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PURPOSE Despite intensive treatment with surgery, radiation therapy, temozolomide (TMZ) chemotherapy, and tumor-treating fields, mortality of newly diagnosed glioblastoma (nGBM) remains very high. SurVaxM is a peptide vaccine conjugate that has been shown to activate the immune system against its target molecule survivin, which is highly expressed by glioblastoma cells. We conducted a phase IIa, open-label, multicenter trial evaluating the safety, immunologic effects, and survival of patients with nGBM receiving SurVaxM plus adjuvant TMZ following surgery and chemoradiation (ClinicalTrials.gov identifier: NCT02455557 ). METHODS Sixty-four patients with resected nGBM were enrolled including 38 men and 26 women, in the age range of 20-82 years. Following craniotomy and fractionated radiation therapy with concurrent TMZ, patients received four doses of SurVaxM (500 μg once every 2 weeks) in Montanide ISA-51 plus sargramostim (granulocyte macrophage colony-stimulating factor) subcutaneously. Patients subsequently received adjuvant TMZ and maintenance SurVaxM concurrently until progression. Progression-free survival (PFS) and overall survival (OS) were reported. Immunologic responses to SurVaxM were assessed. RESULTS SurVaxM plus TMZ was well tolerated with no serious adverse events attributable to SurVaxM. Of the 63 patients who were evaluable for outcome, 60 (95.2%) remained progression-free 6 months after diagnosis (prespecified primary end point). Median PFS was 11.4 months and median OS was 25.9 months measured from first dose of SurVaxM. SurVaxM produced survivin-specific CD8+ T cells and antibody/immunoglobulin G titers. Apparent clinical benefit of SurVaxM was observed in both methylated and unmethylated patients. CONCLUSION SurVaxM appeared to be safe and well tolerated. The combination represents a promising therapy for nGBM. For patients with nGBM treated in this manner, PFS may be an acceptable surrogate for OS. A large randomized clinical trial of SurVaxM for nGBM is in progress.

Neuroendocrine tumors (NETs) are a heterogenous group of tumors. While most NETs have excellent prognosis, certain subsets have aggressive biology and have limited treatment options. We explored the role of survivin in NET as a prognostic and potentially therapeutic marker. Tissue microarrays of 132 patients were stained for survivin using immunohistochemistry (IHC) and correlated with outcomes. Using genomic database, we then correlated survivin (BIRC5) mRNA expression with radiosensitivity index (RSI) in 52 samples of NET. Finally, we studied the effect of radiation on survivin expression in human cell lines and the impact of knock-down of BIRC5 on cell proliferation and radiation sensitivity. We found that survivin positivity by IHC correlated with a shorter survival (overall survival 8.5 years vs. 18.3 years, p < 0.001). There was a positive correlation between BIRC5 expression and RSI (r = 0.234, p < 0.0001). Radiation exposure increased BIRC5 gene expression in a human carcinoid cell line. Knockout of BIRC5 using siRNA reduced proliferation of neuroendocrine cells but did not increase radiation sensitivity. We conclude that survivin expression in NET correlates with an inferior survival and survivin expression in human carcinoid cell lines increases after exposure to ionizing radiation.

Butterfly glioblastoma (bGBM) is a grade 4 glioma with a poor prognosis. Surgical treatment of these cancers has been reviewed in the literature with some recent studies supporting resection as a safe and effective treatment instead of biopsy and adjuvant therapy. This meta-analysis was designed to determine whether there are significant differences in overall survival (OS) and postoperative neurologic deficits (motor, speech, and cranial nerve) following intervention in patients who underwent tumor resection as part of their treatment, compared to patients who underwent biopsy without surgical resection. A literature search was conducted using PubMed (National Library of Medicine) and Embase (Elsevier) to identify articles from each database's earliest records to May 25, 2021, that directly compared the outcomes of biopsy and resection in bGBM patients and met predetermined inclusion criteria. A meta-analysis was conducted to compare the effects of the two management strategies on OS and postoperative neurologic deficits. Six articles met our study inclusion criteria. OS was found to be significantly longer for the resection group at 6 months (odds ratio [OR] 2.94, 95% confidence interval [CI] 1.23-7.05) and 12 months (OR 3.75, 95% CI 1.10-12.76) than for the biopsy group. No statistically significant differences were found in OS at 18 and 24 months. Resection was associated with an increased rate of postoperative neurologic deficit (OR 2.05, 95% CI 1.02-4.09). Resection offers greater OS up to 1 year postintervention than biopsy alone; however, this comes at the cost of higher rates of postoperative neurologic deficits.

2031 Background: High grade gliomas (HGG) including glioblastoma (GBM) are among the most aggressive brain cancers, with patients exhibiting highly variable treatment responses in both newly diagnosed (ND) and recurrent disease. Temozolomide (TMZ) + radiation therapy is the guideline directed standard of care (SOC) in the ND setting; it has remained relatively unchanged for > 15 years, despite variable patient responses. Current available biomarkers do not inform personalized therapy. Functional drug response testing using patient specific tumor cells may have the potential to inform effective therapy selection, thus advancing functional precision oncology. Progression free survival (PFS) is a meaningful surrogate to overall survival (OS) in GBM and therefore, represents a measure of clinical benefit. Methods: The 3D-PREDICT clinical study (NCT03561207) allows enrollment of HGG patients with ECOG ≤ 3, perhaps representing a more accurate real-world population compared to most clinical studies in the same patient cohort. Tumor tissue was prospectively collected during SOC biopsy/resection and analyzed in an ex vivo cell culture test using a panel of agents prescribed as HGG therapeutics. Results: Data pertain to 56 3D-PREDICT patients who had > 6 months of follow up as of December 31, 2021 or experienced progression/death < 6 months post tissue collection. There were 42 3D-PREDICT patients who had IDH wild type ND GBM and received SOC. PFS analysis of these patients showed 3D ex vivo testing was able to prospectively predict TMZ clinical responders vs. non-responders (Kaplan-Meier, p = 0.039; HR 0.516, 95% CI 0.234,1.137). Test predicted TMZ responders had a relative PFS advantage of 3.7 months. Of the 42 patients, 38 had known MGMT methylation status with 23 patients (60%) being unmethylated. Test predicted responders (9) included unmethylated patients; test predicted non-responders (33) included methylated patients. The data suggest ex vivo testing of patient specific tumor tissue may identify ND HGG patients a priori who respond to TMZ, irrespective of MGMT methylation status. Beyond TMZ response prediction, the test assesses tissue response to 11 additional known HGG therapies and therefore may provide a tool to inform potential alternative treatments to TMZ for ND patients. Also evaluated were 14 3D-PREDICT recurrent HGG patients who received test directed salvage therapy; mean PFS after tissue collection from re-resection was 9.0 months (range 2.3 – 24.7 mo) for 9 patients at first recurrence, and 5.7 months (range 1.8 – 11.4 mo) for 5 patients with 2 to 6 recurrences. These examples demonstrate initial test utilization informing salvage therapy selection, correlated with PFS improvements in recurrent HGG. Conclusions: This functional 3D ex vivo cell culture platform provided survival benefit in analyzed ND and recurrent cohorts. Clinical trial information: NCT03561207.

Glioblastoma (GBM) is the most aggressive form of brain cancer with an overall survival (OS) less than 16 months. Glioblastoma associated mesenchymal stem like cells (G-MSC) were identified in human patient samples, and higher presence of these cells in patient samples co-relates with lower overall survival. Our lab and others have also identified these cells in orthotopic GL261 glioblastoma murine models. We hypothesize that infiltration of G-MSC plays a key role in creating the highly immunosuppressive environment seen in GBMs. In order to investigate this, we utilized data from the TCGA database to stratify patients into two groups, showing higher or lower expression of the G-MSC markers (CD73, CD90, CD105). Patients expressing higher levels of G-MSC markers showed higher expression of CD4+ cells, as compared to patients with lower G-MSC marker expression. Further, patients with higher G-MSC markers showed high levels of PTGS2, the gene encoding cyclooxygenase 2 (COX2), a known tumor growth promoting and immunosuppressive molecule. We further investigated CD4+ T cell infiltration using GL261 orthotopic implants and observed that CD4+ T cells positively corelated with levels of G-MSC in these tumors. Our studies indicate that levels of G-MSC co-relate with immune cell infiltration and the expression of immunosuppressive factors such as COX2, underlining the importance of these cells in immunosuppression-driven resistance to therapy. These studies will be later utilized to develop rationale combination therapies to improve the overall survival in GBM.

BACKGROUND Pembrolizumab is a potent humanized immunoglobulin G4 monoclonal antibody with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its interaction with programmed cell death ligand 2 (PD-L2). Survivin is a 16.5 kDa intracellular protein that belongs to the inhibitor of apoptosis protein (IAP) family. It acts in concert with the mitotic spindle apparatus to regulate cell division and localizes to the spindle microtubule organizing center (MTOC) during the G2/M phase of cell cycle progression. Survivin has also been shown to modulate the function of a number of terminal effector cell death proteases (caspases) leading to an inhibition of apoptosis. METHODS This is a Phase II study of two arms in patients with recurrent glioblastoma. Arm A is patients with first recurrence of glioblastoma who have failed prior chemotherapy and radiation but have not received any immunotherapy. Arm B is an exploratory arm of 10 patients who have failed prior anti-PD1 therapy. The ongoing study is a phase II clinical study with a 10 patient, toxicity run-in. All patients will receive the study drug combination consisting of SurVaxM and pembrolizumab with no randomization, stratification or dose escalation. RESULTS So far ten patients have been enrolled on the study as safety run in. Primary endpoint is Progression free survival at 6 months. Safety and tolerability of Pembrolizumab and SurVaxM, Response rates of Pembrolizumab and SurVaxM determined using RANO criteria are secondary endpoints. Additional secondary endpoints include Overall survival and Progression Free survival Exploratory endpoints include Cellular and humoral immune responses during concurrent administration of Pembrolizumab and SurVaxM. CONCLUSION This is an ongoing clinical trial.

Background Brain metastases develop in up to 50% patients with metastatic triple negative breast cancer (TNBC) and HER2+ BC and are an increasing source of morbidity and mortality. HER3, overexpressed in triple negative and HER2+ brain metastatic breast cancer (BMBC), is a resistance factor to HER2-targeted therapies and a driver of CNS metastasis. Disease progression is associated with loss of anti-HER2/3 immunity. We have demonstrated that alphaDC1 loaded with glioma-specific peptides induce intratumoral production of chemokines (CXCL9, CXCL10, CXCL11, CCL5) which attract CXCR3- and CCR5- expressing cytotoxic T-lymphocytes (CTLs) and T-helper 1 (Th1) cells to brain tumors, inducing clinical responses and long-term disease stabilization in patients with aggressive recurrent primary brain tumors. Our preclinical data show that Chemokine modulating (CKM) regimen [rintatolimod, interferon (IFN)-α2b and COX-2 inhibitor] also selectively attracts effector CTLs and Th1 cells (but not suppressive regulatory T-cells or myeloid-derived suppressor cells) into tumors. Importantly, CKM preferentially promotes CTL migration into tumor rather than healthy tissues, providing rationale for its systemic use. We hypothesize that anti-HER2/3 type 1 polarized DC1s in combination with CKM and anti-PD1 will result in improved Th1/CTL response against HER2/3 epitopes, reduce brain recurrence and systemic progression. Methods This is a phase II single-arm, non-randomized multicenter study (NCT04348747). Eligibility includes patients with triple negative and HER2+ BMBC ≥ 18 years, ECOG PS ≤ 1, normal marrow and organ function with asymptomatic untreated brain metastases who receive αDC1 q2 weeks x 3, with CKM [200 mg IV rintatolimod, IFN-α 20 million units/m2 IV, celecoxib 200 mg oral BID] on days 1-3 with second and third dose of αDC1, followed by pembrolizumab 200 mg IV. Thereafter, pembrolizumab is given every 3 weeks, along with αDC1 and CKM every 3 months as booster dose until disease progression, intolerable side effects or withdrawal from study, or up to 24 months. Baseline and 3-week post-CKM treatment peripheral (non-CNS) biopsies are required for six patients. Primary objective is CNS response rate (RR) using RANO-BM criteria. If no CNS response is observed after 12 patients, study will be terminated. If ≥ 1 response observed, then 9 more patients will be enrolled, for a total of 21 patients. If ≥ 3 CR observed, the proposed therapy will be considered promising for further study. Secondary objectives include non-CNS RR per RECIST v1.1, median CNS, non-CNS and overall progression-free survival, overall survival and safety. Analysis of change in intratumoral biomarkers is an exploratory objective. Results N/A Conclusions N/A Trial Registration NCT04348747 Ethics Approval The study was approved by Roswell Park Comprehensive Cancer Center Institution’s Ethics Board, approval number I-19-04120.

Background Biopsy of pineal region neoplasms is frequently accomplished by way of endoscopic transventricular access or using an image-guided, computer-assisted stereotactic approach. Methods We evaluated a nonorthogonal lateral temporal approach for stereotactic biopsy of pineal region tumors as a variation of previously described stereotactic methods. Magnetic resonance imaging–guided frameless stereotaxy was used to plan and perform biopsies of pineal region tumors using a nonorthogonal trajectory extending from the superior or middle temporal gyri through the temporal stem, anterior to the atrium of the lateral ventricle, and posterior to the corticospinal tract. Results All patients had an uncomplicated postoperative course and remained at neurologic baseline. No parenchymal or ventricular hemorrhage was present on postoperative scans. A tissue diagnosis was obtained in all patients. Conclusions This method appears to be a safe alternative to stereotactic biopsy using other trajectories and provides adequate tissue for definitive diagnosis.

Background: To date, the etiology of optic nerve sheath calcifications is unclear and visual loss secondary to optic nerve sheath calcifications has been reported infrequently. Case description: We report the case of a patient with an untreated parathyroid adenoma with longstanding elevated parathormone levels and hypercalcemia. This patient presented with optic atrophy and visual loss bilaterally (right worse than left) with associated exuberant calcification of the optic nerve sheaths and choroid plexus. Conclusions: Our patient demonstrates that metastatic optic nerve sheath calcification can occur in the setting of untreated hyperparathyroidism with longstanding hypercalcemia. Patients who present with optic nerve sheath calcification, with or without visual loss, should be studied for hypercalcemia and the possibility of an occult parathyroid adenoma should be considered as a possible cause. Keywords: Optic nerve sheath, Metastatic calcification, Optic atrophy, Hyperparathyroidism, Hypercalcemia, Visual deficit

A major challenge to developing new therapies for patients with malignant brain tumors is that relatively few small molecule anticancer drugs penetrate the blood–brain barrier (BBB) well enough to provide therapeutically effective concentrations in brain tissue before drug exposure in non-CNS tissues results in unacceptable toxicity. KX2-361, a member of a novel family of compounds with Src-kinase and tubulin polymerization inhibitory activity, demonstrates good oral bioavailability and readily crosses the BBB in mice. The objective of this study was to investigate the activity of KX2-361 against human and murine glioma cells and assess its therapeutic effect in a syngeneic orthotopic model of glioblastoma. In addition to reducing the level of Src autophosphorylation in the GL261 murine glioblastoma cell line, KX2-361 binds directly to tubulin and disrupts microtubule architecture in glioma cells maintained in culture. The drug is active in vivo against orthotopic GL261 gliomas in syngeneic C57BL/6 mice. Long term survival is not observed in mice lacking an adaptive immune system, indicating that KX2-361 works in concert with the host immune system to control tumor growth and promote long-term survival in the GL261 glioma model.

Purpose: Survivin is an inhibitor of apoptosis protein (IAP) that is highly expressed in many cancers and represents an attractive molecule for targeted cancer therapy. Although primarily regarded as an intracellular protein with diverse actions, survivin has also been identified in association with circulating tumor exosomes. Experimental Design: We have reported that active, specific vaccination with a long peptide survivin immunogen leads to the development of survivin-specific CD8-mediated tumor cell lysis and prolongation of survival in tumor-bearing mice. In addition to cellular antitumor responses, circulating anti-survivin antibodies are detected in the serum of mice and human glioblastoma patients following vaccination with the survivin immunogen. Results: Here we demonstrate that survivin is present on the outer cell membrane of a wide variety of cancer cell types, including both murine and human glioma cells. In addition, antibodies to survivin that are derived from the immunogen display antitumor activity against murine GL261 gliomas in both flank and intracranial tumor models and against B16 melanoma as well. Conclusions: In addition to immunogen-induced, CD8-mediated tumor cell lysis, antibodies to the survivin immunogen have antitumor activity in vivo. Cell-surface survivin could provide a specific target for antibody-mediated tumor immunotherapeutic approaches. Clin Cancer Res; 24(11); 2642–52. ©2018 AACR.

The Inhibitor of Apoptosis Protein survivin (svn) is upregulated in nearly all types of cancer and represents a promising therapeutic target. Localization to specific subcellular compartments and interactions with various binding partners allow survivin to play diverse roles in apoptosis resistance and mitosis. Survivin has recently been found in two extracellular compartments: the outer plasma membrane and secreted exosomes. In addition to svn-wt, splice variants svn-dEX3 and svn-2B are also overexpressed in human tumors. Here we show that, similarly to svn-wt, svn-dEX3 and svn-2B can be displayed on the outer plasma membrane, and secreted in exosomes. Additionally, we have identified a novel interaction of all three forms of survivin with secreted tubulin.

For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas.

Recurrent high-grade glioma is a challenging disease process, without consensus on effective second-line therapy options. Individualized, patient-specific, biologically-based data is desirable in driving therapeutic decision-making. Patients with recurrent high-grade glioma and planned surgical re-resection at our institution were prospectively enrolled into the 3D-PREDICT study. Tissue was collected at the time of surgery for ex vivo 3D cell culture assays comprising a panel of agents commonly used for high-grade glioma, including chemotherapies and targeted therapies used in other solid cancers. In all cases, therapeutic agent selection was guided by the neuro-oncologist’s clinical judgement, factoring the patient’s age, performance status, comorbidities, toxicities/side effect profile of potential agents, and drug accessibility, plus ex-vivo drug response RESULTS: We present 3 cases in which the selection of agents was influenced by the tissue-derived 3D cell culture results; treatment led to clinical response observed in terms of progression free survival, quality of life, and pharmacologic tolerability. In Case 1, a patient with recurrent anaplastic astrocytoma was treated with a BRAF inhibitor for 12 months with excellent tolerability and no radiographic progression. Case 2 demonstrates the use of combination bevacizumab and irinotecan after disease progression subsequent to standard treatment. This patient had local radiographic control for 7 months, tolerating the regimen well. In Case 3, an individual with recurrent glioblastoma was treated with combination carboplatin and etoposide based on assay response prediction to both agents; treatment has been tolerated well with radiographic stability at 6 months while maintaining good performance status. This case series represents our institutional experience of utilizing patient-specific, ex-vivo tissue-derived cell drug response profiling to guide choice of therapy for recurrent high-grade glioma patients. Using individualized, tumor-specific drug sensitivity data to guide these decisions is representative of the ongoing paradigm shift into the realm of individualized medicine to improve outcomes in cancer patients.

The aim of this study was to identify racial/ethnic disparities with regard to survival among patients with ependymoma. Data from the Surveillance, Epidemiology and End Results (SEER) registry between the years of 1973–2015 which included 4821 patients diagnosed with ependymoma were analyzed. Multivariable cox proportional hazard ratios were performed to examine overall survival across racial/ethnic groups of patients with ependymoma, mortality risks across specified age groups, and mortality during specified time intervals, all with corresponding 95% confidence intervals. Non-Hispanic black patients (n = 421) have higher risk of overall mortality when compared to non-Hispanic white patients (n = 3255) with ependymoma (HR 1.48, CI 1.17–1.87). Risk of mortality was highest when comparing non-Hispanic black children under the age of 3 to non-Hispanic white children of the same age group (HR 3.05, CI 1.55–5.99). Mortality risk has increased among pediatric non-Hispanic black patients compared to pediatric non-Hispanic white patients between the years of 2006–2015, from previous rates between the years 1973–2005 (HR 1.95, CI 1.15–3.33 and HR 2.35, CI 1.24–4.44). Hispanic patients under 3 years had an increased risk of mortality compared to non-Hispanic white patients of this age group (HR 2.49, CI 1.37–4.53). Asian/Pacific Islander patients (n = 282) had no significant difference in outcomes when compared to non-Hispanic white patients. Our findings showed higher risk of mortality among non-Hispanic black patients compared to non-Hispanic white patients with ependymoma, with highest risk among pediatric patients. These results demonstrate significant need for research in survival outcomes for this disease.

Glioblastoma (GBM) is an aggressive brain cancer, with an overall survival of 14.6 months. The tumor microenvironment in GBM plays major roles in immunosuppression and modulation of the response to therapies. GBM patients with higher levels of mesenchymal stem like cells (G-MSC) show poor overall survival as compared to patients with no/lower G-MSC levels. Our lab found that levels of G-MSC corelate with CD4+ T cells in humans and murine models of GBM, and with immunosuppressive molecules like PTGS2, the gene for cyclooxygenase 2. To investigate the mechanism by which G-MSCs promote immunosuppression, we isolated G-MSCs from an orthotopic mouse model of GBM and subjected them to RNASeq analysis to obtain an unbiased picture of transcriptomic changes occurring upon activation. We identified changes in multiple immune modulating pathways involving antigen presentation, leukocyte migration and activation, and immune checkpoints. Our findings indicate that G-MSCs represent a key immune modulating faction in the microenvironment. Further dissection of the role of these cells in immune modulation will aid us in understanding the biology of the brain tumor microenvironment and identifying potential combination therapies.

The study was designed to evaluate the cumulative dose exposure of brain and hippocampus following multiple stereotactic radiosurgery (SRS) procedures on a single patient. Ninety-four patients who received at least two SRS treatments were evaluated. Their SRS dose plans were summated to obtain dose volume parameters. Hippocampal structures were delineated, in addition to segmentation of the brain. A total of 267 treatments were delivered to 94 patients. The number of SRS procedures per patient varied from 2 to 7 (mean = 2.8), and the total number of lesions treated in a given patient over multiple treatments varied from 2 to 70 (mean = 11). The interval between the first and last SRS treatments varied from 1 to 79 months (mean = 16.2 months). The mean prescription dose was 16.7 Gy prescribed to isodose lines from 40 to 95%. The mean coverage, selectivity, Paddick conformity, and gradient index were 99.6%, 79%, 0.57, and 2.74, respectively. The mean summated dose delivered to the whole brain over the course of multiple treatments was 5.11 Gy. The hippocampal mean dose after summation was 2.95 Gy. Patients with plan PCIs averaging below the mean value of 0.57 had higher V8, V10, V12, and V15 values for a given total tumor volume when compared with more conformal plans (PCI > 0.57). Repeat SRS delivered low cumulative doses to the brain and hippocampus with the lowest normal brain volumes irradiated in highly conformal plans.

Purpose/Objectives: The purpose of this study was to evaluate the effect of the number of brain lesions for which stereotactic radiosurgery (SRS) was performed on the dose volume relationships in normal brain. Materials and Methods: Brain tissue was segmented using the patient's pre-SRS MRI. For each plan, the following data points were recorded: total brain volume, number of lesions treated, volume of brain receiving 8 Gy (V8), V10, V12, and V15. Results: A total of 225 Gamma Knife® treatments were included in this retrospective analysis. The number of lesions treated ranged from 1 to 29. The isodose for prescription ranged from 40 to 95% (mean 55%). The mean prescription dose to tumor edge was 18 Gy. The mean coverage, selectivity, conformity, and gradient index were 97.5%, 0.63, 0.56, and 3.5, respectively. The mean V12 was 9.5 cm3 (ranging from 0.5 to 59.29). There was no correlation between the number of lesions and brain V8, V12, V10, or V15. There was a direct and statistically significant relationship between the brain volume treated (V8, V10, V12, and V15) and total volume of tumors treated (p < 0.001). In our study, the integral dose to the brain exceeded 3 J when the total tumor volume exceeded 25 cm3. Conclusions: The number of metastatic brain lesions treated bears no significant relationship to total brain tissue volume treated when using SRS. The fact that the integral dose to the brain exceeded 3 J when the total tumor volume exceeded 25 cm3 is useful for establishing guidelines. Although standard practice has favored using whole brain radiation therapy in patients with more than 4 lesions, a significant amount of normal brain tissue may be spared by treating these patients with SRS. SRS should be carefully considered in patients with multiple brain lesions, with the emphasis on total brain volume involved rather than the number of lesions to be treated.

Glioblastoma is the most common primary brain cancer. Aggressive treatment with surgery, radiation therapy and chemotherapy provides limited overall survival benefit. Glioblastomas have a formidable tumor microenvironment that is hostile to immunological effector cells and these cancers produce profound systemic immunosuppression. However, surgical resection of these tumors creates conditions that favor the use of immunotherapeutic strategies. Therefore, extensive surgical resection, when feasible, will remain part of the equation to provide an environment in which active specific immunotherapy has the greatest chance of working. Toward that end, a number of vaccination protocols are under investigation. Vaccines studied to date have produced cellular and humoral antitumor responses, but unequivocal clinical efficacy has yet to be demonstrated. In addition, focus is shifting toward the prospect of therapies involving vaccines in combination with immune checkpoint inhibitors and other immunomodulatory agents so that effector cells remain active against their targets systemically and within the tumor microenvironment.

Dysembryoplastic neuroepithelial tumors (DNETs) are low-grade neuroglial tumors that are traditionally considered to be benign hamartoma-like mass lesions. Malignant transformation and disease progression have been reported in complex DNETs. We report a case of a simple DNET with disease progression following subtotal resection. A 34-year-old woman underwent craniotomy with subtotal resection of a large nonenhancing right temporal lobe and insular mass. Histopathological analysis revealed a simple DNET. Magnetic resonance imaging obtained 6 months after surgery demonstrated disease progression with no enhancement or change in signal characteristics. Following concurrent therapy with temozolomide and external beam radiation therapy, a significant radiologic response was observed. Progressive DNET with malignant transformation exhibits predominantly glial transformation and occurs predominantly in complex DNETs. The histological classification of DNETs into simple, complex, and nonspecific are reviewed. Contrast-enhancing regions are more frequently seen in complex tumors, with nonenhancing regions having fewer complex histologic features. Close clinical and radiographic follow-up is important in all cases of DNET. Following tumor progression, radiation therapy with concurrent and adjuvant temozolomide chemotherapy may be an effective treatment.

TPS375 Background: Metastatic neuroendocrine tumors (NETs) have a poor prognosis and there are limited options after first-line treatment with somatostatin analogues (SSA)/chemotherapy. Therefore, new therapies are urgently needed. Survivin is an intracellular protein that alters cell division, function of cell death proteases and inhibits apoptosis. It is undetectable in adult cells and expressed in many tumors, making it an ideal target. SurVaxM is a 15 amino acid synthetic peptide vaccine. It stimulates antigen presentation via intracellular cell-surface target recognition and induces CD8+ & CD4+ T cells and IgG production. It was well tolerated in a phase I trial in recurrent glioma pts (Fenstermaker et al., Neurooncol; 2014). Prelim analysis from a phase II study in glioma patients (pts) showed its efficacy (Ahluwalia et al., Neurooncol; 2018). Targeting survivin in NETs is based on our work with tissue microarrays from gastroenteropancreatic (GEP) and lung NETs that showed that its expression correlated with a worse overall survival (Hanif et al., Oncotarget; 2020). We have an ongoing single-arm phase I trial evaluating the safety and immunogenicity of SurVaxM in metastatic NETs. Methods: Ten eligible pts with any grade metastatic GEP/lung origin NETs that are survivin positive by immunohistochemistry and have progression on SSA within the last 6 months on two CT scans >4 weeks apart per RECIST v1.1 are being enrolled. Pts receive a fixed dose of 500 mcg of SurVaxM in Montanide ISA 51 subcutaneously along with 100 mcg of GM-CSF q2 weeks X 4 doses. SSA is continued at the same dose as before. Pts free of progression and toxicity at 6 months get extra doses of SurVaxM q12 weeks, up to 1 year. Subjects are assessed continuously for safety per NCI CTCAEv5.0. Response assessment via CT scans per RECIST v1.1 q12 weeks. Primary objective is to assess safety of SurVaxM +/- SSA. Secondary objectives are to assess overall response rate, progression free survival, duration of response and vaccine immunological response (anti-survivin antibody titers and survivin-specific CD8 T-cell responses). Safety analysis is per Pocock stopping boundary with the assumption of true toxicity of 0.2 and unacceptable toxicity of 0.3 at a significance level of 0.05.To this date, eight patients were screened out of which five patients were enrolled. One patient did not meet the eligibility criterion due to negative survivin staining and the other two did not meet the RECIST v1.1 progression criterion. Of the five pts enrolled, two were of lung origin, two of GEP, and the remainder one of thymic origin. Three pts had high grade neuroendocrine carcinoma, one patient had atypical bronchial tumor and one with low-grade NET. Currently, two pts remain on the study. The enrollment is ongoing. The trial is funded by The Neuroendocrine Tumor Research Foundation.

Background: BIRC5/survivin is highly expressed in cancer cells and represents a promising therapeutic target. In order to complete a comprehensive survey of its splice variants, we applied a direct RT-PCR approach as well as next generation sequencing (NGS) to tumor cell cDNAs. We have identified 10 novel splice junctions and three novel splice variants of survivin. Methods: Survivin transcripts were amplified from A1207 (glioblastoma) HeLa (cervical adenocarcinoma) and U87 (glioblastoma) cDNAs. For manual identification of splice forms, individual products were subcloned into TOPO vector and sequenced. For NGS analysis, RT-PCR products used to generate libraries which were subjected to sequencing, after which resulting reads were mapped against the human reference genome and assembled by Trinity. Results: Survivin RT-PCR products from A1207 cDNA were isolated and selected for TOPO cloning/sequencing. Of seventeen clones, the canonical isoform was represented by 4, and known variants including Δex3, 2B and 3B were represented by 5. Two novel sequences were identified: 1) 2B/Δex3, which contains a 68 bp shuffled exon 4/3 segment between exons 3 and 4 plus the 2B insert, and 2) 4B, in which exon 4 is extended by 27 bp at its 5' end. Both of these transcripts are predicted to encode full-length proteins: 2B/Δex3 contains the 23 aa 2B insert plus Δex3's unique C-terminus; 4B contains a novel 9 aa motif embedded in survivin's C-terminal alpha helix. RT-PCR products from A1207, HeLa and U87 templates subjected to NGS yielded five full-length BIRC5 contigs, including the canonical isoform, Δex3, 2B, 3B, and the predicted variant 2B/3B. To identify novel splice junctions, sequences were searched excluding canonical exon boundaries. The resulting 151 reads represented 10 novel exon junctions, among which the greatest proportion consisted of exon 1 and 3 (71 reads, 47%), or an extension of exon 2B by 32 bp at its 3' end (35 reads, 23%). Two variants contained the extended version of exon 4 seen in isoform 4B. A primer annealing within exon 4B's unique 27 bp was subsequently used for RT-PCR to validate the expression of the full-length isoform in HeLa, U87, A1207 and HEK293T cells. Conclusions: We have identified multiple novel splice variants of survivin, including Δex3/2B, 4B, and Δex3/4B. Proteins encoded by these transcripts potentially have pro- or anti-oncogenic functions, and further studies are needed to delineate their role in survivin biologies. Citation Format: Sheila Figel, Meaghan Birkemeier, Jesse Luce, Prashant Singh, Jianmin Wang, Cheryl Frank, Sanam Dharma, Emma Steinmetz, Michael Ciesielski, Robert Fenstermaker. Identification of novel BIRC5/survivin splice variants in cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5873.

Background: Previously we found that survivin is expressed on the surface of cancer cells in vitro, and is targetable using certain survivin-specific antibodies. The survivin gene is alternatively spliced into two alternative isoforms, ΔEX3 and 2B, which diverge structurally from the canonical isoform in their C-termini but retain a conserved BIR (Baculovirus IAP Repeat) domain. Methods: In order to characterize plasma membrane survivin (PM-SVN), tagged proteins representing canonical survivin (isoform 1), Δex3 and 2B were transiently expressed in multiple cancer cell line backgrounds. Relative surface expression was measured by flow cytometry staining of intact cells. Mutant constructs were used to determine the structural requirements for translocation. Imaging flow cytometry (Imagestream) was used to visualize survivin isoform localization, and to detect co-localization on the cell surface. Secreted exosomes were examined for expression of survivin isoforms. Results: Isoforms 1, Δex3 and 2B could be detected on the surface of HEK293T embryonic kidney, HeLa cervical adenocarcinoma, U87 glioblastoma, and A1207 glioblastoma cells. PM-SVN expression was variable, however Δex3 showed robust membrane expression across all cell lines. Deletion of a predicted transmembrane sequence in Δex3's unique C-terminus did not impair its translocation, and deletion of the first 10 amino acids, thought to be required for dimerization, disrupted surface expression only in HEK293T cells. Imaging flow cytometry analysis of cells revealed polar localization of PM-SVN, with specific punctate areas seen in 13-20% of cells. Staining with antibodies targeting both isoform 1 and Δex3 showed co-immunofluorescence in cell membrane puncta, indicating the formation of heterodimers. Stressing cells by heat shock increased the proportion of PM-SVN in 293T and A1207 cells; in 293T, this was accompanied by enrichment of survivin protein in secreted exosomes. Conclusions: In addition to canonical survivin, isoforms Δex3 and 2B are displayed on the surface of cancer cells, and can be secreted as exosomal cargo. Membrane translocation may be stress-induced and appears to require the conserved BIR domain. PM-SVN shows a polar distribution on the cell membrane, and isoforms 1 and Δex3 heterodimerize within these puncta. Citation Format: Sheila Figel, Meaghan Birkemeier, Sanam Dharma, Emma Steinmetz, Michael Ciesielski, Robert Fenstermaker. Canonical and noncanonical survivin isoforms translocate to the plasma membrane and are secreted in exosomes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2939.

Integrin αVβ3 is a structural protein of the plasma membrane that transduces signals from extracellular matrix proteins and has recently been shown to contain a novel receptor for thyroid hormone. Thyroid hormone signals are converted by αVβ3 into mitogen-activated protein kinase (MAPK) (ERK1/2) activation and downstream intracellular events in the cell nucleus. The latter include post-translational modification of the nuclear thyroid hormone receptor (TRβ1) and complex cellular or tissue responses, such as hormone-induced angiogenesis via basic fibroblast growth factor release. The integrin receptor for thyroid hormone has been shown to mediate proliferative effects of the hormone on certain tumor cell lines, including murine glioma/glioblastoma cells and human breast cancer (MCF-7) cells. More than one mechanism may account for this hormonal action, but in vitro studies indicate a direct hormonal action on cellular proliferation. Other possible mechanisms involve indirect actions via the release of tumor growth factors and effects on cell migration. In the intact organism, support of tumor growth by thyroid hormone is postulated to include angiogenesis. Crosstalk between the integrin thyroid hormone receptor and the epidermal growth factor receptor on the plasma membrane may be another mechanism by which thyroid hormone may modify tumor cell growth. Tetraiodothyroacetic acid (tetrac) is an iodothyronine analog that has no agonist activity at the integrin receptor, but inhibits binding of l-thyroxine and 3,5,3´-triiodo-l-thyronine to the receptor, preventing MAPK activation and consequent actions downstream of MAPK. In vitro studies and a preliminary in vivo experiment indicate that tetrac blocks the action of thyroid hormone on tumor cell proliferation. Both unmodified tetrac and tetrac reformulated as a nanoparticle that does not gain access to the cell interior are under investigation in animal models as anticancer agents. Also under study is the susceptibility of other human cancer cell lines to induction of proliferation by physiological concentrations of thyroid hormone.

TPS2581 Background: Glioblastoma is the most common primary malignant brain tumor with median survival of approximately 15-16 months. Following first recurrence, progression free survival at six months ~15%. There is no therapy in recurrent glioblastoma associated with any survival benefit and there is an urgent need for better therapeutic options. Immunotherapy is one promising option for patients with cancer. This is being explored in glioblastoma and a number of forms of active specific vaccination and immune checkpoint based approaches have been devised and are being investigated in glioblastoma. Methods: Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor. Survivin is a 16.5 kDa intracellular protein that belongs to the inhibitor of apoptosis protein (IAP) family. SurVaxM is a 15 amino acid antigenic peptide that targets surviving capable of binding several human MHC class I molecules. Primary Objective is to assess clinical activity of Pembrolizumab and SurVaxM in patients with recurrent glioblastoma using progression free survival at 6 months (PFS-6) as determined using RANO criteria. Secondary Objective(s) includes safety and tolerability of combination, response rates, progression free survival and overall survival. Exploratory Objective include measuring cellular and humoral immune responses during concurrent administration of Pembrolizumab and SurVaxM. This is a phase II study of two arms in patients with recurrent glioblastoma. Arm A is patients with first recurrence of glioblastoma who have failed prior chemotherapy and radiation but have not received any immunotherapy. Arm B is an exploratory arm of glioblastoma patients who have failed prior anti-PD1 therapy. This clinical trial will enroll 41 patients with glioblastoma at first recurrence (bevacizumab naïve) in arm 1.This will include a 6-patient toxicity/safety run-in. There will an exploratory cohort of 10 patients who have failed prior PD1 blockade for a total of 51 patients in 2 arms. Key inclusion criteria include diagnosis of glioblastoma, Age ≥18 years old, Previous first line treatment with at least radiotherapy with or without temozolomide and Documented first recurrence of GBM and Karnofsky performance status of 70 and normal organ function. Key exclusion criteria include more than one recurrence of GBM, presence of extracranial metastatic or leptomeningeal disease, patients with > 1 cm midline shift on imaging. Patients must not require > 10 mg daily of prednisone equivalent. Clinical trial information: NCT04013672 .

Background: Papillary tumor of the pineal region (PTPR) is a rare neoplasm with only anecdotal data to guide the treatment. Results of treatment with surgery, radiation therapy, and chemotherapy have been reported to have varying degrees of success. Here we report a patient with a PTPR, who underwent subtotal resection, gamma knife stereotactic radiosurgery, and adjuvant temozolomide chemotherapy. Case Description: During 9 years of clinical and radiographic follow-up, the patient has had regression of residual tumor and remains asymptomatic. Conclusion: When gross total resection of a PTPR is not possible, treatment with gamma knife stereotactic radiosurgery and temozolomide chemotherapy may provide long-term tumor control.

Cell cycle is an evolutionarily conserved process that ensures high-fidelity distribution of DNA to daughter cells. The cycle includes an interphase, consisting of cell growth/DNA repair phases, and DNA replication, as well as a short M phase in which DNA and cytoplasmic division occur. Entry into the cycle is stimulated mitogenically and progression through the phases is driven by the activity of cyclin-dependent kinases (CDKs). CDKs are highly regulated through transcription, the availability of cofactors, direct inhibition, phosphorylation, and protein degradation. Several checkpoints in the process ensure the maintenance of genomic integrity. G1/S and G2/M checkpoints are critically regulated by tumor suppressors Rb and p53. Cell-cycle dysregulation is a hallmark of cancer cells, and malignant glioma cells proliferate rapidly, having overcome the molecular “brakes” that hold normal glial cells in a quiescent state. Genetic analyses have identified a relatively small number of significant mutations in glioblastoma, including several critical cell-cycle molecules. These alterations functionally drive progression through the Rb-dependent G1/S checkpoint and disrupt the p53 checkpoint signaling. Deletion of Rb, p53, and the CDK4/6 inhibitors p16INK4A and ARF and the amplification of CDK4, CDK6, and the MDM family of p53-targeting ubiquitin ligases are common. Traditional chemotherapeutic agents trigger cell-cycle arrest leading to apoptosis through either the overwhelming of DNA damage repair systems, or by direct interference with the mitotic spindle. Targeting therapies have been developed against cell-cycle kinases; however, most of these agents have shown limited clinical efficacy so far.

A major barrier for cancer immunotherapy is the presence of suppressive cell populations in patients with cancer, such as myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM), which contribute to the immunosuppressive microenvironment that promotes tumor growth and metastasis. Tasquinimod is a novel antitumor agent that is currently at an advanced stage of clinical development for treatment of castration-resistant prostate cancer. A target of tasquinimod is the inflammatory protein S100A9, which has been demonstrated to affect the accumulation and function of tumor-suppressive myeloid cells. Here, we report that tasquinimod provided a significant enhancement to the antitumor effects of two different immunotherapeutics in mouse models of cancer: a tumor vaccine (SurVaxM) for prostate cancer and a tumor-targeted superantigen (TTS) for melanoma. In the combination strategies, tasquinimod inhibited distinct MDSC populations and TAMs of the M2-polarized phenotype (CD206+). CD11b+ myeloid cells isolated from tumors of treated mice expressed lower levels of arginase-1 and higher levels of inducible nitric oxide synthase (iNOS), and were less immunosuppressive ex vivo, which translated into a significantly reduced tumor-promoting capacity in vivo when these cells were coinjected with tumor cells. Tumor-specific CD8+ T cells were increased markedly in the circulation and in tumors. Furthermore, T-cell effector functions, including cell-mediated cytotoxicity and IFNγ production, were potentiated. Taken together, these data suggest that pharmacologic targeting of suppressive myeloid cells by tasquinimod induces therapeutic benefit and provide the rationale for clinical testing of tasquinimod in combination with cancer immunotherapies. Cancer Immunol Res; 3(2); 136–48. ©2014 AACR.

Glioma cells release exosomes in culture and into the extracellular matrix in vivo. These nanobodies transport an array of biomolecules and are capable of mediating cell-cell communication. Circulating exosomes in cancer patients may be indicative of disease status and response to therapy. The inhibitor of apoptosis protein (IAP) survivin (SVN) promotes cancer cell proliferation, local immune suppression and resistance to chemotherapy and it is a potential cancer biomarker. We used imaging flow cytometry to perform quantitative measurements of circulating SVN+ exosomes in the serum of malignant glioma patients undergoing investigational treatment with an anti-survivin vaccine (SurVaxM). Serum from glioma patients contained abundant CD9+ exosomes with both SVN and glial fibrillary acidic protein (GFAP) on their surface. Survivin and GFAP were evaluated both independently and together as possible tumor markers on CD9+ exosomes. Patients with longer time to tumor progression generally exhibited a decrease in circulating CD9+/SVN+ and CD9+/GFAP+/SVN+ exosomes immediately following survivin vaccination; whereas, those with early tumor progression had an increase in exosomes, despite anti-survivin immunotherapy. Serum from non-cancer healthy control individuals had very few detectable CD9+/GFAP+/SVN+ exosomes, although CD9+/GFAP+ exosomes were detectable in small numbers. This study demonstrates that patients with malignant gliomas have CD9+/GFAP+/SVN+ and CD9+/SVN+ exosomes that are released into the circulation and that early reductions in their numbers following anti-survivin immunotherapy might be associated with longer progression-free survival.

BACKGROUND: Survivin is an anti-apoptotic protein that is highly expressed in glioblastoma (GBM). We conducted a single-arm, multi-center phase II trial in newly diagnosed GBM (nGBM) to determine 6-month progression-free survival (PFS-6), 12-month overall survival (OS-12) and immunologic response in patients treated with surgery, chemoradiation, adjuvant temozolomide (TMZ) and survivin-targeted immunization. METHODS: Patients with nGBM who hadwith HLA-A*02, -A*03, -A*11 and -A*24 haplotypes and, Karnofsky performance status ≥70 were included. Following craniotomy (3 residual contrast enhancement) and chemoradiation, patients received 4 prime-boost doses of SurVaxM (500 mcg) every 2 weeks, followed by adjuvant TMZ and maintenance SurVaxM every 12 weeks until progression. Immunogenicity of SurVaxM was assessed by measuring anti-survivin antibody levels and survivin-specific CD8+ T-cells using multimers. RESULTS: Sixty-three patients, median age 60 years (range, 20–82), including 38 males were treated. Survivin expression was detectable in all patients (1–40% ([median = 12%]) of tumor cells by immunohistochemistry). The vaccine was highly immunogenic and produced survivin-specific CD8+ T-cells and antibody (IgG) titers. The regimen was well-tolerated and immunogen-related adverse events were mild with no regimen limiting toxicity attributable to SurVaxM. PFS-6 was 96.7% (C.I. = 87.6%- 99.1%) and OS-12 was 94.2% (C.I. =83.0%-98.1%) as measured from diagnosis. In MGMT methylated, PFS6 of 96.9% (C.I. = 99.6% to 79.8%); OS12 of 98.1% (C.I. = 99.0% to 97.2%) and in unmethylated tumors, PFS6 of 96.6% (C.I. = 99.6% to 78%); OS12 of 88.9% (C.I. = 99% to 77.2%) was observed. Methylated patients with higher survivin levels had significantly better PFS-6 than those with low survivin levels (r = 0.4). CONCLUSIONS: SurVaxM is safe and a promising adjunct therapy in nGBM. Compared to historical matched controls, addition of SurVaxM improved PFS-6 and OS-12 in nGBM. Patients with poor prognostic factors (unmethylated MGMT, higher survivin levels) treated with SurVaxM achieved better survival than expected.

2016 Background: SVN53-67/M57-KLH (SurVaxM) is a novel cancer vaccine designed to stimulate an immune response targeting the tumor-specific antigen survivin. A multi-center, single-arm phase 2 clinical trial of SurVaxM in survivin-positive newly diagnosed glioblastoma (nGBM, NCT02455557) is now fully enrolled and data updated. Methods: Patients (n = 63) with nGBM were enrolled at 5 US cancer centers and followed for safety, 6-month progression-free survival (PFS6), 12-month overall survival (OS12) and immunologic response. All patients underwent craniotomy with near-total resection ( < 1 cm3 residual contrast enhancement), TMZ chemoradiation, adjuvant TMZ and SurVaxM. Patients received 4 doses of SurVaxM (500 mcg) in Montanide with sargramostim (100 mcg) biweekly, followed by maintenance SurVaxM with adjuvants every 12 weeks until tumor progression. Immunogenicity of SurVaxM was assessed by detection of survivin-specific antibody (IgG) and CD8+ T-cell levels. Results: Median age was 60 yrs (range, 20-82), 53% methylated MGMT, 46% unmethylated MGMT (1 N/A) and 60% were male. Survivin expression ranged from 1-40% (median 12%) by immunohistochemistry. Median time to first immunization was 3.0 mo (1.9-4.0 mo) from diagnosis. There have been no RLT or grade ≥ 3 SAE attributable to SurVaxM. The most common AE was grade 1-2 injection site reactions. OS12 was 86% from first immunization and 93.4% from diagnosis. OS12 for meMGMT was 93.1% and unMGMT was 78% from first immunization. Median time to tumor progression (mPFS) was 13.9 months from diagnosis. Median OS has not yet been reached. SurVaxM produced an increase in survivin-specific IgG titre from pre-vaccine baseline to ≥ 1:10,000 in 67% of pts and ≥ 1:100,000 in 27%. CD8+ T cell responses were observed. Anti-survivin IgG and OS were correlated. Conclusions: SurVaxM immunotherapy generated encouraging efficacy and immunogenicity in nGBM and has minimal toxicity. A randomized, prospective trial of SurVaxM in nGBM is planned. Clinical trial information: NCT024455557.

There is growing interest in immunotherapy for malignant gliomas. This interest stems from a number of immunological observations, together with the failure of conventional therapeutic agents to produce broad and clinically meaningful improvements in survival and quality of life. The challenges faced in translating laboratory-based immunological observations to Phase I and II clinical trials for immunotherapy of gliomas are substantial. Nevertheless, as our understanding of the effects of active specific vaccination in glioma patients grows, results support optimism that such methods may eventually prove useful as an adjunctive treatment for these cancers. This paper highlights a number of barriers encountered in the translational development of a survivin-targeted peptide vaccine (SurVaxM) for patients with malignant gliomas.

Letter to the Editor.

Primary and metastatic tumors of the central nervous system are a heterogeneous group of neoplasms with varied outcomes and management strategies. Recently, improved survival observed in 2 randomized clinical trials established combined chemotherapy and radiation as the new standard for treating patients with pure or mixed anaplastic oligodendroglioma harboring the 1p/19q codeletion. For metastatic disease, increasing evidence supports the efficacy of stereotactic radiosurgery in treating patients with multiple metastatic lesions but low overall tumor volume. These guidelines provide recommendations on the diagnosis and management of this group of diseases based on clinical evidence and panel consensus. This version includes expert advice on the management of low-grade infiltrative astrocytomas, oligodendrogliomas, anaplastic gliomas, glioblastomas, medulloblastomas, supratentorial primitive neuroectodermal tumors, and brain metastases. The full online version, available at NCCN. org, contains recommendations on additional subtypes.