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Importance Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have become substantially more popular as a medication to treat obesity and type 2 diabetes (T2D). Despite their known association with gastroesophageal reflux disease and vagal nerve stimulation, the association between GLP-1RAs and chronic cough has not been previously studied. Objective To assess the clinical association between GLP-1RAs and chronic cough. Design, Setting, and Participants This large, multicenter cohort study used clinical records from a US-based collection of electronic medical record data from April 28, 2005, to April 15, 2025, from 70 health care organizations. Adults (≥18 years) with T2D and prescription of a GLP-1RA were identified. Additionally, groups with T2D and prescription of another second-line diabetes medication, including dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and sulfonylureas were created. After propensity score matching for various demographic and clinical characteristics, adjusted hazard ratios (aHRs) and 95% CIs were calculated using Cox regression analyses to estimate the risk of new chronic cough or gastroesophageal reflux disease diagnosis. Exposure GLP-1RAs or other second-line diabetes medication. Main Outcomes and Measures Chronic cough. Results Cohorts included 427 555 individuals (mean [SD] age, 55.8 [13.8] years; 251 928 female individuals [58.9%]) with T2D who were prescribed a GLP-1RA and 1 614 495 individuals (mean [SD] age, 63.7 [13.3] years; 712 946 female individuals [44.4%]) with T2D who were prescribed another second-line diabetes medication. After propensity score matching, individuals prescribed a GLP-1RA had significantly increased risk of new chronic cough compared with individuals prescribed any non–GLP-1RA second-line medication (aHR, 1.12; 95% CI, 1.08-1.16), DPP-4 inhibitor (aHR, 1.18; 95% CI, 1.11-1.26), or sulfonylurea (aHR, 1.32; 95% CI, 1.24-1.40) but not compared with SLGT2 inhibitors (aHR, 1.03; 95% CI, 0.98-1.09). After removing patients with a previous diagnosis of gastroesophageal reflux disease from analysis, patients prescribed GLP-1RAs had significantly increased risk of chronic cough compared with those prescribed any non–GLP-1RA (aHR, 1.29; 95% CI, 1.17-1.42), DPP4 inhibitor (aHR, 1.36; 95% CI, 1.17-1.58), SGLT2 inhibitor (aHR, 1.14; 95% CI, 1.02-1.28), or sulfonylurea (aHR, 1.25; 95% CI, 1.09-1.42). Conclusions and Relevance This cohort study suggests an association between GLP-1RA use and chronic cough. Further research is needed to confirm the existence, strength, and mechanisms of this association.

Abstract Background Children’s Oncology Group ACNS0333 treated atypical teratoid/rhabdoid tumor (ATRT) with surgery, chemotherapy (induction and consolidation) and radiation therapy (RT). M0 had focal RT and M+ had physician-selected focal RT or craniospinal (CSI). Methods Forty patients (29 M0, 11 M+) received RT. Pre-RT chemotherapy response was complete, partial, or stable disease. RT timing (age/stage-based) was pre-consolidation (RT-first) or post-consolidation (consolidation-first). Event-free survival (RT-EFS), overall survival (RT-OS), and cumulative incidence of local relapse (CILR) or distant relapse (RT-CIDR) were calculated. Analyses included log-rank tests and relative hazard rates with 95% confidence intervals to estimate proportional hazards regression. Results Four-year RT-EFS was 56.8% and 4-year RT-OS was 58.8% focal RT: 34 patients, CSI: 6 patients). A trend for superior RT-EFS for M+ compared to M0 (P = .0625, RHR 0.26; 95% CI 0.06-1.18) was shown. RT-EFS was improved for consolidation-first compared to RT-first timing (P = .037, RHR 0.43; 95% CI 0.13-1.37). Pre-RT chemotherapy response was associated with improved RT-EFS (P = .031) and RT-OS (P = .0069). Four-year RT-CILR was 7.84%; no differences in RT-CILR were shown for higher primary RT dose (≥5400 cGy, P = .38) or gross total resection (P = .80). 4-year RT-CIDR was 27.8% for M0 and 9.1% for M+ patients (P = .22). M+ had CSI (n = 6) or focal RT (n = 5). Fatal necrosis potentially-attributable to RT occurred in 3 RT-first patients (occuring either 1.6, 4.6, or 16.2 months post-treatment). Conclusions RT with intensive systemic therapy showed promising survival outcomes and effective primary disease control in ATRT. Sequencing RT prior to myeloblative chemotherapy, rather than post-consolidation, may be associated with increased risk of fatal radionecrosis.

Abstract Description Glioblastoma (GBM), the most common and malignant primary brain tumor, exhibits profound immune suppression, hindering immunotherapy efficacy. GBM-derived extracellular vesicles (EVs) play a major role through the immunosuppressive polarization of myeloid cells. Inhibition of EV-myeloid cell interactions thus represents a novel target to mitigate GBM-mediated immune suppression. However, there are multiple mechanisms of EV-target interaction, and downstream pathways of GBM-EV signaling are poorly understood. We explored two pharmacological agents targeting different mechanisms of EV uptake: Methyl-B-cyclodextrin (MBCD), which disrupts lipid rafts, and cytochalasin D, which inhibits actin polymerization. Our results showed immunosuppressive myeloid cell (CD11b+/ CD15-/ HLA-DRlow/ CD14high) populations increased upon GBM-EV treatment. Following cytochalasin D treatment, fewer immunosuppressive myeloid cells were observed (7.40%±1.01 vs. untreated 9.66%±2.86), with rescuing T cell proliferation. Conversely, MBCD treatment increased immunosuppressive myeloid cell levels (10.42%±2.38 vs. untreated 8.87%±3.97) without impacting T cell proliferation. This study demonstrates the feasibility of pharmacologically targeting EV-myeloid cell interactions to rescue tumor mediated immune suppression by inhibiting actin-dependent endocytosis with cytochalasin D. The converse results using MBCD treatment indicate differential importance of different EV uptake pathways in monocyte regulation. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Abstract Description Glioblastoma (GBM), the most common and malignant primary brain tumor, exhibits profound immune suppression, hindering immunotherapy efficacy. GBM-derived extracellular vesicles (EVs) play a major role through the immunosuppressive polarization of myeloid cells. Inhibition of EV-myeloid cell interactions thus represents a novel target to mitigate GBM-mediated immune suppression. However, there are multiple mechanisms of EV-target interaction, and downstream pathways of GBM-EV signaling are poorly understood. We explored two pharmacological agents targeting different mechanisms of EV uptake: Methyl-B-cyclodextrin (MBCD), which disrupts lipid rafts, and cytochalasin D, which inhibits actin polymerization. Our results showed immunosuppressive myeloid cell (CD11b+/ CD15-/ HLA-DRlow/ CD14high) populations increased upon GBM-EV treatment. Following cytochalasin D treatment, fewer immunosuppressive myeloid cells were observed (7.40%±1.01 vs. untreated 9.66%±2.86), with rescuing T cell proliferation. Conversely, MBCD treatment increased immunosuppressive myeloid cell levels (10.42%±2.38 vs. untreated 8.87%±3.97) without impacting T cell proliferation. This study demonstrates the feasibility of pharmacologically targeting EV-myeloid cell interactions to rescue tumor-mediated immune suppression by inhibiting actin-dependent endocytosis with cytochalasin D. The converse results using MBCD treatment indicate differential importance of different EV uptake pathways in monocyte regulation. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

Abstract Description Glioblastoma (GBM), the most common and deadly primary brain tumor in adults, is associated with profound local and systemic immune suppression. Increasing evidence points to tumor-derived extracellular vesicles (EVs) as key mediators of this immunosuppression. In surveying the tumor-immune microenvironment in samples of ultrasonic aspirate collected during surgical resection of GBM (n = 12), we identified several key immunomodulatory markers expressed across a range of immune cells in the tumor microenvironment. Particularly, we found TIGIT, classically understood as a T cell inhibitory protein, expressed across a range of myeloid cell populations, including in myeloid-derived suppressor cells (MDSCs, 46.84±16.78% of total monocytic MDSCs). Co-culture of healthy donor monocytes (n = 10) with patient-derived EVs replicated similar effects (control 11.69±1.87 vs EV treated 23.32±2.0). Furthermore, Induced MDSCs significantly inhibit T cell proliferation (30.65±5.97% proliferation, v/s control 86.47±2.94, p = 0.0001), concomitant with a surge in Th2 immune responses via TIGIT+ suppressive monocytes. Targeted TIGIT inhibition restored T cell proliferation (64.13±1.327% v/s non-inhibited, 30.65±5.97%; p = 0.02) and protective immune response, confirming a pivotal role of TIGIT in immune suppressive GBM microenvironment. Furthermore, TIGIT inhibition may unmask NLRP3 function, potentially contributing to immune rescue. Funding Sources Neurosurgery Research& Education Foundation, K12 grant Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

OBJECTIVE The implementation of robotics and spinal anesthesia (SA) in spine surgery is rapidly expanding, offering significant benefits for an increasingly complex and aging patient population with degenerative spinal disease. Here, the authors present the largest cohort to date evaluating the combined use of these two techniques in minimally invasive (MIS) transforaminal lumbar interbody fusion (TLIF). METHODS The authors retrospectively analyzed surgical outcomes of a series of patients who underwent robot-assisted (RA)–MIS TLIF under SA and general anesthesia (GA) at their institution from 2018 to 2024. Primary outcomes included operative times and postoperative pain intensity. Secondary outcomes included estimated blood loss, intraoperative complications, postoperative functional status, length of stay (LOS), and discharge status. To address potential confounders, a 1:1 propensity score–matching and regression analysis was implemented. Statistical analyses were conducted using Python. RESULTS A total of 209 patients underwent RA-MIS TLIF, with 31 (14.83%) receiving SA and 178 (85.17%) GA. After propensity score matching, the SA cohort demonstrated significantly shorter median total operating room (OR) time, total procedure time, time from entering the OR to skin incision, and time from closure to leaving the OR (all p < 0.01). Additionally, postoperative pain scores were significantly lower (p < 0.01), and LOS was significantly shorter (p < 0.01) in the SA cohort. Regression analysis, adjusting for potential confounders, further supported these findings. CONCLUSIONS RA-MIS TLIF fusion under SA is a safe and effective approach that significantly reduces operative time, postoperative pain, and hospital LOS in patients undergoing surgery for degenerative lumbar spine disease.

Abstract Background DNA methylation profiling can be used to robustly predict postsurgical outcomes and response to radiotherapy (RT) for meningioma patients. To allow for seamless integration of these complementary models into clinical practice, a practical framework is needed. Methods We leveraged a cohort of nearly 2000 surgically-treated meningiomas with DNA methylation profiling and clinical outcomes data. Existing methylation-based prediction models were dichotomized to yield four risk groups: low and high recurrent risk, each with RT sensitive and resistant subgroups. Risk groups were correlated with progression-free survival in the context of existing biomarkers including extent of resection and WHO grade. Results We first demonstrated that all risk groups benefit from gross total resection. All “high-risk, RT sensitive” tumors (n = 306, 15.7%) also benefited from adjuvant RT: after GTR, median PFS increased from 4.68 (4.13-9.48) years to not reached (P = .003); after subtotal resection (STR), from 2.12 (1.59-3.02) to 4.09 (3.41-not reached) years (P = .004). “Low-risk, RT sensitive cases” (n = 1207, 61.8%) also benefited from RT after STR (median PFS 7.39 (6.66-12.8) vs. 16.53 (10.35-not reached) years, P = .03), suggesting that RT be considered in these patients. Neither “low-risk RT resistant” (n = 84, 4.3%) nor “high-risk RT resistant” (n = 356, 18.2%) cases benefited from RT, and the latter group was associated with universally poor outcomes. Conclusions We identify methylation-defined risk groups of meningioma for which additional benefit is gained from adjuvant RT, leading to a clinical decision-making framework for straightforward integration of molecular models into clinical practice.

Abstract BACKGROUND Awake craniotomy with speech mapping remains a gold standard for achieving maximal safe resection of diffuse gliomas located in eloquent cortex. Significant practice variability exists with regards to patient selection, speech mapping paradigms, aggressiveness of resection, and use of other adjuncts. We report our experience with speech mapping procedures for patients with diffuse gliomas, comparing cases performed with and without intraoperative MRI. METHODS A single-surgeon retrospective review of 148 consecutive awake craniotomy procedures, from 2008-2024, was performed. We recorded baseline patient characteristics, speech mapping findings, post-operative course, and volumetric extents of resection. Multivariate regression analyses were performed for factors predictive of permanent aphasia and residual tumor volume. RESULTS Speech mapping was performed in 95% of cases, with positive speech areas found in 49% of cases. Intraoperative MRI cases (75% of total) had significantly greater extent of resection (87.4% vs. 78.6%, p=0.03) despite equivalent pre-operative volumes. Post-operative new/worsened aphasia was 15% for mild and 5% for moderate symptoms, and this was associated with reduced rates of return to work (54% vs 78%, p=0.04). Predictors of recovery from aphasia were extent of resection (OR 1.1, p=0.006) and 90-day disease progression (OR 0.06, p=0.04). Predictors of residual tumor volume were pre-operative tumor volume (β 0.3, p&lt;0.001), identification of after-discharge potentials during speech mapping (β -9.7, p&lt;0.001), and pre-operative functional status (β -0.3, p=0.02). Overall survival was impacted by presence of contrast enhancement (p=0.0002), tissue diagnosis (p&lt;0.0001), and WHO grade (p&lt;0.0001). CONCLUSIONS Awake craniotomy with speech mapping remains a valuable strategy for achieving maximal safe resection of diffuse gliomas, with the majority of patients returning to baseline level of functioning. New/worsened aphasia is the biggest risk of surgery, which significantly impacts patient quality of life. Intraoperative MRI can be considered as an adjunctive tool for awake speech mapping during glioma surgery.

Abstract Glioblastoma (GBM) diagnosis integrates morphology and tumor molecular alterations. Patients with classic morphology are designated as histologic GBM (hGBM). Patients without classic morphology harboring TERT promoter mutation (TERTp), or epidermal growth factor receptor amplification (EGFRamp), or combined gain of chromosome 7 and loss of 10 (+7/-10) designate molecular GBM (mGBM). We compared radiographic features, genomic alterations, and clinical outcome between hGBM and mGBM. 109 mGBM Mayo Clinic cases diagnosed between 1993-2021 were matched to 101 cGBM by age, sex, year of diagnosis, and TERT promoter (TERTp) status. Clinical and radiographic data abstraction was blinded. Progression-free and overall survival were compared across groups in the subset of patients who received standard of care. Contrast enhancement was present on index MRI (MRI at diagnosis) for 98% (96/98) hGBM and 50% (54/107) mGBM (p&lt;0.0001) patients. mGBM tumors harbored fewer total copy number alterations (median of 16.5 vs 20, p=0.029) and were less likely to have CDKN2A/B homozygous deletion (56% vs 77%, p=0.005). Among the 87 mGBM and 82 hGBM receiving standard of care, median overall survival was longer for mGBM versus hGBM (2.24 vs 1.62 years, p=0.016). mGBM patients with +7/-10 (HR=2.60, p=0.035) or CDKN2A/B (HR=3.61, p=0.002) had poorer overall survival compared to mGBM patients without the corresponding alteration. On index MRI mGBM patients without contrast enhancement had better overall survival compared to hGBM (HR=0.50; p=0.003) whereas there was no survival difference between mGBM with enhancement and hGBM. mGBM with enhancement on index MRI likely represent undersampled, or early / evolving hGBM. mGBM patients with non-enhancing MRI, younger than 60, with long symptom profile including seizures, and some combination of non-anaplastic morphology, TERTp only, no homozygous deletion of CDKN2A/B, and low copy number complexity may represent other IDHwt glioma entities. Caution is advised in counseling, management, discussing prognosis, and inclusion in clinical trials.

Abstract OBJECTIVE To demonstrate that Prostate-specific membrane antigen (PSMA) PET imaging, though primarily used in prostate cancer surveillance, can reveal PSMA uptake in non-prostatic tumors due to neovascular PSMA expression. BACKGROUND PSMA PET imaging is increasingly used for staging and monitoring prostate cancer. However, PSMA uptake is not exclusive to prostate carcinoma and may be observed in non-prostatic malignancies, including glioblastoma, due to neovascular expression. CASE REPORT We present a 67-year-old gentleman with metastatic prostate carcinoma, diagnosed in 2014 and treated with neoadjuvant Lupron, prostatectomy, and salvage radiation. In 2019, he developed nodal recurrence in retroperitoneal and bilateral iliac chain nodes, treated with lymphadenopathy, six cycles of Taxotere-based chemotherapy, and consolidative proton beam radiation (56.25 Gy/25 fractions). He later developed progression to the right proximal humerus and left coracoid process, treated with stereotactic body radiation therapy (25Gy/5 fractions). Follow-up PSMA PET/CT revealed no systemic abnormalities but showed a new PSMA-avid lesion in the right medial temporal lobe. Brain MRI confirmed a 3.5 x 1.7 x 2.5 cm ring-enhancing, intra-axial lesion with edema. The patient was asymptomatic. PSA was undetectable on abiraterone/prednisone and leuprolide. He underwent right frontotemporal craniotomy and resection. Pathology confirmed Glioblastoma, IDH-wildtype, CNS WHO Grade 4 with focal epithelioid features and positive MGMT promoter methylation. He received standard-of-care treatment with radiation, temozolomide, and TTF device. Surveillance PSMA PET and MRI showed no residual brain avidity or progression. Discussion: PSMA is a type II transmembrane glycoprotein expressed by prostatic and various non-prostatic tissues. In healthy brain parenchyma, PSMA expression is typically absent but is overexpressed in neovasculature of high-grade gliomas, including glioblastoma, IDH-wildtype, allowing for radiotracer uptake, as seen in this case. CONCLUSION This case illustrates the potential role of PSMA as a diagnostic tool, as it allows for easy identification of glioblastoma neovasculature, as demonstrated in our case report.