or unacceptable toxicity in 30 patients (27 salvage surgeries for recurrent cases and 3 cases of primary surgery for newly diagnosed patients). Availability of tumor tissue pre- and post-nivolumab dosing and from additional patients who did not receive nivolumab allowed the evaluation of changes in the tumor immune microenvironment using multiple molecular and cellular analyses. Neoadjuvant nivolumab resulted in enhanced expression of chemokine transcripts, higher immune cell infiltration and augmented TCR clonal diversity among tumor-infiltrating T lymphocytes, supporting a local immunomodulatory effect of treatment. Although no obvious clinical benefit was substantiated following salvage surgery, two of the three patients treated with nivolumab before and after primary surgery remain alive 33 and 28 months later.