Strategies to Improve Drug Delivery Across the Blood-Brain Barrier for Glioblastoma.

PURPOSE OF REVIEW: Glioblastoma remains resistant to most conventional treatments. Despite scientific advances in the past three decades, there has been a dearth of effective new treatments. New approaches to drug delivery and clinical trial design are needed. RECENT FINDINGS: We discuss how the blood-brain barrier and tumor microenvironment pose challenges for development of effective therapies for glioblastoma. Next, we discuss treatments in development that aim to overcome these barriers, including novel drug designs such as nanoparticles and antibody-drug conjugates, novel methods of drug delivery, including convection-enhanced and intra-arterial delivery, and novel methods to enhance drug penetration, such as blood-brain barrier disruption by focused ultrasound and laser interstitial thermal therapy. Lastly, we address future opportunities, positing combination therapy as the best strategy for effective treatment, neoadjuvant and window-of-opportunity approaches to simultaneously enhance therapeutic effectiveness with interrogation of on-treatment biologic endpoints, and adaptive platform and basket trials as imperative for future trial design. New approaches to GBM treatment should account for the blood-brain barrier and immunosuppression by improving drug delivery, combining treatments, and integrating novel clinical trial designs.

SUPRAMAX-study: supramaximal resection versus maximal resection for glioblastoma patients: study protocol for an international multicentre prospective cohort study (ENCRAM 2201).

INTRODUCTION: A greater extent of resection of the contrast-enhancing (CE) tumour part has been associated with improved outcomes in glioblastoma. Recent results suggest that resection of the non-contrast-enhancing (NCE) part might yield even better survival outcomes (supramaximal resection, SMR). Therefore, this study evaluates the efficacy and safety of SMR with and without mapping techniques in high-grade glioma (HGG) patients in terms of survival, functional, neurological, cognitive and quality of life outcomes. Furthermore, it evaluates which patients benefit the most from SMR, and how they could be identified preoperatively. METHODS AND ANALYSIS: This study is an international, multicentre, prospective, two-arm cohort study of observational nature. Consecutive glioblastoma patients will be operated with SMR or maximal resection at a 1:1 ratio. Primary endpoints are (1) overall survival and (2) proportion of patients with National Institute of Health Stroke Scale deterioration at 6 weeks, 3 months and 6 months postoperatively. Secondary endpoints are (1) residual CE and NCE tumour volume on postoperative T1-contrast and FLAIR (Fluid-attenuated inversion recovery) MRI scans; (2) progression-free survival; (3) receipt of adjuvant therapy with chemotherapy and radiotherapy; and (4) quality of life at 6 weeks, 3 months and 6 months postoperatively. The total duration of the study is 5 years. Patient inclusion is 4 years, follow-up is 1 year. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethics Committee (METC Zuid-West Holland/Erasmus Medical Center; MEC-2020-0812). The results will be published in peer-reviewed academic journals and disseminated to patient organisations and media.

The importance of considering competing risks in recurrence analysis of intracranial meningioma.

BACKGROUND: The risk of recurrence is overestimated by the Kaplan-Meier method when competing events, such as death without recurrence, are present. Such overestimation can be avoided by using the Aalen-Johansen method, which is a direct extension of Kaplan-Meier that accounts for competing events. Meningiomas commonly occur in older individuals and have slow-growing properties, thereby warranting competing risk analysis. The extent to which competing events are considered in meningioma literature is unknown, and the consequences of using incorrect methodologies in meningioma recurrence risk analysis have not been investigated. METHODS: We surveyed articles indexed on PubMed since 2020 to assess the usage of competing risk analysis in recent meningioma literature. To compare recurrence risk estimates obtained through Kaplan-Meier and Aalen-Johansen methods, we applied our international database comprising ~ 8,000 patients with a primary meningioma collected from 42 institutions. RESULTS: Of 513 articles, 169 were eligible for full-text screening. There were 6,537 eligible cases from our PERNS database. The discrepancy between the results obtained by Kaplan-Meier and Aalen-Johansen was negligible among low-grade lesions and younger individuals. The discrepancy increased substantially in the patient groups associated with higher rates of competing events (older patients with high-grade lesions). CONCLUSION: The importance of considering competing events in recurrence risk analysis is poorly recognized as only 6% of the studies we surveyed employed Aalen-Johansen analyses. Consequently, most of the previous literature has overestimated the risk of recurrence. The overestimation was negligible for studies involving low-grade lesions in younger individuals; however, overestimation might have been substantial for studies on high-grade lesions.

Glioma-Immune Cell Crosstalk in Tumor Progression.

Glioma progression is a complex process controlled by molecular factors that coordinate the crosstalk between tumor cells and components of the tumor microenvironment (TME). Among these, immune cells play a critical role in cancer survival and progression. The complex interplay between cancer cells and the immune TME influences the outcome of immunotherapy and other anti-cancer therapies. Here, we present an updated view of the pro- and anti-tumor activities of the main myeloid and lymphocyte cell populations in the glioma TME. We review the underlying mechanisms involved in crosstalk between cancer cells and immune cells that enable gliomas to evade the immune system and co-opt these cells for tumor growth. Lastly, we discuss the current and experimental therapeutic options being developed to revert the immunosuppressive activity of the glioma TME. Knowledge of the complex interplay that elapses between tumor and immune cells may help develop new combination treatments able to overcome tumor immune evasion mechanisms and enhance response to immunotherapies.

Asleep triple-modality motor mapping for perirolandic gliomas: an update on outcomes.

OBJECTIVE: Maximal safe resection of gliomas near motor pathways is facilitated by intraoperative mapping. Here, the authors review their results with triple-modality asleep motor mapping with motor evoked potentials and bipolar and monopolar stimulation for cortical and subcortical mapping during glioma surgery in an expanded cohort. METHODS: This was a retrospective analysis of patients who underwent resection of a perirolandic glioma near motor pathways. Clinical and neuromonitoring data were extracted from the electronic medical records for review. All patients with new or worsened postoperative motor deficits were followed for at least 6 months. Regression analyses were performed to assess factors associated with a persistent motor deficit. RESULTS: Between January 2018 and December 2021, 160 operations were performed in 151 patients with perirolandic glioma. Sixty-four patients (40%) had preoperative motor deficits, and the median extent of resection was 98%. Overall, patients in 38 cases (23.8%) had new or worse immediate postoperative deficits by discharge, and persistent deficits by 6 months were seen in 6 cases (3.8%), all in patients with high-grade gliomas. There were no new persistent deficits in low-grade glioma patients (0%). The risk factors for a persistent deficit included an insular tumor component (OR 8.6, p = 0.01), preoperative motor weakness (OR 8.1, p = 0.03), intraoperative motor evoked potential (MEP) changes (OR 36.5, p < 0.0001), and peri-resection cavity ischemia (OR 7.5, p = 0.04). Most persistent deficits were attributable to ischemic injury despite structural preservation of the descending motor tracts. For patients with persistent motor deficits, there were 3 cases (50%) in which a change in MEP was noted but subsequent subcortical monopolar stimulation still elicited a response in the corresponding muscle groups, suggesting axonal activation distal to a point of injury. CONCLUSIONS: Asleep triple motor mapping results in a low rate of permanent deficits, especially for low-grade gliomas. Peri-resection cavity ischemia continues to be a significant risk factor for permanent deficit despite maintaining appropriate distance for subcortical tracts based on monopolar feedback.

High-volume facilities are not always low risk: comparing risk-standardized mortality rates versus facility volume as quality measures in surgical neuro-oncology.

OBJECTIVE: Risk-standardized mortality rates (RSMRs) have recently been shown to outperform facility case volume as a proxy for surgical quality in lung and gastrointestinal cancer. The aim of this study was to investigate RSMR as a surgical quality metric in primary CNS cancer. METHODS: This retrospective observational cohort study used data from the National Cancer Database, a population-based oncology outcomes database sourced from more than 1500 institutions in the United States, and included adult patients 18 years of age and older who were diagnosed with glioblastoma, pituitary adenoma, or meningioma and were treated with surgery. For each group, RSMR quintiles and annual volume were calculated in a training set (2009-2013) and these thresholds were applied to the validation set (2014-2018). In this paper, the authors compared the effectiveness and efficiency of facility volume-based versus RSMR-based hospital centralization models and evaluated the overlap between the two systems. A patterns-of-care analysis was also performed to explore socioeconomic predictors of being treated at better-performing treating facilities. RESULTS: A total of 37,838 meningioma, 21,189 pituitary adenoma, and 30,788 glioblastoma patients were surgically treated from 2014 to 2018. There were substantial differences between RSMR and facility volume classification schemes among all tumor types. In an RSMR-based centralization model, an average of 36 patients undergoing glioblastoma surgery would need to relocate to a low-mortality hospital to prevent one 30-day mortality following surgery, whereas 46 would need to relocate to a high-volume hospital. For pituitary adenoma and meningioma, both metrics were inefficient in centralizing care to reduce surgical mortality. Additionally, overall survival for glioblastoma patients was better modeled in an RSMR classification scheme. Analyses to investigate the impact of care disparities found that Black and Hispanic patients, patients earning less than $38,000, and uninsured patients were more likely to be treated at high-mortality hospitals. CONCLUSIONS: RSMR is more effective and efficient than a traditional volume-based approach for preventing early postoperative death in glioblastoma surgery. These data have important implications for future quality-related studies in neurosurgical oncology and may be relevant for healthcare/insurance payments, hospital evaluation assessments, healthcare disparities, and the standardization of care across hospitals.

Does waiting for surgery matter? How time from diagnostic MRI to resection affects outcomes in newly diagnosed glioblastoma.

OBJECTIVE: Maximal safe resection is the standard of care for patients presenting with lesions concerning for glioblastoma (GBM) on magnetic resonance imaging (MRI). Currently, there is no consensus on surgical urgency for patients with an excellent performance status, which complicates patient counseling and may increase patient anxiety. This study aims to assess the impact of time to surgery (TTS) on clinical and survival outcomes in patients with GBM. METHODS: This is a retrospective study of 145 consecutive patients with newly diagnosed IDH-wild-type GBM who underwent initial resection at the University of California, San Francisco, between 2014 and 2016. Patients were grouped according to the time from diagnostic MRI to surgery (i.e., TTS): ≤ 7, > 7-21, and > 21 days. Contrast-enhancing tumor volumes (CETVs) were measured using software. Initial CETV (CETV1) and preoperative CETV (CETV2) were used to evaluate tumor growth represented as percent change (ΔCETV) and specific growth rate (SPGR; % growth/day). Overall survival (OS) and progression-free survival (PFS) were measured from the date of resection and were analyzed using the Kaplan-Meier method and Cox regression analyses. RESULTS: Of the 145 patients (median TTS 10 days), 56 (39%), 53 (37%), and 36 (25%) underwent surgery ≤ 7, > 7-21, and > 21 days from initial imaging, respectively. Median OS and PFS among the study cohort were 15.5 and 10.3 months, respectively, and did not differ among the TTS groups (p = 0.81 and 0.17, respectively). Median CETV1 was 35.9, 15.7, and 10.2 cm3 across the TTS groups, respectively (p < 0.001). Preoperative biopsy and presenting to an outside hospital emergency department were associated with an average 12.79-day increase and 9.09-day decrease in TTS, respectively. Distance from the treating facility (median 57.19 miles) did not affect TTS. In the growth cohort, TTS was associated with an average 2.21% increase in ΔCETV per day; however, there was no effect of TTS on SPGR, Karnofsky Performance Status (KPS), postoperative deficits, survival, discharge location, or hospital length of stay. Subgroup analyses did not identify any high-risk groups for which a shorter TTS may be beneficial. CONCLUSIONS: An increased TTS for patients with imaging concerning for GBM did not impact clinical outcomes, and while there was a significant association with ΔCETV, SPGR remained unaffected. However, SPGR was associated with a worse preoperative KPS, which highlights the importance of tumor growth speed over TTS. Therefore, while it is ill advised to wait an unnecessarily long time after initial imaging studies, these patients do not require urgent/emergency surgery and can seek tertiary care opinions and/or arrange for additional preoperative support/resources. Future studies are needed to explore subgroups for whom TTS may impact clinical outcomes.

Surgical management and outcome of newly diagnosed glioblastoma without contrast enhancement (low-grade appearance): a report of the RANO resect group.

BACKGROUND: Resection of the contrast-enhancing (CE) tumor represents the standard of care in newly diagnosed glioblastoma. However, some tumors ultimately diagnosed as glioblastoma lack contrast enhancement and have a 'low-grade appearance' on imaging (non-CE glioblastoma). We aimed to (a) volumetrically define the value of non-CE tumor resection in the absence of contrast enhancement, and to (b) delineate outcome differences between glioblastoma patients with and without contrast enhancement. METHODS: The RANO resect group retrospectively compiled a global, eight-center cohort of patients with newly diagnosed glioblastoma per WHO 2021 classification. The associations between postoperative tumor volumes and outcome were analyzed. Propensity score-matched analyses were constructed to compare glioblastomas with and without contrast enhancement. RESULTS: Among 1323 newly diagnosed IDH-wildtype glioblastomas, we identified 98 patients (7.4%) without contrast enhancement. In such patients, smaller postoperative tumor volumes were associated with more favorable outcome. There was an exponential increase in risk for death with larger residual non-CE tumor. Accordingly, extensive resection was associated with improved survival compared to lesion biopsy. These findings were retained on a multivariable analysis adjusting for demographic and clinical markers. Compared to CE glioblastoma, patients with non-CE glioblastoma had a more favorable clinical profile and superior outcome as confirmed in propensity score analyses by matching the patients with non-CE glioblastoma to patients with CE glioblastoma using a large set of clinical variables. CONCLUSIONS: The absence of contrast enhancement characterizes a less aggressive clinical phenotype of IDH-wildtype glioblastomas. Maximal resection of non-CE tumors has prognostic implications and translates into favorable outcome.

Analysis of upfront resection or stereotactic radiosurgery for local control of solid and cystic cerebellar hemangioblastomas.

OBJECTIVE: The purpose of this study was to identify rates of and risk factors for local tumor progression in patients who had undergone surgery or radiosurgery for the management of cerebellar hemangioblastoma and to describe treatments pursued following tumor progression. METHODS: The authors conducted a retrospective single-center review of patients who had undergone treatment of a cerebellar hemangioblastoma with either surgery or stereotactic radiosurgery (SRS) between 1996 and 2019. Univariate and multivariate regression analyses were performed to examine factors associated with local tumor control. RESULTS: One hundred nine patients met the study inclusion criteria. Overall, these patients had a total of 577 hemangioblastomas, 229 of which were located in the cerebellum. The surgical and SRS cohorts consisted of 106 and 123 cerebellar hemangioblastomas, respectively. For patients undergoing surgery, tumors were treated with subtotal resection and gross-total resection in 5.7% and 94.3% of cases, respectively. For patients receiving SRS, the mean target volume was 0.71 cm3 and the mean margin dose was 18.0 Gy. Five-year freedom from lesion progression for the surgical and SRS groups was 99% and 82%, respectively. The surgical and SRS cohorts contained 32% versus 97% von Hippel-Lindau tumors, 78% versus 7% cystic hemangioblastomas, and 12.8- versus 0.56-cm3 mean tumor volumes, respectively. On multivariate analysis, factors associated with local tumor progression in the SRS group included older patient age (HR 1.06, 95% CI 1.03-1.09, p < 0.001) and a cystic component (HR 9.0, 95% CI 2.03-32.0, p = 0.001). Repeat SRS as salvage therapy was used more often for smaller tumor recurrences, and no tumor recurrences of < 1.0 cm3 required additional salvage surgery following repeat SRS. CONCLUSIONS: Both surgery and SRS achieve high rates of local control of hemangioblastomas. Age and cystic features are associated with local progression after SRS treatment for cerebellar hemangioblastomas. In cases of local tumor recurrence, salvage surgery and repeat SRS are valid forms of treatment to achieve local tumor control, although resection may be preferable for larger recurrences.

"De novo replication repair deficient glioblastoma, IDH-wildtype" is a distinct glioblastoma subtype in adults that may benefit from immune checkpoint blockade.

Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments. Through prospective genomic profiling of 459 consecutive primary treatment-naïve IDH-wildtype glioblastomas in adults, we identified a unique subgroup (2%, 9/459) defined by somatic hypermutation and DNA replication repair deficiency due to biallelic inactivation of a canonical mismatch repair gene. The deleterious mutations in mismatch repair genes were often present in the germline in the heterozygous state with somatic inactivation of the remaining allele, consistent with glioblastomas arising due to underlying Lynch syndrome. A subset of tumors had accompanying proofreading domain mutations in the DNA polymerase POLE and resultant "ultrahypermutation". The median age at diagnosis was 50 years (range 27-78), compared with 63 years for the other 450 patients with conventional glioblastoma (p < 0.01). All tumors had histologic features of the giant cell variant of glioblastoma. They lacked EGFR amplification, lacked combined trisomy of chromosome 7 plus monosomy of chromosome 10, and only rarely had TERT promoter mutation or CDKN2A homozygous deletion, which are hallmarks of conventional IDH-wildtype glioblastoma. Instead, they harbored frequent inactivating mutations in TP53, NF1, PTEN, ATRX, and SETD2 and recurrent activating mutations in PDGFRA. DNA methylation profiling revealed they did not align with known reference adult glioblastoma methylation classes, but instead had unique globally hypomethylated epigenomes and mostly classified as "Diffuse pediatric-type high grade glioma, RTK1 subtype, subclass A". Five patients were treated with immune checkpoint blockade, four of whom survived greater than 3 years. The median overall survival was 36.8 months, compared to 15.5 months for the other 450 patients (p < 0.001). We conclude that "De novo replication repair deficient glioblastoma, IDH-wildtype" represents a biologically distinct subtype in the adult population that may benefit from prospective identification and treatment with immune checkpoint blockade.

Advances in Intraoperative Glioma Tissue Sampling and Infiltration Assessment.

Gliomas are infiltrative brain tumors that often involve functional tissue. While maximal safe resection is critical for maximizing survival, this is challenged by the difficult intraoperative discrimination between tumor-infiltrated and normal structures. Surgical expertise is essential for identifying safe margins, and while the intraoperative pathological review of frozen tissue is possible, this is a time-consuming task. Advances in intraoperative stimulation mapping have aided surgeons in identifying functional structures and, as such, has become the gold standard for this purpose. However, intraoperative margin assessment lacks a similar consensus. Nonetheless, recent advances in intraoperative imaging techniques and tissue examination methods have demonstrated promise for the accurate and efficient assessment of tumor infiltration and margin delineation within the operating room, respectively. In this review, we describe these innovative technologies that neurosurgeons should be aware of.

Targeted gene expression profiling predicts meningioma outcomes and radiotherapy responses.

Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. Here we develop a targeted gene expression biomarker that predicts meningioma outcomes and radiotherapy responses. Using a discovery cohort of 173 meningiomas, we developed a 34-gene expression risk score and performed clinical and analytical validation of this biomarker on independent meningiomas from 12 institutions across 3 continents (N = 1,856), including 103 meningiomas from a prospective clinical trial. The gene expression biomarker improved discrimination of outcomes compared with all other systems tested (N = 9) in the clinical validation cohort for local recurrence (5-year area under the curve (AUC) 0.81) and overall survival (5-year AUC 0.80). The increase in AUC compared with the standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval 0.07 to 0.17, P < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% confidence interval 0.37 to 0.78, P = 0.0001) and suggested postoperative management could be refined for 29.8% of patients. In sum, our results identify a targeted gene expression biomarker that improves discrimination of meningioma outcomes, including prediction of postoperative radiotherapy responses.

Molecular Features of Resected Melanoma Brain Metastases, Clinical Outcomes, and Responses to Immunotherapy.

Importance: Central nervous system (CNS)-penetrant systemic therapies have significantly advanced care for patients with melanoma brain metastases. However, improved understanding of the molecular landscape and microenvironment of these lesions is needed to both optimize patient selection and advance treatment approaches. Objective: To evaluate how bulk and single-cell genomic features of melanoma brain metastases are associated with clinical outcome and treatment response. Design, Setting, and Participants: This cohort study analyzed bulk DNA sequencing and single nuclear RNA-sequencing data from resected melanoma brain metastases and included 94 consecutive patients with a histopathologically confirmed diagnosis of melanoma brain metastasis who underwent surgical resection at a single National Comprehensive Cancer Network cancer center in San Francisco, California, from January 1, 2009, to December 31, 2022. Exposure: A Clinical Laboratory Improvement Amendments-certified targeted sequencing assay was used to analyze tumor resection specimens, with a focus on BRAF V600E alteration. For frozen pathologic specimens from CNS treatment-naive patients undergoing surgical resection, commercial single nuclear RNA sequencing approaches were used. Main Outcomes and Measures: The primary outcome was overall survival (OS). Secondary outcomes included CNS progression-free survival (PFS), microenvironmental composition with decreased T-cell and macrophage populations, and responses to immunotherapy. Results: To correlate molecular status with clinical outcome, Kaplan-Meier survival analysis of 94 consecutive patients (median age, 64 years [range, 24-82 years]; 70 men [74%]) with targeted BRAF alteration testing showed worse median intracranial PFS (BRAF variant: 3.6 months [IQR, 0.1-30.6 months]; BRAF wildtype: 11.0 months [IQR, 0.8-81.5 months]; P < .001) and OS (BRAF variant: 9.8 months [IQR, 2.5-69.4 months]; BRAF wildtype: 23.2 months [IQR, 1.1-102.5 months]; P = .005; log-rank test) in BRAF V600E variant tumors. Multivariable Cox proportional hazards regression analysis revealed that BRAF V600E status was an independent variable significantly associated with both PFS (hazard ratio [HR], 2.65; 95% CI, 1.54-4.57; P < .001) and OS (HR, 1.96; 95% CI, 1.08-3.55; P = .03). For the 45 patients with resected melanoma brain metastases undergoing targeted DNA sequencing, molecular classification recapitulated The Cancer Genome Atlas groups (NRAS variant, BRAF variant, NF1 variant, and triple wildtype) with no subtype enrichment within the brain metastasis cohort. On a molecular level, BRAF V600E variant lesions were found to have a significantly decreased tumor mutation burden. Moreover, single nuclear RNA sequencing of treatment-naive BRAF V600E variant (n = 3) brain metastases compared with BRAF wildtype (n = 3) brain metastases revealed increased immune cell populations in BRAF wildtype tumors (mean [SD], 11% [4.1%] vs 3% [1.6%] CD45-positive cells; P = .04). Survival analysis of postoperative immunotherapy responses by BRAF status revealed that BRAF wildtype lesions were associated with a response to checkpoint inhibition (median OS: with immunotherapy, undefined; without immunotherapy, 13.0 months [range, 1.1-61.7 months]; P = .001; log-rank test) while BRAF variant lesions (median OS: with immunotherapy, 9.8 months [range, 2.9-39.8 months]; without immunotherapy, 9.5 months [range, 2.5-67.2 months]; P = .81; log-rank test) were not. Conclusions and Relevance: This molecular analysis of patients with resected melanoma brain metastases found that BRAF V600E alteration is an important translational biomarker associated with worse clinical outcomes, differential microenvironmental composition, and benefit from immunotherapy. Patients with BRAF V600E variant melanoma brain metastases may thus benefit from alternative CNS-penetrant systemic regimens.

Glioma-neuronal circuit remodeling induces regional immunosuppression.

Neuronal activity-driven mechanisms impact glioblastoma cell proliferation and invasion 1-7 , and glioblastoma remodels neuronal circuits 8,9 . Distinct intratumoral regions maintain functional connectivity via a subpopulation of malignant cells that mediate tumor-intrinsic neuronal connectivity and synaptogenesis through their transcriptional programs 8 . However, the effects of tumor-intrinsic neuronal activity on other cells, such as immune cells, remain unknown. Here we show that regions within glioblastomas with elevated connectivity are characterized by regional immunosuppression. This was accompanied by different cell compositions and inflammatory status of tumor-associated macrophages (TAMs) in the tumor microenvironment. In preclinical intracerebral syngeneic glioblastoma models, CRISPR/Cas9 gene knockout of Thrombospondin-1 (TSP-1/ Thbs1 ), a synaptogenic factor critical for glioma-induced neuronal circuit remodeling, in glioblastoma cells suppressed synaptogenesis and glutamatergic neuronal hyperexcitability, while simultaneously restoring antigen-presentation and pro-inflammatory responses. Moreover, TSP-1 knockout prolonged survival of immunocompetent mice harboring intracerebral syngeneic glioblastoma, but not of immunocompromised mice, and promoted infiltrations of pro-inflammatory TAMs and CD8+ T-cells in the tumor microenvironment. Notably, pharmacological inhibition of glutamatergic excitatory signals redirected tumor-associated macrophages toward a less immunosuppressive phenotype, resulting in prolonged survival. Altogether, our results demonstrate previously unrecognized immunosuppression mechanisms resulting from glioma-neuronal circuit remodeling and suggest future strategies targeting glioma-neuron-immune crosstalk may open up new avenues for immunotherapy.

The surgical management of diffuse gliomas: Current state of neurosurgical management and future directions.

After recent updates to the World Health Organization pathological criteria for diagnosing and grading diffuse gliomas, all major North American and European neuro-oncology societies recommend a maximal safe resection as the initial management of a diffuse glioma. For neurosurgeons to achieve this goal, the surgical plan for both low- and high-grade gliomas should be to perform a supramaximal resection when feasible based on preoperative imaging and the patient's performance status, utilizing every intraoperative adjunct to minimize postoperative neurological deficits. While the surgical approach and technique can vary, every effort must be taken to identify and preserve functional cortical and subcortical regions. In this summary statement on the current state of the field, we describe the tools and technologies that facilitate the safe removal of diffuse gliomas and highlight intraoperative and postoperative management strategies to minimize complications for these patients. Moreover, we discuss how surgical resections can go beyond cytoreduction by facilitating biological discoveries and improving the local delivery of adjuvant chemo- and radiotherapies.

Prognostic evaluation of re-resection for recurrent glioblastoma using the novel RANO classification for extent of resection: A report of the RANO resect group.

BACKGROUND: The value of re-resection in recurrent glioblastoma remains controversial as a randomized trial that specifies intentional incomplete resection cannot be justified ethically. Here, we aimed to (1) explore the prognostic role of extent of re-resection using the previously proposed Response Assessment in Neuro-Oncology (RANO) classification (based upon residual contrast-enhancing (CE) and non-CE tumor), and to (2) define factors consolidating the surgical effects on outcome. METHODS: The RANO resect group retrospectively compiled an 8-center cohort of patients with first recurrence from previously resected glioblastomas. The associations of re-resection and other clinical factors with outcome were analyzed. Propensity score-matched analyses were constructed to minimize confounding effects when comparing the different RANO classes. RESULTS: We studied 681 patients with first recurrence of Isocitrate Dehydrogenase (IDH) wild-type glioblastomas, including 310 patients who underwent re-resection. Re-resection was associated with prolonged survival even when stratifying for molecular and clinical confounders on multivariate analysis; ≤1 cm3 residual CE tumor was associated with longer survival than non-surgical management. Accordingly, "maximal resection" (class 2) had superior survival compared to "submaximal resection" (class 3). Administration of (radio-)chemotherapy in the absence of postoperative deficits augmented the survival associations of smaller residual CE tumors. Conversely, "supramaximal resection" of non-CE tumor (class 1) was not associated with prolonged survival but was frequently accompanied by postoperative deficits. The prognostic role of residual CE tumor was confirmed in propensity score analyses. CONCLUSIONS: The RANO resect classification serves to stratify patients with re-resection of glioblastoma. Complete resection according to RANO resect classes 1 and 2 is prognostic.

Technical Aspects of Motor and Language Mapping in Glioma Patients.

Gliomas are infiltrative primary brain tumors that often invade functional cortical and subcortical regions, and they mandate individualized brain mapping strategies to avoid postoperative neurological deficits. It is well known that maximal safe resection significantly improves survival, while postoperative deficits minimize the benefits associated with aggressive resections and diminish patients' quality of life. Although non-invasive imaging tools serve as useful adjuncts, intraoperative stimulation mapping (ISM) is the gold standard for identifying functional cortical and subcortical regions and minimizing morbidity during these challenging resections. Current mapping methods rely on the use of low-frequency and high-frequency stimulation, delivered with monopolar or bipolar probes either directly to the cortical surface or to the subcortical white matter structures. Stimulation effects can be monitored through patient responses during awake mapping procedures and/or with motor-evoked and somatosensory-evoked potentials in patients who are asleep. Depending on the patient's preoperative status and tumor location and size, neurosurgeons may choose to employ these mapping methods during awake or asleep craniotomies, both of which have their own benefits and challenges. Regardless of which method is used, the goal of intraoperative stimulation is to identify areas of non-functional tissue that can be safely removed to facilitate an approach trajectory to the equator, or center, of the tumor. Recent technological advances have improved ISM's utility in identifying subcortical structures and minimized the seizure risk associated with cortical stimulation. In this review, we summarize the salient technical aspects of which neurosurgeons should be aware in order to implement intraoperative stimulation mapping effectively and safely during glioma surgery.

A Preoperative Scoring System to Predict Function-Based Resection Limitation Due to Insufficient Participation During Awake Surgery.

BACKGROUND: Failure in achieving a function-based resection related to the insufficient patient's participation is a drawback of awake surgery. OBJECTIVE: To assess preoperative parameters predicting the risk of patient insufficient intraoperative cooperation leading to the arrest of the awake resection. METHODS: Observational, retrospective, multicentric cohort analysis enrolling 384 (experimental dataset) and 100 (external validation dataset) awake surgeries. RESULTS: In the experimental data set, an insufficient intraoperative cooperation occurred in 20/384 patients (5.2%), leading to awake surgery failure in 3/384 patients (ie, no resection, 0.8%), and precluded the achievement of the function-based resection in 17/384 patients (ie, resection limitation, 4.4%). The insufficient intraoperative cooperation significantly reduced the resection rates (55.0% vs 94.0%, P < .001) and precluded a supratotal resection (0% vs 11.3%, P = .017). Seventy years or older, uncontrolled epileptic seizures, previous oncological treatment, hyperperfusion on MRI, and mass effect on midline were independent predictors of insufficient cooperation during awake surgery ( P < .05). An Awake Surgery Insufficient Cooperation score was then assessed: 96.9% of patients (n = 343/354) with a score ≤2 presented a good intraoperative cooperation, while only 70.0% of patients (n = 21/30) with a score >2 presented a good intraoperative cooperation. In the experimental data set, similar date were found: 98.9% of patients (n = 98/99) with a score ≤2 presented a good cooperation, while 0% of patients (n = 0/1) with a score >2 presented a good cooperation. CONCLUSION: Function-based resection under awake conditions can be safely performed with a low rate of insufficient patient intraoperative cooperation. The risk can be assessed preoperatively by a careful patient selection.

Glioblastoma induces the recruitment and differentiation of hybrid neutrophils from skull bone marrow.

Tumor-associated neutrophil (TAN) effects on glioblastoma biology remain under-characterized. We show here that 'hybrid' neutrophils with dendritic features - including morphological complexity, expression of antigen presentation genes, and the ability to process exogenous peptide and stimulate MHCII-dependent T cell activation - accumulate intratumorally and suppress tumor growth in vivo . Trajectory analysis of patient TAN scRNA-seq identifies this phenotype as a polarization state which is distinct from canonical cytotoxic TANs and differentiates intratumorally from immature precursors absent in circulation. Rather, these hybrid-inducible immature neutrophils - which we identified in patient and murine glioblastomas - arise from local skull marrow. Through labeled skull flap transplantation and targeted ablation, we characterize calvarial marrow as a potent contributor of antitumoral myeloid APCs, including hybrid TANs and dendritic cells, which elicit T cell cytotoxicity and memory. As such, agents augmenting neutrophil egress from skull marrow - such as intracalvarial AMD3100 whose survival prolonging-effect in GBM we demonstrate - present therapeutic potential.