Citations

Abstract Objectives Pivotal trials have established the effectiveness of the Responsive Neurostimulation System (RNS® System) in treating focal epilepsy. In clinical trials, depth leads were primarily used to treat mesial temporal seizure onsets while cortical strip leads were used to treat neocortical seizure onsets. Here, we systematically analyze the safety and efficacy of stereoelectroencephalography (sEEG)‐guided depth leads to provide responsive stimulation to neocortical gray matter. Methods Patients were stratified as strong responders (>median cohort seizure reduction %), weak responders (>0% and ≤median cohort seizure reduction %), and anti‐responders (≤0%) based on percent seizure reduction at 1 year post‐implant (1‐Y). Pre‐operative T1‐weighted magnetic resonance imaging and post‐operative computed tomography images were merged, and the Euclidean distance between the sEEG epileptic focus (sEEG‐EF) and the nearest RNS System depth lead contacts was calculated. Results A total of 87 depth leads were implanted in 55 patients across neocortical brain regions. The median reduction in clinical seizures improved from 66.7% at 1‐Y to 77.5% at long‐term follow‐up (LTFU: 2.35 ± 0.95 years), with 10 patients (18.2%) achieving complete seizure freedom. Seven patients (12.7%) experienced six serious adverse events. At 1‐Y, shorter Euclidean distance between the sEEG‐EF and RNS System depth leads predicted improved seizure outcome in strong responders ( β = −0.84, p = 0.008) but not in weak responders ( β = 0.21, p = 0.9) or anti‐responders ( β = −20.34, p = 0.11). At LTFU, there was no significant relationship between Euclidean distance and seizure reduction in strong responders ( β = 0.77, p = 0.18), weak responders ( β = 2.05, p = 0.54), or anti‐responders ( β = 0.24, p = 0.99). Exploratory analyses at 1‐Y showed nominal associations between older age ( ρ = 0.32), longer epilepsy duration ( ρ = 0.27), and non‐mesial temporal sEEG‐EFs and greater seizure reduction; however, none survived Bonferroni correction (adjusted α = 0.0027; all post‐correction p > 0.0027), and no associations were observed at LTFU. Significance In this series, neocortical depth leads for RNS therapy had favorable safety and efficacy and proximity to the sEEG‐EF drove initial outcomes for strong responders to RNS therapy. Plain Language Summary In this multi‐center study, patients with difficult‐to‐treat seizures received brain‐responsive stimulation using a device called responsive neurostimulation (RNS), which delivers small electrical pulses to reduce seizures. We focused on patients treated with electrodes placed in the brain's outer regions (the neocortex) and guided by a mapping procedure called sEEG. On average, patients had their seizures cut by two‐thirds after one year and by more than three‐quarters with longer follow‐up, with about one in five becoming seizure‐free. The treatment was safe, and closer electrode placement to the seizure source helped explain early—but not long‐term—improvements.

Objective: To characterize patient outcomes after primary stereotactic radiosurgery (SRS) for the management of sporadic facial nerve schwannoma. Study design: Retrospective cohort study. Setting: Six tertiary referral centers across the United States and United Kingdom. Patients: Adults undergoing SRS from 2000 through 2023 for sporadic facial nerve schwannoma along any segment of the facial nerve were included. Patients with NF2-related schwannomatosis were excluded. Intervention: Stereotactic radiosurgery. Main outcome measure: Long-term tumor control. Results: Among 60 patients meeting inclusion, the median age at SRS was 52 years (IQR: 41 to 64) with a median tumor size of 19.5 mm (IQR: 14.7 to 22.8). Tumors commonly involved the internal auditory canal (73%), cisternal (49%), geniculate/labyrinthine (47%), and tympanic segments (22%). Two patients experienced SRS failure and underwent salvage treatment; salvage-free survival rates (95% CI; number still at risk) at 1, 3, 5, and 10 years after SRS were 100% (100 to 100; 55), 100% (100 to 100; 36), 100% (100 to 100; 18), and 87% (72 to 100; 9), respectively. Among 31 (52%) patients with House-Brackmann (HB) grade I facial function at presentation, only 6 demonstrated worse facial function at a median of 3.2 years (IQR: 1.7 to 6.6) after SRS. Of 18 patients with serviceable hearing (AAO-HNS class A/B) at SRS, 13 maintained serviceable hearing at a median of 1.0 years (IQR: 0.5 to 4.9) of post-SRS audiometric follow-up. Conclusions: Durable tumor control after primary SRS for sporadic facial nerve schwannoma is achieved in most patients. Among those with HB grade I facial function at presentation, treatment with SRS harbors limited additional risk of facial paresis beyond observation alone.

Abstract Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of liquid tumors but faces many challenges against solid tumors including T cell exhaustion and poor CAR durability. Here, we show that engaging the CAR T cell endogenous TCR using an oncolytic virus (OV) enhances CAR T cell functionality, durability, and therapy. Upon combination therapy of solid tumors with CAR T cells and vesicular stomatitis virus (VSV), a subpopulation of antiviral, TCR-primed CAR T cells was generated with enhanced effector functions, altered activation states, and differential gene and protein expression when compared to CAR T cells that do not undergo TCR priming. Single cell RNA-sequencing showed clonal expansion of anti-VSV CAR T cells, selective avoidance of exhaustion, and enhancement of effector-associated genes with VSV-mediated CAR T cell expansion. CD4 T cells played a pivotal role in both the generation and polarization of these TCR-primed CAR T cells. These results provide a strong rationale both for a novel use of intravenous administration of oncolytic viruses with separate applications from their direct oncolytic activity and for directly exploiting the TCR and its endogenous interactions as tools for fine tuning the phenotype and function of CAR T cells, with particular efficacy against solid tumors.

Abstract Polyamines are small molecules that play a critical role in tumor progression and in the regulation of immune responses within the tumor microenvironment. Elevated levels of polyamines in cerebrospinal fluid and tumor tissue have been reported in multiple studies and are shown to correlate with glioma grade. These findings suggest that the polyamine metabolic pathway may represent a therapeutic target in gliomas. Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis, expected to exert antitumor effects through polyamine depletion. Although the impact of DFMO against glioblastoma as a monotherapy appears limited, opportunities for synergy with other therapies remain understudied. In this study, we evaluated the therapeutic efficacy of DFMO using both in vitro and in vivo experiments with a murine glioma model (CT-2A) and patient-derived xenograft (PDX) cell lines. Among the models tested, CT-2A cells exhibited the highest expression of ODC1 and demonstrated strong sensitivity to DFMO in vitro. We compared two CT-2A variants: a commercially available line responsive to immunotherapy, and a widely used subline resistant to PD-1 blockade. While DFMO did not improve survival in mice implanted with the immunotherapy-sensitive commercial CT-2A line, it extended median survival by 8 days in mice bearing tumors derived from the immunotherapy-resistant subline. Transcriptomic analysis revealed that the DFMO-responsive, immunotherapy-resistant tumors exhibited lower baseline expression of immune-related genes, including those involved in interferon-β, interferon-γ, and IL-12 signaling pathways, compared to the immunotherapy-sensitive tumors. The latter showed markedly higher expression of STAT1 and interferon-γ and were enriched for immune-related Gene Ontology terms. These findings suggest that polyamine-targeted therapy may be appropriate for gliomas with an immunosuppressive, “cold” phenotype. Ongoing RNA sequencing analyses aim to further elucidate the immunomodulatory mechanisms of DFMO, and other agents comprising an adaptive toolkit to optimize and sustain anti-tumoral immunity.

Abstract INTRODUCTION Glioblastoma is the most common malignant adult brain tumor with poor prognosis, largely due to its heterogeneous landscape. The AI-RANO and RANO-RGP groups organized the BraTS-Pathology 2024 challenge, providing a publicly-available dataset and a benchmarking environment for AI models to automatically identify six clinically-relevant histopathologic sub-regions in H&E-stained whole slide images (WSIs). METHODS We reclassified the TCGA-GBM and TCGA-LGG data according to the WHO 2021 criteria and identified diagnostic WSIs of 188 glioblastoma (IDH-wt, CNS WHO Gr.4) patients. A well-defined annotation protocol was communicated to eight neuropathologists, across eight institutions, who created “ground truth” annotations for Cellular Tumor (CT), Geographic Necrosis, Cortical Infiltration, Pseudopalisading Necrosis (PN), Microvascular Proliferation, and Penetration into White Matter (PWM). Comprehensive WSI curation for elimination of artifactual content and follow up partitioning resulted in approximately 300,000 data samples/patches. FINDINGS Inter-observer variability assessment highlighted difficulties in establishing a “gold standard”. The least annotated sub-regions (PWM and PN) were the most challenging to the participating methods, whereas all methods achieved their highest accuracy in the most annotated sub-region (CT). The highest average performance across sub-regions was obtained by a foundation model-based method. However, this top-ranked solution achieved an F1 score of 0.51 (Accuracy=0.65, Sensitivity=0.56, Specificity=0.93). CONCLUSIONS Our findings suggest that achieving state-of-the-art performance, in automatically identifying clinically-relevant glioblastoma sub-regions, remains an unsolved research problem. Analysis of the ground-truth annotations underscores the critical need for more precisely defined and neuropathologically standardized annotation protocol. Current AI algorithms are facing difficulties in addressing glioblastoma’s heterogeneous histologic landscape in the absence of large, comprehensively, and consistently annotated data. Building upon these findings, and towards developing more accurate AI algorithms, the 2025 iteration of the BraTS-Path challenge is currently on-going by leveraging two million data samples, aiming to enhance our disease understanding and improve diagnostic accuracy, ultimately contributing to improved patient outcomes.

Background/Objectives: Family history is a known risk factor for multiple myeloma (MM) and its precursor condition, monoclonal gammopathy of undetermined significance (MGUS). Previous genome-wide association studies (GWASs) have identified 35 common loci associated with MM risk and 21 associated with MGUS. The objective of this study was to identify less common and rare genetic loci predisposing to MM/MGUS through whole-exome sequencing (WES)-based linkage analysis. Methods:Multipoint linkage analysis was conducted using the Multipoint Engine for Rapid Likelihood Inference (MERLIN) with the Lander–Green algorithm on germline WES data from 79 pedigrees with 2 or more affected relatives (120 MM, 86 MGUS, and 21 unaffected). Genome-wide linkage was evaluated using 12,946 independent single-nucleotide variants (linkage disequilibrium r2 < 0.05). Results: Significant linkage was observed at chromosome 6q22.33–q24.2 by the non-parametric model (logarithm-of-odds (LOD) = 3.3) and suggestive linkage by the dominant parametric model (heterogeneity LOD (HLOD) = 2.5). Fourteen rare variants within this region were prioritized using family-specific partial LOD scores and in silico functional prediction tools. Nine of these variants, REPS1, THEMIS, TAAR6, AHI1, VNN1, VNN3, MTFR2/FAM54A, LAMA2, and PHACTR2, overlapped immune-regulatory regions in blood cell lines and were not previously identified in GWASs. Conclusions: This study demonstrates the utility of applying a linkage analysis framework to familial WES data for identifying genomic regions and candidate genes that may contribute to MM/MGUS predisposition. These findings provide new insight into the inherited risk and etiology of familial MM and MGUS.

Abstract Background and Aims Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for potentially life-threatening arrhythmic events (AEs) even while treated with β-blockers. The aim was to develop a model for individualized prediction of AEs in patients with RYR2-mediated CPVT on β-blocker monotherapy. Methods The derivation and independent validation cohorts included 743 and 129 patients, respectively. AEs were defined as arrhythmic syncope, appropriate implantable cardioverter–defibrillator shock, sudden cardiac arrest (SCA), and sudden cardiac death. Near-fatal or fatal AEs (nf/fAEs) included all AEs except for arrhythmic syncope. Prediction models using Cox regression were developed and internally and externally validated. Results A total of 102 (13.7%) patients in the derivation cohort and 24 (18.6%) patients in the validation cohort experienced ≥1 AE over a median follow-up of 5.1 [interquartile range (IQR), 7.7] and 2.4 (IQR, 4.4) years, respectively. Predictors of AE were arrhythmic syncope or SCA prior to diagnosis and age at β-blocker initiation. In the derivation and validation cohorts, the optimism-corrected C-indices of the models for AE were 0.67 [95% confidence interval (CI) 0.62–0.72] and 0.59 (95% CI 0.48–0.71), respectively. For nf/fAEs, ventricular arrhythmia severity before β-blocker initiation was a fourth independent predictor, and C-indices of the models in the derivation and validation cohorts were 0.74 (95% CI 0.68–0.80) and 0.60 (95% CI 0.47–0.72), respectively. In the derivation cohort, calibration slopes were 1.00 (95% CI 0.59–1.41) for AE and 1.00 (95% CI 0.69–1.32) for nf/fAE. Conclusions These externally validated risk prediction models using clinical parameters accurately distinguished CPVT patients on β-blocker monotherapy at low and high risk for future AEs while treated with β-blockers. These models provide guidance for implementation of clinical management therapies to prevent AEs in patients with CPVT.

Abstract Background We examined real-world utilization of treat-to-target (TTT) strategies and conducted a quality improvement (QI) project to improve uptake of TTT strategies in a learning health system, IBD Qorus. Methods We implemented a structured QI intervention to increase uptake of TTT in 41 gastroenterology practices in the United States, over a 13-month intervention period (November 2020 to November 2021; modified breakthrough series [BTS] collaborative), and a 10-month post-BTS observation period (December 2021 to October 2022). Through encounter-level surveys, we examined providers’ “intention to TTT” based on discussion of TTT with patients, documentation of inflammation, and intention to change therapy to TTT. We examined changes in rates of “intention to TTT,” and whether improvement in intention to TTT influenced site-level rates of remission. Results Over 13 months, there were 7932 patient visits (55% with Crohn’s disease; 47% in clinical remission); patients in 2160 visits (27%) were not in endoscopic remission. Overall, rates of intention to TTT increased from 31% to 54% (P = .06) with considerable site-to-site variability and was maintained at 49% in the post-BTS observation period. The increased rate was attributable to higher rates of testing for inflammation. Despite an increase in the rate of intention to TTT, there was no significant change in site-level achievement of remission over the same time. Conclusions Through a QI initiative in a learning health system, rates of intention to TTT increased significantly over 12-months, though overall rates remained low. Assessing patient-, provider- and practice-level barriers and facilitators for successful implementation of a TTT strategy is warranted to improve clinical outcomes.

Abstract Repetitive head impacts are common in contact and collision sports and are linked to structural brain changes and an elevated risk of neurodegenerative diseases such as Chronic Traumatic Encephalopathy. Identifying early in vivo structural markers remains challenging. Although diagnosis currently requires post-mortem confirmation, clinical symptoms, including cognitive impairment and behavioural changes, are reflected in the diagnosis of Traumatic Encephalopathy Syndrome. These symptoms align with dysfunction in key brain regions—amygdala, hippocampus and thalamus—which support memory, emotion and behaviour and commonly show tau pathology in Chronic Traumatic Encephalopathy. This study uses shape analysis to examine structural differences in these regions between former American football players and unexposed asymptomatic controls and evaluates the influence of age, head impact exposure and clinical diagnosis on brain structure. We analyzed brain morphology in former American football players (n = 163) and unexposed, asymptomatic controls (n = 53). Structural segmentation was performed with FreeSurfer 7.1, and the shape analysis pipeline was used to generate subregional reconstructions. Vertex-level morphometry, based on the logarithm of the Jacobian determinant and radial distance, quantified local surface area dilation and thickness. Group differences were examined with covariate-adjusted linear regression models contrasting football players and controls, as well as participants with and without a Traumatic Encephalopathy Syndrome diagnosis. Partial correlations examined the influence of age, age of first football exposure and cumulative head impact index metrics, including frequency, linear acceleration and rotational force. Models were adjusted accordingly for age, body mass index, education, race, imaging site, apolipoprotein ϵ4 status and total intracranial volume. Former football players exhibited bilateral surface area contractions in the hippocampus and amygdala, along with reduced amygdala thickness, compared to controls. Older age was associated with widespread surface contractions and thinning across all regions, except for preserved thickness in the left hippocampus. An earlier age of first exposure to football correlated with surface contractions in the thalamus and left hippocampus. Greater cumulative linear acceleration was linked to bilateral hippocampal surface contractions and reduced thickness in the left thalamus, while greater rotational force exposure was associated with hippocampal thinning. No significant structural differences were found between players with and without a diagnosis of Traumatic Encephalopathy Syndrome. These findings extend volume-based research by revealing localized alterations in surface area dilation and thickness and emphasize the roles of age and repetitive head impact exposure in long-term brain changes.