Glioblastoma Therapy: Past, Present and Future.

Glioblastoma (GB) stands out as the most prevalent and lethal form of brain cancer. Although great efforts have been made by clinicians and researchers, no significant improvement in survival has been achieved since the Stupp protocol became the standard of care (SOC) in 2005. Despite multimodality treatments, recurrence is almost universal with survival rates under 2 years after diagnosis. Here, we discuss the recent progress in our understanding of GB pathophysiology, in particular, the importance of glioma stem cells (GSCs), the tumor microenvironment conditions, and epigenetic mechanisms involved in GB growth, aggressiveness and recurrence. The discussion on therapeutic strategies first covers the SOC treatment and targeted therapies that have been shown to interfere with different signaling pathways (pRB/CDK4/RB1/P16ink4, TP53/MDM2/P14arf, PI3k/Akt-PTEN, RAS/RAF/MEK, PARP) involved in GB tumorigenesis, pathophysiology, and treatment resistance acquisition. Below, we analyze several immunotherapeutic approaches (i.e., checkpoint inhibitors, vaccines, CAR-modified NK or T cells, oncolytic virotherapy) that have been used in an attempt to enhance the immune response against GB, and thereby avoid recidivism or increase survival of GB patients. Finally, we present treatment attempts made using nanotherapies (nanometric structures having active anti-GB agents such as antibodies, chemotherapeutic/anti-angiogenic drugs or sensitizers, radionuclides, and molecules that target GB cellular receptors or open the blood-brain barrier) and non-ionizing energies (laser interstitial thermal therapy, high/low intensity focused ultrasounds, photodynamic/sonodynamic therapies and electroporation). The aim of this review is to discuss the advances and limitations of the current therapies and to present novel approaches that are under development or following clinical trials.

Neural Stem Cells as Potential Glioblastoma Cells of Origin.

Glioblastoma multiforme (GBM) is the most malignant brain tumor in adults and it remains incurable. These tumors are very heterogeneous, resistant to cytotoxic therapies, and they show high rates of invasiveness. Therefore, patients face poor prognosis, and the survival rates remain very low. Previous research states that GBM contains a cell population with stem cell characteristics called glioma stem cells (GSCs). These cells are able to self-renew and regenerate the tumor and, therefore, they are partly responsible for the observed resistance to therapies and tumor recurrence. Recent data indicate that neural stem cells (NSCs) in the subventricular zone (SVZ) are the cells of origin of GBM, that is, the cell type acquiring the initial tumorigenic mutation. The involvement of SVZ-NSCs is also associated with GBM progression and recurrence. Identifying the cellular origin of GBM is important for the development of early detection techniques and the discovery of early disease markers. In this review, we analyze the SVZ-NSC population as a potential GBM cell of origin, and its potential role for GBM therapies.

Aneurisma traumático de la arteria meníngea media en el contexto de un hematoma epidural / Traumatic aneurysm of the middle meningeal artery associated with an epidural hematoma

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Radiocirugía con acelerador lineal en el tratamiento del schwannoma vestibular / Linear accelerator radiosurgery for the treatment of vestibular schwannoma

Introducción y objetivo. Entre las opciones terapéuticas para pacientes con schwannoma vestibular se encuentra la radiocirugía. Presentamos así nuestra experiencia en el tratamiento de esta patología con esta técnica. Pacientes y métodos. Estudio retrospectivo de 20 pacientes (11 mujeres y 9 varones; edad media: 55,15 años) con diagnóstico de schwannoma vestibular, que recibieron tratamiento con radiocirugía con acelerador lineal desde abril del 2005 hasta diciembre del 2008. El tiempo de seguimiento fue de 12-42 meses, tanto clínico, con valoración de los pares craneales VII (escala de House-Brackmann) y VIII (escala de Gardner-Robertson), como radiológico (con medición del volumen tumoral). Se emplearon el test exacto de Fisher y la prueba de regresión logística para el análisis estadístico. Resultados. El 25% presentó algún empeoramiento de la audición. Cinco pacientes presentaron tumores grandes en el momento del tratamiento (iguales o mayores que 3,5 cm3), de los cuales cuatro empeoraron de cefalea, inestabilidad, mareos/vértigo, parestesias faciales y acúfenos, con una asociación estadísticamente significativa (p < 0,05) en las pruebas aplicadas. A partir del primer año del tratamiento, se observó una tendencia a la disminución del volumen tumoral, sin observarse ningún crecimiento de la lesión a medio-largo plazo, con control local del 100%. Conclusiones. La radiocirugía se ofrece como una alternativa de tratamiento para pacientes con schwannoma vestibular de tamaño adecuado, con alta seguridad terapéutica, que emplea dosis relativamente bajas de radiación, índice bajo de complicaciones y buen control del crecimiento tumoral a medio plazo (AU)

Introduction and aim. Radiosurgery is among the treatment options for patients with vestibular schwannoma. We present the experience in our institution in the treatment of this disease with this technique. Patients and methods. A retrospective study was made including 20 patients (11 women and 9 men; median age: 55.15 years-old) with vestibular schwannoma who received linear accelerator radiosurgery treatment since April 2005 until December 2008. Follow-up period was between 12 and 42 months, considering clinical examination of cranial nerves VII (House-Brackmann scale) and VIII (Gardner-Robertson scale) as well as radiological findings (considering tumor volume). For statistical analysis, the Fisher’s exact test and logistic regression test were used. Results. Certain worsening of hearing function was present in 25% of the patients. Five patients had large tumors at the moment of the treatment (equal or larger than 3.5 cm3), from which four deteriorated from headache, unsteady gait, dizziness/vertigo, facial numbness and tinnitus, with statistical significance (p < 0.05). From the first year of treatment on, there was a tumor volume decrease tendency, with no tumor growth in the medium/long term follow-up, achieving a local control rate of 100%. Conclusions. Radiosurgery has become an alternative in the treatment of patients with vestibular schwannoma of appropriate size, with high safety level, using low radiation doses, low rate of complications and good tumor control rate in the medium term follow-up (AU)

[Neonatal intracranial haemorrhage secondary to spontaneous rupture of an aneurysm. Illustrative case and literature review]. / Hemorragia intracraneal en el neonato secundaria a rotura aneurismatica espontanea. Caso ilustrativo y revision de la bibliografia.

INTRODUCTION: Intracranial arterial aneurysms are little frequent among the pediatric age group but the frequency is still lower in children under 1 year of age and extremely rare in neonates. We present a case, review literature and propose common characteristics and management of this pathology. CASE REPORT: A term newborn suffered reduction of the level of conscience. After brain ultrasound examination and CT scan was diagnosed with intraparenchymatous hematoma on the 7th day of life. Intraoperative, after evacuation of this hematoma, we discovered, clipped and extirpated a middle cerebral artery aneurysm without any problems. The patient's evolution was satisfactory only presenting a slight paresia of his right arm. CONCLUSION: We review the literature and find 16 cases of neonatal intracranial arterial aneurysms. Mortality rate is about 50%, but keeping in mind better survivals with surgical treatment in the last years. Thus we conclude, when it is possible, in favour of a surgical and precocious treatment of these neonatal aneurysm.

Hemorragia intracraneal en el neonato secundaria a rotura aneurismática espontánea. Caso ilustrativo y revisión de la bibliografía / Neonatal intracranial haemorrhage secondary to spontaneous rupture of an aneurysm. Illustrative case and literature review

Introducción. Los aneurismas intracraneales arteriales son raros en la edad pediátrica, pero mucho más en menores de 1 año, y más extraños aún en neonatos. Presentamos un caso, revisamos la bibliografía y proponemos características comunes, así como recomendaciones terapéuticas. Caso clínico. Recién nacido a término que sufre deterioro del nivel de conciencia y que tras ecografía y tomografía computarizada cerebrales es diagnosticado de hematoma intraparenquimatoso espontáneo al séptimo día de vida. Tras la evacuación del hematoma, intraoperatoriamente se detecta aneurisma de la arteria cerebral media, que se clipa y extirpa sin problemas. El paciente evoluciona de forma favorable, permaneciendo como única secuela a los tres años de seguimiento una ligera paresia en el brazo. Conclusión. Tras revisar la bibliografía, encontramos 16 casos claros de aneurismas neonatales. La mortalidad global es cercana al 50%, pero hay que tener en cuenta que se observan supervivencias mucho mayores tras tratamiento quirúrgico en los últimos años. Por eso concluimos, cuando es posible, a favor de un tratamiento quirúrgico precoz de estas lesiones (AU)

Introduction. Intracranial arterial aneurysms are little frequent among the pediatric age group but the frequency is still ower in children under 1 year of age and extremely rare in neonates. We present a case, review literature and propose common characteristics and management of this pathology. Case report. A term newborn suffered reduction of the level of conscience. After brain ultrasound examination and CT scan was diagnosed with intraparenchymatous hematoma on the 7th day of life. Intraoperative, after evacuation of this hematoma, we discovered, clipped and extirpated a middle cerebral artery aneurysm without any problems. The patient’s evolution was satisfactory only presenting a slight paresia of his right arm. Conclusion. We review the literature and find 16 cases of neonatal intracranial arterial aneurysms. Mortality rate is about 50%, but keeping in mind better survivals with surgical treatment in the last years. Thus we conclude, when it is possible, in favour of a surgical and precocious treatment of these neonatal aneurysm (AU)