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In IDH-wildtype glioblastomas which meet the histopathological or molecular diagnosis criteria, it remains unclear whether the presence of TERT promotor mutations provides additional prognostic information. Based on a multicenter cohort of 466 IDH-wildtype glioblastomas (including 396 with and 70 patients without TERT promotor mutations), we found that TERT promotor mutations were neither associated with progression-free survival nor overall survival. This held true in various treatment-based or molecular subgroups. This argues against standardized analysis for TERT promotor mutation status for the purpose of prognostic or therapeutic relevance in newly diagnosed IDH-wildtype glioblastoma that otherwise meets the histopathological and molecular diagnosis criteria.

INTRODUCTION Recent developments in the biology of malignant gliomas have demonstrated that glioma cells interact with neurons through both paracrine signaling and electrochemical synapses. Glioma-neuron interactions consequently modulate the excitability of local neuronal circuits, and it is unclear the extent to which glioma-infiltrated cortex can meaningfully participate in neural computations. For example, gliomas may result in a local disorganization of activity that impedes the transient synchronization of neural oscillations. Alternatively, glioma-infiltrated cortex may retain the ability to engage in synchronized activity, in a manner similar to normal-appearing cortex, but exhibit other altered spatiotemporal patterns of activity with subsequent impact on cognitive processing. METHODS Here, we acquired invasive electrophysiologic recordings to sample both normal-appearing and glioma-infiltrated cortex during speech initiation in order to measure language task-related circuit dynamics of IDH-wild-type glioblastoma patients. We then applied an information theoretical framework to directly compare the encoding capacity and decodability of signals arising from these regions. RESULTS We find that glioma-infiltrated cortex engages in synchronous activity during task performance in a manner similar to normal-appearing cortex, but recruits a diffuse spatial network. On a temporal scale, we show that glioma-infiltrated cortex has lower capacity for information encoding when performing nuanced tasks such as speech production of monosyllabic versus polysyllabic words. As a result, temporal decoding strategies for distinguishing monosyllabic from polysyllabic words were feasible for signals arising from normal-appearing cortex, but not from glioma-infiltrated cortex. CONCLUSION These findings inform our understanding of cognitive processing in patients with malignant gliomas and have implications for patient survival, neuromodulation, and prosthetics in patients with malignant gliomas.

Background Despite the promising results for treating metastatic cancer with checkpoint inhibitor immunotherapies, there are limited data on surgical outcomes for brain metastases (BMs) that have progressed after prior checkpoint inhibitor treatment. The objective of this study was to identify factors associated with local progression, leptomeningeal disease, and survival for patients undergoing surgical resection of a BM in patients previously treated with checkpoint inhibitor immunotherapy. Methods A retrospective, single-center cohort study was conducted with inclusion of adult patients undergoing surgical resection of a BM in the setting of progression after prior checkpoint inhibitor treatment. Univariate and multivariate analyses were performed to identify factors associated with outcomes of interest. Results Over an 8-year period, 26 patients who underwent resection of 30 BMs met inclusion criteria. Median patient age at surgery was 63.9 years, and median clinical follow-up was 6.9 months (range 0.1 – 52.9). Extracranial disease was present at the time of surgery in 73.3% of cases. There were 6 postoperative complication events (20% of cases) by 30-days. By last follow-up, 65.4% of the cohort had died with a median censored survival of 7.6 months from surgery. Eight patients (30.8%) died within 3 months of surgery. On multivariate analysis, postoperative complications were associated with worse survival (HR 5.33, 95%CI 1.15–24.77, p=0.03). Four BMs had local progression (13.3%), and 60% of procedures were associated with distant progression within a median time of 3.6 months. Leptomeningeal disease developed in 32% of cases. On multivariate analysis, increased time from BM diagnosis to surgery was associated with a greater risk of leptomeningeal disease (OR 1.2, 95%CI 1.00–1.43, p=0.021). Conclusion Patients who require BM resection after prior checkpoint inhibitor treatment have an overall poor prognosis. Although local control rates are acceptable, these patients are at high risk for developing leptomeningeal disease postoperatively.

BACKGROUND The overall prognostic significance of maximal surgical resection in patients with diffuse low-grade glioma has been well established. Nonetheless, prior studies omit the combined importance of molecular subclass, patient characteristics, and chemoradiation. Similar to findings recently published in newly diagnosed glioblastoma, incorporation of these interactive factors may redefine the relative benefit of cytoreductive surgery. METHODS We examine the interactive effects of volumetric extent of resection with molecular and clinical factors to develop a new roadmap for cytoreductive surgery. Based on a 20-year retrospective cohort of 556 patients with WHO II diffuse low-grade glioma treated with surgery at UCSF 444 had complete records for survival modeling and recursive partitioning (RPA) to investigate multivariate relationships of overall and progression free survival. RESULTS Regardless of molecular subtype, patients with tumor volume under 55cm3 and postoperative volume of residual under 1.9cm3 experience the longest OS (median OS: not reached). Patients with volume of residual over 1.9cm3 experience a OS similar to that of patients with large (over 55cm3) oligodendrogliomas (median OS: not reached). Patients faring worst have large (over 55cm3) astrocytic gliomas (median OS: 84.8 months). Patients not treated with chemotherapy and either ATRX wild-type tumors or ATRX-mutant tumors with small (under 1cm3) volume of residual have the longest PFS together with chemotherapy treated patients who receive either no radiation or radiation for p53-mutant tumors under 30cm3 (median PFS 119 months). Patients with the shortest PFS are under 32-years with larger volume of residual (>1cm3), who receive no chemotherapy for ATRX-mutant tumors together with patients who receive both chemoradiation for larger (>30cm3) p53 mutant tumors (median PFS 30.8 months). CONCLUSION This is the first study to combine extent of resection with molecular and clinical information which paves the way for rethinking surgical strategies for individual patients with newly diagnosed low-grade gliomas.

BACKGROUND Metastasis of melanoma to the brain is associated with poor outcomes. Recent trials demonstrate improved survival after treatment with immune checkpoint inhibitors. OBJECTIVE To examine the impact that checkpoint inhibitor treatment has on overall survival (OS) and central nervous system (CNS) progression in a cohort of patients undergoing surgical resection of melanoma brain metastases. METHODS This retrospective, single-center study included patients undergoing first-time surgical resection of melanoma brain metastases. A multivariate Cox proportional model was used to estimate the association of patient and treatment factors with OS and CNS progression. RESULTS 85 patients underwent first-time resection of 97 melanoma brain metastases with a median follow-up of 9.5 months. Checkpoint inhibitors (Pembrolizumab, Ipilimumab, and/or Nivolumab) were used in 55.1% of cases (19 pre-op; 47 post-op; median 9 cycles). Patients treated with checkpoint inhibitors had similar peri-op systemic disease status and KPS but had been treated with more systemic agents and had more instances of CNS progression prior to surgery. Median OS and time to CNS progression for the cohort were 1 year and 237 days, respectively. In a multivariate Cox regression model, age (HR 1.03 by decade; p=0.02), treatment with a checkpoint inhibitor (HR 0.27; p CONCLUSIONS While checkpoint inhibitor treatment was associated with improved survival in this surgical cohort of melanoma brain metastases, patients who require surgical resection after checkpoint inhibitor treatment or radiotherapy are poor surgical candidates.

INTRODUCTION Glioblastoma carries a high economic burden for patients and caregivers. We investigated drivers of hospital costs of surgery for newly-diagnosed glioblastoma. METHODS Retrospective review of GBM patients undergoing first resection at UCSF (2010–2015) and corresponding hospital charges. Our cohort was divided into low (LC) and high cost (HC) groups for total surgical cost. Multivariate regression was used to identify factors driving cost of surgery. RESULTS Of 242 patients, 36.7% (n=86) were females (median age=62 years). The mean total hospital cost for surgery among our patient cohort was $40,384. When comparing the LC and HC groups, mean total hospital cost for surgery for HC patients was almost twice as much as LC group ($51,744 vs $29,023, p< 0.001). Kaplan-Meier analysis revealed that having higher cost of surgery worsened patient prognosis, with a 21% longer overall survival in the LC cohort versus the HC cohort (14.7 vs 17.9 months, p=0.02; HR=1.41 [1.05–1.91], p= 0.023). Tumor diameter at diagnosis was largest for HC group (4.7 cm) versus LC patients (3.9 cm, p=0.002). Multivariate analysis revealed longer hospital stay (F-ratio=8.87; p=0.01), longer ICU stay (F-ratio= 12.34, p< 0.001), younger age at surgery (F-ratio=6.71, p=0.02) and multifocal disease (F-ratio=6.26, p=0.02) to be independent predictors of higher cost of surgery, while having PCP at diagnosis (F-ratio=6.92, p=0.02), health insurance coverage (F-ratio= 4.23, p=0.03) and being married (F-ratio=3.71, p=0.04) were independent predictors of lower cost of surgery. CONCLUSIONS Higher costs of surgery correlate with worse survival outcomes in glioblastoma patients. Beyond the anticipated finding that greater disease burden drives some of this inverse correlation between cost and survival, correctable socioeconomic factors such as PCP and insurance status also drive higher hospital charges for GBM surgery. Manipulation of these factors is necessary to minimize the economic burden of disease and adopt cost-effective surgical treatments for GBM patients.

Although the overall prognostic significance of maximal surgical resection of contrast-enhancing tumor in glioblastoma patients is well established, prior studies have not evaluated the combined importance of resection, molecular markers, patient characteristics, and chemoradiation. Incorporation of these factors may redefine the relative benefit of cytoreductive surgery and establish differing thresholds for extent of resection in varying clinical presentations. In the first study of its kind, we examine the interactive effects of volumetric extent of resection with molecular and clinical factors to develop a new roadmap for cytoreductive surgery. Based on a 20-year retrospective cohort of 850 glioblastoma patients who had initial surgery at UCSF, we employed survival models and recursive partitioning (RPA) to investigate multivariate relationships of overall survival (OS), both in the entire cohort as well as a subset diagnosed since 2005 (Stupp-era) with IDH1 mutation status available (n=470). For the entire cohort and the Stupp-era subset, the RPAs elucidate the combinatorial consequence of treatment, age, IDH1 status (in the subset), and resection of both enhancing and non-enhancing tumor. In the Stupp-era, temozolomide-treated patients that are IDH-wildtype and >65 clearly benefit from a reduction of the enhancing tumor (median OS: 10.1 vs 15.8 months). IDH-wildtype, temozolomide-treated patients under 65 benefit from reduction of both enhancing and non-enhancing tumor with a median survival similar to that of IDH-mutant, temozolomide-treated patients (combined median OS: 33.7 months). The patients faring worst are those that did not receive temozolomide that are >65 and/or have ≥0.3 cm(3) residual enhancing tumor (median OS: 4 months). These risk models outperform all published prognostic models. This is the first study to combine resection of contrast-enhancing and non-enhancing tumor in conjunction with molecular and clinical information in a large single-institution study, and paves the way for rethinking surgical strategies for individual patients with newly diagnosed glioblastoma.

Introduction: Oncolytic virotherapy is an interesting approach for the treatment of cancer, including glioblastoma. Recent studies in this area suggest a synergistic approach to combine oncolytic virotherapy with immunomodulatory approaches. In this study, we have examined the role of platelet-rich fibrin patch (PRF-P) to enhance anti-tumoral immune response in immune-competent murine model C57/BL when used in conjunction with tumor specific oncolytic Ad5RGD-CMV-E1Δ24. This PRF-P is derived from blood, enriched with lymphocytes, platelets, macrophages (M1), and pro-inflammatory cytokines. Application of PRF-P has been shown to enhance immune cell migration and proliferation. HYPOTHESIS: We hypothesize that PRF-P provides local immunomodulation by supplying pro-inflammatory chemokines, as well as recruiting and enhancing proliferation of cytotoxic T cells, which may lead to an enhanced anti-tumoral immune response when combined with oncolytic virotherapy. METHODS: Blood from donor mice bearing GL261-OVA, a murine glioma cell line expressing ovalbumin (OVA), as a model antigen was collected into non-anticoagulant tubes and processed according to platelet-rich fibrin protocol. Five days after tumor implantation, a stereotactic intra-tumor injection of Ad5RGD-CMVΔ24 viral vector was performed. 48 hours post viral vector administration, a craniotomy was performed and the autologous PRF-P was applied over the tumor. For immunological flow and immunohistochemical analyses, mice were sacrificed five days post treatment. Results: We first performed a survival analysis in immuno-competent murine model. Mice injected with oncolytic virus alone had a significantly prolonged survival compared to PBS treated group (P

The dismal clinical prognosis of glioblastoma multiforme (GBM) and severe lack of efficacious therapies demand the development of novel strategies that can directly translate to patient care. Given their role as nature's most potent antigen presenting cells, dendritic cells (DCs) have emerged as essential targets for anti-tumor vaccination over the past four decades. However, realities have thwarted the enthusiasm of DC vaccines: the lack of specific in vivo DC-targeted delivery vehicles and an inability to induce robust effector CD8 + T cell responses have led to an underwhelming anti-tumor T cell response. To surmount this major obstacle, we analyzed DC-induced T cell activation and showed that a CD8α+ DC subset is essential for priming robust CD8 + T cells responses. Based on this understanding, we engineered a CD8α + DC selective vector, Ad5scFv205FF by incorporating a single chain antibody against DEC205 which is selectively expressed in CD8α+ DC subset. After confirming the genetic engineering of the fiber modification via PCR and Western blot analysis, we analyzed the tropism of this novel DC targeted vehicle. This DC targeted Ad5scFv205FF vector lost its natural tropism (coxsackie and adenovirus receptor expressing cells) and gained a new, DC selective tropism. Furthermore, upon subcutaneous administration, Ad5scFv205FF infected an average of 90% of the CD8α+ DCs while a mere 4% of non-DCs (CD45 + /CD11c-) were infected by Ad5scFvDEC205FF-GFP. This work collectively represents a novel anti-glioma vaccination, enhanced by the in vivo selective delivery of the tumor antigen that will provide a platform for the evaluation and translation of highly promising glioma immunotherapy strategies.