Therapeutic potential of pentamidine for glioma-initiating cells and glioma cells through multimodal antitumor effects.

Glioma-initiating cells, which comprise a heterogeneous population of glioblastomas, contribute to resistance against aggressive chemoradiotherapy. Using drug reposition, we investigated a therapeutic drug for glioma-initiating cells. Drug screening was undertaken to select candidate agents that inhibit proliferation of two different glioma-initiating cells lines. The alteration of proliferation and stemness of the two glioma-initiating cell lines, and proliferation, migration, cell cycle, and survival of these two differentiated glioma-initiating cell lines and three different glioblastoma cell lines treated with the candidate agent were evaluated. We also used a xenograft glioma mouse model to evaluate anticancer effects of treated glioma cell lines. Among the 1301 agents, pentamidine-an antibiotic for Pneumocystis jirovecii-emerged as a successful antiglioma agent. Pentamidine treatment suppressed proliferation and stemness in glioma-initiating cell lines. Proliferation and migration were inhibited in all differentiated glioma-initiating cells and glioblastoma cell lines, with cell cycle arrest and caspase-dependent apoptosis induction. The in vivo study reproduced the same findings as the in vitro studies. Pentamidine showed a stronger antiproliferative effect on glioma-initiating cells than on differentiated cells. Western blot analysis revealed pentamidine inhibited phosphorylation of signal transducer and activator of transcription 3 in all cell lines, whereas Akt expression was suppressed in glioma-initiating cells but not in differentiated lines. In the present study, we identified pentamidine as a potential therapeutic drug for glioma. Pentamidine could be promising for the treatment of glioblastomas by targeting both glioma-initiating cells and differentiated cells through its multifaceted antiglioma effects.

Recovery of Visual Field After Awake Stimulation Mapping of the Optic Pathway in Glioma Patients.

Brain mapping during awake craniotomy for gliomas can help preserve neurological functions, including maintenance of central and peripheral vision. However, the consecutive changes in the visual field remain unknown. We retrospectively assessed 14 patients who underwent awake craniotomy for gliomas infiltrating into the optic radiation. Cortico-subcortical direct electrical stimulation (DES) was intraoperatively applied until transient visual symptoms were elicited and recorded. The visual fields were examined consecutively in the preoperative period and postoperative subacute and chronic periods. To evaluate the anatomo-functional validity of the recordings, all DES-elicited points were overlaid onto a three-dimensional template that included the optic radiation, using voxel-based morphometry (VBM) mapping. All patients experienced visual symptoms that were classified as phosphenes, blurred vision, or hallucinations during DES, and surgical resection was limited to within the functional boundaries. In VBM, almost all the subcortical positive mapping points overlapped with the surface of the optic radiation, and the distribution of sites that induced visual phenomena in the upper or lower visual fields could be differentiated in the anatomical space. We observed no postoperative visual deficit in four patients (29%), time-dependent improvements in five out of eight patients that presented transient quadrantanopia or partial visual defect (36% out of 57%), and permanent hemianopsia (14%) in two patients with occipital lesions. Intraoperative DES that identifies and preserves optic radiation in awake craniotomy for gliomas is a reliable and effective technique to reduce risk of permanent deficits, but has a low success rate in patients with occipital involvement.

Intraoperative rupture of intracerebral aneurysm immediately after meningioma resection: a case report.

BACKGROUND: Meningiomas and unruptured cerebral aneurysms (UCAs) rarely coexist. However, the treatment strategy remains to be fully elucidated. This report is a first report that UCA related to the tumor feeder intraoperatively ruptured when the meningioma was resected. CASE PRESENTATION: Herein, we present a case of meningioma coexisting with contralateral UCA related to a tumor feeder. Immediately after the meningioma was resected, intraoperative acute brain swelling due to rupture of the contralateral aneurysm appeared. The swollen brain protruding into the epidural space was resected, following contralateral ruptured aneurysm was performed by endovascular surgery. Intensive neurological treatment was administered and the patient gradually recovered. CONCLUSION: This report highlights the possibility of intraoperative UCA rupture related to the tumor feeder when the meningioma is resected.

Non-occlusive mesenteric ischemia during bevacizumab treatment for glioblastoma: a case report.

Glioblastoma is one of the most aggressive brain tumors in adults. The standard treatment is radiotherapy and chemotherapy based on the Stupp regimen after maximal safe resection. One effective chemotherapeutic drug is bevacizumab, which can prolong progression-free survival in glioblastoma patients but not overall survival. Adverse events of bevacizumab include hypertension, proteinuria, delayed wound healing, bleeding of the nose and gums, and thromboembolism resulting in gastrointestinal perforation. Herein, we describe an autopsy case of a patient with glioblastoma who died from non-occlusive mesenteric ischemia that was presumably caused by bevacizumab.

Late complications of visual impairment and hydrocephalus after flow diverter-assisted coil embolisation for intracranial large aneurysm: a case report and literature review.

Large or giant paraclinoid aneurysms typically have good indication for flow diverter (FD) treatment. Here, we report a very rare case of a patient with an unruptured supraclinoid large aneurysm who underwent FD deployment with coil embolisation that resulted in delayed visual field defect (VFD) and hydrocephalus. A 75-year-old woman with a large right supraclinoid aneurysm presented with severe hemianopia in the right eye. She underwent FD deployment with coil embolisation of the aneurysm. However, permanent left visual field loss occurred four months after surgery. Magnetic resonance imaging (MRI) showed severe oedema surrounding the aneurysm along the optic tract. Inflammation led to postoperative hydrocephalus, requiring ventriculoperitoneal shunt placement. To the best of our knowledge, this is the first report of both a delayed VFD and hydrocephalus following FD treatment. In cases of FD treatment with coil embolisation for large paraclinoid aneurysms, clinicians should keep in mind that postoperative visual impairment or/and hydrocephalus may occur.

Late-onset acute disseminated encephalomyelitis followed by optic neuritis without anti-myelin oligodendrocyte glycoprotein antibodies: a biopsied case report.

BACKGROUND: Acute disseminated encephalomyelitis (ADEM) followed by optic neuritis (ADEM-ON) is characterized by the following features: early onset, monophasic or multiphasic ADEM followed by one or more episodes of ON, and the presence of serum anti-myelin oligodendrocyte glycoprotein (MOG) antibodies. CASE REPORT: We report a case of ADEM-ON without anti-MOG antibodies in a 78-year-old woman. The patient developed acute-onset neurological findings and was diagnosed with ADEM. She was treated with intravenous methylprednisolone (IVMP), and oral corticosteroids. Her clinical symptoms and MRI findings subsequently improved. Left optic neuritis emerged 6 months later, and we made a diagnosis of ADEM-ON. A brain biopsy performed during the acute phase of ADEM showed perivascular infiltration of macrophages with demyelination. CONCLUSION: The majority of the reported ADEM-ON cases are pediatric cases with serum anti-MOG antibodies, but our patient was the elderly, without anti-MOG antibodies. Moreover, the pathological features of our case were similar to those observed in patients with typical ADEM and in patients with anti-MOG antibody-positive ADEM. Although ADEM-ON is related to the presence of anti-MOG antibodies, factors other than anti-MOG antibodies could contribute to the development of ADEM-ON.

A case of rapid deterioration in a subacute period after endoscopic third ventriculostomy.

Background: Although generally a safe procedure, serious postoperative complications after endoscopic third ventriculostomy (ETV) for obstructive hydrocephaly have been rarely reported, such as delayed obstruction of the stoma at the third ventricle floor.Case description: A 20-year-old male was referred to our department because of severe headache and diplopia. A pineal tumour and obstructive hydrocephaly were detected in preoperative imaging. After tumour biopsy and ETV, the reduction of ventricle size and improvement of headaches were immediately observed. On the seventh day, however, he developed a rapidly progressing consciousness disturbance due to severe hydrocephalus leading to urgent secondary ETV. The original ventriculostomy stoma at the third ventricle floor was completely occluded by scar adhesion. The patient recovered well as previously and received additional treatment.Conclusion: Although very rare, occlusion of the ventriculostomy stoma can postoperatively occur in the subacute period. Patients undergoing ETV for obstructive hydrocephalus due to a pineal tumour should be carefully monitored to avoid serious consequences.

Astrocyte-induced mGluR1 activates human lung cancer brain metastasis via glutamate-dependent stabilization of EGFR.

There are limited methods to stably analyze the interactions between cancer cells and glial cells in vitro, which hinders our molecular understanding. Here, we develop a simple and stable culture method of mouse glial cells, termed mixed-glial culture on/in soft substrate (MGS), which serves well as a platform to study cancer-glia interactions. Using this method, we find that human lung cancer cells become overly dependent on metabotropic glutamate receptor 1 (mGluR1) signaling in the brain microenvironment. Mechanistically, interactions with astrocytes induce mGluR1 in cancer cells through the Wnt-5a/prickle planar cell polarity protein 1 (PRICKLE1)/RE1 silencing transcription factor (REST) axis. Induced mGluR1 directly interacts with and stabilizes the epidermal growth factor receptor (EGFR) in a glutamate-dependent manner, and these cells then become responsive to mGluR1 inhibition. Our results highlight increased dependence on mGluR1 signaling as an adaptive strategy and vulnerability of human lung cancer brain metastasis.

Liquid biomarkers in glioma.

An ideal biomarker must meet several parameters to enable its successful adoption; however, the nature of glioma makes it challenging to discover valuable biomarkers. While biomarkers require simplicity for clinical implementation, anatomical features and the complexity of the brain make it challenging to perform histological examination. Therefore, compared to biomarkers from general histological examination, liquid biomarkers for brain disease offer many more advantages in these minimally invasive methods. Ideal biomarkers should have high sensitivity and specificity, especially in malignant tumors. The heterogeneous nature of glioma makes it challenging to determine useful common biomarkers, and no liquid biomarker has yet been adopted clinically. The low incidence of brain tumors also hinders research progress. To overcome these problems, clinical applications of new types of specimens, such as extracellular vesicles and comprehensive omics analysis, have been developed, and some candidate liquid biomarkers have been identified. As against previous reviews, we focused on and reviewed the sensitivity and specificity of each liquid biomarker for its clinical application. Perusing an ideal glioma biomarker would help uncover the common underlying mechanism of glioma and develop new therapeutic targets. Further multicenter studies based on these findings will help establish new treatment strategies in the future.

α-SMA positive vascular mural cells suppress cyst formation in hemangioblastoma.

Approximately 60% of hemangioblastomas (HBs) have peritumoral cysts adjacent to the tumor, which can cause neurological deficits due to the mass effect, and the management of cyst formation is a clinical challenge. Vascular mural cells surrounding endothelial cells consist of vascular smooth muscle cells (vSMCs) and pericytes, which are essential elements that support blood vessels and regulate permeability. This study investigated the involvement of mural cells in cyst formation. We analyzed the expression of α-smooth muscle actin (α-SMA), platelet-derived growth factor receptor-beta (PDGFRB), and CD31 in 39 consecutive human cerebellar HBs, 20 of cystic and 19 of solid type. Solid type HBs showed stronger diffuse expression of α-SMA in precapillary arterioles and capillaries within the tumor than cystic type HBs (p = 0.001), whereas there was no difference in PDGFRB and CD31 expression. Detailed observation with immunofluorescence demonstrated that α-SMA was expressed in vascular mural cells surrounding capillaries in the solid rather than in the cystic type. Multivariate analysis including various clinical and pathological factors showed that lower α-SMA expression was significantly correlated with cyst formation (p < 0.001). Our data suggested that vascular mural cells from precapillary arterioles to capillaries expressing α-SMA may be pericytes and play a crucial role in HB cystogenesis.

COL1A2 inhibition suppresses glioblastoma cell proliferation and invasion.

OBJECTIVE: An extracellular matrix such as collagen is an essential component of the tumor microenvironment. Collagen alpha-2(I) chain (COL1A2) is a chain of type I collagen whose triple helix comprises two alpha-1 chains and one alpha-2 chain. The authors' proteomics data showed that COL1A2 is significantly higher in the blood of patients with glioblastoma (GBM) compared with healthy controls. COL1A2 has many different functions in various types of cancers. However, the functions of COL1A2 in GBM are poorly understood. In this study, the authors analyzed the functions of COL1A2 and its signaling pathways in GBM. METHODS: Surgical specimens and GBM cell lines (T98, U87, and U251) were used. The expression level of COL1A2 was examined using GBM tissues and normal brain tissues by quantitative real-time polymerase chain reaction. The clinical significance of these levels was evaluated using Kaplan-Meier analysis. Small interfering RNA (siRNA) and small hairpin RNA of COL1A2 were transfected into GBM cell lines to investigate the function of COL1A2 in vitro and in vivo. Flow cytometry was introduced to analyze the alteration of cell cycles. Western blot and immunohistochemistry were performed to analyze the underlying mechanisms. RESULTS: The expression level of COL1A2 was upregulated in GBM compared with normal brain tissues. A higher expression of COL1A2 was correlated with poor progression-free survival and overall survival. COL1A2 inhibition significantly suppressed cell proliferation in vitro and in vivo, likely due to G1 arrest. The invasion ability was notably deteriorated by inhibiting COL1A2. Cyclin D1, cyclin-dependent kinase 1, and cyclin-dependent kinase 4, which are involved in the cell cycle, were all downregulated after blockade of COL1A2 in vitro and in vivo. Phosphoinositide 3-kinase inhibitor reduced the expression of COL1A2. Although downregulation of COL1A2 decreased the protein kinase B (Akt) phosphorylation, Akt activator can phosphorylate Akt in siRNA-treated cells. This finding suggests that Akt phosphorylation is partially dependent on COL1A2. CONCLUSIONS: COL1A2 plays an important role in driving GBM progression. COL1A2 inhibition attenuated GBM proliferation by promoting cell cycle arrest, indicating that COL1A2 could be a promising therapeutic target for GBM treatment.

Tumor Microenvironment in Glioma Invasion.

A major malignant trait of gliomas is their remarkable infiltration capacity. When glioma develops, the tumor cells have already reached the distant part. Therefore, complete removal of the glioma is impossible. Recently, research on the involvement of the tumor microenvironment in glioma invasion has advanced. Local hypoxia triggers cell migration as an environmental factor. The transcription factor hypoxia-inducible factor (HIF) -1α, produced in tumor cells under hypoxia, promotes the transcription of various invasion related molecules. The extracellular matrix surrounding tumors is degraded by proteases secreted by tumor cells and simultaneously replaced by an extracellular matrix that promotes infiltration. Astrocytes and microglia become tumor-associated astrocytes and glioma-associated macrophages/microglia, respectively, in relation to tumor cells. These cells also promote glioma invasion. Interactions between glioma cells actively promote infiltration of each other. Surgery, chemotherapy, and radiation therapy transform the microenvironment, allowing glioma cells to invade. These findings indicate that the tumor microenvironment may be a target for glioma invasion. On the other hand, because the living body actively promotes tumor infiltration in response to the tumor, it is necessary to reconsider whether the invasion itself is friend or foe to the brain.

A Rare Case of Chronic Subdural Hematoma Coexisting With Metastatic Tumor.

BACKGROUND: Incidence of chronic subdural hematoma (CSH) associated with metastases of extraneural malignancies is rare. We report a rare case of CSH wherein most of the CSH cavity was occupied with metastatic cancer cells; in addition, we review the literature. CASE DESCRIPTION: A 68-year-old man with a history of gastric cancer presented to our hospital with dysarthria and shoulder paralysis; CSH was diagnosed from preoperative imaging findings. When the hematoma was removed via a small craniotomy, besides the hematoma, we observed an abnormal mass of tissue in the capsule. Pathologically, the mass was consistent with the findings of metastatic gastric cancer. Although the symptoms immediately disappeared postoperatively, a symptomatic acute subdural hematoma with midline shift was observed on postoperative day 27. Emergency craniotomy and hematoma and tumor removal were performed. Pathologic examination showed hemorrhagic necrosis in the tumor, which had not been initially observed. The postoperative course progressed without hematoma recurrence. CONCLUSIONS: To the best of our knowledge, this is the first report of a CSH accompanied by tumor metastasis in most of the CSH cavity. Although rare, if a patient with cancer has CSH, the CSH should be treated considering the possibility of metastasis.

Recurrent Spinal Intramedullary Arachnoid Cyst: Case Report and Literature Review.

BACKGROUND: Symptomatic intramedullary arachnoid cysts are rarely observed lesions, particularly in the pediatric age group. Treatment includes cyst fenestration or resection of the cyst wall, and recurrence after surgery has never been reported. We report a rare case of a spinal intramedullary arachnoid cyst, which recurred after cyst fenestration and required reoperation after a certain period. CASE DESCRIPTION: A 4-year-old boy presented to our hospital with tetraparesis and bladder and rectum disorder. A cystic intramedullary lesion in the cervical spinal cord was detected in preoperative imaging. An emergency fenestration of cyst was performed, and his symptoms were resolved immediately. One month after the operation, the symptoms and cyst recurred. The symptoms improved in the natural course without reoperation. However, the cyst increased in size and the symptoms recurred after 27 months from the first relapse and the cyst was removed urgently. The diagnosis was an arachnoid cyst. After the reoperation, the cyst has disappeared and not recurred. CONCLUSIONS: To the best of our knowledge, this is the first report of recurrence of an intramedullary arachnoid cyst. This case indicates the importance of considering the resection of cyst wall as possible because of the probability of cyst recurrence after fenestration, while careful observation is the option in the short term, especially for children or high-risk cases.

Morphological characteristics of infected subdural hematoma: Comparison with images of chronic subdural hematoma.

OBJECTIVES: Infected subdural hematoma (ISH) is a rare type of subdural empyema, with fewer than 50 cases reported to date. Its radiological features have not been adequately described, making diagnosis challenging. At our institution, two adults presented with ISH, which exhibited a characteristic shape on preoperative imaging. PATIENTS AND METHODS: This study examined ISH cases and chronic subdural hematoma (CSH) cases that underwent surgery at the Ishikawa Prefectural Central Hospital between January 2016 and March 2018. To distinguish ISH from CSH, we focused on three specific radiological features: the biconvex shape of the hematoma, presence of a high-density region at the lower end of the hematoma on plain computed tomography (CT), and presence of a hyper-intense signal within the hematoma on diffusion weighted imaging (DWI). RESULTS: We analyzed 30 ISH (current and previously reported) and 102 CSH cases in our study. We found no statistically significant associations between the hematoma type (ISH or CSH) and the presence of a high-density region at the lower end of the hematoma on plain CT (p = 0.13) or the presence of hyperintensity in the hematoma on DWI (p = 1.00). Conversely, a statistically significant association was found between the hematoma type and the biconvex shape of the hematoma (p < 0.01). CONCLUSION: These results suggest that the shape of the hematoma on imaging provides valuable information that can be used to differentiate ISH from CSH and optimize therapeutic approaches.

Hyperperfusion syndrome after trapping with high-flow bypass for a giant paraclinoid internal carotid artery aneurysm.

BACKGROUND: Hyperperfusion syndrome associated with aneurysm surgery is rare. The occurrence of the syndrome after trapping with high-flow bypass has not been described previously. Herein, we present a case of the syndrome that occurred after trapping with high-flow bypass of an unruptured giant paraclinoid internal carotid artery (ICA) aneurysm. CASE DESCRIPTION: The patient was a 68-year-old woman with progressive loss of vision in her left eye. After a diagnosis of left giant ICA aneurysm, she underwent successful trapping with high-flow bypass. No new neurologic deficits were observed after surgery. Computed tomography on the same day and magnetic resonance imaging on the next day revealed no hemorrhage or infarction. The patient had a headache and transit motor aphasia on postoperative day (POD) 8. Arterial spin-labeling magnetic resonance perfusion imaging on the same day and single photon emission CT on POD 10 demonstrated hyperperfusion in the left cerebral cortex. The symptoms gradually improved over a week, and she had no new neurologic deficits when discharged from hospital. CONCLUSIONS: This report suggests that hyperperfusion syndrome after trapping with high-flow bypass, although rare, should be considered in patients with giant aneurysm if they present with headache and neurologic deficits after a delay.