Citations

Neuroscientist and advocate of inclusion

OBJECTIVEThe authors assessed the prognostic significance of various clinical and radiographic characteristics, including C1–C2 facet malalignment, in terms of surgical outcomes after foramen magnum decompression of adult Chiari malformation type I.METHODSThe electronic medical records of 273 symptomatic patients with Chiari malformation type I who were treated with foramen magnum decompression, C1 laminectomy, and duraplasty at Mayo Clinic were retrospectively reviewed. Preoperative and postoperative Neurological Scoring System scores were compared using the Friedman test. Bivariate analysis was conducted to identify the preoperative variables that correlated with the patient Chicago Chiari Outcome Scale (CCOS) scores. Multiple linear regression analysis was subsequently performed using the variables with p < 0.05 on the bivariate analysis to check for independent associations with the outcome measures. Statistical software SPSS version 25.0 was used for the data analysis. Significance was defined as p < 0.05 for all analyses.RESULTSFifty-two adult patients with preoperative clinical and radiological data and a minimum follow-up of 12 months were included. Motor deficits, syrinx, and C1–C2 facet malalignment were found to have significant negative associations with the CCOS score at the 1- to 3-month follow-up (p < 0.05), while at the 9- to 12-month follow-up only swallowing function and C1–C2 facet malalignment were significantly associated with the CCOS score (p < 0.05). Multivariate analysis showed that syrinx presence and C1–C2 facet malalignment were independently associated with the CCOS score at the 1- to 3-month follow-up. Swallowing function and C1–C2 facet malalignment were found to be independently associated with the CCOS score at the 9- to 12-month follow-up.CONCLUSIONSThe observed results in this pilot study suggest a significant negative correlation between C1–C2 facet malalignment and clinical outcomes evaluated by the CCOS score at 1–3 months and 9–12 months postoperatively. Prospective studies are needed to further validate the prognostic value of C1–C2 facet malalignment and the potential role of atlantoaxial fixation as part of the treatment.

Background: During awake craniotomy, securing the patient’s airway might be necessary electively or emergently. The objective of this study was to compare the feasibility of airway management using a laryngeal mask airway (LMA) and 4 alternative airway management techniques in an awake craniotomy simulation. Methods: After completing a questionnaire, 9 anesthesia providers attempted airway management in a cadaver positioned to simulate awake craniotomy conditions. Following the simulation, participants rated and ranked the devices in their order of preference. Results: Only 3 approaches resulted in the successful securement of an airway device for 100% of participants: LMA (median; interquartile range time to secure the airway 6 s, 5 to 10 s), fiberoptic bronchoscopy through an LMA (41 s; 23 to 51 s), and video laryngoscopy (49 s; 43 to 127 s). In contrast, the oral and nasal fiberoptic approaches demonstrated only 44.4% (154.5 s; 134.25 to 182 s) and 55.6% (75 s; 50 to 117 s) success rates, respectively. The LMA was the fastest and most reliable primary method to secure the airway (P=0.001). After the simulation, 100% of participants reported that an LMA would be their first choice for emergency airway management, followed by fiberoptic intubation through the LMA (7 of 9 participants) if the LMA failed to properly seat. Conclusions: We demonstrated that an LMA was the fastest and most reliable primary method to secure an airway in a laterally positioned cadaver with 3-pin skull fixation. Fiberoptic and video laryngoscope airway equipment should be readily available during awake craniotomy procedures, and an attempt to visualize the vocal cords through the LMA should be attempted before removing it for alternative techniques.

ABSTRACT BACKGROUND AND IMPORTANCE In the setting of intracranial neoplasms, EWSR1-cAMP Response Element-Binding Protein (CREB) transcription factor family fusions have been described in myxoid mesenchymal tumors, extremely rare entities with a close histopathologic and immunologic resemblance to myxoid subtype angiomatoid fibrous histiocytomas (AFH). Controversy exists on whether these central nervous system lesions are a subtype of myxoid AFH or a completely separate entity, which entitles a distinct clinical behavior and, consequently, a different approach to management. Upon review of the literature, only 14 cases of intracranial tumors harboring an EWSR1-CREB family fusion were identified, with only 3 cases presenting in middle-aged adults, none of which reported an EWSR1-CREM fusion mutation. Significant variability in reported radiographic and histopathological characteristics, as well as in clinical outcomes, was noted. Their similarity with other soft tissue tumors, added to the scarce information on its clinical behavior, represents a great diagnostic and therapeutic challenge to the treating physician. CLINICAL PRESENTATION We present a rare case of EWSR1-CREM mutated intracranial myxoid mesenchymal tumor/myxoid subtype AFH presenting as persistent headaches in a 36-yr-old woman with radiographic evidence of rapid growth and extensive vasogenic edema, for which she underwent surgical resection. CONCLUSION This represents a unique case of EWSR1-CREM mutated intracranial myxoid mesenchymal tumor presenting in adulthood, with evidence of aggressive behavior.

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults with a median survival of 14 months despite multimodal treatment. Patients with GBM tumors exhibit a post-resection recurrence rate of almost 100%. The tumor recurrence and treatment resistance properties of GBM reside in a stem-like cell population called Brain Tumor Initiating Cells (BTIC). Among primary GBMs, periventricular tumors exhibit worse survival than tumors distal to the lateral ventricles (LV), the cause for this worse outcome is not known. A potential explanation is the proximity of these tumors to the cerebrospinal fluid (CSF) and the neurogenic niche in the sub-ventricular zone (SVZ). Chemotactic signals present in the cerebrospinal fluid (CSF) regulate neural progenitor cells migratory response and differentiation profile. Our preliminary data show that cancer-derived CSF induces an increase in the migration and proliferation of GBM cells when compared to non-cancer CSF. We evaluated the transcriptome of human GBM cells in response to cancer and non-cancer CSF and identified alpha-1-antichymotrypsin (SERPINA3) as one of the genes that show higher over expression upon cancer CSF-stimulation. SERPINA3 is a circulating anti-protease that is produced and released in different tissues such as liver, prostate, lungs, endometrium and brain that is over-expressed in multiple cancers. We hypothesize that the overexpression of SERPINA3 in response to CSF is a contributing factor to the increase malignancy of periventricular GBM tumors. We tested this hypothesis in silico, in vitro and in vivo. Using TCGA and Rembrandt databases we observed a higher expression of SERPINA3 in brain tumor tissue compared to controls with no differences among GBM subtypes. In GBM patients, expression of SERPINA3 negatively affects survival expectancy. In vitro, Using intraoperative samples, we confirmed that SERPINA3 is overexpressed in brain cancer tissue by western-blot and qRT-PCR. Interestingly, we observed a higher nuclear localization of SERPINA3 in cancer tissue and cells. To determine if SERPINA3 has an effect on the malignancy of GBM cells, we silenced its expression using shRNA. SERPINA3 silencing induced a decrease in cell proliferation (p&lt;0.05), as well as migration (p&lt;0.05), and invasion (p&lt;0.05). Remarkably CD133 expression and stem cell markers were decreased when SERPINA3 is silenced. In contrast, the addition of recombinant SERPINA3 induced an increase in cell migration (p&lt;0.05) of GBM cells. Moreover, cancer CSF is no longer able to induce an increase in GBM cell migration in SERPINA3-KD cells (p&lt;0.05). In vivo, mice orthotopically-injected with SERPINA3-KD cells showed a prolonged overall survival (p&lt;0.05). In summary, our results support the hypothesis that SERPINA3 plays a key role in GBM malignancy in response to CSF and its inhibition results in a better outcome using GBM preclinical models. Targeting the CSF-GBM interaction is a potential therapeutic approach that remains to be explored. Citation Format: Montserrat A. Lara Velazquez, Natanael Zarco, Anna Carrano, Jordan Phillips, Paula Schiapparelli, Emily S. Norton, Stephanie Jeanneret, Teresita Corona, Jose Segovia, Kaisorn Chaichana, Yan Asmann, Alfredo Quinones Hinojosa, Hugo Guerrero-Cazares. Cerebrospinal fluid-responsive factor SERPINA3 induces an increase in the malignancy of glioblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3780.

Abstract Glioblastoma (GBM), also known as grade IV astrocytoma, is the most common and devastating primary cancer of the central nervous system in adults. Despite the most advanced therapeutic strategies combining surgery, chemotherapy, and radiation, survival expectancy of GBM patients averages 14 months, with a recurrence rate of almost 100%. Remarkably, tumor location has great implications in the prognosis of GBM. Approximately 50-60% of GBM tumors infiltrates or contacts the subventricular zone (SVZ). These patients have significantly worse outcomes, in terms of median overall survival, time to progression and reoccurrence. The reason for the worse prognosis of SVZ-infiltrating tumors is unknown. The SVZ is the largest neurogenic niche in the adult brain, here the differentiation and migration of SVZ cells is regulated by direct contact with the cerebrospinal fluid (CSF). We suggest that CSF contribute to enhance GBM malignant characteristics in SVZ-infiltrating tumors. This study evaluated the impact of CSF exposure on GBM cells proliferation, migration in vitro and in vivo, as well as changes in gene expression profile. We demonstrated that CSF affects the malignancy of GBM cells by increasing their ability to proliferate and migrate. GBM cells stimulated with cancer CSF, non-cancer CSF, or control conditions at different time points (24-72 hrs) were evaluated for viability (by Alamar Blue assay) and proliferation rate (Ki67+ immunostaining), as well as for migratory capabilities (by means of transwell assay and time-lapse microscopy). We recapitulated these CSF effects in vivo using an in vivo model in which both female and male nude mice were implanted with GBM cells in suspension with human cancer or non-cancer CSF in an hydrogel as vehicle (n=8 mice per group). Tumor growth was followed via IVIS imaging and then studied by measuring tumor area on H&E slides and immunohistochemistry staining for Ki67, 21 days after tumor implantation. Animals receiving cancer CSF presented with greater tumor size and Ki67 proliferation index. To further dissect the mechanisms behind these observations, we performed a transcriptome analysis of CSF-treated GBM cells. At the molecular level we observed that cancer CSF induced changes in pathways regulating apoptosis, survival, integrins signaling, angiogenesis, glucose metabolism and response to inflammatory stimuli, all of which might be responsible for the increase in GBM malignancy. Taken together, this study provides direct evidence that CSF is an important player in determining tumor growth and invasion through the activation of complex gene expression patterns characteristic of a malignant phenotype. Understanding the interaction of brain tumors and CSF may lead to new therapeutic strategies that will target the CSF components in GBM patients. Citation Format: Anna Carrano, Jordan Phillipps, Montserrat Lara-Velazquez, Natanael Zarco, Paola Suarez-Meade, Kaisorn Chaichana, Alfredo Quinones-Hinojosa, Yan Asmann, Hugo Guerrero-Cázares. The role of human cerebrospinal fluid in glioblastoma malignancy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1574.

AbstractBrain cancer persists as a difficult‐to‐treat condition. In particular, metastatic brain cancer and malignant primary brain tumors such as glioblastoma (GBM) are among the most deadly and still carry a dismal prognosis despite current standard of care with surgery and chemo‐radiation. Recent advances in nanotechnology have led to innovative nanomedicine strategies for the treatment of brain cancers and specifically for GBM. These strategies represent promising alternative or adjunctive therapies for conventional treatment modalities and are increasingly designed to target specific cell types such as brain tumor‐initiating cells and immune cells. This review provides an update on emerging insights into these nanomedicine strategies with a focus on nanoparticles as tools that facilitate 1) drug delivery 2) gene therapy, and 3) engineered‐cellular therapy for GBM and future directions for brain cancer treatment.

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.