Bechtle, Alexandra

Abstract Extra-axial chordoma (EAC) is a very rare, malignant tumor with metastatic potential that arises in the extra-axial skeleton and soft tissues. We report the case of a 51-year-old right-handed male with EAC of the left capitate. He underwent capitate resection and wrist arthrodesis utilizing scaphoid autograft with the treatment goal of minimizing risk of tumor recurrence and metastasis while maximizing hand and wrist function. His radiographic outcome demonstrated union of his arthrodesis site. However, 7 months postoperatively, he started experiencing increased hand and wrist pain and was found to have early tumor reoccurrence. Few cases of EAC have been reported in the literature. EAC is typically treated with resection alone, although there is a limited role for chemotherapy and radiation in the setting of locally reoccurring or metastatic disease. Functional outcomes of the affected extremity and survival outcomes vary widely. This is the first report in the literature of EAC of a single carpal bone and describes an innovative technique for definitive surgical treatment of this rare tumor. Utilization of scaphoid autograft for wrist arthrodesis in the setting of capitate resection allows the use of autograft in a wrist arthrodesis without the additional morbidity of iliac crest bone grafting. This case also demonstrates the importance of appropriate diagnosis and oncologic technique at the index surgery.

ABSTRACT Fixation constructs used in orthopedic surgery are typically evaluated based on their initial mechanical strength. However, fixation failure often occurs under cyclic loading in dynamic environments where early motion and stress concentration are common. In the foot and ankle, nitonal staples and short locking plates have been developed to maximize construct stiffness and accommodate the limited bony surface area available for fixation. The implants have grown in popularity, but unlike other AO constructs, they have not been rigorously studied across multiple mechanical performance domains. Prior studies have not comprehensively compared dynamic nitinol constructs to static plates and screws across key mechanical performance metrics under fatigue conditions. Six fixation constructs (2‐leg staple, 4‐leg staple, 4‐leg + 2‐leg perpendicular staple, 4‐hole titanium plate, 5‐hole titanium plate with cross‐screw, and 4‐leg staple + dynamic disc + cross‐screw) were evaluated using standardized synthetic bone block models ( n = 5/group). Constructs were subjected to 100 cycles of loading. Pre‐ and post‐cycle values for compression ( N ), contact area (mm²), rigidity ( N ), and torque ( N ·cm) were measured. Paired t‐tests assessed intra‐construct degradation as well as post‐cycle inter‐construct differences. Additionally, ANOVA with Tukey HSD identified inter‐construct differences in degradation. Cohen's d quantified effect sizes. The 4‐leg + 2‐leg perpendicular construct had the highest post‐cycle compression (68.0 N) and contact area (447.2 mm²), with small to moderate degradation (d = –1.38; −0.99); the 4‐hole plate showed the greatest degradation ( p = 0.001, d = −3.48; p < 0.001, d = −4.45). Torque and rigidity degraded most in the 5‐hole plate (Δ = −94.4 N·cm, p = 0.0002, d = −6.21; Δ = −237.4 N, p = 0.015, d = −1.83), while dynamic constructs showed better retention. Dynamic nitinol constructs outperformed static plates and screws across all metrics, especially in preserving compression and contact while also resisting fatigue. Dual‐plane constructs—4‐Leg + 2‐Leg perpendicular and 5‐Hole Plate with Screw—demonstrated 2–3× higher initial rigidity than their single‐plane counterparts and showed superior fatigue resistance. Dynamic nitinol constructs demonstrated superior biomechanical durability compared to static plate‐and‐screw constructs, particularly when used in dual‐plane configurations. These findings support a shift in fixation strategy toward implants that maintain mechanical engagement under physiologic loading. In load‐bearing regions like the foot, fixation constructs must retain strength through repetitive stress. Dual‐plane dynamic nitinol implants provide continuous compression and greater fatigue resistance, making them a compelling alternative to static fixation. Future clinical studies should evaluate their impact on outcomes and hardware failure in early weightbearing protocols.

Abstract Confounding results of engineered mesenchymal stem cells (MSCs) used as cellular vehicles has plagued technologies whereby success or failure of novel approaches may be dismissed or inaccurately ascribed solely to the biotechnology platform rather than suitability of the human donor. Polymeric materials were screened for non‐viral engineering of MSCs from multiple human donors to deliver bone morphogenic protein‐4 (BMP4), a protein previously investigated in clinical trials for glioblastoma (GBM) to combat a subpopulation of highly invasive and tumorigenic clones. A “smart technology” that target the migratory and stem‐like nature of GBM will require: (1) a cellular vehicle (MSC) which can scavenge and target residual cells left behind after surgical debulking and deliver; (2) anti‐glioma cargo (BMP4). Multiple MSC donors are safely engineered, though varied in susceptibility to accept BMP4 due to intrinsic characteristics revealed by their molecular signatures. Efficiency is compared via secretion, downstream signaling, differentiation, and anti‐proliferative properties across all donors. In a clinically relevant resection and recurrence model of patient‐derived human GBM, we demonstrate that nanoengineered MSCs are not “donor agnostic” and efficacy is influenced by the inherent suitability of the MSC to the cargo. Therefore, donor profiles hold greater influence in determining downstream outcomes than the technical capabilities of the engineering technology.

AbstractNeurodegenerative disorders are characterized by the gradual decline and irreversible loss of cognitive functions and CNS structures. As therapeutic recourse stagnates, neurodegenerative diseases will cost over a trillion dollars by 2050. A dearth of preventive and regenerative measures to hinder regression and enhance recovery has forced patients to settle for traditional therapeutics designed to manage symptoms, leaving little hope for a cure. In the last decade, pre‐clinical animal models and clinical investigations in humans have demonstrated the safety and promise of an emerging cellular product from subcutaneous fat. The adipose‐derived stromal vascular fraction (SVF) is an early intervention and late‐stage novel ‘at point’ of care cellular treatment, demonstrating improvements in clinical applications for Multiple Sclerosis, Alzheimer's disease, and Parkinson's disease. SVF is a heterogeneous fraction of cells forming a robust cellular ecosystem and serving as a novel and valuable source of point‐of‐care autologous cell therapy, providing an easy‐to‐access population that we hypothesize can mediate repair through ‘bi‐directional’ communication in response to pathological cues. We provide the first comprehensive review of all pre‐clinical and clinical findings available to date and highlight major challenges and future directions. There is a greater medical and economic urgency to innovate and develop novel cellular therapy solutions that enable the repair and regeneration of neuronal tissue that has undergone irreversible and permanent damage.

Metabolic rewiring in glioblastoma (GBM) is linked to intra- and extracellular pH regulation. In this study, we sought to characterize the role of melatonin on intracellular pH modulation and metabolic consequences to identify the mechanisms of action underlying melatonin oncostatic effects on GBM tumor initiating cells. GBM tumor initiating cells were treated at different times with melatonin (1.5 and 3.0 mM). We analyzed melatonin’s functional effects on GBM proliferation, cell cycle, viability, stemness, and chemo-radiosensitivity. We then assessed the effects of melatonin on GBM metabolism by analyzing the mitochondrial and glycolytic parameters. We also measured the intracellular and extracellular pH. Finally, we tested the effects of melatonin on a mouse subcutaneous xenograft model. We found that melatonin downregulated LDHA and MCT4, decreasing lactate production and inducing a decrease in intracellular pH that was associated with an increase in ROS and ATP depletion. These changes blocked cell cycle progression and induced cellular death and we observed similar results in vivo. Melatonin’s cytotoxic effects on GBM were due, at least in part, to intracellular pH modulation, which has emerged as a newly identified mechanism, providing new insights into the oncostatic effect of melatonin on GBM.

Abstract Glioblastoma (GBM) is the most common form of malignant primary brain cancer in adults with a median survival of only 15 months. Therefore, new therapies to suppress malignant brain cancer are needed. Brain Tumor Initiating Cells (BTICs) are a GBM subpopulation of cells with a highly glycolytic profile that are thought to be responsible of the resistance of GBM to treatments. Metabolic reprogramming allows tumor cells to survive in unsupportive microenvironments. Manipulating tumor metabolism to counteract GBM resistance arises as a powerful approach with minimum effects in normal counterparts. At pharmacological concentrations, melatonin displays oncostatic properties. This is thought to be due to an increase in mitochondrial oxidative phosphorylation through the effects of melatonin in mitochondria, key organelle in metabolic homeostasis. We hypothesize that melatonin could alter BTIC metabolism, by inducing an anti-Warburg effect and as consequence, melatonin will decrease the viability of GBM cells and tumor growth. We found that treatment of GBM cell lines with 3mM melatonin significantly altered tumor cell metabolism. We observed that melatonin downregulated the lactate symporter MCT4 (p&lt;0.002), inducing a significant intracellular accumulation of lactate (p&lt;0.002) while decreasing it in the extracellular media (p&lt;0.001). This was followed by a decrease in the internal pH (p&lt;0.002). These effects were compensated by an increase in the oxygen consumption rate (OCR) followed by decay that leaded to an increase in ROS production (p&lt;0.001). All these changes result in a depletion of cellular ATP (p&lt;0.001) and eventually drove to a decrease in the proliferation (p&lt;0.001) and cell death (p&lt;0.001). When applied in vivo we observed a significant reduction in the tumor growth (p&lt;0.001), volume (p&lt;0.002) and weight (p&lt;0.002), as well as a drop in the proliferation marker ki67 (p&lt;0.001) and a fibrosis increase in treated tumors. These results position melatonin as a strong therapeutic candidate for GBM therapy.

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Currently, treatment is focused on achieving maximal safe resection, followed by chemo- and radiotherapy. Although surgery remains the most important therapeutic component, complete surgical resection is virtually impossible, as GBM cells readily infiltrate the adjacent brain parenchyma. One fundamental mechanism for GBM cell migration is the ability of these cells to use cell volume regulation as a driving force of cell infiltration and potentially interfering with apoptosis and cell cycle progression. In this work, we targeted the master regulators of cell volume, the kinases STE20/SPS1-Related Proline-Alanine-Rich Protein Kinase (SPAK) and Oxidative stress-responsive kinase-1) (OSR1) by using a novel proprietary small molecule inhibitor. In order to study the effects of inhibiting SPAK and OSR1, we analyzed cell proliferation and migration. First, we determined the IC50 using six different patient-derived GBM cell lines; we found IC50 values ranging from 0.2–2μM. Next, cell proliferation was determined by cell cycle analysis through Edu labeling. We found a significant decrease in S phase and cell cycle arrest in G2M (p= 0.001, n=6). In addition, cell migration was determined using boyden chamber assay. We found a dose-dependent reduction in cell migration (p=0.001, n=3). These results correlated with the phenomenon observed in an orthotopic murine model of GBM, in which the inhibitor showed a decrease in tumor growth (p=0.0026, n=4) and greater survival rates in vivo (p=0.0046, n=8). When used in combination with radiation therapy, this small molecule inhibitor was capable of radio-sensitizing GBM cells decreasing clonogenicity (p=0.01, n=3) were observed in vitro. In summary, by targeting the SPAK/OSR1 kinases with a small molecule inhibitor, GBM cells become less aggressive, mainly by interfering with cell migration and proliferation and becoming more sensitive to radiation.