Dayong Han

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.

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.

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.

mir-300 Promotes Self-Renewal and Inhibits the Differentiation of Glioma Stem-Like Cells

MicroRNAs (miRNAs) are small noncoding RNAs that have been critically implicated in several human cancers. miRNAs are thought to participate in various biological processes, including proliferation, cell cycle, apoptosis, and even the regulation of the stemness properties of cancer stem cells. In this study, we explore the potential role of miR-300 in glioma stem-like cells (GSLCs). We isolated GSLCs from glioma biopsy specimens and identified the stemness properties of the cells through neurosphere formation assays, multilineage differentiation ability analysis, and immunofluorescence analysis of glioma stem cell markers. We found that miR-300 is commonly upregulated in glioma tissues, and the expression of miR-300 was higher in GSLCs. The results of functional experiments demonstrated that miR-300 can enhance the self-renewal of GSLCs and reduce differentiation toward both astrocyte and neural fates. In addition, LZTS2 is a direct target of miR-300. In conclusion, our results demonstrate the critical role of miR-300 in GSLCs and its functions in LZTS2 inhibition and describe a new approach for the molecular regulation of tumor stem cells.

Harmine hydrochloride inhibits Akt phosphorylation and depletes the pool of cancer stem-like cells of glioblastoma

Harmine hydrochloride (Har-hc), a derivative from Harmine which is a natural extractive from plants, has been considered for treatment of kinds of cancers and cerebral diseases. In this study, we found that Har-hc clearly decreased cell viability, induced apoptosis and inhibited Akt phosphorylation in glioblastoma cell lines. Moreover, Har-hc had the ability to inhibit self-renewal and promote differentiation of glioblastoma stem like cells (GSLCs) accompanied by inhibition of Akt phosphorylation. Especially, we demonstrated that Har-hc inhibited neurosphere formation of human primary GSLCs. In vivo test also confirmed Har-hc decreased the tumorigenicity of GSLCs. Thus we conclude that Har-hc has potent anti-cancer effects in glioblastoma cells, which is at least partially via inhibition of Akt phosphorylation. Administration of Har-hc may act as a new approach to glioblastoma treatment.

Inhibition of Heat Shock Protein Response Enhances PS-341-Mediated Glioma Cell Death

BackgroundPrevious study indicated that PS-341 induces cell death via JNK pathway in vitro in glioma. However, suppressing proteasome complex by PS-341 may induce expression of heat shock proteins (HSPs), which confer potential protection against cellular stress. In this study, we explored whether induction of HSPs could impair PS-341-induced cell death and whether inhibition of HSPs could enhance cell damage induced by PS-341 in glioma cells.MethodsHSP expression in glioma cells was modulated by HSP inhibitor, sublethal heat, or knockdown of heat shock factor1 (HSF1), then PS-341-induced cell damage was examined by different methods. Similar experiments were also performed in HSF1+/+ and HSF1–/– cells. HSP70 expression and HSF1 nuclear localization were compared between glioma and normal brain tissues.ResultsHSP level was upregulated mediated by HSF1 when glioma cells were treated with PS-341. PS-341-mediated cell damage could be significantly augmented by HSP inhibition. Furthermore, HSP70 expression and HSF1 nuclear localization were much more abundant in gliomas than in normal brain tissues.ConclusionsOur results demonstrated that HSP70 impaired cell death induced by PS-341 in glioma cells. Administration of PS-341 in combination with either HSP70 inhibitor or HSF1 knockdown may act as a new approach to treatment of glioma.

Large capillary hemangioma of the temporal bone with a dural tail sign: A case report

The present study reports a rare case of large capillary hemangioma of the temporal bone with a dural tail sign. A 57-year-old female presented with pulsatile tinnitus and episodic vertigo associated with a ten-year history of an intermittent faint headache. Magnetic resonance imaging revealed a mass in the right petrous bone, which was hypointense on T1-weighted images and heterogeneously hyperintense on T2-weighted images, and showed a dural tail sign following gadolinium administration. Pre-operatively, this tumor was believed to be a meningioma. During surgery, the vascular tumor was removed by a modified pterional approach. A histopathological examination indicated that the tumor was a capillary hemangioma. Although intraosseous capillary hemangiomas are rare, they most frequently affect the temporal bone. Hemangiomas of the temporal bone may mimic other more common basal tumors. The diagnosis is most often made during surgical resection. The dural tail sign is not specific for meningioma, as it also occurs in other intracranial or extracranial tumors. The treatment of intratemporal hemangiomas is complete surgical excision, with radiotherapy used for unresectable lesions. To the best of our knowledge, the present study is the fourth case of intraosseous intracranial capillary hemangioma, but the largest intratemporal hemangioma to be reported in the literature to date.

Low-dose arsenic trioxide enhances 5-aminolevulinic acid-induced PpIX accumulation and efficacy of photodynamic therapy in human glioma

Among glioma treatment strategies, 5-aminolevulinic acid (5-ALA)-based fluorescence-guided resection (FGR) and photodynamic therapy (PDT) have been used as effective novel approaches against malignant glioma. However, insufficient intracellular protoporphyrin IX (PpIX) accumulation limits the application of FGR and PDT in the marginal areas of gliomas. To overcome these issues, we assessed the intracellular levels of PpIX in human glioma cell lines and rat cortical astrocytes pretreated with 0.1μM arsenic trioxide (ATO). Apoptosis and cell viability after PDT were evaluated using Annexin V-FITC apoptosis detection kit and MTT assay, respectively. In order to find out the possible mechanism, we investigated the expression of the key enzymes in the heme biosynthesis pathway, which regulates porphyrin synthesis in glioma cells. Our findings showed that the 5-ALA-induced PpIX accumulation in glioma cell lines pretreated with 0.1μM ATO was increased relative to the control groups. No changes in fluorescence intensity were detected in the rat cortical astrocytes pretreated using the same ATO concentration. Apoptosis following PDT in glioma cells pretreated with 0.1μM ATO were significantly higher than in control groups, especially late apoptotic cells, while the cell viability was decreased. The expression of CPOX was upregulated in glioma cells after pretreatment with 0.1μM ATO. We concluded that ATO was a potential optional approach in enhancing intracellular PpIX accumulation and improving the benefits of 5-ALA-induced FGR and PDT in glioma.

Nitazoxanide, an antiprotozoal drug, inhibits late-stage autophagy and promotes ING1-induced cell cycle arrest in glioblastoma

Glioblastoma is the most common and aggressive primary brain tumor in adults. New drug design and development is still a major challenge for glioma treatment. Increasing evidence has shown that nitazoxanide, an antiprotozoal drug, has a novel antitumor role in various tumors and exhibits multiple molecular functions, especially autophagic regulation. However, whether nitazoxanide-associated autophagy has an antineoplastic effect in glioma remains unclear. Here, we aimed to explore the underlying molecular mechanism of nitazoxanide in glioblastoma. Our results showed that nitazoxanide suppressed cell growth and induced cell cycle arrest in glioblastoma by upregulating ING1 expression with a favorable toxicity profile. Nitazoxanide inhibited autophagy through blockage of late-stage lysosome acidification, resulting in decreased cleavage of ING1. A combination with chloroquine or Torin1 enhanced or impaired the chemotherapeutic effect of nitazoxanide in glioblastoma cells. Taken together, these findings indicate that nitazoxanide as an autophagy inhibitor induces cell cycle arrest in glioblastoma via upregulated ING1 due to increased transcription and decreased post-translational degradation by late-stage autophagic inhibition.