High SOX9 Maintains Glioma Stem Cell Activity through a Regulatory Loop Involving STAT3 and PML.

Glioma stem cells (GSCs) are critical targets for glioma therapy. SOX9 is a transcription factor with critical roles during neurodevelopment, particularly within neural stem cells. Previous studies showed that high levels of SOX9 are associated with poor glioma patient survival. SOX9 knockdown impairs GSCs proliferation, confirming its potential as a target for glioma therapy. In this study, we characterized the function of SOX9 directly in patient-derived glioma stem cells. Notably, transcriptome analysis of GSCs with SOX9 knockdown revealed STAT3 and PML as downstream targets. Functional studies demonstrated that SOX9, STAT3, and PML form a regulatory loop that is key for GSC activity and self-renewal. Analysis of glioma clinical biopsies confirmed a positive correlation between SOX9/STAT3/PML and poor patient survival among the cases with the highest SOX9 expression levels. Importantly, direct STAT3 or PML inhibitors reduced the expression of SOX9, STAT3, and PML proteins, which significantly reduced GSCs tumorigenicity. In summary, our study reveals a novel role for SOX9 upstream of STAT3, as a GSC pathway regulator, and presents pharmacological inhibitors of the signaling cascade.

Semisitting position for cerebello-pontine angle surgery: Analysis of complications and how to avoid it.

OBJECTIVE: To analyze the primary complications related to semisitting position in patients undergoing cerebelo-pontine angle surgery. METHODS: Retrospective data analysis from patients undergoing elective tumoral cerebelo-pontine angle surgery in a semisitting position. The incidence, severity, occurrence moment, treatment, duration, and outcomes of venous air embolism (VAE), pneumocephalus, postural hypotension, and other complications were recorded. Neurointensive care unit (NICU), length of stay (LOS), hospital LOS, and modified Rankin scale scores were calculated six months after surgery. RESULTS: Fifty patients were operated on. Eleven (22%) presented VAE (mean duration 8±4.5min): five (10%) during tumor resection, and four (8%) during dural opening. Ten (20%) were resolved by covering the surgical bed, air bubbles aspiration, jugular compression, and one (2%) tilted to a steep Trendelenburg position. One (2%) had intraoperative hemodynamic instability. The only variable associated with VAE was meningioma at histopathology OR=4.58, p=0.001. NICU was higher in patients with VAE (5.5±1.06 vs. 1.9±0.20 days, p=0.01). There were no differences in the Rankin scale. All patients presented postoperative pneumocephalus with a good level of consciousness, except one (2%) who required evacuation. Seven patients (14%) showed postural hypotension, three (6%) after positioning, and one (2%) after developing a VAE; all were reversed with usual vasoactive drugs. No other position-related complications or mortality were registered in this series. CONCLUSIONS: The semisitting position is a safe option with the knowledge, prevention, detection, and early solution of all the possible complications. The development of VAE rarely implies hemodynamic instability or greater disability after surgery. Postoperative pneumocephalus is very common and rarely requires evacuation. Excellent cooperation between anesthesia, nursing, neurophysiology, and neurosurgery teams is essential to manage complications.

Chaperone-Mediated Autophagy Controls Proteomic and Transcriptomic Pathways to Maintain Glioma Stem Cell Activity.

Chaperone-mediated autophagy (CMA) is a homeostatic process essential for the lysosomal degradation of a selected subset of the proteome. CMA activity directly depends on the levels of LAMP2A, a critical receptor for CMA substrate proteins at the lysosomal membrane. In glioblastoma (GBM), the most common and aggressive brain cancer in adulthood, high levels of LAMP2A in the tumor and tumor-associated pericytes have been linked to temozolomide resistance and tumor progression. However, the role of LAMP2A, and hence CMA, in any cancer stem cell type or in glioblastoma stem cells (GSC) remains unknown. In this work, we show that LAMP2A expression is enriched in patient-derived GSCs, and its depletion diminishes GSC-mediated tumorigenic activities. Conversely, overexpression of LAMP2A facilitates the acquisition of GSC properties. Proteomic and transcriptomic analysis of LAMP2A-depleted GSCs revealed reduced extracellular matrix interaction effectors in both analyses. Moreover, pathways related to mitochondrial metabolism and the immune system were differentially deregulated at the proteome level. Furthermore, clinical samples of GBM tissue presented overexpression of LAMP2, which correlated with advanced glioma grade and poor overall survival. In conclusion, we identified a novel role of CMA in directly regulating GSCs activity via multiple pathways at the proteome and transcriptome levels. SIGNIFICANCE: A receptor of chaperone-mediated autophagy regulates glioblastoma stem cells and may serve as a potential biomarker for advanced tumor grade and poor survival in this disease.

Atypical facial pain after cranioplasty: A too perfect design?: Dolor facial atípico asociado a craneoplastia: ¿un encaje demasiado perfecto?

Cranioplasty is a procedure routinely performed in neurosurgery. It is associated with significant morbidity and several types of postsurgical complications. The most common are infections, bone flap resorption and hematomas. Atypical facial pain has not been documented yet as a potential postoperative complication. We present a case of atypical facial pain reported at inmediate postoperative period after cranioplasty. The pain was refractory to medical treatment and sphenopalatine ganglion block. Eventually, the pain totally disappeared after surgical revision of the cranial implant.

CRISPR/Cas9 Deletion of SOX2 Regulatory Region 2 (SRR2) Decreases SOX2 Malignant Activity in Glioblastoma.

SOX2 is a transcription factor associated with stem cell activity in several tissues. In cancer, SOX2 expression is increased in samples from several malignancies, including glioblastoma, and high SOX2 levels are associated with the population of tumor-initiating cells and with poor patient outcome. Therefore, understanding how SOX2 is regulated in cancer cells is relevant to tackle tumorigenesis. The SOX2 regulatory region 2(SRR2) is located downstream of the SOX2 coding region and mediates SOX2 expression in embryonic and adult stem cells. In this study, we deleted SRR2 using CRISPR/Cas9 in glioblastoma cells. Importantly, SRR2-deleted glioblastoma cells presented reduced SOX2 expression and decreased proliferative activity and self-renewal capacity in vitro. In line with these results, SRR2-deleted glioblastoma cells displayed decreased tumor initiation and growth in vivo. These effects correlated with an elevation of p21CIP1 cell cycle and p27KIP1 quiescence regulators. In conclusion, our data reveal that SRR2 deletion halts malignant activity of SOX2 and confirms that the SRR2 enhancer regulates SOX2 expression in cancer.

Methylation of MGMT promoter does not predict response to temozolomide in patients with glioblastoma in Donostia Hospital.

O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status has been considered a prognostic factor in newly diagnosed glioblastoma (GBM). In this study, we evaluated the prognostic and predictive value of MGMT promoter methylation in patients with glioblastoma in Donostia Hospital. Surprisingly, methylation of MGMT promoter did not predict response to temozolomide in patients with glioblastoma in Donostia Hospital. Specifically, overall survival (OS) and progression-free survival (PFS) did not differ significantly by MGMT methylation status in our cohort. In contrast, both were longer in patients who received treatment, received more TMZ cycles, had a better general status and perform at least a partial resection. No association was detected between methylation of MGMT promoter and molecular markers such as ATRX, IDH, p53 and Ki67. These results indicate that MGMT methylation did not influence in patient survival in our cohort.

Primary vertebral tumor of axis: A clinical and surgical challenge. / Tumor vertebral primario de axis: un desafío clínico y quirúrgico.

We report the case of a 17-year-old male presented to the emergency department with a six weeks history of neck pain and no neurogical deficit. Computed tomography and magnetic resonance imaging revealed an expansile lesion in the axis, with soft tissue and spinal cavity invasion, without mielopathy signs. Tomography-guided mass biopsy was taken. Waiting for histopathologic results, the pacient developed acute tetraparesis and sphincter incompetence. Magnetic resonance revealed that the bone mass had grown with epidural compromise, mielopathy and new vertebral lesions. Medular decompression with laminectomy, excision of the posterior elements of axis with the involved soft tissue mass and occipito-cervical fixation was performed. Neurological recovery was complete. Inmunochemistry revealed an Ewing Sarcoma. Chemoteraphy treatment was given, with partial response. Primary Ewing sarcoma of atlas-axis is a rare entity with poor prognosis. Multidisciplinary approach treatment is needed, with a total surgical resection if it is possible, a real challenge for the surgeon.

Posición semisentada en cirugía del ángulo pontocerebeloso: análisis de sus complicaciones y cómo evitarlas / Semisitting position for cerebello-pontine angle surgery: Analysis of complications and how to avoid it

Objetivo: Analizar las complicaciones asociadas a la posición semisentada en pacientes intervenidos de patología del ángulo pontocerebeloso (APC).MétodosEstudio retrospectivo, se analizaron los pacientes operados de patología tumoral del APC por un abordaje retrosigmoideo en posición semisentada. Se analizó la incidencia, gravedad, momento de aparición, forma de resolución, duración y repercusiones del embolismo aéreo venoso (EAV), neumoencéfalo, hipotensión postural y otras complicaciones. Se analizó el tiempo de estancia en unidad de críticos (TUCRI), tiempo de estancia hospitalaria (TEH) y puntuación en escala de Rankin a los seis meses.ResultadosSe intervinieron 50 pacientes, once (22%) presentaron EAV (8 ± 4,5 minutos duración media): cinco (10%) durante la resección tumoral, cuatro (8%) durante la apertura dural. Diez (20%) se resolvieron tapando el lecho quirúrgico, aspirando burbujas y aplicando compresión de yugulares, uno (2%) requirió cambio de posición. Uno (2%) tuvo repercusión hemodinámica intraoperatoria. La única variable asociada con desarrollar EAV fue una anatomía patológica de meningioma OR = 4,58, p = 0,001. El TUCRI fue superior en pacientes con EAV (5,5 ± 1,06 vs. 1,9 ± 0,20 días, p = 0,01). No hubo diferencias en la escala Rankin. Todos presentaron neumoencéfalo posquirúrgico con buen nivel de consciencia, salvo uno (2%) que requirió de evacuación. Siete pacientes (14%) presentaron una hipotensión arterial, tres (6%) tras la colocación y uno (2%) tras un EAV, todos revertieron con vasoactivos. No se registraron otras complicaciones asociadas a la posición ni mortalidad en esta serie. (AU)

Objective: To analyze the primary complications related to semisitting position in patients undergoing cerebelo-pontine angle surgery.MethodsRetrospective data analysis from patients undergoing elective tumoral cerebelo-pontine angle surgery in a semisitting position. The incidence, severity, occurrence moment, treatment, duration, and outcomes of venous air embolism (VAE), pneumocephalus, postural hypotension, and other complications were recorded. Neurointensive care unit (NICU), length of stay (LOS), hospital LOS, and modified Rankin scale scores were calculated six months after surgery.ResultsFifty patients were operated on. Eleven (22%) presented VAE (mean duration 8 ± 4.5 min): five (10%) during tumor resection, and four (8%) during dural opening. Ten (20%) were resolved by covering the surgical bed, air bubbles aspiration, jugular compression, and one (2%) tilted to a steep Trendelenburg position. One (2%) had intraoperative hemodynamic instability. The only variable associated with VAE was meningioma at histopathology OR = 4.58, P = 0.001. NICU was higher in patients with VAE (5.5 ± 1.06 vs. 1.9 ± 0.20 days, P = 0.01). There were no differences in the Rankin scale. All patients presented postoperative pneumocephalus with a good level of consciousness, except one (2%) who required evacuation. Seven patients (14%) showed postural hypotension, three (6%) after positioning, and one (2%) after developing a VAE; all were reversed with usual vasoactive drugs. No other position-related complications or mortality were registered in this series. (AU)

Dolor facial atípico asociado a craneoplastia: ¿un encaje demasiado perfecto? / Atypical facial pain after cranioplasty: A too perfect design?

La craneoplastia es un procedimiento habitual en la práctica neuroquirúrgica. Está asociada a una considerable morbilidad y a varios tipos de complicaciones posquirúrgicas, especialmente infecciones, reabsorción ósea y hematomas. La aparición de dolor facial neuropático no ha sido descrita como complicación posquirúrgica. Presentamos un caso de una paciente que, en el postoperatorio inmediato de una craneoplastia, desarrolló un dolor facial atípico resistente a tratamiento médico y al bloqueo del ganglio esfenopalatino. Finalmente, desapareció tras una revisión quirúrgica de la plastia (AU)

Cranioplasty is a procedure routinely performed in neurosurgery. It is associated with significant morbidity and several types of postsurgical complications. The most common are infections, bone flap resorption and hematomas. Atypical facial pain has not been documented yet as a potential postoperative complication. We present a case of atypical facial pain reported at immediate postoperative period after cranioplasty. The pain was refractory to medical treatment and sphenopalatine ganglion block. Eventually, the pain totally disappeared after surgical revision of the cranial implant (AU)

Tumor vertebral primario de axis: un desafío clínico y quirúrgico / Primary vertebral tumor of axis: A clinical and surgical challenge

Presentamos el caso de un varón de 17 años que acude a urgencias por cervicalgia de 6 semanas de evolución, sin déficit neurológico. La tomografía y resonancia magnética mostraban una masa dependiente de C2 con infiltración de partes blandas e invasión del canal medular, sin signos de mielopatía. Se realizó biopsia guiada con tomografía. Esperando al resultado, el paciente desarrolló una tetraparesia aguda con incompetencia de esfínteres. Una nueva resonancia magnética mostró un aumento de la masa ósea tumoral con extensión epidural, mielopatía y nuevas lesiones vertebrales. Se realizó una resección posterior y descompresión medular de urgencia, con fijación occipito-cervical. La recuperación postoperatoria fue completa. La inmunohistoquímica reveló un sarcoma de Ewing. Se inició quimioterapia con respuesta parcial. El sarcoma de Ewing primario atlantoaxial es una entidad excepcional con mal pronóstico. Su tratamiento es multidisciplinar, incluyendo una resección total si es posible, lo cual supone un reto para el cirujano (AU)

We report the case of a 17-year-old male presented to the emergency department with a six weeks history of neck pain and no neurogical deficit. Computed tomography and magnetic resonance imaging revealed an expansile lesion in the axis, with soft tissue and spinal cavity invasion, without mielopathy signs. Tomography-guided mass biopsy was taken. Waiting for histopathologic results, the pacient developed acute tetraparesis and sphincter incompetence. Magnetic resonance revealed that the bone mass had grown with epidural compromise, mielopathy and new vertebral lesions. Medular decompression with laminectomy, excision of the posterior elements of axis with the involved soft tissue mass and occipito-cervical fixation was performed. Neurological recovery was complete. Inmunochemistry revealed an Ewing Sarcoma. Chemoteraphy treatment was given, with partial response. Primary Ewing sarcoma of atlas-axis is a rare entity with poor prognosis. Multidisciplinary approach treatment is needed, with a total surgical resection if it is possible, a real challenge for the surgeon (AU)