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Patients with glioblastoma (GBM) need bold new approaches to their treatment, yet progress has been hindered by a relative inability to dynamically track treatment response, mechanisms of resistance, evolution of targetable mutations, and changes in mutational burden. We are writing on behalf of a multidisciplinary group of academic neuro-oncology professionals who met at the collaborative Christopher Davidson Forum at Washington University in St Louis in the fall of 2019. We propose a dramatic but necessary change to the routine management of patients with GBM to advance the field: to routinely biopsy recurrent GBM at the time of presumed recurrence. Data derived from these samples will identify true recurrence vs treatment effect, avoid treatments with little chance of success, enable clinical trial access, and aid in the scientific advancement of our understanding of GBM.

The therapeutic promise of oncolytic viruses (OVs) rests on their ability to both selectively kill tumor cells and induce anti-tumor immunity. The potential of tumors to be recognized and eliminated by an effective anti-tumor immune response has been spurred on by the discovery that immune checkpoint inhibition can overcome tumor-specific cytotoxic T cell (CTL) exhaustion and provide durable responses in multiple tumor indications. OV-mediated tumor destruction is now recognized as a powerful means to assist in the development of anti-tumor immunity for two important reasons: (i) OVs, through the elicitation of an anti-viral response and the production of type I interferon, are potent stimulators of inflammation and can be armed with transgenes to further enhance anti-tumor immune responses, and (ii) lytic activity can promote the release of tumor-associated antigens (TAAs) and tumor neoantigens that function as in situ tumor-specific vaccines to elicit adaptive immunity. Oncolytic herpes simplex viruses (oHSVs) are among the most widely studied OVs for the treatment of solid malignancies, and Amgen's oHSV Imlygic® for the treatment of melanoma is the only OV approved in major markets. Here we describe important biological features of HSV that make it an attractive OV, clinical experience with HSV-based vectors, and strategies to increase applicability to cancer treatment.

It has now been nearly 15 years since the last major advance in the treatment of patients with glioma. "The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity". Autophagy is primarily a survival pathway, literally self-eating, that is utilized in response to stress (such as radiation and chemotherapy), enabling clearance of effete protein aggregates and multimolecular assemblies. Promising results have been observed in patients with glioma for over a decade now when autophagy inhibition with chloroquine derivatives coupled with conventional therapy. The application of autophagy inhibitors, the role of immune cell-induced autophagy, and the potential role of novel cellular and gene therapies, should now be considered for development as part of this well-established regimen.

Glioma is one of the most common primary malignant tumors of the central nervous system accounting for approximately 40% of all intracranial tumors. Temozolomide is a conventional chemotherapy drug for adjuvant treatment of patients with high-risk gliomas, including grade II to grade IV. Our bioinformatic analysis of The Cancer Genome Atlas and Chinese Glioma Genome Atlas datasets and immunoblotting assay show that SLC12A2 gene and its encoded Na+-K+-2Cl− cotransporter isoform 1 (NKCC1) protein are abundantly expressed in grade II–IV gliomas. NKCC1 regulates cell volume and intracellular Cl− concentration, which promotes glioma cell migration, resistance to temozolomide, and tumor-related epilepsy in experimental glioma models. Using mouse syngeneic glioma models with intracranial transplantation of two different glioma cell lines (GL26 and SB28), we show that NKCC1 protein in glioma tumor cells as well as in tumor-associated reactive astrocytes was significantly upregulated in response to temozolomide monotherapy. Combination therapy of temozolomide with the potent NKCC1 inhibitor bumetanide reduced tumor proliferation, potentiated the cytotoxic effects of temozolomide, decreased tumor-associated reactive astrogliosis, and restored astrocytic GLT-1 and GLAST glutamate transporter expression. The combinatorial therapy also led to suppressed tumor growth and prolonged survival of mice bearing GL26 glioma cells. Taken together, these results demonstrate that NKCC1 protein plays multifaceted roles in the pathogenesis of glioma tumors and presents as a therapeutic target for reducing temozolomide-mediated resistance and tumor-associated astrogliosis.

The use of mutant strains of oncolytic herpes simplex virus (oHSV) in early-phase human clinical trials for the treatment of glioblastoma multiforme (GBM) has proven safe, but limited efficacy suggests that more potent vector designs are required for effective GBM therapy. Inadequate vector performance may derive from poor intratumoral vector replication and limited spread to uninfected cells. Vector replication may be impaired by mutagenesis strategies to achieve vector safety, and intratumoral virus spread may be hampered by vector entrapment in the tumor-specific extracellular matrix (ECM) that in GBM is composed primarily of type IV collagen. In this report, we armed our previously described epidermal growth factor receptor (EGFR)vIII-targeted, neuronal microRNA-sensitive oHSV with a matrix metalloproteinase (MMP9) to improve intratumoral vector distribution. We show that vector-expressed MMP9 enhanced therapeutic efficacy and long-term animal survival in a GBM xenograft model. Keywords: matrix metalloproteinase 9 = MMP9, extracellular matrix = ECM, Oncolytic vectors = OVs, Glioblastoma multiforme = GBM, OVs derived from herpes simplex virus = oHSV

Background Fluorescein is an agent that accumulates in areas of blood-brain barrier breakdown and is commonly used in neurosurgical oncology to assist with lesion localization and visualizing the extent of resection. It is considered to be cost-effective and has a favorable safety profile. Studies on the utilization of fluorescein demonstrate an improved extent of tumor resection and increased overall survival. Currently, fluorescein detection systems are all microscope based, leading to limitations such as decreased maneuverability, limited visualization of the entire operative field, and significant cost associated with obtaining and maintaining a neurosurgical operating microscope. Methods Three consecutive craniotomy patients for tumor resection were included, and surgery was carried out under loupe fluorescence guidance using the ReVeal 450 System, and also a surgical microscope for comparison. Results Loupe-mounted fluorescence system enabled excellent visualization of fluorescence in all three cases. Conclusions In this manuscript, we describe our experience with a loupe-mounted fluorescein detection system in 3 patients with malignant gliomas. We found that the loupe-mounted system offered excellent ability to visualize fluorescein fluorescence. Although loupe-mounted systems are not an alternative to surgical microscopes, they could be a useful surgical adjunct for superficial lesions and in low-middle income counties.

Although KIT-mutant GISTs can be effectively treated with tyrosine kinase inhibitors (TKIs), many patients develop resistance to imatinib mesylate (IM) as well as the FDA-approved later-line agents sunitinib, regorafenib and ripretinib. Resistance mechanisms mainly involve secondary mutations in the KIT receptor tyrosine kinase gene indicating continued dependency on the KIT signaling pathway. The fact that the type of secondary mutation confers either sensitivity or resistance towards TKIs and the notion that secondary mutations exhibit intra- and intertumoral heterogeneity complicates the optimal choice of treatment in the imatinib-resistant setting. Therefore, new strategies that target KIT independently of its underlying mutations are urgently needed. Homoharringtonine (HHT) is a first-in-class inhibitor of protein biosynthesis and is FDA-approved for the treatment of chronic myeloid leukemia (CML) that is resistant to at least two TKIs. HHT has also shown activity in KIT-mutant mastocytosis models, which are intrinsically resistant to imatinib and most other TKIs. We hypothesized that HHT could be effective in GIST through downregulation of KIT expression and subsequent decrease of KIT activation and downstream signaling. Testing several GIST cell line models, HHT led to a significant reduction in nascent protein synthesis and was highly effective in the nanomolar range in IM-sensitive and IM-resistant GIST cell lines. HHT treatment resulted in a rapid and complete abolishment of KIT expression and activation, while KIT mRNA levels were minimally affected. The response to HHT involved induction of apoptosis as well as cell cycle arrest. The antitumor activity of HHT was confirmed in a GIST xenograft model. Taken together, inhibition of protein biosynthesis is a promising strategy to overcome TKI resistance in GIST.

Over the past decade, the use of induced pluripotent stem cells (IPSCs), as both direct therapeutics and building blocks for 3D in vitro models, has exhibited exciting potential in both helping to elucidate pathogenic mechanisms and treating diseases relevant to neurosurgery. Transplantation of IPSCs is being studied in neurological injuries and diseases, such as spinal cord injury and Parkinson's disease, whose clinical manifestations stem from underlying neuronal and/or axonal degeneration. Both animal models and clinical trials have shown that IPSCs have the ability to regenerate damaged neural tissue. Such evidence makes IPSCs a potentially promising therapeutic modality for patients who suffer from these neurological injuries/diseases. In addition, the cerebral organoid, a 3D assembly of IPSC aggregates that develops heterogeneous brain regions, has become the first in vitro model to closely recapitulate the complexity of the brain extracellular matrix, a 3-dimensional network of molecules that structurally and biochemically support neighboring cells. Cerebral organoids have become an exciting prospect for modeling and testing drug susceptibility of brain tumors, such as glioblastoma and metastatic brain cancer. As patient-derived organoid models are becoming more faithful to the brain, they are becoming an increasingly accurate substitute for patient clinical trials; such patient-less trials would protect the patient from potentially ineffective drugs, and speed up trial results and optimize cost. In this review, we aim to describe the role of IPSCs and cerebral organoids in treating and modeling diseases that are relevant to neurosurgery.

Purpose/Objective(s) Brain metastasis is a frequent cause of morbidity and mortality in stage IV cancer patients. Efforts to treat brain metastasis include surgical resection, whole brain radiation treatment (WBRT), and stereotactic radiosurgery (SRS). In contemporary times, SRS is deployed utilizing conformal, high dose radiation with rapid dose fall off to limit neurocognitive toxicity seen with WBRT. In the combined modality setting wherein surgical resection is required, post-operative SRS is utilized with excellent local control. However, several difficulties may arise from treatment in the post-operative setting. Changes to the tumor bed necessitating increased margin for uncertainty, increased treatment normal brain tissue, treatment in a hypoxic field may portend for less-than-ideal treatment. Therefore, pre-operative SRS is being explored due to potentially better-defined target, less target uncertainty, and reports of less radionecrosis and less leptomeningeal disease. Therefore, our group conducted a phase II clinical trial exploring the efficacy of the preoperative SRS approach in regard to local brain control, distant brain control, and overall survival. Materials/Methods A phase II institutional non-randomized clinical trial was initiated at UPMC Hillman Cancer Center enrolling patients with brain metastasis of any malignant histology. Lymphoma, leukemia, multiple myeloma, or germ cell tumors were excluded due to their radiosensitive nature. Patients were to receive SRS followed by surgical resection. Inclusion criteria included ≥18yo, KPS≥50 with a life expectancy of 12 weeks. Patients could have no more than four lesions measuring 1.5-4.0cm in size. Patients that had tumors Results A total of 24 patients were enrolled on study. One patient was deemed unresectable due to risk to the peri- rolandic location. Median number of brain metastasis treated was one (range 1-3). The most common treated histology was non-small cell lung carcinoma (NSCLC) (9). Median days from consult to SRS was 3.9 days. Median SRS dose and fraction was 16.5Gy [range: 15-24Gy] in a single fraction. The median number of surveillance MRIs performed was 6 [range 1-17]. Local brain control was 90%, 90%, and 74% at 6, 12, and 24 months. Distant brain control at 6, 12, and 24 months was 66%, 60%, and 54% respectively. Progression free survival (PFS) and overall survival (OS) at 6, 12, and 24 months were as followed [46%, 38%, 29%] and [66%, 58%, 50%] respectively. Conclusion Preoperative stereotactic radiosurgery appears to have excellent local control with a 6- and 12-month local control rates of 90%. Further study is warranted in the continued exploration of preoperative radiation therapy.

Background We and others have identified mutually exclusive molecular subgroups of meningiomas; however, the implications of this classification for clinical prognostication remain unclear. Integrated genomic and epigenomic analyses implicate unique oncogenic processes associated with each subgroup, suggesting the potential for divergent clinical courses. The aim of this study was to understand the associated clinical outcomes of each subgroup, as this could optimize treatment for patients. Methods We analyzed outcome data for 469 meningiomas of known molecular subgroup, including extent of resection, postoperative radiation, surveillance imaging, and time to recurrence, when applicable. Statistical relationships between outcome variables and subgroup were assessed. Features previously associated with recurrence were further investigated after stratification by subgroup. We used Kaplan–Meier analyses to compare progression-free survival, and identified factors significantly associated with recurrence using Cox proportional hazards modeling. Results Meningioma molecular subgroups exhibited divergent clinical courses at 2 years of follow-up, with several aggressive subgroups (NF2, PI3K, HH, tumor necrosis factor receptor–associated factor 7 [TRAF7]) recurring at an average rate of 22 times higher than others (KLF4, POLR2A, SMARCB1). PI3K-activated tumors recurred earlier than other subgroups but had intermediate long-term outcome. Among low-grade tumors, HH and TRAF7 meningiomas exhibited elevated recurrence compared with other subgroups. Recurrence of NF2 tumors was associated with male sex, high grade, and elevated Ki-67. Multivariate analysis identified molecular subgroup as an independent predictor of recurrence, along with grade and previous recurrence. Conclusion We describe distinct clinical outcomes and recurrence rates associated with meningioma molecular subgroups. Our findings emphasize the importance of genomic characterization to guide postoperative management decisions for meningiomas.

Background: Leptomeningeal disease (LMD) from melanoma is rapidly fatal with median overall survival between 6.9 weeks and 3.5 months. It is not known whether immune checkpoint inhibitors have a role in treating LMD. Case presentation: We report a 33-year-old male patient who developed LMD from a BRAF V600E-mutated melanoma brain metastasis, despite prior treatment with surgical resection, radiotherapy and dabrafenib/trametinib. He underwent whole brain radiotherapy with stereotactic radiotherapy to the lumbosacral spine, and was started on nivolumab, which led to prolonged remission lasting 2 years and 3 months, before disease progression and death. Conclusion: This is the first case report to highlight a potential long-term efficacy of radiotherapy and anti-PD-1 immunotherapy, in treating LMD from metastatic melanoma that is resistant to targeted therapy.

OBJECTIVEAkin to the nonoperative management of benign intracranial tumors, stereotactic body radiation therapy (SBRT) has emerged as a nonoperative treatment option for noninfiltrative primary spine tumors such as meningioma and schwannoma. The majority of initial series used higher doses of 16–24 Gy in 1–3 fractions. The authors hypothesized that lower doses (such as 12–13 Gy in 1 fraction) might provide an efficacy similar to that found with the dose de-escalation commonly used for intracranial radiosurgery to treat acoustic neuroma or meningioma and with a lower risk of toxicity.METHODSThe authors identified 38 patients in a prospectively maintained institutional radiosurgery database who were treated with definitive SBRT for a total of 47 benign primary spine tumors between 2004 and 2016. SBRT consisted of 9–21 Gy in 1–3 fractions using the CyberKnife (n = 11 [23%]), Synergy S (n = 21 [45%]), or TrueBeam (n = 15 [32%]) radiosurgery platform. For a comparison of SBRT doses, patients were dichotomized into 1 of 2 groups (low-dose or high-dose SBRT) using a cutoff biologically effective dose (BED10Gy) of 30 Gy. Tumor control was calculated from the date of SBRT to the last follow-up using Kaplan-Meier survival analysis, with comparisons between groups completed using a log-rank method. To account for potential indication bias, a propensity score analysis was completed based on the conditional probabilities of SBRT dose selection. Toxicity was graded using Common Terminology Criteria for Adverse Events version 4.0 with a focus on grade 3+ toxicity and the incidence of pain flare.RESULTSFor the 38 patients, the most common histological findings were meningioma (15 patients), schwannoma (13 patients), and hemangioblastoma (7 patients). The median age at SBRT was 58 years (range 25–91 years). The 47 treated lesions were located in the cervical (n = 18), thoracic (n = 19), or lumbosacral (n = 10) spine. Five (11%) lesions were lost to follow-up after SBRT. The median follow-up duration for the remaining 42 lesions was 54 months (range 1.2–133 months). Six (16%) patients (with a total of 8 lesions) experienced pain flare after SBRT; no significant predictor of pain flare was identified. No grade 3+ acute- or late-onset complication was noted. The 5-year local control rate was 76% (95% CI 61%–91%). No significant difference in local control according to dose, fractionation, previous radiation, surgery, tumor histology, age, treatment platform, planning target volume, or spine level treated was found. The 5-year local control rates for low- and high-dose treatments were 73% (95% CI 53%–93%) and 83% (95% CI 61%–100%) (p = 0.52). In propensity score–adjusted multivariable analysis, no difference in local control was identified (HR 0.30, 95% CI 0.02–5.40; p = 0.41).CONCLUSIONSLong-term follow-up of patients treated with SBRT for benign spinal lesions revealed no significant difference between low-dose (BED10Gy ≤ 30) and high-dose SBRT in local control, pain-flare rate, or long-term toxicity.

OBJECTIVERecent large-cohort sequencing studies have investigated the genomic landscape of meningiomas, identifying somatic coding alterations in NF2, SMARCB1, SMARCE1, TRAF7, KLF4, POLR2A, BAP1, and members of the PI3K and Hedgehog signaling pathways. Initial associations between clinical features and genomic subgroups have been described, including location, grade, and histology. However, further investigation using an expanded collection of samples is needed to confirm previous findings, as well as elucidate relationships not evident in smaller discovery cohorts.METHODSTargeted sequencing of established meningioma driver genes was performed on a multiinstitution cohort of 3016 meningiomas for classification into mutually exclusive subgroups. Relevant clinical information was collected for all available cases and correlated with genomic subgroup. Nominal variables were analyzed using Fisher’s exact tests, while ordinal and continuous variables were assessed using Kruskal-Wallis and 1-way ANOVA tests, respectively. Machine-learning approaches were used to predict genomic subgroup based on noninvasive clinical features.RESULTSGenomic subgroups were strongly associated with tumor locations, including correlation of HH tumors with midline location, and non-NF2 tumors in anterior skull base regions. NF2 meningiomas were significantly enriched in male patients, while KLF4 and POLR2A mutations were associated with female sex. Among histologies, the results confirmed previously identified relationships, and observed enrichment of microcystic features among “mutation unknown” samples. Additionally, KLF4-mutant meningiomas were associated with larger peritumoral brain edema, while SMARCB1 cases exhibited elevated Ki-67 index. Machine-learning methods revealed that observable, noninvasive patient features were largely predictive of each tumor’s underlying driver mutation.CONCLUSIONSUsing a rigorous and comprehensive approach, this study expands previously described correlations between genomic drivers and clinical features, enhancing our understanding of meningioma pathogenesis, and laying further groundwork for the use of targeted therapies. Importantly, the authors found that noninvasive patient variables exhibited a moderate predictive value of underlying genomic subgroup, which could improve with additional training data. With continued development, this framework may enable selection of appropriate precision medications without the need for invasive sampling procedures.

In recent years, health care has been increasingly delivered by interprofessional teams in the inpatient, outpatient, and transition-of-care arenas. For many reasons, effective communication between patient-centered care teams and patients is critically important in order to optimize care, ensure patient safety, and prevent medical and medication misadventures. In rapid-paced, high-stress medical environments, it is especially important to carefully evaluate the causes of all misadventures in a manner that avoids assigning blame and identifies the root causes and, through team activity, leads to development of remedies that reduce the likelihood of future misadventures. Using a series of illustrative cases, this paper seeks to bring attention to these issues and provide insights regarding some tools developed to assist in improving patient safety and effective team communication.

BACKGROUND CAN-2409 is a replication-deficient adenovirus that delivers HSV thymidine kinase to cancer cells, resulting in local conversion of orally administered valacyclovir into a toxic metabolite. Previously, a phase 1b/2 clinical trial of CAN-2409 combined with standard-of-care (SOC) demonstrated safety and improved survival in HGG patients. Addition of CAN-2409 to nivolumab has the potential to activate locally recruited lymphocytes and teach them to recognize tumor neoantigens, changing the ‘cold’ immunosuppressive tumor microenvironment, and synergizing with the activity mediated by immune checkpoint inhibitors. This notion is supported by preclinical experiments showing that the combination of CAN-2409 with anti-PD1 therapy was more effective than either treatment alone. METHODS This ongoing phase 1 clinical trial evaluates safety and initial efficacy of CAN-2409 combined with nivolumab and SOC in newly diagnosed HGG. CAN-2409 is injected during neurosurgery into the tumor bed, followed by 14-days of valacyclovir. Radiation starts within 8 (+/-4) days of surgery. Temozolomide is administered to MGMT-methylation positive patients only. Nivolumab is given every 2 weeks, up to 52-weeks. Deep immune profiling studies are ongoing and initial results will be available shortly. RESULTS From February 2019 to March 2021, 41 patients were enrolled and 35 were evaluable for safety from the combination of CAN-2409, nivolumab and SOC: 24 male and 11 female; 34 glioblastoma, 1 diffuse astrocytoma; 33 IDH-wildtype, 2 IDH-mutant; 15 MGMT-methylated, 20 unmethylated. Median age was 62-years (range 28-79), median KPS 90 (range 80-100). With 13 months median follow-up, no unexpected serious adverse events were observed, and 23 patients are still alive. The most frequent possibly related adverse events (>10%) were nausea, fatigue, fever, headache, and increased ALT. CONCLUSIONS The combination of CAN-2409 + nivolumab + SOC was well tolerated. Clinical follow-up and extensive biomarker analyses will provide a better understanding of the therapeutic potential of this approach.

Up to 80% of meningiomas are classified as clinically low-grade, however, a subset of these ‘benign’ cases will ultimately recur and require additional treatment. The role of molecular subgroup in meningioma recurrence has not been thoroughly investigated, despite correlations of this variable with other clinical features. Indeed, epigenetic and transcriptional evidence supports involvement of distinct oncogenic processes within each subgroup, and as shown in other brain tumors, this may result in divergent clinical courses. In the present study, we classified 429 meningiomas into six established molecular subgroups based on genomic driver, and investigated associations of each subgroup with tumor recurrence. At two years of follow-up, we observed differences in progression free survival curves among relatively aggressive (NF2-loss, PI3K-activated, Hedgehog-activated) and quiescent (KLF4-mutant, SMARCB1-mutant, POLR2A-mutant) subgroups (log rank p = 4.3 x 10-2), with the former group recurring at a rate 14x higher. We found PI3K-activated meningiomas recurred significantly earlier than other subgroups (average time to recurrence of 19.2 months; p = 2.2 x 10-2), though we observed an intermediate long-term outcome relative to the Hedgehog and NF2 lesions. Overall, Hedgehog tumors recurred significantly more frequently than other low-grade meningiomas (adj. p = 3.1 x 10-2), and this subgroup was found to be an independent predictor of progression free survival using cox proportional hazards modelling (HR = 3.1; p = 2.4 x 10-2). By contrast, the aggressiveness of NF2 meningiomas was found to depend upon gender, WHO grade, and elevated Ki-67 index, and this subgroup was not an independent prognostic predictor. Our results suggest molecular subgroup is predictive of recurrence in low-grade meningiomas, and thus is an important consideration in post-operative management decisions. Routine genotyping to detect Hedgehog and PI3K mutant lesions may identify patients that would benefit from closer follow-up and consideration of adjuvant therapies.

High-grade gliomas (HGGs) are the most common and deadliest of malignant primary brain tumors. Additionally, brain and central nervous system tumors are the leading cause of cancer-related morbidity and mortality in infants and children. Tumors, including HGGs, co-opt immune checkpoint molecules to evade T-cell killing, and targeting these pathways has led to cures in some patients with cancers. Immunotherapy trials, including the use of checkpoint blockade therapies, have been conducted with limited success in brain tumor patients. Our analysis of data from The Cancer Genome Atlas identified that of over 30 assessed checkpoint molecules, only expression of the genes coding for PD1 and TIGIT, within the tumor, were associated with shorter overall survival and progression-free survival times. Furthermore, using published pediatric glioma resources, we found that TIGIT expression is elevated in pediatric HGGs compared with lower-grade pediatric gliomas, and TIGIT expression was inversely associated with overall survival in children with HGGs. These data led us to hypothesize that glioma-associated T-cells express PD-1 and TIGIT, which can be targeted to reduce glioma growth. To test this, we assessed whether mono/combination therapies with anti-PD-1 and anti-TIGIT could improve survival and immune function in a syngeneic orthotopic GL261 glioma mouse model. Although anti-TIGIT therapy alone failed to prolong survival, mice treated with both anti-PD1 and anti-TIGIT demonstrated improved survival compared with mice receiving anti-PD1 alone. Immunologic analysis of tumor-infiltrating cells in our mouse model revealed high expression levels of PVR, the TIGIT ligand, on cells resembling myeloid-derived suppressor cells (MDSCs), within the tumor. Additionally, TIGIT treatment led to the reduction of a subset of T-regulatory cells and cells resembling MDSCs. Overall, our data suggest that anti-TIGIT may reduce immunosuppressive cells at the tumor site and improve the efficacy of anti-PD1 trials in adults and children with HGGs.

As treatment regimens for primary cancer improve, patients are surviving longer and experiencing increased incidence of spinal column metastases. After the lungs and the liver, the skeletal system is the third most common site for metastases (Witham et al, Nat Clin Pract Neurol 2(2):87–94, 2006), with breast, lung, and prostate cancer accounting for greater than 50% of tumor origin sites (Metastatic Spinal Cord Compression: Diagnosis and Management of Patients at Risk of or with Metastatic Spinal Cord Compression. NICE Clinical Guidelines, No. 75. National Collaborating Centre for Cancer (UK). Cardiff (UK), 2008). The typical symptoms of spinal column metastases are pain, mechanical instability, and neurologic deficits. Surgical management of such lesions often requires circumferential decompression with instrumented fixation, followed by adjuvant radiation therapy to the affected levels.

OBJECTIVES/SPECIFIC AIMS: Gliomas are the most lethal and common primary tumor type in the central nervous system across all age groups; affected adults have a life expectancy of just 14 months. As glioma cells invade the surrounding normal parenchyma they remodel the composition and ultrastructure of the surrounding extracellular matrix (ECM), suggesting that the native (i.e., “normal”) microenvironment is not ideal for their survival and proliferation. Recent reports describe suppressive and/or lethal effects of mammalian ECM hydrogels derived from normal (nonneoplastic) sources upon various cancer types. ECM-based bioscaffolds placed at sites of neoplastic tissue resection in humans have never been reported to facilitate cancer recurrence. The objective of the present research is to evaluate mammalian ECM as a novel approach to glioma therapy. METHODS/STUDY POPULATION: ECM hydrogels from porcine dermis, small intestine, and urinary bladder were produced as described previously. Primary glioma cells were graciously supplied by Drs. Nduka Amankulor and Johnathan Engh, and U-87 MG were ordered through ATCC. Cells were plated onto tissue culture plastic at ~60% confluence and allowed to attach for 24 hours before treatment. The saline-soluble fraction (SSF) of ECM was obtained by mixing lyophilized, comminuted ECM with 0.9% saline for 24 hours then filtering the resulting mixture through a 10 kDa molecular weight cutoff column. All assays and kits were followed according to the manufacturer’s instructions. Cell viability was measured via MTT assay (Vybrant® MTT Cell Proliferation Assay, Invitrogen) and by live/dead staining (LIVE/DEAD® Cell Imaging Kit, Invitrogen). Time lapse videos were created by taking images every 20 minutes for 18 hours (phase-contrast) or every 10 minutes for 12 hours (darkfield). NucView reagent was ordered from Biotium. Temozolomide was ordered through Abmole. All in vivo work was conducted according to protocols approved by the University of Pittsburgh’s IACUC office. RESULTS/ANTICIPATED RESULTS: ECM hydrogels derived from porcine dermis, small intestine, or urinary bladder all decreased the viability of primary glioma cells in vitro, with urinary bladder extracellular matrix (UBM) having the most dramatic effects. The SSF of UBM (UBM-SSF), devoid of the fibrillar, macromolecular components of ECM, was sufficient to recapitulate this detrimental effect upon neoplastic cells in vitro and was used for the remainder of the experiments described herein. In a cell viability assay normalized to the media treatment, non-neoplastic CHME5 and N1E-115 cells scored 103% and 114% after 48 hours when treated with UBM-SSF and 2 primary high-grade glioma cell types scored 17% and 30.5% with UBM-SSF (n=2). Phase-contrast time-lapse video showed CHME5 and HFF thriving in the presence of UBM-SSF for 18 hours while most primary glioma cells shriveled and died within this time. Darkfield time-lapse video of wells containing Nucview dye, fluorescent upon cleavage by active caspase-3, confirmed that within 12 hours most primary glioma cells underwent apoptosis while CHME5 and HFF did not. In culture with primary astrocytes, high grade primary glioma cells, and U-87 MG glioma cells for 24 hours, UBM-SSF was found to significantly increase the population of primary astrocytes compared with media (ppp

Purpose: WHO grade 2 low-grade gliomas (LGG) with high risk factors for recurrence are mostly lethal despite current treatments. We conducted a phase I study to evaluate the safety and immunogenicity of subcutaneous vaccinations with synthetic peptides for glioma-associated antigen (GAA) epitopes in HLA-A2+ adults with high-risk LGGs in the following three cohorts: (i) patients without prior progression, chemotherapy, or radiotherapy (RT); (ii) patients without prior progression or chemotherapy but with prior RT; and (iii) recurrent patients. Experimental Design: GAAs were IL13Rα2, EphA2, WT1, and Survivin. Synthetic peptides were emulsified in Montanide-ISA-51 and given every 3 weeks for eight courses with intramuscular injections of poly-ICLC, followed by q12 week booster vaccines. Results: Cohorts 1, 2, and 3 enrolled 12, 1, and 10 patients, respectively. No regimen-limiting toxicity was encountered except for one case with grade 3 fever, fatigue, and mood disturbance (cohort 1). ELISPOT assays demonstrated robust IFNγ responses against at least three of the four GAA epitopes in 10 and 4 cases of cohorts 1 and 3, respectively. Cohort 1 patients demonstrated significantly higher IFNγ responses than cohort 3 patients. Median progression-free survival (PFS) periods since the first vaccine are 17 months in cohort 1 (range, 10–47+) and 12 months in cohort 3 (range, 3–41+). The only patient with large astrocytoma in cohort 2 has been progression-free for more than 67 months since diagnosis. Conclusion: The current regimen is well tolerated and induces robust GAA-specific responses in WHO grade 2 glioma patients. These results warrant further evaluations of this approach. Clin Cancer Res; 21(2); 286–94. ©2014 AACR.

Scheduled early postoperative computed tomography (EPOCT) after craniotomy for brain tumor resection is standard at many institutions. We analyzed utility of preplanned EPOCT after elective craniotomy for brain tumor resection.We retrospectively analyzed 755 brain tumor resections for which EPOCT was performed within 4 hours of surgery. Postoperative clinical neurologic examination results were classified into expected (baseline or predicted postoperative examination), changed (from baseline examination), and unreliable (sedated or baseline comatose patient). Scans were analyzed for unexpected and/or worrisome findings (e.g., hemorrhagic or ischemic stroke). In cases of unexpected findings, management changes were correlated to patient's neurologic examination. Demographic information, tumor histology, and tumor location were analyzed to determine risk factors for unexpected findings.Rate of unexpected EPOCT findings was 4.1%. Patients with expected postoperative examinations were at significantly lower risk of abnormal findings (odds ratio [OR] = 0.074, P0.001). Patients with intraventricular tumors (OR = 5.7, P = 0.001) were at higher risk compared with patients with metastatic tumors (OR = 0.24, P = 0.06). No unexpected EPOCT findings led to management changes in patients with expected postoperative neurologic examinations. All unexpected EPOCT findings in patients with changed postoperative neurologic examinations led to management changes. Patients with nonreliable neurologic examinations were at significantly higher risk for unexpected findings on EPOCT (OR = 6.33, P 0.001) and subsequent management changes.Routine EPOCT is not indicated for patients undergoing brain tumor resection if postoperative neurologic examination is unchanged, as imaging is unlikely to result in management changes. EPOCT should be obtained in all patients with worrisome changes in examination or nonreliable examinations, as both groups have high rates of unexpected findings on imaging that lead to management changes.

PURPOSE: To document the 5- and 10-year rates of late toxicity and vertebral compression fracture (VCF) in long-term survivors after stereotactic radiosurgery for spine metastases. METHODS AND MATERIALS: A retrospective review was performed on 562 patients treated with SRS for spine metastases between April 2001 and July 2011. Selecting those with at least 5-year survival after SRS, included were 43 patients who collectively underwent 84 treatments at 54 spine sites. Most were treated with single-fraction stereotactic radiosurgery to a median dose of 16 Gy (range, 12-24 Gy), and 56% of sites had received prior external beam radiation therapy. Late toxicities and VCFs occurring in the absence of tumor progression were recorded. Binary logistic regression was used to identify predictors of late complications. RESULTS: Nine patients (17% of treatment sites) developed grade ≥2 late toxicities at a median time of 12.8 months (range, 4.2-59.0 months). Actuarial 5- and 10-year rates of grade ≥2 late toxicity were 17% and 17%, respectively. On multivariate analysis, only cumulative biologically effective dose (BED(3)) > 200 Gy (or EQD2(2Gy) [2-Gy equivalent dose calculated using an α/β ratio of 2] > 130 Gy) was associated with grade ≥2 late toxicity (P = .036). Maximum point BED(3) > 110 Gy (or EQD2(2Gy) > 70 Gy) to spinal cord or cauda equina was associated with grade ≥2 late neuropathy (P = .017). Nine VCFs (18%) occurred at a median time of 10.2 months (range, 3.2-57.2 months), with 5- and 10-year VCF rates of 17% and 17%, respectively. CONCLUSION: Stereotactic radiosurgery for primary treatment and reirradiation of spinal metastases is associated with a moderate risk of late toxicity with 10-year follow-up. Risk of late toxicity significantly increases with cumulative BED(3) > 200 Gy and spinal cord or cauda equina point BED(3) > 110 Gy. Patients remain at moderate risk of VCF up to 5 years after treatment, with a plateau in incidence thereafter up to 10 years.

152 Background: Mutations in the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) are found in > 70% of intermediate grade gliomas. Gain-of-function mutations in IDH1 promote diffuse glioma formation through epigenetic reprogramming of a number of genes, including immune-related genes. Tumor-derived exosomes (TEX) accumulate in the tumor microenvironment (TME) and in body fluids of patients. TEX serve as a communication system between tumor and normal cells. Circulating TEX carry a complex molecular and genetic cargo and interfere with functions of immune cells. This study characterizes TEX produced by IDH mutant glioma spheres and TEX from plasma of patients with IDH mutant gliomas. Methods: TEX produced by patient-derived IDH1(mut) or IDH1(wt) glioma spheres or TEX in patient’s plasma were isolated by mini size exclusion chromatography (mini-SEC). TEX morphology, size, numbers and molecular profile were characterized and the crossing of the blood-brain barrier (BBB) and biodistribution was investigated by in vivo imaging of TEX. Interactions of TEX with endothelial cells, astrocytes and immune cells were demonstrated by confocal microscopy. Results: TEX isolated from supernatants of IDH1(mut) or IDH1(wt) glioma spheres by mini-SEC carried TSG101 and showed the typical size and vesicular morphology of exosomes. BCA protein assays and qNano analysis revealed an elevated exosome production by IDH mutant cells ( p< 0.01). TEX carried immunosuppressive proteins (FasL, CTLA-4 and TRAIL) and IDH mutant exosomes carried higher levels of these proteins and of adenosine pathway components CD39 and CD73. Labeled TEX injected in the white matter of mice crossed the BBB and were detectable in distant organs 24h after injection. TEX were rapidly internalized by endothelial cells and astrocytes, but not by T cells, which interacted with TEX by surface signaling. These results were confirmed by investigating TEX isolated from glioma patient’s plasma. Conclusions: The data suggest that TEX play an important role in IDH mutant gliomas and drive tumor progression in part by inducing suppression of immune cells. Future efforts will focus on characterizing immunosuppressive effects of TEX derived from IDH mutant cells vs gliomas without IDH mutations.

Since the inception of radiosurgery, the management of brain metastases has become a common problem for neurosurgeons. Although the use of stereotactic radiosurgery and/or whole brain radiation therapy serves to control the majority of disease burden, patients who survive longer than 6-8 months sometimes face the problem of symptomatic radiographically regrowing lesions with few treatment options. Here we investigate the feasibility of use of MRI-guided stereotactic laser induced thermotherapy (LITT) as a novel treatment option for these lesions. Six patients who had previously undergone gamma knife stereotactic radiosurgery for brain metastases were selected. All patients had an initial favorable response to radiosurgery but subsequently developed regrowth of at least one lesion associated with recurrent edema and progressive neurological symptoms requiring ongoing steroids for symptom control. All lesions were evaluated for craniotomy, but were deemed unresectable due to deep location or patient's comorbidities. Stereotactic biopsies were performed prior to the thermotherapy procedure in all cases. LITT was performed using the Visualase system and follow-up MRI imaging was used to determine treatment response. In all six patients biopsy results were negative for tumor and consistent with adverse radiation effects also known as radiation necrosis. Patients tolerated the procedure well and were discharged from the hospital within 48 h of the procedure. In 4/6 cases there was durable improvement of neurological symptoms until death. In all cases steroids were weaned off within 2 months. One patient died from systemic causes related to his cancer a month after the procedure. One patient had regrowth of the lesion 3 months after the procedure and required re-initiation of steroids and standard craniotomy for surgical resection. There were no complications directly related to the thermocoagulation procedure. Stereotactic laser induced thermotherapy is a feasible alternative for the treatment of symptomatic regrowing metastatic lesions after radiosurgery. The procedure carries minimal morbidity and, in this small series, shows some effectiveness in the symptomatic relief of edema and neurological symptoms paralleled by radiographic lesional control. Further studies are necessary to elucidate the safety of this technology.

Large calvarial defects in the setting of chronic infection and limited autologous donor sites present challenging problems for the reconstructive surgeon. We report on a novel osteogenic implant as a potential calvarial reconstruction solution. Two patients with an extensive history of severe traumatic brain injury and multiple cranial operations desired delayed calvarial reconstruction subsequent to removal of infected acrylic and titanium implants. These patients underwent harvesting of cancellous femoral bone and bone marrow, which was placed between 2 layers of recombinant bone morphogenic protein 2 impregnated in acellular collagen sponges and an outer layer of sturdily pliable Vicryl mesh to create a moldable osteogenic implant construct. The construct was molded into the shape of the defect and secured with sutures to the skull surrounding the defect. The osteogenic implant showed evidence of bone formation and maintained coverage over the original calvarial defect at 26 months postoperatively as well as subjective satisfaction by both patients and the senior surgeon. This technically straightforward technique with acceptable functional and aesthetic outcomes may be useful to reconstructing selected calvarial defects.

Background The degree of carotid artery stenosis has traditionally been used as a marker of hemodynamic compromise and increased stroke risk. However, the hemodynamic effect of carotid atherosclerotic plaque length on cerebral blood flow has not previously been studied. Objective To determine whether carotid plaque length, in addition to degree of stenosis, significantly affects carotid blood flow in patients with >65% carotid stenosis. Methods Consecutively treated surgical patients with unilateral >65% carotid stenosis at a single institution were analyzed. Quantitative measurements of plaque length, internal carotid artery (ICA) vessel diameter, and degree of stenosis were made from magnetic resonance angiography images. Quantitative phase-contrast magnetic resonance angiography flow maps were generated to estimate ICA flow compromise by calculating a ratio of the ipsilateral/contralateral ICA flow rates. Results Of 38 eligible patients, 23 had full anatomic and ICA flow data sets available for analysis. Univariate regression analysis demonstrated that longer carotid plaques and increasing percentage carotid stenosis were associated with a significant decline in ipsilateral ICA flow (P = .008 and P = .02, respectively). A multivariate regression identified both plaque length and vessel diameter as independent predictors of ICA flow (P = .001 and P = .002, respectively). Conclusion Carotid plaque length and vessel diameter appear to be significant variables, in addition to degree of stenosis, in predicting ipsilateral carotid blood flow compromise in patients undergoing carotid revascularization.

BACKGROUND: Historically, survival for even highly select cohorts of brain metastasis patients selected for SRS alone is

BACKGROUND Postoperative stereotactic radiosurgery for brain metastases potentially offers similar local control rates and fewer long-term neurocognitive sequelae compared to whole brain radiation therapy, although patients remain at risk for distant brain failure (DBF). OBJECTIVE To describe clinical outcomes of adjuvant stereotactic radiosurgery for large brain metastases and identify predictors of intracranial failure and their implications on optimal patient selection criteria. METHODS We performed a retrospective review on 100 large (>3 cm) brain metastases in 99 patients managed by resection followed by postoperative stereotactic radiosurgery to a median dose of 22 Gy (range, 10-28) in 1 to 5 fractions (median, 3). Primary histology was nonsmall cell lung in 40%, breast cancer in 18%, and melanoma in 17%. Forty (40%) patients had uncontrolled systemic disease. RESULTS With a median follow-up of 12.2 months (range, 0.6-87.4), the 1-year Kaplan-Meier local control was 72%, DBF 64%, and overall survival 55%. Nine patients (9%) developed evidence of radiation injury, and 6 (6%) developed leptomeningeal disease. Uncontrolled systemic disease (P=.03), melanoma histology (P=.04), and increasing number of brain metastases (P

A significant number of patients with high-grade gliomas do not respond to standard therapy. For relapsed bevacizumab refractory Glioblastoma (GBM), no effective treatment options exist. Recently, BRAF V600 mutations have been recognized in higher frequency in younger patients with epithelioid GBM (E-GBM) and other primary brain tumors. We describe the case of a 40 year old Caucasian woman with left temporal epithelioid GBM who originally presented at age 39 with seizures. She underwent gross total resection followed by external beam radiation with concurrent temozolomide and two cycles of adjuvant temozolomide. Her tumor recurred 5 months from diagnosis and she underwent radiosurgery followed by bevacizumab. Four months later she developed marked interval radiographic progression associated with a severe non-fluent aphasia. Because molecular analysis of the primary tumor revealed a BRAF V600E mutation, she was placed on the BRAF inhibitor vemurafenib. After only two months of vemurafenib therapy we observed a robust partial radiographic response along with complete recovery of language and return to near normal neurologic function. While not a common mutation, there may be a role for BRAF inhibitors in a subset of GBM with BRAF V600 mutations. BRAF V600E mutational analyses should be performed on GBMs, and prospective trials are warranted.

Background Accuracy in Ommaya reservoir catheter placement is critical to chemotherapy infusion. Most frameless image guidance is light emitting diode (LED) based, requiring a direct line of communication between instrument and tracker, limiting freedom of instrument movement within the surgical field. Electromagnetic neuronavigation may overcome this challenge. Objective To compare Ommaya reservoir ventricular catheter placement using electromagnetic neuronavigation to LED-based optical navigation, with emphasis on placement accuracy, operative time and complication rate. Methods Twenty-eight patients who underwent placement of Ommaya reservoirs at our institution between 2010 and 2014 with either electromagnetic (12 patients) or optical neuronavigation (16 patients) were retrospectively reviewed. Results Half of the patients were male. Their mean age was 56 years (range 28–87 years). Accuracy and precision in catheter tip placement at the target site (foramen of Monro) were both higher ( p =0.038 and p =0.043, respectively) with electromagnetic neuronavigation. Unintended placement of the distal catheter contralateral to the target site occurred more frequently with optical navigation, as did superior or inferior positioning by more than 5mm. Mean operative times were shorter ( p =0.027) with electromagnetic neuronavigation (43.2min) than with optical navigation (51.0min). There were three complications (10.7%) – one case each of cytotoxic edema, post-operative wound infection, and urinary tract infection. The rate of complication did not differ between groups. Conclusion In contrast with optical neuronavigation, frameless and pinless electromagnetic image guidance allows the ability to track instrument depth in real-time. It may increase ventricular catheter placement accuracy and precision, and decrease operative times.

Background context Spine metastases occur frequently in patients with cancer. A variety of surgical approaches, including anterior transcavitary, lateral extracavitary, posterolateral, and/or combined techniques are used for spinal cord decompression and restoration of spinal stability. The incidence of symptomatic hardware failure is unknown for the majority of these approaches. Purpose The purpose of this study was to determine the incidence of symptomatic hardware failure and the associated risk factors in patients with metastatic epidural spinal cord compression (MESCC). Study design/setting This was a retrospective study. Patient sample The current series analyzes a cohort of 318 patients who underwent separation surgery, which involves single-stage posterolateral decompression and posterior segmental instrumentation for MESCC. Outcome measures The event of interest was hardware failure; the competing event was death resulting from any cause. All patients were monitored for survival analysis. A competing risk analysis was conducted to examine univariately a number of potential risk factors associated with hardware failure, including junctional level, gender, construct length, and the presence or absence of prior chest wall resection. Methods A retrospective analysis and chart review were performed for 318 consecutive patients who underwent posterolateral decompression and posterior screw-rod fixation without supplemental anterior fixation from March 2004 to June 2011 at our institution. The median follow-up time for survivors without hardware failure was 399 days (range, 9–2,828), with a mean operative time of 3 hours. A total of 78% of patients died during the 7-year study period. Results Of the 318 patients, nine (2.8%) exhibited signs and symptoms of hardware failure and required revision of the instrumentation. Patients with chest wall resection and those with initial construct length greater than six contiguous spinal levels exhibited a statistically significantly higher risk of symptomatic hardware failure than their counterparts. We observed a trend toward an increased risk of failure in women compared with men (p=.09). Conclusions The incidence of hardware failure is low in patients with MESCC who undergo posterolateral decompression and posterior screw-rod instrumentation. Moreover, the short operative time and low morbidity profile associated with this approach make it a reliable and acceptable method for the surgical treatment of MESCC. Patients with constructs spanning six or more levels or those with prior chest wall resection are at higher risk for instrumentation failure.

Background Hyalinizing clear cell carcinoma (HCCC) is a rare epithelial malignant neoplasm typically arising from the minor salivary glands. Although it has been described as a benign neoplasm, there are increasing reports of malignant features and metastases to the lungs; we present the first case of biopsy-proven spinal metastases from HCCC and an overview of the literature. Case Description This is a single-patient case report in which we used immunohistochemistry and fluorescence in situ hybridization for Ewing sarcoma breakpoint region 1 translocation to confirm the diagnosis of HCCC in a spinal metastasis. The diagnosis of metastatic HCCC was confirmed on the basis of histopathology, immunohistochemistry, and fluorescence in situ hybridization studies. Conclusions We present the first pathologically confirmed case of a spinal metastasis in HCCC. As increasing of metastatic HCCC arise, a reconsideration of HCCC as a potentially high-grade disease seems increasingly necessary as it may impact the current treatment paradigm.

Malignant gliomas remain the most devastating childhood and adult tumors of the central nervous system. Although adult and pediatric gliomas are histologically indistinguishable, they differ in location, behavior, and molecular characteristics. This implies that the molecular pathways and pathophysiology of malignant gliomagenesis in these two populations are distinct. Such differences between adult and pediatric gliomas may predict different therapeutic responses. Therefore, accurate genetically engineered models of adult and pediatric gliomas may help understand the biology of these tumors and evaluate therapeutic agents in preclinical studies. It has been proposed that gliomas arise from the subventricular zone in mice during development. Here, we demonstrate that, in adult mice, gliomas may arise not only when injected in the subventricular zone but also when injected in the cortex and cerebellum. Our work demonstrates a versatile and highly reproducible adult mouse model of glioma, which can be easily incorporated into preclinical studies.

Early phase human clinical trials using several versions of oncolytic herpes simplex virus type 1 (oHSV) have shown promise in the treatment of GBM, but efficacy has been limited. Impediments to oHSV therapy include poor virus spread due in part to the tumor extracellular matrix, and insufficient replication in tumor cells as a result of attenuating mutations. Thus, the central goal of this project is to improve oncolytic vector delivery, replication and spread while maintaining safety and tumor specificity. We have already developed a new class of two stage tumor targeted oHSV combining (i) selective infection through tumor-specific receptors and (ii) selective replication based on differential expression of microRNAs (miRs) in tumor and normal cells. We further modify our vector by arming with the matrix metalloproteinase 9 (MMP9) as a means to reduce vector trapping in the tumor extracellular matrix. Here we show that MMP9 expression (i) enhances Oncolytic vector spreading in GBM neruospheres in vitro and (ii) improves tumor killing in a xenogeneic model of primary human GBM with significant long-term survival (≥50%) comparable to the control. Citation Format: Aofei Li, Marco Marzulli, Mingdi Zhang, William Goins, Balveen Kaur, Chelsea Bolyard, Nduka Amankulor, Daniela Leronni, Paola Sette, Justus Cohen, Joseph Glorioso, Paola Grandi. Arming a tumor targeted oncolytic herpes simplex sirus type 1 with matrix metalloproteinase 9 for enhanced vector distribution and killing activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3546. doi:10.1158/1538-7445.AM2015-3546

Faciogenital dysplasia, also known as Aarskog-Scott syndrome (AAS), is an X-linked dominant congenital disorder characterized by multiple facial, musculoskeletal, dental, neurological and urogenital abnormalities, ocular manifestations, congenital heart defects, low IQ and behavioral problems. Here we describe an unusual presentation of dysplastic carotid artery, basilar artery malformation or occlusion and posterior circulation aneurysm in a 13-year-old male with AAS.

TPS9112 Background: Dabrafenib (D) has clinical activity in patients (pts) with BRAF V600E/K mutation–positive melanoma brain metastases (MBM). The combination of D and trametinib (T) has increased...