Quiñones‐Hinojosa, Alfredo

Abstract We present a surgical video illustrating the technique for en bloc resection of an intradural-extramedullary lumbar tumor. The patient is a 63-yr-old woman presenting with worsening bilateral leg pain. Imaging of her lumbar spine showed an enhancing, circumscribed intradural-extramedullary tumor compressing her cauda equina at the L2 level. With informed patient consent, an L1-L3 laminectomy was performed, and intraoperative ultrasound provided the tumor location in order to plan the dural opening as well as define the tumor boundaries with respect to the surrounding nerve roots. The nerve roots were found to be dorsal to the tumor on the ultrasound and appeared to be separate from the tumor capsule. After the dura was opened, the nerve roots were dissected from the tumor capsule and the filum was identified at its proximal and distal portions relative to the mass. The tumor appeared to be arising from the filum itself. Intraoperative electromyography monitoring and stimulation identified the motor roots around the filum and were dissected away. The filum was isolated and cut proximally in order to prevent upward displacement of the mass above the dural opening. The distal portion was then cut and the tumor was removed en bloc. The patient had good postoperative relief of her leg pain and no new neurologic or genitourinary complications. This case highlights the preoperative and intraoperative surgical planning as well as detailed technical aspects of en bloc intradural-extramedullary lumbar tumor resection with preservation of the tumor capsule in order to achieve gross total resection.

A dual-function microneedle for rapid, high-resolution, and quantitative 3D deep-brain imaging and power-efficient tissue ablation.

Abstract BACKGROUND In treating glioblastoma, irradiation of the neural progenitor cell (NPC) niches is controversial. Lower hippocampal doses may limit neurocognitive toxicity, but higher doses to the subventricular zones (SVZ) may improve survival. OBJECTIVE To prospectively evaluate the impact of limiting radiation dose to the NPC niches on tumor progression, survival, and cognition in patients with glioblastoma. METHODS Patients with glioblastoma received resection followed by standard chemoradiation. Radiation dose to the NPC niches, including the bilateral hippocampi and SVZ, was minimized without compromising tumor coverage. The primary outcome was tumor progression in the spared NPC niches. Follow-up magnetic resonance imaging was obtained bimonthly. Neurocognitive testing was performed before treatment and at 6- and 12-mo follow-up. Cox regression evaluated predictors of overall and progression-free survival. Linear regression evaluated predictors of neurocognitive decline. RESULTS A total of 30 patients enrolled prospectively. The median age was 58 yr. Median mean doses to the hippocampi and SVZ were 49.1 and 41.8 gray (Gy) ipsilaterally, and 16.5 and 19.9 Gy contralaterally. Median times to death and tumor progression were 16.0 and 7.6 mo, and were not significantly different compared to a matched historical control. No patients experienced tumor progression in the spared NPC-containing regions. Overall survival was associated with neurocognitive function ( P ≤ .03) but not dose to the NPC niches. Higher doses to the hippocampi and SVZ predicted greater decline in verbal memory ( P ≤ .01). CONCLUSION In treating glioblastoma, limiting dose to the NPC niches may reduce cognitive toxicity while maintaining clinical outcomes. Further studies are needed to confirm these results.

Abstract Glioblastoma multiforme (GBM) and other solid malignancies are heterogeneous and contain subpopulations of tumor cells that exhibit stem-like features. Our recent findings point to a dedifferentiation mechanism by which reprogramming transcription factors Oct4 and Sox2 drive the stem-like phenotype in glioblastoma, in part, by differentially regulating subsets of miRNAs. Currently, the molecular mechanisms by which reprogramming transcription factors and miRNAs coordinate cancer stem cell tumor-propagating capacity are unclear. In this study, we identified miR-486-5p as a Sox2-induced miRNA that targets the tumor suppressor genes PTEN and FoxO1 and regulates the GBM stem-like cells. miR-486-5p associated with the GBM stem cell phenotype and Sox2 expression and was directly induced by Sox2 in glioma cell lines and patient-derived neurospheres. Forced expression of miR-486-5p enhanced the self-renewal capacity of GBM neurospheres, and inhibition of endogenous miR-486-5p activated PTEN and FoxO1 and induced cell death by upregulating proapoptotic protein BIM via a PTEN-dependent mechanism. Furthermore, delivery of miR-486-5p antagomirs to preestablished orthotopic GBM neurosphere-derived xenografts using advanced nanoparticle formulations reduced tumor sizes in vivo and enhanced the cytotoxic response to ionizing radiation. These results define a previously unrecognized and therapeutically targetable Sox2:miR-486-5p axis that enhances the survival of GBM stem cells by repressing tumor suppressor pathways. Significance: This study identifies a novel axis that links core transcriptional drivers of cancer cell stemness to miR-486-5p–dependent modulation of tumor suppressor genes that feeds back to regulate glioma stem cell survival.

Abstract Extracellular vesicles secreted from adipose‐derived mesenchymal stem cells (ADSCs) have therapeutic effects in inflammatory diseases. However, production of extracellular vesicles (EVs) from ADSCs is costly, inefficient, and time consuming. The anti‐inflammatory properties of adipose tissue‐derived EVs and other biogenic nanoparticles have not been explored. In this study, biogenic nanoparticles are obtained directly from lipoaspirate, an easily accessible and abundant source of biological material. Compared to ADSC‐EVs, lipoaspirate nanoparticles (Lipo‐NPs) take less time to process (hours compared to months) and cost less to produce (clinical‐grade cell culture facilities are not required). The physicochemical characteristics and anti‐inflammatory properties of Lipo‐NPs are evaluated and compared to those of patient‐matched ADSC‐EVs. Moreover, guanabenz loading in Lipo‐NPs is evaluated for enhanced anti‐inflammatory effects. Apolipoprotein E and glycerolipids are enriched in Lipo‐NPs compared to ADSC‐EVs. Additionally, the uptake of Lipo‐NPs in hepatocytes and macrophages is higher. Lipo‐NPs and ADSC‐EVs have comparable protective and anti‐inflammatory effects. Specifically, Lipo‐NPs reduce toll‐like receptor 4‐induced secretion of inflammatory cytokines in macrophages. Guanabenz‐loaded Lipo‐NPs further suppress inflammatory pathways, suggesting that this combination therapy can have promising applications for inflammatory diseases.

Abstract INTRODUCTION The management of glioblastoma (GBM) has changed over time and varies based on geographic location. Despite its universally fatal prognoses, it is unclear if GBM outcomes have changed over time, if they vary by geographic location, and differ based on type of intervention. As a result, we conducted a systematic review of the literature to identify the average survival differences of GBM patients across time, between different continents, and among various treatments. METHODS The systematic review of PubMed included glioblastoma, GBM, and survival. Inclusion criteria consisted of full-text titles with human subjects, GBM/Grade IV astrocytoma, age >18 years old, and with available survival data. RESULTS 9,162 articles were screened for survival data, 1728 were eligible, 405 complied with the inclusion criteria. Of the 405 studies, 179 (44.2%) were conducted in Europe, 151 (37.3%) in the Americas, 61 (15.1%) in Asia, 9 (2.2%) in Oceania, and 1 (0.2%) in Africa. Leading countries are the United States (33.1%), Germany (12.3%), and Italy (11.1%). Asia had the highest median survival (14.9 months), followed by Europe (13.2 months), and the United States (12.9 months) (P=0.003). Regarding treatment, survival was significantly higher after the introduction of the Stupp protocol (P< 0.001). Post-Stupp Studies had longer survival estimates (15.3 months, range: 3.8–29.6) than Pre-Stupp Studies (12.2 months, range: 2.3–28). In the included clinical trials (182), radiation (43.4%), temozolomide (25.3%), or other chemotherapies (24.2%) were the most common interventions. Clinical trial median survival estimates were significantly higher than all other studies (P< 0.017). Bevacizumab (19.3 months) and Temozolomide (15.9 months) had the longest recorded median survival estimates; while radiation (14 months), other chemotherapies, and carmustine (13.2 months) had the shortest (P=0.009). CONCLUSION This epidemiological study describes the current global state of GBM. Important differences regarding survival and treatment of patients with GBM were found.

Abstract Glioblastoma (GBM) is the most aggressive of all the brain tumors with a median patient survival less than 15 months. Despite of surgical resection, radiotherapy, and chemotherapy, recurrence rate is almost 100%. A great percentage of GBM tumors (~60%) infiltrate and contact the ventricular-subventricular zone (V-SVZ). Interestingly, these tumors are the most aggressive, and invariably lead to higher distal recurrence rates, shorter time to tumor progression, and lower overall survival of the patient. The reason for this role of V-SVZ-proximity on the outcome of GBM patients is unknown. We suggest that a potential explanation is the interaction of GBM with the V-SVZ. This region is the largest neurogenic niche in the adult brain where neural stem cells (NSCs) give rise to newborn neuroblasts that migrate toward the olfactory bulb. In GBM there is a cell subpopulation called brain tumor stem cells (BTSCs) with NSCs-like characteristics, but with added potential for tumor initiation, recurrence and invasiveness. Tumor microenvironment plays an important role in migration and invasion process. In the present work, we used the total exosome isolation kit to purify Extracellular Vesicles (EVs) from human primary cultures of BTSCs. We determined that BTSCs-derived EVs contain specific information that is transfer to primary cultures of human Neural Progenitors Cells (NPCs) modulating their proliferation rate, cell viability, and migration. In addition, we identify that NPCs taken up BTSCs-derived EVs and significantly increase the expression levels of stemness-related genes such as Nestin, Nanog, and Sox2, suggesting that a phenotypic transdifferentiation is being carry out. These results support our hypothesis that GBM modulate the tumor microenvironment close to the V-SVZ by releasing EVs that target cellular components in this region and promote their phenotypic transformation, highlighting that NPCs biology changes in the context of tumor environment.