Contrast-Induced Encephalopathy and the Blood-Brain Barrier.

BACKGROUND: Contrast-induced encephalopathy (CIE) is an adverse event associated with diagnostic and therapeutic endovascular procedures. Decades of animal and human research support a mechanistic role for pathological blood-brain barrier dysfunction (BBBd). Here, we describe an institutional case series and review the literature supporting a mechanistic role for BBBd in CIE. METHODS: A literature review was conducted by searching MEDLINE, Web of Science, Embase, CINAHL and Cochrane databases from inception to January 31, 2022. We searched our institutional neurovascular database for cases of CIE following endovascular treatment of cerebrovascular disease during a 6-month period. Informed consent was obtained in all cases. RESULTS: Review of the literature revealed risk factors for BBBd and CIE, including microvascular disease, pathological neuroinflammation, severe procedural hypertension, iodinated contrast load and altered cerebral blood flow dynamics. In our institutional series, 6 of 52 (11.5%) of patients undergoing therapeutic neuroendovascular procedures developed CIE during the study period. Four patients were treated for ischemic stroke and two patients for recurrent cerebral aneurysms. Mechanical stenting or thrombectomy were utilized in all cases. CONCLUSION: In this institutional case series and literature review of animal and human data, we identified numerous shared risk factors for CIE and BBBd, including microvascular disease, increased procedure length, large contrast volumes, severe intraoperative hypertension and use of mechanical devices that may induce iatrogenic endothelial injury.

The Impact of Resistance Exercise on Muscle Mass in Glioblastoma in Survivors (RESIST): Protocol for a Randomized Controlled Trial.

BACKGROUND: Glioblastoma is the most common primary brain malignancy in adults, accounting for approximately 48% of all brain tumors. Standard treatment includes radiation and temozolomide chemotherapy. Glioblastomas are highly vascular and can cause vasogenic brain edema and mass effect, which can worsen the neurologic symptoms associated with the disease. The steroid dexamethasone (DEX) is the treatment of choice to reduce vasogenic edema and intracranial pressure associated with glioblastoma. However high-dose DEX or long-term use can result in muscle myopathy in 10%-60% of glioblastoma patients, significantly reducing functional fitness and quality of life (QOL). There is a wealth of evidence to support the use of exercise as an adjuvant therapy to improve functional ability as well as help manage treatment-related symptoms. Specifically, resistance training has been shown to increase muscle mass, strength, and functional fitness in aging adults and several cancer populations. Although studies are limited, research has shown that exercise is safe and feasible in glioblastoma populations. However, it is not clear whether resistance training can be successfully used in glioblastoma to prevent or mitigate steroid-induced muscle myopathy and associated loss of function. OBJECTIVE: The primary purpose of this study is to establish whether an individualized circuit-based program will reduce steroid-induced muscle myopathy, as indicated by maintained or improved functional fitness for patients on active treatment and receiving steroids. METHODS: This is a 2-armed, randomized controlled trial with repeated measures. We will recruit 38 adult (≥18 years) patients diagnosed with either primary or secondary glioblastoma who are scheduled to receive standard radiation and concurrent and adjuvant temozolomide chemotherapy postsurgical debulking and received any dose of DEX through the neurooncology clinic and the Nova Scotia Health Cancer Center. Patients will be randomly allocated to a standard of care waitlist control group or standard of care + circuit-based resistance training exercise group. The exercise group will receive a 12-week individualized, group and home-based exercise program. The control group will be advised to maintain an active lifestyle. The primary outcome, muscle myopathy (functional fitness), will be assessed using the Short Physical Performance Battery and hand grip strength. Secondary outcome measures will include body composition, cardiorespiratory fitness, physical activity, QOL, fatigue, and cognitive function. All measures will be assessed pre- and postintervention. Participant accrual, exercise adherence, and safety will be assessed throughout the study. RESULTS: This study has been funded by the Canadian Cancer Society Atlantic Cancer Research Grant and the J.D. Irving Limited-Excellence in Cancer Research Fund (grant number 707182). The protocol was approved by the Nova Scotia Health and Acadia University's Research Ethics Boards. Enrollment is anticipated to begin in March 2022. CONCLUSIONS: This study will inform how individualized circuit-based resistance training may improve functional independence and overall QOL of glioblastoma patients. TRIAL REGISTRATION: ClinicalTrails.gov NCT05116137; https://www.clinicaltrials.gov/ct2/show/NCT05116137. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/37709.

Atypical variants in COL1A1 and COL3A1 associated with classical and vascular Ehlers-Danlos syndrome overlap phenotypes: expanding the clinical phenotype based on additional case reports.

The vast majority of reported (likely) pathogenic missense variants in the genes coding for the fibrillar collagens leads to the substitution of one of the obligatory glycine residues in the Gly-Xaa-Yaa repeat sequence of the triple helical domain. Their phenotypic consequences and deleterious effects have been well-documented. However, with increasing access to molecular diagnostic testing based on next-generation sequencing techniques, such as sequencing of multi-gene panels and whole-exome sequencing, non-glycine substitutions are more frequently identified in individuals suspected to have a heritable collagen disorder, but their pathogenic effect is often difficult to predict.Some specific non-glycine substitutions in the proα1(I)- (p.(Arg312Cys)) and proα1(III)- (glutamic acid to lysine at different positions) collagen chain have been identified in a number of individuals presenting a phenotype showing features of both classical and vascular Ehlers-Danlos syndrome. The number of reported individuals with these defects is currently very low, and several of these non-glycine substitutions had initially been categorised as variants of unknown significance (VUS), complicating early diagnosis, accurate counselling, management guidelines, and correct classification. This collaborative study reports on the phenotype of 22 and 7 individuals harbouring these rare variants in COL1A1 and COL3A1, respectively, expanding our knowledge on clinical presentation, phenotypic variability, and natural history, and informing on the risk for potentially life-threatening events, such as vascular, gastro-intestinal, and pregnancy-related complications.

Raloxifene prevents stress granule dissolution, impairs translational control and promotes cell death during hypoxia in glioblastoma cells.

Glioblastoma (GBM) is the most common primary malignant brain tumor, and it has a uniformly poor prognosis. Hypoxia is a feature of the GBM microenvironment, and previous work has shown that cancer cells residing in hypoxic regions resist treatment. Hypoxia can trigger the formation of stress granules (SGs), sites of mRNA triage that promote cell survival. A screen of 1120 FDA-approved drugs identified 129 candidates that delayed the dissolution of hypoxia-induced SGs following a return to normoxia. Amongst these candidates, the selective estrogen receptor modulator (SERM) raloxifene delayed SG dissolution in a dose-dependent manner. SG dissolution typically occurs by 15 min post-hypoxia, however pre-treatment of immortalized U251 and U3024 primary GBM cells with raloxifene prevented SG dissolution for up to 2 h. During this raloxifene-induced delay in SG dissolution, translational silencing was sustained, eIF2α remained phosphorylated and mTOR remained inactive. Despite its well-described role as a SERM, raloxifene-mediated delay in SG dissolution was unaffected by co-administration of ß-estradiol, nor did ß-estradiol alone have any effect on SGs. Importantly, the combination of raloxifene and hypoxia resulted in increased numbers of late apoptotic/necrotic cells. Raloxifene and hypoxia also demonstrated a block in late autophagy similar to the known autophagy inhibitor chloroquine (CQ). Genetic disruption of the SG-nucleating proteins G3BP1 and G3BP2 revealed that G3BP1 is required to sustain the raloxifene-mediated delay in SG dissolution. Together, these findings indicate that modulating the stress response can be used to exploit the hypoxic niche of GBM tumors, causing cell death by disrupting pro-survival stress responses and control of protein synthesis.

Republished: Competitive flow diversion of multiple P1 aneurysms: proposed classification.

We report the case of a patient with subarachnoid hemorrhage and three aneurysms arising from the posterior communicating artery (Pcomm)-P1 complex, treated with endovascular coiling and competitive flow diversion. The largest and likely ruptured Pcomm aneurysm was treated with traditional coiling. Two smaller potentially ruptured aneurysms arose from the distal right posterior cerebral artery (PCA) P1 segment. After a failed attempt to treat with conventional flow diversion across the PCA-P1 segment, the P1 aneurysms were successfully treated with competitive flow diversion distal to the PCA-P1 segment from Pcomm to the P2 segment. Over 12 months, competitive flow diversion redirected flow to the right PCA territory via the internal carotid artery-Pcomm-P2, reducing the size of the PCA-P1 segment and obliterating the P1 aneurysms. Competitive flow diversion treatment should be considered for aneurysms occurring at the circle of Willis when traditional methods are not feasible. Herein, we introduce a novel classification for competitive flow diversion treatment.

Competitive flow diversion of multiple P1 aneurysms: proposed classification.

We report the case of a patient with subarachnoid hemorrhage and three aneurysms arising from the posterior communicating artery (Pcomm)-P1 complex, treated with endovascular coiling and competitive flow diversion. The largest and likely ruptured Pcomm aneurysm was treated with traditional coiling. Two smaller potentially ruptured aneurysms arose from the distal right posterior cerebral artery (PCA) P1 segment. After a failed attempt to treat with conventional flow diversion across the PCA-P1 segment, the P1 aneurysms were successfully treated with competitive flow diversion distal to the PCA-P1 segment from Pcomm to the P2 segment. Over 12 months, competitive flow diversion redirected flow to the right PCA territory via the internal carotid artery-Pcomm-P2, reducing the size of the PCA-P1 segment and obliterating the P1 aneurysms. Competitive flow diversion treatment should be considered for aneurysms occurring at the circle of Willis when traditional methods are not feasible. Herein, we introduce a novel classification for competitive flow diversion treatment.

Cardiogenic Shock in a Healthy Young Woman With Acute Onset Abdominal and Chest Pain.

Takotsubo cardiomyopathy is a relatively common yet poorly understood entity that predominantly affects women. This report presents a case of a spinal cord bleeding that triggered an atypical variant of Takotsubo cardiomyopathy and led to cardiogenic shock. (Level of Difficulty: Intermediate.).

Scalp Seeding Post Craniotomy and Radiosurgery for Solitary Brain Metastasis: A Case Report and Systematic Review.

BACKGROUND: Radiosurgery is being increasingly used post craniotomy for brain metastasis, instead of whole-brain radiation. We report a case of scalp metastasis following craniotomy and radiosurgery, along with a systematic review of the literature. METHODS: Our patient was a 70-year-old male who presented with a scalp metastasis, two years after craniotomy and radiosurgery, for a solitary brain metastasis from esophageal carcinoma. Using Medline® (United States National Library of Medicine, Bethesda, MD), we performed a systematic review of the literature to identify cases of isolated scalp metastases following craniotomy for brain lesions. RESULTS: The scalp metastasis was in close proximity to the craniotomy site. Workup did not show any other site of active disease. Biopsy confirmed it to be a metastasis from esophageal carcinoma. The literature review did not yield any case of isolated scalp metastasis following craniotomy and whole-brain radiotherapy or radiosurgery. However, it yielded six cases of isolated scalp metastases following craniotomy for primary brain tumors. CONCLUSION: Isolated scalp metastasis has not been reported following craniotomy and whole-brain radiotherapy for brain metastases. Our patient likely had surgical seeding during craniotomy. These surgically implanted cells could not be ablated because the radiosurgery treatment volume does not cover the surgical tract. Further research is needed to identify risk factors for surgical seeding.

Epithelial Cell Transforming 2 and Aurora Kinase B Modulate Formation of Stress Granule-Containing Transcripts from Diverse Cellular Pathways in Astrocytoma Cells.

Stress granules are small RNA-protein granules that modify the translational landscape during cellular stress to promote survival. The RhoGTPase RhoA is implicated in the formation of RNA stress granules. Our data demonstrate that the cytokinetic proteins epithelial cell transforming 2 and Aurora kinase B (AurkB) are localized to stress granules in human astrocytoma cells. AurkB and its downstream target histone-3 are phosphorylated during arsenite-induced stress. Chemical (AZD1152-HQPA) and siRNA inhibition of AurkB results in fewer and smaller stress granules when analyzed using high-throughput fluorescent-based cellomics assays. RNA immunoprecipitation with the known stress granule aggregates TIAR and G3BP1 was performed on astrocytoma cells, and subsequent analysis revealed that astrocytoma stress granules harbor unique mRNAs for various cellular pathways, including cellular migration, metabolism, translation, and transcriptional regulation. Human astrocytoma cell stress granules contain mRNAs that are known to be involved in glioma signaling and the mammalian target of rapamycin pathway. These data provide evidence that RNA stress granules are a novel form of epigenetic regulation in astrocytoma cells, which may be targetable by chemical inhibitors and enhance astrocytoma susceptibility to conventional therapy, such as radiation and chemotherapy.

ECT2 and RASAL2 mediate mesenchymal-amoeboid transition in human astrocytoma cells.

Malignant astrocytomas are highly invasive brain tumors. The Rho family of cytoskeletal GTPases are key regulators of astrocytoma migration and invasion; expression of the guanine nucleotide exchange factor ECT2 is elevated in primary astrocytomas and predicts both survival and malignancy. Mice bearing orthotopically implanted astrocytoma cells with diminished ECT2 levels following ECT2 knockdown exhibit longer survival. Although ECT2 is normally expressed in the nucleus, we show that ECT2 is aberrantly localized to the cytoplasm in both astrocytoma cell lines and primary human astrocytomas, and colocalizes with RAC1 and CDC42 at the leading edge of migrating astrocytoma cells. Inhibition of ECT2 expression by RNA interference resulted in decreased RAC1 and CDC42 activity, but no change in RHO activity, suggesting that ECT2 is capable of activating these pro-migratory Rho family members. ECT2 overexpression in astrocytoma cells resulted in a transition to an amoeboid phenotype that was abolished with the ROCK inhibitor, Y-27632. Cytoplasmic fractionation of astrocytoma cells followed by ECT2 immunoprecipitation and mass spectrometry were used to identify protein-binding partners that modulate the activity of ECT2 toward RAC1 and RHO/ROCK. We identified RASAL2 as an ECT2-interacting protein that regulates RHO activity in astrocytoma cells. RASAL2 knockdown leads to a conversion to an amoeboid phenotype. Our studies reveal that ECT2 has a novel role in mesenchymal-amoeboid transition in human astrocytoma cells.

Overexpression of CD99 Increases the Migration and Invasiveness of Human Malignant Glioma Cells.

The malignant glioma is the most common primary human brain tumor, and its migration and invasiveness away from the primary tumor mass are considered a leading cause of tumor recurrence and treatment failure. Recently, gene expression profiling revealed that the transmembrane glycoprotein CD99 is more highly expressed in malignant glioma than in normal brain. Although its function is not completely understood, CD99 is implicated in cell adhesion and migration in a variety of different cell types. CD99 has wild-type and splice variant isoforms. Previous studies have shown that wild-type CD99 may be an oncosuppressor in some tumors, distinct from the role of the splice variant isoform. In this study, our data reveal that only wild-type CD99 is expressed in human glioma cells and tissues. Using a tissue microarray, we validated that gliomas demonstrate higher expression of CD99 compared with nonneoplastic brain. To assess the role of CD99 in glioma migration and invasion, we inhibited CD99 expression by siRNA and demonstrated decreased glioma migration and invasion. In contrast, when CD99 was overexpressed in glioma cells, we observed enhancement of cell migration and invasiveness. An orthotopic brain tumor model demonstrates that CD99 overexpression significantly increases invasiveness and decreases survival rate. Interestingly, Rac activity was decreased and Rho activity was increased in CD99 overexpressing glioma cells, and the proportion of amoeboid cells to mesenchymal cells was significantly increased. Taken together, our findings suggest that CD99 may play an important role in the migration and invasion of human gliomas independent of Akt, ERK, or JNK signaling pathways. Moreover, CD99 might be involved in amoeboid-mesenchymal transition in glioma migration. CD99 may be an important future target to inhibit migration and invasion, especially in CD99-expressing gliomas.

Role of the cofilin activity cycle in astrocytoma migration and invasion.

The cofilin pathway plays a central role in the regulation of actin polymerization and the formation of cell membrane protrusions that are essential for cell migration. Overexpression of cofilin has been linked to the aggressiveness of a variety of different cancers. In these cancers, the phosphorylation of cofilin at Ser3 is a key regulatory mechanism modulating cofilin activity. The activation status of cofilin has been directly linked to tumor invasion. Accordingly, in this study, we examined the expression of cofilin and its activation status in astrocytoma cell lines and astrocytic tumors. We show that cofilin expression was increased and correlated with increasing grade malignant astrocytoma. In addition, both cofilin and LIMK had elevated expression in astrocytoma cell lines. Knockdown of cofilin by siRNA altered astrocytoma cell morphology and inhibited astrocytoma migration and invasion. Conversely, overexpression of a cofilin phosphorylation mutant in an in vivo intracranial xenograft model resulted in a more highly invasive phenotype than those xenographs expressing wild-type cofilin. Animals harboring astrocytomas stably expressing the cofilin phosphorylation mutant (cofilin-S3A) demonstrated marked local invasiveness and spread across the corpus callosum to the contralateral hemisphere in all animals. Taken together, these data indicate that the cofilin activity pathway may represent a novel therapeutic target to diminish the invasion of these highly malignant tumors.

The evolution and application of techniques in molecular biology to human brain tumors: a 25 year perspective.

Since the establishment of the AANS/CNS Section on Tumors in 1984, neurosurgeons have been actively involved in basic science research of human brain tumors that has moved the field forward considerably. Here, we chronicle the major advances that have been made with respect to our understanding of the concepts guiding the biology of human malignant brain tumors. Numerous technical advances in science, such as the development of gene transfer techniques, the polymerase chain reaction, the discovery of oncogenes and tumor suppressor genes, and the refinement of approaches to cancer cytogenetics have enabled researchers to identify many of the non-random genetic alterations associated with brain tumor growth, invasion, immunology, angiogenesis and apoptosis. These data led to some astounding progress, for example with the use of gene therapy, whereby in the 1990s several human clinical trials were conducted for patients with brain tumors. More recently, the human genome project has been completed providing a blueprint for the human species. What has followed are exciting new techniques in molecular biology such as transcriptional profiling, single nucleotide polymorphism (SNP)-arrays, array comparative genomic hybridization (array-CGH), microRNA profiling, and detection of epigenetic silencing of tumor suppressor genes. The cancer genome is now being sequenced at break neck speed using advanced DNA sequencing techniques. We are on the threshold of cataloguing the major genetic alterations observed in all human brain tumors. What will follow is modeling of these genetic alterations in systems that will allow for the development of novel pharmacotherapeutics and translational research therapies.