Exploring the Vital Link Between Glioma, Neuron, and Neural Activity in the Context of Invasion.

Because of their ability to infiltrate normal brain tissue, gliomas frequently evade microscopic surgical excision. The histologic infiltrative property of human glioma has been previously characterized as Scherer secondary structures, of which the perivascular satellitosis is a prospective target for anti-angiogenic treatment in high-grade gliomas. However, the mechanisms underlying perineuronal satellitosis remain unclear, and therapy remains lacking. Our knowledge of the mechanism underlying Scherer secondary structures has improved over time. New techniques, such as laser capture microdissection and optogenetic stimulation, have advanced our understanding of glioma invasion mechanisms. Although laser capture microdissection is a useful tool for studying gliomas that infiltrate the normal brain microenvironment, optogenetics and mouse xenograft glioma models have been extensively used in studies demonstrating the unique role of synaptogenesis in glioma proliferation and identification of potential therapeutic targets. Moreover, a rare glioma cell line is established that, when transplanted in the mouse brain, can replicate and recapitulate the human diffuse invasion phenotype. This review discusses the primary molecular causes of glioma, its histopathology-based invasive mechanisms, and the importance of neuronal activity and interactions between glioma cells and neurons in the brain microenvironment. It also explores current methods and models of gliomas.

Endothelial cell-specific reduction of heparan sulfate suppresses glioma growth in mice.

PURPOSE: Heparan sulfate (HS) is one of the factors that has been suggested to be associated with angiogenesis and invasion of glioblastoma (GBM), an aggressive and fast-growing brain tumor. However, it remains unclear how HS of endothelial cells is involved in angiogenesis in glioblastoma and its prognosis. Thus, we investigated the effect of endothelial cell HS on GBM development. METHODS: We generated endothelial cell-specific knockout of Ext1, a gene encoding a glycosyltransferase and essential for HS synthesis, and murine GL261 glioblastoma cells were orthotopically transplanted. Two weeks after transplantation, we examined the tumor progression and underlying mechanisms. RESULTS: The endothelial cell-specific Ext1 knockout (Ext1 CKO ) mice exhibited reduced HS expression specifically in the vascular endothelium of the brain capillaries compared with the control wild-type (WT) mice. GBM growth was significantly suppressed in Ext1 CKO mice compared with that in WT mice. After GBM transplantation, the survival rate was significantly higher in Ext1 CKO mice than in WT mice. We investigated how the effect of fibroblast growth factor 2 (FGF2), which is known as an angiogenesis-promoting factor, differs between Ext1 CKO and WT mice by using an in vivo Matrigel assay and demonstrated that endothelial cell-specific HS reduction attenuated the effect of FGF2 on angiogenesis. CONCLUSIONS: HS reduction in the vascular endothelium of the brain suppressed GBM growth and neovascularization in mice. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12672-021-00444-3.

Endoscopic third ventriculostomy for hydrocephalus in a patient with achondroplasia: a case report and literature review.

Hydrocephalus, a complication of achondroplasia, requires treatment when it is symptomatic. Hydrocephalus associated with achondroplasia is often treated with ventriculoperitoneal shunting, and endoscopic third ventriculostomy (ETV) is rarely performed in these patients. Here, we report the case of an 18-month-old boy with achondroplasia and progressive hydrocephalus who underwent ETV. He had a family history of achondroplasia and was diagnosed with achondroplasia at birth. Magnetic resonance imaging (MRI) at the age of 1 month showed no hydrocephalus. At the age of 15 months, he was admitted to our hospital due to increased head circumference. He had developmental delays, and MRI showed hydrocephalus with ballooning of the third ventricle. The ETV success score was 80 points; therefore, we performed ETV. Postoperatively, the progression of head circumference increase was controlled. The ventricular size remained unchanged on MRI at 13 months after surgery. Recently, an association between non-communicating hydrocephalus and achondroplasia has been reported. Depending on age and imaging findings, ETV may be effective in some patients with achondroplasia with hydrocephalus.

Glucose transporter Glut1 controls diffuse invasion phenotype with perineuronal satellitosis in diffuse glioma microenvironment.

BACKGROUND: Gliomas typically escape surgical resection and recur due to their "diffuse invasion" phenotype, enabling them to infiltrate diffusely into the normal brain parenchyma. Over the past 80 years, studies have revealed 2 key features of the "diffuse invasion" phenotype, designated the Scherer's secondary structure, and include perineuronal satellitosis (PS) and perivascular satellitosis (PVS). However, the mechanisms are still unknown. METHODS: We established a mouse glioma cell line (IG27) by manipulating the histone H3K27M mutation, frequently harboring in diffuse intrinsic pontine gliomas, that reproduced the diffuse invasion phenotype, PS and PVS, following intracranial transplantation in the mouse brain. Further, to broadly apply the results in this mouse model to human gliomas, we analyzed data from 66 glioma patients. RESULTS: Increased H3K27 acetylation in IG27 cells activated glucose transporter 1 (Glut1) expression and induced aerobic glycolysis and TCA cycle activation, leading to lactate, acetyl-CoA, and oncometabolite production irrespective of oxygen and glucose levels. Gain- and loss-of-function in vivo experiments demonstrated that Glut1 controls the PS of glioma cells, that is, attachment to and contact with neurons. GLUT1 is also associated with early progression in glioma patients. CONCLUSIONS: Targeting the transporter Glut1 suppresses the unique phenotype, "diffuse invasion" in the diffuse glioma mouse model. This work leads to promising therapeutic and potential useful imaging targets for anti-invasion in human gliomas widely.

Specific Deletion of p16INK4a with Retention of p19ARF Enhances the Development of Invasive Oral Squamous Cell Carcinoma.

The cyclin-dependent kinase inhibitor 2A (CDKN2A)/alternate reading frame (ARF) locus consists of two overlapping tumor suppressor genes, p16INK4a and p14ARF (p19ARF in mice), encoding two unrelated proteins in alternative reading frames. Previous reports suggest that p16INK4a and p14ARF alterations independently exhibit differential roles, and p16INK4a is more closely associated with a poor prognosis in oral cancer. However, the role of p16INK4a-specific loss in oral squamous cell carcinogenesis remains unclear. The authors assessed chemical carcinogen 4-nitroquinoline 1-oxide (4NQO)-induced multistep oral squamous cell carcinogenesis in mice carrying p16INK4a-specific loss with retention of the p19ARF gene (p16INK4a-/-). 4NQO-treated p16-/- mice exhibited a higher incidence and multiplicity of oral squamous cell carcinoma (OSCC) development relative to 4NQO-treated wild-type mice. 4NQO-treated p16INK4a-/- OSCC cells exhibited higher proliferation and up-regulation of Arf, transcription factor E2f1, tumor protein p63 (tp63), and oncogenic ΔNp63, an isoform p63, compared with observations in 4NQO-treated wild-type OSCC cells. Furthermore, the overexpression of oncogenic ΔNp63 was associated with human OSCC. In conclusion, these results in mice indicate the biological significance of p16INK4a-specific loss with retention of p19ARF in oral squamous cell carcinogenesis, and ΔNp63 may be a potential target for OSCC.

Treatment Strategies Based on Histological Targets against Invasive and Resistant Glioblastoma.

Glioblastoma (GBM) is the most common and the most malignant primary brain tumor and is characterized by rapid proliferation, invasion into surrounding normal brain tissues, and consequent aberrant vascularization. In these characteristics of GBM, invasive properties are responsible for its recurrence after various therapies. The histomorphological patterns of glioma cell invasion have often been referred to as the "secondary structures of Scherer." The "secondary structures of Scherer" can be classified mainly into four histological types as (i) perineuronal satellitosis, (ii) perivascular satellitosis, (iii) subpial spread, and (iv) invasion along the white matter tracts. In order to develop therapeutic interventions to mitigate glioma cell migration, it is important to understand the biological mechanism underlying the formation of these secondary structures. The main focus of this review is to examine new molecular pathways based on the histopathological evidence of GBM invasion as major prognostic factors for the high recurrence rate for GBMs. The histopathology-based pharmacological and biological targets for treatment strategies may improve the management of invasive and resistant GBMs.

A Rare Case of Symptomatic Carotid Stenosis Caused by Mechanical Stimulation by Thyroid Cartilage and Frequent Swimming.

BACKGROUND: Bony structures around the carotid artery such as the styloid process and hyoid bone can cause dissection, compression, plaque formation, and plaque rupture of the carotid artery. To the best of our knowledge, this case is the first finding of thyroid cartilage being the cause of a lesion corresponding to adjacent common carotid artery (CCA) atherosclerosis. CASE DESCRIPTION: A 51-year-old man with a history of hypertension and dyslipidemia suddenly experienced right facial numbness and dysphasia while front crawl swimming, which he usually did 3 times weekly. Diffusion-weighted magnetic resonance imaging showed high intensity areas in the left frontal and parietal lobes. He was diagnosed with acute cerebral infarction and was administered with tissue plasminogen activator. Angiography of the left CCA revealed mild stenosis with an intravascular filling defect, and carotid duplex ultrasonography of the CCA on the second day after symptom onset showed plaque and intraluminal thrombus at the stenotic site. Plain and contrast-enhanced computed tomography showed that thyroid cartilage contacted the left CCA at the stenotic site, and the left CCA moved backward and forward with the thyroid cartilage during neck rotation. We determined that mechanical stimulation by the thyroid cartilage had induced the plaque during the frequent neck rotation that is a feature of front crawl swimming. CONCLUSIONS: Evaluation of anatomical interactions between the carotid artery and bony structures including the thyroid cartilage is important to ensure that appropriate treatment is selected to prevent further ischemia.

Optimal platelet function test for in-stent tissue protrusion following carotid artery stenting.

Purpose To determine the best platelet function test for in-stent tissue protrusion following carotid artery stenting (CAS). Methods Patients who underwent CAS were recruited prospectively in this observational study. Combination of aspirin 100 mg/day and clopidogrel 75 mg/day was administered for a minimum of 7 days prior to procedure. Platelet aggregation was measured by light transmittance aggregometry (LTA) following stimulation by adenosine diphosphate (ADP), collagen, and thrombin receptor activating peptide (TRAP) and by the point of care assay, VerifyNow which measures aspirin and thienopyridine reaction units. Results In-stent tissue protrusion with maximum projection area of ≥1 mm2 was detected by optical coherence tomography (OCT) in 10/28 (36%) patients. Baseline characteristics were not significantly different between the two in-stent size groups (i.e., ≥1 mm2 vs. <1 mm2) but after stimulation by collagen at 10 and 20 µg/ml, platelet reactivity as measured by LTA was significantly higher in the ≥1 mm2 group compared with the <1 mm2 group. No other differences in platelet function were detected. Conclusions Collagen-induced platelet reactivity was related to in-stent tissue protrusion size following CAS.

Current trends in mouse models of glioblastoma.

Glioblastoma is the most deadly brain tumor type and is characterized by a severe and high rate of angiogenesis, remaining an incurable disease in the majority of cases. Mechanistic understanding of glioblastoma initiation and progression is complicated by the complexity of genetic and/or environmental initiating events and lack of clarity regarding the cell or tissue of origin. To determine these mechanisms, mouse models that recapitulate the molecular and histological characteristics of glioblastoma are required. Unlike in other malignancies, viral-mediated mouse models of glioblastoma rather than chemically induced mouse models have been developed because of its sensitivity to viruses. Based on recent molecular analyses reported for human glioblastoma, this review critically evaluates genetically engineered, xenograft, allograft, viral-mediated, and chemically induced mouse models of glioblastoma. Further, we focus on the clinical value of these models by examining their contributions to studies of glioblastoma prevention, tumorigenesis, and chemoresistance.

Surgical Treatment of Complex Cerebral Aneurysms Using Interposition Short Vein Graft.

BACKGROUND AND AIMS: Cerebral revascularization strategies may become necessary in select patients who present with challenging cerebral aneurysms. In this study, we present the techniques of a moderate-flow extra-intracranial bypass using a short interposition vein graft and concurrent aneurysm management. METHODS: The short interposition vein graft was used for the reconstruction of complex cerebral aneurysms in nine patients. In eight of them, the superficial temporal artery (STA) main trunk was used as a donor site for the anastomosis of a short interposition vein graft, and an extracranial vertebral artery (VA) was used in one case. The vein grafts were implanted into the M2 of the middle cerebral artery (MCA) for the adjunctive treatment of internal carotid artery (ICA) aneurysms in three patients, into the A3 of the anterior cerebral artery (ACA) in one patient, into the P2 of the posterior cerebral artery (PCA) for the adjunctive treatment of complex PCA aneurysms in three patients, into the P3 of the PCA for the adjunctive treatment of a basilar artery (BA) trunk giant aneurysm in 1 patient, and into the postero-inferior cerebellar artery (PICA) for the adjunctive treatment of the VA dissecting aneurysm in one patient. RESULTS: All of the bypasses were patent. Intraoperative flow measurements confirmed a moderate flow-carrying capacity of the short interposition short vein graft (30-70 ml; mean: 43 ml/min). CONCLUSION: The STA main trunk to proximal MCA/PCA bypass and the extracranial VA to PICA bypass using short interposition vein grafts can provide sufficient blood flow and may be a reasonable alternative to the conventional EC-IC bypass/high-flow bypass.

Surgical Approach to Ponto-mesencephalic Cavernoma.

BACKGROUND AND AIMS: The surgical treatment of intrinsic brainstem lesions remains a major challenge. In this article we present the results of using an infratentorial-supracerebellar (ITSC) approach for the resection of intrinsic ponto-mesencephalic lesions. MATERIALS AND METHODS: The authors reviewed the cases of 16 patients. In seven of them, a paramedian ITSC transcollicular approach was used to resect intrinsic mid-brain lesions, and in the other nine patients, an intermediate or lateral ITSC infra-trochlear approach was used for ponto-mesencephalic lesions. RESULTS: All 16 lesions were completely removed. There was no recurrence of bleeding during the follow-up period, and no mortality. In seven patients with mid-brain lesions, the preoperative ocular symptoms improved in three of them, and the neurological deficits - other than ocular symptoms improved - in five of them. The preoperative modified Rankin Scale score of 1.8 improved to 1.3 postoperatively. In nine patients with a ponto-mesencephalic lesion, the preoperative ocular symptoms improved in four of nine patients, and the neurological deficits other than ocular symptoms improved in five of them, while one patient exhibited venous infarction in a cerebellar hemisphere that caused neurological deterioration. The preoperative modified Rankin Scale score of 3.75 improved to 2.5 postoperatively in these patients. CONCLUSION: The ITSC transcollicular or infra-trochlear approach provide a wide operative entry zone and minimize the functional damage to the surrounding structures for access to ponto-mesencephalic lesions.

[Effect of an oral anti-estrogen agent (mepitiostane) on the regression of intracranial meningiomas in the elderly].

We report here the regression of meningioma following treatment with the anti-estrogen agent mepitiostane in a series of cases. The first case was that of a 72-year-old woman who presented with coma status due to non-communicating hydrocephalus. A large presumed meningioma within the cerebello-pontine angle was detected on gadolinium-enhanced magnetic resonance imaging (MRI). The patient recovered from the neurological deficit following endoscopic third ventriculostomy treatment, and was administered mepitiostane (10mg/day) orally. Gadolinium-enhanced MRI showed a marked regression (85%) of the meningioma following 60 months of oral medication. The second case was that of a 79-year-old woman with no neurological deficit; however, a presumed meningioma located in the frontal skull base was detected on gadolinium-enhanced MRI. Mepitiostane (10mg/day) was administered orally. Again, a marked regression (88%) of the meningioma was demonstrated after 115 months of oral medication. The third case was that of a 71-year-old woman who presented with right visual disturbance and a visual field defect. Gadolinium-enhanced MRI demonstrated a presumed meningioma located in the left sphenoidal bone. Mepitiostane (20mg/day) was administered orally. An 79% regression of the meningioma was observed after 21 months of oral medication. In these three cases, the marked reduction in meningioma following anti-estrogen agent (mepitiostane) administration suggested that this oral medication could be an effective therapeutic option in elderly patients.

Selection of carotid artery stenting or endarterectomy based on magnetic resonance plaque imaging reduced periprocedural adverse events.

BACKGROUND: The aim of this study was to elucidate the impact of treatment selection, either carotid stenting or endarterectomy, based on preoperative magnetic resonance (MR) plaque imaging on periprocedural events. METHODS: A total of 205 consecutive patients with high-grade carotid artery stenosis scheduled for elective revascularization with stenting or endarterectomy were retrospectively analyzed. In period 1, 95 patients were treated regardless of preoperative plaque imaging. In period 2, 110 patients received time of flight MR angiography, and endarterectomy was selected when a high-intensity signal in the plaque was observed on MR angiography because it indicated an unstable plaque. Periprocedural clinical results and outcome at 30 days were analyzed. RESULTS: In period 1, 5 patients (5.3%) were treated with endarterectomy and the other 90 patients (94.7%) were treated with stenting. In period 2, 35 patients (31.8%) were treated with endarterectomy and the other 75 patients (68.2%) were treated with stenting. Periprocedural adverse events, including any stroke, myocardial infarction, or death, were significantly more frequent in period 1 than in period 2 (9.5% v 1.8%; P = .034). Ischemic stroke was significantly reduced from period 1 to period 2 (7.4% v 0.9%; P = .043). Multivariate logistic regression analysis revealed "treatment selection by plaque imaging" was the only factor identified as an independent predictor of periprocedural events (P = .043). CONCLUSIONS: Treatment selection based on preoperative plaque imaging appears useful for reducing periprocedural events of carotid artery revascularizations.