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Mild intracranial hypotension can lead to classically recognizable symptoms such as positional headaches, nausea, vomiting, and occasionally blurred vision. Less commonly, severe cerebrospinal fluid (CSF) hypovolemia can lead to a life-threatening condition that mimics intracranial hypertension, including transtentorial herniation and subsequent rapid neurologic decline. In this report we present a unique case of severe intracranial hypotension from a thoracic tumor resection that led to symptoms initially mistaken for intracranial hypertension, however ultimately correctly diagnosed as severe CSF hypovolemia that improved with dural repair. Additionally, we describe a rare angiography finding associated with CSF hypovolemia, kinking of the basilar artery. Here we report a 47-year-old female with neurofibromatosis Type 2 found to have a T3 intradural extramedullary tumor. She initially presented with urinary incontinence and gait/balance difficulty. She underwent thoracic laminectomies at T3 and T4 for the excision of the lesion. She was discharged on postoperative day 4. On postoperative day 9, she was noted to have nausea, vomiting, and decreased consciousness. Head computed tomography (CT) demonstrated acute downward herniation. She was transferred to our institution from a community facility obtunded and was intubated for airway protection. She was placed in the Trendelenburg position with immediate improvement, and declined every time her head was raised. Angiogram showed significant kinking of her basilar artery. A CT myelogram revealed a CSF leak from her recent thoracic surgery. She underwent exploration of her thoracic wound, and a ventral durotomy was repaired. Following this, she began to tolerate the head of bed elevations and recovered back to her neurologic baseline. A postoperative head CT angiography obtained before discharge showed improvement of her basilar kink. Mild intracranial hypotension is a common finding in patients who undergo procedures that enter the CSF space. Severe intracranial hypotension can easily be missed diagnosed as the signs on the exam are similar to patients with signs of intracranial hypertension. It is of paramount importance that the clinician recognizes brain sag, as the treatment algorithms are vastly different from that of intracranial hypertension leading to transtentorial herniation.

OBJECTIVEHyperostosing sphenoid wing meningiomas cause bony hyperostosis that may extend into the orbit, resulting in proptosis, restriction of extraocular movements, and/or compressive optic neuropathy. The extent of bony removal necessary and the optimal reconstruction strategy to prevent enophthalmos is debated. Herein, the authors present their surgical outcomes and reconstruction results.METHODSThis is a retrospective review of 54 consecutive patients undergoing resection of sphenoid wing meningiomas associated with bony hyperostosis. The majority of cases were operated on by the senior author. Extent of tumor resection, volumetric bone resection, radiographic exophthalmos index, complications, and recurrence were analyzed.RESULTSThe median age of the cohort was 52.1 years, with women comprising 83% of patients. Proptosis was a presenting symptom in 74%, and 52% had decreased visual acuity. The WHO grade was I (85%) or II (15%). The median follow-up was 2.6 years. On volumetric analysis, a median 86% of hyperostotic bone was resected. Gross-total resection of the intracranial tumor was achieved in 43% and the orbital tumor in 27%, and of all intracranial and orbital components in 20%. Orbital reconstruction was performed in 96% of patients. Postoperative vision was stable or improved in 98% of patients and diplopia improved in 89%. Postoperative complications occurred in 44% of patients, and 26% of patients underwent additional surgery for complication management. The most frequent complications were medical complications and extraocular movement deficits. The median preoperative exophthalmos index was 1.26, which improved to 1.12 immediately postoperatively and to 1.09 at the 6-month follow-up (p < 0.001). Postoperatively, 18 patients (33%) underwent adjuvant radiotherapy after subtotal resection. Tumors recurred/progressed in 12 patients (22%).CONCLUSIONSResection of hyperostosing sphenoid wing meningiomas, particularly achieving gross-total resection of hyperostotic bone with a good aesthetic result, is challenging and associated with notable medical and ocular morbidity. Recurrence rates in this series are higher than previously reported. Nevertheless, the authors were able to attain improvement in proptosis and visual symptoms in the majority of patients by using a multidisciplinary approach.

Lumbar pneumorrhachis following head injury is rare and commonly asymptomatic but can be indicative of skull fracture and cerebrospinal fluid (CSF) leak, which may warrant intervention. A PubMed review of the literature was performed using a keyword search to identify cases examining lumbar pneumorrhachis following head injury. Our case series included two patients who had lumbar pneumorrhachis between September 2019 and May 2020 at our center. The literature review summarizes 16 patients from 14 prior reports of pneumorrhachis. In our two-patient case series, neither patient required direct intervention for either pneumorrhachis or CSF leak. Pneumorrhachis is rare following an isolated head injury and is associated with basilar skull fractures and CSF leak. Pneumorrhachis should alert clinicians to the possibility of a CSF leak, which may require intervention.

Introduction Meningiomas are more common in females and frequently express progesterone and estrogen receptors. Recent studies have revealed a high incidence of meningiomas in situations in which estrogen/progesterone levels are increased such as pregnancy, gender reassignment therapy, and fertility treatment. While the relationship remains unclear and controversial, these findings suggest exposure to high levels of endogenous or exogenous hormones may increase the risk of developing a meningioma. Patients and Methods A 40-year-old female with a history of endometriosis treated with chronic progesterone therapy presented with a visual deficit and was found to have multiple meningiomas, which regressed after cessation of exogenous progesterone. Conclusion A history of chronic hormone therapy should be included when evaluating patients diagnosed with meningiomas, particularly at a younger age and with multiple meningiomas. Cessation of exogenous progesterone resulting in regression of meningiomas suggests a direct action of progesterone on growth. Future studies are warranted to better elucidate this relationship.

Metastases from cells outside of the central nervous system are the most common cancer found in the brain and are commonly associated with poor prognosis. Although cancer treatment is improving overall, central nervous system metastases are becoming more prevalent and require finesse to properly treat. Physicians must consider the biology of the primary tumor and the complex neurological environment that the metastasis resides in. This can be further complicated by the fact that the practice of cancer management is constantly evolving and therapy that works outside of the blood-brain barrier may not be effective inside of it. Therefore, this review seeks to update the reader on recent advancements made on the three most common sources of brain metastases: lung cancer, breast cancer, and melanoma. Each of these malignancies has been the subject of intriguing and novel avenues of therapy which are reviewed here.

PURPOSE: Meningiomas are more common in females and 70–80% express the progesterone receptor, raising the possibility that high-dose exogenous estrogen/progesterone exposure, such as occurs during fertility treatments, may increase the risk of developing a meningioma. The goal of this study was to report the incidence of prior fertility treatment in a consecutive series of female meningioma patients. METHODS: A retrospective review (2015–2018) was performed of female patients with meningioma, and those with prior fertility treatment were compared to those without fertility treatment using standard statistical methods. RESULTS: Of 206 female patients with meningioma, 26 (12.6%) had a history of fertility treatments. Patients underwent various forms of assisted reproductive technology including: in vitro fertilization (50.0%), clomiphene with or without intrauterine insemination (34.6%), and unspecified (19.2%). Median follow up was 1.8 years. Tumors were WHO grade I (78.6%) or grade II (21.4%). Patients who underwent fertility treatments presented at significantly younger mean age compared to those who had not (51.8 vs 57.3 yrs, p = 0.0135, 2-tailed T-test), and on multivariate analysis were more likely to have multiple meningiomas (OR: 4.97, 95% CI: 1.4–18.1, p = 0.0154) and convexity/falx meningiomas (OR: 4.45, 95% CI: 1.7–11.5, p = 0.0021). CONCLUSIONS: Patients in this cohort with a history of fertility treatment were more likely to present at a younger age and have multiple and convexity/falx meningiomas, emphasizing the importance of taking estrogen/progesterone exposure history when evaluating patients with meningioma. Future clinical studies at other centers in larger populations and laboratory investigations are needed to determine the role of fertility treatment in meningioma development.

BACKGROUND The female predominance of meningiomas may reflect a hormonal influence on tumorigenesis. Obesity alters steroid synthesis and chronically exposes men to hyperestrogenemia. OBJECTIVE Identify differences in males undergoing craniotomy for meningioma compared to other tumors or aneurysms. METHODS The National Surgical Quality Improvement Program was retrospectively queried from 2013–2018 for cases of craniotomy for resection of meningioma, other tumor, and aneurysm by CPT code in male patients and confirmed with postoperative ICD-10 code. Height and weight data were used to create body mass index (BMI): underweight (< 18.5), normal (18.5 to< 25), overweight (25 to< 30), class I obesity (30 to< 35), class II obesity (35 to< 40), and class III obesity (40+). RESULTS We identified 2,458 males who underwent craniotomy for meningioma, 9,889 for other tumor, and 386 for aneurysm. Using multivariable logistic regression, age (OR 1.01 per year, 95% CI 1.01-1.01, p< 0.001), diabetes mellitus (OR 1.32, 95% CI 1.17–1.48, p< 0.001), and increasing BMI (overweight: OR 1.55, 95% CI 1.36–1.76, p< 0.001; class I: OR 2.00, 95% CI 1.75–2.30, p< 0.0001; class II: OR 2.05, 95% CI 1.24–1.76, p< 0.001; class III: OR 1.47, 95% CI 1.24–1.76, p< 0.0001) were significantly and independently associated with craniotomy for meningioma compared to other tumor or aneurysm. For other tumor, higher BMI was associated with lower likelihood (overweight: OR 0.70, 95% CI 0.62–0.79, p< 0.001; class I: OR 0.55, 95% CI 0.49–0.63, p< 0.001; class II: OR 0.52, 95% CI 0.44–0.62, p< 0.001; class III: OR 0.74, 95% CI 0.63–0.87, p< 0.001). For aneurysm, there was no significant difference (overweight p=0.70; class I p=0.65; class II p=0.76; class III p=0.57). CONCLUSIONS BMI independently predicts having craniotomy for meningioma when compared to other tumor or aneurysm amongst US male patients.

BACKGROUND The female predominance of meningiomas may reflect hormonal influences on meningioma development, with known presence of estrogen and progesterone receptors. Progestin-associated meningiomas demonstrate a shift in the mutational landscape and are more frequently located at the skull base. Obesity and increased adipocytes increase aromatase and affect male hormone synthesis, thus increases circulating estrogen. OBJECTIVE Report prevalence of obesity in a consecutive series of male patients presenting with meningioma and the interaction with obesity. METHODS A retrospective review (20012019) was performed of male patients diagnosed with meningioma. Body mass index (BMI) >30 kg/m2 was considered obese. Obese male meningioma patients were characterized and compared to nonobese male meningioma patients. RESULTS Of 239 male patients with meningioma, 97 (40.6%) were obese at the time of surgery with overall mean BMI (30.0 kg/m2). This is above the age-adjusted baseline prevalence of obesity for males in Oregon, which was 34.8% between 2015–2016. Mean age at diagnosis for obese males was 55.3 years and 57.0 years for nonobese males. Within the obese group, most lesions were located on the skull base (48.5% n=47) compared to 34.0% convexity (n=33), 15.4% falx (n=16) and 1.0% multiple (n=1). Tumors were WHO grade I (73.6%), grade II (25.6%) or grade III (1.2%). Of the men in our series, patients with skull base meningiomas were more likely to be obese (OR: 1.7, 95% CI: 1.01–2.9, p=0.0309). CONCLUSIONS There is likely a hormonal influence on the pathogenesis of meningioma, and many men diagnosed with this disease are obese. Of 239 male patients with meningioma in our series, 97 (40.6%) were obese which exceeds the 34% age-adjusted baseline prevalence of obesity for males in Oregon. Patients with skull base meningiomas were more likely to be obese, consistent with prior series and suggestive of a hormone-driven association with skull base meningioma.

BackgroundResection may be appropriate for select patients with recurrent glioblastoma. The incidence of histopathological findings related to prior treatment and their prognostic implications are incompletely characterized.ObjectiveTo quantify the incidence and survival outcomes associated with treatment effect at resection of recurrent glioblastoma (GBM).MethodsPatients who underwent resection for recurrent GBM were retrospectively reviewed, and pathology, treatment history, and survival data were collected. Treatment effect was defined as any component of treatment-related changes on pathology.ResultsIn total, 110 patients underwent 146 reoperations. Median age at first reoperation was 57.2 yr and overall survival from reoperation was 10.8 mo. Treatment effect of any kind was noted in 81 of 146 reoperations (55%). Increased treatment effect was observed closer to radiotherapy; by quartile of time from radiotherapy, the rates of treatment effect were 77.8%, 55.6%, 40.7%, and 44.4% (P=.028). Treatment effect was associated with earlier reoperation (8.9 vs 13.8 mo after radiotherapy, P=.003), and the presence of treatment effect did not impact survival from primary surgery (25.4 vs 24.3 mo, P=.084). Patients treated with bevacizumab prior to reoperation were less likely to have treatment effect (20% vs 65%, P&nbsp

Objectives Foramen magnum meningiomas (FMM) are complex lesions because of their proximity to the brain stem and posterior cerebrovasculature. The objective of this study is to report surgical outcomes and complications after resection of FMM. Methods A retrospective chart review was conducted on patients with FMM from 1998 to 2015. Univariate logistic regression and recursive partitioning analysis were used to identify risk factors associated with complications and extent of resection (EOR). Results We identified 28 patients with FMM. Median follow-up was 5.9 years. Tumors were World Health Organization grade I (92.9%) or grade II (7.1%). The vertebral artery was completely encased (25%), partially encased (11%), or not encased (64%). Median size was 11.9 cm3. EOR was gross total (39%) and subtotal (61%). The observed recurrence rate was 4% (n = 1). There were 38 complications in 12 patients (43%), and 6 patients (21%) had complications requiring additional surgery. Complications included cerebrospinal fluid leak/hydrocephalus (n = 7, 25%), weakness (n = 4, 14%), numbness (n = 4, 14%), and cranial nerve deficits: IX, X (n = 4, 14%), XI (n = 2, 7%), XII (n = 5, 18%). Medical complications included pneumonia (n = 1, 4%) and meningitis (n = 1, 4%). Tumor volume greater than 14 cm3 (odds ratio [OR] = 21.7, p = 0.0010), any vertebral artery encasement (OR 6.1, p = 0.0386), and subtotal resection (OR 6.4, p = 0.0398) were significantly associated with complications. Tumor volume greater than 14 cm3 was also significantly associated with subtotal resection (OR 8.3, p = 0.0201). Conclusions Resection of FMM carries perioperative morbidity that increases with larger tumor size. Despite the morbidity, long-term recurrence-free survival is achievable with maximal safe resection and adjuvant radiation.

BACKGROUND We have identified an HLA-A*02:01-restricted neoantigen epitope encompassing the H3.3K27M mutation and implemented a multi-center clinical trial of the peptide vaccine through the Pacific Pediatric Neuro-Oncology Consortium (PNOC007) for patients with diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG). We sought to characterize vaccine-reactive CD8+T-cells subpopulations using their precise activation and developmental status to find their associations with clinical outcomes. METHODS Mass cytometry (CyTOF) analysis was performed on patient-derived peripheral blood mononuclear cells collected at baseline as well as pre-specified time points throughout the study. Each cell subtype was characterized via tSNE-clustering based on their expression profiles and quantified as a fraction of total CD45+cells. H3.3K27M-reactive CD8+T-cells were evaluated using an H3.3K27M-HLA-A2 dextramer along with a panel of T-cell and myeloid markers. RESULTS Among all 29 patients enrolled, we analyzed samples from all 19 DIPG and 9 of 10 non-brainstem DMG cases, of which 18 had longitudinal samples available (range: 2–5). Utilizing a novel CyTOF-based immuno-monitoring platform, the expansion of H3.3K27M-reactive CD8+T-cells, defined as a 25% increase at any time-point relative to baseline, was observed in 7 of these 18 patients. Survival analyses indicated that the expansion of H3.3K27M-reactive CD8+T-cells, particularly the effector-memory phenotype, positively correlated with longer overall survival (OS) (median: 16.1 vs 9.7 months, p=0.03), whereas an abundance of early and monocytic myeloid-derived suppressor cells at baseline correlated with shorter OS among DIPG patients (9.5 vs 14.3 months, p=0.002). CONCLUSION Our novel immuno-monitoring approach offers insight into how vaccine-induced immune responses impact clinical outcomes.

Diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG) constitutes up to 20% of pediatric brain cancer and has a median survival of less than one year. The ongoing development of immunotherapy has shown significant promise in many fields, including that of gliomas. Genetic studies have revealed that greater than 70% of DIPG cases harbor an amino acid substitution from lysine (K) to methionine (M) at position 27 of histone 3 variant 3 (H3.3). We have previously identified novel HLA-A*02:01-restricted neoantigen epitope encompassing the H3.3K27M mutation. Accordingly, we have implemented a clinical trial through the Pacific Pediatric Neuro-Oncology Consortium (PNOC). Newly diagnosed DIPG patients who are HLA-A2+ and H3.3K27M+ underwent radiation therapy, and then received the H3.3K27M peptide vaccine, combined with the tetanus toxoid (TT) peptide, emulsified in Montanide. The TLR3 agonist, Poly-ICLC, was given concurrently to improve therapeutic effects of the vaccine. Our objective is to characterize vaccine-induced H3.3K27M-specific T cells from peripheral blood at several time points of the study through the evaluation of a large number of analytes utilizing a novel H3.3K27M-specific dextramer-based mass cytometry method. The specificity of the H3.3K27M-specific dextramer was validated through significant binding to H3.3K27M TCR-transduced CD8 T cells and lack of non-specific binding. Subsequently, patient-derived PBMC samples were analyzed using this methodology, revealing a time course-dependent, progressive expansion of CD45RA+ effector memory cells with an inverse downregulation of CD45RO+ in H3.3K27M-specific CD8 T cells. Additionally, progressive upregulation of HLA-DR was observed in several myeloid-derived populations through the course of the trial. Future plans include the longitudinal quantification of IFN-γ and TNF-α expression as a response to the H3.3K27M peptide vaccine at each time point. The development of this methodology may greatly aid in the comprehensive evaluation of immunotherapeutic outcomes on the cellular basis.

OBJECTIVE: Meningiomas are more common in females and 70–80% express the progesterone receptor. They have been reported after gender reassignment therapy, suggesting that high-dose exogenous estrogen/progesterone exposure, such as occurs during fertility treatments, may increase the risk of developing a meningioma. The goal of this study was to report the incidence of prior fertility treatment in a consecutive series of female patients presenting with meningioma. METHODS: A retrospective review of patients presenting with meningioma from 2015–2018 was conducted. Female patients with prior fertility treatments were compared to those who did not receive fertility treatment using standard statistical methods. RESULTS: Of 206 female patients with meningioma, 26 (12.6%) had a history of fertility treatments. Patients underwent various forms of assisted reproductive technology including: in vitro fertilization (50.0%), clomiphene with or without intrauterine insemination (34.6%), and unspecified (3.8%). One patient (3.8%) received supplemental progesterone during her treatment. The most common presenting symptoms were incidental (57.7%) and headache (26.9%). Median follow up was 1.8 years. Tumors were WHO grade I (78.6%) or grade II (21.4%). Patients who underwent fertility treatments presented at significantly younger mean age compared to those who had not (51.8 vs 57.3 yrs, p = 0.0135, 2-tailed T-test) and were more likely to have multifocal (OR: 4.5, 95% CI: 1.4–14.8, p = 0.0196) and non-skull base meningiomas (OR: 4.4, 95% CI: 1.7–11.4, p = 0.0012). CONCLUSIONS: A history of fertility treatment is common in female patients presenting with meningioma. Patients with meningioma and a history of fertility treatment were more likely to present at a younger age and have multifocal and non-skull base tumors. These findings stress the importance of assessing for prior estrogen/progesterone exposure in patients presenting with meningioma. Future large prospective series and laboratory investigations are needed to determine the impact of fertility treatment on meningioma development.

OBJECTIVE: Meningiomas are the most common primary central nervous system tumor, and patients typically live for many years after diagnosis and treatment. Traditionally, patient outcomes are recorded from a clinician’s standpoint, including extent of resection, surgical/radiation complications, progression-free survival, and tumor recurrence. Outcomes from this standpoint will underestimate the impact of disease and treatment on a patient’s quality of life. Thus, we have started a multi-institutional prospective study to assess the quality of life in patients with meningioma. METHODS: A quality of life instrument (QoL-MNG) was developed using questions from the Functional Assessment of Cancer Treatment-Meningioma (FACT-MNG) tumor site specific instrument on a web-based platform. A pre-operative baseline questionnaire is collected for all patients. Subsequently, patients are assigned to treatment (surgery or radiation) or observation groups. All patients complete a baseline questionnaire. The treatment group completes questionnaires at 3-, 6-, 12-, 18-month, and then annually following surgery or radiation. The observation group completes annual questionnaires. Clinical outcomes data are collected at each time point. RESULTS: To date, 55 patients from a single-institution are actively enrolled and have completed baseline questionnaires in the QoL-MNG study using the online-based interface. Approval for the study has been obtained at 18 other sites. We will present patient level data from our first 14 patients who have completed follow up questionnaires. This includes outcomes in physical well-being, social/family well-being, emotional well-being, functional well-being and tumor site specific questions in the following tumor locations: cerebellopontine angle, parasagittal, petroclival, sphenoid wing, and convexity. CONCLUSIONS: Assessing quality of life is fundamental to improving care for patients with meningioma. These are the first preliminary results of our prospective study which we have expanded to eighteen institutions across North America and Europe with the goal of improving our understanding the impact of meningioma on quality of life.

OBJECTIVE: Extracranial meningioma metastases are rare, and patients with meningiomas are not routinely screened for systemic metastases. We report our experience with meningioma metastases and screening for metastases in select patients with recurrent meningiomas. METHODS: All patients undergoing surgical resection or stereotactic radiosurgery for primary or recurrent meningioma from 2009 to 2017 at a single center were retrospectively reviewed. Indications for metastasis screening were patients with recurrent meningioma after 2 prior resections and radiation therapy or symptoms concerning for metastasis. Screening was performed with CT chest/abdomen/pelvis, FDG PET-CT, or somatostatin receptor specific (DOTATATE) PET-CT. RESULTS: Of 1203 patients treated, 929 (77.2%) had WHO grade 1 meningioma by surgical pathology or imaging, 234 (19.5%) had grade 2 and 35 (2.9%) had grade 3 meningioma. A total of 298 meningiomas (24.8%) recurred, with a mean of 1.6 recurrences per patient. Screening for metastases was performed in 28 patients; one (3.6%) had a grade 1 tumor, 16 (57.1%) were grade 2, and 11 (39.3%) were grade 3. Five patients (17.9%) were screened because of systemic symptoms. Of the patients screened, 27 (96.4%) had recurrent meningioma, with a mean 3.2 recurrences. Ten patients (35.7%) had suspicious extracranial lesions by imaging. On biopsy, 8 were meningioma metastases, 1 was a non-meningioma malignancy, and 1 was lost to follow-up. Biopsy-confirmed metastases occurred in: liver (5), lung (3), mediastinum (1) and bone (1). The overall incidence of metastases was 0.67% (n=8). Incidence increased to 2% of WHO grade II tumors and 8.6% of grade 3. Using our indications, the number needed to screen to identify one patient with biopsy-confirmed malignancy was 3.1. CONCLUSIONS: Screening of patients with multiply recurrent meningioma or symptoms concerning for metastasis may identify extracranial metastases in a significant proportion of patients and can inform decision making for additional treatments.

OBJECTIVEExtracranial meningioma metastases are uncommon, occurring in less than 1% of patients diagnosed with meningioma. Due to the rarity of meningioma metastases, patients are not routinely screened for distant disease. In this series, we report their experience with meningioma metastases and results of screening for metastases in select patients with recurrent meningiomas.METHODSAll patients undergoing resection or stereotactic radiosurgery for primary or recurrent meningioma from 2009 to 2017 at a single center were retrospectively reviewed to identify patients who were diagnosed with or underwent imaging to evaluate for systemic metastases. Imaging to evaluate for metastases was performed with CT scanning of the chest, abdomen, and pelvis or whole-body PET/CT using either FDG or 68Ga-DOTA-octreotate (DOTATATE) tracers in 28 patients. Indications for imaging were symptomatic lesions concerning for metastasis or asymptomatic screening in patients with greater than 2 recurrences being evaluated for additional treatment.RESULTSOf 1193 patients treated for meningioma, 922 (77.3%) patients had confirmed or presumed WHO grade I tumors, 236 (19.8%) had grade II tumors, and 35 (2.9%) had grade III tumors. Mean follow-up was 4.3 years. A total of 207 patients experienced recurrences (17.4%), with a mean of 1.8 recurrences. Imaging for metastases was performed in 28 patients; 1 metastasis was grade I (3.6%), 16 were grade II (57.1%), and 11 were grade III (39.3%). Five patients (17.9%) underwent imaging because of symptomatic lesions. Of the 28 patients screened, 27 patients had prior recurrent meningioma (96.4%), with a median of 3 recurrences. On imaging, 10 patients had extracranial lesions suspicious for metastasis (35.7%). At biopsy, 8 were meningioma metastases, 1 was a nonmeningioma malignancy, and 1 patient was lost to follow-up prior to biopsy. Biopsy-confirmed metastases occurred in the liver (5), lung (3), mediastinum (1), and bone (1). The observed incidence of metastases was 0.67% (n = 8). Incidence increased to 2% of WHO grade II and 8.6% of grade III meningiomas. Using the proposed indications for screening, the number needed to screen to identify one patient with biopsy-confirmed malignancy was 3.83.CONCLUSIONSSystemic imaging of patients with multiply recurrent meningioma or symptoms concerning for metastasis may identify extracranial metastases in a significant proportion of patients and can inform decision making for additional treatments.

BACKGROUND: Diffuse Intrinsic Pontine Glioma (DIPG) are rare and aggressive childhood tumors, with an abysmal prognosis and limited experimental models available for study. A recent report showed that DIPG are hypoperfused compared to surrounding brain tissue, suggesting that the tumor cells are exposed to a hypoxic microenvironment. This stimulus may induce widespread transcriptional changes through activation of Hypoxia-inducible Factors (HIF), which have been associated with invasion, metastasis, angiogenesis, and resistance to radiation therapy and chemotherapy. Therefore, in vitro models using DIPG cells cultured in conditions of normal oxygen tension may not be representative of in vivo tumors because of artificial differences in HIF activation. METHODS: To test cellular responses to hypoxia, human DIPG cell lines with H3.1 K27M and H3.3 K27M mutations were treated with the hypoxia-mimetic compound, cobalt (II) chloride, for 24 hours. Simulated hypoxic responses were assayed using Western blot analysis, proliferation assays, and extracellular flux analysis. RESULTS: The H3.3 K27M cell line increased expression of HIF1a with cobalt (II) chloride treatment and correlated with an increase in glycolytic rates and increased expression of proteins involved in glucose transport and glycolysis. The H3.1 K27M cell line increased expression of HIF2a and not HIF1a after cobalt (II) chloride treatment, correlating with an increase in some glycolysis-associated proteins but no change in glycolytic rate. CONCLUSION: These data suggest that the effects of a hypoxic microenvironment should be considered in experimental models using cultured DIPG cell lines to understand differences in cell behavior, patient prognosis, and predicted treatment responses. Activation of specific HIF isoforms may underlie differences in hypoxic responses among cell lines.

Diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG) constitutes up to 20% of pediatric brain cancer and has a median survival of less than one year. We have identified a novel HLA-A*02:01-restricted neoantigen epitope encompassing the H3.3K27M mutation and implemented a pilot clinical trial through the Pacific Pediatric Neuro-Oncology Consortium (PNOC007). Newly diagnosed DIPG patients who are HLA-A2+ and H3.3K27M+ underwent radiation therapy, and then received the H3.3K27M peptide vaccine and tetanus toxoid (TT) peptide emulsified in Montanide in combination with poly-ICLC every 3 weeks for a total of 24 weeks. Our objective is to characterize vaccine-induced H3.3K27M-specific T-cell subpopulations in peripheral blood mononuclear cells through the evaluation of surface markers correlated with activation, memory, and exhaustion phenotypes utilizing a novel H3.3K27M-specific dextramer-based mass cytometry method. Through this approach, the temporal expansion of vaccine-reactive CD8+ T-cells was observed in all of patients (n = 4) who completed a minimum of 18 weeks on the study. These T-cells were subsequently stratified into discrete clusters on a tSNE plot using canonical CD8+ T-cell markers. Resultant clusters were further classified by their expression profiles, revealing distinct effector memory and exhausted subpopulations. Chronological monitoring of these groups indicates the time course-dependent development and persistence of vaccine-reactive exhausted and effector memory CD8+ T-cells in 75% of patients analyzed. Furthermore, a comparative analysis of myeloid subpopulations revealed an inverse correlation between the expansion of monocytic myeloid-derived suppressor cells (M-MDSCs) and length of enrollment in the trial. Future plans include the analysis of regulatory T-cells (Tregs) and MDSCs of all enrolled patients to solidify the relationship between the length of stay on the study and prevalence of immunosuppressive populations. This methodology offers insight into the progression of vaccine-induced patient immune responses and exhibits promise as a platform that may be extrapolated to other immunotherapies.

Heterogeneous expression of target antigens can allow tumor escape from chimeric antigen receptor-transduced T-cell (CART) therapy targeting a single antigen. While epidermal growth factor receptor (EGFR)vIII represents a glioblastoma (GBM)-specific antigen, its expression is heterogeneous within the tumor. On the other hand, most other antigens expressed more uniformly in GBMs are non-mutated, glioma-associated antigens (GAAs), such as EphA2. Although these GAAs are not expressed in the normal brain, they are expressed at low levels in other normal organs. As a way to safely target GAAs in the tumor without attacking normal cells expressing the same GAAs outside of the brain, we adapted a novel synthetic Notch (synNotch) receptor system, and established a “prime and kill” sequential two-receptor CAR circuit: the first is a transcriptional CAR against EGFRvIII, and the second is a CAR against a GAA (e.g. EphA2). When the first CAR binds to EGFRvIII, it induces the expression of the second CAR. While the first CAR does not trigger the cytotoxic function itself, the second CAR mediates the cytotoxicity upon recognition of the target GAA. We have validated this system in vitro using the mixture of U87 GBM cells and those transduced with EGFRvIII. SynNotch CART effectively lysed both EGFRvIII+ and EGFRvIII-negative U87 cells when they are mixed, but never lysed EGFRvIII-negative cells in the absence of EGFRvIII+ cells. In immunocompromised mice bearing intracranial U87-EGFRvIII+/- tumors, intravenous infusion of synNotch CART resulted in long-term (over 60 days) survival and eradication of the heterogenous tumor in 5 of 8 mice. Furthermore, when mice also bear subcutaneous, EGFRvIII-negative U87 tumors along with the intracranial U87-EGFRvIII+/- tumors, synNotch CART did not affect the subcutaneous tumor, indicating the local but not systemic effects of synNotch CART. These data provide a strong basis for developing synNotch CART therapy for GBM.