Safety and efficacy of hydroset cranioplasty as an adjunct to gasket-seal and nasoseptal flap closure of the skull base. A case-controlled study.

BACKGROUND: Cerebrospinal fluid leak after endoscopic skull base surgery remains a significant complication. Several investigators have suggested Hydroset cranioplasty to reduce leak rates. We investigated our early experience with Hydroset and compared the rate of nasal complications and CSF leak rates with case-controlled historic controls. METHODS: We queried a prospective database of patients undergoing first time endoscopic, endonasal resection of suprasellar meningiomas and craniopharyngiomas from 2015 to 2023. We compared cases closed with a gasket seal, Hydroset, and a nasoseptal flap with those closed with only a gasket seal and nasoseptal flap. Demographics, technical considerations and postoperative outcomes (SNOT-22) were compared. RESULTS: Seventy patients met inclusion criteria, twenty patients in the Hydroset group (meningioma n = 12; craniopharyngioma n = 8) and 50 control patients (meningioma n = 25; craniopharyngioma n = 25). CSF diversion was used in fewer Hydroset patients (75%, 15/20) compared with control group (94%, 47/50; p = 0.02). CSF leak was less frequent in the Hydroset than the control group (5% versus 12%, p = 0.38). One Hydroset patient required delayed nasal debridement. SNOT-22 responses demonstrated no significant difference in sinonasal complaints between groups (Hydroset average SNOT-22 score 22.45, control average SNOT-22 score 25.90; p = 0.58). CONCLUSIONS: We demonstrate that hydroxyapatite reconstruction leads to improved CSF leak control above that provided by the gasket-seal and nasoseptal flap, without significant associated morbidity as long as the cement is fully covered with vascularized tissue.

Chordoma: Genetics and Contemporary Management.

Chordomas, arising from notochord remnants, are rare neoplasms with aggressive growth patterns despite their histologically low-grade nature. This review explores their embryological origins, molecular markers like brachyury, and genetic alterations driving pathogenesis. Diagnosis relies on advanced imaging and biopsy confirmation due to overlapping features with chondrosarcoma. The WHO classification distinguishes conventional, dedifferentiated, and poorly differentiated chordomas, each with distinct prognostic implications. Recent genomic analyses uncovered recurrent mutations in PI3K signaling pathways and chromatin remodeling genes, informing prognostic models. Surgery remains the cornerstone of treatment, though adjuvant radiation complements surgical resection. Although chordomas are generally considered refractory to medical therapy, emerging targeted molecular strategies show potential promise in ongoing trials. This review aims to provide a concise yet comprehensive overview of chordomas, guiding clinicians in diagnosis, treatment, and prognostication for improved patient outcomes.

Therapeutic applications of the cancer immunoediting hypothesis.

Since the late 19th century, the immune system has increasingly garnered interest as a novel avenue for cancer therapy, particularly given scientific breakthroughs in recent decades delineating the fundamental role of the immune system in tumorigenesis. The immunoediting hypothesis has articulated this role, describing three phases of the tumor-immune system interaction: Elimination, Equilibrium, and Escape wherein tumors progress from active immunologic surveillance and destruction through dynamic immunologic stasis to unfettered growth. The primary goals of immunotherapy are to restrict and revert progression through these phases, thereby improving the immune system's ability to control tumor growth. In this review, we detail the development and foundation of the cancer immunoediting hypothesis and apply this hypothesis to the dynamic immunotherapy field that includes checkpoint blockade, vaccine therapy, and adoptive cell transfer.

Correction to: Radiation exposure to the surgeon during minimally invasive spine procedures is directly estimated by patient dose.

Unfortunately, the first author surname was incorrectly published as "Harrison Farber" instead of "Farber" in original publication.

Therapeutic Role of Gamma Knife Stereotactic Radiosurgery in Neuro-Oncology.

The Gamma Knife Center of St. Louis has established itself as a key facility offering stereotactic radiosurgery (SRS) for a variety of neuro-oncologic disorders. Since the Gamma Knife unit was first brought to Washington University in 1997, we have treated 5,696 patients. In this review, we discuss the effective role of Gamma Knife SRS in the treatment strategies for patients with neuro-oncologic disorders including brain metastases, meningiomas, pituitary adenomas, and acoustic neuromas. While there is active ongoing research evaluating the most effective treatment for patients with these disorders, it is clear that best management practices may be tailored for individual patients utilizing SRS either alone or in conjunction alternative treatment strategies including open neurosurgical procedures, laser thermos-ablative surgery, and even new medical oncological treatment strategies.

Radiation exposure to the surgeon during minimally invasive spine procedures is directly estimated by patient dose.

PURPOSE: Radiation exposure is a necessary component of minimally invasive spine procedures to augment limited visualization of anatomy. The surgeon's exposure to ionizing radiation is not easily recognizable without a digital dosimeter-something few surgeons have access to. The aim of this study was to identify an easy alternative method that uses the available radiation dose data from the C-arm to accurately predict physician exposure. METHODS: The senior surgeon wore a digital dosimeter during all minimally invasive spine fusion procedures performed over a 12-month period. Patient demographics, procedure information, and radiation exposure throughout the procedure were recorded. RESULTS: Fifty-five minimally invasive spine fusions utilizing 330 percutaneous screws were included. Average radiation dose was 0.46 Rad/screw to the patient. Average radiation exposure to the surgeon was 1.06 ± 0.71 µSv/screw, with a strong positive correlation (r = 0.77) to patient dose. The coefficient of determination (r2) was 0.5928, meaning almost two-thirds of the variability in radiation exposure to the surgeon is explained by radiation exposure to the patient. CONCLUSIONS: Intra-operative radiation exposure to the patient, which is easily identifiable as a continuously updated fluoroscopic monitor, is a reliable predictor of radiation exposure to the surgeon during percutaneous screw placement in minimally invasive spinal fusion surgery and therefore can provide an estimate of exposure without the use of a dosimeter. With this, a surgeon can better understand the magnitude of their exposure on a case-by-case basis rather than on a quarterly basis, or more likely, not at all. These slides can be retrieved under Electronic Supplementary Material.

Emerging immunotherapies for glioblastoma.

INTRODUCTION: Immunotherapy for brain cancer has evolved dramatically over the past decade, owed in part to our improved understanding of how the immune system interacts with tumors residing within the central nervous system (CNS). Glioblastoma (GBM), the most common primary malignant brain tumor in adults, carries a poor prognosis (<15 months) and only few advances have been made since the FDA's approval of temozolomide (TMZ) in 2005. Importantly, several immunotherapies have now entered patient trials based on promising preclinical data, and recent studies have shed light on how GBM employs a slew of immunosuppressive mechanisms that may be targeted for therapeutic gain. Altogether, accumulating evidence suggests immunotherapy may soon earn its keep as a mainstay of clinical management for GBM. AREAS COVERED: Here, we review cancer vaccines, checkpoint inhibitors, adoptive T-cell immunotherapy, and oncolytic virotherapy. EXPERT OPINION: Checkpoint blockade induces antitumor activity by preventing negative regulation of T-cell activation. This platform, however, depends on an existing frequency of tumor-reactive T cells. GBM tumors are exceptionally equipped to prevent this, occupying low levels of antigen expression and elaborate mechanisms of immunosuppression. Therefore, checkpoint blockade may be most effective when used in combination with a DC vaccine or adoptively transferred tumor-specific T cells generated ex vivo. Both approaches have been shown to induce endogenous immune responses against tumor antigens, providing a rationale for use with checkpoint blockade where both primary and secondary responses may be potentiated.

Atlantoaxial Rotatory Subluxation: A Review for the Pediatric Emergency Physician.

Pediatric emergency physicians must have a high clinical suspicion for atlantoaxial rotatory subluxation (AARS), particularly when a child presents with neck pain and an abnormal head posture without the ability to return to a neutral position. As shown in the neurosurgical literature, timely diagnosis and swift initiation of treatment have a greater chance of treatment success for the patient. However, timely treatment is complicated because torticollis can result from a variety of maladies, including: congenital abnormalities involving the C1-C2 joint or the surrounding supporting muscles and ligaments, central nervous system abnormalities, obstetric palsies from brachial plexus injuries, clavicle fractures, head and neck surgery, and infection. The treating pediatrician must discern the etiology of the underlying problem to determine both timing and treatment paradigms, which vary widely between these illnesses. We present a comprehensive review of AARS that is intended for pediatric emergency physicians. Management of AARS can vary widely bases on factors, such as duration of symptoms, as well as the patient's history. The goal of this review is to streamline the management paradigms and provide an inclusive review for pediatric emergency first responders.

Lateral Transorbital Endoscope-Assisted Resection of Anterior Temporal Lobe Neoplasm: 2-Dimensional Operative Video.

Transorbital neuroendoscopic surgery (TONES) is a minimally invasive approach, providing excellent access to extradural pathology of the sphenoid wing, orbital apex, Meckel's cave, and lateral cavernous sinus.1-10 Few cases of intradural pathology, such as gliomas or epileptic foci of the temporal lobe, have been described, apart from cadaveric anatomic studies.11-13 In this video, we present the case of a 63-year-old man with first time seizure. MRI demonstrated a fluid-attenuated inversion recovery hyperintense, noncontrast enhancing medial temporal lobe lesion consistent with low grade glioma. While frontotemporal craniotomy is the standard approach for this lesion, the TONES approach detailed in the video (the patient consented to the procedure and to the publication of his image) provided excellent access to the lesion, which minimized unnecessary trauma or removal of the lateral temporal lobe during the approach.4,14,15 The dura was closed primarily, overlayed with abdominal fat and fibrin glue, and a lumbar drain was left in place for 24 hours. The TONES approach avoided not only temporal lobe violation but also temporalis muscle disruption and any sort of external bone manipulation, which expedited the patient's recovery.16 The patient's eyelid incision was barely visible as early as postoperative day 7 with minimal ecchymosis. Postoperative MRI demonstrated a gross total resection. Pathology was consistent with a central nervous system World Health Organization grade 1 dysembryoplastic neuroepithelial tumor, a low-grade lesion with low risk of recurrence.17,18.

Endonasal endoscopic surgery for pituitary adenomas.

Pituitary adenomas are slow-growing, benign intracranial tumors that can be characterized as functional (hormone-producing) or non-functional (non-hormone producing). Symptoms therefore arise from either endocrinologic abnormalities or mass effect on surrounding structures resulting in symptoms such as visual impairment and headache. In the last two decades, technical innovations have shifted surgical resection of such adenomas to endoscopic endonasal approaches. In this review, we describe the evolving approach to pituitary adenomas in the modern endoscopic era, including preoperative multidisciplinary review, relevant surgical anatomy, and a description of the technical nuances of standard and expanded approaches to the anterior skull base.

Relationship between phenotypic features in Loeys-Dietz syndrome and the presence of intracranial aneurysms.

OBJECTIVE: Loeys-Dietz syndrome (LDS) is a rare autosomal dominant condition characterized by aneurysms of the aorta, aortic branches, and intracranial arteries; skeletal and cutaneous abnormalities; and craniofacial malformations. Previous authors have reported that higher craniofacial severity index (CFI) scores, which indicate more severe craniofacial abnormalities, correlate with the severity of aortic aneurysm pathology. However, the association between syndromic features and the formation of intracranial aneurysms in LDS patients has yet to be determined. In this study, the authors evaluate the incidence of phenotypic abnormalities, craniofacial features, and Chiari malformation type I (CM-I) in a large LDS cohort and explore possible risk factors for the development of intracranial aneurysms. METHODS: This was a retrospective cohort study of all patients with LDS who had been seen at the Marfan Syndrome and Aortopathy Center at Washington University School of Medicine in St. Louis in 2010-2022. Medical records were reviewed to obtain demographic, clinical, and radiographic data. The prevalence of craniofacial, skeletal, and cutaneous pathologies was determined. Bivariate logistic regression was performed to identify possible risk factors for the formation of an intracranial aneurysm. RESULTS: Eighty-one patients with complete medical records and intracranial vascular imaging were included in the analysis, and 18 patients (22.2%) had at least 1 intracranial aneurysm. Patients frequently demonstrated the thin or translucent skin, doughy skin texture, hypertelorism, uvular abnormalities, and joint hypermobility typical of LDS. CM-I was common, occurring in 7.4% of the patients. Importantly, the patients with intracranial aneurysms were more likely to have CM-I (22.2%) than those without intracranial aneurysms (3.2%). The mean CFI score in the cohort with available data was 1.81, with higher means in the patients with the TGFBR1 or TGFBR2 disease-causing variants (2.05 and 3.30, respectively) and lower in the patients with the SMAD3, TGFB2, or TGFB3 pathogenic variants (CFI < 1). No significant CFI difference was observed in patients with or without intracranial aneurysms (2.06 vs 1.74, p = 0.61). CONCLUSIONS: CM-I, and not the CFI, is significantly associated with the presence of intracranial aneurysms in patients with LDS. Surveillance for intracranial aneurysms is essential in all patients with LDS and should not be limited to those with severe phenotypes. Long-term monitoring studies will be necessary to determine whether a correlation between craniofacial abnormalities and adverse outcomes from intracranial aneurysms (growth, intervention, or rupture) exists.

Removal of a Floating and Migrated Plate Screw in a Patient with a Failed Anterior Cervical Discectomy and Fusion.

BACKGROUND: Anterior cervical discectomy and fusion (ACDF) is a commonly performed procedure for degenerative cervical spine disease. Rare complications of ACDF surgery include hardware failure, in the form of screw loosening and migration, or rod breakage. We present a case in which we removed a migrated screw lodged in the esophagus from a patient with a failed anterior cervical fusion. OBJECTIVE: To present a surgical technique and considerations to remove a migrated screw. METHODS: The previous ACDF incision was reopened and exposure was gained under the guidance of a head and neck surgeon. Longus coli were mobilized off the spine bilaterally with electrocautery. After dissection, the screw was found lodged in the longitudinal muscle of the esophageal wall and excised with the use of a 15-blade. The integrity of the esophageal mucosa and submucosa was maintained and subsequently checked with rigid esophagoscopy. Fluoroscopy was used to confirm that all hardware was removed, with the exception of the anterior cages. RESULTS: The dislodged screw, which was embedded in the esophagus, was successfully removed. CONCLUSIONS: Failure of an ACDF carries a risk of screw migration, which may be asymptomatic even if the screw is lodged in the esophagus. Additional considerations are required with potential violations of the adjacent viscera.

Cervical spinal cord compression from subdural hematoma caused by traumatic nerve root avulsion: illustrative case.

BACKGROUND: Posttraumatic intradural hematomas of the cervical spine are rare findings that may yield significant neurological deficits if they compress the spinal cord. These compressive hematomas require prompt surgical evacuation. In certain instances, intradural hematomas may form from avulsion of cervical nerve roots. OBSERVATIONS: The authors present the case of a 29-year-old male who presented with right upper-extremity weakness in the setting of polytrauma after a motor vehicle accident. He had no cervical fractures but subsequently developed right lower-extremity weakness. Magnetic resonance imaging (MRI) demonstrated a compressive hematoma of the cervical spine that was initially read as an epidural hematoma. However, intraoperatively, it was found to be a subdural hematoma, eccentric to the right, stemming from an avulsion of the right C6 nerve root. LESSONS: Posttraumatic cervical subdural hematomas require rapid surgical evacuation if neurological deficits are present. The source of the hematoma may be an avulsed nerve root, and the associated deficits may be unilateral if the hematoma is eccentric to one side. Surgeons should be prepared for the possibility of an intradural hematoma even in instances in which MRI appears consistent with an epidural hematoma.

First-in-human prospective trial of sonobiopsy in high-grade glioma patients using neuronavigation-guided focused ultrasound.

Sonobiopsy is an emerging technology that combines focused ultrasound (FUS) with microbubbles to enrich circulating brain disease-specific biomarkers for noninvasive molecular diagnosis of brain diseases. Here, we report the first-in-human prospective trial of sonobiopsy in high-grade glioma patients to evaluate its feasibility and safety in enriching plasma circulating tumor biomarkers. A nimble FUS device integrated with a clinical neuronavigation system was used to perform sonobiopsy following an established clinical workflow for neuronavigation. Analysis of blood samples collected before and after FUS sonication showed that sonobiopsy enriched plasma circulating tumor DNA (ctDNA), including a maximum increase of 1.6-fold for the mononucleosome cell-free DNA (cfDNA) fragments (120-280 bp), 1.9-fold for the patient-specific tumor variant ctDNA level, and 5.6-fold for the TERT mutation ctDNA level. Histological analysis of surgically resected tumors confirmed the safety of the procedure. Transcriptome analysis of sonicated and nonsonicated tumor tissues found that FUS sonication modulated cell physical structure-related genes. Only 2 out of 17,982 total detected genes related to the immune pathways were upregulated. These feasibility and safety data support the continued investigation of sonobiopsy for noninvasive molecular diagnosis of brain diseases.

First-in-human prospective trial of sonobiopsy in glioblastoma patients using neuronavigation-guided focused ultrasound.

Sonobiopsy is an emerging technology that combines focused ultrasound (FUS) with microbubbles to enrich circulating brain disease-specific biomarkers for noninvasive molecular diagnosis of brain diseases. Here, we report the first-in-human prospective trial of sonobiopsy in glioblastoma patients to evaluate its feasibility and safety in enriching circulating tumor biomarkers. A nimble FUS device integrated with a clinical neuronavigation system was used to perform sonobiopsy following an established clinical workflow for neuronavigation. Analysis of blood samples collected before and after FUS sonication showed enhanced plasma circulating tumor biomarker levels. Histological analysis of surgically resected tumors confirmed the safety of the procedure. Transcriptome analysis of sonicated and unsonicated tumor tissues found that FUS sonication modulated cell physical structure-related genes but evoked minimal inflammatory response. These feasibility and safety data support the continued investigation of sonobiopsy for noninvasive molecular diagnosis of brain diseases.

A pilot study of lymphoscintigraphy with tracer injection into the human brain.

Many groups have reported lymphatic and glymphatic structures in animal and human brains, but tracer injection into the human brain to demonstrate real-time lymphatic drainage and mapping has not been described. We enrolled patients undergoing standard-of-care resection or stereotactic biopsy for suspected intracranial tumors. Patients received peritumoral injections of 99mTc-tilmanocept followed by planar or tomographic imaging. Fourteen patients with suspected brain tumors were enrolled. One was excluded from analysis because of tracer leakage during injection. There was no drainage of 99mTc-tilmanocept to regional lymph nodes in any of the patients. On average, after correcting for radioactive decay, 70.7% (95% CI: 59.9%, 81.6%) of the tracer in the injection site and 78.1% (95% CI: 71.1%, 85.1%) in the whole-head on the day of surgery remained the morning after, with variable radioactivity in the subarachnoid space. The retained fraction was much greater than expected based on the clearance rate from non-brain injection sites. In this pilot study, the lymphatic tracer 99mTc-tilmanocept was injected into the brain parenchyma, and there was no drainage outside the brain to the cervical lymph nodes. Our work demonstrates an inefficiency of drainage from peritumoral brain parenchyma and highlights a therapeutic opportunity to improve immunosurveillance of the brain.

TCR-engineered adoptive cell therapy effectively treats intracranial murine glioblastoma.

BACKGROUND: Adoptive cellular therapies with chimeric antigen receptor T cells have revolutionized the treatment of some malignancies but have shown limited efficacy in solid tumors such as glioblastoma and face a scarcity of safe therapeutic targets. As an alternative, T cell receptor (TCR)-engineered cellular therapy against tumor-specific neoantigens has generated significant excitement, but there exist no preclinical systems to rigorously model this approach in glioblastoma. METHODS: We employed single-cell PCR to isolate a TCR specific for the Imp3D81N neoantigen (mImp3) previously identified within the murine glioblastoma model GL261. This TCR was used to generate the Mutant Imp3-Specific TCR TransgenIC (MISTIC) mouse in which all CD8 T cells are specific for mImp3. The therapeutic efficacy of neoantigen-specific T cells was assessed through a model of cellular therapy consisting of the transfer of activated MISTIC T cells and interleukin 2 into lymphodepleted tumor-bearing mice. We employed flow cytometry, single-cell RNA sequencing, and whole-exome and RNA sequencing to examine the factors underlying treatment response. RESULTS: We isolated and characterized the 3×1.1C TCR that displayed a high affinity for mImp3 but no wild-type cross-reactivity. To provide a source of mImp3-specific T cells, we generated the MISTIC mouse. In a model of adoptive cellular therapy, the infusion of activated MISTIC T cells resulted in rapid intratumoral infiltration and profound antitumor effects with long-term cures in a majority of GL261-bearing mice. The subset of mice that did not respond to the adoptive cell therapy showed evidence of retained neoantigen expression but intratumoral MISTIC T cell dysfunction. The efficacy of MISTIC T cell therapy was lost in mice bearing a tumor with heterogeneous mImp3 expression, showcasing the barriers to targeted therapy in polyclonal human tumors. CONCLUSIONS: We generated and characterized the first TCR transgenic against an endogenous neoantigen within a preclinical glioma model and demonstrated the therapeutic potential of adoptively transferred neoantigen-specific T cells. The MISTIC mouse provides a powerful novel platform for basic and translational studies of antitumor T-cell responses in glioblastoma.

The Conventional Dendritic Cell 1 Subset Primes CD8+ T Cells and Traffics Tumor Antigen to Drive Antitumor Immunity in the Brain.

The central nervous system (CNS) antigen-presenting cell (APC) that primes antitumor CD8+ T-cell responses remains undefined. Elsewhere in the body, the conventional dendritic cell 1 (cDC1) performs this role. However, steady-state brain parenchyma cDC1 are extremely rare; cDCs localize to the choroid plexus and dura. Thus, whether the cDC1 play a function in presenting antigen derived from parenchymal sources in the tumor setting remains unknown. Using preclinical glioblastoma (GBM) models and cDC1-deficient mice, we explored the presently unknown role of cDC1 in CNS antitumor immunity. We determined that, in addition to infiltrating the brain tumor parenchyma itself, cDC1 prime neoantigen-specific CD8+ T cells against brain tumors and mediate checkpoint blockade-induced survival benefit. We observed that cDC, including cDC1, isolated from the tumor, the dura, and the CNS-draining cervical lymph nodes harbored a traceable fluorescent tumor antigen. In patient samples, we observed several APC subsets (including the CD141+ cDC1 equivalent) infiltrating glioblastomas, meningiomas, and dura. In these same APC subsets, we identified a tumor-specific fluorescent metabolite of 5-aminolevulinic acid, which fluorescently labeled tumor cells during fluorescence-guided GBM resection. Together, these data elucidate the specialized behavior of cDC1 and suggest that cDC1 play a significant role in CNS antitumor immunity.

Identification and Management of Aggressive Meningiomas.

Meningiomas are common primary central nervous system tumors derived from the meninges, with management most frequently entailing serial monitoring or a combination of surgery and/or radiation therapy. Although often considered benign lesions, meningiomas can not only be surgically inaccessible but also exhibit aggressive growth and recurrence. In such cases, adjuvant radiation and systemic therapy may be required for tumor control. In this review, we briefly describe the current WHO grading scale for meningioma and provide demonstrative cases of treatment-resistant meningiomas. We also summarize frequently observed molecular abnormalities and their correlation with intracranial location and recurrence rate. We then describe how genetic and epigenetic features might supplement or even replace histopathologic features for improved identification of aggressive lesions. Finally, we describe the role of surgery, radiotherapy, and ongoing systemic therapy as well as precision medicine clinical trials for the treatment of recurrent meningioma.

Corrigendum: Identification and management of aggressive meningiomas.

[This corrects the article DOI: 10.3389/fonc.2022.851758.].