Faculty Bibliography

BACKGROUND:While immune checkpoint inhibitors (ICI) induce potent responses against several systemic malignancies, clinical efficacy against high-grade glioma has been limited by immunosuppression, low mutational burden and limited lymphocyte infiltration into tumors. Laser interstitial thermal therapy (LITT) induces coagulative necrosis and disrupts the peritumoral blood-brain barrier (BBB), creating a potentially antigenic milieu. We hypothesized that neoadjuvant and adjuvant ICI would synergize with LITT to potentiate antitumor immune responses and enhance survival. METHODS:This retrospective study is an exploratory case series that includes 9 adult patients with recurrent IDH wild-type glioblastoma (GBM, n = 6), IDH mutant high-grade astrocytoma (n = 2) and H3K27M mutant diffuse midline glioma (n = 1). All patients received neoadjuvant anti-PD1 ICI prior to LITT and most received adjuvant ICI (8/9). Disease burden was followed through radiographic volume segmentation of gadolinium-enhancing disease. Patients were followed for progression-free (PFS) and overall survival (OS). RESULTS:). There were no perioperative complications. All patients showed an initial increase in gadolinium-enhancing volume after LITT. Seven of 9 (78 %) patients demonstrated subsequent regression in total gadolinium-enhancing volume. Three non-contiguous satellite lesions naïve to laser ablation exhibited complete or near-complete regression in 2 patients. Median PFS was 5.90 months (range 1.00-41.23), and median OS was 9.97 months (range 1.20-41.23). CONCLUSIONS:Combination therapy with neoadjuvant and adjuvant pembrolizumab and LITT is feasible and safe in recurrent high-grade glioma. Responses may be more robust in certain molecular subtypes of glioma. Further studies are needed to investigate this potential synergy.

PURPOSE/OBJECTIVE:In diffusion MRI, vasogenic edema manifests as a major fraction of isotropic water that dilutes the anisotropic intra-axonal portion of the signal. Many tractography algorithms mistake vasogenic edema for the white matter boundary and terminate tracking to prevent producing spurious streamlines. As a result, visual representations of fascicles traversing edema are often compromised, limiting the clinical utility of tractography. METHODS:We address this hurdle with ODF-Fingerprinting (ODF-FP)-a dictionary-based fiber reconstruction algorithm that accommodates variability of neural tissue. By adding a regularization term to the ODF-FP matching formula, we counterbalance the drop of diffusion anisotropy in edematous regions to improve white matter fiber identification. In 19 glioma cases with significant peritumoral vasogenic edema, we quantify the volume of the reconstructed white matter tracts immersed in edema, then we use the cortical regions activated during task-based functional MRI as validation for tractography. To assess the potential for clinical translation, we additionally test the performance of ODF-FP on subsampled single-shell diffusion-weighted images, which contemporary clinical scanners can acquire within a few minutes. RESULTS:Our approach produces high volumes of streamlines traversing vasogenic edema and reaches high overlap with the cortical regions activated at task-based fMRI, significantly outperforming common fiber reconstruction methods in the clinically feasible data set. CONCLUSION/CONCLUSIONS:ODF-FP proves effective on research and clinical quality dMRI, which offers an opportunity for application in neurosurgery.

Optimal treatment of glioma has been a subject of debate over the last few decades, since maximal resection can improve survival, whereas preservation of functional peritumoral brain tissue minimizes the risk of postoperative neurological deficits. Our preliminary study uses tractography and neural tissue microstructure modeling based on diffusion MRI to quantify progressive axonal degeneration in proximity to frontotemporal glioma. For this, we sample major white matter pathways that traverse peritumoral penumbra at two time points. The results show a pattern of decreased intra-axonal water fraction beyond anatomical MRI abnormalities, which may indicate a tumor invasion of normal-appearing white matter that potentially advocates supratotal resection.

Adhesion G protein-coupled receptors (aGPCRs) are key cell-adhesion molecules involved in many cellular functions and contribute to human diseases, including cancer. aGPCRs are characterized by large extracellular regions that could serve as readily accessible antigens. However, the potential of aGPCRs as targets for biologic therapeutics has not been extensively explored. CD97, also known as ADGRE5, is an aGPCR that is upregulated in various cancer types, including acute myeloid leukemia (AML) and glioblastoma (GBM), and their respective cancer stem cells. Here, we developed antibody-drug conjugates (ADCs) targeting CD97 and assessed their efficacy against AML and GBM cells. We generated a panel of synthetic human antibodies targeting distinct epitopes of CD97, from which we identified an antibody that was efficiently internalized. This antibody binds to all isoforms of human CD97 but not to its close homolog, EMR2. Structure determination by single-particle cryo-electron microscopy revealed that this antibody targets the CD97 GPCR autoproteolysis-inducing (GAIN) domain, whose presence is conserved in aGPCRs, through an unconventional binding mode where it extensively utilizes the light chain framework for antigen recognition. Screening of conjugation methods and payloads resulted in a stable ADC that effectively killed AML and GBM cell lines, as well as patient-derived GBM stem cells, with minimal cytotoxicity against peripheral blood mononuclear cells from healthy donors. Our study demonstrates the therapeutic potential of targeting CD97, as well as the aGPCR GAIN domain in general, and uncovers a previously unrecognized surface that an antibody can utilize for antigen recognition.

Protein-based nanocarriers bear highly desirable properties such as biodegradability and ability to facilitate passage through biological barriers such as the blood-brain-barrier. Using modular protein engineering, we develop a strategy for iteratively improving the delivery efficacy of hydrophobic small molecules for the treatment of glioblastoma multiforme (GBM). By increasing the multiplicity m of the coiled-coil and RGD peptide targeting regions from 1 to 2, we can increase both the hydrodynamic micellar size and drug loading capacity of targeted multidomain protein assembly (TMPA) relative to its predecessor thermoresponsive assembled protein (TRAP). An upper limit of m is likely determined by steric interactions. TMPA shows a 1.7-fold increased encapsulation of doxorubicin (Dox) compared to TRAP and demonstrates improved uptake by U87 human GBM cells. Near-infrared (NIR) dye-labelled TMPA (NIR-TMPA) is injected into mice orthotopically implanted with GBM cells and fit to a 2-compartment pharmacokinetic model. NIR-TMPA demonstrates prolonged short-phase half-life in tumor-bearing mice compared to control with similar slow-phase half-life, leading to an increased area-under-the-curve clearance and pointing to its sequestration in the tumor site. Endpoint fluorescence analysis of mouse organs ex vivo also supports this conclusion. TMPA and its future derivatives therefore bear potential for targeted treatment of GBM.

The endoscopic transsphenoidal approach (ETSA) is a commonly used technique that allows for the minimally invasive removal of sellar and parasellar lesions. Augmented reality (AR) applications in ETSA are hypothesized to enhance intraoperative visualization by integrating a 3D-reconstructed model into the operative field. This study describes the workflow and surgical outcomes associated with the Endoscopic Surgical Navigation Advanced Platform (EndoSNAP, Surgical Theater, Cleveland, OH, USA), an AR platform designed for surgical planning and intraoperative navigation in ETSA for sellar and parasellar lesions. We analyzed a cohort of patients who underwent ETSA tumor resection using EndoSNAP. Preoperative MRI and CT scans were reconstructed and merged into a single 360° AR model using the Surgical Rehearsal Platform software. The model was then imported into EndoSNAP, which was integrated with the endoscope and neuronavigation system for real-time intraoperative use. Patient demographics, tumor characteristics, extent of resection (EOR), and endocrinologic and neurologic outcomes were recorded. Eighteen adult patients with newly diagnosed (83%) and recurrent (17%) tumors were included. Pathologies consisted of pituitary adenoma (72%), craniopharyngioma (11%), meningioma (11%), and chordoma (6%). Optic compression was present in 56% of patients, with preoperative visual deficits in 70% of them. Cavernous sinus invasion was observed in 17% of tumors. Preoperative hormonal excess and insufficiency were noted in 56% and 28% of cases, respectively. The mean preoperative tumor volume was 21.4 ± 17 cm³, which decreased to 0.4 ± 0.3 cm³ postoperatively. The mean EOR was 93.6 ± 3.6%. Postoperative complications included CSF leaks requiring surgical repair (17%), seizures related to pre-existing hemispheric trauma (6%), pulmonary embolism (6%), deep venous thrombosis (6%), and sinusitis (6%). These findings suggest that AR-enhanced visualization through EndoSNAP is a feasible and potentially beneficial adjunct in ETSA for sellar and parasellar tumor resection.

Glioblastoma (GBM), an aggressive brain malignancy with a cellular hierarchy dominated by GBM stem cells (GSCs), evades antitumor immunity through mechanisms that remain incompletely understood. Like most cancers, GBMs undergo metabolic reprogramming toward glycolysis to generate lactate. Here, we show that lactate production by patient-derived GSCs and microglia/macrophages induces tumor cell epigenetic reprogramming through histone lactylation, an activating modification that leads to immunosuppressive transcriptional programs and suppression of phagocytosis via transcriptional upregulation of CD47, a "don't eat me" signal, in GBM cells. Leveraging these findings, pharmacologic targeting of lactate production augments efficacy of anti-CD47 therapy. Mechanistically, lactylated histone interacts with the heterochromatin component chromobox protein homolog 3 (CBX3). Although CBX3 does not possess direct lactyltransferase activity, CBX3 binds histone acetyltransferase (HAT) EP300 to induce increased EP300 substrate specificity toward lactyl-CoA and a transcriptional shift toward an immunosuppressive cytokine profile. Targeting CBX3 inhibits tumor growth by both tumor cell-intrinsic mechanisms and increased tumor cell phagocytosis. Collectively, these results suggest that lactate mediates metabolism-induced epigenetic reprogramming in GBM that contributes to CD47-dependent immune evasion, which can be leveraged to augment efficacy of immuno-oncology therapies.

BACKGROUND:Subdural hematoma is a rare manifestation of hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu disease. Here, the authors present a patient with HHT and a large chronic subdural hematoma, for whom nonsurgical management was pursued. OBSERVATIONS/METHODS:A 49-year-old right-handed male with a history of hypertension and familial HHT presented with complaints of mild confusion and left hemiparesis over several days. Noncontrast head computed tomography images demonstrated a large chronic right hemisphere subdural hematoma compressing the right cerebral hemisphere and causing a 1.3-cm midline shift. Due to concerns about surgical complications arising from hemorrhages of cryptic telangiectasias, the patient was treated conservatively with middle meningeal artery embolization and adjuvant tranexamic acid. There was clinical and radiological resolution several months later. LESSONS/CONCLUSIONS:This case highlights the rarity of a subdural hematoma as a manifestation of HHT and the nonsurgical treatment strategy as a mechanism to avoid hemorrhagic complications of surgical evacuation. https://thejns.org/doi/10.3171/CASE24483.

BACKGROUND:Resection of glioblastoma (GBM) in eloquent regions depends on functional mapping to limit perioperative neurological morbidity. When neurological deficits preclude reliable mapping, neurosurgeons should explore potential mitigation strategies. The authors present the case of a patient with a large left cystic temporoinsular GBM and aphasia, for whom the authors used intraoperative language mapping and a staged approach to enable safe tumor resection. OBSERVATIONS/METHODS:A 49-year-old female presented with progressive mixed aphasia for 1 month and new-onset right facial droop. Magnetic resonance imaging (MRI) revealed a large, heterogeneously enhancing, left temporoinsular tumor with a significant cystic component. Her aphasia was profound, and resection without reliable language mapping was deemed unsafe. An initial stereotactic tumoral cyst aspiration was performed, which reduced local mass effect and improved her language function. Cyst decompression thereby enabled both task-based functional MRI and intraoperative awake speech mapping, resulting in a safe resection of her GBM. LESSONS/CONCLUSIONS:Safe resection of eloquently localized GBM is compromised when neurological deficits prohibit intraoperative functional mapping. This case demonstrates a mitigation strategy specific to cystic lesions in which an initial-stage stereotactic cyst aspiration is aimed at generating sufficient interval neurological improvement, such that intraoperative functional mapping can be performed during a second-stage resection. https://thejns.org/doi/10.3171/CASE24362.

OBJECTIVE:Meningiomas are the most common primary brain tumors in adults and a subset are aggressive lesions resistant to standard therapies. Laser interstitial thermal therapy (LITT) has been successfully applied to other brain tumors, and recent work aims to explore the safety and long-term outcome experiences of LITT for both new and recurrent meningiomas. The authors' objective was to report safety and outcomes data of the largest cohort of LITT-treated meningioma patients to date. METHODS:Eight United States-based hospitals enrolled patients with meningioma in the Laser Ablation of Abnormal Neurological Tissue Using Robotic NeuroBlate System (LAANTERN) prospective multicenter registry and/or contributed additional retrospective enrollments for this cohort study. Demographic, procedural, safety, and outcomes data were collected and analyzed using standard statistical methods. RESULTS:Twenty adult patients (12 prospective and 8 retrospective) with LITT-targeted meningiomas were accrued. Patients underwent LITT for new (6 patients) and recurrent (14 patients) tumors (ranging from the 1st to 12th recurrence). The 30-day complication rate was 10%. Twenty percent of patients (4/20) had exhausted all other treatment options. Median length of follow-up was 1.3 years. One-third of new (2/6) and one-half of recurrent (7/14) meningiomas had disease progression during follow-up. One-year estimated local control (LC), progression-free survival, and overall survival rates were 55.3%, 48.4%, and 86.3%, respectively. In the 12 patients who had ≥ 91% ablative coverage, 1-year estimated LC was 61.4%. The complication rate was 10% (2/20), with 1 complication being transient and resolving postoperatively. CONCLUSIONS:This cohort study supports the safety of the procedure for this tumor type. LITT can offer a much-needed treatment option, especially for patients with multiply recurrent meningiomas who have limited remaining alternatives.