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.

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.

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.

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.

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.

Two-Stage Mesh Deep Learning for Automated Tooth Segmentation and Landmark Localization on 3D Intraoral Scans.

Accurately segmenting teeth and identifying the corresponding anatomical landmarks on dental mesh models are essential in computer-aided orthodontic treatment. Manually performing these two tasks is time-consuming, tedious, and, more importantly, highly dependent on orthodontists' experiences due to the abnormality and large-scale variance of patients' teeth. Some machine learning-based methods have been designed and applied in the orthodontic field to automatically segment dental meshes (e.g., intraoral scans). In contrast, the number of studies on tooth landmark localization is still limited. This paper proposes a two-stage framework based on mesh deep learning (called TS-MDL) for joint tooth labeling and landmark identification on raw intraoral scans. Our TS-MDL first adopts an end-to-end iMeshSegNet method (i.e., a variant of the existing MeshSegNet with both improved accuracy and efficiency) to label each tooth on the downsampled scan. Guided by the segmentation outputs, our TS-MDL further selects each tooth's region of interest (ROI) on the original mesh to construct a light-weight variant of the pioneering PointNet (i.e., PointNet-Reg) for regressing the corresponding landmark heatmaps. Our TS-MDL was evaluated on a real-clinical dataset, showing promising segmentation and localization performance. Specifically, iMeshSegNet in the first stage of TS-MDL reached an averaged Dice similarity coefficient (DSC) at 0.964±0.054 , significantly outperforming the original MeshSegNet. In the second stage, PointNet-Reg achieved a mean absolute error (MAE) of 0.597±0.761 mm in distances between the prediction and ground truth for 66 landmarks, which is superior compared with other networks for landmark detection. All these results suggest the potential usage of our TS-MDL in orthodontics.

The safety and efficacy of dexamethasone in the perioperative management of glioma patients.

OBJECTIVE: In this single-institution retrospective cohort study, the authors evaluated the effect of dexamethasone on postoperative complications and overall survival in patients with glioma undergoing resection. METHODS: A total of 435 patients who underwent resection of a primary glioma were included in this retrospective cohort study. The inclusion criterion was all patients who underwent resection of a primary glioma at a tertiary medical center between 2014 and 2019. RESULTS: The use of both pre- and postoperative dexamethasone demonstrated a trend toward the development of postoperative wound infections (3% vs 0% in single use or no use, p = 0.082). No association was detected between dexamethasone use and the development of new-onset hyperglycemia (p = 0.149). On multivariable Cox proportional hazards analysis, dexamethasone use was associated with a greater hazard of death (overall p = 0.017); this effect was most pronounced for preoperative (only) dexamethasone use (hazard ratio 3.0, p = 0.062). CONCLUSIONS: Combined pre- and postoperative dexamethasone use may increase the risk of postoperative wound infection, and dexamethasone use, specifically preoperative use, may negatively impact survival. These findings highlight the potential for serious negative consequences with dexamethasone use.

Synergy between glutamate modulation and anti-programmed cell death protein 1 immunotherapy for glioblastoma.

OBJECTIVE: Immune checkpoint inhibitors such as anti-programmed cell death protein 1 (anti-PD-1) have shown promise for the treatment of cancers such as melanoma, but results for glioblastoma (GBM) have been disappointing thus far. It has been suggested that GBM has multiple mechanisms of immunosuppression, indicating a need for combinatorial treatment strategies. It is well understood that GBM increases glutamate in the tumor microenvironment (TME); however, the significance of this is not well understood. The authors posit that glutamate upregulation in the GBM TME is immunosuppressive. The authors utilized a novel glutamate modulator, BHV-4157, to determine synergy between glutamate modulation and the well-established anti-PD-1 immunotherapy for GBM. METHODS: C57BL/6J mice were intracranially implanted with luciferase-tagged GL261 glioma cells. Mice were randomly assigned to the control, anti-PD-1, BHV-4157, or combination anti-PD-1 plus BHV-4157 treatment arms, and median overall survival was assessed. In vivo microdialysis was performed at the tumor site with administration of BHV-4157. Intratumoral immune cell populations were characterized with immunofluorescence and flow cytometry. RESULTS: The BHV-4157 treatment arm demonstrated improved survival compared with the control arm (p < 0.0001). Microdialysis demonstrated that glutamate concentration in TME significantly decreased after BHV-4157 administration. Immunofluorescence and flow cytometry demonstrated increased CD4+ T cells and decreased Foxp3+ T cells in mice that received BHV-4157 treatment. No survival benefit was observed when CD4+ or CD8+ T cells were depleted in mice prior to BHV-4157 administration (p < 0.05). CONCLUSIONS: In this study, the authors showed synergy between anti-PD-1 immunotherapy and glutamate modulation. The authors provide a possible mechanism for this synergistic benefit by showing that BHV-4157 relies on CD4+ and CD8+ T cells. This study sheds light on the role of excess glutamate in GBM and provides a basis for further exploring combinatorial approaches for the treatment of this disease.

Combination checkpoint therapy with anti-PD-1 and anti-BTLA results in a synergistic therapeutic effect against murine glioblastoma.

Clinical trials involving anti-programmed cell death protein-1 (anti-PD-1) failed to demonstrate improved overall survival in glioblastoma (GBM) patients. This may be due to the expression of alternative checkpoints such as B- and T- lymphocyte attenuator (BTLA) on several immune cell types including regulatory T cells. Murine GBM models indicate that there is significant upregulation of BTLA in the tumor microenvironment (TME) with associated T cell exhaustion. We investigate the use of antibodies against BTLA and PD-1 on reversing immunosuppression and increasing long-term survival in a murine GBM model. C57BL/6 J mice were implanted with the murine glioma cell line GL261 and randomized into 4 arms: (i) control, (ii) anti-PD-1, (iii) anti-BTLA, and (iv) anti-PD-1 + anti-BTLA. Kaplan-Meier curves were generated for all arms. Flow cytometric analysis of blood and brains were done on days 11 and 16 post-tumor implantation. Tumor-bearing mice treated with a combination of anti-PD-1 and anti-BTLA therapy experienced improved overall long-term survival (60%) compared to anti-PD-1 (20%) or anti-BTLA (0%) alone (P = .003). Compared to monotherapy with anti-PD-1, mice treated with combination therapy also demonstrated increased expression of CD4+ IFN-γ (P < .0001) and CD8+ IFN-γ (P = .0365), as well as decreased levels of CD4+ FoxP3+ regulatory T cells on day 16 in the brain (P = .0136). This is the first preclinical investigation into the effects of combination checkpoint blockade with anti-PD-1 and anti-BTLA treatment in GBM. We also show a direct effect on activated immune cell populations such as CD4+ and CD8 + T cells and immunosuppressive regulatory T cells through this combination therapy.

Sustained localized delivery of immunotherapy to lymph nodes reverses immunosuppression and increases long-term survival in murine glioblastoma.

Introduction: Despite the advent of immunotherapy as a promising therapeutic, glioblastoma (GBM) remains resistant to using checkpoint blockade due to its highly immunosuppressive tumor milieu. Moreover, current anti-PD-1 treatment requires multiple infusions with adverse systemic effects. Therefore, we used a PCL:PEG:PCL polymer gel loaded with anti-PD-1 and implanted at the site of lymph nodes in an attempt to maximize targeting of inactivated T cells as well as mitigate unnecessary systemic exposure. Methods: Mice orthotopically implanted with GL261 glioma cells were injected with hydrogels loaded with anti-PD-1 in one of the following locations: cervical lymph nodes, inguinal lymph nodes, and the tumor site. Mice treated systemically with anti-PD-1 were used as comparative controls. Kaplan-Meier curves were generated for all arms, with ex vivo flow cytometric staining for L/D, CD45, CD3, CD4, CD8, TNF-α and IFN-y and co-culture ELISpots were done for immune cell activation assays. Results: Mice implanted with PCL:PEG:PCL hydrogels carrying anti-PD-1 at the site of their lymph nodes showed significantly improved survival outcomes compared to mice systemically treated with anti-PD-1 (P = .0185). Flow cytometric analysis of brain tissue and co-culture of lymph node T cells from mice implanted with gels demonstrated increased levels of IFN-y and TNF-α compared to mice treated with systemic anti-PD-1, indicating greater reversal of immunosuppression compared to systemic treatment. Conclusions: Our data demonstrate proof of principle for using localized therapy that targets lymph nodes for GBM. We propose an alternative treatment paradigm for developing new sustained local treatments with immunotherapy that are able to eliminate the need for multiple systemic infusions and their off-target effects.

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.

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.

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.

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.