The Transtemporal Isthmus Approach for Insular Glioma Surgery.

BACKGROUND AND OBJECTIVES: Maximal and safe removal of insular gliomas by a transinsular cortex approach is challenging. In this article, a new transtemporal isthmus approach to resect insular gliomas is presented. METHODS: We retrospectively examined 53 patients with insular glioma who underwent resection through the temporal isthmus approach using magnetic resonance imaging and functional neuronavigation guidance and intraoperative electrophysiological monitoring. Extent of resection was determined using intraoperative magnetic resonance imaging. RESULTS: Fifty-three patients were included for analysis, 30 men and 23 women. The median (range) age was 45 (26-70) years. Tumor laterality was left in 22 patients and right in 31. All tumors involved at least zone III or IV (Berger-Sanai classification system), including zones I-IV were involved in 29 (54.7%) and zones III and IV in 17 (32.0%). Among the 37 low-grade gliomas, preoperative median (IQR) volume was 45.7 (31.8, 60.3) cm3, and gross total resection was achieved in 24 (64.9%). Among the 16 high-grade gliomas, preoperative median (IQR) volume was 45.3 (40.1, 54.0) cm3, and gross total resection was achieved in 14 (87.5%). The median (IQR) extent of resection of the whole group was 100% (89%-100%). The median (IQR) postoperative Karnofsky performance score 3 months after surgery was 90 (80-90). Mean temporal isthmus width was significantly higher in the affected side (involving tumor) than the contralateral one (21.6 vs 11.3 mm; 95% CI: 9.3 to 11.3, P < .01). Muscle strength was grade 4 or higher, and speech was nearly normal in all patients 3 months after surgery. CONCLUSION: Insular glioma surgery using the transtemporal isthmus approach can achieve safe and maximum resection. A widened temporal isthmus provides a surgical pathway for transisthmic resection of insular tumor.

LINC01138 expresses two novel isoforms and functions as a repressive factor in glioma cells.

Objective: The objective of this study is to investigate the aggressive infiltration of glioblastoma into adjacent brain tissue, considering its challenging prognosis. Initially classified as an intergenic non-coding RNA, we aim to elucidate the functional implications of LINC01138 in glioblastoma. Method: Glioma grading was performed utilizing H&E staining, which unveiled distinct nuclear morphology in high-grade gliomas. The downregulation of LINC01138 in glioma tissues was corroborated through qRT-PCR and gel electrophoresis, concurrently identifying two previously unrecognized LINC01138 isoforms. Expression profiling of all four LINC01138 isoforms was executed in glioma cell lines (A172, SHG-44, U251, U87-MG). The impact of LINC01138 overexpression in U87-MG and U251 cells was evaluated for cell proliferation, migration, and invasion through cell counting, CCK-8 analysis, and Transwell assays. Furthermore, the suppression of LINC01138 in SHG-44 cells substantiated its involvement in fostering tumor malignancy. Transcriptome sequencing revealed the inhibitory influence of LINC01138 on IGF1 expression. These findings contribute to an enriched comprehension of glioma biology by exploring the engagement of LINC01138 through diverse methodologies, thereby elucidating its potential therapeutic significance. Results: Our investigation elucidates the intricate involvement of LINC01138 in gliomas. High-grade gliomas are characterized by elevated cell density and distinctive nuclear features. LINC01138 demonstrates a substantial downregulation in glioma tissues, with the identification of two novel isoforms. The expression of all four LINC01138 isoforms is notably diminished in both glioma tissues and cell lines. Elevated expression of LINC01138 demonstrates inhibitory effects on tumor cell proliferation, migration, and invasion, while its downregulation exacerbates malignancy. The regulatory function of LINC01138 as a repressor of IGF1 expression was elucidated through transcriptome sequencing. Conclusion: The LINC01138 isoforms display notable tumor-suppressive effects, suggesting a promising potential for impeding glioma progression.

Comprehensive analysis of recently discovered lncRNA-associated competing endogenous RNA network in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) arises from the epithelium of the nasopharynx and is characterized by geography-dependent incidence. Despite the high mortality rate, specifically in some ethnic groups, the mechanisms underlying NPC pathogenesis are not thoroughly understood and there is an urgent need to detect the potential and clinically applicable biomarkers to ameliorate the overall survival rate and improve the prognosis of patients. In recent years, research has increasingly focused on the importance of long non-coding RNAs (LncRNAs) in cancer progression. LncRNAs play critical roles in regulating gene expression through mechanisms such as competitively binding to microRNAs (CeRNA). While numerous LncRNAs have been studied in nasopharyngeal carcinoma (NPC), their potential as diagnostic and prognostic biomarkers have not been systematically examined. In the present study, we delve into elucidating the biological functions, molecular mechanisms, and clinical significance of newly identified LncRNAs that serve as sponges for different microRNAs in NPC. We highlight their regulatory mechanisms in promoting cell proliferation, invasion, and metastasis, and discuss their implications in diverse cancer-related signaling pathways. Our overall goal is to emboss the fundamental roles of LncRNA-mediated CeRNA networks in NPC progression, which may open up new avenues for determining the pathogenesis of NPC and developing effective prevention and treatment strategies.

Reorganization of the structural connectome during vision recovery in pituitary adenoma patients post-transsphenoidal surgery.

Pituitary adenomas (PAs) can exert pressure on the optic apparatus, leading to visual impairment. A subset of patients may observe a swift improvement in their vision following surgery. Nevertheless, the alterations in the structural connectome during the early postoperative period remain largely unexplored. The research employed probabilistic tractography, graph theoretical analysis, and statistical methods on preoperative and postoperative structural magnetic resonance imaging and diffusion tensor images from 13 PA patients. Postoperative analysis revealed an increase in global and local efficiency, signifying improved network capacity for parallel information transfer and fault tolerance, respectively. Enhanced clustering coefficient and reduced shortest path length were also observed, suggesting a more regular network organization and shortened communication steps within the brain network. Furthermore, alterations in node graphical properties were detected, implying a restructuring of the network's control points, possibly contributing to more efficient visual processing. These findings propose that rapid vision recovery post-surgery may be associated with significant reorganization of the brain's structural connectome, enhancing the efficiency and adaptability of the network, thereby facilitating improved visual processing.

SMURF1 attenuates endoplasmic reticulum stress by promoting the degradation of KEAP1 to activate NRF2 antioxidant pathway.

Cancer cells consistently utilize the unfolded protein response (UPR) to encounter the abnormal endoplasmic reticulum (ER) stress induced by the accumulation of misfolded proteins. Extreme activation of the UPR could also provoke maladaptive cell death. Previous reports have shown that NRF2 antioxidant signaling is activated by UPR and serves as noncanonical pathway to defense and reduce excessive ROS levels during ER stress. However, the mechanisms of regulating NRF2 signaling upon ER stress in glioblastoma have not been fully elucidated. Here we identify that SMURF1 protects against ER stress and facilitates glioblastoma cell survival by rewiring KEAP1-NRF2 pathway. We show that ER stress induces SMURF1 degradation. Knockdown of SMURF1 upregulates IRE1 and PERK signaling in the UPR pathway and prevents ER-associated protein degradation (ERAD) activity, leading to cell apoptosis. Importantly, SMURF1 overexpression activates NRF2 signaling to reduce ROS levels and alleviate UPR-mediated cell death. Mechanistically, SMURF1 interacts with and ubiquitinates KEAP1 for its degradation (NRF2 negative regulator), resulting in NRF2 nuclear import. Moreover, SMURF1 loss reduces glioblastoma cell proliferation and growth in subcutaneously implanted nude mice xenografts. Taken together, SMURF1 rewires KEAP1-NRF2 pathway to confer resistance to ER stress inducers and protect glioblastoma cell survival. ER stress and SMURF1 modulation may provide promising therapeutic targets for the treatment of glioblastoma.

MR Imaging, MGMT Promoter Methylation Features and Prognostic Analysis of Subventricular Zone Contacting IDH Wild-type Glioblastoma.

BACKGROUND: As the largest concentration of neural stem cells in adult brain, the subventricular zone (SVZ) is considered to be a potential source of glioblastoma (GBM) occurrence in recent years. METHODS: In this study, 116 patients with glioblastoma treated at PLA General Hospital were retrospectively reviewed. The features of SVZ contacting glioblastoma were analyzed in terms of MR imaging and MGMT promoter methylation. We also evaluated the prognostic value of SVZ contacting in GBM patients. RESULTS: GBM with SVZ involvement on MRI is more likely to grow across the midline (36.8% vs. 6.9%, P=0.002), more often multifocal lesion (35.6% vs. 6.9%, P=0.003) and have a lower proportion of MGMT promoter methylation (36.8% vs. 69.0%, P=0.003). The median overall survival and progression- free survival of patients in the SVZ contacting group were 12 months and 7 months, while 25 months and 17 months in the non-contacting group (P<0.001, respectively). There was no significant difference in overall survival (P=0.229) and progression-free survival (P=0.808) between patients with different SVZ contacting regions. Multivariate survival analysis indicated that patients with MRI SVZ involvement showed worse overall survival (HR=2.060, 95%CI 1.195-3.550，P=0.009) and progression- free survival (HR=3.021, 95%CI 1.788-5.104，P＜0.001). CONCLUSION: This study suggested that MRI SVZ involvement at diagnosis is an independent risk factor for overall survival and progression-free survival in IDH wild-type glioblastoma patients. Based on MR imaging, we also found that SVZ contacting glioblastomas had a larger proportion of crossing midline tumors and multifocal lesions. In addition, patients with SVZ contact in our research presented a lower proportion of MGMT promoter methylation.

The transfrontal isthmus approach for insular glioma surgery.

OBJECTIVE: The classic transopercular or transsylvian approach to insular gliomas removes the tumor laterally through the insular cortex. This study describes a new anteroposterior approach through the frontal isthmus for insular glioma surgery. METHODS: The authors detailed the surgical techniques for resection of insular gliomas through the transfrontal isthmus approach. Fifty-nine insular gliomas with at least Berger-Sanai zone I involvement were removed with the new approach, and extent of resection and postoperative neurological outcomes were assessed. RESULTS: Fifty-nine patients were enrolled in the study, including 35 men and 24 women, with a mean (range) age 44.3 (19-75) years. According to the Berger-Sanai classification system, the most common tumor was a giant glioma (67.8%), followed by involvement of zones I and IV (18.6%). Twenty-two cases were Yasargil type 3A/B, and 37 cases were Yasargil type 5A/B. The average angle between the lateral plane of the putamen and sagittal line was 33.53°, and the average width of the isthmus near the anterior insular point was 33.33 mm. The average angle between the lateral plane of the putamen and the sagittal line was positively correlated with the width of the isthmus near the anterior insular point (r = 0.935, p < 0.0001). The median (interquartile range [IQR]) preoperative tumor volume was 67.82 (57.64-92.19) cm3. Of 39 low-grade gliomas, 26 (66.67%) were totally resected; of 20 high-grade gliomas, 19 (95%) were totally resected. The median (IQR) extent of resection of the whole group was 100% (73.7%-100%). Intraoperative diffusion-weighted imaging showed no cases of middle cerebral artery- or lenticulostriate artery-related stroke. Extent of insular tumor resection was positively correlated with the angle of the lateral plane of the putamen and sagittal line (r = -0.329, p = 0.011) and the width of the isthmus near the anterior insular point (r = -0.267, p = 0.041). At 3 months postoperatively, muscle strength grade exceeded 4 in all cases, and all patients exhibited essentially normal speech. The median (IQR) Karnofsky performance score at 3 months after surgery was 90 (80-90). CONCLUSIONS: The transfrontal isthmus approach changes the working angle from lateral-medial to anterior-posterior, allowing for maximal safe removal of insular gliomas.

Endoscope-Assisted Keyhole Surgery for Traumatic Subacute Subdural Hematoma Evacuation in Emergencies.

OBJECTIVE: This study aimed to investigate whether a simple endoscopic method was effective for the evacuation of traumatic subacute subdural hematomas. METHODS: A total of 51 patients with subacute subdural hematomas requiring surgery were enrolled in this study. An endoscopic hematoma evacuation was performed through a small bone window for 22 patients. Hematoma evacuation by open surgery was performed for 29 patients. The postoperative Glasgow Coma Scale scores improvement, surgery times, displacement of midline measurements, and intraoperative blood loss were recorded and analyzed for each patient. RESULTS: The average time from the initial incision to suture completion was 38.41 ± 6.97 minutes for the endoscopic surgery group and 74.66 ± 9.54 minutes for the open-surgery group (P < 0.01). The average total blood loss was 41.36 ± 10.82 ml for the endoscopic group and 250.00 ± 58.25 ml for the open-surgery group (P < 0.01). No postoperative bleeding occurred in either group. The midline displacement measurement showed significant improvement on the day after surgery, with 5.21 ± 1.98 mm in the study group versus 6.75 ± 1.37 mm in the control group (P < 0.01). At the 1-month follow-up appointment, the midline measurement was normal in both groups. Computed tomography scans revealed almost no residual hematomas, representing an average evacuation rate of 100% in both groups. The average Glasgow Coma Scale scores improvement on the day after surgery were 1.77 ± 1.93 in the endoscopic surgery group and 1.66 ± 0.77 in the open-surgery group (P = 0.766). CONCLUSION: Endoscopic subacute subdural hematoma removal through a small bone window achieved satisfactory hematoma removal using a minimally invasive method when compared with an open-surgery method.

The imaging features and prognosis of gliomas involving the subventricular zone: An MRI study.

RATIONALE AND OBJECTIVES: As the largest concentrated region of neural stem cells in the adult brain, the subventricular zone (SVZ) is considered to have a close relationship with the origin of gliomas. An in-depth study of the characteristic manifestations associated with SVZ involvement in glioma may provide new ideas for individualized diagnosis and treatment of this fatal disease. MATERIALS AND METHODS: All 279 patients with glioma who underwent surgical treatment in our department from January 2016 to December 2021 were included. Clinical and imaging data were collected, and telephonic follow-up was conducted to analyze the overall survival and progression-free survival. Prognostic factors including SVZ involvement on glioblastoma patients' survival were analyzed. Next, the relationship between SVZ involvement, a set of unique imaging features and gene status were determined respectively. The chi-squared test, logistics regression, and Cox regression were used for statistical analysis. RESULTS: The patients were divided into the SVZ involvement group (n = 198, 70.97 %) and SVZ non-involvement group (n = 81, 29.03 %). The median overall survival and progression-free survival were 13 months and 7 months for the SVZ involvement group, but 25 months and 17 months for the SVZ non-involvement group, respectively. In multivariate Cox survival analysis, MRI SVZ involvement proved an independent risk factor for the survival of patients with glioblastoma. The patients with SVZ involvement sign had a lower rate of cystic lesion (32.32 % vs. 48.48 %, p = 0.029), and a larger mean maximum diameter (5.88 ± 1.28 vs. 3.28 ± 1.65 cm). Compared with high grade gliomas (HGG), T1 enhancement (25.25 % vs. 10.42 %, p = 0.041) and homogeneous signal on T2WI (14.14 % vs. 43.75 %, p = 0.025) were independently associated with SVZ involvement in WHO grade 2 gliomas(LGG). In the gene status analysis, the SVZ involvement group showed the lower rate of MGMT promoter methylation (57.58 % vs. 79.17 %, p = 0.017). CONCLUSION: SVZ involvement in MRI at diagnosis is an independent negative prognostic indicator for the survival of glioblastoma patients. Some image signs are associated with SVZ involvement in HGG and LGG respectively. The unique imaging and gene features of gliomas with SVZ involvement indicate that this kind of tumor maybe a unique subgroup of gliomas.

Resection of Insular Glioma Through the Transfrontal Limiting Sulcus Approach.

BACKGROUND: The current transsylvian or transopercular approaches make access difficult because of the limited exposure of insular tumors. Hence, maximal and safe removal of insular gliomas is challenging. In this article, a new approach to resect insular gliomas is presented. OBJECTIVE: To determine whether the new transfrontal limiting sulcus approach is helpful for maximal and safe removal of insular gliomas. METHODS: The authors reported surgical techniques for insular gliomas resected through the transfrontal limiting sulcus approach. The authors evaluated the surgical resections of 69 insular gliomas performed through the new approach in their department. The extents of resection and postoperative neurological outcomes were analyzed to determine the value of this new approach. RESULTS: Based on the Berger-Sanai classification, most insular gliomas were giant tumors (59.42%), followed by zone I + IV tumors (24.64%). The median (interquartile range) extent of resection of all patients was 100% (91%, 100%). The total resection rate for all gliomas was (55 of 69, 79.7%), and the total resection rate for low-grade gliomas was (28 of 40, 70%), which was significantly lower than that for high-grade gliomas (27 of 29, 93.1%) (P = .019). All patients had muscle strength greater than grade 4 3 months after surgery. Only 1 patient had a speech disorder 3 months after surgery. The median Karnofsky Performance Status score at the time of the 3-month follow-up was 90. CONCLUSION: The transfrontal limiting sulcus approach can help to achieve maximal and safe removal of insular gliomas.

Deep Learning model-based approach for preoperative prediction of Ki67 labeling index status in a noninvasive way using magnetic resonance images: A single-center study.

OBJECTIVES: Ki67 is an important biomarker of pituitary adenoma (PA) aggressiveness. In this study, PA invasion of surrounding structures is investigated and deep learning (DL) models are established for preoperative prediction of Ki67 labeling index (Ki67LI) status using conventional magnetic resonance (MR) images. METHODS: We reviewed 362 consecutive patients with PAs who underwent endoscopic transsphenoidal surgery, of which 246 patients with primary PA are selected for PA invasion analysis. MRI data from 234 of these PA patients are collected to develop DL models to predict Ki67LI status, and DL models were tested on 27 PA patients in the clinical setting. RESULTS: PA invasion is observed in 46.8% of cases in the Ki67 ≥ 3% group and 33.3% of cases in the Ki67 < 3% group. Three deep-learning models are developed using contrast-enhanced T1-weighted images (ceT1WI), T2-weighted images (T2WI), and multimodal images (ceT1WI+T2WI), respectively. On the validation dataset, the prediction accuracy of the ceT1WI model, T2WI model, and multimodal model were 87.4%, 89.4%, and 89.2%, respectively. In the clinical test, 27 MR slices with the largest tumors from 27 PA patients were tested using the ceT1WI model, T2WI model, and multimodal model, the average accuracy of Ki67LI status prediction was 63%, 77.8%, and 70.4%, respectively. CONCLUSION: Preoperative prediction of PA Ki67LI status in a noninvasive way was realized with the DL model by using MRI. T2WI model outperformed the ceT1WI model and multimodal model. This end-to-end model-based approach only requires a single slice of T2WI to predict Ki67LI status and provides a new tool to help clinicians make better PA treatment decisions.

Smartphone navigated endoscopic port surgery of hypertensive basal ganglia hemorrhage.

OBJECTIVE: Endoscopic port surgery is a promising alternative for the surgical treatment of intracerebral hypertensive basal ganglia hemorrhage (HBGH). The precise location of hematoma is a crucial step for surgery. The authors developed a simple, low-cost navigation method using an Android smartphone for the localization of HBGH. METHODS: All patients' CT DICOM data were processed with an open-source software (3D Slicer). The volume of hematoma, angle, and length of trajectory were calculated automatically. A smartphone running the Android system and the Compass APP was used to help insert the inner introducer. An endoscopic port system was applied to create a working channel for neuro-endoscopic hematoma evacuation. RESULTS: There were 27 patients enrolled in this study (mean age 56). All patients underwent successful surgical evacuation of HBGH with neuroendoscopic evacuation. The mean time taken for the surgical plan was 4 min. The total operation time from skin incision to final suture was 82.6 min. Compared with standard neuronavigation, mean error of trajectory was 5.1 mm. The mean preoperative hematoma volume was 44.8 ml. The optimal trajectory angle averaged 39.5°and the length was 71 mm. Intraoperative blood loss was about 45 ml. Post-operative hematoma volume was 2.9 ml, and the average evacuation rate was 93.6%. One week after surgery, the mean GCS score was improved from 8.2 to 13.8 (p < 0.01). CONCLUSIONS: This simple, low-cost navigation method using 3D Slicer, an Android smartphone with the Compass APP, helps precisely insert the endoscopic working channel to the desired point, which is crucial for satisfactory evacuation of HBGH.

Characteristics of TP53 germline variants and their correlations with Li-Fraumeni syndrome or Li-Fraumeni-like syndrome in Chinese tumor patients.

Li-Fraumeni syndrome (LFS), a rare autosomal-dominant inheritance condition, is associated with a family cancer history as well as pathogenic/likely-pathogenic TP53 germline variants (P/LP TP53 GV). The current clinical methods for detecting LFS are limited. Here, we retrospectively investigate P/LP TP53 GV among Chinese cancer patients by next-generation sequencing and evaluate its relationship with a family cancer history. A total of 270 out of 19,226 cancer patients have TP53 GV, including 53 patients with P/LP TP53 GV. Patients with P/LP TP53 GV are mainly found in male with glioma, lung cancer or sarcoma. The median age of diagnosis for P/LP TP53 GV patients is significantly lower than that of non-P/LP TP53 GV patients (31-years vs. 53-years; P < 0.01). One LFS patient and 3 Li-Fraumeni-like syndrome (LFL) patients are among the 26 followed-up P/LP TP53 GV patients. Among 25 types of P/LP TP53 GV, the highest variant frequencies occurred at codon 175 and 248. p.M237I, p.R158H, p.C238Y and p.C275R, are firstly identified among the Chinese LFS/LFL patients. This study reports the (P/LP) TP53 GV characteristics of Chinese pan-cancer patients. These findings suggest analyzing the P/LP TP53 GV in cancer patients is an effective strategy for identifying cancer predisposition syndrome.

Combined use of multimodal techniques for the resection of glioblastoma involving corpus callosum.

PURPOSE: To compare the multimodal techniques (including neuronavigation, intraoperative MRI [iMRI], and neuromonitoring [IONM]) and conventional approach (only guided by neuronavigation) in removing glioblastoma (GBM) with corpus callosum (CC) involvement (ccGBM), their effectiveness and safety were analyzed and compared. METHODS: Electronic medical records were retrospectively reviewed for ccGBM cases treated in our hospital between January 2016 and July 2020. Patient demographics, tumor characteristics, clinical outcomes, extent of resection (EOR), progression-free survival (PFS), and overall survival (OS) were obtained and compared between the multimodal group (used multimodal techniques) and the conventional group (only used neuronavigation). Both groups only included patients that had maximal safe resection (not biopsy). Postoperative radiochemotherapy was also performed or not. Univariate and multivariate analyses were performed to identify significant prognostic factors and optimal EOR threshold. RESULTS: Finally 56 cases of the multimodal group and 21 cases of the conventional group were included. The multimodal group achieved a higher median EOR (100% versus 96.1%, P = 0.036) and gross total resection rate (60.7% versus 33.3%, P = 0.032) and a lower rate of permanent motor deficits (5.4% versus 23.8%, P = 0.052) than the conventional approach. The multimodal group had the longer median PFS (10.9 versus 7.0 months, P = 0.023) and OS (16.1 versus 11.6 months, P = 0.044) than the conventional group. Postoperative language and cognitive function were similar between the two groups. In multivariate analysis, a higher EOR, radiotherapy, and longer cycles of temozolomide chemotherapy were positive prognostic factors for survival of ccGBM. An optimal EOR threshold of 92% was found to significantly benefit the PFS (HR = 0.51, P = 0.036) and OS (HR = 0.49, P = 0.025) of ccGBM. CONCLUSION: Combined use of multimodal techniques can optimize the safe removal of ccGBM. Aggressive resection of EOR > 92% using multimodal techniques combined with postoperative radiochemotherapy should be suggested for ccGBM.

Exploring the efficacy of tumor electric field therapy against glioblastoma: An in vivo and in vitro study.

AIMS: Tumor electric fields therapy (TTFields) is emerging as a novel anti-cancer physiotherapy. Despite recent breakthroughs of TTFields in glioma treatment, the average survival time for glioblastoma patients with TTFields is <2 years, even when used in conjugation with traditional anti-cancer therapies. To optimize TTFields-afforded efficacy against glioblastoma, we investigated the cancer cell-killing effects of various TTFields paradigms using in vitro and in vivo models of glioblastoma. METHODS: For in vitro studies, the U251 glioma cell line or primary cell cultures prepared from 20 glioblastoma patients were treated with the tumor electric field treatment (TEFT) system. Cell number, volume, and proliferation were measured after TEFT at different frequencies (100, 150, 180, 200, or 220 kHz), durations (24, 48, or 72 h), field strengths (1.0, 1.5, or 2.2V/cm), and output modes (fixed or random sequence output). A transwell system was used to evaluate the influence of TEFT on the invasiveness of primary glioblastoma cells. For in vivo studies, the therapeutic effect and safety profiles of random sequence electric field therapy in glioblastoma-transplanted rats were assessed by calculating tumor size and survival time and evaluating peripheral immunobiological and blood parameters, respectively. RESULTS: In the in vitro settings, TEFT was robustly effective in suppressing cell proliferation of both the U251 glioma cell line and primary glioblastoma cell cultures. The anti-proliferation effects of TEFT were frequency- and "dose" (field strength and duration)-dependent, and contingent on the field sequence output mode, with the random sequence mode (TEFT-R) being more effective than the fixed sequence mode (TEFT-F). Genetic tests were performed in 11 of 20 primary glioblastoma cultures, and 6 different genetic traits were identified them. However, TEFT exhibited comparable anti-proliferation effects in all primary cultures regardless of their genetic traits. TEFT also inhibited the invasiveness of primary glioblastoma cells in transwell experiments. In the in vivo rat model of glioblastoma brain transplantation, treatment with TEFT-F or TEFT-R at frequency of 200 kHz and field strength of 2.2V/cm for 14 days significantly reduced tumor volume by 42.63% (TEFT-F vs. control, p = 0.0002) and 63.60% (TEFT-R vs. control, p < 0.0001), and prolonged animal survival time by 30.15% (TEFT-F vs. control, p = 0.0415) and 69.85% (TEFT-R vs. control, p = 0.0064), respectively. The tumor-bearing rats appeared to be well tolerable to TEFT therapies, showing only moderate increases in blood levels of creatine and red blood cells. Adverse skin reactions were common for TEFT-treated rats; however, skin reactions were curable by local treatment. CONCLUSION: Tumor electric field treatment at optimal frequency, strength, and output mode markedly inhibits the cell viability, proliferation, and invasiveness of primary glioblastoma cells in vitro independent of different genetic traits of the cells. Moreover, a random sequence electric field output confers considerable anti-cancer effects against glioblastoma in vivo. Thus, TTFields are a promising physiotherapy for glioblastoma and warrants further investigation.

Identification of risk factors for poor language outcome in surgical resection of glioma involving the arcuate fasciculus: an observational study.

The arcuate fasciculus is a critical component of the neural substrate of human language function. Surgical resection of glioma adjacent to the arcuate fasciculus likely damages this region. In this study, we evaluated the outcome of surgical resection of glioma adjacent to the arcuate fasciculus under the guidance of magnetic resonance imaging and diffusion tensor imaging, and we aimed to identify the risk factors for postoperative linguistic deficit. In total, 54 patients with primary glioma adjacent to the arcuate fasciculus were included in this observational study. These patients comprised 38 men and 16 women (aged 43 ± 11 years). All patients underwent surgical resenction of glioma under the guidance of magnetic resonance imaging and diffusion tensor imaging. Intraoperative images were updated when necessary for further resection. The gross total resection rate of the 54 patients increased from 38.9% to 70.4% by intraoperative magnetic resonance imaging. Preoperative language function and glioma-to-arcuate fasciculus distance were associated with poor language outcome. Multivariable logistic regression analyses showed that glioma-to-arcuate fasciculus distance was the major independent risk factor for poor outcome. The cutoff point of glioma-to-arcuate fasciculus distance for poor outcome was 3.2 mm. These findings suggest that intraoperative magnetic resonance imaging combined with diffusion tensor imaging of the arcuate fasciculus can help optimize tumor resection and result in the least damage to the arcuate fasciculus. Notably, glioma-to-arcuate fasciculus distance is a key independent risk factor for poor postoperative language outcome. This study was approved by the Ethics Committee of the Chinese PLA General Hospital, China (approval No. S2014-096-01) on October 11, 2014.

The Diagnostic Value of Conventional MRI and CT Features in the Identification of the IDH1-Mutant and 1p/19q Co-Deletion in WHO Grade II Gliomas.

RATIONALE AND OBJECTIVES: The classification of patients based on pathology and molecular features is important for improving WHO grade II glioma patient prognosis, especially for the initially diagnosed patients. Less invasive and more convenient methods for the prediction of the pathological type and gene status are desired. MATERIALS AND METHODS: This study investigates the ability to use conventional magnetic resonance imaging (MRI) and computed tomography (CT) features for determining the Isocitrate Dehydrogenase (IDH)-mutant and 1p/19q-codeletion status, through a retrospective review of information obtained from 189 WHO grade II glioma patients. Diffuse astrocytoma (IDH-mutant), Diffuse astrocytoma (IDH- wildtype) and Oligodendroglioma (IDH-mutant and 1p/19q co-deletion) were included in this cohort. All patients were divided into IDH-mutant group and IDH-wildtype group according to the IDH R132H mutation status. Moreover, all patients were divided into 1p/19q co-deletion group and 1p/19q non-codeletion group according to the 1p and 19q chromosome status. Patients underwent pre-operative CT and MRI scans, followed by operation and histopathological analyses, including immunohistochemistry and polymerase chain reaction analysis for IDH mutants, and fluorescence capillary electrophoresis analysis for the 1p/19q co-deletion. The χ2 test, logistical regression and receiver operating characteristic curve analysis were conducted for statistical analysis. RESULTS: IDH-mutant group patients exhibited a higher calcification frequency (25.2% vs 2.4%, p = 0.006) and lower frequency of T1 enhancement (20.4% vs 38.1%, p = 0.028) comparing patients in IDH-wildtype group, while 1p/19q co-deletion group patients exhibited a higher calcification frequency (46.67% vs 2.6%, p < 0.001) and lower homogenous signal frequency in T2WI (12.0% vs 31.6%, p = 0.014), sharp lesion margins (14.7% vs 43.0%, p = 0.010), T2/fluid attenuated inversion recovery mismatch signs (22.7% vs 50.9%, p = 0.001), and subventricular zone involvement (64.0% vs 15.8%, p = 0.021) comparing patients in 1p/19q non-codeletion group. According to the results of receiver operating characteristic analysis, these features were observed to have certain diagnostic abilities, especially with regard to combination parameters, which had a high diagnostic capability, with an area under the curve of 0.848. CONCLUSION: Conventional MRI and CT features, which still represent the most convenient and widely used predictive method, might be a promising noninvasive predictor for differentiating between varied WHO grade II gliomas. Patients with calcification and T1 nonenhancement are more likely to be IDH-mutant. Moreover, patients with noncalcification, homogenous signal, sharp lesion margins, subventricular zone involvement on T2 and T2/fluid attenuated inversion recovery mismatch signs are more likely to be 1p/19q non-codeletion.

TRIM24 promotes stemness and invasiveness of glioblastoma cells via activating Sox2 expression.

BACKGROUND: Glioblastoma stem cells (GSCs) are a subpopulation of glioblastoma (GBM) cells that are critical for tumor invasion and treatment resistance. However, little is known about the function and mechanism of tripartite motif-containing 24 (TRIM24) in GSCs. METHODS: Immunofluorescence, flow cytometry, and western blot analyses were used to evaluate TRIM24 and cluster of differentiation (CD)133 expression profiles in GBM surgical specimens and GSC tumorspheres. Different TRIM24 expression levels in patients' tumors, as measured by both immunohistochemistry and western blot, were related to their corresponding MRI data. Wound healing, Matrigel invasion, and xenograft immunohistochemistry were conducted to determine GBM cell invasion. RESULTS: We identified that TRIM24 was coexpressed with CD133 and Nestin in GBM tissues and tumorsphere cells. Limiting dilution assays and xenotransplantation experiments illustrated that knockdown of TRIM24 expression reduced GSC self-renewal capacity and invasive growth. TRIM24 expression levels were positively associated with the volumes of peritumoral T2 weighted image abnormality. Rescue experiments indicated TRIM24 participation in GBM infiltrative dissemination. Chromatin immunoprecipitation, reporter gene assay, PCR, western blot, and immunohistochemistry demonstrated that TRIM24 activated the expression of the pluripotency transcription factor sex determining region Y-box 2 (Sox2) to regulate GBM stemness and invasion in vitro and in vivo. Finally, the close relationship between TRIM24 and Sox2 was validated by testing samples enrolled in our study and exploring external databases. CONCLUSIONS: Our findings uncover essential roles of the TRIM24-Sox2 axis in GBM stemness and invasiveness, suggesting TRIM24 as a potential target for effective GBM management.

Glioblastoma extracellular vesicles induce the tumour-promoting transformation of neural stem cells.

Recurrent glioblastomas are frequently found near subventricular zone (SVZ) areas of the brain where neural stem cells (NSCs) reside, and glioblastoma-derived extracellular vesicles (EVs) are reported to play important roles in tumour micro-environment, but the details are not clear. Here, we investigated the possibility that NSCs are involved in glioblastoma relapse mediated by glioblastoma-derived EVs. We studied changes to NSCs by adding glioblastoma-derived EVs into a culture system of NSCs, and found that NSCs differentiated into a type of tumour-promoting cell. These transformed cells had distinguished proliferation activity, a high migration rate, and clone-forming ability revealed by CCK-8, wound healing and soft agar clone formation assays, respectively. In vivo assays indicated that these cells could accelerate tumour formation by Ln229 cells in nude mice. Moreover, to explore the mechanisms underlying NSC transformation, single cell transcriptome sequencing was performed; our results suggest that several key genes such as S100B, CXCL14, EFEMP1, SCRG1, GLIPR1, HMGA1 and CD44 and dysregulated signalling may be important for the transformation of NSCs. It is also indicated that NSCs may be involved in glioblastoma recurrence through EV release by glioblastoma in this work. This could help to illuminate the mechanism of glioblastoma relapse, which occurs in a brief period after surgical excision, and contribute to finding new ways to treat this disease.