NUDT5 promotes the growth, metastasis, and Warburg effect of IDH wild-type glioblastoma multiforme cells by upregulating TRIM47

@#Objective: To explore the regulatory mechanism of NUDT5 in glioblastoma multiforme (GBM). Methods: GEPIA database was used to predict the expressions of NUDT5 and tripartite motif family proteins 47 (TRIM47) in GBM patients. RT-qPCR and Western blot analyses were performed to examine NUDT5 expression in GBM cells. LN-229 cell proliferation, migration as well as invasion were estimated by CCK- 8, colony formation, wound healing, and Transwell assays following interference with NUDT5. ECAR assay, L-lactic acid kit, glucose detection kit, and ATP detection kit were applied for the detection of glycolysis-related indexes. Co-immunoprecipitation experiment was carried out to verify the relationship between NUDT5 and TRIM47. Results: GEPIA database showed that NUDT5 expression was significantly increased in GBM patients. Inhibiting the expression of NUDT5 in GBM cells significantly suppressed the viability, proliferation, invasion, migration, and glycolysis of GBM cells. Moreover, TRIM47 was highly expressed in GBM cells and interacted with NUDT5. Overexpression of TRIM47 partially reversed the inhibitory effect of NUDT5 downregulation on the proliferation, metastasis, and glycolysis of GBM cells. Conclusions: NUDT5 promotes the growth, metastasis, and Warburg effect of GBM cells by upregulating TRIM47. Both NUDT5 and TRIM47 can be used as targets for GMB treatment.

Role of cyclin D1 in glial tumors—A retrospective and observational study

Aim: High-grade glial tumors remain as one of the most lethal malignancies. Cyclin D1 is expressed in some human malignancies and is the potential target of intervention. The present study aims to determine the relationship of cyclin D1 expression with other clinicopathological parameters. Materials and Methods: A cross-sectional study was carried out in a tertiary care center. Biopsy proven 66 cases of glial tumor patients were included in the study. The patients with incomplete clinical details were excluded from the study. Immunohistochemistry using antibodies for IDH 1 and cyclin d1 was done in all the cases. Glial tumors were reclassified according to WHO 2016 classification. Data analysis was performed using SPSS 26.0 for the windows. Result: Among 66 patients, 49 (74.3%) were males and 17 (25.7%) were females. The age of the patients ranged from 20 years to 70 years. Overall, 6.02% were of grade I Glial tumors, 22.7% were of grade II Glial tumors, 19.6% patients were of grade III Glial tumors, and 51.6% patients were of grade IV Glial tumors. Of 66 samples tested cyclin D1 was positive in 25 (37.87%) as high expressers and 7 (10.60%) were low expressers. Our study showed a significant correlation between the expression of cyclin D1 with grade and IDH mutation status, No significant correlation of cyclin D1 was noted with age or sex of the patient. Conclusion: Cyclin D1 was associated with a higher grade of the glial tumor. It can be a potential marker both for prognosis and treatment of glial tumors.

Combination immunotherapy of glioblastoma with dendritic cell cancer vaccines,anti-PD-1 and poly I:C / 药物分析学报

Glioblastoma(GBM)is a lethal cancer with limited therapeutic options.Dendritic cell(DC)-based cancer vaccines provide a promising approach for GBM treatment.Clinical studies suggest that other immu-notherapeutic agents may be combined with DC vaccines to further enhance antitumor activity.Here,we report a GBM case with combination immunotherapy consisting of DC vaccines,anti-programmed death-1(anti-PD-1)and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy,and the patient remained disease-free for 69 months.The patient received DC vaccines loaded with multiple forms of tumor antigens,including mRNA-tumor associated antigens(TAA),mRNA-neoantigens,and hypochlorous acid(HOCl)-oxidized tumor lysates.Furthermore,mRNA-TAAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histo-compatibility complex(MHC)class Ⅰ and Ⅱ antigen presentation.The treatment consisted of 42 DC cancer vaccine infusions,26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions.The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells.No immunotherapy-related adverse events were observed during the treatment.Robust antitumor CD4+and CD8+T-cell responses were detected.The patient remains free of disease progression.This is the first case report on the combination of the above three agents to treat glioblastoma patients.Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient.A large-scale trial to validate these findings is warranted.

OLIG2 expression level could be used as an independent prognostic factor for patients with cerebellar Glioblastoma (cGBM)

Abstract Objectives: The incidence of cerebellar Glioblastoma Multiforme (cGBM) is rare. Database like TCGA have not distinguish cGBM from GBM, our knowledge on cGBM gene expression characteristics is limited. The expression status of Oligodendrocyte Lineage Transcription factor 2 (OLIG2) and its clinical significance in cGBM is still unclear. Methods: The clinical data and tissue specimens of 73 cGBM patients were retrospectively studied. The association between OLIG2 expression level and the demographic characteristics of cGBM patients was identified by the Chi-Square test. The survival curves were drawn by Kaplan-Meier analysis. The independent prognostic factors was calculated according to Cox regression analysis. Results: The OLIG2 high expression was observed in about 57.5% (42/73) of the cGBM patients. Patients with high OLIG2 expression levels had a higher alive ratio at the end of follow-up (alive ratio: 70.6% vs. 29.4%, p = 0.04). The median survival time was 21 months and 13 months for high and low expression of OLIG2 (p < 0 .05). Univariate analysis and Multivariate analysis indicated that EOR (HR = 3.89, 95% CI 1.23−12.26, p = 0.02), low OLIG2 expression (HR = 5.26, 95% CI 1.13−24.59, p = 0.04), and without adjuvant therapy (HR = 4.95, 95% CI 1.22−20.00, p = 0.03) were independent risk factors for the OS of cGBM patients. Conclusion: High expression level of OLIG2 could be used as an independent favorable prognosis indicator in cGBM patients and be recognized as a characteristic biomarker of cGBM.

The Role of Transforming Growth Factor Beta and Smad Receptors in Determining Prognosis in High-Grade Primary Brain Tumors: Glioblastoma Multiforme / O papel do fator de crescimento transformador beta e receptores smad na determinação do prognóstico em tumores cerebrais primários de alto grau: glioblastoma multiforme

Introduction High-grade primary brain tumors cause serious morbidity and mortality. This study aimed to investigate the role of transforming growth factor beta (TGF-ß) and suppressor of mothers against decapentaplegic (Smad) receptors in high-grade primary brain tumors. Material and Method Thirteen patients with a pathological diagnosis of glioblastoma multiforme were included in the study. Pathological preparations of each patient were analyzed retrospectively in histochemistry and immunohistochemistry laboratories. Transforming growth factor beta 1, TGF-ß2, TGF-ß3, Smad 1/2/3, Smad 6, and Smad 7 stainings were evaluated, and the immunoreactivity densities were examined. Result We found out an increase in the expression of TGF-ß1 and TGF-ß3 protein. Regarding the inhibitin receptors, Smad 6 showed much more expression than Smad 7. Thus, we found that Smad 6 has a protective effect and role in the tissue. Immunhistochemically, TGF-ß family stains, which are activated by types I-and -II receptors, and the stainless staining of the Smad family might also be showing that the TGF-ß family is taking action with a secondary pathway other than the Smad family. Conclusion In addition to Smad family receptors, Shc-GBR2, SARA, and Ras-Erk1/2 receptors should be investigated in future research. After that, the prognosis, diagnosis, and patient-based chemotherapy strategies for the treatment of glioblastoma multiforme may take a more prominent role.

Objetivo Tumores cerebrais primários de alto grau causam morbidade e mortalidade graves. Este estudo teve como objetivo investigar o papel dos receptores fato de crescimento transformante beta (TGF-ß) e mães contra homólogo decapentaplégico (Smad, na sigla em inglês) em tumores cerebrais primários de alto grau. Métodos Treze pacientes com diagnóstico patológico de glioblastoma multiforme foram incluídos no estudo. As preparações patológicas de cada paciente foram analisadas retrospectivamente em laboratórios de histoquímica e imunohistoquímica. As colorações de TGF-ß1, TGF-ß2, TGF-ß3, Smad 1/2/3, Smad 6, e Smad 7 foram avaliadas, e as densidades de imunorreatividade foram examinadas. Resultados Encontramos aumento na expressão das proteínas TGF-ß1 e TGF-ß3. Em relação aos receptores de inibitina, o Smad 6 mostrou muito mais expressão do que o Smad 7. Assim, concluímos que o Smad 6 tem efeito e função protetores no tecido. As colorações imunohistoquímicas da família TGF-ß, que são ativadas pelos receptores do tipo I e do tipo II, e as colorações menos da família Smad também podem estar mostrando que a família TGF-ß está agindo com outra via secundária que não a família Smad. Conclusão Assim como os estudos na família Smad, receptores como Shc-GBR2, SARA, Ras-Erk1/2 devem ser investigados em pesquisas futuras. Posteriormente, o prognóstico, o diagnóstico, e as estratégias de quimioterapia baseadas no paciente podem assumir um lugar mais priminente no futuro, no glioblastoma multiforme.

Expression of AEBP1 and its prognostic role in glioma based on the data-mining of TCGA and GTEx databases / 西安交通大学学报(医学版)

【Objective】 To explore the expressions of adipocyte enhancer binding protein 1 （AEBP1） gene and its isoforms in different types of gliomas， and the influence of AEBP1 gene on the prognosis of patients with different types of gliomas. 【Methods】 We used the GEPIA2 visual network analysis tool to analyze AEBP1 gene expression levels in the tumor tissues of glioblastomas （GBM， including classical， mesenchymal， neural， and proneural ones） and low-grade gliomas （LGG， including astrocytoma， oligoastrocytoma， oligodendroglioma） in the TCGA database and normal human tissue samples in the TCGA and GTEx databases by one-way ANOVA. The distribution trend of isoforms of AEBP1 gene in gliomas was analyzed using the violin plot. The Kaplan-Meier survival curve was drawn and the Logrank test was used to analyze the influence of AEBP1 gene expression in GBM and LGG tumor tissues on the prognosis of glioma patients. 【Results】 The expression of AEBP1 in the tumor tissues of overall GBM and the four types of GBM was higher than that in the normal control tissues （P<0.05）. The expression of AEBP1 in astrocytoma and oligodendrocyte astrocytoma tumor tissues was higher than that in normal control tissues （P<0.05）. There were nine isoforms of AEBP1 gene in GBM and LGG， and the expression level in GBM was higher. The overall survival （OS） of the AEBP1 low expression group of GBM patients and the proneuronal GBM patients was better than that of the high expression group （P<0.05）. The OS and progression-free survival of LGG patients and the AEBP1 low-expression group of astroglioma were better than those of the high-expression group （P<0.05）. 【Conclusion】 AEBP1 has an important clinical value in the pathogenesis and development of GBM and LGG， and thus can be used as a diagnostic marker and a candidate gene for targeted therapy.

Efficacy of postoperative radiotherapy with reduced target volume in patients with glioblastoma multiforme / 中国辐射卫生

@#<b>Objective</b> To evaluate the therapeutic efficacy of radiotherapy with reduced target volume in glioblastoma multiforme patients following surgical treatment, and to provide a basis for the development of postoperative radiotherapy regimens for glioblastoma multiforme. <b>Methods</b> The medical records of 29 patients with glioblastoma multiforme receiving postoperative adjuvant radiochemotherapy with a reduced radiation target were retrospectively reviewed. The gross tumor volume (GTV) included postoperative tumor cavity and residual lesions, and the clinical target volume (CTV) was GTV plus 2.5 cm margin with adaptation according to the affected organs and anatomic structures. GTV and CTV received intensity-modulated radiotherapy with concomitant boost at 60 Gy/30 fractions and 54 Gy/30 fractions, respectively. The progression-free survival (PFS) and site of recurrence were analyzed. <b>Results</b> The patients were followed up until March 2022. Among the 29 patients with glioblastoma multiforme, 3 showed recurrence-free survival of 52, 20, and 19 months, respectively. Among the 26 patients with recurrent glioblastoma multiforme, there were no case with recurrence in CTV, 25 cases with recurrence in GTV (including 3 cases with intracranial dissemination), and one case with intracranial dissemination and without recurrence in GTV. The median PFS was 7 months (4 to 15 months). Among the 3 patients with recurrence in GTV and intracranial dissemination, one showed primary lesion in the right frontal parietal lobe and the metastatic lesion in the right occipital lobe, one primary lesion in the right occipital lobe and multiple metastatic lesions in the cerebellum, and one primary lesion in the left frontal lobe and the metastatic lesion in the right frontal lobe. The PFS was 4 to 5 months for seven patients receiving partial resection, and 6 to 15 months for patients receiving total and subtotal resection. The three recurrence-free survivors all underwent total resection. <b>Conclusion</b> Recurrence in target volume still prevails in patients with glioblastoma multiforme receiving postoperative radiotherapy with reduced target volume, and 60 Gy/30 fractions fail to control the tumor cavity and residual lesions of glioblastoma multiforme.

Glioblastoma multiforme con presentación seudovascular / Glioblastoma multiforme with pseudovascular presentation

Introducción: El glioblastoma multiforme es el tumor cerebral primario más frecuente y agresivo en adultos, representa cerca de 25 por ciento de los tumores intracraneales. Las principales manifestaciones clínicas están dadas por cefalea, convulsiones, cambios de conducta y un síndrome focal más definido (frontal, temporal, parietooccipital o del cuerpo calloso). En algunos pacientes, el comienzo es brusco por hemorragia o crecimiento rápido de un quiste intratumoral. El diagnóstico se realiza por resonancia magnética y se confirma con biopsia cerebral. El tratamiento es multidisciplinario e incluye resección quirúrgica, quimioterapia y radioterapia. No obstante, el pronóstico es desfavorable en la mayor parte de los pacientes. Objetivo: Describir el caso de un paciente con glioblastoma multiforme que se presentó en forma seudovascular. Caso clínico: Se presenta el caso de un paciente masculino de 60 años de edad con antecedentes de hipertensión arterial y enfermedad cerebrovascular. Tres días antes de su ingreso comenzó a manifestar dificultad para hablar y alteración en la marcha por pérdida de la fuerza muscular en el hemicuerpo derecho. Por lo anteriormente expuesto fue llevado al Hospital Clínico Quirúrgico Julio Trigo López donde fue ingresado y se diagnosticó un tumor cerebral. El paciente evolucionó tórpidamente y falleció. El estudio anatomopatológico arrojó la presencia de un glioblastoma multiforme. Conclusiones: El caso presentado de glioblastoma multiforme forma de defecto motor ofrece información sobre esta afección que en nuestro centro no es habitual(AU)

Introduction: Glioblastoma multiforme is the most frequent and aggressive primary brain tumor in adults, representing about 25percent of intracranial tumors. The main clinical manifestations are given by headache, seizures, behavior changes and a more defined focal syndrome (frontal, temporal, parieto-occipital or corpus callosum). In some patients, the onset is abrupt due to bleeding or rapid growth of an intratumoral cyst. The diagnosis is made by magnetic resonance imaging and confirmed with brain biopsy. Treatment is multidisciplinary and it includes surgical resection, chemotherapy, and radiation therapy. However, the prognosis is poor in most patients. Objective: To describe the case of a patient with glioblastoma multiforme that presented in a pseudovascular form. Clinical report: The case of a 60-year-old male patient with a history of arterial hypertension and cerebrovascular disease is report. Three days before his admission, he began to show difficulty speaking and gait disturbance due to loss of muscle strength in the right half of his body. For the foregoing, he was taken to Julio Trigo López Surgical Clinical Hospital where he was admitted and diagnosed with a brain tumor. The patient evolved torpidly and died. The pathological study revealed the presence of a glioblastoma multiforme. Conclusions: The reported case of glioblastoma multiforme in the form of a motor defect provides information on this condition that is not common in our center(AU)

Anesthetic management in neurological disorders: is combined spinal-epidural a suitable option? Case report / Manejo anestésico en trastornos neurológicos: ¿es la anestesia espinal-epidural una alternativa apropiada? Reporte de caso

Abstract Tuberous sclerosis (TSC) is a rare disease with multi-systemic involvement, predominantly neurological. Little evidence exists about the anesthetic management of patients with this disorder, particularly in pregnant women. This article discusses a case of a patient with TSC admitted to our hospital for the delivery of a twin gestation. Twenty-four hours after surgery, the patient presented left-side facial-brachial hypoesthesia and headache. A brain CT revealed a right frontal cortical bleeding tumor, which was diagnosed as glioblastoma multiforme. The patient was discharged 15 days after admission and a neurosurgical approach was suggested.

Resumen La esclerosis tuberosa es una enfermedad poco frecuente asociada con compromiso multisistémico, principalmente neurológico. Es poca la evidencia sobre el manejo anestésico de los pacientes con este trastorno, en particular las mujeres embarazadas. En este artículo presentamos el caso de una paciente con esclerosis tuberosa ingresada en nuestro hospital para el parto de una gestación gemelar. Veinticuatro horas después de la cirugía, la paciente presentó hipoestesia facial y braquial izquierda y cefalea. La tomografía cerebral mostró un tumor cortical sangrante en el lóbulo frontal derecho, diagnosticado como glioblastoma multiforme. La paciente fue dada de alta 15 días después de su ingreso y, con recomendación de manejo por neurocirugía.

Caracterización molecular del glioblastoma multiforme de un paciente con larga sobrevida / Molecular characterization of glioblastoma multiforme in a patient with long survival

RESUMEN El glioblastoma multiforme (GBM) es un tumor del sistema nervioso central con alta tasa de recambio celular, infiltración, degradación de la matriz extracelular y resistencia al tratamiento resectivo y quimioterapéutico. La sobrevida general no suele ser superior a los dos años. Sin embargo, en los últimos años se han dilucidado mejor los mecanismos moleculares que sustentan su comportamiento y que, potencialmente, podrían modularse con la terapia. A continuación se presenta el caso de un adulto joven, de 20 años, con diagnóstico de glioblastoma multiforme frontal derecho a los 13 años. El tratamiento incluyó cirugía resectiva, quimioterapia y dieta cetogénica. La caracterización genética del tumor se analiza en el contexto clínico del paciente.

SUMMARY Glioblastoma multiforme is a very aggressive central nervous system tumor with a high celular replacement, local infiltration, degradation of the extracellular matrix and resistance to surgery and chemotherapeutical agents. General survival used to be less than 2 years. However, research in the last years has shown the molecular mechanisms underlying behavior and potentially be a therapeutical targets. We show an adult with 20 years old diagnosed with glioblastoma multiforme when he was 13 years, whose treatment involved resective surgery, chemoterapy and ketogenic diet. Genetic characterization was performed and analyzed in the context of the clinical pathway.

MiR-128-3p Regulates Proliferation, Migration and Apoptosis of Glioblastoma Multiforme by Targeting HOXA5 / 肿瘤防治研究

Objective To investigate the reasons of HOXA5 overexpression in GBM and the molecular mechanism of miR-128-3p regulating the proliferation, invasion and apoptosis of glioblastoma multiforme. Methods After increasing and decreasing miR-128-3p expression in U87 cell lines by lentivirus transfection, the changes of HOXA5 expression were detected by Western blot, to explore the correlation between miR-128-3p and HOXA5 in GBM. The dual-luciferase reporter tests were performed to detect the target interaction of miR-128-3p with HOXA5. Through CCK-8 test, Transwell test, flow cytometric assay and tumor cell xenograft in nude mice, we verified molecular mechanism of miR-128-3p regulating the proliferation, invasion and apoptosis of GBM in vitro and in vivo. Results The expression level of HOXA5 was decreased in U87 cell line after miR-128-3p upregulation. In addition, the expression level of HOXA5 was increased in U87 cell line after miR-128-3p downregulation (P < 0.05). The expression level of HOXA5 was correlated negatively with the expression of miR-128-3p in U87 cell lines. MiR-128-3p targetedly interacted with 3'UTR of HOXA5 and inhibited the expression of HOXA5. The proliferation, invasion and anti-apoptosis of U87 cells were significantly decreased in the miR-128-3p+control group. Conclusion MiR-128-3p regulates negatively the proliferation, invasion and anti-apoptosis of GBM cells by targeting HOXA5. The overexpression of HOXA5 is induced by downregulation of miR-128-3p in GBM.

Mechanism of LncRNA SNHG5 on Proliferation, Invasion and Apoptosis of Glioblastoma Multiforme Cells by Targeting miR-421 / 肿瘤防治研究

Objective To investigate the molecular mechanism of SNHG5 regulating the proliferation, invasion and apoptosis of glioblastoma multiforme (GBM) cells by targeting miR-421. Methods Real-time quantitative PCR test was performed to detect the expression levels of SNHG5 and miR-421 in 31 cases of GBM tissue samples and 32 cases of normal brain tissue samples. After increasing or decreasing SNHG5 expression in U87 cell lines by lentivirus or plasmid transfection, the changes of miR-421 expression were measured by real-time quantitative PCR, to explore the correlation between SNHG5 and miR-421 in GBM. The dual-luciferase reporter test was performed to explore the target interaction of SNHG5 and miR-421. The plasmids with low expression of SNHG5 and miR-421 were cotransfected into U87 cells for the rescue experiment. CCK-8 test, Transwell test, flow cytometry and tumor cell xenograft in nude mice were used to verify molecular mechanism of SNHG5 regulating the proliferation, invasion and apoptosis of GBM in vitro and vivo. Results The expression level of miR-421 was decreased in U87 cell line after SNHG5 upregulation. In addition, the expression level of miR-421 was increased in U87 cell line after SNHG5 downregulation (P < 0.05). The expression level of SNHG5 was correlated negatively with the expression of miR-421 in GBM and U87 cell line. The result of luciferase reporter tests indicated SNHG5 targetedly interacted with miR-421. Rescue experiment results showed that compared with si-SNHG5+miR-421-inhibitor group, the proliferation, invasion and anti-apoptosis ability of U87 cells were significantly inhibited in the si-SNHG5+control-inhibitor group, the expression levels of BAX and p21 were significantly higher, the expression levels of CyclinD1 and Bcl-2 were lower remarkably (P < 0.05). Conclusion SNHG5 promotes the proliferation, invasion and anti-apoptosis of GBM by targeting miR-421 and regulating the expression of CyclinD1, p21, BAX and Bcl-2. Downregulation of miR-421 is related to SNHG5 overexpression in GBM.

Epidemiología descriptiva y cambios en la frecuencia de tumores astrocíticos en el Instituto Nacional de Neurología y Neurocirugía de México / Descriptive epidemiology and frequency variations of astrocytic tumors in the National Institute of Neurology and Neurosurgery of Mexico

Resumen: Objetivo: Determinar distribución, localización y cambios de la frecuencia de tumores astrocíticos (TA) en un instituto mexicano de neurología. Material y métodos: Se revisaron los registros institucionales de TA de cinco décadas. Se compararon las relaciones TA/egresos quirúrgicos (EQ) y TA/total de tumores del sistema nervioso central (TSNC) de 1995 a 2014. Resultados: Se analizaron 2 287 TA (1 356 en hombres y 931 en mujeres). El glioma más común fue el glioblastoma multiforme (GBM), que estuvo presente en adultos jóvenes con una frecuencia mayor a la reportada en otros estudios. La relación TA/EQ y TA/TNSC fue similar entre 1995 y 2014. Conclusiones: En general, la frecuencia de TA atendidos en el Instituto es similar a la reportada internacionalmente. No obstante, los casos de TA en el subgrupo de adultos jóvenes con GBM son más frecuentes (40%) que las incidencias reportadas en otros estudios (menores al 5%). No se encontró variación significativa en la frecuencia de TA durante las últimas dos décadas.

Abstract: Objective: To determine distribution, localization and frequency variations of astrocytic tumors (AT) in a Mexican Institute of neurology. Materials and methods: Institutional registries of AT from five decades were analyzed. AT/Surgical discharges (SD) and AT/Central Nervous System Tumors (CNST) from 1995 to 2014 were compared. Results: Two thousand two hundred and eighty-seven AT (1 356 men and 931 women) were analyzed. The most common glioma was glioblastoma multiforme (GBM), found in young adults with a higher frequency to that reported in other studies. Relation of AT/SD, as well as, relation of AT/CNST was similar between 1995 and 2014. Conclusions: In general, the frequency of AT attended at the Institute is similar to that found worldwide, being only higher the number of GBM in younger adults. There was not significant variation in the frequency of AT during the time studied.

A Dual Genetic Alteration (Mitochondrial and Nuclear DNA): First Case in Malaysia Detected in Glioblastoma Multiforme

@#Although the precise etiology of Glioblastoma multiforme (GBM, WHO grade IV) remains unknown, its progression is believed to be driven by the accumulation of multiple genetic alterations. Here, we report a case of a patient who developed GBM, and associated with dual alterations, particularly 4977-bp deletion in mtDNA (mtDNA4977) and p.Arg132His (R132H) mutation in IDH1. A 35-year old Malaysian woman patient who primary diagnosed with astrocytoma WHO grade I and subsequently after four years developed a GBM, was detected with a mtDNA4977. This deletion appears to be a sporadic mutation. Additionally, analysis of patient’s tumor tissue also found to harbor a heterozygous IDH1 R132H mutation. This represents the first case report of coexisting mtDNA4977 together with IDH1 R132H mutation in a Malaysian patient of GBM. The findings of dual alterations could be of therapeutic benefit if these alterations were justified to be contributing to GBM growth and aggressiveness.

Patterns of recurrence and outcomes of glioblastoma multiforme treated with chemoradiation and adjuvant temozolomide

OBJECTIVES: To assess the patterns of failure and prognostic factors in Brazilian patients with glioblastoma multiforme (GBM) treated with radiotherapy (RT) and concurrent and adjuvant temozolomide (TMZ). METHODS: Patients with diagnosed GBM post-resection received postoperative RT. TMZ was administered concurrently at 75 mg/m2/day for 28 consecutive days and adjuvant therapy at 150-200 mg/m2/day for 5 days every 28 days. Radiographic failure was defined as any new T1-enhancing lesion or biopsy-confirmed progressive enhancement inside of the radiation field. When possible, patients with recurrence were salvaged with metronomic TMZ, either in combination with a local treatment or alone (surgery or re-irradiation). Several prognostic factors were evaluated for overall survival (OS). Univariate and multivariate analyses were performed to identify significant factors. A p-value <0.05 was considered significant. RESULTS: This study included 50 patients. The median follow-up time was 21 months. The median RT dose was 60 Gy and all patients received concomitant TMZ. During follow-up, 41 (83.6%) failures were observed, including 34 (83%) in-field, 4 (9.7%) marginal, and 3 (7.3%) distant failures. Metronomic TMZ was used as salvage treatment in 22 (44%) cases and in combination with local treatment in 12 (24%) cases. The median OS and progression-free survival times for the entire cohort were 17 and 9 months, respectively. In univariate analysis, the following factors were significant for better OS: maximal surgical resection (p=0.03), Karnofsky Performance Score (KPS)>70 at diagnosis (p=0.01), metronomic TMZ treatment (p=0.038), recursive partitioning analysis class III (p=0.03), and time to failure >9 months (p=0.0001). In multivariate analysis, the following factors remained significant for better OS: metronomic TMZ (p=0.01) and time to failure >9 months (p=0.0001). CONCLUSION: The median OS of Brazilian patients with GBM treated with RT and TMZ was satisfactory. Although TMZ therapy has become the standard of care for patients with newly diagnosed GBM, the recurrence rate is extremely high. Metronomic TMZ as salvage treatment improved survival in these patients.

Avances neuroquirúrgicos y biología molecular en el tratamiento del glioblastoma multiforme / Neurosurgical advances and molecular biology in the treatment of glioblastoma multiforme

RESUMEN A pesar de los avances en radioterapia, quimioterapia y los tratamientos de resección quirúrgica agresiva en el glioblastoma multiforme, el pronóstico sigue siendo sombrío. Con la presente revisión se describen, en un marco actual, las principales alternativas de tratamiento del glioblastoma multiforme. Se revisaron los principales artículos publicados en inglés, en revistas de alto impacto a nivel mundial, acerca de los principales avances en el tratamiento de este tumor. Se abordaron los importantes progresos neuroquirúrgicos en la resección del glioblastoma así como las implicaciones de las células madres tumorales en la génesis y control de la proliferación tumoral y el efecto de la hipoxia sobre la dinámica celular tumoral. Se explican las alteraciones del ADN que ocasionan tumorogénesis y las mutaciones del PTEN en el glioblastoma (AU).

SUMMARY Despite advances in radiotherapy, chemotherapy and aggressive surgical resection treatments in glioblastoma multiforme, the prognosis remains discouraging. With the current review, the main alternatives for the treatment of glioblastoma multiforme are described in a current context. The authors reviewed the main articles published in English, in high impact journals worldwide, on the main advances in the treatment of this tumor. The main neurosurgical advances in the resection of glioblastoma were addressed, as well as the implications of tumor stem cells in the genesis and control of tumor proliferation, as well as the effect of hypoxia on tumor cell dynamics. DNA alterations causing tumor genesis and PTEN mutations in glioblastoma are also explained (AU).

Recent advances in molecular markers and targeted therapy in glioblastoma / 中华神经医学杂志

Glioblastoma multiforme (GBM) is one of the most common invasive malignant tumors of the central nervous system.Molecular markers of glioblastoma are screened based on dataset,obtained through a large number of studies and algorithms,and could reflect the occurrence and development of GBM,or monitor the response to treatment.The molecular markers can effectively differentiate the subtypes,malignancy and response to radiotherapy of GBM.Here,we summarize the molecular markers of glioblastoma and discuss the prospects of targeted therapy for GBM.

Gene Expression of Molecules Regulating Apoptotic Pathways in Glioblastoma Multiforme Treated with Umbilical Cord Stem Cell Conditioned Medium

@#Background: Glioblastoma multiforme (GBM) is the most malignant primary brain tumour and there is no definite cure. It has been suggested that there are significant interactions among mesenchymal stem cells (MSCs), their released factors and tumour cells that ultimately determine GBM’s growth pattern. This study aims to analyse the expression of molecules involved in GBM cell apoptotic pathways following treatment with the MSC secretome. Methods: A conditioned medium of umbilical cord-derived MSCs (UCMSC-CM) was generated by culturing the cells on serum-free αMEM for 24 h. Following this, human GBM T98G cells were treated with UCMSC-CM for 24 h. Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was then performed to measure the mRNA expression of survivin, caspase-9, TNF-related apoptosis-inducing ligand (TRAIL), DR4 and DcR1. Results: mRNA expression of caspase-9 in CM-treated T98G cells increased 1.6-fold (P = 0.017), whereas mRNA expression of survivin increased 3.5-fold (P = 0.002). On the other hand, TRAIL protein expression was upregulated (1.2-fold), whereas mRNA expression was downregulated (0.4-fold), in CM-treated cells. Moreover, there was an increase in the mRNA expression of both DR4 (3.5-fold) and DcR1 (1,368.5-fold) in CM-treated cells. Conclusion: The UCMSC-CM was able to regulate the expression of molecules involved in GBM cell apoptotic pathways. However, the expression of anti-apoptotic molecules was more upregulated than that of pro-apoptotic molecules.

Automatic disease stage classification of glioblastoma multiforme histopathological images using deep convolutional neural network

In the field of computational histopathology, computer-assisted diagnosis systems are important in obtaining patient-specific diagnosis for various diseases and help precision medicine. Therefore, many studies on automatic analysis methods for digital pathology images have been reported. In this work, we discuss an automatic feature extraction and disease stage classification method for glioblastoma multiforme (GBM) histopathological images. In this paper, we use deep convolutional neural networks (Deep CNNs) to acquire feature descriptors and a classification scheme simultaneously. Further, comparisons with other popular CNNs objectively as well as quantitatively in this challenging classification problem is undertaken. The experiments using Glioma images from The Cancer Genome Atlas shows that we obtain 96:5% average classification accuracy for our network and for higher cross validation folds other networks perform similarly with a higher accuracy of 98:0%. Deep CNNs could extract significant features from the GBM histopathology images with high accuracy. Overall, the disease stage classification of GBM from histopathological images with deep CNNs is very promising and with the availability of large scale histopathological image data the deep CNNs are well suited in tackling this challenging problem.

Checkpoints in glioblastoma multiforme: a research progress and prospect analysis / 中华神经医学杂志

Glioblastoma is the most common and most invasive primary malignant brain tumor in the central nervous system. Surgical resection, concurrent chemoradiotherapy and adjuvant chemotherapy are the standard treatment options, but the prognosis is very poor. It can be said that the standard treatment cannot safely and specifically eliminate all cancer cells, and only provide patients with limited survival benefits. Therefore, a large number of studies have attempted to use the natural cell killing ability of the immune system to aggressively attack the tumor, which is called "immunotherapy." This treatment concept has spawned a variety of treatment strategies, and is becoming another tumor treatment program after surgery, radiotherapy, chemotherapy and molecular targeted therapy. In recent years, antibodies against immune checkpoints have been shown to produce impressive clinical responses to non-small cell lung cancer, kidney cancer, melanoma, hematological tumors and other malignant tumors; it has raised interest in investigating whether these drugs are also effective in the field of brain tumors. Here, we summarize the current knowledge of central nervous system immune checkpoints and evaluate past and current immunological checkpoint treatment trials. And the future direction of treatment of immune checkpoints is discussed to provide new dawn for patients with malignant glioma.