Betty Tyler

The days following decompression surgery for acute spinal cord injury (SCI) are a critical period for postoperative monitoring. After wound closure, clinicians lack on-demand access to local spinal cord morphology and hemodynamics, and care therefore remains guided largely by systemic surrogates rather than direct postoperative insight into the injured cord. We present the Multimodal Ultrasound System for Injury Care (MUSIC), a temporary epidural ultrasound neural interface placed during standard decompression surgery to enable postoperative brightness-mode imaging, Doppler-derived hemodynamic monitoring, and future device-integrated ultrasound actuation. Across simulations, benchtop, human cadaveric, and porcine studies, MUSIC enabled on-demand visualization of cord structure, hematoma tracking, detection and longitudinal tracking of localized Doppler flow signatures attributable to the sulcal artery region, and, in healthy pigs, proof-of-concept focused ultrasound modulation of blood-flow velocity. MUSIC establishes a temporary postoperative acoustic interface that provides spinal cord information to inform monitoring, future management, and localized intervention strategies after SCI.

Background/Objectives: Glioblastoma (GBM) remains one of the most aggressive primary brain malignancies, with limited therapeutic progress over the past two decades. Systemic administration of temozolomide (TMZ) is a pillar of clinical management but is constrained by poor brain penetration, short half-life, and systemic toxicity. Localized drug delivery systems represent a compelling approach to address these limitations. We report the development and evaluation of an injectable poly(sebacic acid–ricinoleic acid) poly(anhydride-ester) (pSARA) gel for sustained intratumoral delivery of TMZ. Methods: The pSARA gel was synthesized using a one-pot melt polycondensation technique, and its in vitro release dynamics were assessed using spectrophotometry. In vivo efficacy of the TMZ-loaded pSARA gel was evaluated as a monotherapy and as an adjuvant to radiation or surgical resection using an orthotopic 9L gliosarcoma rat model. Results: The formulation exhibits shear-thinning behavior, enabling syringe-based administration, and undergoes surface erosion in aqueous environments to achieve controlled drug release. In vivo, the TMZ-loaded pSARA significantly prolonged survival compared to controls and outperformed paclitaxel-loaded formulations. Furthermore, combination therapy with radiation or surgical resection demonstrated combined survival benefits, including long-term survivors. Conclusions: These findings highlight the translational potential of pSARA-based local delivery systems as an adjunct or alternative to systemic chemotherapy in GBM treatment.

BACKGROUND AND OBJECTIVES: Chemotherapeutic drug delivery to intramedullary spinal cord tumors (IMSCTs) is restricted by the blood–spinal cord barrier. Focused ultrasound (FUS), however, can transiently disrupt the blood–spinal cord barrier. Therefore, this study investigates the feasibility of using FUS-enhanced Abraxane (albumin-bound paclitaxel) delivery to improve the treatment of IMSCTs using a rodent model. METHODS: Twenty-eight F344 rats received an intramedullary injection of 100 000 luciferase-tagged 9L gliosarcoma cells. Rats were classified into 4 cohorts: no-treatment, FUS, Abraxane, and FUS-enhanced Abraxane delivery. Treatments were administered on days 7, 14, and 21. Tumor burden was assessed weekly using bioluminescence-based imaging. Twice a week, nociceptive thresholds were assessed using the Von Frey Filament test, and motor function was assessed using the Basso-Beattie-Bresnahan locomotor scale. RESULTS: The FUS-enhanced Abraxane delivery cohort had significantly decreased tumor burden ([1.52 ± 0.69] × 10 ⁶ photons/s) compared with the no-treatment ([9.03 ± 5.13] × 10 ⁶ photons/s), FUS-only ([8.25 ± 1.58] × 10 ⁶ photons/s) and Abraxane-only ([4.19 ± 1.91] × 10 ⁶ photons/s) groups (day 18, P < .0001). Although all rodents initially demonstrated motor decline, the FUS-enhanced Abraxane group had complete return-to-baseline motor scores (21.0) by day 27, whereas the no-treatment (8.3 ± 1.5), FUS-only (6.0 ± 1.4), and Abraxane-only (16.3 ± 1.3) cohorts maintained decreased Basso, Beattie, and Bresnahan scale scores to day 48. Similarly, while all animals demonstrated initial hypersensitivity to pain, only the FUS-enhanced Abraxane group returned to baseline pain response by day 48 (17.4 ± 6.1 g) when compared with the no-treatment (7.0 ± 6.2 g), FUS-only (5.0 ± 1.4 g), and Abraxane-only (11.2 ± 7.5 g) cohorts. CONCLUSION: FUS-enhanced Abraxane delivery significantly reduced IMSCT tumor burden and improved neurological recovery over intravenous administration alone. Therefore, FUS-mediated chemotherapeutic drug delivery may represent a noninvasive, clinically relevant, and effective treatment paradigm for intramedullary pathologies.

Figure S2: CCR6 expression is enhanced in tumor-infiltrating Tregs co-expressing checkpoints and Ccr6 ablation reduces immunosuppressive phenotype.

Figure S3: Ccr6-/- Tregs are transcriptionally and metabolically distinct from WT Tregs.

Figure S1: CCR6 and CCL20 expression is increased in multiple tumors.

Figure S5: Ccr6 ablation reduces Treg immunosuppression of CD8 T cells in the context of tumor growth.

Figure S4: Ccr6-/- Tregs have reduced glycolysis compared to WT Tregs.

Figure S6: Ccr6 ablation delays tumor growth across multiple tumor models and CCR6CCL20 expression correlates with overall survival in cancer patients.

In chordoma, epidermal growth factor receptor (EGFR) blockade shows significant but incomplete antitumor activity, suggesting that inhibition of other tumor growth–promoting pathways is required for enhanced efficacy. In this study, we detected high expression of cyclin-dependent kinases (CDKs), specifically CDK7 and CDK9, in both sacral and clival chordomas and subsequently explored the efficacy of the CDK inhibitors THZ1 and TG02, both as single agents and in combination with the EGFR inhibitor afatinib in preclinical chordoma models. Monotherapy with THZ1, TG02, and afatinib led to decreased cell viability, proliferative capacity, colony formation, and induced apoptosis across multiple chordoma cell lines, and enhanced activity was observed with THZ1/afatinib and TG02/afatinib cotreatments. Mechanistically, THZ1 and TG02 each attenuated phosphorylation of RNA polymerase II, leading to transcriptional inhibition of the chordoma driver gene brachyury, which was enhanced when combined with afatinib. Both CDK inhibitors also reduced expression of MCL1, which was further suppressed with combination therapy. Importantly, cotreatments exhibited greater inhibition of tumor growth than single treatments in cell line– and patient-derived xenograft models. Taken together, our data revealed that THZ1 or TG02 enhanced the in vitro and in vivo efficacy of afatinib, suggesting a potential novel combination therapeutic strategy for patients with chordoma.