MicroRNA regulating stanniocalcin-1 is a metastasis and dissemination promoting factor in glioblastoma.

BACKGROUND: MicroRNAs (miRs) regulate many biological processes, such as invasion, angiogenesis, and metastasis. Glioblastoma (GBM) patients with metastasis/metastatic dissemination have a very poor prognosis; therefore, inhibiting metastasis/metastatic dissemination has become an important therapeutic strategy for GBM treatment. METHODS: Using 76 GBM tissues, we examined the expression levels of 23 GBM-related miRs and compared the miRs' expression levels between GBMs with metastasis/metastatic dissemination and GBMs without metastasis/metastatic dissemination. Using the bioinformatics web site, we searched the target genes of miRs. To analyze the function of target gene, several biological assays and survival analysis by the Kaplan-Meier method were performed. RESULTS: We found that eight miRs were significantly decreased in GBM with metastasis/metastatic dissemination. By the bioinformatics analysis, we identified stanniocalcin-1 (STC1) as the most probable target gene against the combination of these miRs. Four miRs (miR-29B, miR-34a, miR-101, and miR-137) have predictive binding sites in STC1 mRNA, and mRNA expression of STC1 was downregulated by mimics of these miRs. Also, mimics of these miRs and knockdown of STC1 by siRNA suppressed invasion in GBM cells. GBM with metastasis/metastatic dissemination had significantly higher levels of STC1 than GBM without metastasis/metastatic dissemination. Finally, Kaplan-Meier analysis demonstrated that GBMs with high STC1 level had significantly shorter survival than GBMs with low STC1 level. CONCLUSIONS: STC1 may be a novel metastasis/metastatic dissemination promoting factor regulated by several miRs in GBM. Because STC1 is a secreted glycoprotein and functions via the autocrine/paracrine signals, inhibiting STC1 signal may become a novel therapeutic strategy for GBM.

[Locked-in Syndrome due to Primary Brainstem Injury:A Case Report].

Most cases of the primary brainstem injuries(PBSI)are fatal, and disturbance of consciousness is often prolonged even if lifesaving is obtained. The mechanisms of PBSI are as follows: diffuse axonal injury from acceleration/deceleration, shear strain at the midbrain, direct injury of neurovascular structures by tentorial margin, and lower brainstem injury by hyperextension of the cervical vertebrae. Though we can use both CT and MRI to diagnose, MRI is more helpful than CT in detecting, localizing, and characterizing PBSI. When the location of PBSI is limited in the ventral side of pons, it may occasionally result in locked in syndrome(LIS). Generally it is difficult to diagnose LIS with severe trauma due to the rarity of this syndrome caused by head injury. Here, we report a case of an elderly man with traumatic brainstem hemorrhage, who transiently presented LIS and finally improved.

[Tentorial Dural Arteriovenous Fistula Successfully Treated with Transvenous Embolization Using a Double Catheterization Technique through Venous Drainage:A Case Report].

BACKGROUND: Tentorial dural arteriovenous fistulas(dAVFs)are a rare clinical entity accounting for less than 10% of all intracranial dAVFs. Because these lesions are characterized by high hemorrhagic risk, aggressive treatment should be considered. Although the number of reported cases treated with endovascular transarterial embolization(TAE)using glue has been increasing, little is known about the transvenous approach. Here, we report the case of a patient with a tentorial dAVF who was successfully treated with transvenous embolization(TVE)through venous drainage using a double catheterization technique. CASE PRESENTATION: A 68-year-old male patient who had a history of left putaminal hemorrhage treated with a craniotomy was diagnosed with a tentorial dAVF on a magnetic resonance angiogram. Because the patient refused another craniotomy for surgical interruption of the dAVF, an endovascular approach was considered. We first attempted to perform TAE with glue, but catheterization into the tortuous meningohypophyseal trunk failed. We then performed a TVE of the venous drainage near the shunt with detachable coils and achieved complete obliteration of the fistula. During coil embolization of the venous drainage, insertion of small coils near the shunt was supported by another anchor coil that was delivered using a double catheterization technique. CONCLUSIONS: The method of TVE through venous drainage using a double catheterization technique, which involved placing coils in the fragile drainage vein, was safe and effective in a case of tentorial dAVF. This technique should be considered as another option for the management of complex tentorial dAVFs.

STAT3 activation is associated with cerebrospinal fluid interleukin-10 (IL-10) in primary central nervous system diffuse large B cell lymphoma.

Signal transducers and activators of transcription 3 (STAT3) are activated by various cytokines and oncogenes; however, the activity and pathogenesis of STAT3 in diffuse large B cell lymphoma of the central nervous system have not been thoroughly elucidated. We investigated the phosphorylation levels of STAT3 in 40 specimens of primary central nervous system diffuse large B-cell lymphoma (PCNS DLBCL) and analyzed the association between phsopho-STAT3 (pSTAT3) expression and cerebrospinal fluid (CSF) concentration of interleukin-10 (IL-10) or IL-6. Immunohistochemistry and Western blot analysis revealed that most of the specimens in PCNS DLBCL expressed pSTST3 protein, and a strong phosphorylation levels of STAT3 was statistically associated with high CSF IL-10 levels, but not with CSF IL-6 levels. Next, we demonstrated that recombinant IL-10 and CSF containing IL-10 induced the phosphorylation of STAT3 in PCNS DLBCL cells. Furthermore, molecular subtype classified by Hans' algorithm was correlated with pSTAT3 expression levels and CSF IL-10 levels. These results suggest that the STAT3 activity is correlated with CSF IL-10 level, which is a useful marker for STAT3 activity in PCNS DLBCLs.

Stereotactic radiotherapy of radiation-induced meningioma previously irradiated retrobulbar for Graves' ophthalmopathy: A case report.

A 69-year-old woman was diagnosed with an asymptomatic intracranial tumor nine years ago and has been followed with annual MR imaging studies. Two years ago, the tumor had grown in size, requiring treatment. She experienced ophthalmopathy due to hyperthyroidism 27 years ago and was treated with 20 Gy in 10 fractions using parallel opposed beams to her bilateral posterior eyeballs, supplemented with steroid pulse therapy. The tumor originated in the medial aspect of the right sphenoid border and compressed the temporal lobe, while bone infiltration was observed, partially extending to the soft tissue outside the maxillary sinus. The tumor was removed by craniotomy. The pathological diagnosis was atypical meningioma (WHO grade II). Four months postsurgery, the resection cavity's tumor exhibited growth inclination, necessitating Gamma Knife radiosurgery. Radiation planning was executed at a marginal tumor dose of 30 Gy in 5 fractions. Since the optic nerve had been previously exposed to radiation, a plan was devised to minimize radiation exposure. The dose on the optic nerve was limited to 6.9 Gy in 5 fractions. She did not experience any visual or visual field disruptions postradiation. This is a case of radiation-induced meningioma resulting from radiation therapy for Graves' ophthalmopathy and is the first reported case of a grade II meningioma. The patient's condition calls for adjuvant radiation therapy following surgical removal. Accordingly, a radiation treatment plan that safeguards the optic nerve, which was previously exposed to radiation, was deemed indispensable.

MicroRNA-183 upregulates HIF-1α by targeting isocitrate dehydrogenase 2 (IDH2) in glioma cells.

MicroRNAs (miRs) are small, non-coding RNAs that regulate gene expression and contribute to cell proliferation, differentiation and metabolism. Our previous study revealed the extensive modulation of a set of miRs in malignant glioma. In that study, miR microarray analysis demonstrated the upregulation of microRNA-183 (miR-183) in glioblastomas. Therefore, we examined the expression levels of miR-183 in various types of gliomas and the association of miR-183 with isocitrate dehydrogenase 2 (IDH2), which has complementary sequences to miR-183 in its 3'-untranslated region (3'UTR). In present study, we used real-time PCR analysis to demonstrate that miR-183 is upregulated in the majority of high-grade gliomas and glioma cell lines compared with peripheral, non-tumorous brain tissue. The mRNA and protein expression levels of IDH2 are downregulated via the overexpression of miR-183 mimic RNA in glioma cells. Additionally, IDH2 mRNA expression is upregulated in glioma cells expressing anti-miR-183. We verified that miR-183 directly affects IDH2 mRNA levels in glioma cells using luciferase assays. In malignant glioma specimens, the expression levels of IDH2 were lower in tumors than in the peripheral, non-tumorous brain tissues. HIF-1α levels were upregulated in glioma cells following transfection with miR-183 mimic RNA or IDH2 siRNA. Moreover, vascular endothelial growth factor and glucose transporter 1, which are downstream molecules of HIF-1α, were upregulated in cells transfected with miR-183 mimic RNA. These results suggest that miR-183 upregulation in malignant gliomas induces HIF-1α expression by targeting IDH2 and may play a role in glioma biology.

GC/MS-based metabolomic analysis of cerebrospinal fluid (CSF) from glioma patients.

Metabolomics has recently undergone rapid development; however, metabolomic analysis in cerebrospinal fluid (CSF) is not a common practice. We analyzed the metabolite profiles of preoperative CSF samples from 32 patients with histologically confirmed glioma using gas chromatography/mass spectrometry (GC/MS). We assessed how alterations in the metabolite levels were related to the World Health Organization (WHO) tumor grades, tumor location, gadolinium enhancement on magnetic resonance imaging (MRI), and the isocitrate dehydrogenase (IDH) mutation status. Sixty-one metabolites were identified in the CSF from glioma patients using targeted, quantitative and non-targeted, semi-quantitative analysis. The citric and isocitric acid levels were significantly higher in the glioblastoma (GBM) samples than in the grades I-II and grade III glioma samples. In addition, the lactic and 2-aminopimelic acid levels were relatively higher in the GBM samples than in the grades I-II glioma samples. The CSF levels of the citric, isocitric, and lactic acids were significantly higher in grade I-III gliomas with mutant IDH than in those with wild-type IDH. The tumor location and enhancement obtained using MRI did not significantly affect the metabolite profiles. Higher CSF levels of lactic acid were statistically associated with a poorer prognosis in grades III-IV malignant gliomas. Our study suggests that the metabolomic analysis of CSF from glioma patients may be useful for predicting the glioma grade, metabolic state, and prognosis of gliomas.

Immunohistochemical and molecular genetics study of a granular cell astrocytoma: a case report of malignant transformation to a glioblastoma.

We treated a 56-year-old woman who had a right temporal lobe tumor found by chance after a traffic accident. MRI confirmed a heterogeneously enhanced tumor in the temporal lobe with large peritumoral edema extending to the superior parietal lobe. The patient underwent tumor resection. The tumor consisted largely of distinct cells with discrete borders and granular cytoplasm. In granular cells, the accumulation of PAS-positive granules was observed. Immunohistochemical analysis demonstrated positive staining for GFAP, S-100, and oligodendrocyte transcription factor 2 and negative staining for synaptophysin. CD68 was negative in granular cells, but positive in stromal cells. Ki-67 labeling index was quite low. The tumor was diagnosed as a granular cell astrocytoma (GCA). Postoperative radiotherapy combined with temozolomide was administered. One month after chemoradiotherapy, the tumor occurred in the parietal lobe, and a tumorectomy was performed. The tumor was composed of poorly differentiated astrocytic tumor cells with prominent microvascular proliferation and necrosis. A small number of granular cells were locally observed and the tumor was diagnosed as a glioblastoma. O6-methylguanine-DNA methyltransferase promoter methylation was detected in the GCA but not in the glioblastoma. Isocitrate dehydrogenase mutations were not detected in either tumor. Comparative genomic hybridization analysis demonstrated that no chromosomal abnormality was found in the GCA; however, a gain of chromosomes 7 and 19 and a loss of chromosomes 10 and 9p21 (CDKN2A) were found in the glioblastoma. p53 was strongly expressed in both the GCA and glioblastoma. The tumor progressed despite extensive chemotherapy, and the patient died 1 year after the initial treatment. Our immunohistochemical, genetic and chromosomal analyses indicate that the glioblastoma was transformed from the GCA.

Facial Nerve Neurolymphomatosis That Extends to Both the Brainstem and Extracranial Regions.

A 73-year-old female developed right facial paralysis of House-Brackmann (H-B) grade III and was diagnosed with Bell's palsy. After three months of steroid therapy, she developed progressive hearing loss, and an MRI revealed a tumor in the right internal auditory canal. Within a few months, the right facial nerve palsy recurred, and the patient was treated with Gamma Knife radiosurgery. The tumor in the irradiated region disappeared, but new dysphagia was observed, and a right parotid gland tumor was detected for the first time. Tumors of the right parotid gland and the digastric muscle of the jaw were surgically resected, and a diagnosis of diffuse large B-cell lymphoma was made. The tumor had invaded the cranial nerves and brainstem region, and the patient did not wish to undergo further medical therapy. This was a case of malignant lymphoma that started as facial paralysis and invaded the brainstem, and testing for possible lymphoma at an early stage prior to radiotherapy was desirable.

Long-term recurrence after surgery for schwannoma of the cauda equina.

Background: Cauda equina tumors are rare primary spinal tumors. Histologically, the most common tumor arising from the cauda equina is a schwannoma. However, little is known about the long-term postoperative outcomes of cauda equina schwannoma. Here, we reviewed the median-to-long-term postoperative outcomes of eight of our own patients with schwannomas of the cauda equina. Methods: Between 2007 and 2020, we, retrospectively, reviewed eight patients with cauda equina schwannomas (CESs) undergoing nine operations at our institution. There were five males and three females averaging 56.5 years of age who were followed for over 40 postoperative months. The study included assessment of the following variables: the modified McCormick scale, tumor size, location, extent of resection, treatment of the tumor involving nerve roots, and postoperative observational follow-up. Results: Gross-total resection was achieved in all eight patients; none received adjuvant therapy. The involved nerve roots were completely sacrificed in seven patients and partially resected in one. During a median follow-up of 108 months, only one patient sustained a tumor recurrence 164 months following the index surgery. Conclusion: CESs may recur more than 10 years after the original surgery. Radical resection of the tumor, including complete removal of the involved nerve root during the index surgery, and long-term postoperative follow-up is, therefore, essential.

Gamma knife radiosurgery cured hydrocephalus in non-hemorrhagic brain stem arteriovenous malformation.

A 13-year-old boy, with a history of intermittent headache and transient diplopia, was found to have non-hemorrhagic cerebral arteriovenous malformation in the midbrain tegmental region associated with hydrocephalus. Gamma knife radiosurgery was performed at 16 Gy with 75% marginal dose. Posttreatment course was uneventful. Follow-up MR imaging at one year after the treatment revealed complete disappearance of the abnormal vascular flow voids. The size of each ventricle at the treatment and at one year after treatment were as follows; 60.2 cc and 20.9 cc in the lateral ventricles, 3.7 cc and 2.7 cc in the third ventricle. The hydrocephalus might be caused by obstructive mechanism but mostly by high venous pressure due to the shunt blood flow. The goal of treatment for hydrocephalus should be nidus obstruction and normalizing the vascular flow.

Endovascular Treatment Strategy for Acute Basilar Artery Occlusion with Unexpected Right-Sided Aortic Arch.

A right-sided aortic arch (RAA) is a rare variant of the aortic arch found. We present a case of endovascular treatment (EVT) for acute basilar artery (BA) occlusion with an RAA. A 70-year-old man developed acute ischemic stroke due to BA occlusion. During urgent EVT for BA occlusion with an RAA, which was observed unexpectedly, navigation of the catheter to the target vessel was achieved as a result of an early change in the access route. Flexible treatment strategies are warranted for cases of unexpected anatomical variant in the fight against time for emergent cases, such as acute ischemic stroke.

Glutamic Acid and Total Creatine as Predictive Markers for Epilepsy in Glioblastoma by Using Magnetic Resonance Spectroscopy Before Surgery.

OBJECTIVE: Epilepsy in glioblastoma patients significantly reduces their quality of life; however, little is known about the association between predicting epilepsy and metabolites in tumors. In this study, we used 3.0-T magnetic resonance imaging and 1H-magnetic resonance spectroscopy (MRS) to quantify metabolite concentrations in patients with varying epilepsy histories. METHODS: Fifty-one patients with glioblastoma underwent pretreatment 3.0-T MRI/1H-MRS scanning. Single-voxel (1.5 cm3) MRS, in an enhanced lesion, was acquired using a double-echo point-resolved spectroscopic sequence with chemical-shift selective water suppression. MRS data were quantified with linear combination model (LC-Model) software. We compared the MRS data between groups with and without epilepsy during the postoperative course (EP). RESULTS: The ratios of glutamate (Glu) and glutamate + glutamine (Glx) to total creatine (Glu/tCr and Glx/tCr) in the tumor were associated with epilepsy history. The receiver operating characteristic curve analysis showed that a Glu/tCr value of 1.81 was 70% sensitive and 90% specific for the prediction of EP (area under curve: 0.82). In the analysis excluding patients with preoperative epilepsy, a Glu/tCr value of 1.81 was 75% sensitive and 88% specific for the prediction (area under curve: 0.87). CONCLUSIONS: Intratumoral metabolite concentrations measured using pretreatment 3.0-T MRI/1H-MRS changed characteristically in the group with EP. Our study suggests that the Glu/tCr ratio in tumors has adequate reliability in predicting EP. Pretreatment MRS is a minimally invasive and simple procedure that can provide useful information on glioblastoma patients.

Ostial common carotid artery occlusion and balloon-mounted stenting: Implication of embolic protection device in tandem lesion.

Ostial common carotid artery (CCA) stenosis is rare, compared to extracranial internal carotid artery bifurcation lesions. In cases of a tandem lesion, the proximal lesion usually involves the extracranial internal carotid artery, and the ostial CCA is rarely implicated. A 69-year-old woman who underwent 3 months of antiplatelet therapy for asymptomatic, right ostial, severely calcified CCA stenosis presented with sudden onset left hemiparesis. Radiographic examination revealed an ostial CCA-intracranial artery tandem lesion. After intracranial revascularization using a clot retrieval stent, we performed the endovascular treatment with a balloon-mounted stent using an embolic protection device. This procedure may be superior to others because it is possible to achieve early intracranial revascularization and prevent distal embolism during the complete treatment of proximal lesions.

Lumbar Canal Stenosis Caused by Spondylolisthesis and Intraspinal Canal Calcifications Associated with Psoriatic Arthritis: A Case Report.

Soft tissue calcifications are common findings in patients with various diseases, such as malignant tumors, collagen diseases, trauma, and chronic kidney disease. The majority of these lesions are not clinically significant; however, they can cause specific disorders within a limited space, such as the spinal canal. Here, we report the case of a patient undergoing fusion surgery for lumbar canal stenosis due to degenerative spondylolisthesis and multiple intraspinal canal calcifications associated with psoriatic arthritis (PsA). A 55-year-old female patient presented with pain in the left leg and intermittent claudication for 1 month. One year ago, she was diagnosed with PsA and received outpatient treatment, including biological medication, at the Division of Rheumatology, Department of Internal Medicine of our institution. She was referred to our department, and radiological examination revealed lumbar canal stenosis caused by spondylolisthesis and multiple calcifications in the lumbar spinal canal. We performed posterior lumbar interbody fusion (PLIF) with percutaneous pedicle screw fixation concomitant with removal of the calcifications. The postoperative course was uneventful, and her neurological symptoms improved. Although several prior case reports have noted intraspinal canal calcifications due to collagen disease or chronic kidney disease, calcifications associated with PsA are rare. We discuss the diagnosis of PsA and its relationship with intraspinal canal calcifications by reviewing the previous relevant literature.

Understanding of Pathophysiology and Optimal Treatment for Anterior Circulation Large Vessel Occlusion beyond 24 h from Onset of Stroke.

We report three cases in which endovascular treatment (EVT) was performed for anterior circulation large vessel occlusion (LVO) beyond 24 h from the onset of stroke. Case 1 experienced left hemispatial neglect and gait disorder due to right internal cerebral artery (ICA) occlusion and underlying atherosclerosis. After percutaneous transluminal angioplasty (PTA), revascularization with mild stenosis was achieved. Case 2 complained of reduced activity, motor aphasia, and right-sided hemiparesis due to left middle cerebral artery occlusion. After thrombectomy using a retrieval stent, revascularization with M1 stenosis and distal perfusion delay was observed, which improved after PTA. Case 3 arrived at our hospital 30 h after the onset of dysarthria and gait disturbance due to left ICA occlusion. Since the symptoms were mild, medical treatment was started; however, the patient's symptoms deteriorated 6 h later, and EVT was required. After thrombectomy using a retrieval stent, revascularization was achieved. LVO pathophysiology beyond 24 h of stroke onset varies and may require multimodal treatment. Preserving the pyramidal tract may lead to favorable outcomes, even in cases of anterior circulation LVO. EVT may be effective for anterior circulation LVO because, in some patients, infarct volume continues to increase >24 h after stroke onset.

Metabolic changes and anti-tumor effects of a ketogenic diet combined with anti-angiogenic therapy in a glioblastoma mouse model.

The ketogenic diet (KD) is a high fat and low carbohydrate diet that produces ketone bodies through imitation of starvation. The combination of KD and Bevacizumab (Bev), a VEGF inhibitor, is considered to further reduce the supply of glucose to the tumor. The metabolite changes in U87 glioblastoma mouse models treated with KD and/or Bev were examined using gas chromatography-mass spectrometry. The combination therapy of KD and Bev showed a decrease in the rate of tumor growth and an increase in the survival time of mice, although KD alone did not have survival benefit. In the metabolome analysis, the pattern of changes for most amino acids are similar between tumor and brain tissues, however, some amino acids such as aspartic acid and glutamic acid were different between tumors and brain tissues. The KD enhanced the anti-tumor efficacy of Bev in a glioblastoma intracranial implantation mouse model, based on lowest levels of microvascular density (CD31) and cellular proliferation markers (Ki-67 and CCND1) in KD + Bev tumors compared to the other groups. These results suggested that KD combined with Bev may be a useful treatment strategy for patients with GBM.

Multi-marker algorithms based on CXCL13, IL-10, sIL-2 receptor, and ß2-microglobulin in cerebrospinal fluid to diagnose CNS lymphoma.

Tumor biopsy is essential for the definitive diagnosis of central nervous system (CNS) lymphoma. However, the biopsy procedure carries the risk of complications such as bleeding, convulsions, and infection. Cerebrospinal fluid (CSF) ß2-microglobulin (ß2-MG), soluble IL-2 receptor (sIL-2R), and interleukin-10 (IL-10) are known to be useful diagnostic biomarkers for CNS lymphoma. The C-X-C motif chemokine ligand 13 (CXCL13) was recently reported to be another useful biomarker for CNS lymphoma. The purpose of this study is to establish a diagnostic algorithm that can avoid biopsy by combining these diagnostic biomarkers. In the first, we conducted a case-control study (n = 248) demonstrating that the CSF CXCL13 concentration was significantly increased in CNS lymphoma patients compared with various other brain diseases (AUC = 0.981). We established a multi-marker diagnostic model using CSF CXCL13, IL-10, ß2-MG, and sIL-2R from the results of the case-control study and then applied the model to a prospective study (n = 104) to evaluate its utility. The multi-marker diagnostic algorithms had excellent diagnostic performance: the sensitivity, specificity, positive predictive value, and negative predictive value were 97%, 97%, 94%, and 99%, respectively. In addition, CSF CXCL13 was a prognostic biomarker for CNS lymphoma patients. Our study suggests that multi-marker algorithms are important diagnostic tools for patients with CNS lymphoma.

Tumor-associated macrophage related interleukin-6 in cerebrospinal fluid as a prognostic marker for glioblastoma.

Interleukin-6 (IL-6) is one of the pleiotropic cytokines and has received attention as a critical factor implicated in the invasion and the angiogenesis of various cancers. In glioma, IL-6 is known to be associated with the prognosis; however, the roles of IL-6 in cerebrospinal fluid (CSF) has not been studied sufficiently. We examined the concentration of CSF IL-6 using 75 CSF samples of glioma (54 glioblastomas (GBMs) and 21 other grades of gliomas) and analyzed the association CSF IL-6 with infiltration levels of tumor-associated macrophages (TAMs) and prognosis. The concentration of CSF IL-6 in GBM patients was significantly higher than that in other grades of gliomas. CSF IL-6 levels were associated with the infiltration rate of TAMs in GBMs, and IL-6 levels were increased in the GBM cells co-cultured with TAM-like macrophages. The CSF of GBM patients, which contained high concentration of IL-6, promoted the migration ability of GBM cells, and neutralization antibodies of IL-6 inhibited its migration ability. Finally, in both univariate and multivariate analysis, higher CSF IL-6 levels were associated with poorer prognosis in GBM patients. These results indicated that the concentration of CSF IL-6 is associated with TAMs' infiltration level and may be a useful prognostic biomarker for the GBM patients.