Ependimomas de fosa posterior de tipo lateral en la edad pediátrica / Lateral-type posterior fossa ependymomas in pediatric population

Antecedentes y objetivos: Los ependimomas de fosa posterior de tipo lateral son un subtipo clínico e histológico característico, con un pronóstico poco favorable. Su incidencia es baja y su manejo quirúrgico es particularmente complejo. El objetivo del presente trabajo es revisar nuestra serie de ependimomas de fosa posterior de tipo lateral y contrastar nuestros resultados con la literatura disponible. Materiales y métodos: Sobre una muestra de 30 ependimomas intervenidos en neurocirugía pediátrica en los últimos 10 años, se identifican 7 casos de ependimomas de tipo lateral de la fosa posterior. Sobre esta serie de casos se realiza un estudio descriptivo retrospectivo. Resultados: La edad media de nuestros pacientes al diagnóstico fue de 3,75 años. Seis se presentaron con hidrocefalia. El volumen tumoral medio al diagnóstico fue de 61cm3. En 6 casos se llevó a cabo una resección completa y en un caso una resección casi completa. Cinco pacientes precisaron de forma transitoria una traqueostomía y una gastrostomía. La media de seguimiento fue de 58 meses. Durante este tiempo se produjo un caso de recidiva que posteriormente evolucionó a muerte. Cuatro casos de hidrocefalia posquirúrgica precisaron una derivación ventriculoperitoneal de LCR y 2 casos fueron manejados con ventriculostomía endoscópica. En la última revisión en consulta 4 pacientes llevaban una vida normal y 2 mostraban una restricción leve de la actividad de acuerdo con la escala de Lansky. Conclusiones: El objetivo del tratamiento quirúrgico de los ependimomas de tipo lateral de fosa posterior es la resección completa. Los déficits asociados a la disfunción de los pares bajos en nuestra serie fueron muy frecuentes pero transitorios. La progresiva caracterización molecular de estos tumores puede identificar diferentes grupos de riesgo sobre los que dirigir de forma adecuada la intensidad de los tratamientos adyuvantes.(AU)

Background and aims: Lateral-type posterior fossa ependymomas are a well-defined subtype of tumors both clinically and pathologically, with a poor prognosis. Their incidence is low and surgical management is challenging. The objective of the present work is to review our series of lateral-tye posterior fossa ependymomas and compare our results with those of previous series. Materials and methods: Among 30 cases of ependymoma operated in our pediatric department in the last 10 years, we identified seven cases of lateral-type posterior fossa ependymomas. We then performed a retrospective, descriptive study. Results: Mean age of our patients was 3.75 years. Six cases presented with hydrocephalus. Mean tumor volume at diagnosis was 61cc. A complete resection was achieved in six cases and a near-total resection in one patient. Five patients transiently required a gastrostomy and a tracheostomy. Mean follow-up was 58 months. One case progressed along this period and eventually died. Four cases of hydrocephalus required a ventriculoperitoneal CSF shunt and two were managed with a third ventriculostomy. At last follow-up four patients carried a normal life and two displayed a mild restriction according to Lansky's scale. Conclusions: The aim of surgical treatment in lateral-type posterior fossa ependymomas is complete resection. Neurological deficits associated to lower cranial nerve dysfunction are common but transient. Deeper genetic characterization of these tumors may identify risk factors that guide stratification of adjuvant therapies.(AU)

Effect of doramectin on programmed cell death pathway in glioma cells

Purpose Doramectin (DRM) is a kind of avermectin drugs, and it has been shown that DRM has anti-cancer effects. However, the molecular mechanism of DRM in programmed cell death (PCD) aspects is still unclear. The objective of this study was to confirm whether DRM induced PCD in glioma cells. Methods In this experiment, the MTT assay and Ki-67 assay were used to detect in vitro cell viability and in vivo tumor proliferation. Then, the effect of DRM on PCD was analyzed by transcriptome comparison. Next, Endogenous apoptosis was detected by transmission electron microscopy (TEM), the DNA gel electrophoresis, JC-1 assay, western blotting and qRT-PCR. Meanwhile, necroptosis was detected by TEM, Hoechst 33342, FITC and PI staining assay, western blotting. Results We found DRM induced apoptosis through Bcl-2/Bax/Caspase-3 pathway. And, DRM induced ROS overproduction, then ROS caused necroptosis through RIPK1/RIPK3/MLKL pathway, Mitochondria acted as a bridge between the two pathways. Conclusion Our research provided new insight with the function of anti-cancer of DRM. These results demonstrated DRM may be used as potential therapeutic agents inducing apoptosis and necroptosis for cancer therapy (AU)

SEOM-GEINO clinical guidelines for high-grade gliomas of adulthood (2022)

High-grade gliomas (HGG) are the most common primary brain malignancies and account for more than half of all malignant primary brain tumors. The new 2021 WHO classification divides adult HGG into four subtypes: grade 3 oligodendroglioma (1p/19 codeleted, IDH-mutant); grade 3 IDH-mutant astrocytoma; grade 4 IDH-mutant astrocytoma, and grade 4 IDH wild-type glioblastoma (GB). Radiotherapy (RT) and chemotherapy (CTX) are the current standard of care for patients with newly diagnosed HGG. Several clinically relevant molecular markers that assist in diagnosis and prognosis have recently been identified. The treatment for recurrent high-grade gliomas is not well defined and decision-making is usually based on prior strategies, as well as several clinical and radiological factors. Whereas the prognosis for GB is grim (5-year survival rate of 5–10%) outcomes for the other high-grade gliomas are typically better, depending on the molecular features of the tumor. The presence of neurological deficits and seizures can significantly impact quality of life (AU)

Hemorrhagic presentation of previously silent brain tumors / Presentación hemorrágica de tumores cerebrales anteriormente silenciosos

Introduction and objectives Acute presentation with intracranial hemorrhage owing to a previously silent brain tumor (BT) is rare. Although any BT can bleed, the frequency and type of bleeding varies across tumor types. Materials and methods We aimed to retrospectively review our experience with 55 patients with BTs presenting with ICH. Results Signs of increased intracranial pressure were the most common symptoms. The temporal lobe was the most common lesion site (n=22). Hemorrhages were mainly confined to the tumor margins (HCTs) (n=34). Extensive intraparenchymal hemorrhages (EIHs) were mainly associated with moderately/severely decreased levels of consciousness (LOCs) (n=15/16). High-grade glioma (HGGT) (n=25) was the leading pathological diagnosis followed by metastasis (MBT) (n=16/55). The hemorrhage type was associated with the pathological diagnosis of the tumor. Patients with HGGT (n=19/25) and MBT (n=9/16) mainly presented with HCTs, whereas low-grade gliomas (LGGT) primarily caused EIHs (n=6/7). Conclusions Hemorrhagic presentation is a rare occurrence in BTs. Among all, MBT and HGGT are responsible for majority of the cases. Importantly, despite their relatively benign characteristics, LGGTs mainly result in extensive parenchymal destruction once they bleed. Maximum surgical resection of hemorrhagic BTs and decompression of the affected brain regions followed by histological confirmation of the diagnosis should be the main goals of treatment in cases with hemorrhagic BTs (AU)

Introducción y objetivos La presentación aguda con hemorragia intracraneal debida a un tumor cerebral (BT) anteriormente silencioso es rara. A pesar de que cualquier BT puede sangrar, la frecuencia y el tipo de sangrado varían según el tipo de tumor. Materiales y métodos Nuestro objetivo fue reexaminar retrospectivamente nuestra experiencia con 55 pacientes con los BT que presentaban HIC. Resultados Los síntomas más comunes fueron signos de aumento de la presión intracraneal. El lóbulo temporal fue el sitio de lesión más común (n=22). Las hemorragias se limitaron especialmente a los márgenes tumorales (HCT) (n=34). Las hemorragias intraparenquimatosas extensas (HIE) se asociaron mayormente con niveles de conciencia moderada/severamente disminuidos (LOC) (n=15/16). El glioma de alto grado (HGGT) (n=25) fue el principal diagnóstico patológico después de la metástasis (MBT) (n=16/55). El tipo de hemorragia se asoció con el diagnóstico patológico del tumor. Los pacientes con HGGT (n=19/25) y MBT (n=9/16) presentaron mayormente con HCT, mientras que los gliomas de bajo grado (LGGT) causaron principalmente HIE (n=6/7). Conclusiones La presentación hemorrágica es una ocurrencia rara en los BT. Entre todos, MBT y HGGT son responsables de la mayoría de los casos. Más importante aún, pese a sus características relativamente benignas, los LGGT resultan mayormente una destrucción extensa del parénquima una vez que sangran. La resección quirúrgica máxima de BT hemorrágicos y la descompresión de las regiones cerebrales afectadas con la confirmación histológica del diagnóstico deben ser los objetivos principales del tratamiento en casos con BT hemorrágicos (AU)

The prognostic value of DAAM2 in lower grade glioma, liver cancer, and breast cancer

Purpose Dishevelled-associated activator of morphogenesis 2 (DAAM2) is a formin protein and has a potential role in the tumor metastasis. The prognostic value of DAAM2 in pan-cancer is investigated in this study. Methods TCGA and GTEx database were downloaded to perform bioinformatics analysis and ROC curves. Then we explored protein–protein interaction and GO-KEGG enrichment to figure out the protein pathways associated with DAAM2 and studied DAAM2-related immune infiltration and methylation. Fifteen pairs of BRCA clinical samples were enrolled to determine the expression and distribution of DAAM2 in BRCA sections by immunohistochemistry. Finally, BRCA cells were transfected with siRNA targeting DAAM2 and subsequently subject to cell proliferation, migration, and invasion assays. Results DAAM2 was closely related to the diagnosis and clinical characteristics of lower grade glioma (LGG), liver hepatocellular carcinoma (LIHC), and breast cancer (BRCA). Survival curve analysis demonstrated DAAM2 served as a potential prognostic indicator of LGG and LIHC (P = 0.0029 and P = 0.025, respectively). DAAM2 was mainly participated in signaling pathways mediating cytoskeleton regulation and tumor development. The correlation of DAAM2 with tumor-infiltrating immune cells (TIICs) and methylation levels was conducive to the prediction of novel biomarkers of pan-carcinoma. DAAM2 was highly expressed in BRCA tissues than that in paracancerous tissues. The proliferation, invasion, and migration of BRCA cells were inhibited by DAAM2 siRNA. Conclusion DAAM2 had a specific value in foretelling the prognosis of LGG, LIHC, and BRCA. High expression level of DAAM2 has longer survival rates in LGG and LIHC. The knockdown of DAAM2 retards the proliferation, invasion, and migration of BRCA cells. This study provides a novel sight of DAAM2 into the exploration of a potential biomarker in pan-cancer (AU)

Consenso sobre guías de tratamiento de gliomas de bajo grado elaborado por el grupo de tumores de la SENEC / Low grade gliomas guide-lines elaborated by the tumor section of Spanish Society of Neurosurgery

Los gliomas de bajo grado (Low Grade Gliomas, LGG) del adulto son tumores que se originan a partir de las células gliales del cerebro y cuyo manejo implica gran controversia a día de hoy, comenzando desde el diagnóstico, hasta el tratamiento y seguimiento posterior de estos pacientes. Es por ello que el grupo de tumores de la Sociedad Española de Neurocirugía (GT-SENEC) ha llevado a cabo una reunión de consenso, en la que se han debatido las cuestiones neuroquirúrgicas más relevantes, llegando a recomendaciones basadas en la mejor evidencia científica. Con el fin de obtener el máximo beneficio a estos tratamientos se debe hacer una valoración individualizada de cada paciente por un equipo multidisciplinar, constituido por aquellas especialidades involucradas tanto en el diagnóstico como en el tratamiento. El objetivo de este trabajo es elaborar unas recomendaciones de tratamiento para los pacientes con LGG, para lo cual un experto en cada campo ha descrito lo más relevante de dicha área basado tanto en su experiencia como en la literatura. Se han desarrollado los apartados más relevantes en el manejo de los LGG basados en la mejor evidencia publicada. A pesar de que existe controversia en algunos aspectos del manejo de los LGG, cada vez hay más datos para poder hacer recomendaciones de tratamiento consensuadas. El neurocirujano debe conocer las distintas opciones de tratamientos, sus indicaciones y riesgos para poder participar activamente en la toma de decisiones y poder ofrecer un tratamiento neuroquirúrgico oportuno a cada situación (AU)

Adult low-grade gliomas (Low Grade Gliomas, LGG) are tumors that originate from the glial cells of the brain and whose management involves great controversy, starting from the diagnosis, to the treatment and subsequent follow-up. For this reason, the Tumor Group of the Spanish Society of Neurosurgery (GT-SENEC) has held a consensus meeting, in which the most relevant neurosurgical issues have been discussed, reaching recommendations based on the best scientific evidence. In order to obtain the maximum benefit from these treatments, an individualized assessment of each patient should be made by a multidisciplinary team. Experts in each LGG treatment field have briefly described it based in their experience and the reviewed of the literature. Each area has been summarized and focused on the best published evidence. LGG have been surrounded by treatment controversy, although during the last years more accurate data has been published in order to reach treatment consensus. Neurosurgeons must know treatment options, indications and risks to participate actively in the decision making and to offer the best surgical treatment in every case (AU)

C-Fos-activated circRPPH1 contributes to glioma stemness

Objective Cancer stem cells or cancer stemness has been confirmed to a major obstacle for glioma progression and it has also been reported that circRNAs play an important part in cancer progression. This study mainly focuses on revealing the role of circRPPH1 and the underlying mechanisms in glioma cell stemness. Methods In vitro experiment including RT-qPCR, Western blot, sphere-formation analysis, and ALDH1 activity, and in vivo tumorigenesis experiments were performed to evaluate the effects of circRPPH1 on glioma cell stemness. Luciferase reporter, ChIP, and DNA pull-down analysis were used to reveal the underlying mechanisms. Results It was found that circRPPH1 level was upregulated in glioma cell spheres and facilitated the stemness of glioma cells; C-FOS transcriptionally activated circRPPH1 expression via directly binding to circRPPH1 promoter in glioma cells. Moreover, circRPPH1 promoted the stemness of glioma cells dependent on c-FOS-mediated transcriptional activation. Conclusions This study indicates that c-Fos-activated circRPPH1 contributes to glioma stemness and provides a potential target for glioma progression based on the c-FOS/circRPPH1 regulatory axis (AU)

Fear stress promotes glioma progression through inhibition of ferroptosis by enhancing FSP1 stability

Purpose Patients diagnosed with cancer often suffer from emotional stressors, such as anxiety, depression, and fear of death. However, whether fear stress could influence the glioma progression is still unclear. Methods Xenograft glioma animal models were established in nude mice. Tumor-bearing mice were subjected to fear stress by living closely with cats and then their depressive behaviors were measured using an open field test. Hematoxylin and eosin staining, the TUNEL staining and immunochemical staining were used to detect the histopathological changes of tumor tissues. Gene expression profiling was used to screen the aberrant gene expression. Methylated RNA immunoprecipitation was used to identify the RNA m6A level. Gene expression was measured by western blot and real-time PCR, respectively. Results We found that fear stress promoted glioma tumor progression in mice. Fear stress-induced upregulation of METTL3 and FSP1, increased m6A level of glioma tumor tissues, and inhibited ferroptosis in glioma progression, which were reversed by knockdown of METTL3 and FSP1 in vivo. In addition, we found that when iFSP1 (a ferroptosis inducer by targeting inhibition of FSP1) was introduced to glioma cells, the cells viability of glioma significantly was decreased and ferroptosis was enhanced in glioma cells. Conclusions Fear stress-induced upregulation of METTL3 stabilized FSP1 mRNA by m6A modification, leading to tumor progression through inhibition of ferroptosis. Our study provides a new understanding of psychological effects on glioma development, and new insights for glioma therapy (AU)

Análisis de supervivencia en gliomas de alto grado: papel de la cirugía de rescate / Survival analysis in high-grade glioma: the role of salvage surgery

Objetivos: Analizar la supervivencia en el grupo de pacientes con gliomas de alto grado tratados de forma consecutiva en un mismo centro a lo largo de 10 años. Establecer la relevancia de los factores asociados y el papel de la cirugía de rescate en el momento de la progresión.MétodosFueron analizados de forma retrospectiva los pacientes con gliomas grado III y IV de la Organización Mundial de la Salud (OMS) diagnosticados en el Hospital Gregorio Marañón desde el 1 de enero de 2008 hasta el 31 de diciembre de 2017. Se obtuvieron de la historia clínica los datos clínicos, radiológicos y anatomopatológicos.ResultadosSe completó el seguimiento en 233 pacientes con diagnóstico de glioma de alto grado (III o IV de la OMS). La edad media fue de 62,2 años. La mediana de supervivencia se situó en 15,4 meses. De los 133 pacientes (59,6%) que habían sido intervenidos mediante cirugía resectiva en el momento del diagnóstico, en 43 (32,3%) se efectuó cirugía de rescate en el momento de la progresión. La supervivencia global, así como la supervivencia tras la progresión, resultó mayor en este subgrupo de pacientes. Otras variables relacionadas con una mayor supervivencia fueron la puntuación en la escala de Karnofsky, el grado de resección quirúrgica y el diagnóstico inicial de grado III de la OMS.ConclusionesAlrededor de una tercera parte de los pacientes con gliomas de alto grado pueden ser candidatos a una cirugía de rescate en el momento de la progresión. Ello está asociado a una mayor supervivencia. (AU)

Objectives: This study addresses the survival of consecutive patients with high-grade gliomas treated at the same institution over a period of 10 years. We analyse the importance of associated factors and the role of salvage surgery at the time of progression.MethodsWe retrospectively analysed a series of patients with World Health Organization (WHO) grade III/IV gliomas treated between 2008 and 2017 at Hospital Gregorio Marañón (Madrid, Spain). Clinical, radiological, and anatomical pathology data were obtained from patient clinical histories.ResultsFollow-up was completed in 233 patients with HGG. Mean age was 62.2 years. The median survival time was 15.4 months. Of 133 patients (59.6%) who had undergone surgery at the time of diagnosis, 43 (32.3%) underwent salvage surgery at the time of progression. This subgroup presented longer overall survival and survival after progression. Higher Karnofsky Performance Status score at diagnosis, a greater extent of surgical resection, and initial diagnosis of WHO grade III glioma were also associated with longer survival.ConclusionsAbout one-third of patients with HGG may be eligible for salvage surgery at the time of progression. Salvage surgery in this subgroup of patients was significantly associated with longer survival. (AU)

Epilepsia en el paciente oncológico: prevención primaria e importancia en la selección del paciente de alto riesgo / Epilepsy in cancer patients: primary prevention and the importance of high-risk patient screening

Introducción: La epilepsia en el paciente oncológico presenta una prevalencia del 13%, especialmente elevada en pacientes con tumores cerebrales, así como una mayor morbimortalidad respecto de la epilepsia no tumoral. Sus mecanismos fisiopatógenos son diferenciadores, e incluyen la distorsión de la arquitectura cortical y la alteración del microambiente molecular tumoral y peritumoral favorecedor de glutamato. A pesar de ello, existe evidencia científica escasa e inconsistente acerca de aspectos fundamentales, como la profilaxis primaria postoperatoria, el perfil farmacológico idóneo o el tiempo de retirada de fármacos anticrisis tras la libertad de éstas. Desarrollo: Características como el bajo grado tumoral, el número/tamaño de las lesiones corticales, la localización (frontal, cortical/subcortical o área elocuente), las crisis tempranas y las alteraciones moleculares, como mutación IDH1/2, son factores favorecedores para la aparición de crisis. Dentro del tratamiento, la cirugía aportará citorreducción y control de crisis por escisión del área epileptógena, con libertad de crisis incapacitantes del 75-90%. Aunque sigue siendo un tema controvertido, el uso postoperatorio de fármacos anticrisis está contraindicado por las principales sociedades científicas por la escasa evidencia y el amplio espectro de efectos secundarios. Sin embargo, se emplean frecuentemente en la práctica clínica diaria. Conclusiones: Todo ello nos obliga a establecer un grupo de pacientes de ‘alto riesgo’ de crisis postoperatorias, que precisará seleccionar el fármaco anticrisis idóneo en prevención primaria, con una vía de administración que facilite un rápido efecto de acción y una farmacocinética que evite el metabolismo hepático y la inducción de CYP450 para conseguir un menor número de interacciones con quimioterápicos, corticoides y radioterapia. A pesar de ello, se describen tasas de farmacorresistencia del 20-40% y recidiva del 25-29%.(AU)

Introduction: Epilepsy in cancer patients has a prevalence of 13%, and is especially high in patients with brain tumours, with a higher morbidity and mortality rate compared to non-tumour-related epilepsy. Its physiopathogenic mechanisms are distinct and include distortion of the cortical architecture and alteration of the glutamate-enhancing tumoural and peritumoural molecular microenvironment. Nevertheless, there is scarce and inconsistent scientific evidence on some fundamental aspects, such as primary post-operative prophylaxis, the ideal pharmacological profile or the withdrawal time of antiseizure drugs after their release. Development: Characteristics such as low tumour grade, number/size of cortical lesions, location (frontal, cortical/subcortical or eloquent area), early seizures and molecular alterations, such as IDH1/2 mutation, are factors that favour the occurrence of seizures. Within the treatment, surgery will provide cytoreduction and seizure control by excision of the epileptogenic area, with 75-90% freedom from disabling seizures. Although still a controversial issue, the post-operative use of antiseizure drugs is contraindicated by the main scientific societies due to the scarce evidence and the wide spectrum of side effects. However, they are frequently used in daily clinical practice. Conclusions: All this forces us to establish a group of patients at ‘high risk’ of postoperative seizures, who will need to select the ideal antiseizure drug for primary prevention, with a route of administration that facilitates a rapid action effect and pharmacokinetics that prevents hepatic metabolism and CYP450 induction to achieve a lower number of interactions with chemotherapy, corticosteroids and radiotherapy. Despite this, drug resistance rates of 20-40% and relapse rates of 25-29% have been reported.(AU)

Tumor glioneuronal leptomeníngeo difuso: diagnóstico y tratamiento con un caso ilustrativo / Diffuse leptomeningeal glioneuronal tumor: A review of diagnosis and management with an illustrative case

El tumor glioneuronal leptomeníngeo difuso es una entidad infrecuente, con un curso indolente; fue descrito en la clasificación de los tumores del sistema del sistema nervioso central de la OMS 2016. Presentamos el caso de un varón de 11 años que comienza con un cuadro clínico inespecífico de cefalea, dolor lumbosacro e hidrocefalia comunicante. En el curso clínico aparecen crisis epilépticas con lesiones nodulares en RM craneal; fue diagnosticado de meningitis tuberculosa y tratado con tuberclostáticos. Ante un deterioro clínico progresivo, a pesar del tratamiento, y empeoramiento de los hallazgos en RM craneoespinal, se le realiza biopsia cerebral y de leptomeninges que confirma el diagnóstico de tumor glioneuronal leptomeníngeo difuso. El tumor glioneuronal leptomeníngeo difuso debe incluirse en el diagnóstico diferencial de los cuadros que se presentan con hidrocefalia comunicante y lesiones leptomeníngeas. Se precisa un diagnóstico histológico precoz mediante biopsia para establecer un tratamiento adecuado (AU)

Diffuse leptomeningeal glioneuronal tumors (DLGNTs) are a rare indolent neoplasm described in the 2016 WHO classification of tumors of the central nervous system (CNS). We describe a case of an 11 year old boy who initially presented intermittent headache, low back pain and communicating hydrocephalus, misdiagnosed as having tuberculous meningitis. Further clinical deterioration with seizures was observed and follow-up MRI showed further aggravation of leptomeningeal enhancement in the basal cisterns. Biopsy of the brain and leptomeninges revealed a diffuse leptomeningeal glioneuronal tumor. DLGNT should be considered in the differential diagnosis of conditions presenting as communicating hydrocephalus with nodular lesions and leptomeningeal enhancement. A timely histologic diagnosis through a biopsy of the brain is necessary to confirm the diagnosis (AU)

The road-map for establishment of a prognostic molecular marker panel in glioma using liquid biopsy: current status and future directions

Gliomas are primary intracranial tumors with defined molecular markers available for precise diagnosis. The prognosis of glioma is bleak as there is an overlook of the dynamic crosstalk between tumor cells and components of the microenvironment. Herein, different phases of gliomagenesis are presented with reference to the role and involvement of secreted proteomic markers at various stages of tumor initiation and development. The secreted markers of inflammatory response, namely interleukin-6, tumor necrosis factor-α, interferon-ϒ, and kynurenine, proliferation markers human telomerase reverse transcriptase and microtubule-associated-protein-Tau, and stemness marker human-mobility-group-AThook-1 are involved in glial tumor initiation and growth. Further, hypoxia and angiogenic factors, heat-shock-protein-70, endothelial-growth-factor-receptor-1 and vascular endothelial growth factor play a major role in promoting vascularization and tumor volume expansion. Eventually, molecules such as matrix-metalloprotease-7 and intercellular adhesion molecule-1 contribute to the degradation and remodeling of the extracellular matrix, ultimately leading to glioma progression. Our study delineates the roadmap to develop and evaluate a non-invasive panel of secreted biomarkers using liquid biopsy for precisely evaluating disease progression, to accomplish a clinical translation. (AU)

TLR4 activation inhibits the proliferation and osteogenic differentiation of skeletal muscle stem cells by downregulating LGI1

Skeletal muscle stem cells (SMSCs) are vital to the growth, maintenance, and repair of the muscles; emerging evidence has indicated that Toll-like receptor 4 (TLR4) can potentially regulate muscle regeneration. In present study, in vitro and in vivo experiments were performed to explore the correlation of TLR4 with leucine-rich glioma-inactivated 1 (LGI1) as well as their effects on the proliferation and osteogenesis potential of SMSCs. In order to examine the regulatory mechanisms of TLR4 and LGI1 in SMSCs, the obtained cells were treated with lipopolysaccharide (LPS, used as an activator of TLR4) of different concentration at different time points as well as the siRNA against LGI1. Subsequently, a series of detection was undertaken in order to measure the proliferation and differentiation potential of SMSCs, which involved detection of the related factors, cell activity, and the sphere-forming capability. Following LPS treatment, the increased TLR4 expression and reduced LGI1 expression were observed. Consequently, we also discovered that Erk signaling pathway was inactivated and cell proliferation and osteogenesis capabilities declined, presented by the downregulation of related factors such as cyclin B1 and runt-related transcription factor 2. Moreover, the cell activity and sphere-formation performance of SMSCs were also declined. These results were also validated in rats with cecal ligation and perforation-induced rat models with sepsis. In conclusion, the present study reveals a regulatory mechanism in SMSCs whereby LGI1 expression is reduced by TLR4, thus impeding cell proliferation and osteogenesis, highlighting TLR4 as a potential therapeutic target against many diseases related to SMSCs. (AU)

BRCA2 deficiency increases sensitivity of medulloblastoma to Olaparib by inhibiting RAD51-mediated DNA damage repair system

PurposeBRCA2 defect exists in glioma and regulates drug resistance of glioma to chemotherapy. However, its role in medulloblastoma and the mechanism is not known. To investigate the effects of BRCA2 deficiency combined with Olaparib in medulloblastoma and the mechanism.MethodsBRCA2 was knocked down by RNAi technology and cell proliferation was detected by CCK-8 assay. Cell apoptosis was determined by FACS analysis when the in vivo role of BRCA2 was explored with xenograft mice model. Western blotting technology was used to explore the mechanism of BRCA2.ResultsKnockdown of BRCA2 enhanced the inhibitory effect of Olaparib on proliferation of Daoy and LN229 cells. The inhibition rate of Olaparib on Daoy or LN229 cells was 61.1%, 66.03% in shBRCA2 group, while it was 42.9%, 41.1% in shNC group. Overexpression of RAD51 partially reversed the effect of shBRCA2. In Daoy cells, apoptotic rate was 26.9% in Olaparib group and 58.9% in Olaparib/shBRCA2 group. However, it was 33.4% after RAD51 was overexpressed. It was the same in LN229 cells. In xenograft mice model, tumor volume in Olaparib and Olaparib/shBRCA2 group was 376.12 and 84.95mm3 when tumor weight was 0.46 g and 0.12 g. In addition, the level of RAD51, RAD50, MRE11, and NBS was increased by Olaparib alone but decreased reversely after knockdown of BRCA2 in Daoy cells.ConclusionsKnockdown of BRCA2 increases the sensitivity of medulloblastoma cells to Olaparib and strengthens the efficacy of Olaparib in vitro and in vivo. Knockdown of BRCA2 causes DNA damage repair by regulating RAD51-mediated signaling pathway in Daoy cells.

Heterotopia glial nasal: a propósito de un caso / Nasal glial heterotopia:: case report

Las tumoraciones congénitas de la cara son motivo frecuente de consulta al cirujano plástico pediátrico. La gran mayoría son benignas pero llamativas por su localización. Dentro de éstas, las tumoraciones de la línea media nasal cobran especial importancia por la posibilidad de presentar comunicaciones intracraneanas, porque pueden generar obstrucción al flujo de aire del neonato y porque la demora en su diagnóstico y tratamiento adecuados puede determinar secuelas a largo plazo. Nos centraremos en el diagnóstico y tratamiento de la heterotopia glial nasal a propósito de un caso en paciente de 2 años de edad. (AU)

Congenital face tumors are frequently referred to the pediatric plastic surgeon. Most of them are benign lesions, but they are striking because of their localization. The nasal midline masses are especially important because they may have intracranial connections, they can cause airway obstruction and because the delay in correct diagnosis and treatment may cause long term sequelae. We will focus on the diagnosis and treatment of nasal glial heterotopia: regarding a two-year-old patient. (AU)

High-dose salvage re-irradiation for recurrent/progressive adult diffuse glioma: healing or hurting?

Purpose To report survival outcomes and identify prognostic factors of salvage re-irradiation (re-RT) in recurrent/progressive glioma. Methods Medical records of patients treated with high-dose re-RT as part of multi-modality salvage therapy for recurrence/progression of adult diffuse glioma from 2010 to 2019 were analyzed retrospectively. Results A total of 111 patients developing recurrent/progressive high-grade glioma after adequate upfront treatment at initial diagnosis were included. The first course of radiotherapy (RT) had been delivered to a median dose of 59.4 Gy with an inter-quartile range (IQR) of 54-60 Gy. Median time to recurrence/progression was 4.3 years (IQR = 2.3–7.4 years) while the median time to re-RT was 4.8 years (IQR = 3.6–7.9 years). Re-RT was delivered with intensity-modulated radiation therapy (IMRT) using 1.8 Gy/fraction to a median dose of 54 Gy (IQR = 50.4–55.8 Gy) for a cumulative median equivalent dose in 2-Gy fractions (EQD2) of 104.3 Gy (IQR = 102.6–109.4 Gy). At a median follow-up of 14 months after re-RT, the 1-year Kaplan–Meier estimates of post-re-RT progression-free survival (PFS) and overall survival (OS) were 42.8 and 61.8%, respectively. Univariate analysis identified histological grade at recurrence/progression; histological subtype; disease-free interval (DFI) and time interval between both courses of RT; performance status at re-RT; dose at re-RT and cumulative EQD2; isocitrate dehydrogenase (IDH) mutation; and O6-methyl-guanine DNA methyl transferase (MGMT) gene promoter methylation as significant prognostic factors. Preserved performance status, longer DFI, prolonged time interval between both courses of RT, and presence of IDH mutation were associated with significantly improved PFS on multi-variate analysis. However, only performance status retained independent prognostic significance for OS on multi-variate analysis (AU)

Magnetic resonance imaging evaluation of brain glioma before postoperative radiotherapy

Purpose To investigate the magnetic resonance imaging (MRI) images of brain glioma before postoperative radiotherapy, and to provide reference for the delineation of postoperative radiotherapy target area. Methods Retrospective analysis was performed on 106 cases of brain glioma confirmed by surgery and pathology in our hospital, including 70 cases of high-grade glioma (HGG) and 36 cases of low-grade glioma (LGG). The MRI images of the lesions within 1 month before and after surgery were analyzed, the apparent diffusion coefficient (ADC) values in the near and far tumor areas were measured, respectively, and the corresponding rADC values were calculated. Results The incidence of residual tumors of postoperative HGG and LGG was 0, 15.7% (0/36, 11/70), respectively. The incidence of postoperative reactive enhancement was 11.0% and 52.9% (4/36 and 37/70), respectively. About 30.6% and 81.4% (11/36 and 57/70) of patients with adjacent meningeal enhancement were found in the operative area. Conclusions The MRI images of HGG and LGG before postoperative radiotherapy had certain characteristics, providing a favorable guidance for the delineation of the target area of radiotherapy and the formulation of treatment plan (AU)

Noncoding RNAs as potential biomarkers for DIPG diagnosis and prognosis: XIST and XIST-210 involvement

Purpose Diffuse intrinsic pontine gliomas (DIPGs) are the most fatal primary brainstem tumors in pediatric patients. The identification of new molecular features, mediating their formation and progression, as non-coding RNAs (ncRNAs), would be of great importance for the development of effective treatments. Methods We analyzed the DIPGs transcriptome with the HTA2.0 array and it was compared with pediatric non-brainstem astrocytoma expression profiles (GSE72269). Results More than 50% of the differentially expressed transcripts were ncRNAs and based on this, we proposed a DIPGs ncRNA signature. LncRNAs XIST and XIST-210, and the HBII-52 and HBII-85 snoRNA clusters were markedly downregulated in DIPGs. qPCR assays demonstrated XIST downregulation in all non-brainstem astrocytomas, in a gender, age, and brain location-independent manner, as well as in DIPGs affecting boys; however, DIPGs affecting girls showed both downregulation and upregulation of XIST. Girls’ with longer survival positively correlated with XIST expression. Conclusions The involvement of ncRNAs in DIPGs is imminent and their expression profile is useful to differentiate them from non-neoplastic tissues and non-brain stem astrocytomas, which suggests their potential use as DIPG biomarkers. In fact, XIST and XIST-210 are potential DIPG prognostic biomarkers (AU)

Radiotherapy in adult low-grade glioma: nationwide trends in treatment and outcomes

Background Management of WHO grade II gliomas (LGG) can include a combination of observation, surgery, radiotherapy (RT), and chemotherapy; however, optimal management remains unclear in regards to RT. Objective The current study seeks to investigate the usage of RT in LGG and its effect on survival outcomes. Methods Patients with diagnosis codes specific for LGG were queried from the National Cancer Database (NCDB) during the years 2004–2016. Kaplan–Meier curves with log-rank testing, univariate and multivariate Cox regression analysis, and comparisons of estimated 3- and 7-year survival were performed to investigate the effect of RT on overall survival. Results 19,382 patients with LGG were identified with histologically confirmed disease. Kaplan–Meier testing demonstrated RT impacted survival in patients undergoing biopsy or no surgery (p < 0.0001), no chemotherapy (p < 0.0001), and in regimens with early RT (p < 0.0001) and high-dose RT (p < 0.0001). Cox multivariate regression demonstrated RT and age less than 40 (HR 0.93, 95% CI 0.89–0.97, p = 0.001), no chemotherapy (HR 0.82, 95% CI 0.77–0.87, p < 0.001), and astrocytoma histology (HR 0.72, 95% CI 0.66–0.79, p < 0.001) were associated with improved survival. 3-year survival of RT versus non-RT groups showed increased survival rates for age less than 40 years (+ 5.7%, p < 0.0001), no surgery or biopsy (+ 8.1%, p < 0.0001), no chemotherapy (+ 10.3%, p < 0.0001), mixed glioma (+ 6.7%, p < 0.0001), astrocytoma (+ 7.1%, p < 0.0001), and in regimens with early RT (+ 7.6%, p < 0.0001) and high-dose RT (+ 4.7%, p < 0.0001). Conclusion This nationwide analysis of LGG patients found that RT was associated with improved survival outcomes in patients less than 40 years of age, with histology subtypes of astrocytoma and mixed glioma, undergoing biopsy or no surgery, and in regimens with early RT and high-dose RT (AU)

Positioning error analysis of the fraxion localization system in the intracranial stereotactic radiotherapy of tumors

Objective To investigate positioning error analysis of the Fraxion localization system in the intracranial stereotactic radiotherapy of tumors. Methods 64 patients were divided into two groups: a control group (36 patients with the standard thermoplastic mask) and a model group (28 patients with the Fraxion localization system). 3D images of the treated position were obtained by cone-beam computed tomography (CBCT). Positioning errors were obtained by, respectively, registering these two sets of CBCT images to planning CT images, using a 6°-freedom robotic patient positioning system (HexaPOD Evo RT System). The changes in positioning errors with the Fraxion localization system and with the standard thermoplastic mask were analyzed. Results CBCT scan results of the model group showed that the mean of linear error of three directions [superior-inferior (SI), lateral (LAT), and anterior–posterior (AP)] was 0.710 ± 0.676 mm, 0.817 ± 0.687 mm, and 0.710 ± 0.685 mm, respectively. The corresponding PTV was 1.23 mm, 1.26 mm, and 1.36 mm. The differences between the 3D images and the planned CT images were significant (p < 0.001). Conclusion The Fraxion radiotherapy system can not only improve the positioning accuracy and reduce positioning errors but also narrow the PTV margin and reduce the radiated volume of normal tissue (AU)