Glioblastoma research on zebrafish xenograft models: a systematic review

Glioblastoma (GBM) constitutes the most common primary brain tumor in adults. The challenges in GBM therapeutics have shed light on zebrafish used as a promising animal model for preclinical GBM xenograft studies without a standardized methodology. This systematic review aims to summarize the advances in zebrafish GBM xenografting, compare research protocols to pinpoint advantages and underlying limitations, and designate the predominant xenografting parameters. Based on the PRISMA checklist, we systematically searched PubMed, Scopus, and ZFIN using the keywords “glioblastoma,” “xenotransplantation,” and “zebrafish” for papers published from 2005 to 2022, available in English. 46 articles meeting the review criteria were examined for the zebrafish strain, cancer cell line, cell labeling technique, injected cell number, time and site of injection, and maintenance temperature. Our review designated that AB wild-type zebrafish, Casper transparent mutants, transgenic Tg(fli1:EGFP), or crossbreeding of these predominate among the zebrafish strains. Orthotopic transplantation is more commonly employed. A number of 50–100 cells injected at 48 h post-fertilization in high density and low infusion volume is considered as an effective xenografting approach. U87 cells are used for GBM angiogenesis studies, U251 for GBM proliferation studies, and patient-derived xenograft (PDX) to achieve clinical relevance. Gradual acclimatization to 32–33 °C can partly address the temperature differential between the zebrafish and the GBM cells. Zebrafish xenograft models constitute valuable tools for preclinical studies with clinical relevance regarding PDX. The GBM xenografting research requires modification based on the objective of each research team. Automation and further optimization of the protocol parameters could scale up the anticancer drug trials (AU)

Molecular and clinical characterization of H3 K27M-mutant “non-midline” glioblastoma: A case report and literature review / Estudio molecular y presentación clínica del glioblastoma con mutación H3 K27M «no de línea media»: descripción de un caso y revisión de la literatura

The WHO classification of tumors of the CNS in 2016 defined “diffuse midline glioma, H3 K27M-mutant” as a new tumor entity locating in the CNS midline. However, the H3 K27M-mutation in “non-midline” glioblastoma are rare and their characteristics have been rarely reported. A 16-year-old girl presented a hyper-intense lesion at her left temporal stem on T2WI, FLAIR and DWI. Biopsy was performed and molecular pathological diagnosis was glioblastoma with H3 K27M-mutant. Accordingly, the possibility of H3 K27M-mutant should be examined not only for diffuse glioma without IDH mutation that develops at a midline location, but also in non-midline locations (AU)

La clasificación de la OMS de los tumores del SNC en 2016 definió el «glioma difuso de la línea media, H3 K27M-mutante» como una nueva entidad tumoral que se localiza en la línea media del SNC. Sin embargo, la mutación H3 K27M en el glioblastoma «no de línea media» es infrecuente y sus características han sido raramente reportadas. Una niña de 16 años presentó una lesión hiperintensa en el tronco temporal izquierdo en T2WI, FLAIR y DWI. Se realizó una biopsia y el diagnóstico patológico molecular fue de glioblastoma con mutación H3 K27M. En consecuencia, la posibilidad de mutaciones H3 K27M debe examinarse no sólo en el caso de los gliomas difusos que se desarrollan en una localización de la línea media, sino también en gliomas sin mutación de IDH en localizaciones que no son de la línea media entre los pacientes (AU)

Proyecto REFILAB: Un caso clínico de una hemiplejía secundaria a glioblastoma temporal izquierdo intervenido en Medicina del Trabajo / REFILAB project: a clinical case of hemiplegia secondary to glioblastoma in the left temporal region treated in occupational medicine

REFILAB es un proyecto novedoso aplicado en la medicina laboral para la prevención y readaptación física funcional de los trabajadores de una empresa, que sigue el modelo de intervención de la lesión deportiva. El objetivo del estudio fue analizar los efectos del proyecto REFILAB sobre la aptitud física relacionada con la salud en un trabajador con diagnóstico de hemiplejia derecha secundaria a glioblastoma temporal izquierdo intervenido. El caso clínico fue un hombre de 46 años, operario de limpieza viaria y recogida de residuos de una empresa de servicios urbanos. El trabajador fue intervenido durante 4 meses con REFILAB para combatir las secuelas de su enfermedad. Después de 4 meses de intervención, el trabajador mejoró consideradamente los valores de fuerza, flexibilidad, neuromotor y resistencia. El trabajador con diagnóstico de hemiplejia derecha secundaria a glioblastoma temporal izquierdo intervenido incrementó su autonomía en las actividades de la vida diaria e instrumentales básicas. (AU)

REFILAB is a novel occupational health project for the prevention and functional physical readaptation of workers in a company, following the model of intervention in sports injuries. The aim of the present study was to analyse the effects of the REFILAB project on health-related physical fitness in a subject diagnosed with brain cancer and right hemiplegia. The clinical case involved a 46-year-old man who worked for a municipal service company in street cleaning and refuse collection. The patient was treated with the REFILAB programme for 4 months to combat the sequelae of his disease. After the 4-month intervention, the worker significantly improved his strength, flexibility, neuromotor and endurance values. The worker, who was diagnosed with right hemiplegia as a result of a glioblastoma in the left temporal area, was able to increase his independence in activities of daily living and basic instrumental activities. (AU)

Timing of radiotherapy in glioblastoma based on IMRT and STUPP chemo-radiation: may be no need to rush

To investigate the effect of surgery to radiotherapy interval (SRI) on the prognosis of patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma.MethodsRetrospective analysis of the relationship between SRI and prognosis of patients with IDH wild-type glioblastoma who received postoperative intensity modulated radiotherapy (IMRT) in our center from July 2013 to July 2019. The patients were divided into SRI ≤ 42 days (regular group) and SRI > 42 days (delay group). Kaplan–Meier univariate analysis and Cox proportional hazard model were used to analyze whether SRI was an independent factor influencing the prognosis.ResultsA total of 102 IDH wild-type glioblastoma were enrolled. Median follow-up was 35.9 months. The 1-, 2- and 3-year OS of “regular group” were 69.5%, 34.8%, 19.1%, and “delay group” were 69.8%, 26.1% and 13.4% respectively. Multivariate analysis showed that extent of resection (p = 0.041) was an independent prognostic factor for OS. SRI (p = 0.347), gender (p = 0.159), age (p = 0. 921), maximum diameter (p = 0.637) MGMT promoter methylation status (P = 0.630) and ki-67 expression (P = 0.974) had no effect on OS. Univariate analysis (p = 0.483) and multivariate analysis (p = 0.373) also showed that SRI had no effect on OS in glioblastoma who received gross total resection.ConclusionAppropriate extension in SRI has no negative effect on the OS of IDH wild-type glioblastoma. It is suggested that radiotherapy should be started after a good recovery from surgery. This conclusion needs further confirmed by long-term follow-up of a large sample. (AU)

Efecto de la alteración de los niveles de expresión de microARN neurogénicos y su implicación en la agresividad de glioblastomas localizados en la región paraventricular / The effects of altered neurogenic microRNA levels and their involvement in the aggressiveness of periventricular glioblastoma

Introducción: El glioblastoma multiforme es el tumor cerebral primario más común y con el pronóstico más desfavorable del sistema nervioso central. A pesar de los numerosos estudios y avances en medicina, este sigue siendo letal, con una esperanza de vida promedio de 15 meses posteriores a la quimiorradioterapia.DesarrolloRecientemente, se han estudiado diversos factores asociados al diagnóstico y el pronóstico de pacientes con glioblastoma, como la localización tumoral, principalmente la zona subventricular; una de las áreas neurogénicas más activas del cerebro humano adulto. Los pacientes con glioblastoma asociados a esta zona en particular presentan generalmente una mayor agresividad, lo que resulta en un pronóstico desfavorable y una menor esperanza de vida. Actualmente, se ha profundizado en el estudio de los microARN, los cuales reflejan patrones de expresión distintos en condiciones fisiológicas o fisiopatológicas. Está reportado que los niveles de expresión de ciertos microARN, principalmente aquellos relacionados a procesos neurogénicos, se ven desregulados en eventos oncogénicos, favoreciendo así la gliomagénesis y la agresividad tumoral. En la presente revisión se discuten algunos de los microARN más importantes implicados en procesos neurogénicos de la zona subventricular y su asociación con la agresividad del glioblastoma.ConclusionesLa regulación y función de los microARN desempeña un rol importante en el desarrollo y la progresión del glioblastoma; en consecuencia, la comprensión de las alteraciones de los microARN implicados en la diferenciación, así como en la maduración neural y glial, podrían ayudar a entender mejor las características malignas del glioblastoma. (AU)

Introduction: Glioblastoma multiforme is the most common primary brain tumour, with the least favourable prognosis. Despite numerous studies and medical advances, it continues to be lethal, with an average life expectancy of 15 months after chemo-radiotherapy.DevelopmentRecent research has addressed several factors associated with the diagnosis and prognosis of glioblastoma; one significant factor is tumour localisation, particularly the subventricular zone, which represents one of the most active neurogenic niches of the adult human brain. Glioblastomas in this area are generally more aggressive, resulting in unfavourable prognosis and a shorter life expectancy. Currently, the research into microRNAs (miRNA) has intensified, revealing different expression patterns under physiological and pathophysiological conditions. It has been reported that the expression levels of certain miRNAs, mainly those related to neurogenic processes, are dysregulated in oncogenic events, thus favouring gliomagenesis and greater tumour aggressiveness. This review discusses some of the most important miRNAs involved in subventricular neurogenic processes and their association with glioblastoma aggressiveness.ConclusionsMiRNA regulation and function play an important role in the development and progression of glioblastoma; understanding the alterations of certain miRNAs involved in both differentiation and neural and glial maturation could help us to better understand the malignant characteristics of glioblastoma. (AU)

Glioblastomas de larga supervivencia: un análisis sistemático de la literatura a propósito de un caso / Long-term survival of glioblastoma: A systematic analysis of literature about a case

Introducción: A pesar de las modificaciones introducidas en el tratamiento de los glioblastomas a partir del 2005, los pacientes supervivientes de más de 10 años se han mantenido constantes, siendo dicha cifra muy pobre e inferior al 1% en la mayoría de los estudios.Material y métodos: Se realiza un análisis sistemático de la literatura identificando los factores que pueden influir en los pacientes de larga supervivencia. Se identifica un caso en nuestro medio de más de 20 años de supervivencia realizándose un análisis actual del bloque de parafina que se conservaba del paciente.Resultados: La variable que más se asocia a la larga supervivencia en todos los análisis multivariantes es la edad, aunque, cuando se analiza las características genéticas y moleculares de los tumores, parecen existir otras variables como la metilación del promotor MGMT que juegan un papel muy importante. El análisis anatomo-patológico actual de la muestra comprueba la certeza del diagnóstico en nuestro paciente de muy larga supervivencia.Conclusiones: Múltiples variables son encontradas que influencian la larga supervivencia en distintas series, si bien los estudios analizados son muy heterogéneos resultando muy difícil la comparación entre ellos. La mayoría de los estudios referenciados pertenecen a bases de datos nacionales de distintos países que engloban a cientos de pacientes. Sería interesante fomentar el uso de una única base de datos en España que permita, entre otros, el análisis de estos pacientes de larga supervivencia afectos de glioblastoma (AU)

Introduction: In spite of the changes for the treatment of glioblastoma since 2005, we haven’t seen differences between long-survival patients of more than 10 years showing a value minor than 1%.Material and method: We realize a systematic analysis and identify important factors for long survivor patients. We also show an own case with more of 20 years of survival. We make a new pathological study of the old paraffin block of this patient.Results: The most important variable associated with long-survival between all multivariant studies is the age. When we try to find genetic and molecular alterations in glioblastoma associated with prolongated survival, the MGMT promoter methylation play the most important role. We find a correct diagnosis in the current analysis of our patient's sample with very long survival.Conclusions: Multiple variables are found that affect long survival of glioblastoma series but analyzed studies are very heterogeneous and it is very difficult comparation between them. Most articles we review are obtained from databases of different countries with hundreds of patients. It would be very interesting to promote the use of a single database in Spain that allows us to study these long-term glioblastoma survivors (AU)

An overview of current therapeutic strategies for glioblastoma and the role of CD73 as an alternative curative approach

Glioblastoma multiforme (GBM) is a complicated and heterogeneous brain tumor with short-term survival outcomes. Commercial therapies are not practical due to cell infiltration capacity, high proliferative rate, and blood–brain barrier. In this context, recognition of the molecular mechanism of tumor progression might help the development of new cancer therapeutics. Recently, more evidence has supported CD73 and downstream adenosine A2A/A2B receptor signaling playing a crucial role in glioblastoma pathogenesis; therefore, targeting CD73 in murine tumor models can reduce tumor development. CD73 is an ecto-enzyme inducing tumor metastasis, angiogenesis, and immune escape via the production of extracellular adenosine in the tumor microenvironment. In this review, we provided information about clinical characteristics as well as the therapeutic management of glioblastoma. Then, we focused on newly available experimental evidence distinguishing between the essential role of CD73 on this tumor growth and a new method for the treatment of GBM patients.

Silencing IKBKE inhibits the migration and invasion of glioblastoma by promoting Snail1 degradation

PurposeGlioblastoma multiforme (GBM) is one of the most common malignant brain tumors in adults and has high mortality and relapse rates. Over the past few years, great advances have been made in the diagnosis and treatment of GBM, but unfortunately, the five-year overall survival rate of GBM patients is approximately 5.1%. Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE) is a major oncogenic protein in tumors and can promote evil development of GBM. Snail1, a key inducer of the epithelial-mesenchymal transition (EMT) transcription factor, is subjected to ubiquitination and degradation, but the mechanism by which Snail1 is stabilized in tumors remains unclear. Our study aimed to investigate the mechanism of IKBKE regulating Snail1 in GBM.MethodsFirst, we analyzed the correlation between the expression of IKBKE and the tumor grade and prognosis through public databases and laboratory specimen libraries. Second, immunohistochemistry (IHC) and western blot were used to detect the correlation between IKBKE and Snail expression in glioma samples and cell lines. Western blot and immunofluorescence (IF) experiments were used to detect the quality and distribution of IKBKE and Snail1 proteins. Third, In situ animal model of intracranial glioma to detect the regulatory effect of IKBKE on intracranial tumors.ResultsIn this study, Our study reveals a new connection between IKBKE and Snail1, where IKBKE can directly bind to Snail1, translocate Snail1 into the nucleus from the cytoplasm. Downregulation of IKBKE results in Snail1 destabilization and impairs the tumor cell migration and invasion capabilities.ConclusionOur studies suggest that the IKBKE-Snail1 axis may serve as a potential therapeutic target for GBM treatment.

Impact of prognostic nutritional index on survival in recurrent glioblastoma / Impacto de Prognostic Nutritional Index en la supervivencia de los glioblastomas recurrentes

Background: Primary brain tumors are relatively rare malignancy, with high-grade gliomas (glioblastoma multiforme and anaplastic gliomas) are the most common types. We aimed to evaluate the prognostic value of Prognostic Nutritional Index (PNI), which is calculated by lymphocyte count and albumin, in recurrent glioblastoma patients treated with systemic treatment. Methods: Data of 64 patients with recurrent glioblastoma who received systemic treatment and followed in our clinic between 2012 and 2018 was retrospectively collected and analyzed. PNI was calculated as: [(10×serum albumin (g/dL))+(0.005×total lymphocyte count)]. Patients were categorized according to the median PNI value. We investigated the prognostic role of PNI groups, and survival outcomes. Results: Median value of PNI was 45.7, and median follow-up duration was 9 months (1–68 months). Median overall survival (OS) was 7.9 months (95%CI: 5.5–10.4). Median OS was significantly longer in patients with PNI>45.7 compared to patients with PNI≤45.7 (13.9 months (95%CI: 10.5–17.4), and 4.6 months (95%CI: 2.5–6.8), p<0.001, respectively). In multivariate analysis, PNI was found to be an independent prognostic factor for OS [HR:0.41 (95%CI:0.22–0.74), p=0.03)]. Conclusion: In our study, the PNI was found to be an independent prognostic biomarker in patients with recurrent glioblastoma, but further prospective trials are necessary to validate its prognostic role (AU)

Antecedentes: Los tumores cerebrales primarios son neoplasias malignas relativamente infrecuentes, siendo los gliomas de alto grado (glioblastomas multiformes y gliomas anaplásicos) los tipos más comunes. Nuestro objetivo fue evaluar el valor pronóstico de Prognostic Nutritional Index (PNI), que se calcula mediante el recuento de linfocitos y albúmina en los pacientes con glioblastoma recurrente tratados con terapia sistémica. Métodos: Se recabaron y analizaron retrospectivamente los datos de 64 pacientes con glioblastoma recurrente que recibieron tratamiento sistémico, y a quienes se realizó seguimiento en nuestra clínica entre 2012 y 2018. Se calculó PNI como: (10×albúmina sérica [g/dl]+0,005×recuento linfocitario total). Se categorizó a los pacientes con arreglo al valor medio de PNI. Estudiamos el papel pronóstico de los grupos PNI, y los resultados de supervivencia. Resultados: El valor medio de PNI fue de 45,7, siendo la duración media del seguimiento de 9 meses (1-68 meses). La supervivencia global (SG) fue de 7,9 meses (IC 95%: 5,5-10,4). La SG media fue significativamente más alta en los pacientes con PNI>45,7 en comparación con los pacientes con PNI≤45,7 (13,9 meses, IC 95%: 10,5-17,4 y 4,6 meses, IC 95%: 2,5-6,8; p<0,001, respectivamente). En el análisis multivariante, se encontró que PNI era un factor pronóstico independiente de la SG (HR: 0,41; IC 95%: 0,22-0,74; p=0,03). Conclusión: En nuestro estudio, encontramos que PNI era un biomarcador pronóstico independiente en los pacientes con glioblastoma recurrente, aunque son necesarios más estudios prospectivos para validar su papel pronóstico (AU)

The inverse paradigm and the ancestral cell of IDH-wildtype glioblastoma

Rethinking IDH-wildtype glioblastoma through its unique features can help researchers find innovative and effective treatments. It is currently emerging that, after decades of therapeutic impasse, some traditional concepts regarding IDH-wildtype glioblastoma need to be supplemented and updated to overcome therapeutic resistance. Indeed, multiple clinical aspects and recent indirect and direct experimental data are providing evidence that the supratentorial brain parenchyma becomes entirely and quiescently micro-infiltrated long before primary tumor bulk growth. Furthermore, they are indicating that the known micro-infiltration that occurs during the IDH-wildtype glioblastoma growth and evolution is not at the origin of distant relapses. It follows that the ubiquitous supratentorial brain parenchyma micro-infiltration as a source for the development of widespread distant recurrences is actually due to the silent stage that precedes tumor growth rather than to the latter. All this implies that, in addition to the heterogeneity of the primary bulk, there is a second crucial cause of therapeutic resistance that has never hitherto been identified and challenged. In this regard, the ancestral founder cancer stem cell (CSC) appears as the key cell that can link the two causes of resistance.

Histological, molecular, clinical and outcomes characteristics of Multiple Lesion Glioblastoma. A retrospective monocentric study and review of literature / Características histológicas, moleculares, clínicas y de resultados de lesiones múltiples del glioblastoma. Un estudio monocéntrico retrospectivo y revisión de literatura

Background Multiple lesion glioblastoma (M-GBM) represent a group of GBM patients in which there exist multiple foci of tumor enhancement. The prognosis is poorer than that of single-lesion GBM patients, but this actually is a controversial data. Is unknown whether multifocality has a genetic and molecular basis. Our specific aim is to identify the molecular characteristics of M-GBM by performing a comprehensive multidimensional analysis. Methods The surgical, radiological and clinical outcomes of patients that underwent surgery for GBM at our institution for 2 years have been retrospectively reviewed. We compared the overall survival (OS), progression free survival and extent of resection (EOR) between M-GBM tumors (type I) and S-GBM (single contrast-enhancing lesion, type II). Results A total of 177 patients were included in the final cohort, 12 patients had M-GBM and 165 patients had S-GBM. Although patients with M-GBM had higher tumor volumes and midline location, the EOR was not different between both type of lesions. Higher percentage of tumors with EGFR overexpression was detected in M-GBM. PFS and OS was significantly shorter in M-GBM. Conclusions Considering no differences in EOR, patients with M-GBM showed shorter PFS and OS in comparison with S-GBM. Evidences about the M-GBM origin as a multifocal lesion because its molecular profile are suggested (AU)

Antecedentes El glioblastoma multiforme multifocal (M-GBM) representa un grupo de pacientes con GBM en el que existen múltiples focos de mejora tumoral. El pronóstico es peor que el de los pacientes con GBM de lesión única, pero en realidad es un dato controvertido. Se desconoce si la multifocalidad tiene una base genética y molecular. Nuestro objetivo específico es identificar las características moleculares de M-GBM mediante la realización de un análisis multidimensional integral. Métodos Los resultados quirúrgicos, radiológicos y clínicos de los pacientes que se sometieron a cirugía para GBM en nuestra institución durante 2 años han sido revisados retrospectivamente. Comparamos la supervivencia general (SG), la supervivencia libre de progresión y el grado de resección (EOR) entre los tumores M-GBM (tipo I) y S-GBM (lesión única que mejora el contraste, tipo II). Resultados Un total de 177 pacientes fueron incluidos en la cohorte final, 12 pacientes tenían M-GBM y 165 pacientes tenían S-GBM. Aunque los pacientes con M-GBM tenían mayores volúmenes tumorales y ubicación en la línea media, el EOR no fue diferente entre ambos tipos de lesiones. Se detectó un mayor porcentaje de tumores con sobreexpresión de EGFR en M-GBM. PFS y OS fue significativamente más corto en M-GBM. Conclusiones Teniendo en cuenta que no hay diferencias en EOR, los pacientes con M-GBM mostraron PFS y OS más cortos en comparación con S-GBM. Se sugieren evidencias sobre el origen de M-GBM como una lesión multifocal porque se sugiere su perfil molecular (AU)

Relationship between tumor cell infiltration and 5-aminolevulinic acid fluorescence signals after resection of MR-enhancing lesions and its prognostic significance in glioblastoma

Purpose This study investigated the degree of tumor cell infiltration in the tumor cavity and ventricle wall based on fluorescent signals of 5-aminolevulinic acid (5-ALA) after removal of the magnetic resonance (MR)-enhancing area and analyzed its prognostic significance in glioblastoma. Methods Twenty-five newly developed isocitrate dehydrogenase (IDH)-wildtype glioblastomas with complete resection both of MR-enhancing lesions and strong purple fluorescence on resection cavity were retrospectively analyzed. The fluorescent signals of 5-ALA were divided into strong purple, vague pink, and blue colors. The pathologic findings were classified into massively infiltrating tumor cells, infiltrating tumor cells, suspicious single-cell infiltration, and normal-appearing cells. The pathological findings were analyzed according to the fluorescent signals in the resection cavity and ventricle wall. Results There was no correlation between fluorescent signals and infiltrating tumor cells in the resection cavity (p = 0.199) and ventricle wall (p = 0.704) after resection of the MR-enhancing lesion. The median progression-free survival (PFS) and median overall survival (OS) were 12.5 (± 2.1) and 21.1 (± 3.5) months, respectively. In univariate analysis, the presence of definitive infiltrating tumor cells in the resection cavity and ventricle wall was significantly related to the PFS (p = 0.002) and OS (p = 0.027). In multivariate analysis, the absence of definitive infiltrating tumor cells improved PFS (hazard ratio: 0.184; 95% CI: 0.049–0.690, p = 0.012) and OS (hazard ratio: 0.124; 95% CI: 0.015–0.998, p = 0.050). Conclusions After resection both of the MR-enhancing lesions and strong purple fluorescence on resection cavity, there was no correlation between remnant fluorescent signals and infiltrating tumor cells (AU)

Influence of glioblastoma contact with the subventricular zone on survival and recurrence patterns

Background There is growing evidence that the subventricular zone (SVZ) may be involved in both the initiation and progression of glioblastoma (GB). We aimed to assess tumor proximity to the SVZ as a potential prognostic factor in GB. Method Retrospective study of 133 patients diagnosed with primary GB who underwent surgery followed by temozolomide-based chemoradiation between 2010 and 2016. All lesions were classified according to their anatomic relation with the SVZ. We determined the effect of tumor contact with the SVZ on progression-free survival (PFS), overall survival (OS), type, and patterns of recurrence. Results At a median follow-up of 18.6 months (95% CI 15.9–21.2), PFS and OS were 7.5 (95% CI 6.7–8.3) and 13.9 (95% CI 10.9–16.9) months, respectively. On the univariate analyses, initial contact with the SVZ was a factor for poor prognosis for both PFS (6.1 vs. 8.7 months; p = 0.006) and OS (10.6 vs. 17.9 months; p = 0.037). On the multivariate analysis, tumor contact with the SVZ remained statistically significant for PFS, but not OS. Patients with SVZ-contacting tumors presented a higher rate of aggressive clinical progression (30.9% vs. 11.3%; p = 0.007) and contralateral relapse patterns (23.4% vs. 9.1%; p = 0.048). Conclusions Our results suggest that glioblastoma contact with the SVZ appears to be an independent prognostic factor for poor PFS. The presence of an SVZ-contacting tumor was associated with more aggressive recurrences and a higher rate of contralateral relapses. These findings suggest that this variable may be a new prognostic factor in glioblastoma (AU)

CDC6 is up-regulated and a poor prognostic signature in glioblastoma multiforme

Purpose Glioblastoma multiforme (GBM) represents the most common and the most malignant type of brain tumor. Cell division cycle 6 (CDC6), a gene associated with DNA replication initiation, has been proven to be associated with the prognosis of multiple tumors. In this study, we aim to explore the association between CDC6 expression and GBM carcinogenesis and prognosis. Methods CDC6 expression in normal cells and GBM cells was explored by analyzing TCGA dataset, as well as by RT-PCR and western blot methods. Survival analysis was performed by the Kaplan–Meier method. Multivariate Cox-regression analysis was adopted to estimate the independence of CDC6 as a GBM prognostic factor. Results and conclusions Elevated CDC6 levels in GBM tumor tissues compared with those in normal brain tissues were illustrated by analyzing the gene expression profiles from TCGA dataset, and confirmed by RT-PCR and western blot assays in GBM tumor and normal human astrocyte cell lines. Kaplan–Meier analysis indicated the negative influence of high CDC6 expression on GBM overall survival (OS) probability and days to progression (D2P) after initial treatment, but not on days to recurrence (D2R) after initial treatment. Multivariate Cox regression analysis showed CDC6 as an independent signature marker gene for GBM prognosis. In addition, the combination of CDC6 mRNA expression and CpG island methylator phenotype (CIMP) could sensitively predict 3-year OS and D2P. In conclusion, our study uncovered the role of CDC6 in GBM carcinogenesis and prognosis for the first time, which could shed new light on GBM diagnosis and treatment (AU)

MGMT-inhibitor in combination with TGF-BRI inhibitor or CDK 4/6 inhibitor increases temozolomide sensitivity in temozolomide-resistant glioblastoma cells

Background Glioblastoma (GB) remains an incurable and deadly brain malignancy that often proves resistant to upfront treatment with temozolomide. Nevertheless, temozolomide remains the most commonly prescribed FDA-approved chemotherapy for GB. The DNA repair protein methylguanine-DNA methyl transferase (MGMT) confers resistance to temozolomide. Unsurprisingly temozolomide-resistant tumors tend to possess elevated MGMT protein levels or lack inhibitory MGMT promotor methylation. In this study, cultured human temozolomide resistance GB (43RG) cells were introduced to the MGMT inhibitor O6-benzylguanine combined with temozolomide and either LY2835219 (CDK 4/6 inhibitor) or LY2157299 (TGF-βRI inhibitor) seeking to overcome GB treatment resistance. Methods Treatment effects were assessed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, western blot, cell viability, and cell cycle progression. Results Our in vitro study demonstrated that sequential treatment of O6-Benzylguanine with either LY2385219 or LY2157299-enhanced temozolomide enhanced sensitivity in MGMT+ 43RG cells. Importantly, normal human neurons and astrocytes remained impervious to the drug therapies under these conditions. Furthermore, LY2835219 has additional anti-proliferative effects on cell cycling, including induction of an RB-associated G (1) arrest via suppression of cyclin D-CDK4/6-Rb pathway. LY2157299 enhances anti-tumor effect by disrupting TGF-β–dependent HIF-1α signaling and by activating both Smad and PI3K-AKT pathways towards transcription of S/G2 checkpoints. Conclusion This study establishes the groundwork for the development of a combinatorial pharmacologic approach by using either LY2385219 or LY2157299 inhibitor plus O6-Benzylguanine to augment temozolomide response in temozolomide-resistant GB cells (AU)

Coexpresión de NG2/GFAP tras la diferenciación en células transfectadas con las mutaciones de GFAP y en células procedentes de gliomas indiferenciados / NG2 and GFAP co-expression after differentiation in cells transfected with mutant GFAP and in undifferentiated glioma cells

INTRODUCCIÓN: La enfermedad de Alexander es una enfermedad rara causada por mutaciones en el gen que codifica la proteína glial ácida fibrilar (GFAP). En un estudio previo hemos observado que la diferenciación de neuroesferas transfectadas con estas mutaciones genera un tipo celular que comparte la expresión de GFAP y NG2. OBJETIVOS: Determinar el efecto de las mutaciones en marcadores moleculares en comparación con células de glioma diferenciados que expresan simultáneamente GFAP y NG2. MÉTODOS: Se utilizaron muestras de glioblastoma humana (GLM) y neuroesferas procedentes de rata transfectadas con mutaciones de GFAP para el análisis de la expresión tras diferenciación de GFAP y NG2, así como el análisis inmunocitoquímico de diferenciación de ambos tipos celulares y detección de ambas proteínas, junto a nestina, vimentina, Olig2 y caspasa 3 a los 3 y 7 días de diferenciación. RESULTADOS: Tanto las células transfectadas con mutaciones de GFAP como las células procedentes de GLM mostraron un incremento de NG2 y GFAP. Sin embargo, la expresión de células caspasa 3 positiva era marcadamente mayor entre las células transfectadas que entre las células procedentes de GLM. CONCLUSIÓN: Nuestros resultados parecen indicar que la expresión de GFAP no es el único factor que condiciona la muerte celular en la enfermedad de Alexander y que la expresión de caspasa 3 y el potencial papel de la NG2 en incrementar la resistencia a la apoptosis en las células que coexpresan GFAP y NG2 deben ser considerados en la búsqueda de acciones terapéuticas en esta enfermedad

INTRODUCTION: Alexander disease is a rare disorder caused by mutations in the gene coding for glial fibrillary acidic protein (GFAP). In a previous study, differentiation of neurospheres transfected with these mutations resulted in a cell type that expresses both GFAP and NG2. OBJECTIVE: To determine the effect of molecular marker mutations in comparison to undifferentiated glioma cells simultaneously expressing GFAP and NG2. METHODS: We used samples of human glioblastoma (GBM) and rat neurospheres transfected with GFAP mutations to analyse GFAP and NG2 expression after differentiation. We also performed an immunocytochemical analysis of neuronal differentiation for both cell types and detection of GFAP, NG2, vimentin, Olig2, and aspase-3 at 3 and 7 days from differentiation. RESULTS. Both the cells transfected with GFAP mutations and GBM cells showed increased NG2 and GFAP expression. However, expression of caspase-3-positive cells was found to be considerably higher in transfected cells than in GBM cells. CONCLUSIONS: Our results suggest that GFAP expression is not the only factor associated with cell death in Alexander disease. Caspase-3 expression and the potential role of NG2 in increasing resistance to apoptosis in cells co-expressing GFAP and NG2 should be considered in the search for new therapeutic strategies for the disease

Dilemas en el manejo de glioblastoma espinal primario durante el embarazo / Dilemmas in primary spinal glioblastoma management during pregnancyi

El glioblastoma espinal primario (GBM) es una entidad clínicamente rara, con progresión rápida y resultado inevitable, a pesar de su manejo intensivo. En una mujer embarazada, esta neoplasia es particularmente grave, ya que los beneficios potenciales para la madre que ofrece el tratamiento estándar para GBM deben sopesarse frente a los riesgos para el feto. Existen pocas directrices en la literatura sobre cómo manejar a las pacientes embarazadas con tumores neuroaxiales malignos y, en opinión de los autores, no se han publicado informes hasta la fecha sobre este neoplasma específico en dicha población. Este caso clínico describe el manejo de una paciente embarazada con GBM no diagnosticado previamente, con rápida progresión intramedular, a la que se realizó cesárea electiva para permitir el inicio de tratamiento oncológico. Debatimos los dilemas a los que se enfrentan los anestesistas, con esperanza de aportar directrices ante las futuras decisiones y de optimizar los resultados

Primary spinal glioblastoma (GBM) is a clinically rare entity with rapid progression and a dismal outcome despite aggressive treatment. In a pregnant woman, this malignancy is particularly dramatic because the potential benefits to the mother offered by standard GBM treatment must be balanced against the risks to the fetus. There is little guidance in the literature on how to manage pregnant patients with malignant neuraxial tumours and, to the authors' knowledge, no reports have been published so far regarding this specific neoplasm in such population. This case report describes the management of a pregnant patient with a previously undiagnosed and rapidly progressive intramedullary GBM submitted to an elective caesarean delivery to allow subsequent onset of oncological treatment. Dilemmas faced by anaesthetists are discussed in hope to provide guidance for future decisions and optimize outcomes

Necrosis cutánea por heparina con afectación a distancia del punto de administración / Heparin-Induced Skin Necrosis Occurring at a Distance From Injection Sites

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