NAD+ metabolic enzyme inhibitor as radiosensitizer for malignant meningioma and its modulation of P53 expression.

Surgical resection followed by radiotherapy (RT) is recommended for malignant meningioma but poor outcome is unavoidable. To improve the efficacy of RT in malignant meningioma, a targeted radiosensitizer could be added. Nicotinamide phosphoribosyltransferase (NAMPT), highly expressed in high-grade meningiomas may have a role in determining the radioresponse. Here, we evaluated the impact of NAMPT inhibition on radiosensitivity in malignant meningioma in vivo and in vitro. IOMM-Lee and TTMM705 cells were treated with NAMPT inhibition (FK866 or shRNA NAMPT) before irradiation. The subsequent clonogenic assay demonstrated significantly increased radiosensitivity. Combination treatment with FK866 and irradiation significantly increased the number of G2/M-phase cells, the percentage of apoptotic cells and the γ-H2A.X level compared to FK866 or RT alone. We examined the effect of NAMPT inhibition on NMI and p53 expression in IOMM-Lee and TTMM705 cells. NAMPT inhibition by FK866 and shRNA treatment increased NMI, p53, CDKN1A and BAX expression. Additionally, we assessed the efficacy of FK866/RT combination treatment in vivo. The combination treatment exhibited increased antitumor efficacy compared to either treatment alone. The Ki-67 level was significantly lower and the p53 and γ-H2A.X level was significantly higher in the combination treatment group than in any of the other three groups. In conclusion, these results indicate that FK866 improves radiosensitivity in malignant meningioma, an effect that may be attributed to the increase in p53 expression.

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.

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.

The inhibition of Aurora A kinase regulates phospholipid remodeling by upregulating LPCAT1 in glioblastoma.

Metabolic reprogramming is a common feature of glioblastoma (GBM) progression and metastasis. Altered lipid metabolism is one of the most prominent metabolic alterations in cancer. Understanding the links between phospholipid remodeling and GBM tumorigenesis may help develop new anticancer strategies and improve treatments to overcome drug resistance. We used metabolomic and transcriptomic analyses to systematically investigate metabolic and molecular changes in low-grade glioma (LGG) and GBM. We then re-established the reprogrammed metabolic flux and membrane lipid composition in GBM based on metabolomic and transcriptomic analyses. By inhibiting Aurora A kinase via RNA interference (RNAi) and inhibitor treatment, we investigated the effect of Aurora A kinase on phospholipid reprogramming LPCAT1 enzyme expression and GBM cell proliferation in vitro and in vivo. We found that GBM displayed aberrant glycerophospholipid and glycerolipid metabolism compared with LGG. Metabolic profiling indicated that fatty acid synthesis and uptake for phospholipid synthesis were significantly increased in GBM compared to LGG. The unsaturated phosphatidylcholine (PC) and phosphatidylethanolamine (PE) levels were significantly decreased in GBM compared to LGG. The expression level of LPCAT1, which is required for the synthesis of saturated PC and PE, was upregulated in GBM, and the expression of LPCAT4, which is required for the synthesis of unsaturated PC and PE, was downregulated in GBM. Notably, the inhibition of Aurora A kinase by shRNA knockdown and treatment with Aurora A kinase inhibitors such as Alisertib, AMG900, or AT9283 upregulated LPCAT1 mRNA and protein expression in vitro. In vivo, the inhibition of Aurora A kinase with Alisertib increased LPCAT1 protein expression. Phospholipid remodeling and a reduction in unsaturated membrane lipid components were found in GBM. Aurora A kinase inhibition increased LPCAT1 expression and suppressed GBM cell proliferation. The combination of Aurora kinase inhibition with LPCAT1 inhibition may exert promising synergistic effects on GBM.

Association between preoperative hematocrit and postoperative 30-day mortality in adult patients with tumor craniotomy.

Background: The purpose of this research was to synthesize the American College of Surgeons National Surgical Quality Improvement Program database to investigate the link between preoperative hematocrit and postoperative 30-day mortality in patients with tumor craniotomy. Methods: A secondary retrospective analysis of electronic medical records of 18,642 patients with tumor craniotomy between 2012 and 2015 was performed. The principal exposure was preoperative hematocrit. The outcome measure was postoperative 30-day mortality. We used the binary logistic regression model to explore the link between them and conducted a generalized additive model and smooth curve fitting to investigate the link and its explicit curve shape. We conducted sensitivity analyses by converting a continuous HCT into a categorical variable and calculated an E-value. Results: A total of 18,202 patients (47.37% male participants) were included in our analysis. The postoperative 30-day mortality was 2.5% (455/18,202). After adjusting for covariates, we found that preoperative hematocrit was positively associated with postoperative 30-day mortality (OR = 0.945, 95% CI: 0.928, 0.963). A non-linear relationship was also discovered between them, with an inflection point at a hematocrit of 41.6. The effect sizes (OR) on the left and right sides of the inflection point were 0.918 (0.897, 0.939) and 1.045 (0.993, 1.099), respectively. The sensitivity analysis proved that our findings were robust. The subgroup analysis demonstrated that a weaker association between preoperative hematocrit and postoperative 30-day mortality was found for patients who did not use steroids for chronic conditions (OR = 0.963, 95% CI: 0.941-0.986), and a stronger association was discovered in participants who used steroids (OR = 0.914, 95% CI: 0.883-0.946). In addition, there were 3,841 (21.1%) cases in the anemic group (anemia is defined as a hematocrit (HCT) <36% in female participants and <39% in male participants). In the fully adjusted model, compared with the non-anemic group, patients in the anemic group had a 57.6% increased risk of postoperative 30-day mortality (OR = 1.576; 95% CI: 1.266, 1.961). Conclusion: This study confirms that a positive and nonlinear association exists between preoperative hematocrit and postoperative 30-day mortality in adult patients undergoing tumor craniotomy. Preoperative hematocrit was significantly associated with postoperative 30-day mortality when the preoperative hematocrit was <41.6.

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.

Effects of Sevoflurane and Propofol on Neurological Recovery of Traumatic Brain Injury Patients in the Early Postoperative Stage: A Retrospective Cohort Study.

Objective To investigate the effects of propofol and sevoflurane on neurological recovery of traumatic brain injury (TBI) patients in the early postoperative stage.Methods We retrospectively analyzed the clinical data of TBI patients who underwent craniotomy or decompressive craniectomy. Generalized additive mixed model (GAMM) was used to analyze effects of propofol and sevoflurane on Glasgow Coma Scale (GCS) on postoperative days 1, 3, and 7. Multivariate regression analysis was used to analyze effects of the two anesthetics on Glasgow Outcome Scale (GOS) at discharge.Results A total of 340 TBI patients were enrolled in this study. There were 110 TBI patients who underwent craniotomy including 75 in the propofol group and 35 in the sevoflurane group, and 134 patients who underwent decompressive craniectomy including 63 in the propofol group and 71 in the sevoflurane group. It showed no significant difference in GCS at admission between the propofol and the sevoflurane groups among craniotomy patients (ß = 0.75, 95%CI: -0.55 to 2.05, P = 0.260). However, elevation in GCS from baseline was 1.73 points (95%CI: -2.81 to -0.66, P = 0.002) less in the sevoflurane group than that in the propofol group on postoperative day 1, 2.03 points (95%CI: -3.14 to -0.91, P < 0.001) less on day 3, and 1.31 points (95%CI: -2.43 to -0.19, P = 0.022) less on day 7. The risk of unfavorable GOS (GOS 1, 2, and 3) at discharge was higher in the sevoflurane group (OR = 4.93, 95%CI: 1.05 to 23.03, P = 0.043). No significant difference was observed among two-group decompressive craniectomy patients in GCS and GOS.Conclusions Compared to propofol, sevoflurane was associated with worse neurological recovery during the hospital stay in TBI patients undergoing craniotomy. This difference was not detected in TBI patients undergoing decompressive craniectomy.

Spatial distribution of supratentorial diffuse gliomas: A retrospective study of 990 cases.

Background: Gliomas distribute unevenly in the supratentorial brain space. Many factors were linked to tumor locations. This study aims to describe a more detailed distributing pattern of these tumors with age and pathological factors concerned. Methods: A consecutive series of 990 adult patients with newly-diagnosed supratentorial diffuse gliomas who underwent resection in Beijing Tiantan Hospital between January 2013 and January 2017 were retrospectively reviewed. For each patient, the anatomic locations were identified by the preoperative MRI, and the pathological subtypes were reviewed for histological grade and molecular status (if any) from his medical record. The MNI template was manually segmented to measure each anatomic location's volume, and its invaded ratio was then adjusted by the volume to calculate the frequency density. Factors of age and pathological subtypes were also compared among locations. Results: The insulae, hippocampi, and corpus callosum were locations of the densest frequencies. The frequency density decreased from the anterior to posterior (frontal - motor region - sensory region - parietal - occipital), while the grade (p < 0.0001) and the proportion of IDH-wt (p < 0.0001) increased. More tumors invading the right basal ganglion were MGMT-mt (p = 0.0007), and more of those invading the left frontal were TERT-wt (p = 0.0256). Age varied among locations and pathological subtypes. Conclusions: This study demonstrated more detailed spatial disproportions of supratentorial gliomas. There are potential interactions among age, pathological subtypes, and tumor locations.

Anti-cancer effect of targeting fibroblast activation protein alpha in glioblastoma through remodeling macrophage phenotype and suppressing tumor progression.

INTRODUCTION: Glioblastoma (GBM) is the most malignant form of glioma and has a poor median survival time. Fibroblast activation protein alpha (FAP) is a dual-specificity serine protease that is strongly associated with the development and progression of human carcinomas. However, relatively little is known about the function of FAP and its potential as a therapeutic target in GBMs. AIMS: In this study, we aimed to explore the role of FAP in GBM through a series of experiments and to evaluate the therapeutic effect of PT100, a small molecule inhibitor of FAP, on GBM. RESULTS: Increased FAP expression was associated with poor survival in glioma. In vitro, FAP knockdown inhibited the process of EMT and caused a decrease in the number of M2 macrophages. In vivo, PT100 was confirmed to suppress the progression of GBMs significantly. CONCLUSIONS: FAP could serve as a biomarker and novel therapeutic target for the treatment of GBM and that PT100 is a promising drug for the treatment of GBM.