tbuckley/cabot-search huggingface dataset:
RTHP-26. ANALYSIS OF OUTCOMES FROM RE-IRRADIATION WITH PULSED REDUCED DOSE RATE RADIATION THERAPY FOR HIGH GRADE GLIOMAS
Authors: Adam Burr, H Robins, Steven Howard
Journal: Neuro-Oncology (2018)

Treatment options for recurrent high-grade glioma are limited. We updated a retrospective series of treatment completed pulsed reduced dose rate radiation therapy (PRDR), a method to decrease toxicity and improve efficacy. 103 patients with glioblastoma (GB) and 45 patients with grade 3 gliomas were analyzed (12/2000 to 12/2016). 29 GBs and 16 grade 3 gliomas had transformed from lower grade gliomas. Treatment was with at an apparent dose rate was 6.67 cGy/min. Median re-irradiation dose was 54 Gy (44–54 Gy) with median total dose of 114 Gy (range 69–171.4 Gy). Five GBs and seven grade 3’s received whole brain PRDR. Kaplan Meier method was used to analyze survival. Univariate and multivariate analysis (MVA) used a Cox proportional hazards model. Median survival from initiation of PRDR was 7.1 months in post-Avastin GBs and 6.0 months in Avastin naive GBs. Survival was 7.8 months for grade 3’s from PRDR. Survival from treatment at first progression was 11.9 months in both the Avastin naïve GBs and Avastin treated GBs while grade 3’s survived 16.7 months. A partial response was observed in14.4% of GBs and 20% of grade 3’s while stable disease was seen in 16.5% of GBs and 22% of grade 3’s. Therapy was well tolerated. Toxicity data and MVA analysis, which includes: time from initial to re-irradiation, KPS, transformation from lower grade histology, whole brain PRDR, tumor location, planning treatment volume size, MGMT status, IDH1 status, 1p/19q status, and age will be presented. CONCLUSIONS: In comparison to historical data these results are encouraging. A phase II clinical trial is ongoing to confirm these results prospectively.
EPID-10. TUMORS IN THE CAUDA EQUINA: A SEER ANALYSIS OF TUMOR TYPES AND PREDICTORS OF OUTCOME
Authors: Saurav Das, Beatrice Ugiliweneza, Eric Burton
Journal: Neuro-Oncology (2018)

Cauda equina tumors are histologically diverse. Cauda equina has a dedicated site code (C72.1) in the International Classification of Diseases for Oncology (ICD-O3) and is often excluded during analyses of other primary spinal cord tumors. Therefore, less is known about tumors in this location. Using SEER data, we analyzed the demographic features, tumor types, treatment and survival of primary cauda equina tumors. SEER data from 1997 to 2015 were reviewed for primary cauda equina tumors (C72.1) excluding the tumors of spinal meninges (C70.1). We describe demographic characteristics of the cohort, tumor types and compared these with clinical outcome using univariate analysis. Treatment and survival analysis was performed using Kaplan-Meier curves. Ninety-two patients with primary cauda equina tumors met the inclusion criteria. These tumors comprised ependymoma (73%), glioblastoma (5%), lymphoma (5%), Ewing sarcoma (3%) and solitary occurrences of neurilemmoma, fibrosarcoma, germinoma, teratoma etc. The median age at diagnosis was 49 years (<1 year and 98 years), 55% were males, predominantly white (87%). Eighty percent of the patients received surgery. Median follow up time was 102.5 months. Of the 92 patients, 68 (73%) are still alive. The cause of death is tumor or CNS related in 58% of the patients. Of the 92 patients, 62 patients (67.4%) survived more than 5 years and 19 patients (20.7%) died before 5 years. 11 patients (12.0%) were censored before 5 years. Using univariate analysis, age at diagnosis was independent predictor of increased tumor specific mortality (HR1.03, CI 1.01–1.06), while non-ependymal tumor type (HR 0.14, CI 0.06- 0.33) and surgical intervention (HR 0.18, CI 0.08- 0.40) were independent predictors of improved survival (p<0.001 for each). Cauda equina tumors are predominantly ependymal in origin. Although most patients do well, older age and lack of surgical intervention are associated with worse survival.
EXTH-66. ELUCIDATING THE TRANSLATIONAL POTENTIAL OF LA2O3 NANOPARTICLES AS A NOVEL THERAPY IN GLIOBLASTOMA
Authors: Victor Lu, Kerrie McDonald
Journal: Neuro-Oncology (2018)

Given the current outlook for glioblastoma (GBM) is dismal, novel therapies warrant consideration. Lanthanum oxide (La2O3) nanoparticles (NPs) represent a nanotechnology with greater ability to penetrate the blood brain barrier (BBB), induce a natural anti-cancer effect, and enhance current treatment modalities. The aim of this study was to first validate and describe the therapeutic effect of La2O3 NPs in GBM in vitro, and then explore its translational potential in vivo. La2O3 NPs were first tested for cytotoxicity, synergy with temozolomide (TMZ) and radiosensitization in vitro in 4 GBM patient derived cell lines (PDCLs). Mechanisms were then explored using electron microscopy, flow cytometry, and western blotting. Finally, in vivo studies were conducted in balb/c mice with xenograft GBM PDCL models to establish translational potential. There was significant cytotoxic effect, synergy with TMZ and radiosensitization observed with La2O3 NPs in all PDCLs tested. Analysis indicated that the NPs enter the cell via clathrin-mediated endocytosis and cause intracellular calcium and radical oxygen species imbalance. This triggers mitochondrial apoptotic mechanisms and augments TMZ and radiation effect. In vivo, detectable levels of La2O3 NPs were observed in the xenograft model tumors after intravenous administration of maximal tolerable dose without any serious adverse events. La2O3 NPs represent a novel therapy which can ameliorate the dismal prognosis of GBM. In vitro and in vivo modelling thus far indicates that it does have translational potential in penetrating the BBB to reach glioblastoma and cause anti-cancer effect as a single agent, and in combination with current management strategies. Considerations for in vivo survival studies were thus justified, and are currently underway.
Inhibition of Casein Kinase 1 Alpha in Acute Myeloid Leukemia
Authors: Benjamin L. Ebert, Jan Krönke
Journal: New England Journal of Medicine (2018)

Casein kinase 1 alpha targets the apoptosis-inducing protein P53 for degradation, and a paucity of functional P53 underlies the neoplastic behavior of cancers, including acute myeloid leukemia. Suppression of this kinase is a candidate pathway for drug development.
PDCT-02. COMBINED INHIBITION OF MTORC1/C2 AND MEK PATHWAY IS SYNERGISTIC IN PRECLINICAL TESTING OF PEDIATRIC LOW-GRADE GLIOMA INCLUDING A NOVEL PATIENT-DERIVED NF1 PILOCYTIC ASTROCYTOMA CELL LINE
Authors: Antje Arnold, Ming Yuan, Fausto Rodriguez, Charles Eberhart, Eric Raabe
Journal: Neuro-Oncology (2018)

Pediatric low-grade glioma (PLGG) is the most common brain tumor of childhood. We and others have identified mTOR and MEK-pathway activation in PLGG. The dual mTORC1/2-inhibitor, TAK228, and the FDA approved MEK-inhibitor, trametinib, are promising candidates for targeted PLGG therapy. We treated five different patient-derived PLGG cell models with TAK228 and/or trametinib: JHH_NF1_PA1 (NF1 mutation), BT66_SV40/hTERT (BRAF:KIAA1549 fusion), BT40 (BRAFV600E) Res186 (PTEN deletion) and Res259 (PDGFRα amplification and CDKN2A deletion). Treatment with TAK228 or trametinib reduces cell proliferation in a dose and time depended manner investigated via MTS-assay. Both drugs exert a synergistic effect at 5-20nM in JHH_NF1_PA1, Res186, and Res259 cells as calculated by the method of Chou-Talay. BT66_SV40/hTERT cells have a 70% reduction in cell growth with 10nM TAK228 (p < 0.001 by ANOVA) but not in combination with trametinib. In all cell lines trametinib treatment leads to a pERK inactivation at low nM levels. TAK228 treatment leads to inactivation of mTORC1 and mTORC2. Apoptosis induction was examined through cleaved PARP via western blot and CC-3 via immunocytochemistry. The combination of TAK228 and trametinib increased apoptosis by up to 127% (p < 0.001) in Res186, Res259, and JHH_NF1_PA1 cells. We tested trametinib and TAK228 against the BRAFV600E mutant BT40 patient derived xenograft in immunodeficient mice. In combination TAK228 and trametinib decreased significantly BT40 tumor growth compared to vehicle or either agent alone, (p < 0.01 by ANOVA). Striking was the reduced vascularization of the tumor tissue after combination treatment compare the vehicle control and single agent treatment. Vascularization differences will be evaluated with immunohistochemistry staining for PDGFα and PECAM-1. Our results show that PLGG-derived cell lines are sensitive to TORC1/2 kinase inhibition and MEK inhibition. Further, our in vivo experimentation provides the first strong rationale for combination therapy of these agents in aggressive PLGG.
Abstract 16165: Embryonic Stem Cell-derived Cardiomyocytes Increase Viable Myocardium but Do Not Improve Function in a Mouse Model of Chagasic Cardiomyopathy
Authors: Adriana B Carvalho, Guilherme V Brasil, Danubia Silva-dos-Santos, Fernanda P Mesquita, Tais H Kasai-Brunswick, Sandro T Cunha, Regina S Goldenberg, Antonio C Campos de Carvalho
Journal: Circulation (2015)

Chagas disease is a parasitic infection caused by Trypanosoma cruzi ( T. cruzi ). It is endemic in Latin America but cases have been increasing in the United States due to the migration of infected individuals. The objective of this work was to evaluate the effects of cell therapy with cardiomyocytes derived from mouse embryonic stem cells (CM-mESC) in a mouse model of chronic chagasic cardiomyopathy. CD1 mice were infected with the Brazil strain of T. cruzi . After 5 months, cardiac function was evaluated by magnetic resonance imaging (MRI) (Table 1). Left ventricular ejection fraction (LVEF) was decreased in infected animals when compared to non-infected controls, while LV end-diastolic volume (EDV) and LV end-systolic volume were increased. Right ventricular (RV) EF was not altered. However, RVEDV and RVESV were increased in the infected group when compared to non-infected animals. mESC E14TG2A line was differentiated into cardiomyocytes and efficiency was confirmed by troponin T staining. 8x10^5 CM-mESC were delivered by echocardiography-guided intramyocardial injection only if cardiomyocyte differentiation efficiency was above 70%. Cell tracking was performed by bioluminescence and MRI using luciferase-transduced cells and iron oxide nanoparticles, respectively. CM-mESC were detected in the heart for at least 8 days. After 45 days, MRI data showed no changes in LV or RV EF and volumes (Table 1). Sirius red staining was performed and the areas of viable myocardium and fibrosis were quantified by morphometry. Although no functional improvement was detected by MRI, there was a significant increase in viable myocardium when CM-mESC-treated mice were compared to placebo-treated animals. In conclusion, a single injection of CM-mESC in a mouse model of chagasic cardiomyopathy contributes to myocardial repair. However, this was insufficient to promote an improvement of cardiac function, which may require multiple cardiomyocyte injections.
Abstract 18077: Lineage Tracing Analysis of c-kit+ Stem/Progenitor Cells Revealed a Contribution to Vascular Injury-Induced Neointimal Lesions
Authors: Qishan Chen, Mei Yang, Jianhua Zhu, Li Zhang
Journal: Circulation (2017)

Introduction: Accumulating evidence indicates the presence of vascular stem/progenitor cells that may play a role in endothelial repair and lesion formation in injured artery, in which c-kit+ stem/...
NCOG-13. NEUROCOGNITIVE EVALUATION OF BRAIN METASTASES PATIENTS TREATED WITH POST-RESECTION STEREOTACTIC RADIOSURGERY: A PROSPECTIVE SINGLE ARM CLINICAL TRIAL
Authors: Andrew Kanner, Assaf Berger, Shlomit Ben Moshe, Benjamin W Corn, Dror Limon, Nathan Shtraus, Ido Strauss, Tal Shahar
Journal: Neuro-Oncology (2018)

Post-operative radiation therapy for brain metastases (BM) has become standard treatment. Concerns regarding the deleterious cognitive effects of Whole Brain Radiation Therapy (WBRT) spurred a trend to use focal therapies such as stereotactic radiosurgery (SRS). The purpose of this study was to prospectively evaluate the neuropsychological fluctuations that follow post-resection SRS treatment since limited data exist in this context. We conducted a prospective single arm cohort study of patients with 1–2 BM, who underwent resection of a single BM between May 2015 to December 2016. Patients were evaluated for cognitive functions (NeuroTrax test) and quality of life (QOL; QLQ-30, QLQ-BN20) before and 3 months following post-resection SRS. Twelve out of 14 patients completed pre- and post SRS neurocognitive assessments. Overall, we did not detect significant neurocognitive or QOL changes 3 months following SRS. In a subgroup analysis, cognitive changes among patients at the age of 60 or over (n=7) were compared to younger ones (n=5). Both age groups were similar in terms of gender, pre-treatment KPS and ECOG, total SRS treatment volume, lesion eloquence and post-SRS survival. Among patients younger than 60 years, median global cognitive score increased from a pre-treatment score of 88 (72–102) to 95 (79–102), 3 months following SRS treatment, p=0.019; Wilcoxon paired non-parametric test. Immediate verbal memory and executive functions scores increased from 86 (72–98) to 98 (92–112) and 86 (60–101) to 95 (73–108), respectively, p=0.043. No significant cognitive changes were discovered among patients at the age of 60 or older. Post-resection radiosurgery has a safe neuro-cognitive profile and is associated with a relatively preserved quality of life. Patients younger than 60 years benefit more than older ones and may even regain some cognitive functions within a few months after treatment.
CSIG-19. DETECTION OF IDH1 R132H VIA FLOW CYTOMETRY IN INTRAOPERATIVE AND ARCHIVAL GLIOMA SPECIMENS
Authors: Justine Sinnaeve, Alan Simmons, Kyle Weaver, Reid Thompson, Lola Chambless, Ken Lau, Bret Mobley, Rebecca Ihrie
Journal: Neuro-Oncology (2018)

Gliomas are the most common adult primary brain tumor and remain incurable. One critical challenge in the study of glioma is separating the biological effects of diverse cells that make up a tumor. Mass cytometry is a method used to simultaneously detect 37 or more epitopes per-cell on tens of thousands of cells isolated from patient tumor samples. This technology has been widely used in blood cancers and has recently been employed in solid tumors including glioma patient samples. However, a definitive protein marker that can distinguish glioma versus non-glioma stromal cells in flow cytometry does not exist. The isocitrate dehydrogenase 1 (IDH1) enzyme is mutated in approximately 80% of grade II and III gliomas and 10% of glioblastomas, with R132H as the most common mutation. Mutant IDH1 is found exclusively in cancerous cells and, when incorporated in flow cytometry experiments, positively identifies these cells in IDH-mutant tumors. We have developed a protocol to detect the IDH1 R132H antigen in fluorescence and mass cytometry. This protocol has been successfully combined with other staining and preparation steps to identify CD45-positive immune cells, CD31-positive endothelial cells, and IDH R132H-positive tumor cells in engineered cell lines, primary patient samples, and material extracted from paraffin blocks. These cell populations can be computationally separated for further analysis of protein expression, high dimensional phenotypes, signaling features, and cell abundance. Flow cytometry can be used to confidently identify a subset of cancer lineage cells and compare their protein phenotypes to other cells within the tumor as well as to other patient samples. This technique will ultimately provide a useful complement to other single-cell approaches and enable tracking of mutant IDH1 expression over the duration of functional assays such as drug response or engraftment.
Familial Trigeminal Neuralgia Cases Implicate Genetic Factors in Disease Pathogenesis
Authors: Shreyas Panchagnula, Agata K. Sularz, Kristopher T. Kahle
Journal: JAMA Neurology (2018)

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CBMT-07. EVALUATION OF GLYCOLYTIC RESPONSE TO SEVEN CLASSES OF ANTI-GLIOBLASTOMA DRUGS BY NON-INVASIVE MEASUREMENT OF PYRUVATE KINASE M2
Authors: Corinne Beinat, Chirag Patel, Yuanyang Xie, Sanjiv Gambhir
Journal: Neuro-Oncology (2018)

INTRODUCTION: Pyruvate kinase M2 (PKM2) catalyzes the final and rate-limiting step in glycolysis, a key step in tumor growth and metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) cells with minimal expression in the healthy brain, making it an important marker of cancer glycolytic re-programming. Our laboratory has developed 1-((2-fluoro-6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23), a novel radiotracer to noninvasively measure the expression of PKM2 and are currently conducting first-in-human studies with positron emission tomography (PET) imaging. In this study we evaluated the ability of [18F]DASA-23 to detect GBM metabolic changes in response to seven classes of anti-GBM chemotherapy (n=11 drugs total). Human U87 GBM cells were subjected to the IC50 of alkylating agents (temozolomide [TMZ], carmustine, lomustine), a topoisomerase I inhibitor (irinotecan), inhibitors of vascular endothelial and epidermal growth factor receptors (cediranib and erlotinib, respectively) an anti-metabolite (5-fluorouracil), an anti-microtubule agent (vincristine), and metabolic therapies (AG-120 and dichloroacetate). After three or six days of exposure (n≥5/condition), the cellular uptake of [18F]DASA-23 was evaluated and PKM2 protein expression determined. PKM2 protein expression was compared via correlation analysis between two methods, [18F]DASA-23 uptake and Western blot. Two-way ANOVA was used with corrections for multiple comparisons. Results are reported as mean±SD. There was a significant interaction between the interventions (n=13 including vehicle, media-only, and 11 drugs) and treatment duration (3 or 6 days) on PKM2 expression as measured by [18F]DASA-23 uptake (p=0.0001). The most significant change in [18F]DASA-23 uptake at XX minutes was evident in response to treatment with alkylating agents (p=0.0003), irinotecan (p=0.0055), erlotinib (p=0.04), and 5-fluorouracil (p=0.02). Western blot analysis revealed a moderate correlation between PKM2 protein expression [18F]DASA-23 uptake (R2=0.44, p=0.15, Pearson correlation). These studies highlight the potential for evaluation of PKM2 expression with [18F]DASA-23 as a means to non-invasively monitor response to multiple classes of anti-GBM agents.
PDTM-04. THERAPEUTIC MODULATION OF CHOLESTEROL HOMEOSTASIS IN DIPG THROUGH MASSIVE GENERATION OF 24,25-EPOXYCHOLESTEROL
Authors: Richard Phillips, Ryan Smith, Kosuke Funato, Yupu Liang, Bonne Thompson, Matthew Mitsche, McDonald Jeffrey, Viviane Tabar, C David Allis
Journal: Neuro-Oncology (2018)

Diffuse intrinsic pontine glioma (DIPG) remains a uniformly fatal childhood tumor for which novel pharmacological treatments are desperately needed. In recent work, we performed a small molecule screen in a pre-clinical DIPG model, identifying MI-2 as the top ‘hit’, showing anti-tumor activity in vitro and in vivo. MI-2 was developed as an inhibitor of the protein menin, an epigenetic regulator which has oncogenic activity in acute leukemia. Here, we characterize the mechanism of action of MI-2 in DIPG. We generated menin knockout patient-derived DIPG cell-lines using CRISPR/Cas9 and observed that they retained sensitivity to MI-2 at nanomolar concentrations (comparable to wild-type parental cells), suggesting a menin-independent mechanism of action in DIPG. Transcriptome analysis of DIPG cells after MI-2 treatment revealed significant upregulation of gene targets of LXR (liver X receptor), a ligand-activated transcription factor which promotes cholesterol efflux to reduce cellular cholesterol. Consistent with a cholesterol depleting activity of MI-2, we showed markedly reduced cholesterol in DIPG cells following MI-2 treatment, and rescue of MI-2 induced cell-death by provision of exogenous cholesterol. To investigate how LXR is activated, we performed LC-MS analysis of major sterols species in MI-2 treated cells, and observed massive upregulation of 24,25-epoxycholesterol, an oxysterol known to be a potent endogenous activator of LXR. These findings characterize MI-2 as a novel cholesterol depleting agent, acting via an epoxycholesterol-LXR axis to promote cholesterol efflux from tumor cells. Our work suggests DIPG may be uniquely sensitive to perturbations in cholesterol homeostasis and implicates LXR activation as a potential therapeutic strategy in DIPG.
STEM-01. PROSPECTIVE ANALYSIS OF CANCER STEM CELL DRUG RESPONSE ASSAY FOR GLIOBLASTOMA PATIENTS
Authors: Tulika Ranjan, Candace M. Howard, Jagan Valluri, Alexander Yu, Khaled Aziz, David Jho, Terrence Julien, Jody Leonardo, Anthony Alberico, Antonio Cortese, Krista Denning, Pier Paolo Claudio
Journal: Neuro-Oncology (2018)

Over the past 20 years even with the aggressive standard of care (SoC) Stupp treatment protocol the prognosis of glioblastoma (GBM) has only minimally improved from 12 to 14 months. This is due in large part to the presence of chemo- and radiation-resistant GBM cancer stem cells (CSCs) that contribute to tumor propagation, maintenance, and treatment resistance. We are using ChemoID, a CLIA certified and CAP accredited drug response assay to identify the most effective chemotherapy treatment against CSCs and bulk of tumor cells from of a panel of chemotherapies, offering great promise for individualized cancer management. A prospective study was conducted evaluating the use of the ChemoID drug response assay in glioblastoma patients. Fresh tissue samples were collected for drug sensitivity testing from 61 glioblastoma patients enrolled in IRB approved protocol. Patients were prospectively monitored for tumor response, time to recurrence, progression-free survival (PFS), and overall survival (OS). Odds Ratio (OR) associations of 12-month recurrence, PFS, and OS outcomes were estimated for CSCs, bulk tumor and combined assay responses to treatment; sensitivities/specificities, areas under the curve (AUC) were examined. The data suggests that ChemoID guided treatment significantly enhanced tumor response. For every 5% increase in cell kill of CSCs by assay-guided chemotherapy, 12-month patient response (non-recurrence of cancer) increased 2.5-fold, OR=2.3 (p=0.01). Bulk of tumor assay was found not statistically significant. Median recurrence time was 20 months for patients with a positive (>40% cell kill) CSCs test versus only 3 months with a negative CSCs test, whereas median recurrence time was 13 months versus 4 months for patients with a positive (>55% cell kill) bulk test versus negative. Similar favorable results for the CSC test were observed for PFS and OS outcomes. CONCLUSIONS: The ChemoID CSCs drug response assay has the potential to increase the accuracy of bulk tumor assays to help guide individualized chemotherapy choices. Glioblastoma cancer recurrence may occur quickly if the CSC test has a low cell kill rate, even if the bulk tumor test cell kill rate is high.