Vertebral Artery Mobilization During Transcondylar Extreme Far Lateral Approach for Excision of Large Foramen Magnum Meningioma: 2-Dimensional Operative Video.

Foramen magnum meningiomas are challenging lesions owing to their proximity to the lower brainstem, vertebrobasilar system, and lower cranial nerves.1,2 Tumor size, origin, morphology, relationship to neurovascular structures, and bony anatomy determine the optimal surgical approach.2,3 Classically, far lateral approaches have been the workhorse approach to the foramen magnum. Variations of the far lateral including transcondylar and extended transcondylar (paracondylar), with or without transposition of the vertebral artery, are sometimes used for a more lateral approach to the brainstem and clivus. Here, we present a 60-year-old male patient presenting with a large foramen magnum meningioma. Preoperative workup includes computed tomography and MRI with angiography to assess for posterior circulation dominance, anatomic variants including posterior inferior cerebellar artery origin, venous, and bony anatomy.1,4 An extreme far lateral provides access anterior to the vertebral artery to extend exposure beyond the standard far lateral approach. This comprised transcondylar drilling, bony mobilization of the V3 Vertebral artery from C1 foramen transversarium, and dural mobilization of vertebral artery with a dural cuff at its site of dural entry. The patient tolerated the procedure, gross total resection was achieved, and the patient was discharged home. This video demonstrates in detail the steps of exposure, condylar drilling, vertebral artery transposition, and dural opening. These maneuvers can be difficult to conceptualize yet are key to successful extended transcondylar exposure. The patient gave informed consent for surgery and video recording. Institutional Review Board approval was deemed unnecessary.

Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells.

Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. In this study, we investigated functional drivers of post-treatment recurrent GBM through integrative genomic analyses, genome-wide genetic perturbation screens in patient-derived GBM models and independent lines of validation. Specific genetic dependencies were found consistent across recurrent tumor models, accompanied by increased mutational burden and differential transcript and protein expression compared to its primary GBM predecessor. Our observations suggest a multi-layered genetic response to drive tumor recurrence and implicate PTP4A2 (protein tyrosine phosphatase 4A2) as a modulator of self-renewal, proliferation and tumorigenicity in recurrent GBM. Genetic perturbation or small-molecule inhibition of PTP4A2 acts through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1) and its downstream molecular players, exploiting a functional dependency on ROBO signaling. Because a pan-PTP4A inhibitor was limited by poor penetrance across the blood-brain barrier in vivo, we engineered a second-generation chimeric antigen receptor (CAR) T cell therapy against ROBO1, a cell surface receptor enriched across recurrent GBM specimens. A single dose of ROBO1-targeted CAR T cells doubled median survival in cell-line-derived xenograft (CDX) models of recurrent GBM. Moreover, in CDX models of adult lung-to-brain metastases and pediatric relapsed medulloblastoma, ROBO1 CAR T cells eradicated tumors in 50-100% of mice. Our study identifies a promising multi-targetable PTP4A-ROBO1 signaling axis that drives tumorigenicity in recurrent GBM, with potential in other malignant brain tumors.

T2 mapping magnetic resonance imaging of cartilage in hemophilia.

Background: In hemophilia, recurrent hemarthrosis may lead to irreversible arthropathy. T2 mapping MRI may reflect cartilage changes at an earlier reversible stage of arthropathy as opposed to structural MRI. Objectives: To evaluate interval changes of T2 mapping compared with the International Prophylaxis Study Group (IPSG) structural MRI scores of ankle cartilage in boys with hemophilia receiving prophylaxis. Methods: Eight boys with hemophilia A (median age, 13; range, 9-17 years), 7 age- and sex-matched healthy boys (controls, median age, 15; range, 7-16 years). A multiecho spin-echo T2-weighted MRI sequence at 3.0T was used to obtain T2 maps of cartilage of boys with hemophilia and controls. Structural joint status was evaluated using the IPSG MRI score. Results: T2 relaxation times of ankle cartilage increased significantly over time in both persons with hemophilia and controls (P = .002 and P = .00009, respectively). Changes in T2 relaxation time strongly correlated with changes in IPSG cartilage scores (rs = 0.93 to rs = 0.78 [P = .0007 to P = .023]), but not with changes in age (P = .304 to P = .840). Responsiveness of T2 relaxation times were higher than that of IPSG cartilage scores, with standardized response means >1.4 for T2 mapping in all regions-of-interest compared with 0.84 for IPSG cartilage scores. Baseline T2 relaxation time strongly correlated with timepoint 2 IPSG cartilage score (rs = 0.93 to rs = 0.82 [P = .001 to P = .012]) and T2 relaxation time (rs = 0.98 to rs = 0.88 [P = .00003 to P = .004]) changes in most regions-of-interest. Conclusion: T2 mapping shows sensitivity to biochemical changes in cartilage prior to detectable damage using conventional MRI, offering potential for early detection of bleed-related cartilage damage in boys with hemophilia.

In vitro evaluation of CAR-T cells in patient-derived glioblastoma models.

Advances in chimeric antigen receptor (CAR) T cell therapies have led to the modality dominating translational cancer research; however, a standardized protocol for evaluating such therapies in vitro is needed. This protocol details the in vitro preclinical evaluation of CAR-T cell therapies for glioblastoma (GBM), including target cell cytotoxicity and T cell proliferation, activation, and cytokine release assays. For complete details on the use and execution of this protocol, please refer to Vora et al. (2020).

Advances in Immunotherapy for Adult Glioblastoma.

Despite aggressive multimodal therapy, glioblastoma (GBM) remains the most common malignant primary brain tumor in adults. With the advent of therapies that revitalize the anti-tumor immune response, several immunotherapeutic modalities have been developed for treatment of GBM. In this review, we summarize recent clinical and preclinical efforts to evaluate vaccination strategies, immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR) T cells. Although these modalities have shown long-term tumor regression in subsets of treated patients, the underlying biology that may predict efficacy and inform therapy development is being actively investigated. Common to all therapeutic modalities are fundamental mechanisms of therapy evasion by tumor cells, including immense intratumoral heterogeneity, suppression of the tumor immune microenvironment and low mutational burden. These insights have led efforts to design rational combinatorial therapies that can reignite the anti-tumor immune response, effectively and specifically target tumor cells and reliably decrease tumor burden for GBM patients.