Partially thrombosed distal posterior cerebral artery aneurysm treated with surgical trapping through occipital transtentorial approach assisted by endovascular coil embolization.

Background: Posterior cerebral artery (PCA) aneurysms are relatively rare. PCA aneurysms tend to be large, giant, fusiform, and partially thrombosed. Surgical treatments, such as neck clipping and trapping with or without bypass surgery, are curative treatments for thrombosed intracranial aneurysms. Few cases of surgical treatment of distal PCA aneurysms have been reported. We treated a partially thrombosed distal PCA aneurysm by trapping through the occipital transtentorial approach (OTA) assisted by endovascular coil embolization. Case Description: A 21-year-old woman presented with a sudden headache. Brain computed tomography, magnetic resonance imaging, and a cerebral angiogram revealed a partially thrombosed aneurysm in the left PCA P3 segment. Her headaches had improved once within several days, but reoccurred due to an enlarged thrombosed aneurysm. Endovascular coil embolization was performed to assist the surgery. The aneurysm and the distal artery of the aneurysm were embolized to interrupt the blood flow into the aneurysm. The following day, trapping of the aneurysm was performed through the OTA. Eventually, we performed aneurysm excision because trapping alone was considered to have the potential for regrowth of the aneurysm. The patient's postoperative course was uneventful. No recurrence of the aneurysm was observed at the 2-year follow-up. Conclusion: OTA could be useful for the treatment of distal PCA aneurysms, whereas coil embolization may support the surgical treatment of partially thrombosed intracranial aneurysms.

Endodermal Cyst with a Non-enhancing Nodule in the Quadrigeminal Cistern Developed in an Octogenarian.

BACKGROUND: Intracranial endodermal cysts are congenital lesions that generally develop in the cerebellopontine angle and ventral brainstem of the posterior fossa, whereas endodermal cysts in the quadrigeminal cistern are very rare. We report a rare case of an endodermal cyst in the quadrigeminal cistern with a non-enhancing nodule that developed in patient over 80 years of age. CASE DESCRIPTION: An 85-year-old man presented to our hospital with progressing gait disturbance and urinary incontinence. Preoperative images showed a cystic mass lesion with a nodule in the quadrigeminal cistern and hydrocephalus. There was no enhanced portion in the lesion, and the intensity of the cyst on magnetic resonance imaging revealed a high protein concentration. Subtotal resection was performed due to the adhesion of the cyst to the brainstem. It was diagnosed as an endodermal cyst. The postoperative course was uneventful, and hydrocephalus improved. CONCLUSIONS: This is a rare case of an intracranial endodermal cyst in terms of location and age of onset compared with previous reports. This case demonstrates that endodermal cysts should be considered as a differential diagnosis for lesions in the quadrigeminal cistern with high protein concentration in the cyst and nodule representing chronic inflammation, regardless of enhancing effects.

Identification of 2-Fluoropalmitic Acid as a Potential Therapeutic Agent Against Glioblastoma.

BACKGROUND: Glioblastomas (GBMs) are aggressive malignant brain tumors. Although chemotherapy with temozolomide (TMZ) can extend patient survival, most patients eventually demonstrate resistance. Therefore, novel therapeutic agents that overcome TMZ chemoresistance are required to improve patient outcomes. PURPOSE: Drug screening is an efficient method to find new therapeutic agents from existing drugs. In this study, we explored a novel anti-glioma agent by drug screening and analyzed its function with respect to GBM treatment for future clinical applications. METHODS: Drug libraries containing 1,301 diverse chemical compounds were screened against two glioma stem cell (GSC) lines for drug candidate selection. The effect of selected agents on GSCs and glioma was estimated through viability, proliferation, sphere formation, and invasion assays. Combination therapy was performed to assess its ability to enhance TMZ cytotoxicity against GBM. To clarify the mechanism of action, we performed methylation-specific polymerase chain reaction, gelatin zymography, and western blot analysis. RESULTS: The acyl-CoA synthetase inhibitor 2-fluoropalmitic acid (2-FPA) was selected as a candidate anti-glioma agent. 2-FPA suppressed the viability and stem-like phenotype of GSCs. It also inhibited proliferation and invasion of glioma cell lines. Combination therapy of 2-FPA with TMZ synergistically enhanced the efficacy of TMZ. 2-FPA suppressed the expression of phosphor-ERK, CD133, and SOX-2; reduced MMP-2 activity; and increased methylation of the MGMT promoter. CONCLUSION: 2-FPA was identified as a potential therapeutic agent against GBM. To extend these findings, physiological studies are required to examine the efficacy of 2-FPA against GBM in vivo.

Identification of GSK3ß inhibitor kenpaullone as a temozolomide enhancer against glioblastoma.

Cancer stem cells are associated with chemoresistance and rapid recurrence of malignant tumors, including glioblastoma (GBM). Although temozolomide (TMZ) is the most effective drug treatment for GBM, GBM cells acquire resistance and become refractory to TMZ during treatment. Therefore, glioma stem cell (GSC)-targeted therapy and TMZ-enhancing therapy may be effective approaches to improve GBM prognosis. Many drugs that suppress the signaling pathways that maintain GSC or enhance the effects of TMZ have been reported. However, there are no established therapies beyond TMZ treatment currently in use. In this study, we screened drug libraries composed of 1,301 existing drugs using cell viability assays to evaluate effects on GSCs, which led to selection of kenpaullone, a kinase inhibitor, as a TMZ enhancer targeting GSCs. Kenpaullone efficiently suppressed activity of glycogen synthase kinase (GSK) 3ß. Combination therapy with kenpaullone and TMZ suppressed stem cell phenotype and viability of both GSCs and glioma cell lines. Combination therapy in mouse models significantly prolonged survival time compared with TMZ monotherapy. Taken together, kenpaullone is a promising drug for treatment of GBM by targeting GSCs and overcoming chemoresistance to TMZ.

Potential Strategies Overcoming the Temozolomide Resistance for Glioblastoma.

Glioblastoma (GBM) is a highly malignant type of primary brain tumor with a high mortality rate. Although the current standard therapy consists of surgery followed by radiation and temozolomide (TMZ), chemotherapy can extend patient's post-operative survival but most cases eventually demonstrate resistance to TMZ. O6-methylguanine-DNA methyltransferase (MGMT) repairs the main cytotoxic lesion, as O6-methylguanine, generated by TMZ, can be the main mechanism of the drug resistance. In addition, mismatch repair and BER also contribute to TMZ resistance. TMZ treatment can induce self-protective autophagy, a mechanism by which tumor cells resist TMZ treatment. Emerging evidence also demonstrated that a small population of cells expressing stem cell markers, also identified as GBM stem cells (GSCs), contributes to drug resistance and tumor recurrence owing to their ability for self-renewal and invasion into neighboring tissue. Some molecules maintain stem cell properties. Other molecules or signaling pathways regulate stemness and influence MGMT activity, making these GCSs attractive therapeutic targets. Treatments targeting these molecules and pathways result in suppression of GSCs stemness and, in highly resistant cases, a decrease in MGMT activity. Recently, some novel therapeutic strategies, targeted molecules, immunotherapies, and microRNAs have provided new potential treatments for highly resistant GBM cases. In this review, we summarize the current knowledge of different resistance mechanisms, novel strategies for enhancing the effect of TMZ, and emerging therapeutic approaches to eliminate GSCs, all with the aim to produce a successful GBM treatment and discuss future directions for basic and clinical research to achieve this end.

Inflow hemodynamics evaluated by using four-dimensional flow magnetic resonance imaging and the size ratio of unruptured cerebral aneurysms.

PURPOSE: Prediction of the rupture risk is critical for the identification of unruptured cerebral aneurysms (UCAs) eligible for invasive treatments. The size ratio (SR) is a strong morphological predictor for rupture. We investigated the relationship between the inflow hemodynamics evaluated on four-dimensional (4D) flow magnetic resonance (MR) imaging and the SR to identify specific characteristics related to UCA rupture. METHODS: We evaluated the inflow jet patterns and inflow hemodynamic parameters of 70 UCAs on 4D flow MR imaging and compared them among 23 aneurysms with an SR ≧2.1 and 47 aneurysms with an SR ≦2.0. Based on the shape of inflow streamline bundles with a velocity ≧75% of the maximum flow velocity in the parent artery, the inflow jet patterns were classified as concentrated (C), diffuse (D), neck-limited (N), and unvisualized (U). RESULTS: The incidence of patterns C and N was significantly higher in aneurysms with an SR ≧2.1. The rate of pattern U was significantly higher in aneurysms with an SR ≦2.0. The maximum inflow rate and the inflow rate ratio were significantly higher in aneurysms with an SR ≧2.1. CONCLUSIONS: The SR affected the inflow jet pattern, the maximum inflow rate, and the inflow rate ratio of UCAs. In conjunction with the SR, inflow hemodynamic analysis using 4D flow MR imaging may contribute to the risk stratification for aneurysmal rupture.

Identification of antipsychotic drug fluspirilene as a potential anti-glioma stem cell drug.

Glioma stem cell (GSC)-targeted therapy is expected to be one of the most innovative approaches to treat patients with glioblastoma (GBM). A number of the drugs that restrain the signaling pathway essential for GSC maintenance have been under clinical trials. Here, we identified fluspirilene, a traditional antipsychotic drug, as a GSC-targeting agent, selected from thousands of existing drugs, and investigated its therapeutic effects against GBM with the purpose of drug repositioning. To develop novel therapeutics targeting GSCs, we initially screened drug libraries for small-molecule compounds showing a greater efficacy, compared to that of controls, in inhibiting the proliferation and survival of different GSC lines using cell proliferation assay. Drugs already reported to show therapeutic effects against GBM or those under clinical trials were excluded from subsequent screening. Finally, we found three drugs showing remarkable antiproliferative effects on GSCs at low concentrations and investigated their therapeutic effects on GSCs, glioma cell lines, and in a GBM mouse model. Of the three compounds, fluspirilene demonstrated a significant inhibitory effect on the proliferation and invasion of glioma cells as well as in the model mice treated with the drug. These effects were associated with the inactivation of the signal transducer and activator of transcription 3 (STAT3). Redeveloping of fluspirilene is a promising approach for the treatment of GBM.

Detection of the development of late-onset idiopathic aqueductal stenosis (LIAS) by chronological magnetic resonance imaging: a case report.

Late-onset idiopathic aqueductal stenosis (LIAS) has been recognized as one of the clinical entities of adulthood hydrocephalus for decades, although there have been no radiological reports that show normal ventricular systems before the development of LIAS. We present here an adolescent case of LIAS with a previously normal ventricular system on magnetic resonance imaging (MRI). A 17-year-old boy had been suffering from chronic headaches and mild intellectual disability (MID) since he became a teenager, and this had prevented him from leading an ordinary school life. MRIs on admission showed triventriculomegaly from the aqueductal stenosis that had not been detected on previous MRIs, at least until the age of 6. An endoscopic third ventriculostomy was successfully performed, which improved both the headache and the MID. The developmental mechanism of LIAS remains unclear, although the membranous ependymal-like tissue observed in the aqueduct suggested the preceding existence of an inflammatory process around this region. To the best of our knowledge, this case was noteworthy because the development of LIAS was clearly demonstrated on MRI for the first time.

[Awake surgery with line bisection task for two cases of parietal glioma in the non-dominant hemisphere].

Awake surgery for lesions in the non-dominant parietal lobe is rare. We report two cases of right parietal lobe glioma for which awake surgery was performed in order to avoid ataxie optique and hemispatial neglect due to injury in the superior and inferior parietal lobule, respectively. Among several tests to assess the dysfunction of spatial recognition, line bisection test was selected for the task during awake surgery because of its simplicity, easy repetition, and utility. The tumor was successfully removed without any neurological deficit in both the cases. The line bisection test is simple and useful for preserving spatial recognition during an awake surgery.