Safe Region of Craniotomy to Access the Cerebellopontine Region by Retrosigmoid Approach: A Radiological and Anatomical Study.

Accurately positioning the sigmoid sinus (SS), transverse sinus (TS), and vertebral artery (VA) is significantly important during the retrosigmoid (RS) approach. This study aimed to use emissary vein and digastric point as landmarks in high-resolution computer topographic image to locate the SS, TS, and VA to help surgeons to avoid injuring these vascular structures during RS craniotomy. Computed topographic (CT) angiography images of 107 individuals were included, the measurement was performed on coronal, sagittal, and axis planes after the multiplanar reformation. Distance from the emissary vein and digastric point to the posterior boundary of the SS, inferior boundary of the TS were measured by CT angiography preoperatively and in the skull intraoperatively. The VA was also located by emissary vein and digastric point. No significant difference was identified between the distances measured in the CT and skull. Our findings provide anatomical information for locating the boundary of the SS, TS, and V3-VA based on the fixed bony landmarks. Verified by skull measurement, high-resolution CT scan is a cost-effective and reliable tool for identifying the location of the arteries and sinus, which could be widely used to guarantee the safety of RS approach craniectomy.

Glioma Imaging by O-(2-18F-Fluoroethyl)-L-Tyrosine PET and Diffusion-Weighted MRI and Correlation With Molecular Phenotypes, Validated by PET/MR-Guided Biopsies.

Gliomas exhibit high intra-tumoral histological and molecular heterogeneity. Introducing stereotactic biopsy, we achieved a superior molecular analysis of glioma using O-(2-18F-fluoroethyl)-L-tyrosine (FET)-positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging (DWI). Patients underwent simultaneous DWI and FET-PET scans. Correlations between biopsy-derived tumor tissue values, such as the tumor-to-background ratio (TBR) and apparent diffusion coefficient (ADC)/exponential ADC (eADC) and histopathological diagnoses and those between relevant genes and TBR and ADC values were determined. Tumor regions with human telomerase reverse transcriptase (hTERT) mutation had higher TBR and lower ADC values. Tumor protein P53 mutation correlated with lower TBR and higher ADC values. α-thalassemia/mental-retardation-syndrome-X-linked gene (ATRX) correlated with higher ADC values. 1p/19q codeletion and epidermal growth factor receptor (EGFR) mutations correlated with lower ADC values. Isocitrate dehydrogenase 1 (IDH1) mutations correlated with higher TBRmean values. No correlation existed between TBRmax/TBRmean/ADC/eADC values and phosphatase and tensin homolog mutations (PTEN) or O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. Furthermore, TBR/ADC combination had a higher diagnostic accuracy than each single imaging method for high-grade and IDH1-, hTERT-, and EGFR-mutated gliomas. This is the first study establishing the accurate diagnostic criteria for glioma based on FET-PET and DWI.

First-in-Human Trial of EphA2-Redirected CAR T-Cells in Patients With Recurrent Glioblastoma: A Preliminary Report of Three Cases at the Starting Dose.

Glioblastoma is the most common primary brain malignancy with limited treatment options. EphA2 is a tumor-associated-antigen overexpressed in glioblastoma. Pre-clinical studies have demonstrated the promise of EphA2-redirected CAR T-cells against glioblastoma. We conduct the first-in-human trial of EphA2-redirected CAR T-cells in patients with EphA2-positive recurrent glioblastoma and report the results of three patients enrolled as the first cohort receiving the starting dosage (1×106 cells/kg). A single infusion of EphA2-redirected CAR T-cells was administrated intravenously, with the lymphodepletion regimen consisting of fludarabine and Cyclophosphamide. In two patients, there was grade 2 cytokine release syndrome accompanied by pulmonary edema, which resolved completely with dexamethasone medication. Except that, there was no other organ toxicity including neurotoxicity. In both the peripheral blood and cerebral-spinal-fluid, we observed the expansion of CAR T-cells which persisted for more than four weeks. In one patient, there was a transit diminishment of the tumor. Among these three patients, one patient reported SD and two patients reported PD, with overall survival ranging from 86 to 181 days. At the tested dose level (1×106 cells/kg), intravenously infusion of EphA2-rediretected CAR T-cells were preliminary tolerable with transient clinical efficacy. Future study with adjusted dose and infusion frequency of CAR T-cells is warranted. TRIAL REGISTRATION NUMBERS: NCT03423992.

Somatic MAP3K3 and PIK3CA mutations in sporadic cerebral and spinal cord cavernous malformations.

Cavernous malformations affecting the CNS occur in ∼0.16-0.4% of the general population. The majority (85%) of cavernous malformations are in a sporadic form, but the genetic background of sporadic cavernous malformations remains enigmatic. Of the 81 patients, 73 (90.1%) patients were detected carrying somatic missense variants in two genes: MAP3K3 and PIK3CA by whole-exome sequencing. The mutation spectrum correlated with lesion size (P = 0.001), anatomical distribution (P < 0.001), MRI appearance (P = 0.004) and haemorrhage events (P = 0.006). PIK3CA mutation was a significant predictor of overt haemorrhage events (P = 0.003, odds ratio = 11.252, 95% confidence interval = 2.275-55.648). Enrichment of endothelial cell population was associated with a higher fractional abundance of the somatic mutations. Overexpression of the MAP3K3 mutation perturbed angiogenesis of endothelial cell models in vitro and zebrafish embryos in vivo. Distinct transcriptional signatures between different genetic subgroups of sporadic cavernous malformations were identified by single cell RNA sequencing and verified by pathological staining. Significant apoptosis in MAP3K3 mutation carriers and overexpression of GDF15 and SERPINA5 in PIK3CA mutation carriers contributed to their phenotype. We identified activating MAP3K3 and PIK3CA somatic mutations in the majority (90.1%) of sporadic cavernous malformations and PIK3CA mutations could confer a higher risk for overt haemorrhage. Our data provide insights into genomic landscapes, propose a mechanistic explanation and underscore the possibility of a molecular classification for sporadic cavernous malformations.

Dural plasmacytoma as the initial presentation of multiple myeloma: A case report and review of the literature.

Dural plasmacytoma is a type of multiple myeloma of the central nervous system. Our patient presented with symptoms of headache. Imaging findings suspected glioblastoma, whereas pathological findings revealed mucosa-associated lymphoid tissue lymphoma associating with plasma cell differentiation. Further in-depth studies confirmed a diagnosis of dural plasmacytoma. This case indicates that morphological variations may occur in the extramedullary involvement of CD20-positive multiple myeloma. The multidisciplinary team contributes to the diagnosis of hematological diseases.

Simultaneous FET-PET and contrast-enhanced MRI based on hybrid PET/MR improves delineation of tumor spatial biodistribution in gliomas: a biopsy validation study.

PURPOSE: Glioma treatment planning requires precise tumor delineation, which is typically performed with contrast-enhanced (CE) MRI. However, CE MRI fails to reflect the entire extent of glioma. O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) PET may detect tumor volumes missed by CE MRI. We investigated the clinical value of simultaneous FET-PET and CE MRI in delineating tumor extent before treatment planning. Guided stereotactic biopsy was used to validate the findings. METHODS: Conventional MRI and 18F-FET PET were performed simultaneously on a hybrid PET/MR in 33 patients with histopathologically confirmed glioma. Tumor volumes were quantified using a tumor-to-brain ratio ≥ 1.6 (VPET) and a visual threshold (VCE). We visually assessed abnormal areas on FLAIR images and calculated Dice's coefficient (DSC), overlap volume (OV), discrepancy-PET, and discrepancy-CE. Additionally, several stereotactic biopsy samples were taken from "matched" or "mismatched" FET-PET and CE MRI regions. RESULTS: Among 31 patients (93.94%), FET-PET delineated significantly larger tumor volumes than CE MRI (77.84 ± 51.74 cm3 vs. 34.59 ± 27.07 cm3, P < 0.05). Of the 21 biopsy samples obtained from regions with increased FET uptake, all were histopathologically confirmed as glioma tissue or tumor infiltration, whereas only 13 showed enhancement on CE MRI. Among all patients, the spatial similarity between VPET and VCE was low (average DSC 0.56 ± 0.22), while the overlap was high (average OV 0.95 ± 0.08). The discrepancy-CE and discrepancy-PET were lower than 10% in 28 and 0 patients, respectively. Eleven patients showed VPET partially beyond abnormal signal areas on FLAIR images. CONCLUSION: The metabolically active biodistribution of gliomas delineated with FET-PET significantly exceeds tumor volume on CE MRI, and histopathology confirms these findings. Our preliminary results indicate that combining the anatomic and molecular information obtained from conventional MRI and FET-PET would reveal a more accurate glioma extent, which is critical for individualized treatment planning.

A Mistaken Diagnosis of Secondary Glioblastoma as Parasitosis.

Background: Glioblastoma is a malignant brain tumor with poor prognosis requiring early diagnosis. Secondary glioblastoma refers to cases that progressed from low-grade glioma. Evidence shows that timely resection correlates with increased survival. Case presentation: We describe a case of a patient with secondary glioblastoma who was mistakenly diagnosed with Angiostrongylus cantonensis infection until 7 years after disease onset. The patient presented with non-specific clinical manifestations at disease onset. A conventional magnetic resonance imaging (MRI) in the primary survey provided insufficient information, and thus failed to identify the malignancy. During follow-up, unfortunately, clinicians were misled by the patient's raw food diet, a positive serum parasite antibody and a result of low glucose metabolism on Fluorodeoxyglucose-positron emission tomography-computed tomography (FDG-PET-CT). The patient was diagnosed with parasitosis. However, his condition kept getting worse under antiparasitic treatment. Preoperative magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) failed to reverse the mistaken impression. Final diagnosis was confirmed until intraoperative and postoperative pathological findings indicated glioblastoma. Conclusion: We ascribe the incorrect diagnosis to insufficient understanding on imaging manifestations of brain neoplasm as well as clinical features of parasitosis. Thus, we review the MRI, FDG-PET-CT, MRS, and DTI data of this case according to the timeline, refer to relevant studies, and point out the pitfalls. With a long course of slowly progressing, this was a rare case of secondary glioblastoma with the absence of isocitrate dehydrogenase 1 (IDH1) gene mutation.

RELA Fusion in Supratentorial Extraventricular Ependymomas: A Morphologic, Immunohistochemical, and Molecular Study of 43 Cases.

Supratentorial extraventricular ependymomas (STEEs) are relatively rare ependymomas, and their pathologic and genetic characteristics are still poorly understood. The aim of this study was to determine the histologic, immunohistochemical, and RELA fusion features, as well as to clarify in more detail the clinical courses of STEEs. Data from a total of 43 patients with STEEs was analyzed retrospectively. The status of RELA fusion was evaluated using fluorescence in situ hybridization. The expression levels of L1CAM, p65, cyclin D1, and p53 were assessed using immunohistochemistry. Progression-free survival and overall survival were calculated via Kaplan-Meier estimation using the log-rank test. Among all 43 STEEs, 65.1% (28/43) are positive for RELA fusion. Interestingly, almost half of the patients with RELA fusion-positive ependymomas are adults (13/28), and 89.3% (25/28) cases are anaplastic ependymomas, which suggests that RELA fusion testing is necessary in adults with STEEs. We investigated the immunohistochemical status of p65, L1CAM and CCND1 protein expression for their ability to predict RELA fusion status. RELA fusion-positive STEEs are frequently associated with expression of p65 (85.2%), L1CAM (85.2%), and CCND1 (81.5%). The accuracy of predicting RELA fusion status was much higher when the expression of p65 and L1CAM was combined, that is, when both were immunopositive. The status of RELA fusion, p53 overexpression, and extent of tumor resection are significantly associated with prognosis.

H3 K27M-mutant diffuse midline gliomas in different anatomical locations.

The histone H3 K27M mutation has been frequently reported in most diffuse midline gliomas. However, the relationship between the H3 K27M mutation and clinical outcomes of gliomas from different anatomical locations is still not fully understood. A total of 120 patients with diffuse midline gliomas were selected for this retrospective observational study. The status of H3 K27M, ATRX, TP53, and IDH was evaluated using immunohistochemistry and Sanger sequencing. Of the 120 patients aged from 4 to 76 years (median, 27 years), 61 (50.8%) were harboring the H3 K27M mutation. Tumors were mainly located in the brainstem, ATRX thalamus, and spinal cord, but also in the cerebellum, corpus callosum, and the lateral ventricle. Patients with H3 K27M-mutant diffuse midline gliomas had a significantly shorter overall survival than H3 wild-type counterparts (P = .001). However, the H3 K27M mutation was mainly associated with a poorer prognosis in infratentorial gliomas compared with the corresponding H3 wild-type gliomas (P < .0001), but not in supratentorial gliomas (P = .603). Moreover, patients with H3 K27M-mutant gliomas in unusual anatomical locations had a better prognosis than did those with corresponding tumors in the brainstem. This study may provide guidance for better treatment stratification decisions for diffuse gliomas bearing the H3 K27M mutation, which arise in different locations of the brainstem, thalamus, spinal cord, or other sites.

Gliosarcomas with the BRAF V600E mutation: a report of two cases and review of the literature.

Gliosarcoma, which is regarded as a variant of glioblastoma, is a rare malignant neoplasm of the central nervous system. Both its sarcomatous component and glial component are reported to share significant clinical and genetic similarities. However, gliosarcomas are considered to be characterised by a lack of the BRAF V600E mutation. Here, we report two cases of gliosarcoma harbouring the BRAF V600E mutation, of which one case appears to have arisen de novo, while the other likely arose from ganglioglioma. Interestingly, the BRAF V600E mutation was detected only in the glial component in the first case, but was present in both the glial and the sarcomatous components in the recurrent gliosarcoma. Furthermore, the different mutation state of BRAF V600E in our two cases suggests that the malignant transformation of gliosarcoma might have different underlying genetic alterations and mechanisms in de novo versus recurrent gliosarcoma.

Effects of simulated microgravity on human brain nervous tissue.

During spaceflight, the negative effects of space microgravity on astronauts are becoming more and more prominent, and especially, of which on the nervous system is urgently to be solved. For this purpose tissue blocks and primary cells of nervous tissues obtained from glioma of patients were cultivated after culturing for about 7days, explanted tissues and cells were then randomly divided into two groups, one for static culture (control group, C), and the other for rotary processing for 1day, 3days, 5days, 7days and 14days (experiment group, E). Figures captured by inverted microscope revealed that, with short time rotating for 1day or 3days, morphology changes of tissue blocks were not obvious. When the rotary time was extended to 7days or 14days, it was found that cell somas is significantly larger and the ability of adhesion is declined in comparison with that in control group. Additionally, the arrangement of cells migrated from explanted tissues was disorganized, and the migration distance became shorter. In immunofluorescence analysis, ß-tubulin filaments in control group appeared to organize into bundles. While in experiment group, ß-tubulin was highly disorganized. In conclusion, simulated microgravity treatment for a week affected the morphology of nervous tissue, and caused highly disorganized distribution of cytoskeleton and the increase of cell apoptosis. These morphological changes might be one of the causes of apoptosis induced by simulated microgravity.

Simulation-based airway management training: application and looking forward.

Within the airway management field, simulation has been used as a tool of training for over 40 years. Simulation training offers a chance of active involvement for the trainees. It can effectively enhance and upgrade the knowledge and skills of the trainees in airway management, and subsequently decrease medical errors and improve patients' outcomes and safety through a variety of airway management training modalities, such as common airway skills, difficult airway management strategies, and crisis management skills. To perform simulation-based airway management training effectively, not only are task trainers and high-fidelity simulators required but also instructors with rich experience in airway management simulation training and optimal curriculum design are essential.

Serine/Threonine Protein Phosphatase-5 Accelerates Cell Growth and Migration in Human Glioma.

Glioma is the most common type of primary central nervous system tumor. Ser/Thr protein phosphatase 5 (PP5) has been shown to regulate multiple signaling cascades that suppress growth and facilitate apoptosis in several human cancer cells. However, the role of PP5 in human gliomas remains unclear. Herein, the relationship between PP5 expression and glioma cell growth was investigated, and the therapeutic value of PP5 in glioma was further evaluated. We employed a short hairpin RNA targeting PPP5C gene to knock down PP5 expression in human glioma cell lines U251 and U373. Depletion of PPP5C via RNAi remarkably inhibited glioma cell proliferation and colony formation, and arrested cell cycle in the G0/G1 phase. Moreover, knockdown of PP5 markedly suppressed glioma cell migration, as determined by Transwell assay. Our findings suggest that PPP5C could be essential for glioma cell growth and serve as a promising therapeutic target in human gliomas.

Extended transsphenoidal approach for pituitary adenomas invading the anterior cranial base, cavernous sinus, and clivus: a single-center experience with 126 consecutive cases.

OBJECT: The standard transsphenoidal approach has been successfully used to resect most pituitary adenomas. However, as a result of the limited exposure provided by this procedure, complete surgical removal of pituitary adenomas with parasellar or retrosellar extension remains problematic. By additional bone removal of the cranial base, the extended transsphenoidal approach provides better exposure to the parasellar and clival region compared with the standard approach. The authors describe their surgical experience with the extended transsphenoidal approach to remove pituitary adenomas invading the anterior cranial base, cavernous sinus (CS), and clivus. METHODS: Retrospective analysis was performed in 126 patients with pituitary adenomas that were surgically treated via the extended transsphenoidal approach between September 1999 and March 2008. There were 55 male and 71 female patients with a mean age of 43.4 years (range 12-75 years). There were 82 cases of macroadenoma and 44 cases of giant adenoma. RESULTS: Gross-total resection was achieved in 78 patients (61.9%), subtotal resection in 43 (34.1%), and partial resection in 5 (4%). Postoperative complications included transient cerebrospinal rhinorrhea (7 cases), incomplete cranial nerve palsy (5), panhypopituitarism (5), internal carotid artery injury (2), monocular blindness (2), permanent diabetes insipidus (1), and perforation of the nasal septum (2). No intraoperative or postoperative death was observed. CONCLUSIONS: The extended transsphenoidal approach provides excellent exposure to pituitary adenomas invading the anterior cranial base, CS, and clivus. This approach enhances the degree of tumor resection and keeps postoperative complications relatively low. However, radical resection of tumors that are firm, highly invasive to the CS, or invading multidirectionally remains a big challenge. This procedure not only allows better visualization of the tumor and the neurovascular structures but also provides significant working space under the microscope, which facilitates intraoperative manipulation. Preoperative imaging studies and new techniques such as the neuronavigation system and the endoscope improve the efficacy and safety of tumor resection.

Intraventricular pre-treatment with rAAV-VEGF induces intracranial hypertension and aggravates ischemic injury at the early stage of transient focal cerebral ischemia in rats.

OBJECTIVE: To examine the effects of intraventricular pre-treatment with recombinant adeno-associated virus vectors encoding VEGF (rAAV-VEGF) on early stroke in a rat model of transient middle cerebral artery occlusion (tMCAO). METHODS: rAAV-VEGF, rAAV-null or physiologic saline was delivered into the lateral ventricle of 93 Wistar rats, respectively. Eight weeks later, the rats were subjected to tMCAO for 2 hours. During the early stage following ischemic reperfusion, intracranial pressure (ICP) and brain water content were measured to make a correlation analysis, T2-weighted MRI was performed to observe cerebral edema volume, and TTC-derived cerebral infarct volume and modified neurological severity scores (NSS) were determined to evaluate the therapeutic efficacy of rAAV-VEGF in tMCAO. RESULTS: Twenty-four hours following tMCAO, the rAAV-VEGF group, with VEGF overexpression in the rats brain, showed a significantly increase in ICP, brain water content and cerebral edema volume compared with two control groups (p<0.05). The ICP significantly correlated with the brain water content in the infarct hemisphere in all three groups during 24 hours following tMCAO (r=0.93, p<0.05). Forty-eight hours following tMCAO, a 1.3-fold larger infarct volume and 1.3-fold higher NSS were observed in the rAAV-VEGF group than both control groups (p<0.05). CONCLUSION: Our results indicate that intraventricular rAAV-VEGF pre-treatment can result in deleterious intracranial hypertension and augment secondary ischemic insults at the early stage of tMCAO, and pre-ischemic VEGF gene transfer via intraventricular approach may not be a favorable therapeutic strategy for tMCAO which should be adopted with caution or avoided in experimental stroke.

[Study on trans-differentiation of adult human myoblasts into neural precursor cells and its implantation in rats].

OBJECTIVE: To investigate the feasibility of inducing adult human myoblasts into neural precursor cells. METHODS: The myoblasts were isolated with mixed digestive enzyme from minced human temporal muscle samples, cultured and purified clonally. The 3rd passage cells were incubated with serum free medium including basic fibroblast growth factor (bFGF), epidermal growth factor (EGF) and leukemia inhibitory factor (LIF). Morphological change was investigated during incubation period. Immunofluorescence cytochemistry and RT-PCR analysis were used to assess cell differentiation and trans differentiation. RESULTS: After the induction, cells became non-adherent aggregates as neurospheres. The myoblast-derived neurospheres was immuno-positive for nestin. In differentiation condition, they looked like neurons and glial cells and expressed neuronal (microtubule associated protein 2, MAP-2), astrocytic (Glial fibrillary acidic protein, GFAP) and oligodendrocytic (Galactocerebroside, Galc) markers by immunocytochemistry. The result by RT-PCR was coincident with immunocytochemistry. The myoblast-derived neurospheres expressed MAP-2 and GFAP after they were transplanted into the brain of rats with cerebral ischemia. CONCLUSION: Adult human myoblasts can be inducted to trans-differentiate into neural precursor cells.

[Expression of enhanced green fluorescent protein in rat brain transduced by recombinant adeno-associated viruses type 1 and type 2].

OBJECTIVE: To explore the expression of enhanced green fluorescent protein (EGFP) transduced into the brain via recombinant adeno-associated virus (rAAV) type 1 and rAAV type 2 vectors so as to select the better rAAV serotype and feasible gene transfer route to central nervous system (CNS). METHODS: Twenty-four SD male adult rats were randomly divided into 4 equal groups: rAAV1 intra-hippocampus injection group, rAAV1 intra-ventricular injection group, rAAV2 intra-hippocampus injection group, and rAAV2 intra-ventricular injection group to be injected stereotactically with titer and volume matched rAAV1-EGFP and rAAV2-EGFP vectors respectively. The rats were sacrificed respectively 2 and 4 weeks after injection and their brains were removed to be made into serial frozen coronal sections. Fluorescence microscopy was used to observe the expression of EGFP in the brain and to calculate the expression volume of EGFP in different parts of the brain. RESULTS: Two weeks after injection EGFP was expressed in a small amount or not expressed in all groups. Four weeks after injection the EGFP expression volume were (7.00 +/- 0.98) mm(3) and (0.81 +/- 0.28) mm(3) in the rAAV1 and rAAV2 intra-hippocampus injection groups respectively (P < 0.01), and were (12.72 +/- 0.28) mm(3) and (0.24 +/- 0.13) mm(3) in the rAAV1 and rAAV2 intra-ventricular injection groups respectively (P < 0.001). CONCLUSION: As gene-transducing vector in CNS rAAV1 is superior to rAAV2. High expression can be achieved by intra-ventricular injection with rAAV1 vectors.

Proliferation and differentiation of neural stem cells in adult rats after cerebral infarction.

OBJECTIVE: To investigate proliferation and differentiation of neural stem cells in adult rats after cerebral infarction. METHODS: Models of cerebral infarction in rats were made and the time-course expression of bromodeoxyuridine (BrdU), Musashi1, glial fibrillary acidic protein (GFAP), and neuronal nuclear antigen (NeuN) were determined by immunohistochemistry and immunofluorescence staining. BrdU and Musashi1 were used to mark dividing neural stem cells. GFAP and NeuN were used to mark differentiating neural stem cells. RESULTS: Compared with controls, the number of BrdU-labeled and BrdU-labeled with Musashi 1-positive cells increased strikingly 1 day after cerebral infarction; approximately 6 fold with a peak 7 days later; markedly decreased 14 days later, but was still elevated compared with that of controls; decling to the control level 28 days later. The number of BrdU-labeled with GFAP-positive cells nearly remained unchanged in the hippocampus after cerebral infarction. The number of BrdU-labeled with NeuN-positive cells increased strikingly 14 days after cerebral infarction, reached maximum peak in the hippocampus 28 days after cerebral infarction in rats. CONCLUSION: Cerebral infarction stimulate proliferation of inherent neural stem cells and most proliferated neural stem cells differentiate into neurons.