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Laser interstitial thermal therapy (LITT) for glioblastoma (GBM) has been reserved for poor surgical candidates and deep "inoperable" lesions. We present the first reported series of LITT for surgically accessible recurrent GBM (rGBM) that would otherwise be treated with surgical resection.To evaluate the use of LITT for unifocal, lobar, first-time rGBM compared with a similar surgical cohort.A retrospective institutional database was used to identify patients with unifocal, lobar, first-time rGBM who underwent LITT or resection between 2013 and 2020. Clinical and volumetric lesional characteristics were compared between cohorts. Subgroup analysis of patients with lesions ≤20 cm 3 was also completed. Primary outcomes were overall survival and progression-free survival.Of the 744 patients with rGBM treated from 2013 to 2020, a LITT cohort of 17 patients were compared with 23 similar surgical patients. There were no differences in baseline characteristics, although lesions were larger in the surgical cohort (7.54 vs 4.37 cm 3 , P = .017). Despite differences in lesion size, both cohorts had similar extents of ablation/resection (90.7% vs 95.1%, P = .739). Overall survival (14.1 vs 13.8 months, P = .578) and progression-free survival (3.7 vs 3.3 months, P = 0. 495) were similar. LITT patients had significantly shorter hospital stays (2.2 vs 3.0 days, P = .004). Subgroup analysis of patients with lesions ≤20 cm 3 showed similar outcomes, with LITT allowing for significantly shorter hospital stays.We found no difference in survival outcomes or morbidity between LITT and repeat surgery for surgically accessible rGBM while LITT resulted in shorter hospital stays and more efficient postoperative care.

Purpose:Liquid biopsy offers a minimally invasive tool to diagnose and monitor the heterogeneous molecular landscape of tumors over time and therapy. Detection of TERT promoter mutations (C228T, C250T) in cfDNA has been successful for some systemic cancers but has yet to be demonstrated in gliomas, despite the high prevalence of these mutations in glioma tissue (>60% of all tumors).Experimental Design:Here, we developed a novel digital droplet PCR (ddPCR) assay that incorporates features to improve sensitivity and allows for the simultaneous detection and longitudinal monitoring of two TERT promoter mutations (C228T and C250T) in cfDNA from the plasma of patients with glioma.Results:In baseline performance in tumor tissue, the assay had perfect concordance with an independently performed clinical pathology laboratory assessment of TERT promoter mutations in the same tumor samples [95% confidence interval (CI), 94%–100%]. Extending to matched plasma samples, we detected TERT mutations in both discovery and blinded multi-institution validation cohorts with an overall sensitivity of 62.5% (95% CI, 52%–73%) and a specificity of 90% (95% CI, 80%–96%) compared with the gold-standard tumor tissue–based detection of TERT mutations. Upon longitudinal monitoring in 5 patients, we report that peripheral TERT-mutant allele frequency reflects the clinical course of the disease, with levels decreasing after surgical intervention and therapy and increasing with tumor progression.Conclusions:Our results demonstrate the feasibility of detecting circulating cfDNA TERT promoter mutations in patients with glioma with clinically relevant sensitivity and specificity.

Supplementary File Figure legends

Supplementary Figure 4. Correlations between (a) progression free survival, (b) overall survival, (c) tumor grade, (d) contrast enhancement, (e) type of TERT mutation, (f) tumor volume, (g) duration of disease, (h) age. Contingency tables are provided for (i) Discovery Sample Set 1 (j) Discovery Sample Set 2 (k) MultiInstitution Validation Cohort (l) Overall Combined Cohort. (m) 4 replicates of 4 uL of cfDNA from matched CSF samples (n=4; n=3 TERT mutant and n=1 WT) was used as input for absolute quantification of TERT mutant and wildtype copies. MAF is calculated using the formula described in Methods. Copies/mL for plasma samples are plotted against Study ID, classified by SNapSHOT/Pathology as floating bars, with line at the mean copies/mL. (n) Contingency table for matched CSF plasma.

OBJECTIVE Neurosurgeons generate an enormous amount of data daily. Within these data lie rigorous, valid, and reproducible evidence. Such evidence can facilitate healthcare reform and improve quality of care. To measure the quality of care provided objectively, evaluating the safety and efficacy of clinical activities should occur in real time. Registries must be constructed and collected data analyzed with the precision akin to that of randomized clinical trials to accomplish this goal. METHODS The Quality Outcomes Database (QOD) Tumor Registry was launched in February 2019 with 8 sites in its initial 1-year pilot phase. The Tumor Registry was proposed by the AANS/CNS Tumor Section and approved by the QOD Scientific Committee in the fall of 2018. The initial pilot phase aimed to assess the feasibility of collecting outcomes data from 8 academic practices across the United States; these outcomes included length of stay, discharge disposition, and inpatient complications. RESULTS As of November 2019, 923 eligible patients have been entered, with the following subsets: intracranial metastasis (17.3%, n = 160), high-grade glioma (18.5%, n = 171), low-grade glioma (6%, n = 55), meningioma (20%, n = 184), pituitary tumor (14.3%, n = 132), and other intracranial tumor (24%, n = 221). CONCLUSIONS The authors have demonstrated here, as a pilot study, the feasibility of documenting demographic, clinical, operative, and patient-reported outcome characteristics longitudinally for 6 common intracranial tumor types.

Health systems were abruptly plunged into a crisis as SARS-CoV-2 exploded into a pandemic in spring 2020. In March-April 2020, Metropolitan Detroit was a US "hotspot." As a large health system with five hospitals and two behavioural health inpatient facilities, a health insurance company, a medical group and physician network, and 41 ambulatory clinics normally hosting over 10,000 daily patient encounters, the Henry Ford Health System deployed numerous strategies in the management of this upheaval. As hospitals and Emergency Departments were inundated with COVID-19 patients, other services and activities needed to shut down as state-mandated policies were promulgated, new internal and external communication networks established, and management of employees and resources such as ventilators, ICU beds, personal protective equipment, and laboratory supplies became critical challenges. We describe herein the system-wide strategies implemented and lessons learned in the operation of a health system in the initial throes of a global pandemic.

BACKGROUND Predicting survival of patients with spinal metastases would help stratify treatments from aggressive to palliation. OBJECTIVE To evaluate whether sarcopenia predicts survival in patients with lung, breast, prostate, or multiple myeloma spinal metastases. METHODS Psoas muscle measurements in patients with spinal metastasis were taken from computed tomography scans at 2 time points: at first episode of stereotactic body radiation therapy (SBRT) and from the most recent scan available. Overall survival and hazard ratios were calculated with multivariate cox proportional hazards regression analyses. RESULTS In 417 patients with spinal metastases, 40% had lung cancer, 27% breast, 21% prostate, and 11% myeloma. Overall survival was not associated with age, sex, ethnicity, levels treated, or SBRT volume. Multivariate analysis showed patients in the lowest psoas tertile had shorter survival (222 d, 95% CI = 185-323 d) as compared to the largest tertile (579 d, 95% CI = 405-815 d), (HR1.54, P = .005). Median psoas size as a cutoff value was also strongly predictive for survival (HR1.48, P = .002). Survival was independent of tumor histology. The psoas/vertebral body ratio was also successful in predicting overall survival independent of tumor histology and gender (HR1.52, P

Today, stereotactic radiosurgery is an effective therapy for a variety of intracranial pathology that were treated solely with open neurosurgery in the past. The technique was developed from the combination of therapeutic radiation and stereotactic devices for the precise localization of intracranial targets. Although stereotactic radiosurgery was originally performed as a partnership between neurosurgeons and radiation oncologists, this partnership has weakened in recent years, with some procedures being performed without neurosurgeons. At the same time, neurosurgeons across the United States and Canada have found their stereotactic radiosurgery training during residency inadequate. Although neurosurgeons, residency directors, and department chairs agree that stereotactic radiosurgery education and exposure during neurosurgery training could be improved, a limited number of resources exist for this kind of education. This review describes the history of stereotactic radiosurgery, assesses the state of its use and education today, and provides recommendations for the improvement of neurosurgical education in stereotactic radiosurgery for the future.

Target population Adult patients (older than 18 yr of age) with newly diagnosed brain metastases. Question If whole brain radiation therapy (WBRT) is used, is there an optimal dose/fractionation schedule? Recommendations Level 1: A standard WBRT dose/fractionation schedule (ie, 30 Gy in 10 fractions or a biological equivalent dose [BED] of 39 Gy10) is recommended as altered dose/fractionation schedules do not result in significant differences in median survival or local control. Level 3: Due to concerns regarding neurocognitive effects, higher dose per fraction schedules (such as 20 Gy in 5 fractions) are recommended only for patients with poor performance status or short predicted survival. Level 3: WBRT can be recommended to improve progression-free survival for patients with more than 4 brain metastases. Question What impact does tumor histopathology or molecular status have on the decision to use WBRT, the dose fractionation scheme to be utilized, and its outcomes? Recommendations There is insufficient evidence to support the choice of any particular dose/fractionation regimen based on histopathology. Molecular status may have an impact on the decision to delay WBRT in subgroups of patients, but there is not sufficient data to make a more definitive recommendation. Question Separate from survival outcomes, what are the neurocognitive consequences of WBRT, and what steps can be taken to minimize them? Recommendations Level 2: Due to neurocognitive toxicity, local therapy (surgery or SRS) without WBRT is recommended for patients with ≤4 brain metastases amenable to local therapy in terms of size and location. Level 2: Given the association of neurocognitive toxicity with increasing total dose and dose per fraction of WBRT, WBRT doses exceeding 30 Gy given in 10 fractions, or similar biologically equivalent doses, are not recommended, except in patients with poor performance status or short predicted survival. Level 2: If prophylactic cranial irradiation (PCI) is given to prevent brain metastases for small cell lung cancer, the recommended WBRT dose/fractionation regimen is 25 Gy in 10 fractions, and because this can be associated with neurocognitive decline, patients should be told of this risk at the same time they are counseled about the possible survival benefits. Level 3: Patients having WBRT (given for either existing brain metastases or as PCI) should be offered 6 mo of memantine to potentially delay, lessen, or prevent the associated neurocognitive toxicity. Question Does the addition of WBRT after surgical resection or radiosurgery improve progression-free or overall survival outcomes when compared to surgical resection or radiosurgery alone? Recommendations Level 2: WBRT is not recommended in WHO performance status 0 to 2 patients with up to 4 brain metastases because, compared to surgical resection or radiosurgery alone, the addition of WBRT improves intracranial progression-free survival but not overall survival. Level 2: In WHO performance status 0 to 2 patients with up to 4 brain metastases where the goal is minimizing neurocognitive toxicity, as opposed to maximizing progression-free survival and overall survival, local therapy (surgery or radiosurgery) without WBRT is recommended. Level 3: Compared to surgical resection or radiosurgery alone, the addition of WBRT is not recommended for patients with more than 4 brain metastases unless the metastases' volume exceeds 7 cc, or there are more than 15 metastases, or the size or location of the metastases are not amenable to surgical resection or radiosurgery.The full guideline can be found at: https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter_3.

Please see the full-text version of this guideline https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter_2) for the target population of each recommendation listed below. SURGERY FOR METASTATIC BRAIN TUMORS AT NEW DIAGNOSIS QUESTION: Should patients with newly diagnosed metastatic brain tumors undergo surgery, stereotactic radiosurgery (SRS), or whole brain radiotherapy (WBRT)? Recommendations Level 1: Surgery + WBRT is recommended as first-line treatment in patients with single brain metastases with favorable performance status and limited extracranial disease to extend overall survival, median survival, and local control. Level 3: Surgery plus SRS is recommended to provide survival benefit in patients with metastatic brain tumors Level 3: Multimodal treatments including either surgery + WBRT + SRS boost or surgery + WBRT are recommended as alternatives to WBRT + SRS in terms of providing overall survival and local control benefits. SURGERY AND RADIATION FOR METASTATIC BRAIN TUMORS QUESTION: Should patients with newly diagnosed metastatic brain tumors undergo surgical resection followed by WBRT, SRS, or another combination of these modalities? Recommendations Level 1: Surgery + WBRT is recommended as superior treatment to WBRT alone in patients with single brain metastases. Level 3: Surgery + SRS is recommended as an alternative to treatment with SRS alone to benefit overall survival. Level 3: It is recommended that SRS alone be considered equivalent to surgery + WBRT. SURGERY FOR RECURRENT METASTATIC BRAIN TUMORS QUESTION: Should patients with recurrent metastatic brain tumors undergo surgical resection? Recommendations Level 3: Craniotomy is recommended as a treatment for intracranial recurrence after initial surgery or SRS. SURGICAL TECHNIQUE AND RECURRENCE QUESTION A: Does the surgical technique (en bloc resection or piecemeal resection) affect recurrence? Recommendation Level 3: En bloc tumor resection, as opposed to piecemeal resection, is recommended to decrease the risk of postoperative leptomeningeal disease when resecting single brain metastases. Question b Does the extent of surgical resection (gross total resection or subtotal resection) affect recurrence? Recommendation Level 3: Gross total resection is recommended over subtotal resection in recursive partitioning analysis class I patients to improve overall survival and prolong time to recurrence. The full guideline can be found at https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter_2.

Glioma surgery at its nascency relied predominantly on visual and tactile feedback for the removal of grossly abnormal tissue. This technique has inherent limitations in delineating infiltrative tumor from normal brain, thus limiting the ability to achieve a gross total resection consistently. Since extent of resection (EOR) is consistently correlated with measures of survival, fluorescence-guided surgery shows promise in improving our ability to treat high-grade gliomas (HGG). 5-Aminolevulinic acid (5-ALA) is a prodrug preferentially metabolized by glioma cells that allows direct, real-time visualization of pathologic tissue through fluorescence under blue light. To report the relationship between 5-ALA and EOR in newly diagnosed HGG. To report our institutional experience including nuances of workflow. The authors performed a systematic review of the available literature between 1998 and 2018 to isolate studies addressing the impact of fluorescence-guided surgery with 5-ALA on the EOR in newly diagnosed HGG. Search strategy was in adherence to the preferred reporting items for systematic reviews and meta-analyses methodology. Out of 741 unique articles, eight fulfilled our strict inclusion criteria. Fluorescence-guided resection led to greater EOR in all studies, with six demonstrating statistical significance (p

Supplemental Digital Content is available in the text, Objective: Examine the effect of a universal facemask policy for healthcare workers (HCW) and incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positivity. Methods: Daily number of symptomatic HCW tested, SARS-CoV-2 positivity rates, and HCW job-descriptions were collected pre and post Universal HCW facemask policy (March 26, 2020). Multiple change point regression was used to model positive-test-rate data. SARS-CoV-2 testing and positivity rates were compared for pre-intervention, transition, post-intervention, and follow-up periods. Results: Between March 12 and August 10, 2020, 19.2% of HCW were symptomatic for COVID-19 and underwent SARS-CoV-2 testing. A single change point was identified ∼March 28–30 (95% probability). Before the change point, the odds of a tested HCW having a positive result doubled every 4.5 to 7.5 days. Post-change-point, the odds of a tested HCW having a positive result halved every 10.5 to 13.5 days. Conclusions: Universal facemasks were associated with reducing HCW's risk of acquiring COVID-19.

OBJECTIVE Greater extent of resection (EOR) is associated with longer overall survival in patients with high-grade gliomas (HGGs). 5-Aminolevulinic acid (5-ALA) can increase EOR by improving intraoperative visualization of contrast-enhancing tumor during fluorescence-guided surgery (FGS). When administered orally, 5-ALA is converted by glioma cells into protoporphyrin IX (PPIX), which fluoresces under blue 400-nm light. 5-ALA has been available for use in Europe since 2010, but only recently gained FDA approval as an intraoperative imaging agent for HGG tissue. In this first-ever, to the authors’ knowledge, multicenter 5-ALA FGS study conducted in the United States, the primary objectives were the following: 1) assess the diagnostic accuracy of 5-ALA–induced PPIX fluorescence for HGG histopathology across diverse centers and surgeons; and 2) assess the safety profile of 5-ALA FGS, with particular attention to neurological morbidity. METHODS This single-arm, multicenter, prospective study included adults aged 18–80 years with Karnofsky Performance Status (KPS) score > 60 and an MRI diagnosis of suspected new or recurrent resectable HGG. Intraoperatively, 3–5 samples per tumor were taken and their fluorescence status was recorded by the surgeon. Specimens were submitted for histopathological analysis. Patients were followed for 6 weeks postoperatively for adverse events, changes in the neurological exam, and KPS score. Multivariate analyses were performed of the outcomes of KPS decline, EOR, and residual enhancing tumor volume to identify predictive patient and intraoperative variables. RESULTS Sixty-nine patients underwent 5-ALA FGS, providing 275 tumor samples for analysis. PPIX fluorescence had a sensitivity of 96.5%, specificity of 29.4%, positive predictive value (PPV) for HGG histopathology of 95.4%, and diagnostic accuracy of 92.4%. Drug-related adverse events occurred at a rate of 22%. Serious adverse events due to intraoperative neurological injury, which may have resulted from FGS, occurred at a rate of 4.3%. There were 2 deaths unrelated to FGS. Compared to preoperative KPS scores, postoperative KPS scores were significantly lower at 48 hours and 2 weeks but were not different at 6 weeks postoperatively. Complete resection of enhancing tumor occurred in 51.9% of patients. Smaller preoperative tumor volume and use of intraoperative MRI predicted lower residual tumor volume. CONCLUSIONS PPIX fluorescence, as judged by the surgeon, has a high sensitivity and PPV for HGG. 5-ALA was well tolerated in terms of drug-related adverse events, and its application by trained surgeons in FGS for HGGs was not associated with any excess neurological morbidity.

Background The detection of somatic mutations in cell-free DNA (cfDNA) from liquid biopsy has emerged as a noninvasive tool to monitor the follow-up of cancer patients. However, the significance of cfDNA clinical utility remains uncertain in patients with brain tumors, primarily because of the limited sensitivity cfDNA has to detect real tumor-specific somatic mutations. This unresolved challenge has prevented accurate follow-up of glioma patients with noninvasive approaches. Methods Genome-wide DNA methylation profiling of tumor tissue and serum cfDNA of glioma patients. Results Here, we developed a noninvasive approach to profile the DNA methylation status in the serum of patients with gliomas and identified a cfDNA-derived methylation signature that is associated with the presence of gliomas and related immune features. By testing the signature in an independent discovery and validation cohorts, we developed and verified a score metric (the “glioma-epigenetic liquid biopsy score” or GeLB) that optimally distinguished patients with or without glioma (sensitivity: 100%, specificity: 97.78%). Furthermore, we found that changes in GeLB score reflected clinicopathological changes during surveillance (eg, progression, pseudoprogression, and response to standard or experimental treatment). Conclusions Our results suggest that the GeLB score can be used as a complementary approach to diagnose and follow up patients with glioma.

INTRODUCTION Laser Interstitial thermal therapy (LITT) is a minimal-access procedure for intracranial tumors that are either refractory to standard treatment paradigms or difficult to access via conventional open surgery. OBJECTIVE To evaluate predictors of local disease control following LITT in patients with primary and secondary brain tumors. METHODS Single-center retrospective cohort study of all consecutive LITT ablations between 2014 and 2019. Demographic and procedural characteristics analyzed with respect to local disease control at 6 months. Chi-square tests for categorical variables, T-tests/Wilcoxon Rank-Sum tests for continuous variables for parametric and non-parametric data, respectively. Poisson regression models were used to approximate relative risk (RR) with 95% confidence intervals. RESULTS A total of 76 patients underwent LITT with a median follow up of 12.3 months; pathology at time of ablation was glioblastoma multiforme (GBM, 36%), WHO grade III primary CNS (24%), low grade CNS (20%), and metastatic lesions (19%) with respective local control rates of 26%, 20%, 29%, and 26%. Pathology of GBM (RR 0.46, 0.21-1.02, p=0.055) and a 5-year increase in age at the time of ablation (RR 0.91, 0.83-0.99, p=0.028) were associated with a lower likelihood of local control at 6 months. Preoperative Karnofsky performance status (KPS) of 100 (RR 2.04, 1.13-3.69, p=0.019) was associated with a higher likelihood of local control. Extent of ablation (EOA) demonstrated a direct relationship with local control; when EOA=100% local control was 59%, with this rate dropping down to 21% when EOA=90%. Tumor location, lesion volume, gender, BMI, ethnicity, or whether there existed multiple foci of disease at the time of ablation had no strong association with local control. CONCLUSION Our series demonstrates that preoperative performance status and age were strong predictors of local disease control following LITT. Incomplete ablation and histology of high-grade glioma portended a higher risk of local recurrence.

Purpose: Liquid biopsy offers a minimally invasive tool to diagnose and monitor the heterogeneous molecular landscape of tumors over time and therapy. Detection of TERT promoter mutations (C228T, C250T) in cfDNA has been successful for some systemic cancers but has yet to be demonstrated in gliomas, despite the high prevalence of these mutations in glioma tissue (>60% of all tumors). Experimental Design: Here, we developed a novel digital droplet PCR (ddPCR) assay that incorporates features to improve sensitivity and allows for the simultaneous detection and longitudinal monitoring of two TERT promoter mutations (C228T and C250T) in cfDNA from the plasma of patients with glioma. Results: In baseline performance in tumor tissue, the assay had perfect concordance with an independently performed clinical pathology laboratory assessment of TERT promoter mutations in the same tumor samples [95% confidence interval (CI), 94%–100%]. Extending to matched plasma samples, we detected TERT mutations in both discovery and blinded multi-institution validation cohorts with an overall sensitivity of 62.5% (95% CI, 52%–73%) and a specificity of 90% (95% CI, 80%–96%) compared with the gold-standard tumor tissue–based detection of TERT mutations. Upon longitudinal monitoring in 5 patients, we report that peripheral TERT-mutant allele frequency reflects the clinical course of the disease, with levels decreasing after surgical intervention and therapy and increasing with tumor progression. Conclusions: Our results demonstrate the feasibility of detecting circulating cfDNA TERT promoter mutations in patients with glioma with clinically relevant sensitivity and specificity.

What is the role of temozolomide in the management of adult patients (aged 65 and under) with newly diagnosed glioblastoma? These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. Level I: Concurrent and post-irradiation Temozolomide (TMZ) in combination with radiotherapy and post-radiotherapy as described by Stupp et al. is recommended to improve both PFS and OS in adult patients with newly diagnosed GBM. There is no evidence that alterations in the dosing regimen have additional beneficial effect. Is there benefit to adjuvant temozolomide treatment in elderly patients (> 65 years old?). These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. Level III: Adjuvant TMZ treatment is suggested as a treatment option to improve PFS and OS in adult patients (over 70 years of age) with newly diagnosed GBM. What is the role of local regional chemotherapy with BCNU biodegradable polymeric wafers in adult patients with newly diagnosed glioblastoma? These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. Level III: There is insufficient evidence for the use of BCNU wafers following resection in patients with newly diagnosed glioblastoma who undergo the Stupp protocol after surgery. Further studies of higher quality are suggested to understand the role of BCNU wafer and other locoregional therapy in the setting of Stupp Protocol. What is the role of bevacizumab in the adult patient with newly diagnosed glioblastoma? These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. Level I: Bevacizumab in general is not recommended in the initial treatment of adult patients with newly diagnosed GBM. It continues to be strongly recommended that patients with newly diagnosed GBM be enrolled in properly designed clinical trials to assess the benefit of novel chemotherapeutic agents compared to standard therapy.

The American Board of Neurological Surgery (ABNS) was incorporated in 1940 in recognition of the need for detailed training in and special qualifications for the practice of neurological surgery and for self-regulation of quality and safety in the field. The ABNS believes it is the duty of neurosurgeons to place a patient’s welfare and rights above all other considerations and to provide care with compassion, respect for human dignity, honesty, and integrity. At its inception, the ABNS was the 13th member board of the American Board of Medical Specialties (ABMS), which itself was founded in 1933. Today, the ABNS is one of the 24 member boards of the ABMS.To better serve public health and safety in a rapidly changing healthcare environment, the ABNS continues to evolve in order to elevate standards for the practice of neurological surgery. In connection with its activities, including initial certification, recognition of focused practice, and continuous certification, the ABNS actively seeks and incorporates input from the public and the physicians it serves. The ABNS board certification processes are designed to evaluate both real-life subspecialty neurosurgical practice and overall neurosurgical knowledge, since most neurosurgeons provide call coverage for hospitals and thus must be competent to care for the full spectrum of neurosurgery.The purpose of this report is to describe the history, current state, and anticipated future direction of ABNS certification in the US.

BACKGROUND Opioids are prescribed routinely after cranial surgery despite a paucity of evidence regarding the optimal quantity needed. Overprescribing may adversely contribute to opioid abuse, chronic use, and diversion. OBJECTIVE To evaluate the effectiveness of a system-wide campaign to reduce opioid prescribing excess while maintaining adequate analgesia. METHODS A retrospective cohort study of patients undergoing a craniotomy for tumor resection with home disposition before and after a 2-mo educational intervention was completed. The educational initiative was composed of directed didactic seminars targeting senior staff, residents, and advanced practice providers. Opioid prescribing patterns were then assessed for patients discharged before and after the intervention period. RESULTS A total of 203 patients were discharged home following a craniotomy for tumor resection during the study period: 98 who underwent surgery prior to the educational interventions compared to 105 patients treated post-intervention. Following a 2-mo educational period, the quantity of opioids prescribed decreased by 52% (median morphine milligram equivalent per day [interquartile range], 32.1 [16.1, 64.3] vs 15.4 [0, 32.9], P

BackgroundDistinct genome-wide methylation patterns have consistently clustered pituitary neuroendocrine tumors (PT) into molecular groups associated with specific clinicopathological features. Here we aim to identify, characterize and validate the methylation signatures that objectively classify PT into those molecular groups.MethodsCombining in-house and publicly available data, we conducted an analysis of the methylome profile of a comprehensive cohort of 177 tumor and 20 non-tumor specimens from the pituitary gland. We also retrieved methylome data from an independent pituitary tumor (PT) cohort (N=86) to validate our findings.ResultsWe identified three methylation clusters associated with functional status and adenohypophyseal cell lineages using an unsupervised approach. We also identified signatures based on differentially methylated CpG probes (DMP), some of which overlapped with pituitary-specific transcription factors genes (SF1 and Tpit), that significantly distinguished pairs of clusters related to functional status and adenohypophyseal cell lineage. These findings were reproduced in an independent cohort, validating these methylation signatures. The DMPs were mainly annotated in enhancer regions associated with pathways and genes involved in cell identity and tumorigenesis.ConclusionsWe identified and validated methylation signatures that distinguished PT by distinct functional status and adenohypophyseal cell lineages. These signatures, annotated in enhancer regions, indicate the importance of these elements in pituitary tumorigenesis. They also provide an unbiased approach to classify pituitary tumors according to the most recent classification recommended by the WHO 2017 using methylation profiling.Key-pointsDistinct methylation landscapes define PT groups with specific functional status/subtypes and adenohypophyseal lineages subtypes.Methylation abnormalities in each cluster mainly occur in CpG annotated in distal regions overlapping predicted enhancers regions associated with pathways and genes involved in cell identity and tumorigenesis.DNA methylation signatures provide an unbiased approach to classify PT.Importance of the studyThis study harnessed the largest methylome data to date from a comprehensive cohort of pituitary specimens obtained from four different institutions. We identified and validated methylation signatures that distinguished pituitary tumors into molecular groups that reflect the functionality and adenohypophyseal cell lineages of these tumors. These signatures, mainly located in enhancers, are associated with pathways and genes involved in cell identity and tumorigenesis. Our results show that methylome profiling provides an objective approach to classify PT according to the most recent classification of PT recommended by the 2017 WHO.

BACKGROUND: Several reports have indicated that distinct epigenomic patterns of pituitary tumors (PT), specifically DNA methylation, distinguish these tumor tissues according to their functionality and could be involved in their pathogenesis. Thus far, molecular diagnosis and classification criteria that guide clinical management of these tumors rely on the tissue profiling obtained by invasive surgical approaches (e.g. excision). However, increasing evidence confirmed that central nervous system (CNS) tumors release cell material into the circulation creating an opportunity for molecular profiling of these tumors using a blood-based liquid biopsy. Considering that 1) the pituitary portal system and the invasion of the cavernous system by PT may facilitate the spillage of tumor cell material into the bloodstream and 2) the stability, cell-specificity and reportedly the role of DNA methylation in PT, we hypothesized that liquid biopsy would be feasible to detect and define specific methylation-based signatures in the serum of patients harboring PT. Methods and Findings: We conducted analyses of the methylomes of paired serum circulating cell-free DNA (cfDNA) and tumor tissue from patients harboring PT (EPIC array) to identify serum-derived pituitary tumor-specific methylation-based signatures (sPTMet n=37) in a cohort comprised by 13 patients with pituitary macroadenomas (9 males; median age: 62; 9 Nonfunctioning/4functioning, 6 invasive/7noninvasive), 4 controls (non-tumor) and patients with other CNS tumors or conditions (114 gliomas, 6 meningiomas, 1 brain metastasis, 1 colloid cyst, 6 radiation necrosis). Unsupervised and supervised analysis indicated that the serum methylome from patients harboring PT was distinct from controls and other CNS diseases. Using the sPTMet as input into a machine learning algorithm, we generated a PT score that classified the serum of an independent cohort as PT or non-PT, with high accuracy. We identified serum-derived differentially methylated probes (DMP, n=3288) that distinguished PT according to their function (functioning and nonfunctioning). When overlapped with an independent cohort, these DMP also distinguished PT tissue according to their functional status. Conclusion: Our results showed the feasibility to identify PT-specific methylation signatures by profiling the methylome of serum cfDNA from patients with PT. These signatures distinguished PT from other CNS tumors and according to their subtypes. These results underpin the potential role of methylation profile and liquid biopsy as a noninvasive approach to assess clinically relevant molecular features. Potentially, tumor-specific serum-derived methylation signature may be used as a diagnostic, prognostic and surveillance tool as well to identify actionable molecular markers in patients with PT.

Author(s): Cloughesy, Timothy F; Landolfi, Joseph; Vogelbaum, Michael A; Ostertag, Derek; Elder, James B; Bloomfield, Stephen; Carter, Bob; Chen, Clark C; Kalkanis, Steven N; Kesari, Santosh; Lai, Albert; Lee, Ian Y; Liau, Linda M; Mikkelsen, Tom; Nghiemphu, Phioanh; Piccioni, David; Accomando, William; Diago, Oscar R; Hogan, Daniel J; Gammon, Dawn; Kasahara, Noriyuki; Kheoh, Thian; Jolly, Douglas J; Gruber, Harry E; Das, Asha; Walbert, Tobias | Abstract: Background:Vocimagene amiretrorepvec (Toca 511) is an investigational gamma-retroviral replicating vector encoding cytosine deaminase that, when used in combination with extended-release 5-fluorocytosine (Toca FC), results preclinically in local production of 5-fluorouracil, depletion of immune-suppressive myeloid cells, and subsequent induction of antitumor immunity. Recurrent high-grade glioma (rHGG) patients have a high unmet need for effective therapies that produce durable responses lasting more than 6 months. In this setting, relapse is nearly universal and most responses are transient. Methods:In this Toca 511 ascending-dose phase I trial (NCT01470794), HGG patients who recurred after standard of care underwent surgical resection and received Toca 511 injected into the resection cavity wall, followed by orally administered cycles of Toca FC. Results:Among 56 patients, durable complete responses were observed. A subgroup was identified based on Toca 511 dose and entry requirements for the follow-up phase III study. In this subgroup, which included both isocitrate dehydrogenase 1 (IDH1) mutant and wild-type tumors, the durable response rate is 21.7%. Median duration of follow-up for responders is 35.7+ months. As of August 25, 2017, all responders remain in response and are alive 33.9+ to 52.2+ months after Toca 511 administration, suggesting a positive association of durable response with overall survival. Conclusions:Multiyear durable responses have been observed in rHGG patients treated with Toca 511 + Toca FC in a phase I trial, and the treatment will be further evaluated in a randomized phase III trial. Among IDH1 mutant patients treated at first recurrence, there may be an enrichment of complete responders.

The goals of therapeutic and biomarker development form the foundation of clinical trial design, and change considerably from early-phase to late-phase trials. From these goals, decisions on specific clinical trial design elements, such as endpoint selection and statistical approaches, are formed. Whereas early-phase trials might focus on finding a therapeutic signal to make decisions on further development, late-phase trials focus on the confirmation of therapeutic impact by considering clinically meaningful endpoints. In this guideline from the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group, we highlight issues related to, and provide recommendations for, the design of clinical trials on local therapies for CNS metastases from solid tumours. We discuss endpoint selection criteria, the analysis appropriate for early-phase and late-phase trials, the association between tumour-specific and clinically meaningful endpoints, and possible issues related to the estimation of local control in the context of competing risks. In light of these discussions, we make specific recommendations on the clinical trial design of local therapies for brain metastases.

Background Vestibular schwannomas (VS) are uncommon lesions that are a substantial challenge to the neurosurgeons, otologists, and radiation oncologists who undertake their clinical management. A starting point to improving the current knowledge is to define the benchmarks of the current research studying VS management using evidence-based techniques in order to allow meaningful points of departure for future scientific and clinical research. Objective To establish the best evidence-based management of VS, including initial otologic evaluation, imaging diagnosis, use of surgical techniques, assessment of tumor pathology, and the administration of radiation therapy. Methods Multidisciplinary writing groups were identified to design questions, literature searches, and collection and classification of relevant findings. This information was then translated to recommendations based on the strength of the available literature. Results This guideline series yielded some level 2 recommendations and a greater number of level 3 recommendations directed at the management of VS. Importantly, in some cases, a number of well-designed questions and subsequent searches did not yield information that allowed creation of a meaningful and justifiable recommendation. Conclusion This series of guidelines was constructed to assess the most current and clinically relevant evidence for the management of VS. They set a benchmark regarding the current evidence base for this type of tumor while also highlighting important key areas for future basic and clinical research, particularly on those topics for which no recommendations could be formulated. The full guidelines can be found at: https://www.cns.org/guidelines/guidelines-management-patients-vestibular-schwannoma.

Background Novel methods in predicting survival in patients with spinal metastases may help guide clinical decision-making and stratify treatments regarding surgery vs palliative care. Objective To evaluate whether the frailty/sarcopenia paradigm is predictive of survival and morbidity in patients undergoing surgery for spinal metastasis. Methods A total of 271 patients from 4 tertiary care centers who had undergone surgery for spinal metastasis were identified. Frailty/sarcopenia was defined by psoas muscle size. Survival hazard ratios were calculated using multivariate analysis, with variables from demographic, functional, oncological, and surgical factors. Secondary outcomes included improvement of neurological function and postoperative morbidity. Results Patients in the smallest psoas tertile had shorter overall survival compared to the middle and largest tertile. Psoas size (PS) predicted overall mortality more strongly than Tokuhashi score, Tomita score, and Karnofsky Performance Status (KPS). PS predicted 90-d mortality more strongly than Tokuhashi score, Tomita score, and KPS. Patients with a larger PS were more likely to have an improvement in deficit compared to the middle tertile. PS was not predictive of 30-d morbidity. Conclusion In patients undergoing surgery for spine metastases, PS as a surrogate for frailty/sarcopenia predicts 90-d and overall mortality, independent of demographic, functional, oncological, and surgical characteristics. The frailty/sarcopenia paradigm is a stronger predictor of survival at these time points than other standards. PS can be used in clinical decision-making to select which patients with metastatic spine tumors are appropriate surgical candidates.

BACKGROUND Detection of distinct epigenetic features in circulating cell-free DNA (cfDNA) of liquid biopsy specimens (e.g. blood) provides an opportunity to diagnose and prognosticate central nervous system (CNS) tumors. Utilization of distinctive cell-type genome-wide DNA methylation patterns allows for development of machine-learning (ML) models with the ability to predict tumor diagnosis and prognosis, and remains widely unexplored in meningiomas using LB. METHODS We profiled the cfDNA methylome (EPIC array) in serum specimens from patients with meningiomas, other CNS tumors and nontumor conditions (n= 63, 190 and 18, respectively) and harnessed internal and external meningioma tissue methylome data. For diagnostic model development, we identified “meningioma specific” signatures through comparison of meningioma and non-meningioma serum specimens (Wilcoxon rank-sum test) which exhibited tissue methylation similarities named Meningioma- epigenetic Liquid Biopsy (MeLB), and were then employed to develop and cross-validate a Random-Forest derived “MeLB” score to discriminate meningiomas from the other conditions. To predict recurrence risk (RR), we classified a meningioma tissue cohort as ‘favorable’ or ‘unfavorable’ (low and high RR, respectively), using a validated ML outcome model and identified outcome-specific methylation markers with serum subgroup specificities used as input to train a Random-Forest to predict RR in serum-based specimens. RESULTS Prediction models based on meningioma-specific methylation markers detected in the serum presented a high accuracy in classification of samples as meningioma or not (Accuracy: 89.6%, Sensitivity: 80%, Specificity: 93.8%). The prognostic model using tissue-serum matching methylation markers was validated across an independent tissue-based cohort (Accuracy: 88%, Sensitivity: 86%, Specificity: 88%) and allowed for classification of serum samples according to RR. CONCLUSIONS Machine-learning models using DNA methylation markers identified in the serum can accurately diagnose and predict prognosis in patients with meningioma. After validation in an external cohort, these approaches may improve presurgical diagnosis and therapeutic management of patients with this type of tumor.

Surgical excision of brain tumors provides a means of cytoreduction and diagnosis while minimizing neurologic deficit and improving overall survival. Despite advances in functional and three-dimensional stereotactic navigation and intraoperative MRI, delineating tissue in real time with physiologic confirmation is challenging. Raman spectroscopy has potential to be an important modality in the intraoperative evaluation of tissue during surgical resection. In vitro experimental studies have shown that this technique can be used to differentiate normal brain tissue from tissue with infiltrating cancer cells and dense cancerous masses with high specificity, indicating the feasibility of this method for in vivo application.

// Shlomit Brodie 1 , Hae Kyung Lee 2 , Wei Jiang 2 , Simona Cazacu 2 , Cunli Xiang 2 , Laila M. Poisson 3 , Indrani Datta 3 , Steve Kalkanis 2 , Doron Ginsberg 1, * and Chaya Brodie 1, 2, * 1 Everard and Mina Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel 2 Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Department of Neurosurgery, Detroit, MI, USA 3 Department of Public Health Sciences, Center for Bioinformatics, Henry Ford Hospital, Detroit, MI, USA * These authors have contributed equally to this work Correspondence to: Chaya Brodie, email: chaya@brodienet.com Keywords: TALNEC2, long non-cording RNAs, glioblastoma, glioma stem cells, mesenchymal transformation Received: October 07, 2016 Accepted: February 06, 2017 Published: March 07, 2017 ABSTRACT Despite advances in novel therapeutic approaches for the treatment of glioblastoma (GBM), the median survival of 12-14 months has not changed significantly. Therefore, there is an imperative need to identify molecular mechanisms that play a role in patient survival. Here, we analyzed the expression and functions of a novel lncRNA, TALNEC2 that was identified using RNA seq of E2F1-regulated lncRNAs. TALNEC2 was localized to the cytosol and its expression was E2F1-regulated and cell-cycle dependent. TALNEC2 was highly expressed in GBM with poor prognosis, in GBM specimens derived from short-term survivors and in glioma cells and glioma stem cells (GSCs). Silencing of TALNEC2 inhibited cell proliferation and arrested the cells in the G1\S phase of the cell cycle in various cancer cell lines. In addition, silencing of TALNEC2 decreased the self-renewal and mesenchymal transformation of GSCs, increased sensitivity of these cells to radiation and prolonged survival of mice bearing GSC-derived xenografts. Using miRNA array analysis, we identified specific miRNAs that were altered in the silenced cells that were associated with cell-cycle progression, proliferation and mesenchymal transformation. Two of the downregulated miRNAs, miR-21 and miR-191, mediated some of TALNEC2 effects on the stemness and mesenchymal transformation of GSCs. In conclusion, we identified a novel E2F1-regulated lncRNA that is highly expressed in GBM and in tumors from patients of short-term survival. The expression of TALNEC2 is associated with the increased tumorigenic potential of GSCs and their resistance to radiation. We conclude that TALNEC2 is an attractive therapeutic target for the treatment of GBM.

ObjectiveWe aimed to characterize the socioeconomic impact of glioma for patients with clinical and radiographic evidence of disease stability, using the standardized Medical Expenditure Panel Survey–Household Component (MEPS-HC).MethodsThe MEPS-HC questionnaire was used to investigate the degree of economic hardship referable to the patient's brain tumor and treatment. The questionnaire included demographic variables such as age at diagnosis, ethnicity, highest level of education, and annual household income. Descriptive statistics were used to characterize variables and between-group comparisons were evaluated using Fisher exact test.ResultsOf 127 prescreened patients, 89 of 107 eligible patients completed the survey. Pathology at diagnosis was predominantly low grade (60%). Most patients were insured at time of diagnosis (91%), married (76%), and employed (79%), with annual household incomes slightly higher than the national average. Despite this, nearly a quarter incurred debt referable to brain tumor care (24%), 53% required extended unpaid time off, and 46% retired or were no longer working. Financial burden and workforce morbidity were insensitive to tumor location, laterality, and annual household income. Patients with gross total resection at initial surgery were less likely to report ongoing limitations in daily activities (45% vs 83%, p = 0.004).ConclusionsEven in a population of stable, high-functioning glioma survivors, financial burden and workforce morbidity was ubiquitous across all tumor subtypes, treatment paradigms, and income levels.

Pituitary tumors are the second most common CNS neoplasia (~15%). Despite mostly benign and slow-growing, they may be nonfunctioning and invade surrounding structures resulting in significant comorbidities. Currently, classification of PT according to their risk for aggressiveness is mainly based on invasiveness detected by imaging methods and histopathological features which requires surgically resected tumor. Being able to detect molecular markers associated with tumor subtypes and behavior pre-surgically using minimally invasive approaches (blood draw) is desirable in these tumors and may help to address current diagnostic and therapeutic challenges. In tissue specimens, distinct DNA methylation patterns distinguish PT according to their functional status but their role in invasiveness is still unclear. We hypothesized that profiling cell-free DNA (cfDNA) released by PT into the bloodstream allow the identification of epigenetic markers associated with relevant clinicopathological features. Genome-wide methylome profile of paired serum cfDNA (EPIC array) and tissue from 13 patients with pituitary macroadenomas (9 males; median age: 62; 9 Nonfunctioning/4 functioning, 6 invasive/7 noninvasive) and 3 controls serum (patients with epilepsy). Unsupervised analysis of the serum methylome from patients harboring PT was distinct from controls and other diseases (hypopituitarism, glioma and colorectal cancer) and supervised analysis (Wilcoxon Rank-sum Test) identified significant differentially methylated probes (DMP) that segregated PT from control serum specimens. Nonfunctioning and invasive-specific DMPs identified in the serum also defined functional, and less prominently invasive status, in the tissue of an independent cohort of PT. This is the first study to show the feasibility to profile the serum methylome from patients with PT using cfDNA. In addition, we identified unique methylation signatures that distinguished PT according to functional and invasiveness subtypes. These results underpin the potential role of methylation profile and liquid biopsy as a noninvasive approach to assess clinically relevant molecular features in the serum of patients harboring PT.

INTRODUCTION Neuro-oncologic conditions have dismal outcomes, ineffective treatments, poor access to clinical trials, and variability in care. Clinical trials do not capture a patient’s complete journey and are restricted to select populations. ‘Real-world-evidence’ (RWE) attempts to inform point of care decisions through routine collection of data with a clinical-trial-like rigor. RWE complements existing knowledge through broad patient participation, collection throughout disease course, and creation of large multidimensional datasets “knowledge network of disease” 1,2. RWE implementation is hindered by unstructured data, uncertainty of relevant features, and semantic heterogeneity. Clinical attributes were selected from trial inclusion criteria and prioritized for structuring in clinic notes for abstraction. METHOD We queried Clinicaltrials.gov from 1/1/2018-12/31/2018, refined to North America, recruiting, interventional, and adult. Meningioma, pituitary, glioblastoma, astrocytoma, oligodendroglioma, and ependymoma were chosen based on incidence3. Lymphoma and nerve sheath tumors were omitted. “Brain tumor” and “glioma” were added. ‘K-nearest-neighbor’ tokenization parsed inclusion criteria4. Document term matrix (n-gram) converted text to vectors5. A generative probabilistic model using ‘Latent Dirichlet Allocation’ plotted words into 10 clusters6. Hierarchal clustering was used to compare histology with terms. RESULTS 401 trials parsed into 3676 statements and 4008 keywords. 10 clusters of terms were similarly distributed amongst histologies, suggesting generalizability across tumor types. Cluster revealed 8 categories: 1) Time: enrollment; 2) Performance status: KPS; 3) Testing: mutations, upper limit of normal, routine hematologic laboratory assays; 4) Imaging: extent of surgery; 5) Pregnancy/childbearing; 6) Tumor grade; 7) Treatment history: recurrence, chemotherapy, radiation, time; 8) Informed consent CONCLUSIONS Dissecting the compendium of clinical trials using machine learning can identify general parameters for trial enrollment to guide RWE clinical collection. Using practical definitions of the most germane trial data, specific information can be sought after and defined to improve research quality, maximize research yields and improve patient care whilst minimizing wasted research and clinical endeavors.

Introduction of polymeric nanoparticles in cancer therapeutics is widely investigated since nanomedicine often enables the intratumoral delivery of drugs with increased efficacy with minimal side effects. In this study MRI monitoring was employed to study the therapeutic effect of nanocombretastatin (G3-CA4) in an orthotopic glioma model. Water insoluble combretastatin (CA4) was conjugated to a small-sized water soluble G3-succinamic acid PAMAM dendrimer. Nanoconstruct sizes were determined by TEM to be 3 to 5 nm. Intravenous (i.v.) delivery of G3-CA4 in an orthotopic glioma model produced a long-lived ischemia accompanied by necrosis at the core of the tumor but leaving a rim of viable tissue. In contrast, delivery of CA4 alone has no therapeutic effect in an experimental rat model of glioma.

This chapter explores the current consensus on the management and treatment of brain metastases and of leptomeningeal metastasis.

INTRODUCTION Glioblastoma (GBM) is uniformly associated with a poor prognosis and inevitable recurrence. Management of recurrent GBM remains unclear, with repeat surgery often employed with varying degrees of success. We evaluated the efficacy of Laser Interstitial Thermal Therapy (LITT) for recurrent GBM when compared to a carefully matched cohort of patients treated with repeat surgical resection. METHODS A retrospective single-institution database was used to identify patients who underwent LITT or surgical resection of recurrent GBM between 2014-2019. LITT patients were matched with surgical resection patients according to baseline demographics, comorbidities, tumor location, and eloquence. Subgroup analysis matching similar patients for tumor volume was also completed. Overall survival (OS) and progression-free survival (PFS) were the primary endpoints. RESULTS A LITT cohort of 20 patients was matched to 50 similar patients who underwent repeat surgical resection. Baseline characteristics were similar between both cohorts apart from tumor volume, which was larger in the surgical cohort (17.5 cc vs. 4.7 cc, p< 0.01). On long-term follow-up, there was no difference in OS (HR, 0.72; 95%CI, 0.36-1.45) or PFS (HR, 0.67; 95%CI, 0.29-1.53) between the LITT and surgical cohorts when controlling for tumor volume. Subgroup analysis of 23 LITT patients matched according to tumor volume with 23 surgical patients with similar clinical characteristics also found no difference in OS (HR, 0.66; 95%CI, 0.33-1.30) or PFS (HR, 0.58; 95%CI, 0.90-1.05) between the cohorts. LITT patients had shorter length of stays (1 vs. 4 days, p< 0.001) and a higher rate of home discharge (84% vs. 67%, p=0.172) compared to the surgical cohort. CONCLUSION After matching for demographic, clinical, and tumor characteristics, there was no difference in outcomes between patients undergoing LITT compared to surgical resection for recurrent GBM. LITT patients had similar survival outcomes yet shorter hospital stays and more favorable dispositions, potentially mitigating post-treatment complications.

Meningiomas are mostly benign CNS tumors however, a subset of these tumors may become atypical or malignant. The standard of care to monitor patients after diagnosis requires serial MRI assessments, which have limited value in distinguishing malignant tumors from benign disease. Therefore the discovery of non-invasive methodologies that reflect meningioma tumor burden and its dynamic evolution in real-time is highly desirable. Liquid biopsy (LB) could be used to fine-tune surveillance and treatment with minimal risk to patients. Evidence of circulating tumor cells and cell-free (cf) tumor DNA in the blood has been shown in several tumor types however, limited progress has been made for brain tumors with known biomarkers; possibly due to the unlikelihood of capturing point mutations in circulating DNA fragments. On the other hand, DNA methylation signatures are maintained even in small DNA fragments, which suggests that DNA methylation is an attractive biomarker to be studied in liquid biopsy of brain cancers. In order to identify DNA methylation-based biomarkers using archival serum and tissue specimens, we generated and analyzed the epigenome (Illumina Human EPIC array) of patients with meningioma (including primary (n=6); recurrent (n=8)) and non-meningioma (including non-tumor patients (n=5), pituitary tumor (n=13), colorectal cancer (n=2) and other CNS diseases (n=6), such as inflammatory tissue and radiation necrosis). cfDNA fragment size distribution revealed peaks with 150~200bp on average. By randomly selecting 70% of our cohort as a discovery set, we identified 500 CpGs (FDR Citation Format: Thais S. Sabedot, Tathiane M. Malta, Ruicong She, James Snyder, Tobias Walbert, Ian Lee, Steven Kalkanis, James Ewing, AnaValeria Castro, Houtan Noushmehr. Methylation-based liquid biopsy of meningioma primary and recurrent samples [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 781.

Background: Several reports have indicated that distinct epigenomic patterns of pituitary tumor (PT) tissue, specifically DNA methylation, distinguish these tumors according to their functionality and could be involved in their pathogenesis. Thus far, molecular diagnosis and classification systems that guide clinical management of these tumors rely on the tissue profiling obtained by invasive surgical approaches (e.g., excision). However, increasing evidence showed that CNS tumors release cell material into the circulation, despite the existence of the blood-brain barrier, creating an opportunity for molecular profiling using a liquid biopsy. Although the pituitary portal system and the invasion of the cavernous system by PT may facilitate the spillage of tumor cell material into the bloodstream, until now liquid biopsy has not been described in pituitary tumors. Considering the stability, the cell specificity, and the reported role of DNA methylation in PT, we investigated the feasibility to detect and define PT-specific methylation-based signatures in the serum of patients harboring these tumors. Methods and Findings: In order to identify PT-specific methylation-based signatures in the serum of patients with PT, we conducted unsupervised and supervised analysis of the methylome profile of paired serum cfDNA (EPIC array) and/or tissue from 13 patients with pituitary macroadenomas (9 males; median age: 62; 9 nonfunctioning/4 functioning, 6 invasive/7 noninvasive), 4 controls serum (nontumor and healthy), and patients with other CNS tumors or conditions (114 gliomas, 6 meningiomas, 1 brain metastasis, 1 colloid cyst, 6 radiation necrosis). Serum PT-tissue-specific methylation was also used as input into a machine learning algorithm to generate a PT score, which was tested in an independent cohort. Unsupervised and supervised analysis indicated that the serum methylome from patients harboring PT was distinct from controls and other CNS diseases. A generated PT score using the 37 identified PT tissue-specific methylation probes was able to distinguish serum from patients harboring PT from other CNS tumors. Serum-derived PT function-specific DMP also distinguished PT according to functional status. Serum-derived invasive-specific DMPs were less prominent to define invasive status in an independent cohort of PT, most probably due to the limited number of cases. Conclusion: This is the first study to show the feasibility of profiling methylome in the serum of patients with PT using cfDNA. In addition, we identified unique methylation signatures that distinguished PT from other CNS tumors and according to distinct PT subtypes. These results underpin the potential role of methylation profile and liquid biopsy as a noninvasive approach to assess clinically relevant molecular features that can be used as diagnostic, prognostic, and surveillance in patients with PT. Citation Format: Michael Wells, Karam Asmaro, Jack Rock, Thais Sabedot, Maritza Mosella, Tathiane Malta, Kevin Nelson, James Snyder, Steven Kalkanis, Ana Valeria Castro, Houtan Noushmehr. Serum cell-free DNA methylome-based signatures distinguish pituitary tumor from other neoplasias and by clinicopathologic features [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A11.

Genome-wide DNA-methylation profiling has shown that epigenetic abnormalities are biologically and clinically important signs in glioma and can be used to classify these tumors into distinct prognostic groups. Thus far, DNA methylation profiling of gliomas has required surgically resected tissue. Because gliomas release tumoral material into biofluids, such as blood, we developed a method using a liquid biopsy (LB) for minimally invasive surveillance of the tumor. We performed a genome-wide CpG methylation profile of cell-free DNA extracted from serum of patients with primary glioma (N=48) and during clinical follow-up (N=33). We used a supervised machine learning (ML) approach to identify glioma-specific epigenetic signatures in the LB (eLB) (N=1000, false-discovery rate < 0.003) to distinguish patients with glioma from those without glioma. The epigenetic profiles of matched tumor tissue showed that there was 67% concordance between the eLB signatures of the glioma in serum and tissue. Using these signatures as input for ML, we derived the glioma epigenetic liquid biopsy (GeLB) score. An independent validation study (68 gliomas and 65 nongliomas) showed that a GeLB score ≥ 50% could predict with 96% accuracy (sensitivity = 97.1% and specificity = 95.9%) whether a patient had glioma or not. Changes in GeLB score also reflected clinicopathologic changes observed during surveillance (e.g., progression, pseudoprogression, or response to a clinical trial drug). Our results suggest that the GeLB score could be used as a complementary approach to diagnose glioma and follow up patients postsurgically. Finally, we provide an online tool for predicting glioma based on the cell-free DNA methylome (hbtc.shinyapps.io/GeLB/). Citation Format: Thais Sabedot, Tathiane Malta, James Snyder, Kevin Nelson, Michael Wells, Ana deCarvalho, Abir Mukherjee, Dhan Chitale, Maritza Mosella, Karam Asmaro, Adam Robin, Mark Rosenblum, Tom Mikkelsen, Jack Rock, Laila Poisson, Ian Lee, Tobias Walbert, Steven Kalkanis, Ana Valeria Castro, Houtan Noushmehr. Glioma cell-free DNA methylation marker for diagnosis and monitoring [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A10.

Meningiomas are mostly benign CNS tumors; however, a subset of these tumors may become atypical or malignant. The standard of care to monitor patients after diagnosis requires serial MRI assessments, which have limited value in distinguishing malignant tumors from benign disease. Therefore, the discovery of noninvasive methodologies that reflect meningioma tumor burden and its dynamic evolution in real-time is highly desirable. Liquid biopsy (LB) could be used to fine-tune surveillance and treatment with minimal risk to patients. Evidence of circulating tumor cells and cell-free (cf) tumor DNA in the blood has been shown in several tumor types; however, limited progress has been made for brain tumors with known biomarkers, possibly due to the unlikelihood of capturing point mutations in circulating DNA fragments. On the other hand, DNA methylation signatures are maintained even in small DNA fragments, which suggests that DNA methylation is an attractive marker to be studied in liquid biopsy of brain cancers. In order to identify DNA methylation-based biomarkers, we used archival serum and matching tissue specimens from primary (n=10) and recurrent (n=4) meningiomas. From isolated cfDNA from meningiomas and epileptic patients (n=5) as a control, we generated epigenetic data using Illumina Human EPIC array. cfDNA fragment size distribution revealed peaks with 150~200bp on average. We identified 482 CpGs (FDR Citation Format: Thais S. Sabedot, Tathiane M. Malta, James Snyder, Tobias Walbert, Ian Lee, Steven Kalkanis, Ana Valeria Castro, Houtan Noushmehr. DNA methylation-based liquid biopsy detects primary and recurrent meningioma [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A12.

Toca 511 (vocimagene amiretrorepvec) is a cancer selective, retroviral replicating vector encoding a codon optimized, heat stabilized cytosine deaminase that converts Toca FC (extended-release 5- fluorocytosine, 5-FC) into the anticancer agent 5-fluorouracil. Preclinical evidence demonstrates that the Toca 511 & Toca FC regimen kills cancer cells and immunosuppressive myeloid cells in the tumor microenvironment, leading to durable antitumor immune responses that can be adoptively transferred to untreated animals. In an ascending dose trial (NCT01470794) in patients with recurrent high grade glioma (rHGG), Toca 511 was injected into the resection cavity walls at the time of resection, and then multiple courses of oral Toca FC were administered. Multiyear durable and complete responses by independent radiology review have been reported. Human immune monitoring results support an immunologic mechanism of action and identify potential biomarkers related to patient outcomes. Measurements included the quantification of peripheral blood and tumor infiltrating leukocyte subsets by flow cytometry, immunohistochemistry, and deconvolution of DNA and RNA sequencing data. In addition, systemic cytokine levels were assessed in peripheral blood serum by multiplex digital ELISA. Univariate comparisons and multivariate models revealed immunologic trends associated with patient outcomes. Pre-treatment tumor infiltrating cell subsets, quantified via deconvolution of RNA sequencing data, were associated with both objective responses and survival. Subsequent exploratory models applied to selected patient data indicate that a combined biomarker using mRNA signatures from multiple leukocyte subsets may predict patient outcomes with high sensitivity and selectivity. In addition, post-treatment serum cytokine time-course results suggest that differences and temporal modulations are associated with both objective response and survival. These results support an immune-related mechanism of action for the Toca 511 & Toca FC regimen. Potentially predictive and/or prognostic biomarkers of patient outcomes will be evaluated in the ongoing randomized Phase 3 Toca 5 trial in patients with rHGG (NCT02414165).