All-trans retinoic acid induces durable tumor immunity in IDH-mutant gliomas by rescuing transcriptional repression of the CRBP1-retinoic acid axis.

Diffuse gliomas are epigenetically dysregulated, immunologically cold, and fatal tumors characterized by mutations in isocitrate dehydrogenase (IDH). Although IDH mutations yield a uniquely immunosuppressive tumor microenvironment, the regulatory mechanisms that drive the immune landscape of IDH mutant (IDHm) gliomas remain unknown. Here, we reveal that transcriptional repression of retinoic acid (RA) pathway signaling impairs both innate and adaptive immune surveillance in IDHm glioma through epigenetic silencing of retinol binding protein 1 (RBP1) and induces a profound anti-inflammatory landscape marked by loss of inflammatory cell states and infiltration of suppressive myeloid phenotypes. Restorative retinoic acid therapy in murine glioma models promotes clonal CD4 + T cell expansion and induces tumor regression in IDHm, but not IDH wildtype (IDHwt), gliomas. Our findings provide a mechanistic rationale for RA immunotherapy in IDHm glioma and is the basis for an ongoing investigator-initiated, single-center clinical trial investigating all-trans retinoic acid (ATRA) in recurrent IDHm human subjects.

Chiari Type I Revision Decompressive Surgery Indications and Operative Technique: Experience in a Large Adult Cohort.

BACKGROUND: Chiari malformation is characterized by inferior displacement of the cerebellar tonsils through the foramen magnum, frequently resulting in strain related headaches, and motor/sensory dysfunction. Chiari decompression technique varies significantly, possibly contributing to frequent revisions. We reviewed revision Chiari decompressions at our institution to determine the primary indications for revision and outcomes after revision. METHODS: We retrospectively reviewed patients who underwent revision of Chiari decompression at our institution from 2005 to 2020. Demographics, indications for revision surgery, operative techniques, imaging findings, and preoperative/postoperative symptoms were collected. χ2 test was performed to determine statistical significance using a P < 0.05. Independent predictors of operative outcomes were identified. RESULTS: A total of 46 patients (91% females, mean age 38.8 years) were included for analysis. The median time to revision surgery was 69.1 months (range 0-364 months) with headache (n = 37, 80%) being the most commonly recurring symptom. Large craniectomy (n = 28, 61%) was the most frequent indication for revision surgery. Thirty-two (70%) patients underwent cranioplasty, 20 (43%) required duraplasty, 15 (33%) required arachnoid dissection, and 15 (33%) required tonsillar reduction during revision surgery. Postrevision follow-up (at 8.9 ± 5.2 months average, range 1-18 months), revealed an average reduction in all Chiari-related symptoms relative to symptoms before the revision. CONCLUSIONS: The most common indication for revision Chiari decompression was a large craniectomy resulting in cerebellar ptosis. We found that tonsillar reduction paired with modest craniectomy achieved near-complete resolution of symptoms with minimal complications. For patients with recurrent or persistent sequelae of Chiari malformation after decompression, revision may reduce symptom severity.

Novel endovascular transmural technique for pharmacological block of superior cervical ganglion prevents sympathetic-mediated cerebral vasospasm.

BACKGROUND: Sympathetic-mediated vasoconstriction from the superior cervical ganglion (SCG) is a significant contributor to cerebral vasospasm. Inhibition of the SCG has been shown to improve cerebral blood flow and reverse cerebral vasospasm in swine models. We evaluated the efficacy of a novel minimally invasive endovascular approach to target and pharmacologically inhibit the SCG, using a Micro-Infusion Device for transmural drug delivery. METHODS: Eight SCGs in four Yorkshire swine were surgically identified. After confirming appropriate sympathetic-mediated intracranial vasoconstriction response with SCG stimulation, an endovascular Micro-Infusion Device was used for transmural targeting of the SCG and delivery of 1.5-2 mL of 1% lidocaine-contrast mixture to the perivascular space. Digital subtraction angiography was obtained at: (1) baseline; (2) with SCG stimulation; and (3) after lidocaine delivery to the SCG using the Micro-Infusion Device with concurrent SCG stimulation. Vessel diameters were measured and compared. RESULTS: Endovascular transmural delivery of lidocaine to the SCG and carotid perivascular tissue using the Micro-Infusion Device successfully inhibited sympathetic-mediated vasoconstriction response. Measured vessel diameters after lidocaine delivery were comparable to baseline despite SCG stimulation. CONCLUSION: A novel endovascular technique of transmural delivery of lidocaine to the SCG and carotid artery perivascular tissues successfully inhibits the sympathetic input to the cerebral vasculature and modulates sympathetic-mediated cerebral vasospasm. These results suggest promising steps towards translation to potential clinical use for patients suffering from cerebral vasospasm.

Brain and lung metastasis of uterine leiomyosarcoma: illustrative case.

BACKGROUND: Uterine leiomyosarcoma is a rare, extremely aggressive tumor with a high rate of metastasis. Five-year survival for individuals with metastatic disease is only 10%-15%. Metastases to the brain are exceptionally rare and are associated with poor survival. OBSERVATIONS: The authors report a case of uterine leiomyosarcoma that metastasized to the brain in a 51-year-old woman. A single lesion on magnetic resonance imaging was discovered in the right posterior temporo-occipital region 44 months after resection of the primary uterine tumor. The patient underwent a right occipital craniotomy with gross-total resection of the tumor and is receiving adjuvant stereotactic radiosurgery and chemotherapy with gemcitabine and docetaxel. At 8 months postresection, the patient remains alive and asymptomatic with no sign of recurrence. A literature review of prior reported cases was conducted to analyze patterns of approach to patient treatment and survival. LESSONS: The authors found an apparent survival benefit in patients receiving adjuvant radiation therapy.

Upper lumbar spine far lateral disc herniations masquerading as peripheral nerve sheath tumors: illustrative cases.

BACKGROUND: Migratory disc herniations can mimic neoplasms clinically and on imaging. Far lateral lumbar disc herniations usually compress the exiting nerve root and can be challenging to distinguish from a nerve sheath tumor due to the proximity of the nerve and characteristics on magnetic resonance imaging (MRI). These lesions can occasionally present in the upper lumbar spine region at the L1-2 and L2-3 levels. OBSERVATIONS: The authors describe 2 extraforaminal lesions in the far lateral space at the L1-2 and L2-3 levels, respectively. On MRI, both lesions tracked along the corresponding exiting nerve roots with avid postcontrast rim enhancement and edema in the adjacent muscle tissue. Thus, they were initially concerning for peripheral nerve sheath tumors. One patient underwent fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) screening and demonstrated moderate FDG uptake on PET-CT scan. In both cases, intraoperative and postoperative pathology revealed fibrocartilage disc fragments. LESSONS: Differential diagnosis for lumbar far lateral lesions that are peripherally enhancing on MRI should include migratory disc herniation, regardless of the level of the disc herniations. Accurate preoperative diagnosis can aid in decision making for management, surgical approach, and resection.

Endovascular transmural access to carotid artery perivascular tissues: safety assessment of a novel technique.

BACKGROUND: Recent advances in endovascular devices have allowed access and targeting of perivascular tissues of the peripheral circulation. The perivascular tissues of the cervical and cranial circulations have many important structures of clinical significance, yet the feasibility and safety of such an approach has not been demonstrated. OBJECTIVE: To evaluate the safety of a novel endovascular transmural approach to target the perivascular tissues of the common carotid artery in swine. METHODS: A micro-infusion device was positioned in the carotid arteries of three Yorkshire pigs (six carotid arteries in total), and each carotid artery was punctured 10 times in the same location to gain access to the perivascular tissues. Digital subtraction angiography was used to evaluate vessel injury or contrast extravasation. MRI and MR angiography were used to evaluate evidence of cerebral ischemia or vessel injury. Post-mortem tissue analysis was performed to assess the level of extravascular hematoma and intravascular dissection. RESULTS: None of the tested carotid arteries showed evidence of vessel injury (dissection or perforation) or intravascular thrombosis. MRI performed after repeated puncture was negative for neck hematoma and brain ischemia. Post-mortem tissue analysis of the carotid arteries showed mild adventitial staining with blood, but without associated hematoma and without vessel dissection. CONCLUSION: Repeated puncture of the carotid artery to gain access to the perivascular tissues using a novel endovascular transmural approach is safe in a swine model. This represents a novel approach to various tissues in close proximity to the cervical and cranial vasculature.

Postoperative Outcomes of Patients with Thin Bone Overlying the Superior Semicircular Canal: A Single Institution's Experience.

BACKGROUND: Superior semicircular canal dehiscence (SSCD) is defined by a bony defect overlying the superior semicircular canal (SSC) in the middle cranial fossa floor, causing a myriad of vestibular and auditory symptoms. Patients with thin bone without full dehiscence overlying the SSC also present with similar symptoms. There are currently no guidelines for surgical management of patients with thin bone. The authors offer their experience with thin bone patients to characterize their symptomatology and explore whether these patients benefit from surgical intervention typically offered to SSCD patients. METHODS: Two hundred fifty-six patients evaluated for SSCD from 2011 to 2019 were reviewed. High-resolution coronal computed tomography scans with 0.6-mm slice thickness of the temporal bones were assessed to determine whether the patient had a true dehiscence or a thin bone covering overlying the SSC. Bone that was ≤0.5 mm was considered to be "thin bone." Parameters of interest included patient demographics as well as preoperative and postoperative symptomatology. A P value < 0.05 was considered statistically significant. RESULTS: Forty-eight patients met inclusion criteria of having "thin bone." The mean age was 48.13 ± 12.03 years, and 65.5% of patients were female. Of the preoperative symptoms evaluated, the greatest postoperative symptomatic resolution was noted in hearing loss (92.3%), vertigo (94.4%), and oscillopsia (100%). Dizziness (56.5%) had the lowest symptomatic resolution rate. CONCLUSIONS: Surgical management of thin bone patients via middle fossa craniotomy, a similar technique to SSCD repair, provides significant symptomatic resolution. Therefore, surgery should be considered in thin bone patients with debilitating symptoms, albeit not having a true dehiscence.

The "Bright Falx" Sign-Midline Embolic Penetration Is Associated With Faster Resolution of Chronic Subdural Hematoma After Middle Meningeal Artery Embolization: A Case Series.

BACKGROUND: Chronic subdural hematomas (CSDHs) are common in the elderly population and patients taking antiplatelet/anticoagulation medications. Middle meningeal artery (MMA) embolization has become an adjunctive treatment to observation and surgery. Despite many embolization techniques, best practices for optimal CSDH resolution remain unknown. OBJECTIVE: To report a retrospective case series of MMA embolization for CSDHs regarding rate of hematoma improvement and the significance of distal embolic penetration into the falx. METHODS: Retrospective chart review was performed on all patients who underwent MMA embolization for CSDHs between January 2017 and June 2021. Patient demographics, clinical presentation, anticoagulant use, and radiographic features were collected. Pre-embolization and postembolization computed tomography scans were analyzed for volumetric changes and assessed for midline penetration of embolic material in the falx. RESULTS: MMA embolization was performed in 37 patients and 53 hemispheres. Older patients took longer to obtain complete resolution of CSDHs (r = 0.47, P = .03). Patients with larger pre-embolization (r = 0.57, P = .007) and postembolization (r = 0.56, P = .008) CSDH volumes took longer to completely resolve. Patients who had n-butyl cyanoacrylate embolization with midline penetration, as evidenced by the "bright falx" sign, had faster improvement rates than those who did not (5.64 cm 3 /d vs 1.2 cm 3 /d, P = .02). CONCLUSION: Distal penetration of embolic material, particularly n-butyl cyanoacrylate, into the falx may lead to more rapid improvement of CSDH.

In vivo efficacy of decitabine as a natural killer cell-mediated immunotherapy against isocitrate dehydrogenase mutant gliomas.

OBJECTIVE: Isocitrate dehydrogenase (IDH) mutations are found in more than 80% of low-grade gliomas and in the majority of secondary glioblastomas. IDH mutation (IDHmut) leads to aberrant production of an oncogenic metabolite that promotes epigenetic dysregulation by inducing hypermethylation to suppress transcription of various tumor suppressor genes. Hypermethylation in IDHmut gliomas leads to transcriptional repression of NKG2D ligands, especially UL16-binding protein (ULBP)-1 and ULBP-3, and subsequent evasion of natural killer (NK) cell-mediated lysis. The demethylating agent 5-aza-2'deoxycytodine (decitabine [DAC]) is a DNA methyltransferase 1 inhibitor that prevents hypermethylation and is capable of restoring NKG2D ligand expression in IDHmut gliomas to resensitize them to NK cells. Given its capacity for sustained epigenetic reprogramming, the authors hypothesized that DCA would be an effective immunotherapeutic agent in treating IDHmut gliomas in an NK cell-dependent manner by upregulating epigenetically repressed activating NKG2D ligands in IDHmut tumors. In this study, the authors sought to use a glioma stem cell, preclinical animal model to determine the efficacy of DAC in IDHmut and IDH wild-type (IDHwt) tumors, and to characterize whether the activity of DAC in gliomas is dependent on NK cell function. METHODS: Xenograft models of IDHwt and IDHmut gliomas were established in athymic-nude mice. When tumors were grossly visible and palpable, mice were treated with either DCA or dimethylsulfoxide intraperitoneally every 7 days. Tumor sizes were measured every 2 to 3 days. After the animals were euthanized, xenografts were harvested and analyzed for the following: tumor expression of NKG2D ligands, tumor susceptibility to human and murine NK cells, immunohistochemistry for NK infiltration, and tumor-infiltrating lymphocyte characterization. RESULTS: DAC significantly inhibited the growth of IDHmut xenografts in the athymic nude mice. This effect was abrogated with NK cell depletion. Ex vivo analysis of tumor cells from harvested xenografts confirmed that DAC increased NKG2D ligand ULBP-1 and ULBP-3 expressions, and enhanced susceptibility to lysis of both human and murine IDHmut glial cells with corresponding NK cells. Immunohistochemical analysis of the xenografts indicated that DCA-treated IDHmut gliomas had a greater level of NK infiltration into the tumor compared with the negative control. Finally, DCA radically altered the tumor-infiltrating lymphocyte landscape of IDHmut glioma xenografts by increasing NK cells, dendritic cells, and M1 macrophages, while decreasing suppressive monocyte infiltration. CONCLUSIONS: DCA displayed novel immunotherapeutic functions in IDHmut gliomas. This effect was critically dependent on NK cells. Additionally, DCA significantly altered the tumor immune landscape in IDHmut gliomas from suppressive to proinflammatory.

Autophagy inhibition is the next step in the treatment of glioblastoma patients following the Stupp era.

It has now been nearly 15 years since the last major advance in the treatment of patients with glioma. "The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity". Autophagy is primarily a survival pathway, literally self-eating, that is utilized in response to stress (such as radiation and chemotherapy), enabling clearance of effete protein aggregates and multimolecular assemblies. Promising results have been observed in patients with glioma for over a decade now when autophagy inhibition with chloroquine derivatives coupled with conventional therapy. The application of autophagy inhibitors, the role of immune cell-induced autophagy, and the potential role of novel cellular and gene therapies, should now be considered for development as part of this well-established regimen.

Updates in the management of cranial dural arteriovenous fistula.

Dural arteriovenous fistula (dAVF) accounts for approximately 10% of all intracranial vascular malformations. While they can be benign lesions, the presence of retrograde venous drainage and cortical venous reflux makes the natural course of these lesions aggressive high risk of haemorrhage, neurological injury and mortality. Endovascular treatment is often the first line of treatment for dAVF. Both transarterial and transvenous approaches are used to cure dAVF. The selection of treatment approach depends on the angioarchitecture of the dAVF, the location, the direction of venous flow. Surgery and, to a lesser extent, stereotactic radiosurgery are used when endovascular approaches are impossible or unsuccessful.

Visual Outcomes After Pituitary Surgery.

Visual signs and symptoms are a common manifestation of pituitary adenomas from compression or ischemia of the optic nerves and optic chiasm. Although bitemporal hemianopsia is a classic presenting visual field deficit, additional visual disturbances can result from these tumors. After endoscopic endonasal pituitary surgery, most patients have improvement in visual symptoms. Preoperative factors including retinal nerve fiber layer thickness, severity of preoperative deficit, duration of visual symptoms, tumor size, extent of resection, and patient age serve as possible predictors of postoperative visual outcomes.

Utility of surveillance imaging for spontaneous intracerebral hemorrhage.

INTRODUCTION: Management of spontaneous intracerebral hemorrhage involves reversal of coagulopathy, neurological examinations and repeated imaging. Repeated imaging is employed to identify patients prior to neurological deterioration, however, there is no data to support this practice. As such, we strive to identify the utility of surveillance imaging as well as the risks factors that are associated with higher likelihood of developing a clinically significant hematoma progression. METHODS: A retrospective chart analysis of 200 consecutive patients was performed on patients with non-traumatic intracerebral hemorrhage. Patients with non-parenchymal hemorrhage, vascular malformations, patients that required surgical intervention based on the initial scan/neurological exam, and trauma were excluded. Patient demographics, blood pressure, presence of a new neurological deficit, progression of hematoma, surgical intervention and mortality were gathered from the chart. RESULTS: Hematoma progression of greater than 5 mL was seen in 24 patients (12%) on repeat imaging. Large initial hematoma volume, early time from symptom onset to initial imaging, and new neurological deterioration between scans were significantly associated with significant hematoma progression. Of the 24 patients with hematoma progression greater 5 mL, five patients did not develop neurological deterioration. None of these patients required intervention. CONCLUSION: Routine imaging in patients with spontaneous intracerebral hemorrhages does not alter clinical management. Rather, careful neurologic monitoring may be safe and more clinically useful in these patients.

IDH mutant gliomas escape natural killer cell immune surveillance by downregulation of NKG2D ligand expression.

BACKGROUND: Diffuse gliomas are poorly immunogenic, fatal brain tumors. The basis for insufficient antitumor immunity in diffuse gliomas is unknown. Gain-of-function mutations in isocitrate dehydrogenases (IDH1 and IDH2) promote diffuse glioma formation through epigenetic reprogramming of a number of genes, including immune-related genes. Here, we identify epigenetic dysregulation of natural killer (NK) cell ligand genes as significant contributors to immune escape in glioma. METHODS: We analyzed the database of The Cancer Genome Atlas for immune gene expression patterns in IDH mutant or wild-type gliomas and identified differentially expressed immune genes. NKG2D ligand expression levels and NK cell-mediated lysis were measured in IDH mutant and wild-type patient-derived glioma stem cells and genetically engineered astrocytes. Finally, we assessed the impact of hypomethylating agent 5-aza-2'deoxycytodine (decitabine) as a potential NK cell sensitizing agent in IDH mutant cells. RESULTS: IDH mutant glioma stemlike cell lines exhibited significantly lower expression of NKG2D ligands compared with IDH wild-type cells. Consistent with these findings, IDH mutant glioma cells and astrocytes are resistant to NK cell-mediated lysis. Decitabine increases NKG2D ligand expression and restores NK-mediated lysis of IDH mutant cells in an NKG2D-dependent manner. CONCLUSIONS: IDH mutant glioma cells acquire resistance to NK cells through epigenetic silencing of NKG2D ligands ULBP1 and ULBP3. Decitabine-mediated hypomethylation restores ULBP1 and ULBP3 expression in IDH mutant glioma cells and may provide a clinically useful method to sensitize IDH mutant gliomas to NK cell-mediated immune surveillance in patients with IDH mutated diffuse gliomas.