Vanishing hyperintensity in MRI: Vascular or epileptic origin?

Status Epilepticus and epilepsy-related MRI vanishing changes have been reported in the literature since the 1980s; hypoxia and hypoperfusion have been related to these image modifications. These alterations and their disappearing characteristics can cause trouble among work up and their diagnosis, especially if there is no exact etiology of what is causing seizures. We present a case of a 37-year-old righthanded man with a 6-year history followed up after seizure debut, with no exact etiology at the first event, considering an ischemic event as etiology. After a six-year follow-up seizure-free and no sequels, the patient newly developed aphasia, seizures, and status epilepticus, with a now evident vascular abnormality (cavernous cerebral malformation) etiology in MRI imaging. The cumbersomeness of the clinical picture in its presentation, the seriousness to which it reached, and the complete resolution of the problem with medical treatment make this clinical case especially attractive.

Uncovering a Key Role of ETS1 on Vascular Abnormality in Glioblastoma

Glioblastoma (GBM) is the most aggressive type of brain tumor. Microvascular proliferation and abnormal vasculature are the hallmarks of the GBM, aggravating disease progression and increasing patient morbidity. Here, we uncovered a key role of ETS1 on vascular abnormality in glioblastoma. ETS1 was upregulated in endothelial cells from human tumors compared to endothelial cells from paired control brain tissue. Knockdown of Ets1 in mouse brain endothelial cells inhibited cell migration and proliferation, and suppressed expression of genes associated with vascular abnormality in GBM. ETS1 upregulation in tumor ECs was dependent on TGFβ signaling, and targeting TGFβ signaling by inhibitor decreased tumor angiogenesis and vascular abnormality in CT-2A glioma model. Our results identified ETS1 as a key factor regulating tumor angiogenesis, and suggested that TGFβ inhibition may suppress the vascular abnormality driven by ETS1.

Aortic arch uncrossing using a tracheal resection procedure

One category of vascular rings is the right aortic arch associated with the diverticulum of Kommerell from which the left subclavian artery usually originates. In some cases, the right aortic arch crosses behind the trachea and the esophagus from right to left. The trachea and esophagus are compressed by the right aortic arch, the left ligamentum, and the posterior crossing aorta, which causes the typical symptoms of noisy breathing, dyspnea on exertion, dysphagia, and frequent upper respiratory tract infections. Division of the atretic arch segment between the diverticulum of Kommerell and the left common carotid artery may relieve the symptoms temporarily but does not relieve the compression produced by this vascular abnormality. Indeed, at the age of 10 months, this patient underwent anterior arch division and posterior aortopexy via a posterolateral thoracotomy in order to relieve the compression caused by the vascular ring. Several months after the initial operation, the patient had recurrent respiratory symptoms as a result of residual vascular compression from the circumflex arch. A CT scan and airway endoscopy confirmed tracheal compression; in addition, the tracheoscopy showed tracheomalacic changes in the compressed segment of the trachea. To relieve the symptoms and the compression, we decided to resect the tracheomalacic segment of the trachea and translocate the aortic arch anterior to the trachea and esophagus.

Treatment of an Elusive Symptomatic Sinus Pericranii: Case Report and Review of the Literature

Sinus pericranii (SP) are abnormal vascular connections between extracranial scalp venous channels and intracranial dural sinuses. This vascular abnormality rarely results in significant sequelae, but in select cases, it can be symptomatic. We describe the case of a 7-year-old girl with an SP who experienced intermittent visual, motor, and sensory symptoms not previously described in the literature. Her symptoms resolved after surgical treatment of the SP. We propose a mechanism for her symptoms and the rationale for the role of neurosurgical intervention along with a review of the literature.

EXTH-37. PAK4 INHIBITION REPROGRAMS VASCULAR MICROENVIRONMENT AND IMPROVES CAR T IMMUNOTHERAPY IN GLIOBLASTOMA

Malignant solid tumors are characterized by aberrant vascularity that inhibits T cell adhesion to vasculature and impedes T cell delivery into the tumors, contributing to glioblastoma (GBM) resistance to T cell-based immunotherapy such as adoptive chimeric antigen receptor (CAR)–T transfer. Vascular abnormality is driven by pro-angiogenic pathway activation and genetic reprogramming in tumor endothelial cells (ECs). Here, our kinome-wide functional screening of mesenchymal-like transcriptional activation in human GBM-derived ECs identifies p21-activated kinase 4 (PAK4) as a selective regulator of genetic programming and aberrant vascularization in tumor. Genetic ablation of PAK4 reprograms EC transcriptome and inhibits mesenchymal-like transformation. Interestingly, deficiency of PAK4 induces adhesion protein re-expression in tumor ECs, reduces vascular abnormalities in tumors, improves T cell infiltration into the tumors, and inhibits GBM growth in mice. Moreover, pharmacological PAK4 inhibition normalizes the tumor vascular microenvironment and sensitizes GBM to Egfrviii CAR–T cell immunotherapy. Finally, we reveal a MEF2D/ZEB1- and SLUG-mediated mechanism by which PAK4 reprograms the EC transcriptome and downregulates claudin-14 and VCAM-1 expression, enhancing vessel permeability and reducing T cell adhesion to the endothelium. Thus, targeting PAK4-mediated EC plasticity may offer exciting opportunities to recondition the vascular microenvironment and strengthen cancer immunotherapy.

Renal arteriovenous malformation and venous thrombosis: a tumour-like presentation

Renal arteriovenous malformation is a primarily congenital renal vascular abnormality. It is usually diagnosed incidentally on imaging, and the most common subtype is ‘cirsoid’, consisting of multiple, enlarged arterial feeders interconnecting with draining veins. We present a 74-year-old woman with an incidental finding of what was at first considered a hypervascularised kidney tumour but turned out to be a left intrarenal arteriovenous malformation associated with a left renal vein thrombosis. Selective endovascular embolisation was performed. The cause-consequence relationship between the arteriovenous malformation and the thrombosis is unique. To our knowledge, no such case has ever been reported.

Role of RNF213 polymorphism in defining quasi-moyamoya disease and definitive moyamoya disease

OBJECTIVE Quasi-moyamoya disease (QMMD) is moyamoya disease (MMD) associated with additional underlying diseases. Although the ring finger protein 213 (RNF213) c.14576G>A mutation is highly correlated with MMD in the Asian population, its relationship to QMMD is unclear. Therefore, in this study the authors sought to investigate the RNF213 c.14576G>A mutation in the genetic diagnosis and classification of QMMD. METHODS This case-control study was conducted among four core hospitals. A screening system for the RNF213 c.14576G>A mutation based on high-resolution melting curve analysis was designed. The prevalence of RNF213 c.14576G>A was investigated in 76 patients with MMD and 10 patients with QMMD. RESULTS There were no significant differences in age, sex, family history, and mode of onset between the two groups. Underlying diseases presenting in patients with QMMD were hyperthyroidism (n = 6), neurofibromatosis type 1 (n = 2), Sjögren’s syndrome (n = 1), and meningitis (n =1). The RNF213 c.14576G>A mutation was found in 64 patients (84.2%) with MMD and 8 patients (80%) with QMMD; no significant difference in mutation frequency was observed between cohorts. CONCLUSIONS There are two forms of QMMD, one in which the vascular abnormality is associated with an underlying disease, and the other in which MMD is coincidentally complicated by an unrelated underlying disease. It has been suggested that the presence or absence of the RNF213 c.14576G>A mutation may be useful in distinguishing between these disease types.

Neurovascular imaging with QUTE-CE MRI in APOE4 rats reveals early vascular abnormalities

Cerebrovascular abnormality is linked to Alzheimer’s disease and related dementias (ADRDs). ApoE-Ɛ4 (APOE4) is known to play a critical role in neurovascular dysfunction, however current medical imaging technologies are limited in quantification. This cross-sectional study tested the feasibility of a recently established imaging modality, quantitative ultra-short time-to-echo contrast-enhanced magnetic resonance imaging (QUTE-CE MRI), to identify small vessel abnormality early in development of human APOE4 knock-in female rat (TGRA8960) animal model. At 8 months, 48.3% of the brain volume was found to have significant signal increase (75/173 anatomically segmented regions; q<0.05 for multiple comparisons). Notably, vascular abnormality was detected in the tri-synaptic circuit, cerebellum, and amygdala, all of which are known to functionally decline throughout AD pathology and have implications in learning and memory. The detected abnormality quantified with QUTE-CE MRI is likely a result of hyper-vascularization, but may also be partly, or wholly, due to contributions from blood-brain-barrier leakage. Further exploration with histological validation is warranted to verify the pathological cause. Regardless, these results indicate that QUTE-CE MRI can detect neurovascular dysfunction with high sensitivity with APOE4 and may be helpful to provide new insights into health and disease.

ELTD1-deletion reduces vascular abnormality and improves T-cell recruitment after PD-1 blockade in glioma

Background Tumor vessels in glioma are molecularly and functionally abnormal, contributing to treatment resistance. Proteins differentially expressed in glioma vessels can change vessel phenotype and be targeted for therapy. ELTD1 (Adgrl4) is an orphan member of the adhesion G-protein-coupled receptor family upregulated in glioma vessels, and has been suggested as a potential therapeutic target. However, the role of ELTD1 in regulating vessel function in glioblastoma is poorly understood. Methods ELTD1 expression in human gliomas and its association with patient survival was determined using tissue microarrays and public databases. The role of ELTD1 in regulating tumor vessel phenotype was analyzed using orthotopic glioma models and ELTD1 -/- mice. Endothelial cells isolated from murine gliomas were transcriptionally profiled to determine differentially expressed genes and pathways. The consequence of ELTD1-deletion on glioma immunity was determined by treating tumor bearing mice with PD-1-blocking antibodies. Results ELTD1 levels were upregulated in human glioma vessels, increased with tumor malignancy, and were associated with poor patient survival. Progression of orthotopic gliomas was not affected by ELTD1-deletion, however, tumor vascular function was improved in ELTD1 -/- mice. Bioinformatic analysis of differentially expressed genes indicated increased inflammatory response and decreased proliferation in tumor endothelium in ELTD1 -/- mice. Consistent with an enhanced inflammatory response, ELTD1-deletion improved T-cell infiltration in GL261-bearing mice after PD-1 checkpoint blockade. Conclusion Our data demonstrate that ELTD1 participates in inducing vascular dysfunction in glioma, and suggests that targeting of ELTD1 may normalize the vessels and improve the response to immunotherapy.