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Objective: Laser interstitial thermal therapy (LITT) is an emerging tool for treating a variety of focal brain lesions, including recurrent high-grade glioma (HGG). While the efficacy and uses of LITT have been well studied, the impact of this treatment on patient functional outcomes has not been analyzed in detail. This study sought to better define the role of LITT in treating patients with recurrent HGG, examining which patients exhibit good functional outcomes after LITT, and to determine risk factors for worsening neurological function., Methods: The medical records of patients treated with LITT for recurrent HGG at a single tertiary care center were retrospectively reviewed. Functional status was assessed using the Karnofsky Performance Scale (KPS). Demographic, clinical, and radiological data were examined for associations with change in KPS score assessed 4-6 weeks following surgery., Results: Forty-seven patients were included in the study with histopathologically confirmed recurrent HGG. The mean age was 57 years, and 21 (45%) patients were female. The pre-LITT KPS scores were as follows: 100 in 4 (9%) patients, 90 in 15 (32%) patients, 80 in 10 (21%) patients, 70 in 13 (28%) patients, and 60 in 5 (11%) patients. Overall, 59% of patients showed a stable or improved KPS score after undergoing LITT. Tumor volume was the sole predictor of decreased KPS score after LITT. Notably, tumor location including eloquent location, preoperative KPS score, and other comorbidities were not independently associated with change in functional status., Conclusions: The majority of patients undergoing LITT for recurrent HGG had a favorable functional outcome at the initial follow-up visit. The treated tumor volume was inversely and independently associated with post-LITT functional outcome. This information may help guide patient selection and treatment optimization in the setting of LITT-based approaches for recurrent HGG.

Malignant gliomas (MGs) are the most common primary brain tumors in adults. Despite recent advances in understanding the biology and potential therapeutic vulnerabilities of MGs, treatment options remain limited as the delivery of drugs is often impeded by the blood-brain barrier (BBB), and safe, complete surgical resection may not always be possible, especially for deep-seated tumors. In this review, the authors highlight emerging applications for MR imaging-guided focused ultrasound (MRgFUS) as a noninvasive treatment modality for MGs. Specifically, the authors discuss MRgFUS's potential role in direct tumor cell killing, opening the BBB, and modulating antitumor immunity., Competing Interests: Disclosure The authors have no relevant disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The history of focused ultrasound is a parallel history of neuroradiology, functional neurosurgery, and physics and engineering. Multiple pioneers collaborated as ultrasound transitioned from a wartime technology to a therapeutic one, particularly in using it to ablate the brain to treat movement disorders. Several competing technologies ensured that this "ultrasonic neurosurgery" remained in a lull. An algorithm and other advancements that obviated a craniectomy for ultrasonic neurosurgery allowed magnetic resonance-guided focused ultrasound to flourish to its modern phase., Competing Interests: Disclosure D. Gandhi reports grants from Microvention, the Focused Ultrasound Foundation, United States, the NIH, United States and University of Calgary, United States/NoNo Therapeutics. All other authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Implementation of standardized protocols in neurooncology during the surgical resection of brain tumors is needed to advance the clinical treatment paradigms that use tissue for diagnosis, prognosis, bio-banking, and treatment. Currently recommendations on intraoperative tissue procurement only exist for diffuse gliomas but management of other brain tumor subtypes can also benefit from these protocols. Fresh tissue from surgical resection can now be used for intraoperative diagnostics and functional precision medicine assays. A multidisciplinary neuro-oncology perspective is critical to develop the best avenues for practical standardization. This perspective from the multidisciplinary Oncology Tissue Advisory Board (OTAB) discusses current advances, future directions, and the imperative of adopting standardized protocols for diverse brain tumor entities. There is a growing need for consistent operating room practices to enhance patient care, streamline research efforts, and optimize outcomes., Competing Interests: The authors, except WJS, are members of an advisory board sponsored by Nico Corporation. However, Nico Corporation was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. CB is a consultant for Depuy-Synthes, Bionaut Labs, Haystack Oncology and Privo Technologies. CB is a co-founder of OrisDx and Belay Diagnostics. HB is a chairman of the Medical Advisory Board for Insightec. Insightec is developing focused ultrasound treatments for brain tumors. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict-of-interest policies. HB has consultation agreements with Insightec, Candel Therapeutics, Inc., Catalio Nexus Fund II, LLC, LikeMinds, Inc*, and Nurami Medical*, Intragel *includes equity or options. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Rodriguez, Ahluwalia, Bettegowda, Brem, Carter, Chang, Das, Eberhart, Garzon-Muvdi, Hadjipanayis, Hawkins, Jacques, Khalessi, McDermott, Mikkelsen, Orr, Phillips, Rosenblum, Shelton, Solomon, von Deimling, Woodworth and Rutka.)

We introduce a two-pronged strategy comprising focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening and long-circulating biodegradable nanoparticles (NPs) for systemic delivery of nucleic acids to the brain. Biodegradable poly(β-amino ester) polymer-based NPs were engineered to stably package various types of nucleic acid payloads and enable prolonged systemic circulation while retaining excellent serum stability. FUS was applied to a predetermined coordinate within the brain to transiently open the BBB, thereby allowing the systemically administered long-circulating NPs to traverse the BBB and accumulate in the FUS-treated brain region, where plasmid DNA or mRNA payloads produced reporter proteins in astrocytes and neurons. In contrast, poorly circulating and/or serum-unstable NPs, including the lipid NP analogous to a platform used in clinic, were unable to provide efficient nucleic acid delivery to the brain regardless of the BBB-opening FUS. The marriage of FUS-mediated BBB opening and the long-circulating NPs engineered to copackage mRNA encoding CRISPR-associated protein 9 and single-guide RNA resulted in genome editing in astrocytes and neurons precisely in the FUS-treated brain region. The combined delivery strategy provides a versatile means to achieve efficient and site-specific therapeutic nucleic acid delivery to and genome editing in the brain via a systemic route.

Purpose: Glioblastoma (GBM) is the most common and aggressive primary adult brain tumor. The standard treatment approach is surgical resection to target the enhancing tumor mass, followed by adjuvant chemoradiotherapy. However, malignant cells often extend beyond the enhancing tumor boundaries and infiltrate the peritumoral edema. Traditional supervised machine learning techniques hold potential in predicting tumor infiltration extent but are hindered by the extensive resources needed to generate expertly delineated regions of interest (ROIs) for training models on tissue most and least likely to be infiltrated., Approach: We developed a method combining expert knowledge and training-based data augmentation to automatically generate numerous training examples, enhancing the accuracy of our model for predicting tumor infiltration through predictive maps. Such maps can be used for targeted supra-total surgical resection and other therapies that might benefit from intensive yet well-targeted treatment of infiltrated tissue. We apply our method to preoperative multi-parametric magnetic resonance imaging (mpMRI) scans from a subset of 229 patients of a multi-institutional consortium (Radiomics Signatures for Precision Diagnostics) and test the model on subsequent scans with pathology-proven recurrence., Results: Leave-one-site-out cross-validation was used to train and evaluate the tumor infiltration prediction model using initial pre-surgical scans, comparing the generated prediction maps with follow-up mpMRI scans confirming recurrence through post-resection tissue analysis. Performance was measured by voxel-wised odds ratios (ORs) across six institutions: University of Pennsylvania (OR: 9.97), Ohio State University (OR: 14.03), Case Western Reserve University (OR: 8.13), New York University (OR: 16.43), Thomas Jefferson University (OR: 8.22), and Rio Hortega (OR: 19.48)., Conclusions: The proposed model demonstrates that mpMRI analysis using deep learning can predict infiltration in the peri-tumoral brain region for GBM patients without needing to train a model using expert ROI drawings. Results for each institution demonstrate the model's generalizability and reproducibility., (© 2024 Society of Photo-Optical Instrumentation Engineers (SPIE).)

Nanotherapeutics have gained significant attention for the treatment of numerous cancers, primarily because they can accumulate in and/or selectively target tumors leading to improved pharmacodynamics of encapsulated drugs. The flexibility to engineer the nanotherapeutic characteristics including size, morphology, drug release profiles, and surface properties make nanotherapeutics a unique platform for cancer drug formulation. Polymeric nanotherapeutics including micelles and dendrimers represent a large number of formulation strategies developed over the last decade. However, compared to liposomes and lipid-based nanotherapeutics, polymeric nanotherapeutics have had limited clinical translation from the laboratory. One of the key limitations of polymeric nanotherapeutics formulations for clinical translation has been the reproducibility in preparing consistent and homogeneous large-scale batches. In this review, we describe polymeric nanotherapeutics and discuss the most common laboratory and scale-up formulation methods, specifically those proposed for clinical cancer therapies. We also provide an overview of the major challenges and opportunities for scaling polymeric nanotherapeutics to clinical-grade formulations. Finally, we will review the regulatory requirements and challenges in advancing nanotherapeutics to the clinic.

Infiltrating gliomas are challenging to treat, as the blood-brain barrier significantly impedes the success of therapeutic interventions. While some clinical trials for high-grade gliomas have shown promise, patient outcomes remain poor. Microbubble-enhanced focused ultrasound (MB-FUS) is a rapidly evolving technology with demonstrated safety and efficacy in opening the blood-brain barrier across various disease models, including infiltrating gliomas. Initially recognized for its role in augmenting drug delivery, the potential of MB-FUS to augment liquid biopsy and immunotherapy is gaining research momentum. In this review, we will highlight recent advancements in preclinical and clinical studies that utilize focused ultrasound to treat gliomas and discuss the potential future uses of image-guided precision therapy using focused ultrasound.

Glioblastoma (GBM) is hard to treat due to cellular invasion into functioning brain tissues, limited drug delivery, and evolved treatment resistance. Recurrence is nearly universal even after surgery, chemotherapy, and radiation. Photodynamic therapy (PDT) involves photosensitizer administration followed by light activation to generate reactive oxygen species at tumor sites, thereby killing cells or inducing biological changes. PDT can ablate unresectable GBM and sensitize tumors to chemotherapy. Verteporfin (VP) is a promising photosensitizer that relies on liposomal carriers for clinical use. While lipids increase VP's solubility, they also reduce intracellular photosensitizer accumulation. Here, a pure-drug nanoformulation of VP, termed "NanoVP", eliminating the need for lipids, excipients, or stabilizers is reported. NanoVP has a tunable size (65-150 nm) and 1500-fold higher photosensitizer loading capacity than liposomal VP. NanoVP shows a 2-fold increase in photosensitizer uptake and superior PDT efficacy in GBM cells compared to liposomal VP. In mouse models, NanoVP-PDT improved tumor control and extended animal survival, outperforming liposomal VP and 5-aminolevulinic acid (5-ALA). Moreover, low-dose NanoVP-PDT can safely open the blood-brain barrier, increasing drug accumulation in rat brains by 5.5-fold compared to 5-ALA. NanoVP is a new photosensitizer formulation that has the potential to facilitate PDT for the treatment of GBM., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Purpose/objective(s): Treatment related lymphopenia is a known toxicity for glioblastoma (GBM) patients and several single-institution studies have linked lymphopenia with poor survival outcomes. We performed a systematic review and pooled analysis to evaluate the association between lymphopenia and overall survival (OS) for GBM patients undergoing chemotherapy and radiation therapy (RT)., Materials/methods: Following PRISMA guidelines, a systematic literature review of the MEDLINE database and abstracts from ASTRO, ASCO, and SNO annual meetings was conducted. A pooled analysis was performed using inverse variance-weighted random effects to generate a pooled estimate of the hazard ratio of association between lymphopenia and OS., Results: Ten of 104 identified studies met inclusion criteria, representing 1,718 patients. The lymphopenia cutoff value varied (400-1100 cells/uL) and as well as the timing of its onset. Studies were grouped as time-point (i.e., lymphopenia at approximately 2-months post-RT) or time-range (any lymphopenia occurrence from treatment-start to approximately 2-months post-RT. The mean overall pooled incidence of lymphopenia for all studies was 31.8%, and 11.8% vs. 39.9% for time-point vs. time-range studies, respectively. Lymphopenia was associated with increased risk of death, with a pooled HR of 1.78 (95% CI 1.46-2.17, P < 0.00001) for the time-point studies, and a pooled HR of 1.38 (95% CI 1.24-1.55, P < 0.00001) for the time-point studies. There was no significant heterogeneity between studies., Conclusion: These results strengthen observations from previous individual single-institution studies and better defines the magnitude of the association between lymphopenia with OS in GBM patients, highlighting lymphopenia as a poor prognostic factor., (© 2024. The Author(s).)

Purpose: Preoperative stereotactic radiosurgery (SRS) is a feasible alternative to postoperative SRS for resected brain metastases (BM). Most reported studies of preoperative SRS used single-fraction SRS (SF-SRS). The goal of this study was to compare outcomes and toxicity of preoperative SF-SRS with multifraction (3-5 fractions) SRS (MF-SRS) in a large international multicenter cohort (Preoperative Radiosurgery for Brain Metastases-PROPS-BM)., Methods and Materials: Patients with BM from solid cancers, of which at least 1 lesion was treated with preoperative SRS followed by planned resection, were included from 8 institutions. SRS to synchronous intact BM was allowed. Exclusion criteria included prior or planned whole brain radiation therapy. Intracranial outcomes were estimated using cumulative incidence with competing risk of death. Propensity score matched (PSM) analyses were performed., Results: The study cohort included 404 patients with 416 resected index lesions, of which SF-SRS and MF-SRS were used for 317 (78.5%) and 87 patients (21.5%), respectively. Median dose was 15 Gy in 1 fraction for SF-SRS and 24 Gy in 3 fractions for MF-SRS. Univariable analysis demonstrated that SF-SRS was associated with higher cavity local recurrence (LR) compared with MF-SRS (2-year: 16.3% vs 2.9%; P = .004), which was also demonstrated in multivariable analysis. PSM yielded 81 matched pairs (n = 162). PSM analysis also demonstrated significantly higher rate of cavity LR with SF-SRS (2-year: 19.8% vs 3.3%; P = .003). There was no difference in adverse radiation effect, meningeal disease, or overall survival between cohorts in either analysis., Conclusions: Preoperative MF-SRS was associated with significantly reduced risk of cavity LR in both the unmatched and PSM analyses. There was no difference in adverse radiation effect, meningeal disease, or overall survival based on fractionation. MF-SRS may be a preferred option for neoadjuvant radiation therapy of resected BMs. Additional confirmatory studies are needed. A phase 3 randomized trial of single-fraction preoperative versus postoperative SRS (NRG-BN012) is ongoing (NCT05438212)., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Objectives: Intracranial meningiomas are a diverse group of tumors, which vary by grade, genetic composition, location, and vasculature. Expanding the understanding of the supply of skull base (SBMs) and non-skull base meningiomas (NSBMs) will serve to further inform resection strategies. We sought to delineate the vascular supply of a series of intracranial meningiomas by tumor location., Methods: A retrospective study of intracranial meningiomas that were studied using preoperative digital subtraction angiograms before surgical resection at a tertiary referral center was performed. Patient, tumor, radiologic, and treatment data were collected, and regression models were developed., Results: One hundred sixty-five patients met inclusion criteria. The mean age was 57.1 years (SD: 12.6). The mean tumor diameter was 4.9 cm (SD: 1.5). One hundred twenty-six were World Health Organization Grade I, 37 Grade II, and 2 Grade III. Arterial feeders were tabulated by Al-Mefty's anatomic designations. SBMs were more likely to derive arterial supply from the anterior circulation, whereas NSBMs were supplied by external carotid branches. NSBMs were larger (5.61 cm vs 4.45 cm, P = <.001), were more often presented with seizure (20% vs 8%, P = .03), were higher grade ( P = <.001) had more frequent peritumoral brain edema (84.6% vs 66%, P = .04), and had more bilateral feeders (47.7% vs 28%, P = .01) compared with SBMs. More arterial feeders were significantly associated with lower tumor grade ( P = .023, OR = 0.59). Higher tumor grade (Grade II/III) was associated with fewer arterial feeders ( P = .017, RR = 0.74)., Conclusion: Meningioma location is associated with specific vascular supply patterns, grade, and patient outcomes. This information suggests that grade I tumors, especially larger tumors, are more likely to have diverse vascular supply patterns, including internal carotid branches. This study may inform preoperative embolization and surgical considerations, particularly for large skull base tumors., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

The TWEAK receptor, Fn14, is a promising candidate for active targeting of cancer nanotherapeutics to many solid tumor types, including metastatic breast and primary brain cancers. Targeting of therapeutic nanoparticles (NPs) has been accomplished using a range of targeting moieties including monoclonal antibodies and related fragments, peptides, and small molecules. Here, we investigated a full-length Fn14-specific monoclonal antibody, ITEM4, or an ITEM4-Fab fragment as a targeting moiety to guide the development of a clinical formulation. We formulated NPs with varying densities of the targeting moieties while maintaining the decreased nonspecific adhesivity with receptor targeting (DART) characteristics. To model the conditions that NPs experience following intravenous infusion, we investigated the impact of serum exposure in relation to the targeting moiety type and surface density. To further evaluate performance at the cancer cell level, we performed experiments to assess differences in cellular uptake and trafficking in several cancer cell lines using confocal microscopy, imaging flow cytometry, and total internal reflection fluorescence microscopy. We observed that Fn14-targeted NPs exhibit enhanced cellular uptake in Fn14-high compared to Fn14-low cancer cells and that in both cell lines uptake levels were greater than observed with control, nontargeted NPs. We found that serum exposure increased Fn14-targeted NP specificity while simultaneously reducing the total NP uptake. Importantly, serum exposure caused a larger reduction in cancer cell uptake over time when the targeting moiety was an antibody fragment (Fab region of the monoclonal antibody) compared with the full-length monoclonal antibody targeting moiety. Lastly, we uncovered that full monoclonal antibody-targeted NPs enter cancer cells via clathrin-mediated endocytosis and traffic through the endolysosomal pathway. Taken together, these results support a pathway for developing a clinical formulation using a full-length Fn14 monoclonal antibody as the targeting moiety for a DART cancer nanotherapeutic agent.

Importance: Preoperative stereotactic radiosurgery (SRS) has been demonstrated as a feasible alternative to postoperative SRS for resectable brain metastases (BMs) with potential benefits in adverse radiation effects (AREs) and meningeal disease (MD). However, mature large-cohort multicenter data are lacking., Objective: To evaluate preoperative SRS outcomes and prognostic factors from a large international multicenter cohort (Preoperative Radiosurgery for Brain Metastases-PROPS-BM)., Design, Setting, and Participants: This multicenter cohort study included patients with BMs from solid cancers, of which at least 1 lesion received preoperative SRS and a planned resection, from 8 institutions. Radiosurgery to synchronous intact BMs was allowed. Exclusion criteria included prior or planned whole-brain radiotherapy and no cranial imaging follow-up. Patients were treated between 2005 and 2021, with most treated between 2017 and 2021., Exposures: Preoperative SRS to a median dose to 15 Gy in 1 fraction or 24 Gy in 3 fractions delivered at a median (IQR) of 2 (1-4) days before resection., Main Outcomes and Measures: The primary end points were cavity local recurrence (LR), MD, ARE, overall survival (OS), and multivariable analysis of prognostic factors associated with these outcomes., Results: The study cohort included 404 patients (214 women [53%]; median [IQR] age, 60.6 [54.0-69.6] years) with 416 resected index lesions. The 2-year cavity LR rate was 13.7%. Systemic disease status, extent of resection, SRS fractionation, type of surgery (piecemeal vs en bloc), and primary tumor type were associated with cavity LR risk. The 2-year MD rate was 5.8%, with extent of resection, primary tumor type, and posterior fossa location being associated with MD risk. The 2-year any-grade ARE rate was 7.4%, with target margin expansion greater than 1 mm and melanoma primary being associated with ARE risk. Median OS was 17.2 months (95% CI, 14.1-21.3 months), with systemic disease status, extent of resection, and primary tumor type being the strongest prognostic factors associated with OS., Conclusions and Relevance: In this cohort study, the rates of cavity LR, ARE, and MD after preoperative SRS were found to be notably low. Several tumor and treatment factors were identified that are associated with risk of cavity LR, ARE, MD, and OS after treatment with preoperative SRS. A phase 3 randomized clinical trial of preoperative vs postoperative SRS (NRG BN012) has began enrolling (NCT05438212).

Background: Augmented reality (AR) technology is a new and promising option to advance and expand neurosurgical training because of recent advances in computer vision technology, improved AR software and hardware, and growing acceptance of this technology in clinical practice., Objective: To analyze the current status of AR use cases with the goal of envisioning future uses of AR in neurosurgical education., Methods: Articles applying to AR technology use in neurosurgical education were identified using PubMed, Google Scholar, and Web of Science databases following the Preferred Reporting Items of Systematic Reviews and Meta-Analyses guidelines. Articles were included for review based on applicable content related to neurosurgical or neuroanatomy training. Assessment of literature quality was completed using standardized MERSQI scoring., Results: The systematic search identified 2648 unique articles. Of these, 12 studies met inclusion criteria after extensive review. The average MERSQI score was 10.2 (SD: 1.7). The most common AR platform identified in this study was the Microsoft Hololens. The primary goals of the studies were to improve technical skills and approaches to surgical planning or improve understanding of neuroanatomy., Conclusion: Augmented reality has emerged as a promising training tool in neurosurgery. This is demonstrated in the wide range of cases in technical training and anatomic education. It remains unclear how AR-based training compares directly with traditional training methods; however, AR shows great promise in the ability to further enhance and innovate neurosurgical education and training., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Triple-negative breast cancer (TNBC) patients with brain metastasis (BM) face dismal prognosis due to the limited therapeutic efficacy of the currently available treatment options. We previously demonstrated that paclitaxel-loaded PLGA-PEG nanoparticles (NPs) directed to the Fn14 receptor, termed "DARTs", are more efficacious than Abraxane─an FDA-approved paclitaxel nanoformulation─following intravenous delivery in a mouse model of TNBC BM. However, the precise basis for this difference was not investigated. Here, we further examine the utility of the DART drug delivery platform in complementary xenograft and syngeneic TNBC BM models. First, we demonstrated that, in comparison to nontargeted NPs, DART NPs exhibit preferential association with Fn14-positive human and murine TNBC cell lines cultured in vitro . We next identified tumor cells as the predominant source of Fn14 expression in the TNBC BM-immune microenvironment with minimal expression by microglia, infiltrating macrophages, monocytes, or lymphocytes. We then show that despite similar accumulation in brains harboring TNBC tumors, Fn14-targeted DARTs exhibit significant and specific association with Fn14-positive TNBC cells compared to nontargeted NPs or Abraxane. Together, these results indicate that Fn14 expression primarily by tumor cells in TNBC BMs enables selective DART NP delivery to these cells, likely driving the significantly improved therapeutic efficacy observed in our prior work.

Glioma stem cells (GSCs) promote tumor progression and therapeutic resistance and exhibit remarkable bioenergetic and metabolic plasticity, a phenomenon that has been linked to their ability to escape standard and targeted therapies. However, specific mechanisms that promote therapeutic resistance have been somewhat elusive. We hypothesized that because GSCs proliferate continuously, they may require the salvage and de novo nucleotide synthesis pathways to satisfy their bioenergetic needs. Here, we demonstrate that GSCs lacking EGFR (or EGFRvIII) amplification are exquisitely sensitive to de novo pyrimidine synthesis perturbations, while GSCs that amplify EGFR are utterly resistant. Furthermore, we show that EGFRvIII promotes BAY2402234 resistance in otherwise BAY2402234 responsive GSCs. Remarkably, a novel, orally bioavailable, blood-brain-barrier penetrating, dihydroorotate dehydrogenase (DHODH) inhibitor BAY2402234 was found to abrogate GSC proliferation, block cell-cycle progression, and induce DNA damage and apoptosis. When dosed daily by oral gavage, BAY2402234 significantly impaired the growth of two different intracranial human glioblastoma xenograft models in mice. Given this observed efficacy and the previously established safety profiles in preclinical animal models and human clinical trials, the clinical testing of BAY2402234 in patients with primary glioblastoma that lacks EGFR amplification is warranted., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Glioblastoma (GBM) is the most common malignant adult brain cancer with no curative treatment strategy. A significant hurdle in GBM treatment is effective therapeutic delivery to the brain-invading tumor cells that remain following surgery within functioning brain regions. Developing therapies that can either directly target these brain-invading tumor cells or act on other cell types and molecular processes supporting tumor cell invasion and recurrence are essential steps in advancing new treatments in the clinic. This review highlights some of the drug delivery strategies and nanotherapeutic technologies that are designed to target brain-invading GBM cells or non-neoplastic, invasion-supporting cells residing within the GBM tumor microenvironment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Laser interstitial thermal therapy (LITT) guided by magnetic resonance imaging (MRI) is a new treatment option for patients with brain and non-central nervous system (non-CNS) tumors. MRI guidance allows for precise placement of optical fiber in the tumor, while MR thermometry provides real-time monitoring and assessment of thermal doses during the procedure. Despite promising clinical results, LITT complications relating to brain tumor procedures, such as hemorrhage, edema, seizures, and thermal injury to nearby healthy tissues, remain a significant concern. To address these complications, nanoparticles offer unique prospects for precise interstitial hyperthermia applications that increase heat transport within the tumor while reducing thermal impacts on neighboring healthy tissues. Furthermore, nanoparticles permit the co-delivery of therapeutic compounds that not only synergize with LITT, but can also improve overall effectiveness and safety. In addition, efficient heat-generating nanoparticles with unique optical properties can enhance LITT treatments through improved real-time imaging and thermal sensing. This review will focus on (1) types of inorganic and organic nanoparticles for LITT; (2) in vitro, in silico, and ex vivo studies that investigate nanoparticles' effect on light-tissue interactions; and (3) the role of nanoparticle formulations in advancing clinically relevant image-guided technologies for LITT. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Implantable Materials and Surgical Technologies > Nanoscale Tools and Techniques in Surgery., (© 2022 The Authors. WIREs Nanomedicine and Nanobiotechnology published by Wiley Periodicals LLC.)

Pediatric glioblastoma is relatively rare compared with its adult counterpart but is associated with a similarly grim prognosis. Available data indicate that pediatric glioblastomas are molecularly distinct from adult tumors, and relatively little is known about the pediatric glioblastoma tumor microenvironment (TME). Cancer immunotherapy has emerged as a new pillar of cancer treatment and is revolutionizing the care of patients with many advanced solid tumors, including melanoma, non-small cell lung cancer, head and neck cancer, and renal cell carcinoma. Unfortunately, attempts to treat adult glioblastoma with current immunotherapies have had limited success to date. Nevertheless, the immune milieu in pediatric glioblastoma is distinct from that found in adult tumors, and evidence suggests that pediatric tumors are less immunosuppressive. As a result, immunotherapies should be specifically evaluated in the pediatric context. The purpose of this review is to explore known and emerging mechanisms of immune evasion in pediatric glioblastoma and highlight potential opportunities for implementing immunotherapy in the treatment of these devastating pediatric brain tumors., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The present protocol describes a standardized paradigm for rodent brain tumor resection and tissue preservation. In clinical practice, maximal tumor resection is the standard-of-care treatment for most brain tumors. However, most currently available preclinical brain tumor models either do not include resection, or utilize surgical resection models that are time-consuming and lead to significant postoperative morbidity, mortality, or experimental variability. In addition, performing resection in rodents can be daunting for several reasons, including a lack of clinically comparable surgical tools or protocols and the absence of an established platform for standardized tissue collection. This protocol highlights the use of a multi-functional, non-ablative resection device and an integrated tissue preservation system adapted from the clinical version of the device. The device applied in the present study combines tunable suction and a cylindrical blade at the aperture to precisely probe, cut, and suction tissue. The minimally invasive resection device performs its functions via the same burr hole used for the initial tumor implantation. This approach minimizes alterations to regional anatomy during biopsy or resection surgeries and reduces the risk of significant blood loss. These factors significantly reduced the operative time (<2 min/animal), improved postoperative animal survival, lower variability in experimental groups, and result in high viability of resected tissues and cells for future analyses. This process is facilitated by a blade speed of ~1,400 cycles/min, which allows the harvesting of tissues into a sterile closed system that can be filled with a physiologic solution of choice. Given the emerging importance of studying and accurately modeling the impact of surgery, preservation and rigorous comparative analysis of regionalized tumor resection specimens, and intra-cavity-delivered therapeutics, this unique protocol will expand opportunities to explore unanswered questions about perioperative management and therapeutic discovery for brain tumor patients.

Background: Focused ultrasound (FUS) is an emerging technology, offering the capability of tuning and prescribing thermal and mechanical treatments within the brain. While early works in utilizing this technology have mainly focused on maximizing the delivery of therapeutics across the blood-brain barrier (BBB), the potential therapeutic impact of FUS-induced controlled thermal and mechanical stress to modulate anti-tumor immunity is becoming increasingly recognized., Objective: To better understand the roles of FUS-mediated thermal and mechanical stress in promoting anti-tumor immunity in central nervous system tumors, we performed a comprehensive literature review on focused ultrasound-mediated immunomodulation and immunotherapy in brain tumors., Methods: First, we summarize the current clinical experience with immunotherapy. Then, we discuss the unique and distinct immunomodulatory effects of the FUS-mediated thermal and mechanical stress in the brain tumor-immune microenvironment. Finally, we highlight recent findings that indicate that its combination with immune adjuvants can promote robust responses in brain tumors., Results: Along with the rapid advancement of FUS technologies into recent clinical trials, this technology through mild-hyperthermia, thermal ablation, mechanical perturbation mediated by microbubbles, and histotripsy each inducing distinct vascular and immunological effects, is offering the unique opportunity to improve immunotherapeutic trafficking and convert immunologically "cold" tumors into immunologically "hot" ones that are prone to generate prolonged anti-tumor immune responses., Conclusions: While FUS technology is clearly accelerating concepts for new immunotherapeutic combinations, additional parallel efforts to detail rational therapeutic strategies supported by rigorous preclinical studies are still in need to leverage potential synergies of this technology with immune adjuvants. This work will accelerate the discovery and clinical implementation of new effective FUS immunotherapeutic combinations for brain tumor patients., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Brain tumors are particularly challenging malignancies, due to their location in a structurally and functionally distinct part of the human body - the central nervous system (CNS). The CNS is separated and protected by a unique system of brain and blood vessel cells which together prevent most bloodborne therapeutics from entering the brain tumor microenvironment (TME). Recently, great strides have been made through microbubble (MB) ultrasound contrast agents in conjunction with ultrasound energy to locally increase the permeability of brain vessels and modulate the brain TME. As we elaborate in this review, this physical method can effectively deliver a wide range of anticancer agents, including chemotherapeutics, antibodies, and nanoparticle drug conjugates across a range of preclinical brain tumors, including high grade glioma (glioblastoma), diffuse intrinsic pontine gliomas, and brain metastasis. Moreover, recent evidence suggests that this technology can promote the effective delivery of novel immunotherapeutic agents, including immune check-point inhibitors and chimeric antigen receptor T cells, among others. With early clinical studies demonstrating safety, and several Phase I/II trials testing the preclinical findings underway, this technology is making firm steps towards shaping the future treatments of primary and metastatic brain cancer. By elaborating on its key components, including ultrasound systems and MB technology, along with methods for closed-loop spatial and temporal control of MB activity, we highlight how this technology can be tuned to enable new, personalized treatment strategies for primary brain malignancies and brain metastases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Brain metastases (BMs) are the most common type of brain tumor, and the incidence among breast cancer (BC) patients has been steadily increasing over the past two decades. Indeed, ~ 30% of all patients with metastatic BC will develop BMs, and due to few effective treatments, many will succumb to the disease within a year. Historically, patients with BMs have been largely excluded from clinical trials investigating systemic therapies including immunotherapies (ITs) due to limited brain penetration of systemically administered drugs combined with previous assumptions that BMs are poorly immunogenic. It is now understood that the central nervous system (CNS) is an immunologically distinct site and there is increasing evidence that enhancing immune responses to BCBMs will improve patient outcomes and the efficacy of current treatment regimens. Progress in IT for BCBMs, however, has been slow due to several intrinsic limitations to drug delivery within the brain, substantial safety concerns, and few known targets for BCBM IT. Emerging studies demonstrate that nanomedicine may be a powerful approach to overcome such limitations, and has the potential to greatly improve IT strategies for BMs specifically. This review summarizes the evidence for IT as an effective strategy for BCBM treatment and focuses on the nanotherapeutic strategies currently being explored for BCBMs including targeting the blood-brain/tumor barrier (BBB/BTB), tumor cells, and tumor-supporting immune cells for concentrated drug release within BCBMs, as well as use of nanoparticles (NPs) for delivering immunomodulatory agents, for inducing immunogenic cell death, or for potentiating anti-tumor T cell responses., (© 2021. The Author(s).)

Purpose: Preoperative radiosurgery (SRS) is a feasible alternative to postoperative SRS, with potential benefits in adverse radiation effect (ARE) and leptomeningeal disease (LMD) relapse. However, previous studies are limited by small patient numbers and single-institution designs. Our aim was to evaluate preoperative SRS outcomes and prognostic factors from a large multicenter cohort (Preoperative Radiosurgery for Brain Metastases [PROPS-BM])., Methods and Materials: Patients with brain metastases (BM) from solid cancers who had at least 1 lesion treated with preoperative SRS and underwent a planned resection were included from 5 institutions. SRS to synchronous intact BM was allowed. Radiographic meningeal disease (MD) was categorized as either nodular or classical "sugarcoating" (cLMD)., Results: The cohort included 242 patients with 253 index lesions. Most patients (62.4%) had a single BM, 93.7% underwent gross total resection, and 98.8% were treated with a single fraction to a median dose of 15 Gray to a median gross tumor volume of 9.9 cc. Cavity local recurrence (LR) rates at 1 and 2 years were 15% and 17.9%, respectively. Subtotal resection (STR) was a strong independent predictor of LR (hazard ratio, 9.1; P < .001). One and 2-year rates of MD were 6.1% and 7.6% and of any grade ARE were 4.7% and 6.8% , respectively. The median overall survival (OS) duration was 16.9 months and the 2-year OS rate was 38.4%. The majority of MD was cLMD (13 of 19 patients with MD; 68.4%). Of 242 patients, 10 (4.1%) experienced grade ≥3 postoperative surgical complications., Conclusions: To our knowledge, this multicenter study represents the largest cohort treated with preoperative SRS. The favorable outcomes previously demonstrated in single-institution studies, particularly the low rates of MD and ARE, are confirmed in this expanded multicenter analysis, without evidence of an excessive postoperative surgical complication risk. STR, though infrequent, is associated with significantly worse cavity LR. A randomized trial between preoperative and postoperative SRS is warranted and is currently being designed., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Pharmacological treatment of gliomas and other brain-infiltrating tumors remains challenging due to limited delivery of most therapeutics across the blood-brain barrier (BBB). Transcranial MRI-guided focused ultrasound (FUS), an emerging technology for noninvasive brain treatments, enables transient opening of the BBB through acoustic activation of circulating microbubbles. Here, we evaluate the safety and utility of transcranial microbubble-enhanced FUS (MB-FUS) for spatially targeted BBB opening in patients with infiltrating gliomas. In this Phase 0 clinical trial (NCT03322813), we conducted comparative and quantitative analyses of FUS exposures (sonications) and their effects on gliomas using MRI, histopathology, microbubble acoustic emissions (harmonic dose [HD]), and fluorescence-guided surgery metrics. Contrast-enhanced MRI and histopathology indicated safe and reproducible BBB opening in all patients. These observations occurred using a power cycling closed feedback loop controller, with the power varying by nearly an order of magnitude on average. This range underscores the need for monitoring and titrating the exposure on a patient-by-patient basis. We found a positive correlation between microbubble acoustic emissions (HD) and MR-evident BBB opening ( P = 0.07) and associated interstitial changes ( P < 0.01), demonstrating the unique capability to titrate the MB-FUS effects in gliomas. Importantly, we identified a 2.2-fold increase of fluorescein accumulation in MB-FUS-treated compared to untreated nonenhancing tumor tissues ( P < 0.01) while accounting for vascular density. Collectively, this study demonstrates the capabilities of MB-FUS for safe, localized, controlled BBB opening and highlights the potential of this technology to improve the surgical and pharmacologic treatment of brain tumors., Competing Interests: The authors declare no competing interest.

High-grade gliomas (HGGs) are aggressive, treatment-resistant, and often fatal human brain cancers. The TNF-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible 14 (Fn14) signaling axis is involved in tissue repair after injury and constitutive signaling has been implicated in the pathogenesis of numerous solid cancers. The Fn14 gene is expressed at low levels in the normal, uninjured brain but is highly expressed in primary isocitrate dehydrogenase wild-type and recurrent HGGs. Fn14 signaling is implicated in numerous aspects of glioma biology including brain invasion and chemotherapy resistance, but whether Fn14 overexpression can directly promote tumor malignancy has not been reported. Here, we used the replication-competent avian sarcoma-leukosis virus/tumor virus A system to examine the impact of Fn14 expression on glioma development and pathobiology. We found that the sole addition of Fn14 to an established oncogenic cocktail previously shown to generate proneural-like gliomas led to the development of highly invasive and lethal brain cancer with striking biological features including extensive pseudopalisading necrosis, constitutive canonical and noncanonical NF-κB pathway signaling, and high plasminogen activator inhibitor-1 (PAI-1) expression. Analyses of HGG patient datasets revealed that high human PAI-1 gene (SERPINE1) expression correlates with shorter patient survival, and that the SERPINE1 and Fn14 (TNFRSF12A) genes are frequently co-expressed in bulk tumor tissues, in tumor subregions, and in malignant cells residing in the tumor microenvironment. These findings provide new insights into the potential importance of Fn14 in human HGG pathobiology and designate both the NF-κB signaling node and PAI-1 as potential targets for therapeutic intervention. MAIN POINTS: This work demonstrates that elevated levels of the TWEAK receptor Fn14 in tumor-initiating, neural progenitor cells leads to the transformation of proneural-like gliomas into more aggressive and lethal tumors that exhibit constitutive NF-κB pathway activation and plasminogen activator inhibitor-1 overexpression., (© 2021 Wiley Periodicals LLC.)

Gliomas are the most common primary intrinsic brain tumors occurring in adults. Of all malignant gliomas, glioblastoma (GBM) is considered the deadliest tumor type due to diffuse brain invasion, immune evasion, cellular, and molecular heterogeneity, and resistance to treatments resulting in high rates of recurrence. An extensive understanding of the genomic and microenvironmental landscape of gliomas gathered over the past decade has renewed interest in pursuing novel therapeutics, including immune checkpoint inhibitors, glioma-associated macrophage/microglia (GAMs) modulators, and others. In light of this, predictive animal models that closely recreate the conditions and findings found in human gliomas will serve an increasingly important role in identifying new, effective therapeutic strategies. Although numerous syngeneic, xenograft, and transgenic rodent models have been developed, few include the full complement of pathobiological features found in human tumors, and therefore few accurately predict bench-to-bedside success. This review provides an update on how genetically engineered rodent models based on the replication-competent avian-like sarcoma (RCAS) virus/tumor virus receptor-A (tv-a) system have been used to recapitulate key elements of human gliomas in an immunologically intact host microenvironment and highlights new approaches using this model system as a predictive tool for advancing translational glioma research., (© 2021 Wiley Periodicals LLC.)

Background: Sport-related structural brain injury (SRSBI) is intracranial pathology incurred during sport. Management mirrors that of non-sport-related brain injury. An empirical vacuum exists regarding return to play (RTP) following SRSBI., Objective: To provide key insight for operative management and RTP following SRSBI using a (1) focused systematic review and (2) survey of expert opinions., Methods: A systematic literature review of SRSBI from 2012 to present in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and a cross-sectional survey of RTP in SRSBI by 31 international neurosurgeons was conducted., Results: Of 27 included articles out of 241 systematically reviewed, 9 (33.0%) case reports provided RTP information for 12 athletes. To assess expert opinion, 31 of 32 neurosurgeons (96.9%) provided survey responses. For acute, asymptomatic SRSBI, 12 (38.7%) would not operate. Of the 19 (61.3%) who would operate, midline shift (63.2%) and hemorrhage size > 10 mm (52.6%) were the most common indications. Following SRSBI with resolved hemorrhage, with or without burr holes, the majority of experts (>75%) allowed RTP to high-contact/collision sports at 6 to 12 mo. Approximately 80% of experts did not endorse RTP to high-contact/collision sports for athletes with persistent hemorrhage. Following craniotomy for SRSBI, 40% to 50% of experts considered RTP at 6 to 12 mo. Linear regression revealed that experts allowed earlier RTP at higher levels of play (β = -0.58, 95% CI -0.111, -0.005, P = .033)., Conclusion: RTP decisions following structural brain injury in athletes are markedly heterogeneous. While individualized RTP decisions are critical, aggregated expert opinions from 31 international sports neurosurgeons provide key insight. Level of play was found to be an important consideration in RTP determinations., (© Congress of Neurological Surgeons 2021.)

Following a decompressive craniectomy, the autologous bone flap is generally considered the reconstructive material of choice in pediatric patients. Replacement of the original bone flap takes advantage of its natural biocompatibility and the associated low risk of rejection, as well as the potential to reintegrate with the adjacent bone and subsequently grow with the patient. However, despite these advantages and unlike adult patients, the replaced calvarial bone is more likely to undergo delayed bone resorption in pediatric patients, ultimately requiring revision surgery. In this review, we describe the materials that are currently available for pediatric cranioplasty, the advantages and disadvantages of autologous calvarial replacement, the incidence and classification of bone resorption, and the clinical risk factors for bone flap resorption that have been identified to date., (© Congress of Neurological Surgeons 2021.)

Background: Hypofractionated-SRS (HF-SRS) may allow for improved local control and a reduced risk of radiation necrosis compared to single-fraction-SRS (SF-SRS). However, data comparing these two treatment approaches are limited. The purpose of this study was to compare clinical outcomes between SF-SRS versus HF-SRS across our multi-center academic network., Methods: Patients treated with SF-SRS or HF-SRS for brain metastasis from 2013 to 2018 across 5 radiation oncology centers were retrospectively reviewed. SF-SRS dosing was standardized, whereas HF-SRS dosing regimens were variable. The co-primary endpoints of local control and radiation necrosis were estimated using the Kaplan Meier method. Multivariate analysis using Cox proportional hazards modeling was performed to evaluate the impact of select independent variables on the outcomes of interest. Propensity score adjustments were used to reduce the effects confounding variables. To assess dose response for HF-SRS, Biologic Effective Dose (BED) assuming an α/β of 10 (BED 10 ) was used as a surrogate for total dose., Results: One-hundred and fifty six patients with 335 brain metastasis treated with SF-SRS (n = 222 lesions) or HF-SRS (n = 113 lesions) were included. Prior whole brain radiation was given in 33% (n = 74) and 34% (n = 38) of lesions treated with SF-SRS and HF-SRS, respectively (p = 0.30). After a median follow up time of 12 months in each cohort, the adjusted 1-year rate of local control and incidence of radiation necrosis was 91% (95% CI 86-96%) and 85% (95% CI 75-95%) (p = 0.26) and 10% (95% CI 5-15%) and 7% (95% CI 0.1-14%) (p = 0.73) for SF-SRS and HF-SRS, respectively. For lesions > 2 cm, the adjusted 1 year local control was 97% (95% CI 84-100%) for SF-SRS and 64% (95% CI 43-85%) for HF-SRS (p = 0.06). On multivariate analysis, SRS fractionation was not associated with local control and only size ≤2 cm was associated with a decreased risk of developing radiation necrosis (HR 0.21; 95% CI 0.07-0.58, p < 0.01). For HF-SRS, 1 year local control was 100% for lesions treated with a BED 10  ≥ 50 compared to 77% (95% CI 65-88%) for lesions that received a BED 10  < 50 (p = 0.09)., Conclusions: In this comparison study of dose fractionation for the treatment of brain metastases, there was no difference in local control or radiation necrosis between HF-SRS and SF-SRS. For HF-SRS, a BED 10 ≥ 50 may improve local control.

Fluorescence-guided surgery (FGS) is routinely utilized in clinical centers around the world, whereas the combination of FGS and photodynamic therapy (PDT) has yet to reach clinical implementation and remains an active area of translational investigations. Two significant challenges to the clinical translation of PDT for brain cancer are as follows: (1) Limited light penetration depth in brain tissues and (2) Poor selectivity and delivery of the appropriate photosensitizers. To address these shortcomings, we developed nanoliposomal protoporphyrin IX (Nal-PpIX) and nanoliposomal benzoporphyrin derivative (Nal-BPD) and then evaluated their photodynamic effects as a function of depth in tissue and light fluence using rat brains. Although red light penetration depth (defined as the depth at which the incident optical energy drops to 1/e, ~37%) is typically a few millimeters in tissues, we demonstrated that the remaining optical energy could induce PDT effects up to 2 cm within brain tissues. Photobleaching and singlet oxygen yield studies between Nal-BPD and Nal-PpIX suggest that deep-tissue PDT (>1 cm) is more effective when using Nal-BPD. These findings indicate that Nal-BPD-PDT is more likely to generate cytotoxic effects deep within the brain and allow for the treatment of brain invading tumor cells centimeters away from the main, resectable tumor mass., (© 2019 American Society for Photobiology.)

Development of effective tumor cell-targeted nanodrug formulations has been quite challenging, as many nanocarriers and targeting moieties exhibit nonspecific binding to cellular, extracellular, and intravascular components. We have developed a therapeutic nanoparticle formulation approach that balances cell surface receptor-specific binding affinity while maintaining minimal interactions with blood and tumor tissue components (termed "DART" nanoparticles), thereby improving blood circulation time, biodistribution, and tumor cell-specific uptake. Here, we report that paclitaxel (PTX)-DART nanoparticles directed to the cell surface receptor fibroblast growth factor-inducible 14 (Fn14) outperformed both the corresponding PTX-loaded, nontargeted nanoparticles and Abraxane, an FDA-approved PTX nanoformulation, in both a primary triple-negative breast cancer (TNBC) model and an intracranial model reflecting TNBC growth following metastatic dissemination to the brain. These results provide new insights into methods for effective development of therapeutic nanoparticles as well as support the continued development of the DART platform for primary and metastatic tumors., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

High-grade gliomas (HGGs) are aggressive primary brain tumors that confer poor prognoses. Despite aggressive combined modality treatment, HGGs invariably recur. Considerable research efforts and resources have focused on identification of novel therapies for HGGs; however, standard treatments have not changed significantly in more than 10 years, since the introduction of concurrent chemoradiation therapy with temozolomide. Hyperthermia (HT) has been shown to enhance the efficacy of radiation treatment (RT) in numerous cancer types through multiple mechanisms, including impairment of DNA repair pathways, increased perfusion/oxygenation of tumors, and immune system activation. In the 1980s and 1990s, the combination of HT with external-beam RT and interstitial brachytherapy was extensively evaluated in HGG, culminating in a randomized controlled trial that demonstrated superior survival in patients receiving combined HT and RT. However, HT was not adopted into common practice for HGG because of the need at that time for invasive implantation procedures, challenges to monitoring and maintaining a homogeneous, localized temperature elevation within the tumor tissue, as well as other technical and logistic challenges. Magnetic resonance imaging-guided focused ultrasound (MRgFUS) is a relatively new technology in clinical use that is capable of highly accurate transcranial HT and has the potential to overcome many of the limitations faced in previous trials combining HT and RT in HGG. In this review, we detail and compile the previous clinical results of combined HT and RT in HGG patients. We also introduce and discuss the potential of MRgFUS as a noninvasive method for HT to radiosensitize HGG., Competing Interests: Declaration of Competing Interest Dr. Mishra reports personal speaking fees from Varian outside the submitted work., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Necrotic foci with surrounding hypoxic cellular pseudopalisades and microvascular hyperplasia are histological features found in glioblastoma (GBM). We have previously shown that monocarboxylate transporter 4 (MCT4) is highly expressed in necrotic/hypoxic regions in GBM and that increased levels of MCT4 are associated with worse clinical outcomes., Methods: A combined transcriptomics and metabolomics analysis was performed to study the effects of MCT4 depletion in hypoxic GBM neurospheres. Stable and inducible MCT4-depletion systems were used to evaluate the effects of and underlining mechanisms associated with MCT4 depletion in vitro and in vivo, alone and in combination with radiation., Results: This study establishes that conditional depletion of MCT4 profoundly impairs self-renewal and reduces the frequency and tumorigenicity of aggressive, therapy-resistant, glioblastoma stem cells. Mechanistically, we observed that MCT4 depletion induces anaplerotic glutaminolysis and abrogates de novo pyrimidine biosynthesis. The latter results in a dramatic increase in DNA damage and apoptotic cell death, phenotypes that were readily rescued by pyrimidine nucleosides supplementation. Consequently, we found that MCT4 depletion promoted a significant prolongation of survival of animals bearing established orthotopic xenografts, an effect that was extended by adjuvant treatment with focused radiation., Conclusions: Our findings establish a novel role for MCT4 as a critical regulator of cellular deoxyribonucleotide levels and provide a new therapeutic direction related to MCT4 depletion in GBM., (© The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Photosensitizing biomolecules (PSBM) represent a new generation of light-absorbing compounds with improved optical and physicochemical properties for biomedical applications. Despite numerous advances in lipid-, polymer-, and protein-based PSBMs, their effective use requires a fundamental understanding of how macromolecular structure influences the physicochemical and biological properties of the photosensitizer. Here, we prepared and characterized three well-defined PSBMs based on a clinically used photosensitizer, benzoporphyrin derivative (BPD). The PSBMs include 16:0 lysophosphocholine-BPD (16:0 Lyso PC-BPD), distearoyl-phosphoethanolamine-polyethylene-glycol-BPD (DSPE-PEG-BPD), and anti-EGFR cetuximab-BPD (Cet-BPD). In two glioma cell lines, DSPE-PEG-BPD exhibited the highest singlet oxygen yield but was the least phototoxic due to low cellular uptake. The 16:0 Lyso PC-BPD was most efficient in promoting cellular uptake but redirected BPD's subcellular localization from mitochondria to lysosomes. At 24 h after incubation, proteolyzed Cet-BPD was localized to mitochondria and effectively disrupted the mitochondrial membrane potential upon light activation. Our results revealed the variable trafficking and end effects of PSBMs, providing valuable insights into methods of PSBM evaluation, as well as strategies to select PSBMs based on subcellular targets and cytotoxic mechanisms. We demonstrated that biologically informed combinations of PSBMs to target lysosomes and mitochondria, concurrently, may lead to enhanced therapeutic effects against gliomas., Competing Interests: The manuscript was written through the contributions of all authors. All authors have approved the final version of the manuscript. The authors declare no potential conflict of interest.

Therapeutic efficacy of nanoparticle-drug formulations for cancer applications is significantly impacted by the extent of intra-tumoral accumulation and tumor tissue penetration. We advanced the application of surface plasmon resonance to examine interfacial properties of various clinical and emerging nanoparticles related to tumor tissue penetration. We observed that amine-terminated or positively-charged dendrimers and liposomes bound strongly to tumor extracellular matrix (ECM) proteins, whereas hydroxyl/carboxyl-terminated dendrimers and PEGylated/neutrally-charged liposomes did not bind. In addition, poly(lactic-co-glycolic acid) (PLGA) nanoparticles formulated with cholic acid or F127 surfactants bound strongly to tumor ECM proteins, whereas nanoparticles formulated with poly(vinyl alcohol) did not bind. Unexpectedly, following blood serum incubation, this binding increased and particle transport in ex vivo tumor tissues reduced markedly. Finally, we characterized the protein corona on PLGA nanoparticles using quantitative proteomics. Through these studies, we identified valuable criteria for particle surface characteristics that are likely to mediate their tissue binding and tumor penetration., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Emerging evidence suggests that effective treatment of glioblastoma (GBM), the most common and deadly form of adult primary brain cancer, will likely require concurrent treatment of multiple aspects of tumor pathobiology to overcome tumor heterogeneity and the complex tumor-supporting microenvironment. Recent studies in non-central nervous system (CNS) tumor cells have demonstrated that oxaliplatin (OXA) can induce multi-faceted anti-tumor effects, in particular at drug concentrations below those required to induce apoptosis. These findings motivated re-investigation of OXA for the treatment of GBM., Methods: The effects of OXA on murine KR158 and GL261 glioma cells including cell growth, cell death, inhibition of signal transducer and activator of transcription (STAT) activity, O-6-methylguanine-DNA methyltransferase (MGMT) expression, and immunogenic cell death (ICD) initiation, were evaluated by cytotoxicity assays, Western blot analysis, STAT3-luciferase reporter assays, qRT-PCR assays, and flow cytometry. Chemical inhibitors of endoplasmic reticulum (ER) stress were used to investigate the contribution of this cell damage response to the observed OXA effects. The effect of OXA on bone marrow-derived macrophages (BMDM) exposed to glioma conditioned media (GCM) was also analyzed by Western blot analysis., Results: We identified the OXA concentration threshold for induction of apoptosis and from this determined the drug dose and treatment period for sub-cytotoxic treatments of glioma cells. Under these experimental conditions, OXA reduced STAT3 activity, reduced MGMT levels and increased temozolomide sensitivity. In addition, there was evidence of immunogenic cell death (elevated EIF2α phosphorylation and calreticulin exposure) following prolonged OXA treatment. Notably, inhibition of ER stress reversed the OXA-mediated inhibition of STAT3 activity and MGMT expression in the tumor cells. In BMDMs exposed to GCM, OXA also reduced levels of phosphorylated STAT3 and decreased expression of Arginase 1, an enzyme known to contribute to pro-tumor functions in the tumor-immune environment., Conclusions: OXA can induce notable multi-faceted biological effects in glioma cells and BMDMs at relatively low drug concentrations. These findings may have significant therapeutic relevance against GBM and warrant further investigation.

Purpose/objective(s): To compare the performance of five prognostic models [RTOG recursive partitioning analysis (RPA), Score Index for Radiosurgery in Brain Metastases (SIR), Barnholtz-Sloan-Kattan nomogram (BSKN), diagnosis-specific Graded Prognostic Assessment (dsGPA), and Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (Lung-molGPA)] against actual survival in patients with brain metastases treated with SRS +/- WBRT., Materials/methods: 100 consecutive patients treated with SRS +/- WBRT between January 2006 and July 2012 were retrospectively analyzed. Patients were binned according to 33 percentiles of the predicted survival distribution for the BSKN and dsGPA models to compare with LungmolGPA, RPA and SIR. Pearson's correlation coefficients between predicted and observed survival were estimated to quantify the proportion of variance in observed survival., Results: Median survival for the entire cohort was 13.5 months, with predicted vs actual MS by BSKN, SIR, dsGPA, RPA, adenocarcinoma Lung-molGPA, and nonadenocarcinoma Lung-molGPA was 3.8 vs 15.6 months, 7 vs 13.5 months, 9.4 vs 13.5 months, 10.3 vs 13.5 months, 13.7 vs 13.7 months, and 9.8 vs 9.7 months, respectively. The BSKN model and adenocarcinoma LungmolGPA created three groups with a statistically significantly different MS (p = 0.002 and p = 0.01, respectively)., Conclusion: All models under-predicted MS and only the BSKN and Lung-molGPA model stratified patients into three risk groups with statistically significant actual MS. The prognostic groupings of the adenocarcinoma Lung-molGPA group was the best predictor of MS, and showed that we are making improvements in our prognostic ability by utilizing molecular information that is much more widely available in the current treatment era.

Glioblastoma (GBM) is one of the most common, deadly, and difficult-to-treat adult brain tumors. Surgical removal of the tumor, followed by radiotherapy (RT) and temozolomide (TMZ) administration, is the current treatment modality, but this regimen only modestly improves overall patient survival. Invasion of cells into the surrounding healthy brain tissue prevents complete surgical resection and complicates treatment strategies with the goal of preserving neurological function. Despite significant efforts to increase our understanding of GBM, there have been relatively few therapeutic advances since 2005 and even fewer treatments designed to effectively treat recurrent tumors that are resistant to therapy. Thus, while there is a pressing need to move new treatments into the clinic, emerging evidence suggests that key features unique to GBM location and biology, the blood-brain barrier (BBB) and intratumoral molecular heterogeneity, respectively, stand as critical unresolved hurdles to effective therapy. Notably, genomic analyses of GBM tissues has led to the identification of numerous gene alterations that govern cell growth, invasion and survival signaling pathways; however, the drugs that show pre-clinical potential against signaling pathways mediated by these gene alterations cannot achieve effective concentrations at the tumor site. As a result, identifying BBB-penetrating drugs and utilizing new and safer methods to enhance drug delivery past the BBB has become an area of intensive research. Repurposing and combining FDA-approved drugs with evidence of penetration into the central nervous system (CNS) has also seen new interest for the treatment of both primary and recurrent GBM. In this review, we discuss emerging methods to strategically enhance drug delivery to GBM and repurpose currently-approved and previously-studied drugs using rational combination strategies.

Background: Glioblastoma (GBM) is a difficult to treat brain cancer that nearly uniformly recurs, and recurrent tumors are largely therapy resistant. Our prior work has demonstrated an important role for the tumor necrosis factor-like weak inducer of apoptosis (TWEAK) receptor fibroblast growth factor-inducible 14 (Fn14) in GBM pathobiology. In this study, we investigated Fn14 expression in recurrent GBM and in the setting of temozolomide (TMZ) resistance., Methods: Fn14 mRNA expression levels in nonneoplastic brain, primary (newly diagnosed) GBM, and recurrent GBM (post-chemotherapy and radiation) specimens were obtained from The Cancer Genome Atlas data portal. Immunohistochemistry was performed using nonneoplastic brain, patient-matched primary and recurrent GBM, and gliosarcoma (GSM) specimens to examine Fn14 protein levels. Western blot analysis was used to compare Fn14 expression in parental TMZ-sensitive or matched TMZ-resistant patient-derived xenografts (PDXs) established from primary or recurrent tumor samples. The migratory capacity of control and Fn14-depleted TMZ-resistant GBM cells was assessed using the transwell migration assay., Results: We found that Fn14 is more highly expressed in recurrent GBM tumors than their matched primary GBM counterparts. Fn14 expression is also significantly elevated in GSM tumors. GBM PDX cells with acquired TMZ resistance have higher Fn14 levels and greater migratory capacity than their corresponding parental TMZ-sensitive cells, and the migratory difference is due, at least in part, to Fn14 expression in the TMZ-resistant cells., Conclusions: This study demonstrates that the Fn14 gene is highly expressed in recurrent GBM, GSM, and TMZ-resistant GBM PDX tumors. These findings suggest that Fn14 may be a valuable therapeutic target or drug delivery portal for treatment of recurrent GBM and GSM patients.

The TNF receptor superfamily member Fn14 is overexpressed by many solid tumor types, including glioblastoma (GBM), the most common and lethal form of adult brain cancer. GBM is notable for a highly infiltrative growth pattern and several groups have reported that high Fn14 expression levels can increase tumor cell invasiveness. We reported previously that the mesenchymal and proneural GBM transcriptomic subtypes expressed the highest and lowest levels of Fn14 mRNA, respectively. Given the recent histopathological re-classification of human gliomas by the World Health Organization based on isocitrate dehydrogenase 1 (IDH1) gene mutation status, we extended this work by comparing Fn14 gene expression in IDH1 wild-type (WT) and mutant (R132H) gliomas and in cell lines engineered to overexpress the IDH1 R132H enzyme. We found that both low-grade and high-grade (i.e., GBM) IDH1 R132H gliomas exhibit low Fn14 mRNA and protein levels compared to IDH1 WT gliomas. Forced overexpression of the IDH1 R132H protein in glioma cells reduced Fn14 expression, while treatment of IDH1 R132H-overexpressing cells with the IDH1 R132H inhibitor AGI-5198 or the DNA demethylating agent 5-aza-2'-deoxycytidine increased Fn14 expression. These results support a role for Fn14 in the more aggressive and invasive phenotype associated with IDH1 WT tumors and indicate that the low levels of Fn14 gene expression noted in IDH1 R132H mutant gliomas may be due to epigenetic regulation via changes in DNA methylation.

Generating spatially controlled, non-destructive changes in the interstitial spaces of the brain has a host of potential clinical applications, including enhancing the delivery of therapeutics, modulating biological features within the tissue microenvironment, altering fluid and pressure dynamics, and increasing the clearance of toxins, such as plaques found in Alzheimer's disease. Recently we demonstrated that ultrasound can non-destructively enlarge the interstitial spaces of the brain ex vivo. The goal of the current study was to determine whether these effects could be reproduced in the living brain using non-invasive, transcranial MRI-guided focused ultrasound (MRgFUS). The left striatum of healthy rats was treated using MRgFUS. Computer simulations facilitated treatment planning, and targeting was validated using MRI acoustic radiation force impulse imaging. Following MRgFUS treatments, Evans blue dye or nanoparticle probes were infused to assess changes in the interstitial space. In MRgFUS-treated animals, enhanced dispersion was observed compared to controls for 70 nm (12.8 ± 0.9 mm3 vs. 10.6 ± 1.0 mm3, p = 0.01), 200 nm (10.9 ± 1.4 mm3 vs. 7.4 ± 0.7 mm3, p = 0.01) and 700 nm (7.5 ± 0.4 mm3 vs. 5.4 ± 1.2 mm3, p = 0.02) nanoparticles, indicating enlargement of the interstitial spaces. No evidence of significant histological or electrophysiological injury was identified. These findings suggest that transcranial ultrasound can safely and effectively modulate the brain interstitium and increase the dispersion of large therapeutic entities such as particulate drug carriers or modified viruses. This has the potential to expand the therapeutic uses of MRgFUS.

Glioma is a unique neoplastic disease that develops exclusively in the central nervous system (CNS) and rarely metastasizes to other tissues. This feature strongly implicates the tumor-host CNS microenvironment in gliomagenesis and tumor progression. We investigated the differences and similarities in glioma biology as conveyed by transcriptomic patterns across four mammalian hosts: rats, mice, dogs, and humans. Given the inherent intra-tumoral molecular heterogeneity of human glioma, we focused this study on tumors with upregulation of the platelet-derived growth factor signaling axis, a common and early alteration in human gliomagenesis. The results reveal core neoplastic alterations in mammalian glioma, as well as unique contributions of the tumor host to neoplastic processes. Notable differences were observed in gene expression patterns as well as related biological pathways and cell populations known to mediate key elements of glioma biology, including angiogenesis, immune evasion, and brain invasion. These data provide new insights regarding mammalian models of human glioma, and how these insights and models relate to our current understanding of the human disease.

The most common and deadly form of primary brain cancer, glioblastoma (GBM), is characterized by significant intratumoral heterogeneity, microvascular proliferation, immune system suppression, and brain tissue invasion. Delivering effective and sustained treatments to the invasive GBM cells intermixed with functioning neural elements is a major goal of advanced therapeutic systems for brain cancer. Previously, we investigated the nanoparticle characteristics that enable targeting of invasive GBM cells. This revealed the importance of minimizing non-specific binding within the relatively adhesive, 'sticky' microenvironment of the brain and brain tumors in particular. We refer to such nanoformulations with decreased non-specific adhesivity and receptor targeting as 'DART' therapeutics. In this work, we applied this information toward the design and characterization of biodegradable nanocarriers, and in vivo testing in orthotopic experimental gliomas. We formulated particulate nanocarriers using poly(lactic-co-glycolic acid) (PLGA) and PLGA-polyethylene glycol (PLGA-PEG) polymers to generate sub-100nm nanoparticles with minimal binding to extracellular brain components and strong binding to the Fn14 receptor - an upregulated, conserved component in invasive GBM. Multiple particle tracking in brain tissue slices and in vivo testing in orthotopic murine malignant glioma revealed preserved nanoparticle diffusivity and increased uptake in brain tumor cells. These combined characteristics also resulted in longer retention of the DART nanoparticles within the orthotopic tumors compared to non-targeted versions. Taken together, these results and nanoparticle design considerations offer promising new methods to optimize therapeutic nanocarriers for improving drug delivery and treatment for invasive brain tumors., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Glioblastoma (GBM) is a highly aggressive and lethal form of primary brain cancer. Numerous barriers exist to the effective treatment of GBM including the tightly controlled interface between the bloodstream and central nervous system termed the 'neurovascular unit,' a narrow and tortuous tumor extracellular space containing a dense meshwork of proteins and glycosaminoglycans, and genomic heterogeneity and instability. A major goal of GBM therapy is achieving sustained drug delivery to glioma cells while minimizing toxicity to adjacent neurons and glia. Targeted nanotherapeutics have emerged as promising drug delivery systems with the potential to improve pharmacokinetic profiles and therapeutic efficacy. Some of the key cell surface molecules that have been identified as GBM targets include the transferrin receptor, low-density lipoprotein receptor-related protein, α v β 3 integrin, glucose transporter(s), glial fibrillary acidic protein, connexin 43, epidermal growth factor receptor (EGFR), EGFR variant III, interleukin-13 receptor α chain variant 2, and fibroblast growth factor-inducible factor 14. However, most targeted therapeutic formulations have yet to demonstrate improved efficacy related to disease progression or survival. Potential limitations to current targeted nanotherapeutics include: (1) adhesive interactions with nontarget structures, (2) low density or prevalence of the target, (3) lack of target specificity, and (4) genetic instability resulting in alterations of either the target itself or its expression level in response to treatment. In this review, we address these potential limitations in the context of the key GBM targets with the goal of advancing the understanding and development of targeted nanotherapeutics for GBM. WIREs Nanomed Nanobiotechnol 2017, 9:e1439. doi: 10.1002/wnan.1439 For further resources related to this article, please visit the WIREs website., (© 2016 Wiley Periodicals, Inc.)

Previously rodent preclinical research in gliomas frequently involved implantation of cell lines such as C6 and 9L into the rat brain. More recently, mouse models have taken over, the genetic manipulability of the mouse allowing the creation of genetically accurate models outweighed the disadvantage of its smaller brain size that limited time allowed for tumor progression. Here we illustrate a method that allows glioma formation in the rat using the replication competent avian-like sarcoma (RCAS) virus / tumor virus receptor-A (tv-a) transgenic system of post-natal cell type-specific gene transfer. The RCAS/tv-a model has emerged as a particularly versatile and accurate modeling technology by enabling spatial, temporal, and cell type-specific control of individual gene transformations and providing de novo formed glial tumors with distinct molecular subtypes mirroring human GBM. Nestin promoter-driven tv-a (Ntv-a) transgenic Sprague-Dawley rat founder lines were created and RCAS PDGFA and p53 shRNA constructs were used to initiate intracranial brain tumor formation. Tumor formation and progression were confirmed and visualized by magnetic resonance imaging (MRI) and spectroscopy. The tumors were analyzed using histopathological and immunofluorescent techniques. All experimental animals developed large, heterogeneous brain tumors that closely resembled human GBM. Median survival was 92 days from tumor initiation and 62 days from the first point of tumor visualization on MRI. Each tumor-bearing animal showed time dependent evidence of malignant progression to high-grade glioma by MRI and neurological examination. Post-mortem tumor analysis demonstrated the presence of several key characteristics of human GBM, including high levels of tumor cell proliferation, pseudopalisading necrosis, microvascular proliferation, invasion of tumor cells into surrounding tissues, peri-tumoral reactive astrogliosis, lymphocyte infiltration, presence of numerous tumor-associated microglia- and bone marrow-derived macrophages, and the formation of stem-like cell niches within the tumor. This transgenic rat model may enable detailed interspecies comparisons of fundamental cancer pathways and clinically relevant experimental imaging procedures and interventions that are limited by the smaller size of the mouse brain.