tbuckley/cabot-search huggingface dataset:
TMOD-32. GENERATION OF GLIOBLASTOMA PATIENT DERIVED INTRACRANIAL XENOGRAFTS FOR PRECLINICAL STUDIES
Authors: Amber Kerstetter-Fogle, Harris Peggy, Andrew Sloan
Journal: Neuro-Oncology (2018)

Glioblastoma multiforme (GBM) is the most malignant primary brain cancer affecting adults. Therapy options for GBM have remained the same for over a decade with no significant advancements. In vitro cell line models have minimal success for screening potential therapies. Many therapies that were successful in culture have failed in the clinic, likely due to the complex microenvironment in the brain, which has yet to be reproduced in any culture model. Furthermore, high passage number of cultured cells and clonal selection fail to recapitulate the molecular and genomic signatures of GBM. We have been able to successfully establish 37 patient derived xenografts (PDX) intracranially from GBM patient tissue. Tumor derived glial stem cells isolated from patient resected tissue and implanted intracranially into an immunosuppressed mouse strain. Of the 69 patient samples analyzed, we were successful in passaging three or more generations through mice 53.6% of the time. After characterization of the xenografted tumor tissue, two different tumor growth patterns emerged: highly invasive or localized. This phenotype was likely dependent on malignancy, and previous treatment of the patient from which the xenograft was derived. Physiologically, mice exhibited symptoms more quickly with each subsequent passage, particularly in the localized tumors. Development of these physiologically relevant mice, will enable therapy screenings in a microenvironment that more closely resembles GBM and may allow development of individualized patient models which can be used for simulating treatment effectors. Once established, intracranial PDX may also be useful for personalizing medicine.
NCMP-11. NEURODEGENERATION AND CHEMOBRAIN: PREDICTING THE PROBABILITY OF ALZHEIMERS DISEASE IN BREAST CANCER SURVIVORS
Authors: Rebecca Harrison, Arvind Rao, Vikram Rao, William Ray, Shelli Kesler
Journal: Neuro-Oncology (2018)

Chemotherapy treatment for cancer has been associated with significant alterations in brain structure and function that result in cognitive impairments. Many of the candidate mechanisms for chemotherapy-related brain injury are closely associated with aging. Therefore, it has been suggested that chemotherapy may alter or even accelerate the brain aging trajectory. Accordingly, certain epidemiological studies have suggested that chemotherapy treated patients are at higher risk for pathologic neurodegenerative processes such as Alzheimers disease (AD). Other studies have failed to replicate these findings so empirical evidence for increased AD risk following chemotherapy remains limited. In this retrospective study, we obtained brain MRI data from 47 females age 69 +/- 7 years who were later diagnosed with AD and 47 matched female controls who did not develop AD. Using random forest classification, we created a model of brain network organization, APOE genotype and age that could successfully discriminate between AD converters and controls with 86% accuracy (p < .0001, ROC = .96). We then applied this model to data obtained from 78 breast cancer survivors to calculate predicted probability of AD for each individual. Chemotherapy-treated survivors demonstrated significantly higher probability of AD compared to chemotherapy naïve survivors (p = .007) even after stratifying for APOE e4 genotype (p = .014). Cognitive dysfunction was significantly associated with higher AD probability, older age and chemotherapy treatment (r = .74, p = .04). These findings suggest that chemotherapy-treated survivors who have a particular profile of brain network organization may be at higher risk for AD, regardless of other risk factors including age and genotype.
DDIS-09. IDENTIFICATION OF GSK3β INHIBITOR KENPAULLONE AS A TEMOZOLOMIDE ENHANCER AGAINST GLIOBLASTOMA
Authors: Tomohiro Kitabayashi, Yu Dong, Takuya Furuta, Hemragul Sabit, Shabierjiang Jiapaer, Jiakang Zhang, Guangtao Zhang, Mitsutoshi Nakada
Journal: Neuro-Oncology (2018)

Cancer stem cells are associated with chemoresistance and rapid recurrence of malignant tumors including glioblastoma (GBM). Although temozolomide (TMZ) is the most effective drug against GBM to date, GBM cells acquire resistance and become refractory to TMZ during treatment. Therefore, glioma stem cell (GSC)-targeted therapy and TMZ enhancing therapy may be effective approaches to improve prognosis of GBM. Many drugs that suppress the signaling pathway related to maintain GSC or enhance the effect of TMZ have been reported. However, there are no established therapies. Here, we screened drug libraries that are composed of 1,301 existing drugs using cell viability assay using GSCs, then extracted Kenpaullone, a kinase inhibitor, as a TMZ enhancer targeting GSCs. Kenpaullone efficiently suppressed activity of glycogen synthase kinase (GSK)3β. Combination therapy of Kenpaullone and TMZ demonstrated suppression of stem cell properties and proliferation of both GSCs and glioma cell lines. Combination therapy for the mouse models significantly prolonged survival time compared with TMZ monotherapy. Taken together, Kenpaullone is a promising drug for the treatment of GBM by targeting GSCs and overcoming chemoresistance against TMZ.
SAT0057 The effect of exosomes from bone marrow mesenchymal stem cells on osteoarthritis
Authors: H. Zhu, J. Ji, T. Fu, J. Yang, Z. Gu
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Mesenchymal stem cells (MSCs) exert chondroprotective effects in clinical models of osteoarthritis (OA), but the exact mechanisms were still unclear. Exosomes that serve as carriers of genetic information have been implicated in many diseases and are known to participate in many physiological processes. <h3>Objectives</h3> Here, we investigate the therapeutic potential of exosomes from human bone marrow MSCs in alleviating OA and explore the mechanism. <h3>Methods</h3> Exosomes were harvested from conditioned culture media of BM-MSCs by a sequential centrifugation process. The anterior cruciate ligament transection and destabilisation of the medial meniscus (DMM) surgery were performed on the knee joints of SD female rat as an OA model. After four weeks, the animals were followed by intra-articular injection of either BM-MSCs or their exosomes every week for four weeks. Cartilage destruction, matrix degradation and subchondral bone changes were evaluated with histological staining and micro-CT at the post-surgery 8 weeks. Primary human chondrocytes treated with IL-1β were used as an <i>in vitro</i> model to evaluate the effects of exosomes for 24 hours. <h3>Results</h3> We found that intra-articular injection of BM-MSCs and BM-MSCs derived exosomes improve cartilage destruction and subchondral bone remodelling in ACLT+DMM model. BM-MSCs and exosomes equally protected rat from joint damage. These exosomes maintained the chondrocyte matrix by increasing collagen type II synthesis and decreasing ADAMTS5, MMP13 and Col II expression in the presence of IL-1β <i>in vitro</i>. In addition, BM-MSCs derived exosomes were also shown to protect chondrocytes from apoptosis and senescence. <h3>Conclusions</h3> The exosomes from BM-MSCs exert a beneficial therapeutic effect on OA by not only repairing the degenerative cartilage, but also improving subchondral bone remodelling, which in turn provides a new target for OA drug and drug-delivery system development. <h3>References</h3> [1] Trounson A, McDonald C. Stem Cell Therapies in Clinical Trials: Progress and Challenges. Cell stem cell2015;17:11–22. [2] Stoorvogel W, Kleijmeer MJ, Geuze HJ, Raposo G. The biogenesis and functions of exosomes. Traffic2002;3:321–30. [3] Lai RC, Yeo RW, Lim SK. Mesenchymal stem cell exosomes. Seminars in cell &amp; developmental biology2015;40:82–8. [4] Zhang S, Chu WC, Lai RC, Lim SK, Hui JH, Toh WS. Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration. Osteoarthritis and cartilage2016;24:2135–40. [5] Wang Y, Yu D, Liu Z, et al. Exosomes from embryonic mesenchymal stem cells alleviate osteoarthritis through balancing synthesis and degradation of cartilage extracellular matrix. Stem cell research &amp; therapy2017;8:189. <h3>Acknowledgements</h3> No. <h3>Disclosure of Interest</h3> None declared
GENE-19. GAINING A BETTER UNDERSTANDING OF DNA METHYLATION FEATURES ASSOCIATED WITH SEX DIFFERENCES IN GLIOBLASTOMA
Authors: Lindsay Stetson, Justin Lathia, Joshua Rubin, James Connor, Kristin Waite, Michael Berens, Jill Barnholtz-Sloan
Journal: Neuro-Oncology (2018)

Glioblastoma displays strong sexual dimorphism with male having an increased prevalence and poorer prognosis. While sex based methylation differences in the MGMT promoter have been described in GBM patients, we expanded on these findings with a full genome interrogation of sex-based DNA methylation differences in GBM patients (n = 56 females, n = 77 males). Using Illumina 450k DNA methylation data from The Cancer Genome Atlas (TCGA), we found 359 probes and 12 regions significantly differentially methylated between males and females (sex chromosomes were excluded from the analysis). Males had three times the number of probes significantly differentially hypermethylated than females. In males hypermethylated probes occurred in known enhancer regions at a rate of 4:1 as compared to females. Areas of hypermethylation in females predominately (65%) occurred in CpG islands. An analysis of DNA motif binding sites showed multiple zinc finger transcription factor binding sites located in genomic regions hypermethylated males. Binding sites of KLF6, an important tumor suppressor known to increase p21 expression through a p53 independent pathway, were located in areas significantly hypermethylated in males. We established significant correlation between expression of p21 and methylation of KLF6 binding sites. These findings provide a potential biological basis for our previous observation of increased p21 activity and cell cycle arrest in response to DNA damage in female, but not male GBM astrocytes. Additionally, we found that NFAT5 transcription factor binding sites were significantly hypermethylated in females. These results point to possible protective biology in females, where repression of NFAT5 results in reduced integrin-induced cell dispersion and increased p21 expression results in decreased proliferation. Understanding the molecular basis for sex-based differences will improve our understanding of tumor biology and pave the way for novel diagnostics and a personalized approach for the development of more effective therapies.
Abstracts cont.
Authors: M Al-Agamy, D Ashour Bonn, N Delgado, J Mun ˜oz Bellido, M Garcı ´a Garcı ´a, S Mun ˜oz Criado, M Sa ´enz Gonza ´lez, J Garcı ´a Rodrı ´guez Salamanca, T Collyns, F M'zali, C Nice, D Roberts, M Leeds, N Camino, T Alarco ´n, C Toro, A Morente, M Martı ´nez-Padial, V Soriano, M Baquero Madrid, S Gu, F Kolayli, K Demirdag, M Gu, M Altindis, R Caylan, S Hosoglu, H Vahaboglu, E Coman, S Besier, A Ludwig, V Brade, T Wichelhaus, M Castanheira, M Toleman, R Mendes, R Jones, T Walsh, J Patzer
Journal: Clinical Microbiology and Infection (2004)
IMMU-38. TARGETING HYPOXIA DOWNSTREAM SIGNALING PROTEIN, CAIX FOR CAR-T CELL THERAPY AGAINST GLIOBLASTOMA (GBM)
Authors: Jing Cui, Qi Zhang, Qi Song, Herui Wang, Xiaoyu Cao, Timothy Westlake, Kaiyong Yang, Jared Rosenblum, Yu Yao, Mark Gilbert, Zhengping Zhuang
Journal: Neuro-Oncology (2018)

The need for novel therapies for GBM treatment is well established. While chimeric antigen receptor (CAR)-engineered T cells represent a promising cancer treatment modality, highly expressed unique cell surface antigens are essential. We postulated that tumor-specific surface antigens related to hypoxia signaling may have potential. Carbonic Anhydrase IX (CAIX) is active in settings of unbalanced pH driving proton transport to the extracellular medium in response to decreased oxygen tension. We provide evidence that CAIX is highly expressed in GBM and thus a potentially suitable target which we investigated using CAIX-specific CAR-T cells against GBM cells. Patient GBM tissues were evaluated for CAIX protein expression. Antitumor CAIX-specific CAR T cells were developed and tested against four GBM cell lines: U251, LN 229, T98G, and A172. Cytotoxicity of CAIX CAR-T cells was assessed using the levels of IFN-γ, TNF-α, and IL-2 released when co-cultured with tumor cells. Direct intra-tumor injection of CAR-T cells into intracranial GBM xenograft mouse model was used for in vivo testing. We confirmed high expression of CAIX in of human GBM. The viral construct of CAIX-specific CAR-T cells generated was tested against GBM cell lines. In vitro, CAIX-specific CAR-T cells displayed enhanced GBM cells cytolysis and increased IFN-γ, TNF-α, and IL-2 production. The CAR-T cells showed a specific CAIX-dependent recognition of GBM cells. Direct intra-tumor injection of the CAR-T cells into an intracranial GBM xenograft mouse model efficiently suppressed the growth of GBM cells and significantly prolonged mouse survival. In approximately 20%, CAIX specific CAR-T cells completely eradicated GBM tumors. The present study demonstrates the specificity of CAIX under hypoxic conditions in GBM. The results also show that CAIX represents a viable target for CAR-T cells and may be a promising strategy to treat GBM.
Symptom-based interventions to promote quality survivorship
Authors: Christina Amidei
Journal: Neuro-Oncology (2018)

Survival alone is no longer an adequate outcome for persons with brain tumors; the quality of the survivorship experience should be viewed with equal importance. Symptom management is a significant component of quality survivorship care. Regardless of their histology, brain tumors and therapies used to treat them produce symptoms that affect an individual's ability to function in everyday life. Common symptoms include fatigue, cognitive impairment, distress, and sleep disturbance. Symptom-based interventions for persons with brain tumors focus on prevention, self-management, and prescriptive interventions targeted to these problems. Unfortunately, little evidence exists to support many interventions, making it challenging for clinicians to provide concrete recommendations. Research is needed to provide evidence in support of symptom-based interventions while novel approaches to these challenging problems are developed.
GENE-20. A NOVEL K-M ENHANCER REGULATES TEMOZOLOMIDE RESISTANCE AND TUMOR GROWTH IN GLIOBLASTOMA
Authors: Xiaoyue Chen, Minjie Zhang, Haiyun Gan, Jeong-Heon Lee, Dong Fang, Gaspar Kitange, Lihong He, Zeng Hu, Zhiguo Zhang, Jann Sarkaria
Journal: Neuro-Oncology (2018)

Emergence of temozolomide (TMZ) resistance and increased tumor aggressiveness are common in recurrent glioblastoma. However, mechanisms promoting these phenomena are incompletely understood. Previously, we described in vivo models of acquired TMZ resistance in GBM patient derived xenografts (PDXs), including MGMT expressing TMZ resistant subline (GBM12-3080) and TMZ naïve subline (GBM12-5199). To identify mechanisms associated with MGMT upregulation, the epigenetic differences between these lines were analyzed by ChIP-seq. Compared to GBM12-5199, GBM12-3080 displays H3K4me3 within the MGMT promoter region and H3K36me3 within the MGMT gene body region, indicative of an active epigenetic landscape. In addition, a genomic region localized between the promoters of MKI67, which encodes Ki-67 protein, and MGMT acquired active enhancer marks (H3K4me1 and H3K27ac) in GBM12-3080. Similar histone marks increase within this putative enhancer region were identified in paired samples from TMZ naïve and recurrent tumors in three out of eight PDX models and one out of three recurrent patient tumors. Using H3K27ac occupancy as a guide, tiled fragments of the putative enhancer were cloned into a luciferase reporter system, which ultimately identified a 1.5 kb region with robust enhancer activity. In parallel, a chromatin conformation capture assay demonstrated physical interaction between this 1.5 kb enhancer region and the MGMT promoter, which was only detectable in GBM12-3080. Finally, deletion of this enhancer by CRISPR/Cas9 in both GBM12-3080 and MGMT expressing glioblastoma cell line (SKMG3) reduced MGMT expression by greater than 90% and reduced the TMZ IC50 by 71% and 97%, respectively. Consistently, the expression of the adjacent gene, MKI67, was reduced by approximately 40% in both lines, and tumorigenicity of GBM12-3080 deletion clones was markedly suppressed. In conclusion, K-M enhancer regulates MGMT and Ki-67 expression independent of DNA methylation. Inhibition of this enhancer may sensitize tumors to TMZ and reduce tumor growth in a sub-population of recurrent glioblastoma.
Abstract 19423: Deletion of LRP1 in Airway Epithelium Exacerbates Smoke-Induced Oxidative Damage
Authors: Itsaso Garcia-Arcos, Roger Alvarez-Buve, Lillian Chow, Ira J Goldberg, Robert F Foronjy
Journal: Circulation (2017)

The LDL receptor related protein 1 (LRP1) is a multiligand receptor that partakes in diverse cellular events, ranging from endocytosis of lipoproteins to inflammation signaling. The regulation of L...
NCMP-19. PERIOPERATIVE SEIZURE OF BRAIN TUMOR SURGERY AND ITS PREVENTION.: A SINGLE INSTITUTE EXPERIENCE
Authors: Kanji Mori, Tomofumi Takenaka, Hideki Kuroda, Maki Kobayashi, Tetsuya Kumagai, Shingo Toyoya, Takuyu Taki
Journal: Neuro-Oncology (2018)

Standard care for prevention of perioperative seizure in brain tumor surgery is not established and prophylactic use of antiepileptic drug in seizure-naïve patients is controversial. To examine the efficacy and problem of perioperative antiepileptic therapy, we retrospectively studied brain tumor patients who received surgical treatment in our institution between July 2016 and May 2018. Among 128 patients who underwent tumor resection or biopsy, sixty-five (50.1%) were received antiepileptic drug therapy. Twenty-six patients had preoperative seizure (Group A). Histopathological diagnoses of Group A were metastatic brain tumor (11 patients: 42.3%), meningioma (7 patients: 26.9%), gliomas (5 patients: 19.2), and malignant lymphoma (3 patients: 11.5%). Eighteen patients (69.2%) of them were treated with levetiracetam (LEV) monotherapy, followed by valproic acid (VPA). Thirty-eight patients (29.7%) received prophylactic use (Group B). Histopathological diagnoses of Group B were 9 metastases (23.7%), 18 meningiomas (47.4%), 9 gliomas (23.7%), and 2 malignant lymphomas (0.5%). Thirty-four patients (87.2%) were initially treated with LEV, followed by phenytoin, and VPA was not used. We treated Group A patients with same manner as before surgery, and convulsion occurred 6 patients (23.1%) within a week after surgery. Three patents were added other drugs and all were successfully treated after seizure. On the other hand, no seizure was observed in Group B. Mild adverse effect (dizziness) occurred in two patients in Group B. One was reduced drug amount and the other was changed drug. Recently, novel antiepileptic drugs have been introduced and they can be used in Japan. Further study will be needed to lower the seizure rate in perioperative period of tumor burden patients by those drugs. Complete seizure prevention and low complication would allow prophylactic treatment on basis of our institutional strategy.
EPID-03. THE MINORITY ADVANTAGE -DISPARITIES IN PRIMARY BRAIN TUMOR SURVIVAL IN TEXAS STATE 1995–2013
Authors: Solomon Ambe, Olalekan Olanipekun, Ekokobe Fonkem
Journal: Neuro-Oncology (2018)

This paper examines demographic and geographic disparities in primary brain tumor survival in Texas state, predictors of survival and hazard ratios and will reflect differences at the local level that would have otherwise been masked in a national report. IMPACT: Our study reveals evidence of genetic and environmental basis in primary brain tumor survival. Insights into specific disparities can guide research especially on poorly understood entities, health policy implementation and local practice. Data was obtained from the Texas cancer registry 1995–2013.event was death from malignant primary brain tumor and cause specific survival was used. SAS version 9.3 and SEER*Stat 8.3.2 were used for the analysis. Kaplan Meier survival estimates with the Log-Rank test was used to compare the survival rates. The Cox regression proportional hazard model estimated the hazard ratios. There is significant demographic difference in survival curves. White males were at greatest hazard of dying from malignant brain tumors. Median survival is least among Non-Hispanic whites: 20 months (95% CI: 19, 21) and greatest among Asian: 92 months (95% CI: 72, 142). 5 year survival was White(38.9%), Blacks (44.3%) American Indian/Alaskan native (55.9%) Asian (56.7%). There is observed inverse relationship between socio-economic status and survival. Other significant predictors of survival were age, sex and geographic location. Ethnic minorities and lower socio-economic class demonstrated survival advantage. Non- Hispanic white males have worse survival of primary brain tumors. Survival curves differed significantly by sex, geographic location and race. Race, age, sex, geographic location and poverty level significantly predict the hazard of death reflecting strong genetic and environmental influence.
HOUT-26. SURVIVAL OUTCOMES IN GLIOBLASTOMA PATIENTS USING TTFIELDS: THE BAYLOR SCOTT &amp; WHITE MEDICAL CENTER IN CENTRAL TEXAS EXPERIENCE
Authors: Akhilesh Padhye, Dong-Ho Gwak, Ekokobe Fonkem
Journal: Neuro-Oncology (2018)

Glioblastoma is a CNS cancer with extremely poor survival rates despite advances in chemoradiation therapy. TTFields (Optune) are an FDA approved option for treatment of glioblastoma. PURPOSE: This article aims to determine whether Optune compliance rates in patients with both newly diagnosed and recurrent glioblastoma affects survival. METHODS/ANALYSIS: A comprehensive list of glioblastoma patients was extracted from the Baylor Scott & White tumor registry from 2012–2018. Data on compliance, demographics, IDH/MGMT status and survival was compiled on Optune users. These variables were analyzed using the Welch T-test to ascertain their impact on compliance and survival. A Pearson correlation coefficient was calculated to determine the relationship between compliance and survival post-Optune. 37 patients were identified (median age: 60, range: 21–86). Males were more affected (60.0%), the frontal lobe was the most common site (35.1%), and the median survival was 17 months. There was no statistical difference in survival length (months) based on gender (males = 21.5, females = 18.9, p = 0.52), MGMT status (methylated = 21.8, unmethylated = 17.8, p = 0.40), and IDH status (wild = 19.1, mutated = 30.2, p = 0.41). The average Optune compliance was 66.2%, with no statistical difference based on age (age < 50 = 54.1%, age > 50 = 71.1%, p = 0.06) and gender (male = 66.6%, female = 65.6%, p = 0.89). The correlation coefficient comparing compliance and survival post-Optune was R = -0.247 (p = 0.141). Studies have shown that Optune compliance of 75% or greater can improve outcomes. In our own limited study, the average compliance was markedly below at 66.2%, with no impact on the median 17-month survival. Age and gender did not play a role in compliance rates. This illustrates that further education is required in central Texas to improve compliance and patient outcomes.