Gallego-Perez-Larraya, J. (Jaime)
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- Síndrome CLIPPERS. A propósito de un caso(Elsevier, 2020) Esparragosa-Vázquez, I. (I.); Gallego-Perez-Larraya, J. (Jaime); Valentí-Azcarate, R. (Rafael); Riverol-Fernández, M. (M.)Presentamos el caso de un varón de 44 años, con antecedentes personales de linfohistiocitosis hemofagocítica primaria (portador homocigótico de mutación Ala91Val), resuelta tras esplenectomía. Presenta un cuadro de inicio brusco y curso progresivo, de 2 meses de evolución, de sensación de adormecimiento y hormigueo en ambas plantas de los pies, rigidez en las piernas que se desencadena con la actividad física y sensación de inestabilidad. Además, desde hace 48 h, asocia adormecimiento y hormigueo de ambas palmas. Niega antecedentes epidemiológicos de interés.
- 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.
- Oncolytic virotherapy for the treatment of pediatric brainstem gliomas(Elsevier, 2023) Alonso, M.M. (Marta M.); Garcia-Moure, M. (Marc); Gallego-Perez-Larraya, J. (Jaime)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.
- Clasificación de los trastornos del sueño(Gobierno de Navarra. Departamento de Salud, 2007) Iriarte, J. (Jorge); Urrestarazu, E. (Elena); Gallego-Perez-Larraya, J. (Jaime); Toledo, J.B. (J.B.)Sleep disorders are frequent processes, both as a symptom associated with other diseases and as independent disorders. However, only in the last 4 decades has Sleep medicine gained its position among the medical specialties. In fact, it was only in these years that significant advances were obtained in the study of the etiology and treatment of these disorders. Similarly, the different classifications have been evolving over the years. First, they were based upon the clinical symptom; later on, more emphasis was given to the diseases. Finally, in 2005, the new classification was once again based on the symptoms. More than 90 disorders are listed in this latest classification, and an attempt is made to include the symptoms and the diseases of sleep, as well as those in which sleep disorders are fundamental. It is essential to have a clear idea of this complete classification of sleep disorders in order to deal with these patients appropriately.
- Facial diplegia and vestibular neuritis secondary to HIV seroconversion syndrome(Canadian Journal of Neurological Sciences, 2009) Gallego-Perez-Larraya, J. (Jaime); Riverol, M. (Mario)
- Agrypnia Excitata and Supranuclear Vertical Gaze Palsy Linked to Anti-Ma Encephalitis(Wiley Periodicals LLC, 2024) Arbizu, J. (Javier); Espinoza-Vinces, C. (Christian); Horrillo-Maysonnial, A. (Alejandro); Aviles-Olmos, I. (Iciar); Calvo-Imirizaldu, M. (Marta); Pérez-Álvarez, A.I (Ángel Ignacio); Urrestarazu, E. (Elena); Gallego-Perez-Larraya, J. (Jaime)Paraneoplastic neurological syndromes result from cancer’s immune impact on the nervous system.1 Anti-Ma-associated encephalitis causes diencephalic, brainstem, and limbic symptoms such as memory loss, narcolepsy and rapid eye movement (REM) behavior disorder (RBD), eye movement abnormalities, and parkinsonism. It can precede cancer diagnosis, often linked to testicular tumors. Agrypnia excitata (AE) is a unique electroclinical syndrome that can disrupt sleep structure with changes in physiological cyclic organization, autonomic overactivity, and oneiric stupor episodes. We report on a patient with anti-Ma encephalitis who exhibits a diencephalic syndrome and AE, not previously reported to our knowledge.
- 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.
- 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).
- The influence of obesity on the assessment of carotid intima-media thickness(Wiley-Blackwell, 2012) Irimia, P. (Pablo); Diez-Martinez, J. (Javier); Viñes, J.J. (José Javier); Barba, J. (Joaquín); Guembe, M.J. (María Jesús); Martinez-Vila, E. (Eduardo); Gallego-Perez-Larraya, J. (Jaime); Castellano, J.M. (José María); Varo-Cenarruzabeitia, M.N. (Miren Nerea)BACKGROUND.: The assessment of carotid intima-media thickness (CIMT) may improve cardiovascular risk prediction. The optimal protocol for CIMT measurement is unclear. CIMT may be measured in the common carotid artery (CCA), carotid bifurcation (CB), and internal carotid artery (ICA), but measurements from CB and ICA are more difficult to obtain. We studied the influence of body mass index (BMI) and atheroma plaques on the capacity to obtain CIMT measurements at different carotid sites. METHODS.: Using an automatic system, CIMT was measured in 700 subjects aged 45-75, in the near and far walls of CCA, CB, and ICA bilaterally. The presence of atheroma plaques, BMI and vascular risk factors were recorded. RESULTS.: CIMT measurements in CCA were possible in all except one subject. It was not possible to obtain CIMT measurements at CB or ICA in 24.1% of normal weight and 58.8% of obese subjects. The likelihood of obtaining CIMT measurement at all carotid sites decreased as the BMI increased. Atheroma plaques in a carotid segment did not preclude CIMT measurement at this site. CONCLUSIONS.: CIMT measurements in distal carotid segments are more challenging in obese subjects. Measuring CIMT at CCA remains feasible in obese subjects and should be the primary endpoint in these subjects. Nevertheless, CB and ICA measurements, when feasible, would improve risk classification.
- 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).