Clinical features, angio-architectural phenotypes, and treatment strategy of foramen magnum dural arteriovenous fistulas: a retrospective case series study.

Background: The rarity and complex angioarchitecture of foramen magnum dural arteriovenous fistulas (DAVFs) make its treatment difficult and controversial. We aimed to describe their clinical features, angio-architectural phenotypes, and treatments, through a case series study. Methods: We first retrospectively studied cases of foramen magnum DAVFs treated in our Cerebrovascular Center, and then reviewed the published cases on Pubmed. The clinical characteristics, angioarchitecture, and treatments were analyzed. Results: A total of 55 patients were confirmed with foramen magnum DAVFs, which included 50 men and 5 women, with a mean age of 52.8 years. Most patients presented with subarachnoid hemorrhage (SAH) (21/55) or myelopathy (30/55), depending on the venous drainage pattern. In this group, 21 DAVFs were supplied by only the vertebral artery (VA), three by only the occipital artery (OA), three by only the ascending pharyngeal artery (APA), and the remaining 28 DAVFs were supplied by two or three of these feeding arteries. Most cases (30/55) were treated with only endovascular embolization, 18 cases (18/55) with only surgical disconnection, five cases (5/55) with combined therapy, and two cases rejected treatment. The angiographic outcome of complete obliteration was achieved in most patients (50/55). In addition, two cases of foramen magnum DAVFs were treated by us in a Hybrid Angio-Surgical Suite (HASS) with good outcomes. Conclusions: Foramen magnum DAVFs are rare and their angio-architectural features are complicated. The treatment option (microsurgical disconnection or endovascular embolization) should be weighed carefully, and combined therapy in HASS could be a more feasible and less invasive treatment option.

Spontaneous cerebrospinal fluid rhinorrhea associated with an incidental pituitary adenoma.

Spontaneous cerebrospinal fluid (CSF) rhinorrhea presenting as the sole symptom of untreated pituitary adenoma is rare, with only 15 cases having been reported in the English literature. All these untreated pituitary adenoma contributing to spontaneous CSF rhinorrhea were diagnosed by the preoperative neuroimaging. Herein, we described an extraordinary rare patient with a pituitary microadenoma, presenting with spontaneous CSF rhinorrhea as the sole symptom. However, this pituitary microadenoma was only found incidentally at surgery, not preoperatively. To the best knowledge of us, this is the first reported case of spontaneous CSF rhinorrhea associated with an untreated pituitary adenoma diagnosed at surgery.

Metformin enhances anti-cancer effects of cisplatin in meningioma through AMPK-mTOR signaling pathways.

Cisplatin is currently used to treat inoperable recurrent meningiomas, but its side effects and drug resistance limit its use. Metformin has recently been identified as a chemosensitizing agent. However, the combined treatment of cisplatin and metformin in high-grade meningiomas has not been reported. Herein, our findings demonstrate metformin significantly enhanced cisplatin-induced inhibition of proliferation in meningioma cells, which was associated with the induction of G0/G1 cell cycle arrest. Additionally, metformin activated adenosine monophosphate activated protein kinase (AMPK) and repressed the mammalian target of rapamycin (mTOR) signaling pathways via an AMPK-dependent mechanism. Furthermore, our xenograft murine model confirmed that metformin enhanced cisplatin's anti-cancer effect by upregulation of AMPK and downregulation of mTOR signaling pathways. In addition, in 63 patients with atypical meningiomas, the activation of AMPK was significantly associated with tumor recurrence and short disease-free survival (DFS). These results demonstrate metformin enhanced the anti-cancer effect of cisplatin in meningioma in vitro and in vivo, an effect mediated through the activation of AMPK and repression of mTOR signaling pathways. Our study suggests the combined treatment of metformin and cisplatin is an effective and safe treatment for high-grade meningiomas.

LINC00174 is a favorable prognostic biomarker in glioblastoma via promoting proliferative phenotype.

OBJECTIVE: To investigate the expression pattern, prognostic value and biological functional of LINC00174 in glioma. METHODS: In total, 140 glioma samples were collected as discovery cohort. TCGA RNA sequence dataset was obtained as validation set. Kaplan-Meier survival and multivariate Cox analysis were performed to evaluate survival difference. Furthermore, the biological function of LINC00174 was analyzed by clonogenic and intracranial tumor model assays. RESULTS: Overexpressed LINC00174 was significantly correlated with tumor grade as well as the higher mortality in survival analysis both in the discovery and the validation GBM cohorts. Besides, LINC00174 served as an independent prognostic indicator in glioblastoma patients. Additionally, knock down of LINC00174 expression significantly suppressed GBM cells' proliferation both in vitro and vivo. CONCLUSION: LINC00174 acts as an oncogene in glioma and may be a new potential therapeutic target.

SOX9-activated PXN-AS1 promotes the tumorigenesis of glioblastoma by EZH2-mediated methylation of DKK1.

Increasing evidence has validated the essential regulation of long non-coding RNAs (lncRNAs) in the biological process of tumours. LncRNA PXN-AS1 has been discovered to be as a tumour suppressor in pancreatic cancer; however, its function and mechanism remain greatly unknown in glioblastoma (GBM). Our present study indicated that PXN-AS1 was highly expressed in GBM tissues and cells. Besides, the knock-down of PXN-AS1 was closely associated with the inhibitory proliferation and inducing apoptosis of GBM cells. PXN-AS1 inhibition was also found to restrain GBM tumour growth. Importantly, SOX9 functioned as a transcription factor and activated PXN-AS1 expression, and overexpressed PXN-AS1 rescued the inhibitory role of down-regulated SOX9 in GBM cell growth. Subsequently, it was discovered that PXN-AS1 activated Wnt/ß-catenin pathway. DKK1 was widely known as an inhibitor gene of Wnt/ß-catenin pathway, and its expression was negatively associated with PXN-AS1 and SOX9. Interestingly, we found that PXN-AS1 could recruit EZH2 to mediate the H3K27me3 level of DKK1 promoter. Restoration experiments manifested that DKK1 knock-down counteracted PXN-AS1 depletion-mediated repression in GBM cell growth. All facts pointed out that PXN-AS1 might be of importance in exploring the therapeutic strategies of GBM.

Inhibition of PP2A with LB-100 Enhances Efficacy of CAR-T Cell Therapy Against Glioblastoma.

Chimeric antigen receptor (CAR)-engineered T cells represent a promising modality for treating glioblastoma. Recently, we demonstrated that CAR-T cells targeting carbonic anhydrase IX (CAIX), a protein involved in HIF-1a hypoxic signaling, is a promising CAR-T cell target in an intracranial murine glioblastoma model. Anti-CAIX CAR-T cell therapy is limited by its suboptimal activation within the tumor microenvironment. LB-100, a small molecular inhibitor of protein phosphatase 2A (PP2A), has been shown to enhance T cell anti-tumor activity through activation of the mTOR signaling pathway. Herein, we investigated if a treatment strategy consisting of a combination of LB-100 and anti-CAIX CAR-T cell therapy produced a synergistic anti-tumor effect. Our studies demonstrate that LB-100 enhanced anti-CAIX CAR-T cell treatment efficacy in vitro and in vivo. Our findings demonstrate the role of LB-100 in augmenting the cytotoxic activity of anti-CAIX CAR-T cells and underscore the synergistic therapeutic potential of applying combination LB-100 and CAR-T Cell therapy to other solid tumors.

Bilateral remote cerebellar hemorrhage following surgical clipping a ruptured supratentorial aneurysm.

Remote cerebellar hemorrhage (RCH) is a rare and severe complication after supratentorial surgery, with various risk factors and mechanisms remaining uncertain. Herein, we report a 64-year-old female patient suffered bilateral RCH following surgical clipping a ruptured aneurysm of internal carotid artery bifurcation. RCH is considered as venous in origin, and is likely the result of intra-operative or post-operative loss of CSF. Thus, appropriate control and close monitor the intra-operative and post-operative loss of CSF is of great importance for preventing the occurrence of RCH.

Remote Intracranial Hemorrhage Secondary to Brain Tumor Surgery.

Postoperative remote intracranial hemorrhage (rICH) secondary to craniotomy surgery is an extremely rare but catastrophic complication. The present study aimed to investigate the incidence and the possible pathophysiological mechanism of rICH after brain tumor surgery. The clinical data from 9 rICH cases among 4588 patients undergoing brain tumor surgery were collected retrospectively. Remote intracranial hemorrhage occurred in 9 cases, including 6 cases of remote epidural hemorrhage (rEDH), 2 cases of remote subdural hemorrhage (rSDH), and 1 case of remote cerebellar hemorrhage (rCBH). Among the 9 cases, 2 were males and 7 were females, with an age range of 22 to 63 years (mean of 44.3 years). The incidence of rICH in the patients with ventricular system opening/drainage (4/258) was much higher than the patients without ventricular system opening/drainage (5/4330), and the difference was statistically significant (P < 0.01). Hematoma evacuation was performed in 7 patients with serious neurological status or massive hematoma. The outcome for most of the rICH cases was good, and the Glasgow outcome scale scores of 4-5 were found in 8 cases with a 3-month-long follow-up. Our results suggest that brain tumor surgery with ventricular system opening/drainage was more susceptible to rICH. Paying particlular attention to gradual reduction of intracranial pressure and avoiding excessive loss of cerebrospinal fluid may aid to prevent the occurrence of rICH. The authors suggest that a high index of suspicion, a prompt diagnosis, and emergent management is of vital importance to achieve good prognosis for rICH patients secondary to brain tumor surgery.

Blocking lncRNA MALAT1/miR-199a/ZHX1 Axis Inhibits Glioblastoma Proliferation and Progression.

Zinc fingers and homeoboxes 1 (ZHX1) is a transcription repressor that has been implicated in the tumorigenesis and progression of diverse tumors. The functional role and regulating mechanism of ZHX1 has not been elucidated in glioblastoma (GBM). Previous reports have suggested that a large number of non-coding RNAs play a vital role in glioma initiation and progression. This study aimed to investigate the functional role and co-regulatory mechanisms of the metastasis-associated lung adenocarcinoma transcript-1 (MALAT1)/ microRNA-199a (miR-199a)/ZHX1 axis in GBM. We analyzed the expression of the MALAT1/miR-199a/ZHX1 axis and its correlation with patients' overall survival using two different glioma gene-expression datasets. A series of in vitro and in vivo studies including dual luciferase reporter assay, fluorescence in situ hybridization (FISH), RNA immunoprecipitation, and pull-down experiments were completed to elucidate the biological significance of the MALAT1/miR-199a/ZHX1 axis in promoting glioma proliferation and progression. Elevated ZHX1 expression correlated with poor prognosis in GBM patients, and in vitro studies demonstrated that ZHX1 attenuated GBM cell apoptosis by downregulation of pro-apoptotic protein (Bax) and upregulation of anti-apoptotic protein (Bcl-2). Furthermore, knockdown of MALAT1 inhibited GBM proliferation and progression in vitro and reduced tumor volume and prolonged survival in an orthotopic GBM murine model. Finally, we demonstrated that MALAT1 promoted ZHX1 expression via acting as a competing endogenous RNA by sponging miR-199a. The MALAT1/miR-199a/ZHX1 axis promotes GBM cell proliferation and progression in vitro and in vivo, and its expression negatively correlates with GBM patient survival. Blocking the MALAT1/miR-199a/ZHX1 axis can serve as a novel therapeutic strategy for treating GBM.

Targeting hypoxia downstream signaling protein, CAIX, for CAR T-cell therapy against glioblastoma.

BACKGROUND: Glioblastoma survival remains unchanged despite continuing therapeutic innovation. Herein, we aim to (i) develop chimeric antigen receptor (CAR) T cells with a specificity to a unique antigen, carbonic anhydrase IX (CAIX), which is expressed in the hypoxic microenvironment characteristic of glioblastoma, and (ii) demonstrate its efficacy with limited off-target effects. METHODS: First we demonstrated expression of CAIX in patient-derived glioblastoma samples and available databases. CAR T cells were generated against CAIX and efficacy was assessed in 4 glioblastoma cell lines and 2 glioblastoma stem cell lines. Cytotoxicity of anti-CAIX CAR T cells was assessed via interferon gamma, tumor necrosis factor alpha, and interleukin-2 levels when co-cultured with tumor cells. Finally, we assessed efficacy of direct intratumoral injection of the anti-CAIX CAR T cells on an in vivo xenograft mouse model using the U251 luciferase cell line. Tumor infiltrating lymphocyte analyses were performed. RESULTS: We confirm that CAIX is highly expressed in glioblastoma from patients. We demonstrate that CAIX is a suitable target for CAR T-cell therapy using anti-CAIX CAR T cells against glioblastoma in vitro and in vivo. In our mouse model, a 20% cure rate was observed without detectable systemic effects. CONCLUSIONS: By establishing the specificity of CAIX under hypoxic conditions in glioblastoma and highlighting its efficacy as a target for CAR T-cell therapy, our data suggest that anti-CAIX CAR T may be a promising strategy to treat glioblastoma. Direct intratumoral injection increases anti-CAIX CAR T-cell potency while limiting its off-target effects.

Blocking lncRNA H19-miR-19a-Id2 axis attenuates hypoxia/ischemia induced neuronal injury.

Elevated expression of lncRNA H19 (H19) in the setting of hypoxia has been implicated as a promising therapeutic target for various cancers. However, little is known about the impact and underlying mechanism of H19 in ischemic brain stroke. This study found that H19 levels were elevated in the serum of stroke patients, as well as in the ischemic penumbra of rats with middle cerebral artery occlusion/reperfusion (MCAO/R) injury and neuronal cells with oxygen glucose deprivation (OGD). Further, knockdown of H19 with siRNA alleviated cell apoptosis in OGD neuronal cells, and inhibition of H19 in MCAO/R rats significantly decreased neurological deficit, brain infarct volume and neuronal apoptosis. Lastly, with gain and loss of function studies, dual luciferase reported assay, RNA immunoprecipitation (RIP) and pull-down experiments, we demonstrated the dual competitive interaction of miR-19a with H19 and the 3'-UTR of Id2 mRNA, resulting in the identification of the H19-miR-19a-Id2 axis. With biological studies, we also revealed that H19-miR-19a-Id2 axis modulated hypoxia induced neuronal apoptosis. This study demonstrates that the identified H19-miR-19a-Id2 axis plays a critical role in hypoxia induced neuronal apoptosis, and blocking this axis may serve as a novel therapeutic strategy for ischemic brain injury.

Delayed Dural Arteriovenous Fistula at the Transverse-Sigmoid Sinus Secondary to Petroclival Meningioma Surgery Via Far Lateral Approach.

Intracranial dural arteriovenous fistulas (DAVFs) are typified by pathological anastomoses between meningeal arteries and dural venous sinuses or cortical veins. There are many causes contributing to the etiology of DAVFs. Among the variable causes, acquired DAVFs secondary to craniotomy had rarely been reported, especially for delayed DAVFs at the transverse-sigmoid sinus. Till now, there are only 12 published cases of delayed DAVFs at the transverse-sigmoid sinus secondary to craniotomy. Herein, the authors describe such an extraordinary rare case secondary to petroclival meningioma resection via far lateral approach, and to the best knowledge of us, this is the first well-documented case of delayed DAVF at the transverse-sigmoid sinus following far lateral craniotomy. Furthermore, cases of delayed DAVFs at the transverse-sigmoid sinus secondary to craniotomy were reviewed and investigated, and the clinical characteristics and treatment were also broadly discussed.

Identification of a multidimensional transcriptome signature for survival prediction of postoperative glioblastoma multiforme patients.

BACKGROUND: Glioblastoma multiform (GBM) is a devastating brain tumor with maximum surgical resection, radiotherapy plus concomitant and adjuvant temozolomide (TMZ) as the standard treatment. Diverse clinicopathological and molecular features are major obstacles to accurate predict survival and evaluate the efficacy of chemotherapy or radiotherapy. Reliable prognostic biomarkers are urgently needed for postoperative GBM patients. METHODS: The protein coding genes (PCGs) and long non-coding RNA (lncRNA) gene expression profiles of 233 GBM postoperative patients were obtained from The Cancer Genome Atlas (TCGA), TANRIC and Gene Expression Omnibus (GEO) database. We randomly divided the TCGA set into a training (n = 76) and a test set (n = 77) and used GSE7696 (n = 80) as an independent validation set. Survival analysis and the random survival forest algorithm were performed to screen survival associated signature. RESULTS: Six PCGs (EIF2AK3, EPRS, GALE, GUCY2C, MTHFD2, RNF212) and five lncRNAs (CTD-2140B24.6, LINC02015, AC068888.1, CERNA1, LINC00618) were screened out by a risk score model and formed a PCG-lncRNA signature for its predictive power was strongest (AUC = 0.78 in the training dataset). The PCG-lncRNA signature could divide patients into high- risk or low-risk group with significantly different survival (median 7.47 vs. 18.27 months, log-rank test P < 0.001) in the training dataset. Similar result was observed in the test dataset (median 11.40 vs. 16.80 months, log-rank test P = 0.001) and the independent set (median 8.93 vs. 16.22 months, log-rank test P = 0.007). Multivariable Cox regression analysis verified that it was an independent prognostic factor for the postsurgical patients with GBM. Compared with IDH mutation status, O-(6)-methylguanine DNA methyltransferase promoter methylation status and age, the signature was proved to have a superior predictive power. And stratified analysis found that the signature could further separated postoperative GBM patients who received TMZ-chemoradiation into high- and low-risk groups in TCGA and GEO dataset. CONCLUSIONS: The PCG-lncRNA signature was a novel prognostic marker to predict survival and TMZ-chemoradiation response in GBM patients after surgery.

Preoperative neutrophil-lymphocyte ratio correlated with glioma grading and glioblastoma survival.

BACKGROUND: Neutrophil-lymphocyte ratio (NLR) is a simple, low-cost and easily measured inflammation marker, corresponding with pathological tumor grading and clinical prognosis in various cancers. OBJECTIVES: This study aimed to investigate the relationship between preoperative NLR and glioma grading and also the correlation between NLR and glioblastoma survival. METHODS: The preoperative NLR was analyzed retrospectively in 239 gliomas of different grades, and receiver operating characteristic (ROC) curve analysis was adopted to investigate the prediction of glioma grading. Univariate and multivariate analyses were performed to analyze the variables of overall survival (OS) of glioblastoma patients. RESULTS: There were significant differences in the preoperative NLR values among the four glioma groups, with the highest values observed in the glioblastoma group (p < 0.05). ROC curve analysis showed the NLR value of 2.36 was a cutoff point for predicting glioblastoma. The OS of patients with high NLR (≥ 4.0) was shorter compared with that with low NLR (< 4.0) (mean 11.23 vs. 18.56 months, p < 0.05). Univariate analysis and multivariate analysis indicated age≥ 60, NLR≥ 4.0, Karnofsky Performance Scores (KPS) ≤ 70, incomplete tumor resection, incomplete Stupp protocol accomplishment and the isocitrate dehydrogenase 1 (IDH1) wild-type as independent prognostic indicators for poor outcome (each p < 0.05). CONCLUSION: The preoperative NLR was correlated with glioma grading, and the elevated NLR was an independent predictive factor for poor outcome of glioblastoma patients. Abbreviation IDH1: Isocitrate dehydrogenase 1IL-8: Interleukin-8KPS: Karnofsky Performance ScoresNLR: Neutrophil-lymphocyte ratioOS: Overall survivalROC: Receiver operating characteristicSD: Standard deviationsWHO: World Health Organization.

Delayed Intracerebral Hemorrhage Secondary to Ventriculoperitoneal Shunt: A Retrospective Study.

BACKGROUND: Postoperative delayed intracerebral hemorrhage (DICH) secondary to ventriculoperitoneal (VP) shunt is a rare but severe event. The present study aimed to investigate the incidence and risk factors related to DICH after placement of the VP shunt. METHODS: The clinical data from 532 patients with VP shunt were collected retrospectively. All clinical variables were examined by univariate analysis, and a binary logistic regression analysis was performed to identify the risk factors related to DICH. RESULTS: DICH occurred in 20 patients, from 3 to 10 days after placement of the VP shunt. Univariate analysis showed significant differences between the patients with DICH and without DICH with respect to age, history of hypertension, history of craniotomy, and features of the first computed tomography (CT) scans after placement of the VP shunt (all P < 0.05). The binary logistic regression analysis showed that age, history of craniotomy, and features of first CT scans after placement of the VP shunt were independent risk factors for DICH (all P < 0.05). The prognosis for patients with DICH was consistent with the hematoma volume and the neurologic status at the time of hospital admission (all P < 0.05). CONCLUSIONS: DICH is a rare and potentially severe complication secondary to VP shunt, and a repeat of cranial CT scans after placement of the VP shunt is recommended. Advanced age, craniotomy history, and brain edema around the catheter on the first cranial CT scan after placement of the VP shunt served as independent risk factors for DICH. The patients with DICH with poor neurologic status at the time of hospital admission or large hematoma volume were associated with poor outcome.

Posttraumatic Intradiploic Pseudomeningocele of the Occipito-Cervical Region.

Pseudomeningocele is a collection of the cerebrospinal fluid in the extradural space due to a defect in the dura-arachnoid layer of the meninge, and manifests as a fibrous capsule in the space of subcutaneous tissues. Classically, growing skull fracture caused by the pseudomeningocele is not uncommon in the pediatric age group. However, a posttraumatic intradiploic pseudomeningoceles is extremely rare, and only a few patients have been described. Herein, the authors present a 6-year-old girl who developed an intradiploic pseudomeningocele of the occipito-cervical region after a severe head trauma.

Bundling potent natural toxin cantharidin within platinum (IV) prodrugs for liposome drug delivery and effective malignant neuroblastoma treatment.

Neuroblastoma (NB) is one of the most commonly seen malignancies in childhood and infancy. Cantharidin is a highly potent natural toxin that possesses potent anti-tumor properties on various cancers including NB. However, exposure to cantharidin can cause severe chemical burns and application of cantharidin for cancer therapy is limited. Here we report a strategy of bundling cantharidin within a hybrid platinum (IV) prodrug conjugate. This hydrophobic drug conjugate, ie, CanPt can be further formulated into liposome for drug delivery to minimize the exposure of cantharidin to normal cells for efficient chemotherapeutic agent against NB.

Primary Spinal Oligoastrocytoma.

Astrocytomas are the most common intramedullary spinal cord tumors in pediatric and adolescent patients and the incidence decreases with age. Spinal oligoastrocytoma, which is a mixed glioma with distinct astrocytic and oligodendroglial components, is an extremely rare pathology of the spinal cord. To authors' best of knowledge, there are only 7 spinal oligoastrocytomas reported in the English literature. Here, the authors report a patient of a pathologically confirmed spinal oligoastrocytoma, who presented with severe left leg pain and numbness. This patient reminds us of the rarity of spinal oligoastrocytoma, and the treatment and prognosis were also investigated and reviewed.