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Xiao Yue, FengMing Lan, Man Hu, Qiang Pan, Qiong Wang and JinHuan Wang

OBJECT

Circulating microRNAs (miRNAs) are a new class of highly promising cancer biomarkers. Malignant glioma is one of the most devastating and lethal forms of intrinsic CNS tumor. Here, the authors evaluated serum miRNA 205 (miR-205) levels in patients with glioma.

METHODS

Sixty-four patients in whom glioma was diagnosed and 45 healthy controls were recruited between October 2011 and March 2012 and randomly assigned to the screening cohort or the validation cohort. Cohorts of patients with other brain tumors, including meningioma (n = 8), primary diffuse large B-cell lymphoma of the CNS (n = 6), and pituitary adenoma (n = 5), were investigated and compared. miR-205 extraction from serum was detected by real-time quantitative reverse-transcription polymerase chain reaction. The Kaplan-Meier method was applied to perform survival analysis, the risk factors were analyzed by using a Cox regression model, and the receiver operating characteristic working curve was used to analyze the value of miR-205 in the prognostic evaluation of the patients.

RESULTS

The authors first demonstrated that serum miR-205 expression was significantly lower in patients with glioma than in healthy controls (p < 0.001). It is important to note that serum miR-205 expression demonstrated a stepwise decrease with ascending pathological grades. The serum miR-205 biomarker had high sensitivity, specificity, and accuracy in patients with glioma. Serum levels of miR-205 were identified as an individual diagnostic marker and were significantly lower in the glioma cohort than in the other brain tumor cohorts. Serum miR-205 levels were significantly increased in postoperative samples over those in the preoperative samples and were reduced again during glioblastoma recurrences. Statistical analysis revealed a significant correlation between low serum miR-205 expression and both ascending pathological grades (p = 0.002) and low Karnofsky Performance Scale scores (p = 0.01). Patients with glioma at an advanced pathological grade (Grade III or IV) and a higher miR-205 serum level showed longer overall survival than those with a lower miR-205 serum concentration (p < 0.01). Furthermore, Cox regression analysis revealed that miR-205 serum levels were independently associated with overall survival.

CONCLUSIONS

These data indicate that serum miR-205 expression is a novel and valuable biomarker for the diagnosis of glioma and a prognostic factor for those with a tumor at an advanced pathological grade.

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Bang-ping Qian, Ji-chen Huang, Yong Qiu, Bin Wang, Yang Yu, Ze-zhang Zhu, Sai-hu Mao and Jun Jiang

OBJECTIVE

To describe the incidence of complications in spinal osteotomy for thoracolumbar kyphosis caused by ankylosing spondylitis (AS) and to investigate the risk factors for these complications.

METHODS

From April 2000 to July 2017, 342 consecutive AS patients with a mean age (± SD) of 35.4 ± 9.8 years (range 17–71 years) undergoing spinal osteotomy were enrolled. Patients with complications within the 1st postoperative year were identified. Demographic, radiological, and surgical data were compared between patients with and without complications. The complications were classified into intraoperative and postoperative complications.

RESULTS

A total of 310 consecutive pedicle subtraction osteotomy (PSO) and 37 multiple Smith-Petersen osteotomy (SPO) procedures were performed in 342 patients. Overall, 47 complications were identified in 47 patients (13.7%), including 31 intraoperative complications and 16 postoperative complications. Patients with complications were older than those without (p = 0.006). A significant difference was observed in preoperative global kyphosis (GK), lumbar lordosis (LL), sagittal vertical axis (SVA), and the correction of these radiographic parameters between patients with and without complications (p < 0.05). Two-level PSO (p = 0.022) and an increased number of instrumented vertebrae (p = 0.019) were significantly associated with an increased risk of complications.

CONCLUSIONS

The overall incidence of complications was 13.7%. Age; preoperative GK, LL, and SVA; the correction of GK, LL, and SVA; 2-level PSO; and number of instrumented vertebrae were risk factors. Therefore, the potential risk of extensive surgeries with large correction and long fusion in older AS patients with severe GK should be seriously considered in surgical decision-making.

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Xiaohui Ren, Junmei Wang, Mengqing Hu, Haihui Jiang, Jun Yang and Zhongli Jiang

Object

Intracranial and intraspinal malignant peripheral nerve sheath tumors (MPNSTs) are rarely reported because of their extremely low incidence. Knowledge about these tumors is poor. In this study the authors aimed to analyze the incidence and clinical, radiological, and pathological features of intracranial and intraspinal MPNSTs.

Methods

Among 4000 cases of intracranial and intraspinal PNSTs surgically treated between 2004 and 2011 at Beijing Tiantan Hospital, cases of MPNST were chosen for analysis and were retrospectively reviewed. To determine which parameters were associated with longer progression-free survival (PFS) and overall survival (OS), statistical analysis was performed.

Results

Malignant PNSTs accounted for 0.65% of the entire series of intracranial and intraspinal PNSTs. Twenty-four (92.3%) of these 26 MPNSTs were primary. Radiologically, 26.9% (7 of 26) of the MPNSTs were misdiagnosed as nonschwannoma diseases. Twenty-one patients were followed up for 1.5 to 102 months after surgery. Twelve patients experienced tumor recurrence, and median PFS was 15.0 months. The 2- and 3-year PFS rates were 47.7% and 32.7%, respectively. Five patients died of tumor recurrence, and median OS was not available. The 2- and 3-year OS rates were 74.7% and 64.0%, respectively. Univariate analysis revealed that female sex, total tumor removal, and primary MPNSTs were significantly associated with a better prognosis. Multivariate analysis revealed that only total removal was an independent prognostic factor for both PFS and OS.

Conclusions

Malignant PNST within the skull or spinal canal is a rare neoplasm and is seldom caused by benign schwannomas. Radiologically, intracranial or intraspinal MPNST should be differentiated from meningioma, chordoma, fibrous dysplasia of bone, and ear cancer. Total resection whenever possible is necessary for the prolonged survival of patients, especially males.

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Xiao-Qiang Wang, Cheng-Chuan Jiang, Lin Zhao, Ye Gong, Jie Hu and Hong Chen

Object

High-grade meningiomas in childhood are rare, and their clinical features are unknown. The objective of this study was to determine the clinical characteristics and prognosis of childhood high-grade meningiomas.

Methods

Twenty-three patients with childhood high-grade meningiomas were treated at the Huashan Hospital. Clinical data were collected, tumor samples were reexamined, and prognoses were attained through follow-up visits and telephone interviews. Survival probability was calculated using the Kaplan-Meier method. A 2-sided probability level of 0.05 was chosen for statistical significance.

Results

The series included 18 males and 5 females (mean age 12.1 years). The most common symptoms were headache and vomiting (43%). Three patients had accompanying neurofibromatosis Type II (NF2). The high-grade meningioma cases with NF2 had larger tumor diameters than those without NF2 (p = 0.010). The skull base was the most common tumor site (39%). Complete resections were achieved in 11 patients after their initial operations. Adjuvant radiation therapy was performed in 9 cases. Follow-up evaluations were performed for 20 patients (mean follow-up 70 months). Ten patients experienced recurrences, 2 patients had lung metastases, and 7 patients died of the recurrence. The extent of surgery was significantly related to progression-free survival (PFS; p = 0.038). A negative progesterone receptor combined with strongly positive Bcl-2 immunoreactivity was significantly related to PFS (p = 0.001) and overall survival (p = 0.002). The MIB-1 labeling index was significantly related to overall survival (p = 0.018), whereas postoperative radiation therapy was not significantly related to PFS (p = 0.087) and overall survival (p = 0.40).

Conclusions

Childhood high-grade meningioma is a rare tumor type. Childhood high-grade meningioma has a male predominance and the basilar region is the most common tumor location. Patients with these tumors have high recurrence and mortality rates. The extent of resection is an important prognosis factor. A negative progesterone receptor combined with a strongly positive Bcl-2 immunoreaction might predict cancer recurrence. The MIB-1 labeling index correlates with the prognosis, and an MIB-1 labeling index > 3% increases the risk of recurrence in childhood high-grade meningioma. More cases should be collected, and longer follow-up periods should be obtained, to evaluate the effects of postoperative radiation therapy in childhood high-grade meningioma.

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Zhuo-jie Liu, Bang-ping Qian, Yong Qiu, Sai-hu Mao, Jun Jiang and Bin Wang

OBJECTIVE

Relocation of the apex is often found in patients with ankylosing spondylitis (AS)–associated thoracolumbar/lumbar kyphosis after corrective surgery. This study evaluates the influence of different postoperative apex locations on surgical and clinical outcomes of osteotomy for patients with AS and thoracolumbar kyphosis.

METHODS

Sixty-two patients with a mean age of 34.6 ± 9.7 years (range 17–59 years) and a minimum of 2 years of follow-up, who underwent 1-level lumbar pedicle subtraction osteotomy for AS-related thoracolumbar kyphosis, were enrolled in the study, as well as 62 age-matched healthy individuals. Patients were divided into 2 groups according to the postoperative location of the apex (group 1, T8 or above; group 2, T9 or below). Demographic data, radiographic measurements (including 3 postoperative apex-related parameters), and clinical outcomes were compared between the 2 groups preoperatively, postoperatively, and at the last follow-up. Furthermore, a subgroup analysis was performed among patients with a postoperative apex located at T6–11 and postoperatively the entire AS cohort was compared with normal controls regarding the apex location of the thoracic spine.

RESULTS

In the majority of the enrolled patients, the apex location changed from T12–L2 preoperatively to T6–9 postoperatively. The sagittal vertical axis (SVA) differed significantly both postoperatively (25.7 vs 59.0 mm, p = 0.001) and at the last follow-up (34.6 vs 59.9 mm, p = 0.003) between the 2 groups, and the patients in group 1 had significantly smaller horizontal distance between the C7-vertical line and the apex (DCA) than the patients in group 2 (67.5 vs 103.7 mm, p = 0.001). Subgroup analysis demonstrated similar results, showing that the patients with a postoperative apex located at T8 or above had an average SVA < 47 mm. Notably, a significant correlation was found between postoperative SVA and DCA (r = 0.642, p = 0.001). Patients who underwent an osteotomy at L3 had limited apex relocation but larger SVA correction than those at L1 or L2. However, no significant difference was found in health-related quality of life between the 2 groups.

CONCLUSIONS

AS patients with an apex located at T8 or above after surgery tended to have better SVA correction (within 47 mm) than those who had a more caudally located apical vertebra. For ideal postoperative apex relocation, a higher (closer to or at the preoperative apex) level of osteotomy is more likely to obtain the surgical goal.

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Xiaochun Jiang, Yukui Yan, Minghua Hu, Xiande Chen, Yaxian Wang, Yi Dai, Degang Wu, Yongsheng Wang, Zhixiang Zhuang and Hongping Xia

OBJECT

Increased levels of H19 long noncoding RNA (lncRNA) have been observed in many cancers, suggesting that overexpression of H19 may be important in the development of carcinogenesis. However, the role of H19 in human glioblastoma is still unclear. The object of this study was to examine the level of H19 in glioblastoma samples and investigate the role of H19 in glioblastoma carcinogenesis.

METHODS

Glioblastoma and nontumor brain tissue specimens were obtained from tissue obtained during tumor resection in 30 patients with glioblastoma. The level of H19 lncRNA was detected by real-time quantitative reverse transcription polymerase chain reaction. The role of H19 in invasion, angiogenesis, and stemness of glioblastoma cells was then investigated using commercially produced cell lines (U87 and U373). The effects of H19 overexpression on glioblastoma cell invasion and angiogenesis were detected by in vitro Matrigel invasion and endothelial tube formation assay. The effects of H19 on glioblastoma cell stemness and tumorigenicity were investigated by neurosphere formation and an in vivo murine xenograft model.

RESULTS

The authors found that H19 is significantly overexpressed in glioblastoma tissues, and the level of expression was associated with patient survival. In the subsequent investigations, the authors found that overexpression of H19 promotes glioblastoma cell invasion and angiogenesis in vitro. Interestingly, H19 was also significantly overexpressed in CD133+ glioblastoma cells, and overexpression of H19 was associated with increased neurosphere formation of glioblastoma cells. Finally, stable overexpression of H19 was associated with increased tumor growth in the murine xenograft model.

CONCLUSIONS

The results of this study suggest that increased expression of H19 lncRNA promotes invasion, angiogenesis, stemness, and tumorigenicity of glioblastoma cells. Taken together, these findings indicate that H19 plays an important role in tumorigenicity and stemness of glioblastoma and thus could be a therapeutic target for treatment of glioblastoma in the future.

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Dimin Zhu, Zheng Xiao, Zongming Wang, Bin Hu, Chengbin Duan, Ziyan Zhu, Nailin Gao, Yonghong Zhu and Haijun Wang

OBJECTIVE

To date, long noncoding RNAs (lncRNAs) have proven to function as key regulators in tumorigenesis. Among these lncRNAs, MEG3 displays low levels in various neoplasms and tumor cell lines. However, the regulatory mechanism of MEG3 and MIR-376B-3P, one of the microRNAs from downstream gene clusters of the DLK1-MEG3 locus, remains insufficiently defined.

METHODS

The authors used quantitative real-time polymerase chain reaction analysis to analyze whether decreased MEG3 and MIR-376B-3P expression levels were associated with the invasiveness of clinical nonfunctioning pituitary adenomas (CNFPAs) in 30 patients. Furthermore, functional experiments unveiled the pathophysiological role of MEG3, MIR-376B-3P, and HMGA2 in pituitary-derived folliculostellate (PDFS) cell lines. Moreover, dual-luciferase reporter assay, Western blot analysis, and immunofluorescence were applied to reveal the correlations among MEG3, MIR-376B-3P, and HMGA2.

RESULTS

MEG3 and MIR-376B-3P were decreased in patients with CNFPA, and their transcriptional levels were highly associated with invasive CNFPAs. Moreover, excessive expression of MEG3 and MIR-376B-3P inhibited tumorigenesis and promoted apoptosis in PDFS cells. Importantly, the authors found that MEG3 acted as an enhancer of MIR-376B-3P expression. Furthermore, as a target gene of MIR-376B-3P, HMGA2 served as an oncogene in pituitary adenoma and could be negatively regulated by MEG3 via enriching MIR-376B-3P.

CONCLUSIONS

This study offers a novel mechanism of an MEG3/MIR-376B-3P/HMGA2 regulatory network in CNFPAs, which may become a breakthrough for anticancer treatments.

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Hanjin Cui, Ali Yang, Huajun Zhou, Yang Wang, Jiekun Luo, Jun Zhou, Tao Liu, Pengfei Li, Jing Zhou, En Hu, Zehui He, Wang Hu and Tao Tang

OBJECTIVE

Thrombin is a unique factor that triggers post-intracerebral hemorrhage (ICH) angiogenesis by increasing hypoxia-inducible factor–1α (HIF-1α) at the protein level. However, HIF-1α mRNA remains unchanged. MicroRNAs (miRNAs) mediate posttranscriptional regulation by suppressing protein translation from mRNAs. This study aimed to determine if miRNAs might be involved in thrombin-induced angiogenesis after ICH by targeting HIF-1α or its upstream prolyl hydroxylase domains (PHDs).

METHODS

The study was divided into two parts. In part 1, rats received an injection of thrombin into the right globus pallidus. An miRNA array combined with miRNA target prediction, luciferase activity assay, and miRNA mimic/inhibitor transfection were used to identify candidate miRNAs and target genes. Part 2 included experiments 1 and 2. In experiment 1, rats were randomly divided into the sham group, ICH group, and ICH+hirudin–treated (thrombin inhibitor) group. In experiment 2, the rats were randomly divided into the sham group, ICH group, ICH+antagomir group, ICH+antagomir-control group, and ICH+vehicle group. Western blotting and quantitative real-time polymerase chain reaction were used to determine the expression of protein and miRNA, respectively. The coexpression of miR-24–1-5p (abbreviated to miR-24) and von Willebrand factor was detected by in situ hybridization and immunohistochemical analysis. The angiogenesis was evaluated by double-labeling immunofluorescence. Neurological function was evaluated by body weight, modified Neurological Severity Scores, and corner turn and foot-fault tests.

RESULTS

In part 1, it was shown that miR-24, which is predicted to target PHD1, was upregulated (fold-change of 1.83) after thrombin infusion, and that the miR-24 mimic transfection decreased luciferase activity and downregulated PHD1 expression (p < 0.05). miR-24 inhibitor transfection increased PHD1 expression (p < 0.05). In part 2, it was shown that miR-24 was expressed in endothelial cells. The HIF-1α protein level and proliferating cell nuclear antigen–positive (PCNA+) nuclei in vessels were increased, while the PHD1 protein level was decreased after ICH, and these effects were reversed by hirudin (p < 0.05). The antagomiR-24–treated rats exhibited a markedly lower body weight and significantly poorer recovery from neurological deficit compared with those in ICH groups (p < 0.05). AntagomiR-24 intervention also led to lower miR-24 expression, a higher PHD1 protein level, and fewer PCNA+ nuclei in vessels compared with those in ICH groups (p < 0.05).

CONCLUSIONS

The present study suggests that thrombin reduces HIF-1α degradation and initiates angiogenesis by increasing miR-24, which targets PHD1 after ICH.

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Jingjian Ma, Tianqiang Song, Wang Hu, Michael Edgar Muhumuza, Wenping Zhao, Shuyuan Yang, Jingwen Bai and Haixian Yang

Object

The authors conducted a study to develop a safe and effective intracranial venous sinus reconstruction for extensive clinical use.

Methods

After resecting the superior sagittal sinus (SSS), it was reconstructed in eight dogs by performing either a tube-insertion technique or end-to-end anastomosis procedure, in both of which a thin-walled silicone tube was used for repair. The patency of the SSS reconstruction was observed on digital subtraction angiography and transcranial Doppler ultrasonography, preoperatively and at 1, 2, 4, and 8 weeks postoperatively. Histological and ultrastructural changes were observed using light and electron microscopy.

In five dogs the reconstructed SSS was patent, in one it was narrowed, in one it was completely occluded at the proximal site of the anastomosis, and one dog escaped from the laboratory 1 week postoperatively. The authors found no evidence of any additional neurological deficits, signs of toxicity, or side effects. Histological and ultrastructural studies generally showed vascular endothelial proliferation. No thrombosis occurred in the inner surface, at the site of anastomosis, or in the lumen of silicone tube nor in the sagittal sinus at up to 8 weeks postoperatively.

Conclusions

The use of a thin-walled silicone tube as an artificial substitute for intracranial dural venous sinus reconstruction seems to be a valuable technique. The silicone tubes were found to have good biological compatibility, nonthrombogenic effects, and a high patency rate. The method was found to be simple and effective as well as practicable in the clinic for the short term (8 weeks). The authors emphasize that Phase I clinical trials involving silicone tube–assisted SSS reconstruction require further research.

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Chao-hu Wang, Song-Tao Qi, Jun Fan, Jun Pan, Jun-Xiang Peng, Jing Nie, Yun Bao, Ya-Wei Liu, Xi’an Zhang and Yi Liu

OBJECTIVE

Nuclear β-catenin, a hallmark of active canonical Wnt signaling, can be histologically detected in a subset of cells and cell clusters in up to 94% of adamantinomatous craniopharyngioma (ACP) samples. However, it is unclear whether nuclear β-catenin–containing cells within human ACPs possess the characteristics of tumor stem cells, and it is unknown what role these cells have in ACP.

METHODS

Primary ACP cells were cultured from 12 human ACP samples. Adamantinomatous CP stem cell–like cells (CSLCs) showing CD44 positivity were isolated from the cultured primary ACP cells by performing magnetic-activated cell sorting. The tumor sphere formation, cell cycle distribution, stemness marker expression, and multidifferentiation potential of the CD44− cells and the CSLCs were analyzed.

RESULTS

Compared with the CD44− cells, the cultured human CSLCs formed tumor spheres and expressed CD44 and CD133; moreover, these cells demonstrated nuclear translocation of β-catenin. In addition, the CSLCs demonstrated osteogenic and adipogenic differentiation capacities compared with the CD44− cells. The CSLCs also displayed the capacity for tumor initiation in human–mouse xenografts.

CONCLUSIONS

These results indicate that CSLCs play an important role in ACP development, calcification, and cystic degeneration.