Treatment of adult and pediatric high-grade gliomas with Withaferin A: antitumor mechanisms and future perspectives

Resistance mechanisms employed by high-grade gliomas allow them to successfully evade current standard treatment of chemotherapy and radiation treatment. Withaferin A (WA), utilized in Ayurvedic medicine for centuries, is attracting attention for its antitumor capabilities. Here we review pertinent literature on WA as a high-grade glioma treatment, and discuss the cancerous mechanisms it affects. WA is relatively nontoxic and has shown potential in crossing the blood-brain barrier. WA prevents p53 alterations and inactivates overexpressed MDM2 through ARF and ROS production. Furthermore, WA upregulates Bax, inducing mitochondrial death cascades, inhibits mutated Akt, mTOR, and NF-κB pathways, and inhibits angiogenesis in tumors. Therapy with WA for high-grade gliomas is supported through the literature. Further investigation is warranted and encouraged to fully unearth its abilities against malignant gliomas

Current applications and future perspectives of robotics in cerebrovascular and endovascular neurosurgery

Advances in robotic medicine have been adopted by various surgical subspecialties as the benefits of this technology become more readily apparent: precision in narrow operative windows, tremor controlled movements, and modestly improved outcomes, among others. Vascular neurosurgery, in particular, remains open to newer and more cutting edge treatment options for complex pathologies, and robotics may be on the horizon for such advances. We seek to provide a broad overview of these innovations in vascular neurosurgery for both practitioners well acquainted with robotics and those seeking to become more familiar. Technologies under development for cerebrovascular and endovascular neurosurgery include robot assisted angiography, guided operative microscopes, coil insertion systems, and endoscopic clipping devices. Additionally, robotic systems in the fields of interventional cardiology and radiology have potential applications to endovascular neurosurgery but require proper modifications to navigate complex intracerebral vasculature. Robotic technology is not without drawbacks, as broad implementation may lead to increased cost, training time, and potential delays in emergency situations. Further cultivation of current multidisciplinary technologies and investment into newer systems is necessary before robotics can make a sizable impact in clinical practice

Abstract 5864: Targeting brain cancer stem cells by potentiating radiation-induced ER stress

Abstract Background. Glioblastoma (GBM) is one of the most malignant brain tumors occurring in both children and adults. Despite an aggressive treatment regimen consisting of surgical resection, radiation therapy and chemotherapy the five-year survival rate is less than 5%. This poor outcome has been attributed to the existence of therapy-resistant GBM stem-like cells (GSCs), which are believed to be responsible for tumor recurrence and patient relapse. Understanding the resistance mechanisms employed by brain tumor stem cells and developing novel methods to target these cells is necessary for prolonged patient survival. Recent evidence suggests that the endoplasmic reticulum stress response pathway may mediate therapeutic resistance in cancer. Here we sought to examine the ER stress response pathway of GSCs in response to ionizing radiation and to increase the extent of ER stress in an effort to promote cell death using the glycolytic inhibitor, 2-deoxy glucose (2-DG). Methods. GSC lines were derived from resected tumor sections. GSCs were irradiated using the Rad Source 2000 Series Biological Irradiator. Transmission Electron Microscopy (TEM) was used to investigate the ultra-structural alterations of GSCs following exposure to 8 Gy radiation. Viability was determined using trypan blue exclusion, MTS and LDH assays. Cell signaling pathways were investigated by western blot analysis. Results. Consistent with previous findings, minimal cell death was observed in GSCs exposed to 2-20 Gy radiation. TEM analysis revealed that exposure to 8 Gy significantly increased ER lumen dilation, suggestive of ER stress. Western blot analysis indicated an increase in ER stress markers GRP78, GRP94 and CHOP, confirming that radiation induces ER stress in GSCs. Treatment with 2-DG induced an increase in ER lumen diameter and ER stress markers. Combined 2-DG (0.5mM and 2mM) and radiotherapy (8 Gy) significantly increased ER luminal diameter and ER stress marker expression over radiation or 2-DG alone. In addition, combined radiation and 2-DG (0.1-2mM) significantly reduced GSC viability compared to radiation or 2-DG alone. Conclusion. The ER stress response pathway is an adaptive mechanism and thought to mediate therapeutic resistance. Here we demonstrate that radiation induces ER stress response pathway including ER lumen dilation and an increase in molecular chaperone expression in GSCs. Potentiating ER stress can switch the pathway from one of adaptation to cell death. 2-DG increased radiation-induced ER stress and promoted cell death. Our data suggests that targeting this adaptive response could increase the efficacy of radiotherapy and prolong patient survival Note: This abstract was not presented at the meeting. Citation Format: Regina M. Graham, Sumedh S. Shah, Alexis J. Musick, Winston Walters, Ricardo J. Komotar, Jeffery S. Prince, Steven Vanni. Targeting brain cancer stem cells by potentiating radiation-induced ER stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5864. doi:10.1158/1538-7445.AM2017-5864</jats:p

Clinical trials using oncolytic viral therapy to treat adult glioblastoma: a progress report

OBJECTIVEAdult glioblastoma (GBM) has proven refractory to decades of innovation. Oncolytic viral therapy represents a novel therapy that uses viral vectors as both a delivery and therapeutic mechanism to target GBM cells. Despite the growing body of basic science data supporting the feasibility of viral therapy to treat GBM, the reporting of clinical trial results is heterogeneous. Correspondingly, the aim of this study was to present a contemporary summary of the progress all clinical trials have made to date.METHODSThe ClinicalTrials.gov database was reviewed in August 2020 for all possible interventional clinical trials involving viral vector–based therapy to treat adult GBM. These were then screened against selection criteria to identify pertinent clinical trials.RESULTSA total of 29 oncolytic viral therapy trials treating adult GBM were identified. The median start and expected completion years were 2014 and 2020, respectively. At the time of this writing, 10 (35%) trials were reported to have completed recruitment, whereas 7 (24%) were actively recruiting. The median target enrollment number was 36 (range 13–108), with the majority of trials being phase I (n = 18, 62%), and involving secondary GBM among other malignant glioma (n = 19, 66%). A total of 10 unique viral vectors were used across all trials, with the most common being adenovirus (n = 16, 55%). Only 2 (7%) phase I trials to date have reported outcomes on the ClinicalTrials.gov portal. Results of 12 additional clinical trials were found in academic publications, with median progression-free and overall survival times of 3 and 15 months, respectively, after the first viral dose at recurrence. The coordination of the large majority of trials originated from the US (n = 21, 72%), and the median number of testing sites per trial was 1 (range 1–15), via industry funding (n = 18 trials, 62%).CONCLUSIONSThere are multiple early-stage oncolytic viral therapy clinical trials for adult GBM currently active. To date, limited results and outcomes are promising but scarce. The authors expect this to change in the near future because many trials are scheduled to have either nearly or actually reached their expected recruitment completion time. How exactly oncolytic viral therapy will fit into the current treatment paradigms for primary and secondary GBM remains to be seen, and will not be known until safety and toxicity profiles are established by these clinical trials

The Use of Vycor Tubular Retractors in the Management of Deep Brain Lesions: A Review of Current Studies

BACKGROUND: Traditional manual retraction to access deep-seated brain lesions has been associated with complications related to vascular compromise of cerebral tissue. Various techniques have been developed over time to minimize injury, such as self-sustaining retractors, neuronavigation, and endoscopic approaches. Recently, tubular retractors such as the ViewSite Brain Access System (VBAS; Vycor Medical Inc.) have been developed to reduce mechanical damage from retraction by dispersing the force of the retractor radially over the parenchyma, thus we sought to review the current literature to accurately assess the indications, benefits, and complications associated with use of VBAS retractors. METHODS: A literature search for English articles published between 2005 and 2019 was performed using the MEDLINE database archive with the search terminology Vycor OR ViewSite OR Brain-Access-System NOT glass . The Vycor VBAS website was also examined. Only articles detailing neurosurgical procedures using the VBAS tubular retractor system alone, or in combination with other retractors were included. Post-operative morbidity and mortality were analyzed to estimate complications linked to using the retractor. RESULTS: Twelve publications (n=106 patients) met the inclusion criteria. The VYCOR retractor was used for tumor resections, hematoma evacuations, cyst removal, foreign body extractions, and lesion resection in toxoplasmosis and multiple sclerosis. These cases were subdivided into groups based on lesion location, size, and resection volume for further analysis. Gross-total resection was achieved in 63% of tumor excisions and subtotal resection in 37%. Hematoma evacuation was successful in all cases. There were 3 short-term postoperative complications linked to the retractor with an overall complication rate of 2.8%. CONCLUSIONS: This report is the first formal assessment of the VBAS, highlighting technical considerations of the retractor from the surgeon\u27s perspective, patient outcomes, and complications. VYCOR retractor is a safe, efficacious tubular retraction system that can be used for tumor biopsy and resection, colloid cyst removal, hematoma evacuation, and removal of foreign bodies. However, further randomized controlled trials are indicated to accurately assess complication rates and outcomes