Association of body mass index with clinical outcome of primary WHO grade 4 glioma.

Background: The prognostic value of body mass index (BMI) in primary WHO grade 4 gliomas is not widely acknowledged. This study aims to assess the survival outcomes of patients with different BMIs. Methods: Real-world data of patients diagnosed with primary WHO grade 4 (2021 version) glioma was assessed. All 127 patients admitted in this study were administered with standard-of-care from September 2018 to September 2021. The outcomes of overall survival and progression-free survival were analyzed. Results: The baseline characteristics of clinical features, molecular features, and secondary treatment in BMI subsets showed no significant difference. The survival analyses showed a significantly superior overall survival (OS) in the overweight group compared to the normal weight group. A trend of better OS in the overweight group compared to the obesity group was observed. The univariate Cox regression demonstrated patients of round-BMI 25 and 26 had superior OS outcomes. Conclusion: In this real-world setting, patients with a BMI between 24 and 28 have superior overall survival. Patients in the proper BMI range may acquire survival benefits undergoing standard-of-care of primary WHO grade 4 gliomas. The prospective studies on a larger scale on these subsets of patients are necessary to solve the paradox of BMI in glioma.

Identification of MGMT promoter methylation as a specific lipid metabolism biomarker, reveals the feasibility of atorvastatin application in glioblastoma.

BACKGROUND: Glioblastoma is one of the deadliest tumors, and limited improvement in managing glioblastoma has been achieved in the past decades. The unmethylated promoter area of 6-O-Methylguanine-DNA Methyltransferase (MGMT) is a significant biomarker for recognizing a subset of glioblastoma that is resistant to chemotherapy. Here we identified MGMT methylation can also work as a specific biomarker to classify the lipid metabolism patterns between methylated and unmethylated glioblastoma and verify the potential novel therapeutic strategy for unmethylated MGMT glioblastoma. METHODS: Liquid Chromatograph Mass Spectrometer has been applied for non-targeted metabolome and targeted lipidomic profiling to explore the metabolism pattern correlated with MGMT promoter methylation. Transcriptome has been performed to explore the biological differences and the potential mechanism of lipid metabolism in glioblastoma samples. In vivo and ex vivo assays were performed to verify the anti-tumor activity of atorvastatin in the administration of glioblastoma. RESULTS: Multi-omics assay has described a significant difference in lipid metabolism between MGMT methylated and unmethylated glioblastoma. Longer and unsaturated fatty acyls were found enriched in MGMT-UM tumors. Lipid droplets have been revealed remarkably decreased in MGMT unmethylated glioblastoma. In vivo and ex vivo assays revealed that atorvastatin and also together with temozolomide showed significant anti-tumor activity, and atorvastatin alone was able to achieve better survival and living conditions for tumor-hosting mice. CONCLUSIONS: MGMT promoter methylation status might be a well-performed biomarker of lipid metabolism in glioblastoma. The current study can be the basis of further mechanism studies and implementation of clinical trials, and the results provide preclinical evidence of atorvastatin administration in glioblastoma, especially for MGMT unmethylated tumors.

B7H3-targeting chimeric antigen receptor modification enhances antitumor effect of Vγ9Vδ2 T cells in glioblastoma.

BACKGROUND: Glioblastoma (GBM) is a highly aggressive primary brain tumor with a poor prognosis. This study investigates the therapeutic potential of human Vγ9Vδ2 T cells in GBM treatment. The sensitivity of different glioma specimens to Vγ9Vδ2 T cell-mediated cytotoxicity is assessed using a patient-derived tumor cell clusters (PTCs) model. METHODS: The study evaluates the anti-tumor effect of Vγ9Vδ2 T cells in 26 glioma cases through the PTCs model. Protein expression of BTN2A1 and BTN3A1, along with gene expression related to lipid metabolism and glioma inflammatory response pathways, is analyzed in matched tumor tissue samples. Additionally, the study explores two strategies to re-sensitize tumors in the weak anti-tumor effect (WAT) group: utilizing a BTN3A1 agonistic antibody or employing bisphosphonates to inhibit farnesyl diphosphate synthase (FPPS). Furthermore, the study investigates the efficacy of genetically engineered Vγ9Vδ2 T cells expressing Car-B7H3 in targeting diverse GBM specimens. RESULTS: The results demonstrate that Vγ9Vδ2 T cells display a stronger anti-tumor effect (SAT) in six glioma cases, while showing a weaker effect (WAT) in twenty cases. The SAT group exhibits elevated protein expression of BTN2A1 and BTN3A1, accompanied by differential gene expression related to lipid metabolism and glioma inflammatory response pathways. Importantly, the study reveals that the WAT group GBM can enhance Vγ9Vδ2 T cell-mediated killing sensitivity by incorporating either a BTN3A1 agonistic antibody or bisphosphonates. Both approaches support TCR-BTN mediated tumor recognition, which is distinct from the conventional MHC-peptide recognition by αß T cells. Furthermore, the study explores an alternative strategy by genetically engineering Vγ9Vδ2 T cells with Car-B7H3, and both non-engineered and Car-B7H3 Vγ9Vδ2 T cells demonstrate promising efficacy in vivo, underscoring the versatile potential of Vγ9Vδ2 T cells for GBM treatment. CONCLUSIONS: Vγ9Vδ2 T cells demonstrate a robust anti-tumor effect in some glioma cases, while weaker in others. Elevated BTN2A1 and BTN3A1 expression correlates with improved response. WAT group tumors can be sensitized using a BTN3A1 agonistic antibody or bisphosphonates. Genetically engineered Vγ9Vδ2 T cells, i.e.,  Car-B7H3, show promising efficacy. These results together highlight the versatility of Vγ9Vδ2 T cells for GBM treatment.

Surgical site infections after elective craniotomy for brain tumor: a study on potential risk factors and related treatments.

BACKGROUND: Surgical site infection (SSI) is a common complication following craniotomy that increases morbidity, mortality, and medical expenses. The objectives of this study were to determine the relevant risk factors associated with SSI after elective craniotomy for brain tumor and analyse the treatments for SSI. METHODS: A retrospective nested case‒control study was conducted using data from patients who underwent craniotomy for brain tumor resection at the Neurosurgical Oncology Department No. 6 of Beijing Tiantan Hospital, Capital Medical University, between January 2019 and December 2021. Risk factors for SSI were determined using multivariate logistic regression analysis. We analyzed microbiological and related treatment data for different SSI types. RESULTS: Among 2061 patients who underwent craniotomy for brain tumor, 31 had SSI (1.50%). In the multivariate logistic regression analysis, body mass index (BMI) and operative duration were identified as independent risk factors for SSI. The most common microorganism isolated from SSIs was Staphylococcus epidermidis (22.9%), and drug sensitivity results showed that gram-positive bacteria were sensitive to linezolid, vancomycin and tigecycline, whereas gram-negative bacteria were sensitive to meropenem, cefepime and ceftazidime. Six of the seven patients who underwent bone flap removal due to osteomyelitis were infected with gram-negative bacteria. CONCLUSIONS: BMI and operative duration were identified as independent risk factors for SSI. Diabetes mellitus, previous ratio therapy, type of incision, recurrence tumor and other risk factors were not found to be associated with the occurrence of SSI in this study.

Surgical Resection of Large Primary Intraosseous Meningiomas (6 Case Reports).

OBJECTIVE: The clinical features and surgical techniques related to patients undergoing resection of extracranial large primary intraosseous meningiomas are studied. METHODS: The clinical characteristics, treatment, and prognosis of 6 patients with primary intraosseous meningiomas larger than 5 cm in diameter were retrospectively reviewed in the 10th Neurosurgical Department of Beijing Tiantan Hospital, Capital Medical University. RESULTS: Five males and one female (18-57 years old) suffered from large primary intraosseous meningiomas. The main symptoms were headaches accompanied by head swelling. CT showed irregular thickening of the bone diploe with increased density and uneven surface. MRI showed partial bone destruction of the skull, local thickening of the internal and external plates, shell and palisade changes of the external cranial plate, and enhancement of the adjacent meninges. A horseshoe or coronary incision plus the "Mercedes-Benz" incision were chosen to expose the skull bone, and drilling was performed in the normal skull bone at the transition zone between abnormal and normal skull bone. After drilling, the sub flap dura was dissected, the hyperplastic skull was dissected with a milling cutter, and the residual tumor was then resected. A cranioplasty was performed 6 months to 1 year later. CONCLUSIONS: Surgical treatment and precise perioperative management can achieve a better prognosis for large intraosseous meningiomas.

Exome-wide Analysis of De Novo and Rare Genetic Variants in Patients With Brain Arteriovenous Malformation.

BACKGROUND AND OBJECTIVES: Brain arteriovenous malformation (bAVM) is a congenital disorder and a leading cause of hemorrhagic stroke. Germline genetic variants play an essential role in the pathogenesis of bAVM. However, the biological relevance of disease-associated genes identified in previous studies is elusive. In this study, we aim to systematically investigate the contribution of germline variants to bAVM and explore the critical molecular pathways underlying the pathogenesis of bAVM. METHODS: Probands with sporadic bAVM were consecutively recruited into this study from November 2015 to November 2018 and underwent exome sequencing. The controls were aggregated from individuals who were not known to have vascular malformation and underwent exome sequencing for clinical or research purposes. The retained control dataset included 4,609 individuals, including 251 individuals with parental samples sequenced. We first analyzed de novo variants in cases and controls and performed a pathway enrichment analysis. A gene-based rare variant association analysis was then performed to identify genes whose variants were significantly enriched in cases. RESULTS: We collected an exome-sequenced bAVM cohort consisting of 152 trios and 40 singletons. By first focusing on de novo variants, we observed a significant mutational burden of likely gene-disrupting variants in cases vs controls. By performing a pathway enrichment analysis of all nonsynonymous de novo variants identified in cases, we found the angiopoietin-like protein 8 (ANGPTL8) regulatory pathway to be significantly enriched in patients with bAVM. Through an exome-wide rare variant association analysis utilizing 4,394 in-house exome data as controls, we identified SLC19A3 as a disease-associated gene for bAVM. In addition, we found that the SLC19A3 variants in cases are preferably located at the N' side of the SLC19A3 protein. These findings implicate a phenotypic expansion of SLC19A3-related disorders with a domain-specific effect. DISCUSSION: This study provides insights into the biological basis of bAVM by identifying novel molecular pathways and candidate genes.

CircularRNA circPARP4 promotes glioblastoma progression through sponging miR-125a-5p and regulating FUT4.

Circular RNA (circRNA) is a widely expressed non-coding RNA element characterized by a covalently closed continuous loop. Emerging evidence suggests important roles of circRNAs in the pathogenesis of human cancers. However, the functions and underlying mechanisms of circRNAs in glioma remain largely unclear. Previously, our studies uncovered a batch of abnormally expressed circRNAs in glioma tissue, among which circPARP4 was significantly upregulated with the top fold change. Here, we focused on the functional investigation toward circPARP4 in glioblastoma progression and looked for insight into its underlying mechanisms. The results confirmed the elevated expression of circPARP4 in glioma and found its association with glioma pathological grade. Gain- and loss-of-function strategies showed that circPARP4 could obviously promote glioma cell proliferation, migration, invasion, and epithelial-mesenchymal transition. Mechanistically, in vivo and in vitro studies demonstrated that circPARP4, as a miRNA sponge, directly interacted with miR-125a-5p, which then regulated FUT4 to exert the oncogenic effect on glioma behavior. Our findings illustrate functions of circPARP4 in modulating glioma progression through miR-125a-5p/FUT4 pathway, which provides a novel and potential target for glioma therapy.

Up-regulation of circular RNA hsa_circ_01844 induces apoptosis and suppresses proliferation and migration of glioblastoma cells.

BACKGROUND: Previous studies have demonstrated that various circular RNAs are involved in the malignant proliferation of cancers, such as liver cancer, lung cancer, breast cancer, and others. The potential role of circular RNAs in glioblastoma, however, is still uncertain. In this study, we aimed to study the potential role of hsa_circ_01844 in glioblastoma. METHODS: Using reverse transcription-polymerase chain reaction (RT-PCR) method, hsa_circ_01844 expression was measured in five glioblastoma samples and five normal brain samples. To evaluate the potential function of hsa_circ_01844 in glioblastoma, hsa_circ_01844 was overexpressed in glioblastoma cell lines (U251 and U87 cells). Using these two cell lines, in vitro experiments including the flow cytometry assay, 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay, Transwell assay, and cell apoptosis assay were performed to investigate the role of hsa_circ_01844 in glioblastoma. Student t test and one-way analysis of variance were used for statistical analysis. RESULTS: The expression of circular RNA hsa_circ_01844 was lower in glioblastoma tissues when compared with the normal brain tissues by RT-PCR method (0.034 ±â€Š0.036 vs. 1.630 ±â€Š0.891, P < 0.001). Using two glioblastoma cell lines, we found that overexpression of hsa_circ_01844 in glioblastoma cells suppressed their proliferation, colony formation, migration, and increased the apoptotic rate compared with empty vector group and blank control group (all P < 0.05). CONCLUSION: Hsa_circ_01844 shows decreased expression in glioblastoma and its overexpression induces apoptosis and inhibits proliferation, migration, and invasion of glioblastoma cells.

The Metabolic Activity of Caudate and Prefrontal Cortex Negatively Correlates with the Severity of Idiopathic Parkinson's Disease.

Positron emission tomography (PET) scan with tracer [18F]-fluorodeoxy-glucose (18F-FDG) is widely used to measure the glucose metabolism in neurodegenerative disease such as Idiopathic Parkinson's disease (IPD). Previous studies using 18F-FDG PET mainly focused on the motor or non-motor symptoms but not the severity of IPD. In this study, we aimed to determine the metabolic patterns of 18F-FDG in different stages of IPD defined by Hoehn and Yahr rating scale (H-Y rating scale) and to identify regions in the brain that play critical roles in disease progression. Fifty IPD patients were included in this study. They were 29 men and 21 women (mean±SD, age 57.7±11.1 years, disease duration 4.0±3.8 years, H-Y 2.2±1.1). Twenty healthy individuals were included as normal controls. Following 18F-FDG PET scan, image analysis was performed using Statistical Parametric Mapping (SPM) and Resting-State fMRI Data Analysis Toolkit (REST). The metabolic feature of IPD and regions-of-interests (ROIs) were determined. Correlation analysis between ROIs and H-Y stage was performed. SPM analysis demonstrated a significant hypometabolic activity in bilateral putamen, caudate and anterior cingulate as well as left parietal lobe, prefrontal cortex in IPD patients. In contrast, hypermetabolism was observed in the cerebellum and vermis. There was a negative correlation (p=0.007, r=-0.412) between H-Y stage and caudate metabolic activity. Moreover, the prefrontal area also showed a negative correlation with H-Y (P=0.033, r=-0.334). Thus, the uptake of FDG in caudate and prefrontal cortex can potentially be used as a surrogate marker to evaluate the severity of IPD.

Circular RNA hsa_circ_0008344 regulates glioblastoma cell proliferation, migration, invasion, and apoptosis.

BACKGROUND: Recent studies have found circular RNAs (circRNAs) involved in the biological process of cancers. However, little is known about their functional roles in glioblastoma. METHODS: Human circRNA microarray analysis was performed to screen the expression profile of circRNAs in IDH1 wild-type glioblastoma tissue. The expression of hsa_circ_0008344 in glioblastoma and normal brain samples was quantified by qRT-PCR. Functional experiments were performed to investigate the biological functions of hsa_circ_0008344, including MTT assay, colony formation assay, transwell assay, and cell apoptosis assay. RESULTS: CircRNA microarray revealed a total of 417 abnormally expressed circRNAs (>1.5-fold, P < .05) in glioblastoma tissue compared with the adjacent normal brain. Hsa_circ_0008344, among the top differentially expressed circRNAs, was significantly upregulated in IDH1 wild-type glioblastoma. Further in vitro studies showed that knockdown of hsa_circ_0008344 suppressed glioblastoma cell proliferation, colony formation, migration, and invasion, but increased cell apoptotic rate. CONCLUSIONS: Hsa_circ_0008344 is upregulated in glioblastoma and may contribute to the progression of this malignancy.

Surgical strategies and outcomes of spinal ependymomas of different lengths: analysis of 210 patients: clinical article.

OBJECT: The aim of this study was to investigate the surgical strategies and outcomes for spinal ependymomas of different lengths. METHODS: The authors used data from 210 patients with spinal ependymomas (WHO Grades II and III) in this 10-year retrospective study (January 1999 to December 2008), dividing them into 3 different groups according to length (spinal ependymomas < 5 cm, 5-10 cm, and > 10 cm). All patients underwent tumor resection. The basic characteristics of the patients were reviewed and the functional status was assessed using the McCormick classification. RESULTS: There were 89, 81, and 40 patients, respectively, in the 3 groups (< 5 cm, 5-10 cm, and > 10 cm). Grosstotal resections (GTRs) were performed in 172 patients (81.9% overall, or 86.5%, 79.0%, and 77.5% in the 3 groups, respectively). Subtotal and partial resections were achieved in 38 patients (18.1%). Eight patients with medulla oblongata or upper cervical cord tumors received a tracheotomy postoperatively. The follow-up period ranged from 56 to 176 months. One hundred thirty-five patients (76.7%) experienced improvement, (88.2%, 83.8%, and 34.4% in the < 5 cm, 5-10 cm, and > 10 cm groups, respectively). Thirty-three patients (18.8%) maintained their pretreatment status, and 8 patients (4.5%) showed deterioration following tumor resection at 6 months. Tumor recurrence or progression was observed in 6 (2.9%) of the 210 patients. Among the 6 patients, recurrent tumors were located in the conus (n = 3), thoracic (n = 1), and medullocervical cord (n = 2). CONCLUSIONS: Radical resection of spinal ependymomas could be performed in most patients, and the rate of GTR was significantly different in the different-length groups (< 10 cm vs > 10 cm, p = 0.032). Patients with longer tumors had worse surgical results compared with those with small tumors (p < 0.001), and more postoperative neuropathic pain and proprioceptive deficits could usually be observed in patients harboring larger tumors. Early diagnosis and timely operation are critical to achieving better neurological outcomes. For tumors with dense adhesions, complete removal should be performed cautiously because of the significant incidence of neurological deterioration.

[Characteristics of combining loss of heterozygosity of 1p/19q in glioma].

OBJECTIVES: To find possible factors correlated with combined loss of heterozygosity (LOH) of 1p and 19q. METHODS: The status of 1p and 19q of 138 glioma specimen from January 2009 to December 2009 was evaluated by Fluorescence in situ hybridization (FISH) method, and the frequencies of combining LOH of 1p/19q were compared between different pathologies, brain sub-regions, genders and ages. RESULTS: The frequencies of combined LOH of 1p and 19q of oligodendroglial (81.3%) and oligo astrocytic tumors (55.8%) were significantly higher than that of astrocytic tumor (22.2%) (P < 0.01), and the frequency of oligodendroglial tumor was significantly higher than that of oligo astrocytic tumor (P < 0.05). The frequency of combining LOH of 1p and 19q in frontal lobe (61.8%) was higher than that in temporal (31.8%) and insular lobes (34.6%) (P < 0.05). CONCLUSION: Combining LOH of 1p and 19q has significant correlation with the pathologies and brain sub-regions.

[Microsurgical treatment of adult craniopharyngiomas in 156 cases].

OBJECTIVE: To explore the clinical features, surgical approaches and outcomes of craniopharyngioma in adults. METHODS: A total of 156 cases of adult craniopharyngioma underwent microsurgery at our hospital were retrospectively reviewed and classified into four types according to the location of tumor relative to sellar diaphragm and the third ventricle. They were divided into four groups: intrasellar type (n = 6), suprasellar & extraventricular type (n = 59), intraventricular type (n = 63) and mixed type (n = 28). Unilateral subfrontal approach was chosen in 9 cases, anterior interhemispheric approach in 14 cases, pterional approach in 102 cases, transcallosal approach in 28 cases and transsphenoidal approach in 3 cases. RESULTS: Tumors were totally removed in 124 cases (79.5%), subtotally removed in 25 cases (16%) and partially removed in 7 cases (4.5%). Two patients died after surgery. Pituitary stalk was identified and protected intraoperatively in 69 cases, and postoperative diabetes insipidus occurred in 109 cases. The follow-up period ranged from 3 months to 5 years. 75.3% of the cases were capable of normal work and life and tumor recurred in 26 cases. CONCLUSION: Selection of appropriate approach is the key to successful microsurgery for craniopharyngioma according to the site and growth pattern of tumor.

Change of extracellular glutamate and gamma-aminobutyric acid in substantia nigra and globus pallidus during electrical stimulation of subthalamic nucleus in epileptic rats.

OBJECTIVE: To study the neurochemical change during high-frequency stimulation of the subthalamic nucleus in epileptic rats. METHODS: Two animal groups - 12 rats with epilepsy induced by the systemic administration of kainic acid and 12 normal rats - were used. Concentric bipolar electrodes were stereotaxically implanted in the unilateral subthalamic nucleus (STN), stimulated by high frequencies of 130 and 260 Hz in each group. The microdialysis probes were unilaterally lowered into the globus pallidus (GP) and the substantia nigra pars reticulata (SNr). The concentrations of glutamate (Glu) and gamma-aminobutyric acid (GABA) in dialysate samples were determined by high-performance liquid chromatography. RESULTS: Electrical stimulation of the STN induced increases in GABA content in the SNr of each group, while GABA remained stable in the GP. The extracellular GABA level in the epileptic group was significantly higher than that of the normal group. In addition, the frequency of 130 Hz provoked the maximum increase in Glu contents both in the GP and SNr, whereas 260 Hz had less effect. CONCLUSIONS: This study demonstrates the neurochemical modifications in STN targets during electrical STN stimulation and shows that different frequencies of high-frequency stimulation have different effects on the neurotransmitters.