Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, and despite optimized treatment options, median survival remains dismal. Contemporary evidence suggests disease recurrence results from expansion of a robustly radioresistant subset of GBM progenitor cells, termed GBM stem cells (GSCs). In this study, we utilized transmission electron microscopy to uncover ultrastructural effects on patient-derived GSC lines exposed to supratherapeutic radiotherapy levels. Elevated autophagosome formation and increased endoplasmic reticulum (ER) internal diameter, a surrogate for ER stress and activation of unfolded protein response (UPR), was uncovered. These observations were confirmed via protein expression through Western blot. Upon interrogating genomic data from an open-access GBM patient database, overexpression of UPR-related chaperone protein genes was inversely correlated with patient survival. This indicated controlled UPR may play a role in promoting radioresistance. To determine if potentiating UPR further can induce apoptosis, we exposed GSCs to radiation with an ER stress-inducing drug, 2-deoxy-D-glucose (2-DG), and found dose-dependent decreases in viability and increased apoptotic marker expression. Taken together, our results indicate GSC radioresistance is, in part, achieved by overexpression and overactivation of ER stress-related pathways, and this effect can be overcome via potentiation of UPR, leading to loss of GSC viability.

Pediatric brain tumors remain a significant source of morbidity and mortality. Though developments have been made in treating these malignancies, the blood–brain barrier, intra- and inter-tumoral heterogeneity, and therapeutic toxicity pose challenges to improving outcomes. Varying types of nanoparticles, including metallic, organic, and micellar molecules of varying structures and compositions, have been investigated as a potential therapy to circumvent some of these inherent challenges. Carbon dots (CDs) have recently gained popularity as a novel nanoparticle with theranostic properties. This carbon-based modality is highly modifiable, allowing for conjugation to drugs, as well as tumor-specific ligands in an effort to more effectively target cancerous cells and reduce peripheral toxicity. CDs are being studied pre-clinically. The ClinicalTrials.gov site was queried using the search terms: brain tumor and nanoparticle, liposome, micelle, dendrimer, quantum dot, or carbon dot. At the time of this review, 36 studies were found, 6 of which included pediatric patients. Two of the six studies investigated nanoparticle drug formulations, whereas the other four studies were on varying liposomal nanoparticle formulations for the treatment of pediatric brain tumors. Here, we reviewed the context of CDs within the broader realm of nanoparticles, their development, promising pre-clinical potential, and proposed future translational utility.

Glioblastoma (GBM) has a dismal prognosis and successful elimination of GBM stem cells (GSCs) is a high-priority as these cells are responsible for tumor regrowth following therapy and ultimately patient relapse. Natural products and their derivatives continue to be a source for the development of effective anticancer drugs and have been shown to effectively target pathways necessary for cancer stem cell self-renewal and proliferation. We generated a series of curcumin inspired bis-chalcones and examined their effect in multiple patient-derived GSC lines. Of the 19 compounds synthesized, four analogs robustly induced GSC death in six separate GSC lines, with a half maximal inhibitory concentration (IC50) ranging from 2.7–5.8 μM and significantly reduced GSC neurosphere formation at sub-cytotoxic levels. Structural analysis indicated that the presence of a methoxy group at position 3 of the lateral phenylic appendages was important for activity. Pathway and drug connectivity analysis of gene expression changes in response to treatment with the most active bis-chalcone 4j (the 3,4,5 trimethoxy substituted analog) suggested that the mechanism of action was the induction of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) mediated cell death. This was confirmed by Western blot analysis in which 4j induced robust increases in CHOP, p-jun and caspase 12. The UPR is believed to play a significant role in GBM pathogenesis and resistance to therapy and as such represents a promising therapeutic target.

Spinal epidural hematoma is a rare cause of spinal cord compression and acute para- or quadriplegia. Traumatic spinal epidural hematomas are usually seen in older men with a history of ankylosing spondylitis and vertebral fracture. Spontaneous spinal epidural hematomas are commonly associated with coagulopathies, tumors, or vascular malformations. There have been only five previously published case reports in the English-language literature of spontaneous spinal epidural hematomas in conjunction with pregnancy. We present the case of a 24-year-old woman at 20 weeks' gestation who presented to our service with a spontaneous cervicothoracic spinal epidural hematoma and complete quadriplegia. The patient was taken to the operating room for urgent surgical decompression and evacuation of the spinal epidural hematoma. The patient made a complete neurological recovery in long-term follow-up. In the meantime, she carried her pregnancy to term and gave birth to a healthy baby. Therefore, we advocate aggressive and early surgical intervention, similar to the five previously reported cases in the English-language literature, in the case of a spinal epidural hematoma causing cord compression and devastating neurological deficit in a pregnant woman.

The current prognosis for glioblastoma is dismal. Treatment-resistant glioblastoma stem cells (GSCs) and the failure of most drugs to reach therapeutic levels within the tumor remain formidable obstacles to successful treatment. Chalcones are aromatic ketones demonstrated to reduce malignant properties in cancers including glioblastoma. Nanomedicines can increase drug accumulation and tumor cell death. Carbon-dots are promising nanocarriers that can be easily functionalized with tumor-targeting ligands and anti-cancer drugs. Therefore, we synthesized a series of 4′-amino chalcones with the rationale that the amino group would serve as a “handle” to facilitate covalent attachment to carbon-dots and tested their cytotoxicity toward GSCs. We generated 31 chalcones (22 4′-amino and 9 4′ derivatives) including 5 novel chalcones, and found that 13 had an IC₅₀ below 10 µM in all GSC lines. After confirming that the 4-amino group was not part of the active pharmacophore, chalcones were attached to transferrin-conjugated carbon-dots. These conjugates were significantly more cytotoxic than the free chalcones, with the C-dot-transferrin-2,5, dimethoxy chalcone conjugate inducing up to 100-fold more GSC death. Several of the tested chalcones represent promising lead compounds for the development of novel anti-GSC drugs. Furthermore, designing amino chalcones for carbon-dot mediated drug delivery is a rational and effective methodology.

Pseudomeningocele is a rare but well-known complication of lumbar spine surgery, which arises in 0.068%–0.1% of individuals in large series of patients undergoing laminectomy and in up to 2% of patients with postlaminectomy symptoms. In symptomatic pseudomeningoceles, surgical reexploration and repair of the dural defect are typically necessary. Whereas the goals of pseudomeningocele repair, which are extirpation of the pseudomeningocele cavity and elimination of extradural dead space, can typically be achieved by primary closure performed using nonabsorbable sutures, giant pseudomeningoceles (> 8 cm) can require more elaborate repair in which fibrin glues, dural substitute, myofascial flaps, or all of the above are used. The authors present 2 cases of postsurgical symptomatic giant pseudomeningoceles that were repaired using a fast-resorbing polymer mesh–supported reconstruction technique, which is described here for the first time.