Combination immunotherapy strategies for glioblastoma.

INTRODUCTION: Despite recent advances in treatment for a number of cancers with immune checkpoint blockade (ICB), immunotherapy has had limited efficacy in glioblastoma (GBM). The recent multi-centered CheckMate 143 trial in first time recurrent GBM and the Checkmate 498 trial in newly diagnosed unmethylated GBM showed that antibodies against programmed cell death protein 1 (PD-1) failed to improve overall survival in patients with GBM. Recent preclinical and clinical studies have explored combining ICB with several other therapies including additional ICB against alternative checkpoint molecules, activation of costimulatory checkpoint molecules such as 4-1BB, radiation-induced tumor cell lysis and immunogenic recruitment, local chemotherapy, neoadjuvant ICB therapy, and myeloid cell reactivation. METHODS: We have reviewed the literature on ICB seminal to the progression of several preclinical studies and clinical trials in order to provide a compendium of the current state of combination immunotherapy for GBM. For ongoing clinical trials without associated publications, we searched clinicaltrials.gov for ongoing studies using the keywords, "GBM" and "glioblastoma", as well as names of checkpoint molecules. RESULTS: Recent trends from clinical trials demonstrate that despite a variety of different combination strategies involving ICB, GBM remains largely elusive to current immunotherapies. There is a discordance of survival outcomes between GBM pre-clinical models and clinical trials, likely due to the heterogeneity of GBM in patients as well as other adaptive immune mechanisms not otherwise represented in murine models. However, in clinical studies, neoadjuvant ICB in GBM was found to diversify the T cell receptor (TCR) repertoire and increase chemokine mRNA transcripts when comparing pre- and post- surgical time points. Moreover, an increase in peripheral and tumor-infiltrating lymphocyte (TIL) clonotypes were also observed when comparing adjuvant and neoadjuvant cohorts. DISCUSSION: Despite the lack of clinical survival benefit, immune modulation was observed in multiple different combination strategies for GBM in both preclinical and clinical studies, indicating that ICB combination therapy results in a significant immunological impact on the tumor microenvironment.

Machine learning from clinical data sets of a contemporary decision for orthodontic tooth extraction.

OBJECTIVE: To examine the robustness of the published machine learning models in the prediction of extraction vs non-extraction for a diverse US sample population seen by multiple providers. SETTING AND SAMPLE POPULATION: Diverse group of 838 patients (208 extraction, 630 non-extraction) were consecutively enrolled. MATERIALS AND METHODS: Two sets of input features (117 and 22) including clinical and cephalometric variables were identified based on previous studies. Random forest (RF) and multilayer perception (MLP) models were trained using these feature sets on the sample population and evaluated using measures including accuracy (ACC) and balanced accuracy (BA). A technique to identify incongruent data was used to explore underlying characteristics of the data set and split all samples into 2 groups (G1 and G2) for further model training. RESULTS: Performance of the models (75%-79% ACC and 72%-76% BA) on the total sample population was lower than in previous research. Models were retrained and evaluated using G1 and G2 separately, and individual group MLP models yielded improved accuracy for G1 (96% ACC and 94% BA) and G2 (88% ACC and 85% BA). RF feature ranking showed differences between top features for G1 (maxillary crowding, mandibular crowding and L1-NB) and G2 (age, mandibular crowding and lower lip to E-plane). CONCLUSIONS: An incongruent data pattern exists in a consecutively enrolled patient population. Future work with incongruent data segregation and advanced artificial intelligence algorithms is needed to improve the generalization ability to make it ready to support clinical decision-making.

A systematic review and meta-analysis of supratotal versus gross total resection for glioblastoma.

PURPOSE: Due to the infiltrative nature of glioblastoma (GBM) outside of the contrast-enhancing region on MRI, there is interest in exploring supratotal resections (SpTR) that extend beyond the contrast-enhancing portion of the tumor. However, there is currently no consensus on the potential survival benefit of SpTR in GBM compared to gross total resection (GTR). In this study, we compare the impact of SpTR versus GTR on overall survival (OS) of GBM patients. METHODS: We performed a systematic review and meta-analysis of literature published on PubMed, Embase, The Cochrane Library, Web of Science, Scopus, and ClinicalTrials.gov, from inception to August 16, 2018, to identify articles comparing OS after SpTR versus GTR. RESULTS: We identified 8902 unique citations, of which 11 articles met study inclusion criteria. 810 patients underwent SpTR out of a total of 2056 patients. 9 of 11 studies demonstrated improved outcomes with SpTR compared to GTR (median improvement in OS of 10.5 months), with no significant difference in postoperative complication rate. Overall study quality was variable, with ten studies presenting level IV evidence and one study presenting level IIIb evidence. Subgroup meta-analysis based on SpTR definition demonstrated a statistically significant 35% lower risk of mortality in patients who underwent anatomical SpTR compared to patients who underwent GTR (Hazard ratio = 0.65, 95% CI 0.47- 0.91, p = 0.003). CONCLUSION: Our systematic review indicates SpTR may be associated with improved OS compared to GTR for GBM, especially with anatomical SpTR. However, this is limited by variable study design and significant clinical and methodological heterogeneity among studies. There is need for prospective clinical data to further guide parameters regarding the use of SpTR in GBM.

Minimally invasive resection of intracranial lesions using tubular retractors: a large, multi-surgeon, multi-institutional series.

PURPOSE: Lesions located in subcortical areas are difficult to safely access. Tubular retractors have been increasingly used successfully with low complication profile to access lesions by minimizing brain retraction trauma and distributing pressure radially. Both binocular operative microscope and monocular exoscope are utilized for lesion visualization through tubular retractors. We present the largest multi-surgeon, multi-institutional series to determine the efficacy and safety profile of a transcortical-transtubular approach for intracranial lesion resections with both microscopic and exoscopic visualization. METHODS: We reviewed a multi-surgeon, multi-institutional case series including transcortical-transtubular resection of intracranial lesions using either BrainPath (NICO, Indianapolis, Indiana) or ViewSite Brain Access System (VBAS, Vycor Medical, Boca Raton, Florida) tubular retractors (n = 113). RESULTS: One hundred thirteen transtubular resections for intracranial lesions were performed. Patients presented with a diverse number of pathologies including 25 cavernous hemangiomas (21.2%), 15 colloid cysts (13.3%), 26 GBM (23.0%), two meningiomas (1.8%), 27 metastases (23.9%), 9 gliomas (7.9%) and 9 other lesions (7.9%). Mean lesion depth below the cortical surface was 4.4 cm, and mean lesion size was 2.7 cm. A gross total resection was achieved in 81 (71.7%) cases. Permanent complication rate was 4.4%. One patient (0.8%) experienced one early postoperative seizure (< 1 week postop). No patients experienced late seizures (> 1 week follow-up). Mean post-operative hospitalization length was 4.1 days. CONCLUSION: Tubular retractors provide a minimally invasive operative corridor for resection of intracranial lesions. They provide an effective tool in the neurosurgical armamentarium to resect subcortical lesions with a low complication profile.

Trends in glioblastoma: outcomes over time and type of intervention: a systematic evidence based analysis.

INTRODUCTION: Despite aggressive treatment with chemoradiotherapy and maximum surgical resection, survival in patients with glioblastoma (GBM) remains poor. Ongoing efforts are aiming to prolong the lifespan of these patients; however, disparities exist in reported survival values with lack of clear evidence that objectively examines GBM survival trends. We aim to describe the current status and advances in the survival of patients with GBM, by analyzing median overall survival through time and between treatment modalities. METHODS: A systematic review was conducted according to PRISMA guidelines to identify articles of newly diagnosed glioblastoma from 1978 to 2018. Full-text glioblastoma papers with human subjects, ≥ 18 years old, and n ≥ 25, were included for evaluation. RESULTS: The central tendency of median overall survival (MOS) was 13.5 months (2.3-29.6) and cumulative 5-year survival was 5.8% (0.01%-29.1%), with a significant difference in survival between studies that predate versus postdate the implementation of temozolomide and radiation, [12.5 (2.3-28) vs 15.6 (3.8-29.6) months, P < 0.001]. In clinical trials, bevacizumab [18.2 (10.6-23.0) months], tumor treating fields (TTF) [20.7 (20.5-20.9) months], and vaccines [19.2 (15.3-26.0) months] reported the highest central measure of median survival. CONCLUSION: Coadministration with radiotherapy and temozolomide provided a statistically significant increase in survival for patients suffering from glioblastoma. However, the natural history for GBM remains poor. Therapies including TTF pooled values of MOS and provide means of prolonging the survival of GBM patients.

How the EMERGE guideline on medication adherence can improve the quality of clinical trials.

Medication adherence in drug trials is suboptimal, affecting the quality of these studies and adding significant costs. Nonadherence in this setting can lead to null findings, unduly large sample sizes and the need for dose modification after a drug has been approved. Despite these drawbacks, adherence behaviours are not consistently measured, analysed or reported appropriately in trial settings. The ESPACOMP Medication Adherence Reporting Guideline (EMERGE) offers a solution by facilitating a sound protocol design that takes this crucial factor into account. This article summarises key evidence on traditional and newer measurements of adherence, discusses implementation in clinical trial settings and makes recommendations about the analysis and interpretation of adherence data. Given the potential benefits of this approach, the authors call on regulators and the pharmaceutical industry to endorse the EMERGE guideline.

Differential preventive activity of sulindac and atorvastatin in Apc+/Min-FCCCmice with or without colorectal adenomas.

OBJECTIVE: The response of subjects to preventive intervention is heterogeneous. The goal of this study was to determine if the efficacy of a chemopreventive agent differs in non-tumour-bearing animals versus those with colorectal tumours. Sulindac and/or atorvastatin was administered to Apc+/Min-FCCC mice with known tumour-bearing status at treatment initiation. DESIGN: Male mice (6-8 weeks old) underwent colonoscopy and received control chow or chow with sulindac (300 ppm), atorvastatin (100 ppm) or sulindac/atorvastatin. Tissues were collected from mice treated for 14 weeks (histopathology) or 7 days (gene expression). Cell cycle analyses were performed on SW480 colon carcinoma cells treated with sulindac, atorvastatin or both. RESULTS: The multiplicity of colorectal adenomas in untreated mice bearing tumours at baseline was 3.6-fold higher than that of mice that were tumour free at baseline (P=0.002). Atorvastatin completely inhibited the formation of microadenomas in mice that were tumour free at baseline (P=0.018) and altered the expression of genes associated with stem/progenitor cells. Treatment of tumour-bearing mice with sulindac/atorvastatin led to a 43% reduction in the multiplicity of colorectal adenomas versus untreated tumour-bearing mice (P=0.049). Sulindac/atorvastatin increased the expression of Hoxb13 and Rprm significantly, suggesting the importance of cell cycle regulation in tumour inhibition. Treatment of SW480 cells with sulindac/atorvastatin led to cell cycle arrest (G0/G1). CONCLUSIONS: The tumour status of animals at treatment initiation dictates response to therapeutic intervention. Atorvastatin eliminated microadenomas in tumour-free mice. The tumour inhibition observed with Sul/Atorva in tumour-bearing mice was greater than that achieved with each agent.

Glycolytic enzymes localize to ribonucleoprotein granules in Drosophila germ cells, bind Tudor and protect from transposable elements.

Germ cells give rise to all cell lineages in the next-generation and are responsible for the continuity of life. In a variety of organisms, germ cells and stem cells contain large ribonucleoprotein granules. Although these particles were discovered more than 100 years ago, their assembly and functions are not well understood. Here we report that glycolytic enzymes are components of these granules in Drosophila germ cells and both their mRNAs and the enzymes themselves are enriched in germ cells. We show that these enzymes are specifically required for germ cell development and that they protect their genomes from transposable elements, providing the first link between metabolism and transposon silencing. We further demonstrate that in the granules, glycolytic enzymes associate with the evolutionarily conserved Tudor protein. Our biochemical and single-particle EM structural analyses of purified Tudor show a flexible molecule and suggest a mechanism for the recruitment of glycolytic enzymes to the granules. Our data indicate that germ cells, similarly to stem cells and tumor cells, might prefer to produce energy through the glycolytic pathway, thus linking a particular metabolism to pluripotency.

Evaluating extent of resection in pediatric glioblastoma: a multiple propensity score-adjusted population-based analysis.

PURPOSE: The benefit of radical resections for glioblastoma patients remains a source of contention in the literature. Few studies have been conducted in pediatric patients, and it is becoming increasingly evident that data regarding adult glioblastoma (GB) patients cannot be generalized to pediatric patients affected by this neoplasm. A comparative effectiveness study is performed for different extent of resection (EOR) groups in the largest cohort of pediatric GB (pGB) patients. METHODS: The Surveillance, Epidemiology, and End Results (SEER) cancer registry was used to identify pGB patients from 1988 through 2009. Multivariate- and multiple propensity score (mPS)-adjusted analyses were used to determine the effect of gross total resection (GTR), partial resection (PR), and biopsy (Bx) on overall survival. Survival prospects were summarized using direct adjusted survival curves. RESULTS: A total of 342 pGB patients were identified, and 35.4 % of patients received a GTR, 28.8 % PR, 17.3 % Bx, and 17.0 % did not undergo surgery. In our cohort, a median overall survival of 12 months was observed with 1-, 2-, and 5-year survival rates of 51.7, 28.3, and 15.7 %, respectively. EOR was a predictor of survival in both the multivariate- (P < 0.001) and mPS-adjusted model (P < 0.001). Compared to the GTR group, a higher mortality rate was observed in patients who underwent a PR (HR 1.50; 95 % CI, 1.02-2.21) or Bx (HR 1.87; 95 % CI, 1.18-2.98). There were no significant differences in (adjusted) mortality risk between the PR and Bx groups. CONCLUSION: Our study suggests that GTR is independently associated with improved survival for pediatric patients with glioblastoma.

Hypophysitis Secondary to Small Vessel ANCA Vasculitis Treated With Rituximab.

Background/Objective: Antineutrophil cytoplasmic antibody (ANCA) associated vasculitis is a rare small vessel vasculitis that can cause pituitary hypophysitis. Hypophysitis is difficult to treat, often requiring high doses of glucocorticoids with frequent flaring as glucocorticoids are tapered. We present a case of ANCA vasculitis involving the pituitary gland successfully treated with rituximab. Case Report: Fifty-one-year-old woman developed progressive frontal headaches, congestion, and epistaxis. Sinus computed tomography scan showed pituitary enlargement and chronic mucosal disease. Pituitary magnetic resonance imaging (MRI) confirmed a diffusely enlarged pituitary with a thickened pituitary stalk. Serologic evaluation revealed elevated inflammatory markers, positive perinuclear ANCA (p-ANCA), and an elevated serum anti-proteinase 3 (anti-PR3) antibody. The patient underwent pituitary biopsy, which showed adenohypophysitis with dense lymphoplasmacytic infiltration, some arranged perivascularly, compatible with involvement of the pituitary gland by ANCA vasculitis. The patient began rituximab and reported resolution of daily headaches, congestion, and epistaxis. Pituitary MRI scan 6 months after rituximab showed reduction in pituitary gland size and stalk thickening. Discussion: ANCA vasculitis is a rare etiology of pituitary hypophysitis, which can present a diagnostic and therapeutic challenge. Pituitary involvement of ANCA vasculitis can be identified through p-ANCA or cytoplasmic ANCA (c-ANCA) and biopsy of the involved tissue. Rituximab, a monoclonal antibody against CD20, has been successfully used to treat ANCA vasculitis and in this case, led to clinical improvements and reduction in the size of the pituitary gland. Conclusion: Pituitary biopsy enabled confirmation of ANCA hypophysitis and facilitated treatment with a steroid-sparing agent.

Impact of Frailty on Postoperative Outcomes in Extended Endonasal Skull Base Surgery for Suprasellar Pathologies.

OBJECTIVE: Frailty metrics estimate a patient's ability to tolerate physiologic stress and there are limited frailty data in patients undergoing expanded endonasal approaches (EEA) for suprasellar pathologies. Elevated frailty metrics have been associated with increased perioperative complications in patients undergoing craniotomies. We sought to examine this potential relationship in EEA. STUDY DESIGN: Retrospective cohort study. SETTING: Two tertiary academic skull base centers. METHODS: Cases of patients undergoing EEA for suprasellar pathologies were reviewed. Demographic, treatment, survival, and postoperative outcomes data were recorded. Frailty was calculated using validated indexes, including the American Society of Anesthesiologists (ASA) classification, the modified 5-item frailty index (mFI-5), and the Charlson comorbidity index (CCI). Primary outcomes included 30-day medical and surgical complications. RESULTS: A total of 88 patients were included, with 59 (67%) female patients and a mean age of 54 ± 15 years. The most common pathologies included 53 meningiomas (60.2%) and 21 craniopharyngiomas (23.9%). Most patients were ASA class 3 (54.5%) with mean mFI-5 0.82 ± 1.01 and CCI 4.18 ± 2.42. There was no association between increased frailty and 30-day medical or surgical outcomes (including postoperative cerebrospinal fluid leak), prolonged length of hospital stay, or mortality (all P > .05). Higher mFI-5 was associated with an increased risk for 30-day readmission (odds ratio: 2.35, 95% confidence Interval: 1.10-5.64, P = .04). CONCLUSION: Despite the patient population being notably frail, we only identified an increased risk for 30-day readmission and observed no links with deteriorating surgical, medical, or mortality outcomes. This implies that conventional frailty metrics may not effectively align with EEA outcomes.

Endoscopic endonasal repair of encephaloceles of the lateral sphenoid sinus: multiinstitution confirmation of a new classification.

OBJECTIVE: Encephaloceles of the lateral sphenoid sinus are rare. Originally believed to be due to defects in a patent lateral craniopharyngeal canal (Sternberg canal), they are now thought to originate more commonly from idiopathic intracranial hypertension, not unlike encephaloceles elsewhere in the skull base. A new classification of these encephaloceles was recently introduced, which divided them in relation to the foramen rotundum. Whether this classification can be applied to a larger cohort from multiple institutions and whether it might be useful in predicting outcome is unknown. Thus, the authors' goal was to divide a multiinstitutional cohort of patients with lateral sphenoid encephaloceles into four subtypes to determine their incidence and any correlation with surgical outcome. METHODS: A multicenter retrospective review of prospectively acquired databases was carried out across three institutions. Cases were categorized into one of four subtypes (type I, Sternberg canal; type II, medial to rotundum; type III, lateral to rotundum; and type IV, both medial and lateral with rotundum enlargement). Demographic and outcome metrics were collected. Kaplan-Meyer curves were used to determine the rate of recurrence after surgical repair. RESULTS: A total of 49 patients (71% female) were included. The average BMI was 32.8. All encephaloceles fell within the classification scheme. Type III was the most common (71.4%), followed by type IV (16.3%), type II (10.2%), and type I (2%). Cases were repaired endonasally, via a transpterygoidal approach. Lumbar drains were placed in 78% of cases. A variety of materials was used for closure, with a nasoseptal flap used in 65%. After a mean follow-up of 47 months, there were 4 (8%) CSF leak recurrences, all in patients with type III or type IV leaks and all within 1 year of the first repair. Two leaks were fixed with ventriculoperitoneal shunt and reoperation, 1 with ventriculoperitoneal shunt only, and 1 with a lumbar drain only. Of 45 patients in whom detailed information was available, there were 12 (26.7%) with postoperative dry eye or facial numbness, with facial numbness occurring in type III or type IV defects only. CONCLUSIONS: Endoscopic endonasal repair of lateral sphenoid wing encephaloceles is highly successful, but repair may lead to dry eye or facial numbness. True Sternberg (type I) leaks were uncommon. Failures and facial numbness occurred only in patients with type III and type IV leaks.

A multi-institutional machine learning algorithm for prognosticating facial nerve injury following microsurgical resection of vestibular schwannoma.

Vestibular schwannomas (VS) are the most common tumor of the skull base with available treatment options that carry a risk of iatrogenic injury to the facial nerve, which can significantly impact patients' quality of life. As facial nerve outcomes remain challenging to prognosticate, we endeavored to utilize machine learning to decipher predictive factors relevant to facial nerve outcomes following microsurgical resection of VS. A database of patient-, tumor- and surgery-specific features was constructed via retrospective chart review of 242 consecutive patients who underwent microsurgical resection of VS over a 7-year study period. This database was then used to train non-linear supervised machine learning classifiers to predict facial nerve preservation, defined as House-Brackmann (HB) I vs. facial nerve injury, defined as HB II-VI, as determined at 6-month outpatient follow-up. A random forest algorithm demonstrated 90.5% accuracy, 90% sensitivity and 90% specificity in facial nerve injury prognostication. A random variable (rv) was generated by randomly sampling a Gaussian distribution and used as a benchmark to compare the predictiveness of other features. This analysis revealed age, body mass index (BMI), case length and the tumor dimension representing tumor growth towards the brainstem as prognosticators of facial nerve injury. When validated via prospective assessment of facial nerve injury risk, this model demonstrated 84% accuracy. Here, we describe the development of a machine learning algorithm to predict the likelihood of facial nerve injury following microsurgical resection of VS. In addition to serving as a clinically applicable tool, this highlights the potential of machine learning to reveal non-linear relationships between variables which may have clinical value in prognostication of outcomes for high-risk surgical procedures.

CCR2 and CCR5 co-inhibition modulates immunosuppressive myeloid milieu in glioma and synergizes with anti-PD-1 therapy.

Immunotherapy has revolutionized the treatment of cancers. Reinvigorating lymphocytes with checkpoint blockade has become a cornerstone of immunotherapy for multiple tumor types, but the treatment of glioblastoma has not yet shown clinical efficacy. A major hurdle to treat GBM with checkpoint blockade is the high degree of myeloid-mediated immunosuppression in brain tumors that limits CD8 T-cell activity. A potential strategy to improve anti-tumor efficacy against glioma is to use myeloid-modulating agents to target immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. We found that the co-inhibition of the chemokine receptors CCR2 and CCR5 in murine model of glioma improves the survival and synergizes robustly with anti-PD-1 therapy. Moreover, the treatment specifically reduced the infiltration of monocytic-MDSCs (M-MDSCs) into brain tumors and increased lymphocyte abundance and cytokine secretion by tumor-infiltrating CD8 T cells. The depletion of T-cell subsets and myeloid cells abrogated the effects of CCR2 and CCR5 blockade, indicating that while broad depletion of myeloid cells does not improve survival, specific reduction in the infiltration of immunosuppressive myeloid cells, such as M-MDSCs, can boost the anti-tumor immune response of lymphocytes. Our study highlights the potential of CCR2/CCR5 co-inhibition in reducing myeloid-mediated immunosuppression in GBM patients.

The use of aprepitant for the prevention of postoperative nausea and vomiting in endoscopic transsphenoidal pituitary surgery.

BACKGROUND: Postoperative nausea and vomiting (PONV) are adverse effects after surgery, which may increase the risk of complications. Aprepitant is a neurokinin-1 receptor blocker and has been shown to reduce chemotherapy-related nausea and vomiting and PONV. However, its role in endoscopic skull base surgery remains unclear. The purpose of this study was to evaluate the effect of aprepitant in reducing PONV in endoscopic transsphenoidal (TSA) pituitary surgery. METHODS: A retrospective chart review between July 2021 and January 2023 of 127 consecutive patients who underwent TSA was performed at a tertiary academic institution. Patients were divided into 2 groups based on preoperative aprepitant use. Two groups were matched based on known risk factors of PONV (age, sex, nonsmoking, and history of PONV). The primary outcome was the incidence of PONV. Secondary outcome measures included the number of anti-emetic use, length of stay, and postoperative cererebrospinal fluid (CSF) leak. RESULTS: After matching, 48 patients were included in each group. The aprepitant group demonstrated a significantly lower incidence of vomiting than the non-aprepitant group (2.1% vs 22.9%, p = 0.002). The number of nausea episodes and anti-emetic use decreased with aprepitant use (p < 0.05). There was no difference in the incidence of nausea, length of stay, or postoperative CSF leak. Multivariate analysis demonstrated that aprepitant decreased the incidence of postoperative vomiting with odds ratio of 0.107. CONCLUSION: Aprepitant may serve as a useful preoperative treatment to reduce PONV in patients undergoing TSA. Further studies are needed to evaluate its impact in other arenas of endoscopic skull base surgery.

Distinct Myeloid Derived Suppressor Cell Populations Promote Tumor Aggression in Glioblastoma.

The diversity of genetic programs and cellular plasticity of glioma-associated myeloid cells, and thus their contribution to tumor growth and immune evasion, is poorly understood. We performed single cell RNA-sequencing of immune and tumor cells from 33 glioma patients of varying tumor grades. We identified two populations characteristic of myeloid derived suppressor cells (MDSC), unique to glioblastoma (GBM) and absent in grades II and III tumors: i) an early progenitor population (E-MDSC) characterized by strong upregulation of multiple catabolic, anabolic, oxidative stress, and hypoxia pathways typically observed within tumor cells themselves, and ii) a monocytic MDSC (M-MDSC) population. The E-MDSCs geographically co-localize with a subset of highly metabolic glioma stem-like tumor cells with a mesenchymal program in the pseudopalisading region, a pathognomonic feature of GBMs associated with poor prognosis. Ligand-receptor interaction analysis revealed symbiotic cross-talk between the stemlike tumor cells and E-MDSCs in GBM, whereby glioma stem cells produce chemokines attracting E-MDSCs, which in turn produce growth and survival factors for the tumor cells. Our large-scale single-cell analysis elucidated unique MDSC populations as key facilitators of GBM progression and mediators of tumor immunosuppression, suggesting that targeting these specific myeloid compartments, including their metabolic programs, may be a promising therapeutic intervention in this deadly cancer. One-Sentence Summary: Aggressive glioblastoma harbors two unique myeloid populations capable of promoting stem-like properties of tumor cells and suppressing T cell function in the tumor microenvironment.

Contact endoscopy as a novel technique for intra-operative identification of normal pituitary gland and adenoma.

Intraoperative distinction of pituitary adenoma from normal gland is critical in maximizing tumor resection without compromising pituitary function. Contact endoscopy provides a noninvasive technique that allows for real-time in vivo visualization of differences in tissue vascularity. Two illustrative cases of endoscopic endonasal approaches (EEAs) for resection of pituitary adenoma illustrate the use of contact endoscopy in identifying tumor from gland and differentiating a thin section of normal gland draped over the underlying tumor, thereby allowing for safe extracapsular tumor resection. Contact endoscopy may be used as an adjunct for intraoperative, in vivo differentiation of pituitary gland and adenoma. The video can be found here: https://stream.cadmore.media/r10.3171/2021.10.FOCVID21199.

Approach selection for resection of petroclival meningioma.

Petroclival meningiomas are surgically challenging tumors because of their deep location and involvement of critical neurovascular structures. A variety of approaches have been described, and selection of approach should be tailored to the location of the tumor relative to neurovascular structures and surgical experience. The authors present two patients with petroclival meningiomas with varying relationships to cranial nerves and skull base anatomy who underwent endoscopic endonasal and open petrosectomy approaches, to demonstrate the complementarity of the endonasal transpetrous and open transpetrosal corridors. Proficiency in both open and endonasal approaches is critical to appropriate approach selection and maximal safe resection. The video can be found here: https://stream.cadmore.media/r10.3171/2022.1.FOCVID21252.