Rechberger, Julian S.

OBJECTIVE Glucagon-like peptide-1 (GLP-1) agonists are established therapeutics for weight loss that are increasingly used for BMI optimization prior to spine surgery. However, emerging evidence has suggested that GLP-1 agonists might reduce bone mineral density (BMD), increasing the risk of postoperative biomechanical complications. CT-based Hounsfield units (HUs) have gained popularity as a method for measuring spinal BMD. The aim of this study was to evaluate the effects of GLP-1 agonist–induced weight loss on spinal BMD as measured by opportunistic CT-based HUs. METHODS Patients who were treated with any GLP-1 agonist (2017–2022) for > 3 months were retrospectively identified. Patient body weight (BW), BMI, and HU measurements in the L1 vertebral body were measured before and after GLP-1 therapy. Patients were grouped according to the percentage of weight loss during GLP-1 therapy. One-way ANOVA was used to compare the mean changes in spinal HUs across the groups. RESULTS Among the 102 included patients, the mean ± standard error of the mean BW reduction was 14.5 ± 2.5 kg over 15.9 ± 1.2 months of GLP-1 agonist therapy. Of these, 7 patients (6.9%) lost > 20% BW (mean decrease of 31.9 ± 7.0 HU, p = 0.011), 14 (13.7%) lost 15%–20% BW (mean decrease of 19.1 ± 8.3 HU, p = 0.038), 14 (13.7%) lost 10%–15% BW (mean decrease of 12.2 ± 5.1 HU, p = 0.036), 24 (23.5%) lost 5%–10% BW (mean decrease of 15.7 ± 3.3 HU, p < 0.0001), 26 (25.5%) lost < 5% BW (mean decrease of 14.7 ± 6.0 HU, p = 0.022), and 17 (16.7%) gained BW during GLP-1 therapy (mean decrease of 6.3 ± 5.0 HU, p = 0.229). One-way ANOVA testing did not show a significant difference in HU reduction across the weight loss groups (F = 1.12, p = 0.355). In addition, there was a significant correlation between the decrease in L1 HUs and the duration of GLP-1 therapy (r = −0.38, p = 0.0001) but not the amount of weight loss (r = −0.18, p = 0.070). In the multivariate analysis, the duration of GLP-1 therapy (p = 0.032) was a significant independent predictor of vertebral HU reduction, but the amount of weight loss (p = 0.664) was not. CONCLUSIONS Despite similar pretreatment BW and HU measurements, all weight loss groups had significant decreases in vertebral HUs following GLP-1 agonist therapy, with a significant correlation observed between HU reduction and treatment duration. This suggests that long-term GLP-1 agonist therapy can significantly diminish spinal BMD regardless of the amount of weight loss achieved.

Abstract Pontine H3 K27-altered diffuse midline gliomas (DMGs) are rare, fatal pediatric brain tumors resistant to systemic therapies due to the blood-brain barrier (BBB) and efflux transporters (ETs), which actively clear drugs from the brain. Convection-enhanced delivery (CED) bypasses the BBB by directly infusing therapeutics into the tumor, but maintaining adequate drug concentrations remains a challenge. This study explores strategies to enhance drug-tumor residence time and improve treatment efficacy. Using chemical modeling, FDA-approved drugs identified in prior high-throughput screening efforts were classified based on physiochemical properties impacting CED pharmacokinetics, including BBB penetration and ET substrate status. Drug behavior was validated in patient-derived in vitro and in vivo DMG models. The impact of systemic drug co-administration on drug retention and therapeutic efficacy was evaluated using multiple patient-derived orthotopic xenograft (PDOX) models. ET substrate drugs exhibited rapid elimination from the brain post-CED, limiting their therapeutic potential. However, systemic everolimus administration prolonged drug retention and potentiated the effects of efflux substrate drugs delivered via CED (e.g., topotecan, ponatinib). This combinatorial approach significantly enhanced anticancer effects in multiple PDOX models, demonstrating improved tumor control compared to monotherapy. Overall, these findings suggest that pharmacological inhibition of ETs via systemic everolimus administration can enhance drug retention in DMG when combined with CED. The observed synergistic effects highlight a promising strategy to overcome drug clearance limitations and improve treatment outcomes. Further clinical investigation is warranted to validate this approach in patients.

Background For large vessel occlusion (LVO) ischemic strokes, three major techniques of mechanical thrombectomy (MT) have demonstrated efficacy. Here we compare the safety and efficacy of stent retrievers (SR), contact aspiration (Asp), and a combined mechanical thrombectomy (cMT) for LVO ischemic stroke. Methods Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we queried the PubMed, EMBASE, Scopus, and Web of Science databases for studies published prior to December 2024 describing patients with ischemic stroke who underwent MT using SR, Asp, or cMT. Results Twnety-four studies comprising a total of 12 845 patients were included in the analysis. Compared with cMT, Asp was associated with a lower rate of first pass effect (FPE) (risk ratio (RR) 0.67; 95% CI 0.46 to 0.96), shorter procedure duration (mean difference (MD) −13.35 min; 95% CI −20.83 to –5.87), and lower risk of arterial dissection (RR 0.50; 95% CI 0.29 to 0.87). Additionally, SR use was linked to a higher procedure duration compared with Asp (MD 13.39 min; 95% CI 5.55 to 21.22) and a lower symptomatic intracranial hemorrhage rate (RR 0.75; 95% CI 0.59 to 0.96). No significant differences were observed between groups in terms of number of passes, successful recanalization, 90-day functional outcomes, mortality, arterial perforation, or embolization to new territory. Conclusions All three techniques demonstrated similar recanalization rates and functional outcomes. However, Asp was associated with shorter procedure times and fewer arterial dissection complications, while cMT showed a higher FPE. Given the comparable overall efficacy, the choice of technique should be guided by the physician’s preference, expertise, and confidence, tailored to the individual patient’s profile.

Background Facial synkinesis is characterized by involuntary co-contraction of facial muscles during voluntary movements, impairing both function and aesthetics following facial paralysis. It affects approximately 21% of individuals following Bell's palsy, with symptoms such as involuntary eye closure when smiling. While the pathophysiology remains unclear, therapeutic options range from conservative approaches like botulinum toxin to surgical interventions. A bibliometric analysis offers insights into research trends, key contributors, and knowledge gaps in this field. Materials & Methods A systematic search was conducted in the Scopus database up to July 2024, identifying 100 most-cited articles on facial synkinesis. Articles were categorized as basic science (BSc), clinical (CL), or review articles, with additional data extracted on study focus, journal type, citation metrics, and authorship. Statistical analyses included Pearson's χ2 and Wilcoxon rank sum tests. Results The articles spanned 1952–2020, with the highest publication frequency in 2017. Clinical studies constituted 76%, focusing on conservative treatments (35%), diagnostics (28%), and surgical interventions (19%). Plastic surgery and ENT journals accounted for 76% of publications. The most-cited article, published in neurology (1975), investigated electrophysiologic diagnostics. Citation metrics revealed a mean citation count of 38.3 and a median publication year of 2010. The 50 newer articles demonstrated a trend toward surgical management of synkinesis. Conclusions This bibliometric analysis highlights the evolution of research on facial synkinesis, emphasizing the predominance of clinical studies, focus on conservative treatments and gaps in basic science research. Further research is needed to fill knowledge gaps to improve outcomes for affected patients.

Central nervous system (CNS) tumors are the leading cause of cancer-related mortality in children, with prognosis remaining dismal for some of these malignancies. Though the past two decades have seen advancements in surgery, radiation, and targeted therapy, major unresolved hurdles continue to undermine the therapeutic efficacy. These include challenges in suboptimal drug delivery through the blood–brain barrier (BBB), marked intra-tumoral molecular heterogeneity, and the elusive tumor microenvironment. Drug repurposing or re-tasking FDA-approved drugs with evidence of penetration into the CNS, using newer methods of intracranial drug delivery facilitating optimal drug exposure, has been an area of intense research. This could be a valuable tool, as most of these agents have already gone through the lengthy process of drug development and the evaluation of safety risks and the optimal pharmacokinetic profile. They can now be used and tested in clinics with an accelerated and different approach. Conclusions: The next-generation therapeutic strategy should prioritize repurposing oncologic and non-oncologic drugs that have been used for other indication, and have demonstrated robust preclinical activity against pediatric brain tumors. In combination with novel drug delivery techniques, these drugs could hold significant therapeutic promise in pediatric neurooncology.

Abstract Giant intracranial aneurysms require complex treatment strategies including clipping, coiling, stenting, parent artery occlusion, bypass, or combined procedures. Neurovascular hybrid operating rooms (h-OR) combine a conventional operating theatre with high-resolution digital subtraction angiography (DSA). We describe a one-step combined surgical and endovascular treatment in a h-OR for a pediatric internal carotid artery (ICA) giant aneurysm that can be an optimal solution to manage such challenging cases. An 11-year-old boy presented with rapid onset right hemiparesis and left eyelid ptosis. A 3-month history of headache associated with sporadic vomit was reported. A giant, unruptured, left ICA aneurysm was detected on imaging. The patient underwent surgical trapping of the aneurysm. Intraoperative DSA showed residual backflow from the posterior communicating artery and coils were placed to completely exclude the aneurysm. At 18-month follow-up, the patient showed a complete recovery and magnetic resonance imaging showed a progressive reduction of the sac aneurysm. Due to their morphological variability, intracranial giant aneurysms may require a different procedural strategy instead of direct clipping or coiling. The introduction of h-OR allows combined treatments to be performed simultaneously in the same room setting. The present case shows that combined treatment in a neurovascular h-OR can be an optimal solution to manage challenging cases, such as giant aneurysms, reducing operative time with the added benefit of selecting an appropriate strategy adjustment in a multidisciplinary effort.

Abstract Advancements in understanding H3 K27-altered diffuse midline glioma (DMG) biology have not yet translated into effective therapies for these tumors likely due to delivery challenges across the blood-brain barrier (BBB) and variable tumor genetics. This study systematically probes convective-enhanced delivery (CED) as a means to administer small molecule drugs directly to DMG tumors, circumventing constraints imposed by the BBB. Our findings emphasize the necessity of strategic drug selection and pharmacokinetic analysis in refining CED approaches, advocating for precision medicine techniques specialized for DMG. We demonstrate that while most small molecule drugs are rapidly cleared from the brain following CED, their retention and effectiveness are substantially improved by co-administration of systemic efflux transporter (ET) inhibitors such as everolimus. The synergistic potential of combining everolimus with topotecan or ponatinib offers a novel therapeutic pathway, advocating for further investigation into this DMG management strategy.