Search

Chiari Malformation Type I (CMI) is a congenital malformation diagnosed by MRI findings of at least 5 mm of cerebellar ectopy below the foramen magnum. CM1 is frequently associated with syringomyelia. Herein, we discuss the history of CMI and syringomyelia, including early pathological and surgical studies. We also describe recent investigations into the pathogenesis and pathophysiology of CMI and their practical implications on management and surgical intervention. We also highlight the recent development of the Common Data Elements for CMI, providing a framework for ongoing investigations. Finally, we discuss current controversies of surgical management in CMI.

Background Glioblastoma survival remains unchanged despite continuing therapeutic innovation. Herein, we aim to (i) develop chimeric antigen receptor (CAR) T cells with a specificity to a unique antigen, carbonic anhydrase IX (CAIX), which is expressed in the hypoxic microenvironment characteristic of glioblastoma, and (ii) demonstrate its efficacy with limited off-target effects. Methods First we demonstrated expression of CAIX in patient-derived glioblastoma samples and available databases. CAR T cells were generated against CAIX and efficacy was assessed in 4 glioblastoma cell lines and 2 glioblastoma stem cell lines. Cytotoxicity of anti-CAIX CAR T cells was assessed via interferon gamma, tumor necrosis factor alpha, and interleukin-2 levels when co-cultured with tumor cells. Finally, we assessed efficacy of direct intratumoral injection of the anti-CAIX CAR T cells on an in vivo xenograft mouse model using the U251 luciferase cell line. Tumor infiltrating lymphocyte analyses were performed. Results We confirm that CAIX is highly expressed in glioblastoma from patients. We demonstrate that CAIX is a suitable target for CAR T-cell therapy using anti-CAIX CAR T cells against glioblastoma in vitro and in vivo. In our mouse model, a 20% cure rate was observed without detectable systemic effects. Conclusions By establishing the specificity of CAIX under hypoxic conditions in glioblastoma and highlighting its efficacy as a target for CAR T-cell therapy, our data suggest that anti-CAIX CAR T may be a promising strategy to treat glioblastoma. Direct intratumoral injection increases anti-CAIX CAR T-cell potency while limiting its off-target effects.

Previously we identified the p.Thr61Ile mutation in coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) in a Chinese family with autosomal dominant Parkinson’s disease. But the mechanism is still unclear. In this study, we explored the effects of CHCHD2 p.Thr61Ile mutation in cells and its association with coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10). We found that overexpression of Parkinson’s disease–associated T61I mutant CHCHD2 did not produce mitochondrial dysfunction. Rather, its protective effect from stress was abrogated. And, the level of the CHCHD2 protein and mRNA in patient fibroblasts was not significantly different from control. In addition, CHCHD2 T61I mutation caused increased interaction with CHCHD10 and reduced CHCHD10 level. The mitochondrial ultrastructural alterations in CHCHD2 T61I mutant patient fibroblasts are similar to that of CHCHD10 mutations. We therefore propose that CHCHD10 is involved in the development of Parkinson’s disease caused by CHCHD2 loss-of-function mutation p.T61I.

The inner ear is a complex organ housed within the petrous bone of the skull. Its intimate relationship with the brain enables the transmission of auditory and vestibular signals via cranial nerves. Development of this structure from neural crest begins in utero and continues into early adulthood. However, the anatomy of the murine inner ear has only been well-characterized from early embryogenesis to post-natal day 6. Inner ear and skull base development continue into the post-natal period in mice and early adulthood in humans. Traditional methods used to evaluate the inner ear in animal models, such as histologic sectioning or paint-fill and corrosion, cannot visualize this complex anatomy in situ. Further, as the petrous bone ossifies in the postnatal period, these traditional techniques become increasingly difficult. Advances in modern imaging, including high resolution Micro-CT and MRI, now allow for 3D visualization of the in situ anatomy of organs such as the inner ear. Here, we present a longitudinal atlas of the murine inner ear using high resolution ex vivo Micro-CT and MRI.

BACKGROUND AND PURPOSE: A new transtentorial venous system consisting of medial, intermediate, and lateral tentorial veins, connecting infra- and supratentorial compartments, was recently shown in 2 cadaver dissections and 2 patient scans. We sought to characterize the venous patterns within the tentorium and their relation to measures of skull development in a cohort of healthy adults. MATERIALS AND METHODS: We retrospectively reviewed tentorial venous anatomy of the head using CTA/CTV performed for routine care or research purposes in 238 patients. Included studies had adequate contrast opacification of venous structures and a section thickness of ≤2 mm; we excluded cases with space-occupying lesions and vascular pathologies. Tentorial angle, dural sinus configurations, and measures of skull base development were assessed as predictors of tentorial venous anatomy variation via Cramér V association, the binary encoded Pearson correlation, and nearest-point algorithm with the Euclidean distance metric for clustering. RESULTS: Tentorial vein development was related to the ringed configuration of the tentorial sinuses (P

Atypical teratoid rhabdoid tumor (ATRT) is a pediatric brain tumor with a high mortality rate characterized by mutations in/ deletions of SWI/SNF matrix-associated actin-dependent regulator of chromatin sub-family B member 1 (SMARCB1). We previously showed that loss of SMARCB1 causes up-regulation and release of HML-2 subfamily of human endogenous retrovirus K envelope protein (HML-2 ENV), resulting in maintenance of pluripotency. Here, we investigated intracellular trafficking and release of HML-2 ENV. Further, we demonstrate two potential therapeutic strategies to decrease intracellular HML-2 ENV: 1) inhibition of calcium influx by ouabain, a cardiac glycoside toxic to neural stem cells, and 2) targeted inhibition of cyclin-dependent kinase 5 (CDK5), which is restricted to neurons by p35, its activator protein, by TP5. ATRT cell lines and tumor tissue obtained from patients were confirmed for SMARCB1 loss and increased HML-2 ENV. Cell viability and intracellular HML-2 ENV concentration were measured after treatment with ouabain and TP5 (CDK5 antagonist). We evaluated the calcium-mediated effect of ouabain on HML-2 intracellular concentration by treating the cells with ouabain, the calcium chelators calcimycin and EGTA, and calpeptin, a calpain inhibitor, which activates CDK5, and measuring HML-2 ENV and p35. We evaluated HML-2 ENV for a CDK5 consensus phosphorylation site and performed co-immunoprecipitation to evaluate direct interaction. We evaluated activity of CDK5 in ATRT cell lines by autoradiography. Both Ouabain and TP5 caused a decrease in cell viability in a dose-dependent manner. Further, ouabain treatment decreased HML-2 ENV intracellular concentration. We found that HML-2 ENV contains a consensus phosphorylation site for CDK5. We discovered that HML-2 ENV was bound to CDK5. We established that ATRT cell lines had hyperactive CDK5. Finally, we established that the effect of ouabain on HML-2 ENV was due to indirect inhibition of calcium-mediated activation of calpain and thus CDK5.

Background Described variations of tentorial venous anatomy impact surgical sectioning of the tentorium in skull base approaches; however, described configurations do not consistently explain postoperative complications. To understand the outcomes of 2 clinical cases we studied the tentorial venous anatomy of 2 cadavers. Methods The venous anatomy of the tentorium isolated in 2 uninjected fresh cadaver head specimens with preserved bridging veins was observed by transillumination before and after methylene blue injection of the dural sinuses and tentorial veins. Our findings in cadavers were applied to explain the clinical and radiologic (magnetic resonance imaging and computed tomographic venography) findings in the 2 cases presented. Results A consistent transtentorial venous system, arising from transverse and straight sinuses, communicating with supra- and infratentorial bridging veins was seen in the cadaver and patient radiography (magnetic resonance imaging and computed tomographic venography). Our first patient had a cerebellar venous infarct from compromise of the venous drainage from the adjacent brain after ligation of a temporal lobe bridging vein to the tentorium. Our second patient suffered no clinical effects from bilateral transverse sinus occlusion due to drainage through the accessory venous system within the tentorium. Conclusions Herein, we elaborate on transtentorial venous anatomy. These veins, previously reported to obliterate in completed development of the tentorium, remain patent with consistent observed configuration. The same transtentorial venous system was observed in both cases and provided insight to their outcomes. These findings emphasize the importance of the transtentorial venous system physiologically and in surgical approaches.

Background Hypertrophic olivary degeneration (HOD) is a rare phenomenon in the dento-rubro-olivary pathway caused by lesion or disruption of the fibers of the Guillain-Mollaret triangle. Hemorrhage of pontine and midbrain cavernous angiomas can rarely lead to HOD portending neurologic deterioration and possible concomitant life-threatening complications; for this reason, it may define a poignant consideration in planning intervention. Case Description The patient was a 57-year-old woman with known midbrain-pontine cavernous angioma. For several years, the lesion had been stable, as shown by imaging follow-up, until 10 months before the patient presented with falls, dysarthria, and headache. Imaging showed some decrease in size as well as blood product around the cavernous angioma, suggesting interim period hemorrhage and interval development of HOD. Conclusions The literature regarding imaging recommendations for stable cavernous angioma in the midbrain-pontine junction is reviewed. The implication of HOD for patient outcome is discussed and a comment is made on how the development of HOD may affect management of the cavernous angioma.

Patients with von Hippel Lindau (VHL) disease develop multiple central nervous system hemangioblastomas (HB). The surgical resection of VHL-HBs is the standard of clinical care when these HBs become symptomatic due to tumor growth, edema, or cyst formation. VHL-HBs frequently present at the obex of the brainstem, making this a challenging surgical problem. Here, we present a case of a large symptomatic brainstem VHL-HB that was resected using a dorsal midline approach and midline myelotomy. This 35-year-old man with VHL disease and multiple prior resections of cerebellar hemangioblastomas presented with progressive bilateral upper extremity weakness, ataxia, and dysphagia. The accompanying two-dimensional (2D) video demonstrates the key techniques for resection of this brainstem hemangioblastoma, including recognizing the pial presentation, sharp pial/subpial dissection, and en bloc removal. Subsequently, we discuss circumferential dissection, identification, and division of feeding vessels. We also demonstrate key maneuvers to recognize and divide the main arterial pedicle while preserving the anterior spinal artery. The patient tolerated the resection without complication and the patient was discharged home after 6 days at his baseline neurologic function. This work was supported by the Intramural Research Program of the National Institutes of Health.The link to the video can be found at: https://youtu.be/mb2VqcLpxDQ.

BACKGROUND: The need for novel therapies for GBM treatment is well established. While chimeric antigen receptor (CAR)-engineered T cells represent a promising cancer treatment modality, highly expressed unique cell surface antigens are essential. We postulated that tumor-specific surface antigens related to hypoxia signaling may have potential. Carbonic Anhydrase IX (CAIX) is active in settings of unbalanced pH driving proton transport to the extracellular medium in response to decreased oxygen tension. We provide evidence that CAIX is highly expressed in GBM and thus a potentially suitable target which we investigated using CAIX-specific CAR-T cells against GBM cells. METHODS: Patient GBM tissues were evaluated for CAIX protein expression. Antitumor CAIX-specific CAR T cells were developed and tested against four GBM cell lines: U251, LN 229, T98G, and A172. Cytotoxicity of CAIX CAR-T cells was assessed using the levels of IFN-γ, TNF-α, and IL-2 released when co-cultured with tumor cells. Direct intra-tumor injection of CAR-T cells into intracranial GBM xenograft mouse model was used for in vivo testing. RESULTS: We confirmed high expression of CAIX in of human GBM. The viral construct of CAIX-specific CAR-T cells generated was tested against GBM cell lines. In vitro, CAIX-specific CAR-T cells displayed enhanced GBM cells cytolysis and increased IFN-γ, TNF-α, and IL-2 production. The CAR-T cells showed a specific CAIX-dependent recognition of GBM cells. Direct intra-tumor injection of the CAR-T cells into an intracranial GBM xenograft mouse model efficiently suppressed the growth of GBM cells and significantly prolonged mouse survival. In approximately 20%, CAIX specific CAR-T cells completely eradicated GBM tumors. CONCLUSIONS: The present study demonstrates the specificity of CAIX under hypoxic conditions in GBM. The results also show that CAIX represents a viable target for CAR-T cells and may be a promising strategy to treat GBM.