A brave new framework for glioma drug development.

Patients with brain tumours are motivated to participate in clinical trials involving repeat tissue sampling. Normalising the use of neoadjuvant and staged surgical trials necessitates collaboration among patients, regulatory agencies, and researchers. Initial and repetitive tissue sampling plays a crucial role in enhancing our understanding of resistance mechanisms and vulnerabilities in brain tumour therapy. Standardising biopsy techniques and ensuring technical uniformity across institutions are vital for effective interinstitutional collaboration. Although liquid biopsy technologies hold promise, they are not yet ready to replace tissue analysis. Clear communication about the risks and benefits of biopsies is essential, particularly regarding potential postoperative deficits. Changes in mindset and neurosurgical culture are imperative to achieve much needed breakthroughs in the development of new, effective therapies for brain tumours.

Evaluation of two-stage designs of Phase 2 single-arm trials in glioblastoma: a systematic review.

BACKGROUND: Due to economical and ethical reasons, the two-stage designs have been widely used for Phase 2 single-arm trials in oncology because the designs allow us to stop the trial early if the proposed treatment is likely to be ineffective. Nonetheless, none has examined the usage for published articles that had applied the two-stage designs in Phase 2 single-arm trials in brain tumor. A complete systematic review and discussions for overcoming design issues might be important to better understand why oncology trials have shown low success rates in early phase trials. METHODS: We systematically reviewed published single-arm two-stage Phase 2 trials for patients with glioblastoma and high-grade gliomas (including newly diagnosed or recurrent). We also sought to understand how these two-stage trials have been implemented and discussed potential design issues which we hope will be helpful for investigators who work with Phase 2 clinical trials in rare and high-risk cancer studies including Neuro-Oncology. The systematic review was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)-statement. Searches were conducted using the electronic database of PubMed, Google Scholar and ClinicalTrials.gov for potentially eligible publications from inception by two independent researchers up to May 26, 2022. The followings were key words for the literature search as index terms or free-text words: "phase II trials", "glioblastoma", and "two-stage design". We extracted disease type and setting, population, therapeutic drug, primary endpoint, input parameters and sample size results from two-stage designs, and historical control reference, and study termination status. RESULTS: Among examined 29 trials, 12 trials (41%) appropriately provided key input parameters and sample size results from two-stage design implementation. Among appropriately implemented 12 trials, discouragingly only 3 trials (10%) explained the reference information of historical control rates. Most trials (90%) used Simon's two-stage designs. Only three studies have been completed for both stages and two out of the three completed studies had shown the efficacy. CONCLUSIONS: Right implementation for two-stage design and sample size calculation, transparency of historical control and experimental rates, appropriate selection on primary endpoint, potential incorporation of adaptive designs, and utilization of Phase 0 paradigm might help overcoming the challenges on glioblastoma therapeutic trials in Phase 2 trials.

Three-Dimensional Printable Conductive Semi-Interpenetrating Polymer Network Hydrogel for Neural Tissue Applications.

Intrinsically conducting polymers (ICPs) are widely used to fabricate biomaterials; their application in neural tissue engineering, however, is severely limited because of their hydrophobicity and insufficient mechanical properties. For these reasons, soft conductive polymer hydrogels (CPHs) are recently developed, resulting in a water-based system with tissue-like mechanical, biological, and electrical properties. The strategy of incorporating ICPs as a conductive component into CPHs is recently explored by synthesizing the hydrogel around ICP chains, thus forming a semi-interpenetrating polymer network (semi-IPN). In this work, a novel conductive semi-IPN hydrogel is designed and synthesized. The hybrid hydrogel is based on a poly(N-isopropylacrylamide-co-N-isopropylmethacrylamide) hydrogel where polythiophene is introduced as an ICP to provide the system with good electrical properties. The fabrication of the hybrid hydrogel in an aqueous medium is made possible by modifying and synthesizing the monomers of polythiophene to ensure water solubility. The morphological, chemical, thermal, electrical, electrochemical, and mechanical properties of semi-IPNs were fully investigated. Additionally, the biological response of neural progenitor cells and mesenchymal stem cells in contact with the conductive semi-IPN was evaluated in terms of neural differentiation and proliferation. Lastly, the potential of the hydrogel solution as a 3D printing ink was evaluated through the 3D laser printing method. The presented results revealed that the proposed 3D printable conductive semi-IPN system is a good candidate as a scaffold for neural tissue applications.

Surgical strategy for insular glioma.

PURPOSE: The goal of this article is to review the outcomes of insular glioma surgery and discuss strategies to minimize postoperative morbidity. METHODS: The authors reviewed the published literature on low- and high-grade insular gliomas with a focus on glioma biology, insular anatomy, and surgical technique. RESULTS: Maximal safe resection of insular gliomas is associated with improved survival and is the primary goal of surgery. Protecting patient speech and motor function during insular glioma resection requires versatile integration of insular anatomy, cortical mapping, and microsurgical technique. Both the transsylvian and transcortical corridors to the insula are associated with low morbidity profiles, but the transcortical approach with intraoperative mapping is more favorable for gliomas within the posterior insular region. CONCLUSIONS: Surgical strategy for insular gliomas is dependent on biological, anatomical, and clinical factors. Technical mastery integrated with intraoperative technologies can optimize surgical results.

Gliosarcoma vs. glioblastoma: a retrospective case series using molecular profiling.

BACKGROUND: Gliosarcoma (GS) refers to the presence of mesenchymal differentiation (as seen using light microscopy) in the setting of glioblastoma (GB, an astrocytoma, WHO Grade 4). Although the same approach to treatment is typically adopted for GS and GB, there remains some debate as to whether GS should be considered a discrete pathological entity. Differences between these tumors have not been clearly established at the molecular level. METHODS: Patients with GS (n=48) or GB (n=1229) underwent molecular profiling (MP) with a pan-cancer panel of tests as part of their clinical care. The methods employed included next-generation sequencing (NGS) of DNA and RNA, copy number variation (CNV) of DNA and immunohistochemistry (IHC). The MP comprised 1153 tests in total, although results for each test were not available for every tumor profiled. We analyzed this data retrospectively in order to determine if our results were in keeping with what is known about the pathogenesis of GS by contrast with GB. We also sought novel associations between the MP and GS vs. GB which might improve our understanding of pathogenesis of GS. RESULTS: Potentially meaningful associations (p<0.1, Fisher's exact test (FET)) were found for 14 of these tests in GS vs. GB. A novel finding was higher levels of proteins mediating immuno-evasion (PD-1, PD-L1) in GS. All of the differences we observed have been associated with epithelial-to-mesenchymal transition (EMT) in other tumor types. Many of the changes we saw in GS are novel in the setting of glial tumors, including copy number amplification in LYL1 and mutations in PTPN11. CONCLUSIONS: GS shows certain characteristics of EMT, by contrast with GB. Treatments targeting immuno-evasion may be of greater therapeutic value in GS relative to GB.

Handheld line-scanned dual-axis confocal microscope with pistoned MEMS actuation for flat-field fluorescence imaging.

A handheld line-scanned dual-axis confocal (LS-DAC) microscope has been developed for high-speed (16 frames/s) fluorescence imaging of tissues with sub-nuclear resolution. This is the first miniature fluorescence LS-DAC system that has been fully packaged for handheld clinical use on patients. A novel micro-electro-mechanical system scanning mechanism, with synchronized tilting and pistoning, is used to achieve flat-field en face imaging. We show that this facilitates video mosaicking to generate images that sample an extended lateral field of view.

Fluorescence-guided surgery with aminolevulinic acid for low-grade gliomas.

INTRODUCTION: Fluorescence guided surgery has developed over the last 2 decades as a formidable augmentation strategy to promote maximal safe resection and diagnostic accuracy within gliomas. The majority of the literature evidence supporting this modality utilizes 5-aminolevulinic acid in the setting of high-grade gliomas. The role for fluorescence guided surgery in low-grade gliomas is less well defined. RESULTS: This review describes the existing literature discussing the utilization of 5-aminolevulinic acid for fluorescence guided surgery in low-grade gliomas, including its pertinence in identification of anaplastic foci and potential role in guiding resection following combination with augmentation strategies for detection. CONCLUSION: The advance in operative technology and growth of research analyzing 5-aminolevulinic acid will continue to enhance the role of fluorescence guided surgery within the standard of surgical management for low-grade gliomas.

Visualization technologies for 5-ALA-based fluorescence-guided surgeries.

INTRODUCTION: 5-ALA-based fluorescence-guided surgery has been shown to be a safe and effective method to improve intraoperative visualization and resection of malignant gliomas. However, it remains ineffective in guiding the resection of lower-grade, non-enhancing, and deep-seated tumors, mainly because these tumors do not produce detectable fluorescence with conventional visualization technologies, namely, wide-field (WF) surgical microscopy. METHODS: We describe some of the main factors that limit the sensitivity and accuracy of conventional WF surgical microscopy, and then provide a survey of commercial and research prototypes being developed to address these challenges, along with their principles, advantages and disadvantages, as well as the current status of clinical translation for each technology. We also provide a neurosurgical perspective on how these visualization technologies might best be implemented for guiding glioma surgeries in the future. RESULTS: Detection of PpIX expression in low-grade gliomas and at the infiltrative margins of all gliomas has been achieved with high-sensitivity probe-based visualization techniques. Deep-tissue PpIX imaging of up to 5 mm has also been achieved using red-light illumination techniques. Spectroscopic approaches have enabled more accurate quantification of PpIX expression. CONCLUSION: Advancements in visualization technologies have extended the sensitivity and accuracy of conventional WF surgical microscopy. These technologies will continue to be refined to further improve the extent of resection in glioma patients using 5-ALA-induced fluorescence.

Rethinking medulloblastoma from a targeted therapeutics perspective.

INTRODUCTION: Medulloblastoma is an aggressive but potentially curable central nervous system tumor that remains a treatment challenge. Analysis of therapeutic targets can provide opportunities for the selection of agents. METHODS: Using multiplatform analysis, 36 medulloblastomas were extensively profiled from 2009 to 2015. Immunohistochemistry, next generation sequencing, chromogenic in situ hybridization, and fluorescence in situ hybridization were used to identify overexpressed proteins, immune checkpoint expression, mutations, tumor mutational load, and gene amplifications. RESULTS: High expression of MRP1 (89%, 8/9 tumors), TUBB3 (86%, 18/21 tumors), PTEN (85%, 28/33 tumors), TOP2A (84%, 26/31 tumors), thymidylate synthase (TS; 80%, 24/30 tumors), RRM1 (71%, 15/21 tumors), and TOP1 (63%, 19/30 tumors) were found in medulloblastoma. TOP1 was found to be enriched in metastatic tumors (90%; 9/10) relative to posterior fossa cases (50%; 10/20) (p = 0.0485, Fisher exact test), and there was a positive correlation between TOP2A and TOP1 expression (p = 0.0472). PD-1 + T cell tumor infiltration was rare, PD-L1 tumor expression was uncommon, and TML was low, indicating that immune checkpoint inhibitors as a monotherapy should not necessarily be prioritized for therapeutic consideration based on biomarker expression. Gene amplifications such as those of Her2 or EGFR were not found. Several unique mutations were identified, but their rarity indicates large-scale screening efforts would be necessary to identify sufficient patients for clinical trial inclusion. CONCLUSIONS: Therapeutics are available for several of the frequently expressed targets, providing a justification for their consideration in the setting of medulloblastoma.