Changbin Shi

Intraoperative Fluorescence-Guided Resection of High-Grade Malignant Gliomas Using 5-Aminolevulinic Acid–Induced Porphyrins: A Systematic Review and Meta-Analysis of Prospective Studies

Background We performed a systematic review and meta-analysis to address the (added) value of intraoperative 5-aminolevulinic acid (5-ALA)-guided resection of high-grade malignant gliomas compared with conventional neuronavigation-guided resection, with respect to diagnostic accuracy, extent of tumor resection, safety, and survival. Methods and Findings An electronic database search of Medline, Embase, and the Cochrane Library was undertaken. The review process followed the guidelines of the Cochrane Collaboration. 10 studies matched all selection criteria, and were thus used for qualitative synthesis. 5-ALA-guided resection demonstrated an overall sensitivity of 0.87 (95% confidence interval [CI], 0.81–0.92), specificity of 0.89 (95% CI, 0.79–0.94), positive likelihood ratio (LR) of 7.62 (95% CI, 3.87–15.01), negative LR of 0.14 (95% CI, 0.09–0.23), and diagnostic odds ratio (OR) of 53.06 (95% CI, 18.70–150.51). Summary receiver operating characteristic curves (SROC) showed an area under curve (AUC) of 94%. Contrast-enhancing tumor was completely resected in patients assigned 5-ALA as compared with patients assigned white light. Patients in the 5-ALA group had higher 6-month progression free survival and overall survival than those in the white light group. Conclusion Based on available literature, there is level 2 evidence that 5-ALA-guided surgery is more effective than conventional neuronavigation-guided surgery in increasing diagnostic accuracy and extent of tumor resection, enhancing quality of life, or prolonging survival in patients with high-grade malignant gliomas.

MiR-106a inhibits glioma cell growth by targeting E2F1 independent of p53 status

MicroRNAs are single-stranded small non-coding RNA molecules which regulate mammalian cell growth, differentiation, and apoptosis by altering the expression of other genes and play a role in tumor genesis and progression. MiR-106a is upregulated in several types of malignancies and provides a pro-tumorigenic effect. However, its role in glioma is largely unknown. Our findings demonstrate that the low expression of miR-106a in human glioma specimens is significantly correlated with high levels of E2F1 protein and high-grade glioma. Here, we present the first evidence that miR-106a provides a tumor-suppressive effect via suppressing proliferation of and inducing apoptosis in human glioma cells. We further show that E2F1 is a direct functional target of miR-106a, suggesting that the effect of miR-106a on the glioma suppressive effect may result from inhibition of E2F1 via post-transcriptional regulation. In addition, our results reveal that miR-106a can increase p53 expression via E2F1 inhibition, whereas the effect of miR-106a on the proliferation of glioma cells is independent of p53 status. Further investigations will focus on the therapeutic use of miR-106a-mediated antitumor effects in glioma.

Increased Expression of ABCB6 Enhances Protoporphyrin IX Accumulation and Photodynamic Effect in Human Glioma

BackgroundGlioma recurrence usually occurs close to the tumor resection margins as a result of residual infiltrating glioma cells. 5-aminolevulinic acid (ALA) fluorescence-guided resection of gliomas has been demonstrated to enhance discrimination of tumor tissue and to improve survival. ALA-based photodynamic therapy is an effective albeit still experimental adjuvant treatment option for gliomas. However, insufficient protoporphyrin IX (PpIX) accumulation may limit the benefits of fluorescence-guided resection and photodynamic therapy.MethodsWe investigated the expression of the ATP-binding cassette transporter ABCB6, which regulates porphyrin synthesis, in surgical specimens from human gliomas and manipulated ABCB6 in human glioma cell lines.ResultsOur findings demonstrated that expression levels of ABCB6 were greatly elevated in human gliomas compared with normal brain tissues and correlated with World Health Organization histologic grade. A previously undescribed finding was that ABCB6 mRNA expression in solidly fluorescing tumor tissues was higher than that in vaguely fluorescing tumors, suggesting that ABCB6 may be at least in part responsible for PpIX accumulation in glioma cells. Accordingly, ABCB6 overexpression in glioma cell lines caused a marked increase in intracellular levels of PpIX, and was more sensitive to ALA-induced photodynamic therapy—events that could be prevented by silencing ABCB6 via siRNA treatment.ConclusionsOur findings indicate a crucial role of ABCB6 in ALA metabolism and accumulation of PpIX in glioma. ABCB6 overexpression is a potential approach to enhance accumulation of PpIX for optimizing the subjective discrimination of vague fluorescence and improving the efficacy of ALA-based photodynamic therapy.

Arsenic trioxide depletes cancer stem-like cells and inhibits repopulation of neurosphere derived from glioblastoma by downregulation of Notch pathway.

Notch signaling has been demonstrated to have a central role in cancer stem-like cells (CSLCs) in glioblastoma multiforme (GBM). We have recently demonstrated the inhibitory effect of arsenic trioxide (ATO) on CSLCs in glioblastoma cell lines. In this study we used neurosphere recovery assay that measured neurosphere formation at three time points to assess the capacity of the culture to repopulate after ATO treatment. Our results provided strong evidence that ATO depleted CSLCs in GBM, and inhibited neurosphere recovery and secondary neurosphere formation. ATO inhibited the phosphorylation and activation of AKT and STAT3 through Notch signaling blockade. These data show that the ATO is a promising new approach to decrease glioblastoma proliferation and recurrence by downregulation of Notch pathway.

A predictive value of hyponatremia for poor outcome and cerebral infarction in high-grade aneurysmal subarachnoid haemorrhage patients

Background The clinical significance of hyponatremia has not been investigated in high-grade aneurysmal subarachnoid haemorrhage (aSAH) patients. Thus, we assessed the predictive value of hyponatremia for poor outcome or cerebral infarction in high grade patients (the World Federation of Neurological Surgeons Scale (WFNS) grade 4 or 5) after aSAH. Methods Patients with WFNS grade 4 or 5 after aSAH were selected into this study between January 2005 and January 2008. In the same period, patients with WFNS grade 1, 2 or 3 after aSAH (low grade) were also chosen into this study. Hyponatremia was determined with serum sodium measurements obtained within 9 days after aSAH. Prognosis of patients was estimated with Glasgow Outcome Scale at 3 months. The relationship between hyponatremia and poor outcome and association of hyponatremia and cerebral infarction were analysed, respectively. Results A total of 124 high-grade patients were included in this study. Of those, 78 patients developed hyponatremia. Hyponatremia developed in 32.3% of cases between days 1 and 3 after aSAH, and 30.6% developed hyponatremia after 3 days post-aSAH. Multivariable analysis revealed that hyponatremia was not correlated with poor outcome in high-grade aSAH patients. Furthermore, only late-onset hyponatremia was correlated with cerebral infarction in these patients. Meanwhile, there was no significant correlation between hyponatremia and poor outcome or cerebral infarction in 259 low-grade aSAH patients. Conclusions Hyponatremia does not predict poor outcome in all-grade aSAH patients. However, late-onset hyponatremia in high-grade aSAH patients is associated with cerebral infarction. Therefore, the appropriate management of hyponatremia could be beneficial in those patients.

Inhibition of heme oxygenase-1 enhances anti-cancer effects of arsenic trioxide on glioma cells

We have previously reported that arsenic trioxide (ATO) could inhibit glioma growth both in vitro and in vivo, and demonstrated its potent therapeutic effects on gliomas. In this study we showed that ATO induced cell damage and heme oxygenase-1 (HO-1) expression in glioma cells via ROS generation. HO-1 inducer clearly protected from ATO-induced cell death and ROS generation, and HO-1 inhibitor led to a significant increase in cell death and ROS generation induced by ATO. In addition, knockdown of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) strongly inhibited HO-1 expression induced by ATO, and significantly enhanced ATO-induced oxidative damage. Our results demonstrated, for the first time, that HO-1 inhibition or Nrf2 knockdown significantly potentiated ATO’s effects on glioma cells. Considering that HO-1 is highly expressed in glioma tissues, administration of ATO in combination with either HO-1 inhibitor or Nrf2 knockdown may act as a new approach to the treatment of glioma.

MiR-106a is an independent prognostic marker in patients with glioblastoma

BACKGROUND Very little is known regarding correlation of micro RNA (miR)-106a with clinical outcomes of patients with glioblastoma multiforme (GBM). This study determined whether miR-106a could be used as an independent prognostic biomarker in those patients. METHODS A total of 156 GBM patients were divided into 2 cohorts. In the first cohort, matched fresh frozen and formalin-fixed paraffin-embedded (FFPE) samples were collected from 24 GBM patients, while in the second cohort, only FFPE samples were collected from 132 GBM patients. MiR-106a expression levels were examined by quantitative real-time PCR in the 2 cohorts and further validated by in situ hybridization assay in the second cohort. The correlation between miR-106a expression levels and overall survival was evaluated in the second cohort of 114 GBM patients available for follow-up by a log-rank test and a multivariate Cox proportional hazards model. RESULTS Our data showed a very good correlation of miR-106a or U6 expression between fresh frozen and FFPE GBM specimens, with Pearsons correlation coefficients of 0.849 and 0.823, respectively (P < .001). Their expression levels in archival FFPE samples were quite stable for at least 7 years when stored at room temperature. Multivariate analysis revealed that the expression level of miR-106a was an independent and significant predictor of overall survival in GBM patients (P = .011). CONCLUSIONS MiR-106a expression was relatively abundant and stable in a large cohort of archival FFPE GBM specimens and could be used as an independent prognostic biomarker in those patients. Thus, miR-106a can be used to predict prognosis and treatment response in individual GBM patients.

Aminoguanidine inhibition of iNOS activity ameliorates cerebral vasospasm after subarachnoid hemorrhage in rabbits via restoration of dysfunctional endothelial cells

BACKGROUND This study was to delineate the therapeutic efficacy and potential cellular and molecular mechanisms of aminoguanidine (AG), a relatively selective inhibitor of iNOS activity, in cerebral vasospasm after subarachnoid hemorrhage (SAH) in rabbits. METHODS SAH was induced by a single injection of autologous arterial blood into the cisterna magna of adult male rabbits. An intravenous bolus injection of AG (150 mg/kg) was administrated 1h after SAH, and this dosage was repeated on the following day. Vasospasm was verified by computed tomography angiography (CTA) day 2 after SAH. Rabbit basilar arteries were harvested for transmission electron microscopy (TEM), immunohistochemical examination, RT-PCR, and western blot analysis. RESULTS CTA data revealed that cerebral vasospasm of SAH rabbits was significantly prevented via AG treatment. TEM results demonstrated the ultrastructural morphological changes of endothelial cells of SAH rabbits were ameliorated by AG treatment. In parallel, AG treatment increased eNOS mRNA and protein levels along with the reduced immunoreactivity of nitrotyrosine in rabbit basilar arteries. CONCLUSIONS Our discovery suggested AG inhibition of iNOS activity could significantly reverse cerebral vasospasm after SAH via restoration of dysfunctional endothelial cells by the upregulation of eNOS, indicating a regulatory cross-talk between eNOS and iNOS in the pathogenesis of SAH.

Targeting X box‐binding protein‐1 (XBP1) enhances sensitivity of glioma cells to oxidative stress

Y. Liu, X. Zhang, Y. Liang, H. Yu, X. Chen, T. Zheng, B. Zheng, L. Wang, L. Zhao, C. Shi and S. Zhao (2011) Neuropathology and Applied Neurobiology37, 395–405 
Targeting X box‐binding protein‐1 (XBP1) enhances sensitivity of glioma cells to oxidative stress

Multiple Meningiomas Characterized by Benign and Malignant Tumor Entities

Meningiomas are the most common intracranial tumors, accounting for about 30% of all reported brain tumors [1]. Most meningiomas are benign sporadic solitary, and multiple meningiomas (MMs) occurs in 1–9% of all meningiomas [2]. However, MMs consisting of both benign and malignant meningiomas are extremely rare [2–4] Here, we presented a unique case of an adult who exhibited both intraparenchymal fibrous meningioma and anaplastic meningioma. A 67-year-old man presented with hemiparesis of the right limbs, associated with a 2-month history of aconuresis and a 1-month history of intermittent fever and vomiting. Neurological examination revealed bilateral moderate papilledema, a mild mental confusion, and right hemiparesis with a positive Babinski sign. He had no family history of neurofibromatosis, and no evidence of cafe au lait spots. A CT scan revealed a mixed-dense tumor at the left frontal lobe and a mixed-density lesion with a surrounding edema at the left insular lobe (Figure 1A). Magnetic resonance imaging (MRI) confirmed the presence of an ovalshaped cystic tumor (43 9 52 9 45 mm) in the left insular lobe. The lesion appeared to be nonhomogeneous, hypointense on the T1-weighted images, and hyperintense on T2-weighted images with surrounding edema. There was strong ring enhancement of the cyst wall following gadolinium administration, and dural tail sign was not noticed. We observed the cyst within the tumor that was isointense to cerebrospinal fluid. Magnetic resonance imaging also showed a small (40 9 21 9 52 mm) strongly enhanced tumor that was hyperintense in both T1-weighted and T2weighted images and was attached to the superior sagittal sinus in the left frontal lobe (Figure 1B). A bifrontal craniotomy approach was performed. First, a grayish white and poor-defined solid tumor was excised at the left frontal lobe. The tumor tightly adhered to the dura mater approaching central line, and the dura infiltrated by the tumor was also removed. Then, through Sylvian fissure, a slightly gray tumor with slightly rich vascularity was excised. After the insular tumor totally removed, a yellow fluid flowed out from the tumor. No connection between the surface of the insular lobe tumor and the dura was found. Postoperatively, the patient remained neurologically intact. Histological examination showed that the tumors were in two different histological types, which were fibrous meningioma at the left insular lobe and anaplastic meningioma at the left frontal lobe. The insular tumor was composed of fibroblast-like spindleshaped cells and showed fascicular growth pattern (Figure 1C). The left frontal tumor revealed obvious malignant cytology, focal necrosis, and high mitotic rate (>20 mitosis/10 HPF), which is similar to sarcoma. Immunohistochemical staining showed both tumors were positive for vimentin, epithelial membrane antigen (EMA), and S-100 protein, but negative for glial fibrillary acidic protein (GFAP) and cytokeratin (CK), suggesting meningiomas. The MIB-1 labeling index of the insular lobe tumor was less than 1%, while the index of the frontal tumor was about 20%. In addition, the insular tumor did not express mutant-p53-positive cells, whereas the frontal lobe tumor did. The frontal tumor was negative for progesterone receptor (PR), while the insular lobe tumor positive. Moreover, the frontal tumor was positive for sox-2, musashi, and nestin, while the insular lobe tumor was negative (Figure 1C).