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Gross total resection (GTR) of contrast-enhancing tumor is associated with significantly increased overall survival in primary glioblastoma (GBM). Even when achieved, recurrence is likely, in part due to malignant cells infiltrating outside enhanced regions. Subsequently, there has been increasing interest in performing supratotal resections (SpTRs) for GBM. Published results have varied in part due to a lack of consensus on the definition of SpTR in GBM and its appropriate use. A crowdsourcing approach was used to survey 21 academic neurosurgical oncologists representing 13 health systems nationwide. Participants’ demographics including fellowship training status, years of experience, and operative volume with various techniques was collected. Participants were presented with 11 definitions of SpTR from published, peer-reviewed studies and asked to rate the appropriateness of each definition. Subsequently, participants reviewed T1-weighed post-contrast and FLAIR MR imaging videos in the axial, coronal, and sagittal planes for 22 GBMs. Participants were asked to assess eloquence of the tumor’s location, perceived equipoise of enrolling patients in a randomized clinical trial comparing GTR to SpTR, and their own personal surgical treatment plans. Most neurosurgeons surveyed (n=18, 85.7%) agree or strongly agree that GTR plus resection of some non-contrast enhancement is an appropriate definition for SpTR. Overall, there was only moderate inter-rater agreement, measured using sample variance and the index of qualitative variation, regarding eloquence, equipoise, and personal treatment plans. Neurosurgeons who performed more than 10 SpTRs for GBMs in the past year were more likely than counterparts to recommend it as their personal treatment plan (p< 0.005). Anterior temporal and right frontal GBMs were considered the best randomization candidates. We established a consensus definition for SpTR of GBM and identified anatomically distinct locations deemed most amenable to SpTR. These results will be used to plan prospective trials further investigating the potential clinical utility of SpTR for GBMs.

INTRODUCTION: There is a rapidly evolving portfolio of immune therapeutic modulators, but the relative incidence of immune targets in human gliomas is unknown. To prioritize available immune therapeutics, comprehensive immune profiling across glioma grades was conducted. METHODS: CD4+ and CD8+ T-cells and CD11b+ monocytes/macrophages were isolated from the blood of healthy donors (n= 6) and the blood and tumors of newly diagnosed and recurrent grade II (n= 7), III (n= 6) and IV glioma patients (n= 12), and profiled for the expression of 30 immune modulatory targets. RESULTS: In CD4+ and CD8+T-cells, PD-1 and the adenosine pathway showed high expression levels in tumor-infiltrating lymphocytes (TILs) across glioma grades and treatment states. The mean fluorescent intensity (MFI) of A2aR was appreciably upregulated in the TIL and in the CD11b+ glioma-infiltrating monocytes/macrophages (GIM) compared to healthy donors (CD4+ p= 0.0201; CD8+ p= 0.0233; CD11b+ p= 0.0009) and matched peripheral blood (CD4+ p= 0.0054; CD8+ p= 0.019; CD11b+ p< 0.0001). LAG3 and TIM3 TIL expression frequency was low and not associated with glioma grade. TIGIT CD8+TIL were more frequent in high-grade gliomas (grade III and IV). CD39 was upregulated in the TIL compared to healthy donors (CD4+ p=0.0032; CD8+ p=0.0006) and matched peripheral blood (CD4+ p= 0.0002; CD8+ p< 0.0001). B7-H3 (p= 0.0167) and Galectin-9 GIM expression (p= 0.0042) are frequently upregulated in glioblastoma. Regardless of glioma grade, the T-cell co-stimulatory molecule CD86 is down-regulated in the GIM (p= 0.0019). Many immune modulatory markers were not frequently upregulated but exceptionally high in individual patients. CONCLUSION: Predicated on expression frequency, immune therapeutics targeting PD-1 and the adenosine pathway would be applicable to most glioma patients regardless of grade or prior treatment status. Clinical trials considering the use of other immune targets, such as LAG3, TIM3, TIGIT, BTLA, B7-H3, and Galectin-9 need to consider a companion biomarker for enrollment enrichment.

SURG-04. BETTER IN THE BUCKET: EXTENSIVE RESECTION IMPROVES SURVIVAL IN GLIOBLASTOMAA SYSTEMATIC REVIEW AND META-ANALYSIS OF THE WORLD’S LITERATURE Timothy Brown1,2, Matthew Brennan3, Ephraim Church4, Nicholas Brandmeir4, Kevin Rakszawski5, Dima Suki6, Michael Li7, Elias Rizk4, Raymond Sawaya6, and Michael Glantz3,4; The Pennsylvania State University College of Medicine, Hershey, PA, USA; Department of Medicine, The University of Texas Southwestern Medical School, Dallas, TX, USA; Division of Hematology & Oncology, Department of Medicine, Penn State Hershey Cancer Institute, Hershey, PA, USA; Department of Neurosurgery, Penn State Milton S Hershey Medical Center, Hershey, PA, USA; Department of Medicine, Penn State Milton S Hershey Medical Center, Hershey, PA, USA; Department of Neurosurgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY, USA INTRODUCTION: Glioblastoma multiforme (GBM) remains an inescapably fatal disease notwithstanding optimal surgical and medical therapy. The relationship between extent of tumor resection (EOR) and outcome remains controversial despite many relevant studies. We present the results of a quantitative systematic review addressing the effect of EOR on survival in patients with GBM. METHODS: The terms "glioblastoma," "extent of resection," and "resection" were entered into search engines systematically with the guidance of an expert librarian. Articles were reviewed by all authors independently and then in consensus fashion. Data were analyzed to assess survival following gross total resection (GTR), subtotal resection (STR), and biopsy as defined by the individual studies. The overall body of evidence was evaluated according to GRADE criteria and PRISMA guidelines. RESULTS: Our search yielded 46 articles suitable for inclusion in the meta-analysis. There werenoclass I studies, 3 class II studies, and44class III or IVstudies.Ourmetaanalysis revealed improved oneand two-year survival for GTR compared to STR (RR 1⁄4 0.63, 95% CI 1⁄4 0.56-0.69; RR 1⁄4 0.85, 0.79-0.90) and STR compared to biopsy (RR 1⁄4 0.85, 0.80-0.91; RR 1⁄4 0.99, 0.97-1.00). Oneand two-year survival was also improved for any resection compared to biopsy alone (RR 1⁄4 0.77, 0.71-0.84; RR 1⁄4 0.94, 0.89-1.00). These outcomes were unaltered by the inclusion of SEER and RTOG population studies, or when restricted to the class II studies. The quality of the total body of evidence by GRADE criteria was "poor". CONCLUSIONS: Ours represents the largest systematic review and meta-analysis ever performed on this subject. Greater EOR unquestionably correlates with improved one and two-year survival, but the qualityof evidence is poor. Randomized trials have not proved feasible. Further cohort studies will not provide additional useful data, and should not be performed. A prospective registry of GBM patients represents a valuable alternative and is a critical priority for the neuro-oncology community. Neuro-Oncology 17:v214–v220, 2015. doi:10.1093/neuonc/nov235.4 Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2015.

INTRODUCTION: IOM of language pathways is the gold standard for the safe resection of gliomas; navigated TMS has been shown to be useful in generating speech maps prior surgery. This study test the clinical utility of nTMS for mapping language and its concordance with intraoperative stimulation. METHODS: We describe 12 patients with gliomas adjacent to language areas. All cases were performed with nTMS, DES for language mapping. We analyzed, positive and negative sites preoperatively and intraoperatively, and correlated them to the extent of resection and a 1-mo follow-up. RESULTS: Navigated TMS positive maps, was achieved in 11 (92%), and 8 (80%) of cases had language errors during DES. 3527 site were stimulated during nTMS mapping, 225 (7%) was positive, 77 (34%) speech arrest, 78 (35%) performance errors and 70 (31%) semantic errors. TP correlation was achieved in 8 (67%) of cases, TN correlation 1 (8%) and FP correlation was achieved in 1 (8%) of cases. In TP cases, GTR was achieved in 6 (75%) of cases and after 1-mo follow-up 1 (14%) case developed new deficit and improvement was seen in 1(14%) case. In the only case of TN correlation, GTR resection was achieved, without deficits after 1-mo follow-up. CONCLUSION: nTMS correlated well with DES in generated language mapping, with a rate of TP according 67% and the only case with negative response in nTMS was TN. We have shown that nTMS has a high rate of concordance with DES; nTMS has 100% sensitivity, and 50% specificity when compared with DES. PPV at 89% and NPV 100%. The majority of positive sites were achieved in Broca's area and Wernicke's area. Additionally, if the nTMS reveal speech arrest distant from surgical exposure, this may be an additional utility for nTMS in explaining apparent negative mapping results in intraoperative stimulation.

Background Surgery for tumors in eloquent brain faces immense challenges when attempting to maximize resection and avoid neurological deficits. Objective In order to give the surgeon real-time atlas-based anatomic information linked to the patient's anatomy, we developed a software-based interface between deformable anatomic templates (DATs) and an intraoperative navigation system. Methods Magnetic resonance imaging (MRI), diffusion tensor imaging, and/or functional MRI were performed on 3 patients preoperatively for the purposes of tumor resection by the use of neuronavigation. The DAT was registered to the patients' navigation coordinate system and utilized coordinates from the navigation system during surgery. This provided the surgeon with a list of proximal anatomic and functional structures and a real-time image of the atlas at that location fused to the patient's MRI. The clinical feasibility of this approach was evaluated during the resection of 3 eloquent tumors (right postcentral gyrus, left inferior frontal gyrus, and left occipital cuneus gyrus). Results Tumor resection was performed successfully in all 3 patients. With the use of the coordinates from the navigation system, anatomic and functional structures and their distances were visualized interactively during tumor resection by using the DAT. Conclusion This is a proof of concept that an interactive atlas-based navigation can provide detailed anatomic and functional information that supplements MRI, diffusion tensor imaging, and functional MRI. The atlas-based navigation generated distances to important anatomic structures from the navigation probe tip. It can be used to guide direct electrical stimulation and highlight areas to avoid during tumor resection. Abbreviations DAT, deformable anatomic templateDES, direct electrical stimulationDTI, diffusion tensor imagingfMRI, functional magnetic resonance imaging.

Intracranial stereotactic radiosurgery (SRS) is a technique that delivers a high dose of precisely targeted radiation using highly focused γ- or x-ray beams to a specific area of the brain to treat a tumor or another abnormality while minimizing the radiation effect on the surrounding normal brain tissue. As its radiobiology, mechanism of effect, and complication aspects have become better understood, SRS has become popular, and its use has increased markedly for treating brain lesions. Therefore, it is mandatory for practicing physicians to know the role and the results of SRS when treating intracranial lesions with this modality. The textbook Intracranial Stereotactic Radiosurgery was edited by L. Dade Lunsford and Jason P. Sheehan, neurosurgeons who have vast experience in the evaluation and treatment of patients with different disorders of the brain. This work includes 20 chapters by 56 contributing authors who are respected clinicians (mostly from the field of neurosurgery) in the United States and abroad; these authors give a broad perspective on surgical and SRS treatment of diseases while also describing the risks and benefits of each procedure. The book succeeds in addressing the essential knowledge related to the intracranial use of SRS. Because focal radiation therapy can be applied to different parts of the body for a variety of disorders, consideration of SRS for intracranial use is reasonable, and the title of the book is appropriate. However, we wished that at least an overview of spinal radiosurgery had been included in such a well-written book because the use of SRS has been increasing in the clinical practice of neurosurgery and radiation oncology. The first three chapters of this book focus on the basics of radiosurgery, including the history and evolution of neurosurgical radiosurgery, radiobiology, and histopathological changes related to radiosurgical treatment. Particularly in Chapter 3, histological changes after radiosurgery are outlined very briefly and effectively with color pictures of tumor specimens resected after radiation treatment, making the effect of radiation on the lesions clear to the readers. This basic information provides the foundation for the following chapters. However, a chapter in the first part of the book focusing on general considerations and basic knowledge of dosing and radiosurgical planning of the lesions would have been useful. Distinct disorders of the brain, including tumoral and vascular lesions, are included in the text. The use of radiosurgery is reviewed for the lesions in which the effect of radiosurgery is already well established; in addition, the disorders for which the use of radiosurgery is still controversial or for which data on the use of radiosurgery are lacking are reviewed, providing a good level of understanding to the readers. Also, the chapters on radiosurgical treatment for movement disorders and epilepsy are very helpful; the authors review the existing literature on this relatively new treatment modality for these entities and briefly describe the indications for radiosurgery as well as its benefits and complications. Despite being written by many authors, in general, there is a consistency in writing style and presentation of knowledge from one chapter to the next. Each chapter presents background information on the specific disorder, reviews the indications for radiosurgery, compares radiosurgery with current treatment options, and discusses complications and outcomes, with an extensive literature review and description of the experience with each disorder at the authors' institution. Also, there are tables summarizing the existing literature, and those that show tumor control rate, overall survival, and complications are very useful for readers. Furthermore, the most recent technological advances in radiosurgery modalities, such as Cyberknife and Gamma Knife Perfexion, are detailed for some of the intracranial lesions. In addition, in the chapter on SRS for skull-base chordomas and chondrosarcomas, a new focal radiation treatment modality, proton beam therapy, is described. In this well-designed chapter, the biological properties, technical aspects, treatment planning, and clinical results of proton beam therapy are very thoroughly detailed, with useful figures and tables. The last three chapters describe radiosurgical treatment for gliomas, brain metastases, and pediatric brain tumors. Although these chapters could be expanded into books themselves, each topic is explained briefly, highlighting the current treatment modalities and existing therapeutic controversies. Also, a chapter on SRS for ocular disorders is included in this book, which should be informative for radiation oncologists but less so for neuro-oncologists and neurosurgeons. Some chapters are inconsistent in terms of the content and length of the text. For example, Chapter 7, on cavernomas, includes very comprehensive text, whereas the chapter on meningiomas basically consists of a description of the authors' own series, without sufficient background information. Also, in the chapter on movement disorders, there ought to have been descriptive images for SRS planning and more samples of radiological images to permit a better understanding of the technique. In addition, there are some typesetting errors in the text, and there is a reversal of values in one table that may cause misunderstanding. For example, in the chapter on brain metastases, Table 19.1 (comparing the studies of surgery vs whole-brain radiation therapy [WBRT] vs stereotactic radiosurgery) contains an error: on the line detailing the study by Sanghavi et al., the median survival times for WBRT and WBRT + radiosurgery should be 7.1 and 16.1 months, respectively, not 16.1 and 7.1 months, as shown, and for the study by Andrews et al., the median survival times for WBRT and WBRT + radiosurgery should be 4.9 and 6.5 months, respectively, not 6.5 and 4.9 months, as shown. In summary, this textbook provides valuable information about ISR. The information presented is up to date. The book is well written and easy to navigate. The target audience is clinicians such as neurosurgeons, radiation oncologists, and neuro-oncologists who treat patients with intracranial disorders. This book is also recommended to residents and fellows in these fields because it makes available the most recent information on this topic, including a comprehensive literature review.

Macrophages (MΦs)/microglia that constitute the dominant tumor-infiltrating immune cells in glioblastoma are recruited by tumor-secreted factors and are induced to become immunosuppressive and tumor supportive (M2). Glioma cancer stem cells (gCSCs) have been shown to suppress adaptive immunity, but their role in innate immunity with respect to the recruitment and polarization of MΦs/microglia is unknown. The innate immunosuppressive properties of the gCSCs were characterized based on elaborated MΦ inhibitory cytokine-1 (MIC-1), transforming growth factor (TGF-β1), soluble colony-stimulating factor (sCSF), recruitment of monocytes, inhibition of MΦ/microglia phagocytosis, induction of MΦ/microglia cytokine secretion, and the inhibition of T-cell proliferation. The role of the signal transducer and activator of transcription 3 (STAT3) in mediating innate immune suppression was evaluated in the context of the functional assays. The gCSCs produced sCSF-1, TGF-β1, and MIC-1, cytokines known to recruit and polarize the MΦs/microglia to become immunosuppressive. The gCSC-conditioned medium polarized the MΦ/microglia to an M2 phenotype, inhibited MΦ/microglia phagocytosis, induced the secretion of the immunosuppressive cytokines interleukin-10 (IL-10) and TGF-β1 by the MΦs/microglia, and enhanced the capacity of MΦs/microglia to inhibit T-cell proliferation. The inhibition of phagocytosis and the secretion of IL-10 were reversed when the STAT3 pathway was blocked in the gCSCs. The gCSCs modulate innate immunity in glioblastoma by inducing immunosuppressive MΦs/microglia, and this capacity can be reversed by inhibiting phosphorylated STAT3.