bluuebunny/crossref_metadata_2025 huggingface dataset:
EPID-06. IMMUNE-RELATED PLASMA BIOMARKERS IN GLIOBLASTOMA
Authors: Bjørnbak Holst Camilla , Jarle Christensen Ib , Skjoeth-Rasmussen Jane , Skovgaard Poulsen Hans , Hamerlik Petra , Sidenius Johansen Julia
Published: November 2019

BACKGROUND

Glioblastoma (GBM) is an aggressive and malignant primary brain tumor with limited treatment options and a dismal prognosis. Immunotherapy is advancing in other types of cancer but has not yet proven effective in glioblastoma. Prognostic and predictive biomarkers and new treatment targets are urgently needed.

MATERIAL AND METHODS

158 patients with glioma WHO grade II-IV were included in the study. Plasma was analyzed for interleukin (IL)-6, YKL-40 (Gene: CHI3L1) and 91 other immune-related protein biomarkers by ELISA or/and Olink technology. CHI3L1 rs4950928 genotyping was analyzed on DNA extracted from whole-blood.

RESULTS

Fourteen of 92 immune-related biomarkers in plasma detected with the Olink immuno-oncology array were related with tumor grade or/and type (p< 0.05) (corrected for age), whereas plasma IL-6 and YKL-40 did not change with tumor grade. In univariate analysis of plasma from 94 patients with newly diagnosed GBM higher baseline IL-6 was associated with short OS (HR=1.19 (per 2-fold change in IL-6), p=0.04), YKL-40 showed a similar trend (HR=1.20 (per 2-fold change in YKL-40), p=0.056) and high/low baseline levels of additional 15 immune-related biomarkers (e.g. CD244, Granzyme B, ICOS ligand, IL-8 and Pleiotrophin) were associated with short OS (p< 0.05). Genetic variation in YKL-40 was associated with plasma YKL-40 levels (+/+ vs. -/+ vs. -/-, p=0.0004) but not with OS in patients with GBM (HR= 0.78 (+/+ vs. -/+), p=0.32).

CONCLUSION

High levels of several immune-related biomarkers in plasma including IL-6, IL-8, CD244, Granzyme B, ICOS ligand, and Pleiotrophin from patients with glioblastoma were related or inversely related to OS.
EPID-11. OCCURRENCE OF SYSTEMIC CANCER IN PATIENTS WITH GLIOBLASTOMA: POPULATION CHARACTERIZATION AND COMPLICATIONS
Authors: Horta Erika , Walbert Tobias , Snyder James
Published: November 2019

It is unclear how the diagnosis of a second cancer influences the treatment and complications of patients with glioblastoma (GBM). A chart review of adults with primary or secondary GBM and another systemic cancer seen in the last five years was performed. Demographic data, thromboembolic events, cytopenia and deviations from the standardized GBM treatment protocol (EBRT with 60 Gy plus concurrent temozolomide followed by adjuvant temozolomide) were analyzed. Exclusion criteria was the diagnosis of genetic syndromes that predispose to tumorigenesis. A total of 56 GBM patients with 61 systemic cancers were identified. The most common systemic cancers were breast and prostate each representing 27 %. Men were 55% of patients (p=0.3) but older (69+11 years, p=0.003) than when compared to CBTRUS data. Systemic cancer was diagnosed before GBM in 82% of the cases. Age at the diagnosis of systemic cancer was 64 +11 years. Patients with systemic cancer diagnosed prior to GBM, had shorter survival (1.15+1.08 years versus 4.4+ 3.4 years, p < 0.001), but survival was not shorter than expected when compared to historical survival of GBM. Thromboembolism was seen in 27% of patients, only once it was seen before the diagnosis of GBM. Although all patients with hematological malignancies had low platelets, thrombocytopenia was not associated to prior chemotherapy. Deviation of GBM treatment was seen in 15% of the cases, a delay in the systemic cancer once. This is the largest documented series of patients with GBM and systemic cancer. We conclude that although this population is older than expected, thromboembolism rates and survival are similar to the literature for patients with GBM. In the light of all those considerations, patients with GBM and the diagnosis of a systemic cancer should be treated according to guideline.
EPID-12. IMPACT OF RACE AND GEOGRAPHIC LOCATION ON IDH MUTATIONS AND GLIOBLASTOMA SURVIVAL
Authors: McCormack Ryan , Zhu Ping , Takayasu Takeshi , Hines Gabriella , Zeineddine Hussein , Tandon Nitin , Moreno Jimenez Sergio , Gonzalez Alberto , Ballester Leomar Y , Esquenazi Yoshua
Published: November 2019

Glioblastoma (GBM) is the most common primary malignant brain tumor of the central nervous system with a 5-year survival of < 5%. Population studies have demonstrated that among all ethnicities, non-Hispanic whites (NHW) have the worst prognosis; however, differences within the oncogenome based on ethnicity have not been assessed. We utilized the Texas Cancer Registry (TCR) for population-based analysis including 4,134 GBM patients between the years of 1995 to 2013 with 75.6% NHW and 16.5% Hispanics. In accordance with previously published findings, within the TCR we detected a 12% relative survival improvement in Hispanics compared to NHW when controlling for known survival mediators including age, resection, chemotherapy, and radiation. In order to assess for oncogenic differences, we utilized a prospectively maintained database of 257 GBM patients within the city of Houston, TX (14.9% Hispanic) and 48 GBM patients from the National Institute of Neurology and Neurosurgery in Mexico City, Mexico (100% Hispanic) to assess for oncogenomic differences attributable to ethnicity. Next generation sequencing of GBM within the Houston cohort, for 315 tumor-related genes, identified no significant differences in genomic alterations owing to ethnicity. However, when we compared the multigenerational, mixed-heritage Hispanics present in the Houston cohort to the Mexico cohort (Sanger sequencing), a significant difference was found in the frequency of IDH1and IDH2mutations (29.8 % Mexico Hispanics, 7.9% Houston Hispanics; p=0.014). In particular, the rate of IDH2mutations is significantly enriched in the Mexico population (19%) when compared to the Houston population (0%) or to previously published rates of IDH2 mutations in GBM (~3%). Ultimately, these findings highlight the need for multiethnic trial enrollment as well as the need for improved testing of IDH2 mutations in patients of distinct ethnicities. Future studies are needed to identify the mechanisms promoting the increased frequency of IDH2 mutations in Mexican Hispanics.
EPID-15. GUIDELINES FOR THE OPTIMAL USE OF SOCIAL MEDIA FOR NEURO-ONCOLOGISTS
Authors: Hamidi Nima , Mansouri Alireza
Published: November 2019

BACKGROUND

Approximately 80,000 new Americans are diagnosed with a brain tumor annually. Social media (SM) has emerged as a powerful tool for patient empowerment. Its effective utilization by healthcare professionals is vital for better connection to patients and dissemination of evidence-based information. OBJECTIVES: To develop guidelines for optimal utilization of SM by neuro-oncologists, through a review of user engagement with content posted on SM relating to brain tumors.

METHODS

Facebook (FB) and Twitter (TW) were searched using the term Brain Tumor. Page/account information such as user type, media (image/video) utilization in posts, and audience size (likes / followers) were recorded. Average activity and account annual growth (AAG) were calculated. Top qualitative themes were assigned. Correlations were assessed with Pearson’s test.

RESULTS

FB was predominantly used by organizations (64% of accounts) and provided a larger audience (67 pages,581 likes) than TW (25 accounts, 67,295 followers), which had similar proportion of personal (44%) and organizational accounts (52%). Charity & Fundraising (67%) was the top FB theme. Education & Research (72%) was the top TW theme. In FB, the page’s annual growth (PAG) was not related to rate of monthly posting or the length of activity on FB, but presence on other concurrent platforms (Rho: 0.59) was influential for PAG and audience size (p < 0.05). In TW, quantity of monthly tweets (Rho: 0.66) and media utilization (Rho: 0.78) significantly correlated with audience size and AAG (p-values < 0.05).

CONCLUSION

A multi-platform SM presence and use of relatable images/videos have a strong impact on both FB and TW engagement. FB is a stronger platform for organizations valuable for charity and fundraising. Multi-platform presence is more important than frequent posts on FB. TW is equally used by organizations and individuals, serving as an excellent medium for dissemination of research and educational material.
EPID-18. NATIONAL TRENDS IN THE USE OF TARGETED AND IMMUNOTHERAPY IN THE UP FRONT MANAGEMENT OF GLIOBLASTOMA
Authors: Wegner Rodney , White Richard , Abel Stephen , Yu Alexander , Xu Linda , Karlovits Stephen , Ranjan Tulika
Published: November 2019

BACKGROUND

Current standard of care for GBM involves an aggressive multimodality approach including surgical resection followed by adjuvant chemoradiation. Despite this approach, overall survival remains poor and treatment approaches continue to evolve. Given the successes of immunotherapy in other disease sites, implementation in GBM management may improve outcomes.

METHODS

We conducted this retrospective NCDB study to analyze treatment trends and outcomes from 2004–2015 regarding immunotherapy for GBM. We excluded patients treated without surgery, extracranial radiation, or chemotherapy as well as those lost to follow up.

RESULTS

Of the 39,317 eligible patients in this study, 511 were treated with immunotherapy and 38,806 lack thereof. Median overall survival for all patients was 15 months with a 2 and 5 year survival rate of 29% and 8%, respectively. Factors influencing delivery of immunotherapy included younger age, higher income, facility location in a metropolitan location, greater distance to the treatment facility, treatment at an academic facility, treatment outside of the years 2007 to 2009, and Caucasian race. On propensity matched analysis, survival was 18 months and 17 months with and without immunotherapy, respectively (p=0.15). Higher comorbidity, lower income, and male gender predicted for worse survival.

CONCLUSIONS

The results of this analysis show an initial decrease and then increase in the use of immunotherapy in the management of GBM. Propensity-matched analyses did not show an overall survival benefit.
EPID-32. IS THERE ANY EVIDENCE OF REPORTING AND CITATION BIAS AMONG COMPLETED PHASE III INTERVENTIONAL BRAIN TUMOR TRIALS?
Authors: Rayi Appaji , Alnahhas Iyad , Smith Rachel , Giglio Pierre , Puduvalli Vinay
Published: November 2019

OBJECTIVE

Reporting and citation bias based on positive versus negative outcome among completed phase III interventional brain tumor trials (IBTTs) have not been previously reported. Thus, we aimed to assess the evidence.

METHODS

Clinicaltrials.gov was used to obtain all phase III IBTTs completed prior to December 31st 2016. Trials closed due to poor accrual or non-phase III were excluded. Data about the funding source, type of intervention, conducted at U.S or Non-U.S locations, patients enrolled, primary completion date, time to dissemination of results in months (either reported on clinicaltrials.gov or published in a journal), citations per year (from web of science) and outcome (positive or neutral/negative) were abstracted. Median time to dissemination was estimated using Kaplan-Meier estimates and a log rank test for statistical significance. The number of citations per year for positive and negative/neutral studies was compared using a t-test.

RESULTS

65 studies were analyzed. The median time from primary completion to dissemination of results for trials with a positive outcome was 20 months (n = 20; 95% CI: 12–31) compared to 30 months for trials with a negative outcome (n=35; 95 % CI: 22 – 37) (p = 0.095). The average number of citations per year for trials with a positive outcome is 62.4 (n = 21; range 1.1 – 614.8) compared to 25.0 for trials with a negative outcome (n=35; range 0.14 - 158.8) (p = 0.213). There was no significant difference in time to dissemination based on the funding source, type of intervention or the location where the trial was conducted.

CONCLUSION

Positive phase III IBTTs results are disseminated earlier and are cited more frequently compared to negative trials. However, there is no statistically significant evidence of reporting or citation bias.
EXTH-01. A SYNGENIC MOUSE MODEL TO STUDY THE EFFICACY OF KETOGENIC DIET IN HIGH GRADE GLIOMAS
Authors: Salmaggi Andrea , Vasco Chiara , Rizzo Ambra , Padelli Francesco , Zucca Ileana , Pellegatta Serena , Massa Giorgio , Fariselli Laura , Bruzzone Mariagrazia , Ciusani Emilio
Published: November 2019

Glioblastoma multiforme is the most malignant subtype of brain tumor. Despite multimodal treatment (surgical resection and chemo/radiotherapy) the prognosis remains unsatisfactory. Based on the Warburg hypothesis, ketogenic diet (KD) has been suggested in the treatment of GBM. The syngenic, orthotopic GL261 mouse glioma model was used to evaluate the effects of KD on 7T magnetic resonance imaging/spectroscopy and metabolic response of the tumor to diet. Mice were injected with 10^5 GL261 cells into the caudate nucleus. Following implantation, animals were fed standard chow for five days then were randomly assigned to standard diet or ketogenic diet. 18 days after diet start, mice fed at KD displayed significantly higher plasmatic levels of ketone bodies. Mice fed with KD survived longer than those fed with standard diet (p< 0.05). Decreased concentrations of gamma-aminobutyric acid, N Acetyl Aspartate and N-acetylaspartylglutamate were found in tumor tissue after 9 days from the beginning of the KD diet while a huge increase in beta-hydroxybutyrate (bHB) was detected in tumor tissue as compared to normal brain. The addition of bHB at various concentrations to low-glucose culture medium did not significantly improve GL261 in vitro growth suggesting that this cell line has a limited ability to use bHB as a carbon source. The accumulation of bHB in the tumor tissue in KD fed mice, may suggest either elevated uptake of/release of bHB by tumor cells or inability of tumor cells in this context to use it in mitochondrial metabolism; the latter hypothesis is supported by the observation that GL261 cells did not display an increase in in vitro proliferation when exposed to bHB. The far less evident peak of bHB at MRI spectroscopy in the healthy brain tissue of KD fed mice, on the other hand suggests that normal brain is able to use bHB as energy source.
EXTH-17. TREATMENT OF MALIGNANT GLIOMAS WITH DRUG-LOADED MICROBUBBLES: CONCEPTION OF A PROMISING FUTURE THERAPEUTIC STRATEGY
Authors: Schulz Ellina , Mawamba Viviane , Sturm Volker , Ernestus Ralf-Ingo , Schatzschneider Ulrich , Löhr Mario , Hagemann Carsten
Published: November 2019

The major obstacles for an effective chemotherapy of glioblastomas (GBM) are the blood-brain barrier (BBB) and serious systemic side effects of the cytotoxic drugs. A new promising strategy could be the delivery of the chemotherapeutics across the BBB to the tumor site encapsulated in microbubbles. The microbubbles will shield the drug from detrimental systemic effects. Low intensity focused ultrasound (LIFU) allows opening of the BBB and a targeted release of the drugs within the brain tumor. We synthesized microbubbles ≤ 2 µm in diameter by thin-film hydration of lipids, which could be disintegrated applying LIFU. The toxicity was tested on GBM cell lines and neither the intact bubbles nor the lipids alone showed any toxic effects. Additionally, these cells were treated with 6 platinum(II) and palladium(II) complexes conjugated to lipophilic side chains of different length (C1, C8, C10) for 72 h. Cell viability was evaluated with MTT assay and in real-time utilizing the impedance-based xCELLigence DP-System. EC50 values were calculated from both assays and all six drugs were highly effective. Especially the palladium(II) compound with the C1-chain had a very low EC50 value (< 10 µM), while the longer chains and the platinum(II) compounds were less effective (EC50 10 - 30 µM). The real time proliferation assay of the drugs revealed an early and concentration-dependent onset of the cytotoxic effect, about 30 h after application. The lipophilic side chains of the drugs should allow encapsulating them into the microbubbles to develop an effective drug-delivery system for the treatment of GBM.
EXTH-18. PEPTIDE NANO-STRUCTURES ENHANCE PEDIATRIC BRAIN TUMOR CHEMOTHERAPEUTIC EFFICACY
Authors: XI Guifa , Mahenthiran Ashorne , Best Benjamin , Nayak Sonali , Smith Cara , McClendon Mark , Mania-Farnell Barbara , Kessler John , James Charles , Stupp Samuel , Tomita Tadanori
Published: November 2019

Pediatric gliomas, particularly high-grade gliomas, which include diffuse intrinsic pontine gliomas (DIPGs), are among the most formidable and devastating cancers in children. These tumors remain incurable, despite many treatment approaches. We recently identified a small population of glioma cells with stem-like features in pediatric gliomas (glioma stem cells: GSCs), that may be responsible, for therapeutic resistance. Bone morphogenetic protein 4 (BMP4), essential for CNS development, increases GSC therapeutic sensitivity and is a promising adjuvant for glioma treatment. Mechanisms through which BMP4 increases therapeutic sensitivity need to be elucidated, as this can lead to identification of additional treatment targets and delivery systems for BMP4 administration in a clinical setting. Additionally, extension of BMP4 short half-life would enhance its’ clinical application. Here we show that BMP4 increases chemosensitivity by decreasing H3K4me3 at the promoter of multidrug resistant gene 1 (MDR1), resulting in decreased MDR1 expression. BMP4 appears to bring about this effect by decreasing hSETD1A, an H3K4me3 methyltransferase. Our work also demonstrates the first use of a novel sulfated glycopeptide (glyco-PA) nanostructure as a vector for BMP4 delivery. Glyco-PA markedly extended and enhanced BMP4 function, and increased chemotherapeutic anti-tumor activity against pediatric malignant glioma cells in culture. Overall, this work illuminates BMP4 effects on pediatric glioma therapeutic sensitivity through epigenetic mechanisms, and demonstrates the potential of bioactive glyco-PA nanostructures as a delivery mechanism for treating pediatric malignant gliomas and other tumors.
EXTH-21. DIFFERENTIAL PROTEIN EXPRESSION LEVELS OF ABC AND SOLUTE CARRIER TRANSPORTERS AT THE BLOOD-BRAIN BARRIER OF HUMAN BRAIN AND GLIOBLASTOMA
Authors: Bao Xun , Wu Jianmei , Xie Youming , Kim Seongho , Michelhaugh Sharon , Jiang Jun , Mittal Sandeep , Sanai Nader , Li Jing
Published: November 2019

BACKGROUND

Mechanistic understanding and quantitative prediction of drug penetration across the human blood-brain barrier (BBB) is critical to rational drug development and treatment for brain cancer especially glioblastoma. However, prediction of drug brain/tumor penetration has been significantly hindered mainly due to the lack of quantitation data on transporter protein expression levels at the human BBB. This study was to determine protein expression levels of major transporters and markers at the BBB of human brain and glioblastoma.

METHOD

The absolute protein expression levels of major transporters and markers were determined in isolated microvessels of human brain (N=30), glioblastoma (N=47), rat (N=10) and mouse brain (N=10), using liquid chromatography with tandem mass spectrometry (LC-MS/MS) based targeted proteomics.

RESULTS

In isolated microvessels of 30 human brain specimens, the median protein abundances for ABCB1, ABCG2, GLUT1, GLUT3, LAT1, MCT1, Na/K ATPase, and Claudin-5 were 3.38, 6.21, 54.51, 7.17, 3.42, 5.71, 32.14, and 1.15 fmol/µg protein, respectively. In glioblastoma microvessels, ABCB1, ABCG2, MCT1, GLUT1, Na/K ATPase, and Claudin-5 protein levels were significantly reduced, while LAT1 was increased and GLU1 remained the same. ABCC4, OATP1A2, OATP2B1, and OAT3 were undetectable in isolated microvessels of both human brain and glioblastoma. There was species difference in transporter protein expression levels in isolated microvessels of human, rat and mouse brain. Specifically, rodent BBB expressed significantly higher ABCB1 but similar ABCG2, as compared to human BBB.

CONCLUSION

The physical and biochemical barriers of the BBB in glioblastomas are largely disrupted, as indicated by the loss or significant reduction in protein expression of the tight junction marker (claudin-5), brain endothelial cell marker (GLUT1), and major efflux transporters (ABCB1 and ABCG2) as compared to normal human BBB. Differential BBB transporter protein expression levels provides mechanistic and quantitative basis for the prediction of heterogeneous drug penetration into human normal brain and glioblastoma.
EXTH-23. COMBINED EFFECTS OF NICLOSAMIDE AND TEMOZOLOMIDE AGAINST HUMAN GLIOBLASTOMA TUMORSPHERES
Authors: Cheol Oh Hyeong , Yoo Jihwan , Shim Jin-Kyoung , Park Junseong , Lee Ji-hyun , Joo Choi Ran , sil Kim Hyun , hee Kim Nam , Hyung Moon Ju , Hyun Kim Eui , Hee Chang Jong , Kang Seok-Gu , In Yook Jong
Published: November 2019

PURPOSE

Glioblastoma (GBM) is the most aggressive type of brain tumor and has poor survival outcomes, even after a combination of surgery, radiotherapy, and chemotherapy. Temozolomide is the only agent that has been shown to be effective against GBM, suggesting that combination of temozolomide with other agents may be more effective. Niclosamide, an FDA approved anthelmintic agent, has shown anti-cancer effects against human colon, breast, prostate cancers as well as GBM. However, the efficacy of the combination of niclosamide with temozolomide against GBM tumorspheres (TSs) has not been determined. We hypothesized that the combined treatment could effectively suppress GBM TSs.

METHODS

Effects of niclosamide and/or temozolomide on GBM TSs were evaluated. Viability, stemness, and invasive properties of GBM TSs were examined. In vivo anticancer efficacy was tested in a mouse orthotopic xenograft model.

RESULTS

The combination of niclsoamide and temozolomide significantly inhibited the viability, sphere formation, expression of stemness-related proteins, and invasive properties of GBM TSs. This combination significantly down-regulated the expression of epithelial mesenchymal transition-related proteins. Bioluminescence imaging further showed that compared with either agent alone, combination of niclosamide and temozolomide significantly reduced the tumor burden in orthotopic xenograft models.

CONCLUSIONS

The combination of niclosamide and temozolomide effectively decreased the stemness and invasive properties of GBM TSs, suggesting that this regimen may be therapeutically effective in treating patients with GBM. KEYWORDS: Glioblastoma; Invasion; Niclosamide; Temozolomide; Tumorsphere
EXTH-38. ENGINEERED EXOSOMES FOR THERAPEUTIC GENE DELIVERY IN BRAIN TUMORS
Authors: McDonald Malcolm , Hasan Irtiza , Adachi Satoshi , Gumin Joy , Ledbetter Daniel , Daou Marc , Gopakumar Sricharan , Momin Eric , Long Lihong , Phillips Lynette , Parker-Kerrigan Brittany , Hossain Anwar , Lang Frederick
Published: November 2019

The poor outcome of patients with glioblastoma (GBM) is at least partly due to the inability to deliver therapeutic agents to the tumor. We have shown that exosomes, naturally occurring nano-size extracellular vesicles, are capable of delivering antiglioma microRNAs (MiRs) to brain tumors (Lang, FM et al. Neuro Oncol, 2018;20(3):380–390). However, our studies suggested that there is significant opportunity to increase packaging efficiency and delivery specificity of exosomes. To this end, we engineered exosomes to express specific viral proteins (called eExos) in order to enhance packaging and delivery capabilities of antiglioma genes. These eExos are created by transfecting HEK 293 cells with plasmids containing viral proteins and a plasmid of the therapeutic gene. After 72 hrs, differential ultracentrifugation was used to isolate the exosomes. To test the efficacy of these novel eExos, we transfected them with a plasmid containing Cre recombinase (as the therapeutic gene), and treated U87 cells harboring a dsRed/eGFP Cre recombinase/LoxP site (U87dsR/GFP). In in vitro studies, treatment of U87dsR/GFP with a single dose of eExos resulted in 82% conversion rate of cells from red to green, compared to control exosomes (< 18% green cells). In in vivo studies, a single intratumoral injection of eExos into mice harboring 7-day old intracranial U87dsR/GFP gliomas, resulted in significant increases in green cells compared to control exosomes when tumors were harvested at day 10. Mechanistic studies employing florescent microscopy demonstrate that in contrast to natural exosomes, eExos deliver their cargo to the nucleus rather than to lysosomes, avoiding degradation of the delivered agent and facilitating expression of the plasmid. We conclude that eExos, engineered to contain specific viral proteins, are capable of packaging and delivering antiglioma genes more effectively than natural exosomes and may overcome the current inability to deliver biological therapeutic agents to brain tumors.
EXTH-45. THERAPEUTIC EFFICACY OF MUTANT ISOCITRATE DEHYDROGENASE 1 (IDH1) INHIBITOR SYC-435 WITH STANDARD THERAPY IN PATIENT-DERIVED IDH1 MUTANT GLIOMA XENOGRAFT MOUSE MODELS
Authors: Kogiso Mari , Qi Lin , Zhang Huiyuan , Braun Frank , Du Yuchen , Huang Lei , Guo Lei , Huang Yulun , Lindsay Holly B , Zhao Sibo , Injac Sarah , Baxter Patricia , Su Jack , Perlaky Laszlo , Parsons Williams , Chintagumpala Murali , Adekunle Adesina , Wang Jialiang , Song Yongcheng , Li Xiao-Nan
Published: November 2019

Mutation in isocitrate dehydrogenase 1 (IDH1) occurs in >70% of WHO grade II/III astrocytomas, oligodendrogliomas and secondary glioblastoma. The mutant enzyme catalyzes the reduction of α-ketoglutaric acid to D-2-hydroxyglutaric acid, leading to cancer initiation. In this study, we examined therapeutic efficacy of SYC-435 (1-hydroxypyridin-2-one), a newly developed mutant IDH1inhibitor, in IDH1 mutant gliomas. IDH1 R132H mutation (homozygous) was detected in BT142 anaplastic oligoastrocytoma (AOA) and R132C mutation (mutant allele frequency 39–50%) in V0914AOA by pyrosequencing. Suppression of cell growth by SYC-435 was observed with more sensitive of mutant over wild-type IDH1. Patient-derived orthotopic xenograft mouse models of BT142AOA and V0914AOA were treated with vehicle, SYC-435 (15 mg/kg/day x 28 days), temozolomide (50 mg/kg/day x 5 days)/fractionated radiation (2 Gy/day x 5 days) (standard therapy), and SYC-435/standard therapy starting 2 weeks after intracranial tumor implantation. Log rank analysis showed SYC-435 alone did not alter survival times. Although standard therapy significantly prolonged survival times in both models (P< 0.0005), SYC-435/standard therapy further extended survival times (P< 0.05) in V0914AOA and exhibited similar trend in BT142AOA. Elevation of 2-HG/α-KG ratio and methylation of H3K4/H3K9 in V0914AOA tumor compared to wild-type model was detected at the end of treatments. SYC-435 with/without standard therapy tended to reduce 2-HG/α-KG ratio and dramatically reduced methylation of H3K4/H3K9. RNA-seq analysis showed sirtuin signaling pathway, mitochondrial dysfunction and oxidative phosphorylation pathways with mitochondrial DNA (mtDNA) encoded molecules were highly affected by all treatments. However, mtDNA regulation did not correlate to survival benefits. In conclusion, SYC-435 possesses anti-tumor effects that are more sensitive in IDH1 mutant gliomas and generated strong synergistic activities with standard therapies for survival benefits with reduced methylation of H3K4/H3K9. Treatments significantly affected mtDNA but significance to survival benefits remains to be elucidated. Our data support the clinical testing of SYC-435 in patients with IDH1 mutant glioma.
EXTH-68. INTRANASAL DELIVERY OF DRUG-LOADED LIPOSOMES SENSITIZES TUMORS TO IRRADIATION IN SYNGENEIC MODEL OF GLIOMA.
Authors: Zhang Peng , Zannikou Markella , Lesniak Maciej S , Balyasnikova Irina
Published: November 2019

Tumor-associated myeloid cells (TAMCs) are appealing therapeutic target in glioblastoma (GBM) due to their immunosuppressive function and robust presence in the tumor tissue. We designed a lipid nanoparticle (LNP) modified with anti-PD-L1 antibody (αPD-L1) for targeted delivery to PD-L1 expressing cells within the tumor. We demonstrate that αPD-L1-LNP are effectively and specifically taken up by TAMCs. The encapsulation of dinaciclib, an inhibitor of a cyclin-dependent kinase, into αPD-L1-LNP, leads to a robust depletion of TAMCs upon local delivery. We next investigated the therapeutic relevance of non-invasive intranasal delivery of αPD-L1-LNP drug nano formulation in a GL261 syngeneic model of glioma. We show that intranasal administration of αPD-L1-LNP/dinaciclib alone did not significantly affect the survival of tumor-bearing mice, whereas a regimen combing with fractionated irradiation led to a significantly improved animal survival of mice bearing GL261 glioma over monotherapies. Histological analysis of tissue demonstrated about a four-fold increase in the uptake of nanoparticles within the tumor bed but not in the normal brain in mice treated with fractionated irradiation over the control mice. These results warrant further development and validation of intranasal delivery of therapeutic nanoformulations targeting TAMCs in preclinical animal models to improve the outcome in GBM patients.
EXTH-72. MANZAMINE A-DERIVED COMPOUNDS AS POTENTIAL ANTI-BRAIN TUMOR AGENTS AND IT MECHANISM STUDY
Authors: Huang Chiung-Yin , Chen Pin-Yuan , Wei Kuo-Chen , Hwang Tsong-Long
Published: November 2019

Glioma is a severe disease with poor prognosis. Chemotherapy plays an important role but very few drugs are effective. There are two major issues: (1) the specialized blood-brain barrier blocks most large molecules from penetrating into target area; (2) tumor cells frequently develop drug resistant. Therefore, developing new chemotherapeutic agents for malignant brain tumor treatment may significantly improve the current difficulties. Compounds derived from nature products have been considered as potential sources for new discovery of anti-cancer drug. Manzamine A-derived compounds, showed significant anticancer activities against colon adenocarcinoma DLD cells, lung large cell carcinoma NCI-H661 cells, and hepatoma HepG2/A2 cells. In this study, we used in vitro model for screening these compounds and discovered both cytotoxic and anti-proliferative effects against brain tumor cells, such as A172, U87MG, and GL261 cell lines. We then used animal models to test the toxicities and treatment effect of compound A3 in vivo, and delivered the agent by convection-enhanced delivery to improve drug concentration in brain. Survival benefit for brain tumor-bearing animal was found for optimal dosage of compound A3. Details of anti-tumor mechanism need further evaluation.
GENE-04. THE ONCOGENIC FUNCTIONS OF YAP1-GENE FUSIONS CAN BE INHIBITED BY DISRUPTION OF YAP1-TEAD INTERACTION
Authors: Szulzewsky Frank , Hoellerbauer Pia , Wu Hua-Jun , Cimino P J , Michor Franziska , Paddison Patrick , Vasioukhin Valeri , Holland Eric
Published: November 2019

Supratentorial ependymoma can be sub-stratified into clinically relevant subtypes characterized by distinct molecular features. The subtype defined by high YAP1 activity harbored two distinct YAP1 gene fusions, YAP1-MAMLD1 and YAP1-FAM118B. In addition, YAP1 gene fusions have been detected in several other cancer types, including Epithelioid Hemangioendothelioma and Endocervical Adenocarcinoma. YAP1 is a key transcriptional co-activator and proto-oncogene that is negatively regulated by the Hippo pathway. Here, we show that both YAP1-MAMLD1 and YAP1-FAM118B, as well as additional YAP1 fusion genes found in other cancer types, are potent oncogenic drivers that cause tumor formation in the brain and the hindlimb in mice upon overexpression by somatic cell gene transfer. Using different in vitro assays, including Luciferase, RNA-, and ChIP Seq, we show that both the N-terminal YAP1 part and the C-terminal fusion partners exert activity. We can show that the YAP1 activity still relies on the binding to TEAD transcription factors, whereas the C terminal activity does not. Furthermore, the different fusion proteins have become independent from negative Hippo pathway signaling by constitutive nuclear localization and protection from degradation. In addition, by introducing point mutations and truncations to block the YAP1 and the MAMLD1 function we can show that the activity of both halves contributes to the oncogenic function of YAP1-MAMLD1. Using in vitro and in vivo assays we can show that pharmacological and genetic ablation of YAP-TEAD interaction diminishes the oncogenic potential of the fusions, indicating that this might be a potential therapeutic approach for these tumors in the future.
GENE-05. THE LOSS OF SUCCINATE DEHYDROGENASE B EXPRESSION IS FREQUENTLY IDENTIFIED IN HEMANGIOBLASTOMA OF THE CENTRAL NERVOUS SYSTEM
Authors: Kim Se-Hyuk , Hoon Roh Tae , Yim Hyunee , Roh Jin , Beom Lee Kyi , Jeong Seon-Yong , Kim Jang-Hee , Hyun Park So
Published: November 2019

Succinate dehydrogenase (SDH) is a mitochondrial enzyme that plays an important role in both the Krebs cycle and the electron transport chain. SDH inactivation is associated with tumorigenesis in certain types of tumor. SDH consists of subunits A, B, C and D (SDHA, SDHB, SDHC, and SDHD, respectively). Immunohistochemistry for SDHB is a reliable method for detecting the inactivation of SDH by mutations in SDHA, SDHB, SDHC, SDHD and SDH complex assembly factor 2 (SDHAF2) genes with high sensitivity and specificity. SDHB immunohistochemistry has been used to examine the inactivation of SDH in various types of tumors. However, data on central nervous system (CNS) tumors are very limited. In the present study, we investigated the loss of SDHB immunoexpression in 90 cases of CNS tumors. Among the 90 cases of CNS tumors, only three cases of hemangioblastoma showed loss of SDHB immunoexpression. We further investigated SDHB immunoexpression in 35 cases of hemangioblastoma and found that 28 (80%) showed either negative or weak-diffuse pattern of SDHB immunoexpression, which suggests the inactivation of SDH. Our results suggest that SDH inactivation may represent an alternative pathway in the tumorigenesis of hemangioblastoma.
GENE-08. SECONDARY GLIOBLASTOMA, IDH-WILDTYPE ARISING IN DIFFUSE ASTROCYTOMA, IDH-MUTANT: A CASE REPORT
Authors: Sang Lee Kyu , Choe Gheeyoung
Published: November 2019

Primary glioblastoma develops de novo without clinical or histological evidence of a low-grade precursor lesion, while secondary glioblastoma develops from a low-grade glioma. The same IDH mutation is observed in almost secondary glioblastomas that occurs in low-grade gliomas with IDH mutation. Present report is an extraordinary case of secondary glioblastoma, IDH-wildtype arising in diffuse astrocytoma, IDH-mutant. A 31-year-old female presented with seizure 3 months ago, who had a history of operation for diffuse astrocytoma, IDH-mutant on the left frontal lobe 6 years ago. Magnetic resonance imaging test revealed new infiltrative lesions (6.5cm) in left frontal lobe and corpus callosum, in addition to the non-enhancing mass (3.4cm). New infiltrative lesion suspected anaplastic change and the patient underwent tumorectomy. Microscopically, non-enhancing lesion showed high cellularity, moderate nuclear atypia and brisk mitosis. Microvascular proliferation and necrosis were absent that can be diagnosis as anaplastic astrocytoma. However, new infiltrative lesion showed microvascular proliferation and necrosis that acceptable for diagnosis as glioblastoma. IDH-1 immunohistochemistry (IHC) was positive in anaplastic astrocytoma but negative in glioblastoma. In addition, we assessed NGS based on the SNUBH Brain v1.0 (Macrogen, Seoul, South Korea) panel. Similar to IHC result, IDH-1 (p.Arg132His) mutation was found in anaplastic astrocytoma but not in glioblastoma. Interestingly, ATRX (p.Gln1670Ter) and TP53 (p.His193Arg) mutations were found in both lesions. Additionally, PTEN (p.His296Pro) mutation was identified in glioblastoma component only. Until now, it is well-known hypothesis that the IDH mutation initiated in glial progenitor cell and the other genetic mutations occur sequentially in pathogenesis of secondary glioblastoma. Notably, this is the first case report that other genetic alterations can be initiated before IDH mutation contrary to previous hypothesis. In our case, mutation of ATRX and TP53 might be initiated, and PTEN and IDH-1 mutations were sequentially occurred in glioblastoma and anaplastic astrocytoma, respectively.
GENE-09. LONG NONCODING RNA lncHLX2-7 A PUTATIVE MOLECULAR MARKER AND A THERAPEUTIC TARGET FOR GROUP III MEDULLOBLASTOMA
Authors: Katsushima Keisuke , Joshi Piyush , Lee Bongyong , Stapleton Stacie , Jallo George , Raabe Eric , Eberhart Charles , Perera Ranjan
Published: November 2019

Medulloblastoma (MB), a central nervous system tumor that predominantly affects children, requires aggressive therapy. It can recur as resistant disease and is recurrent medulloblastoma is frequently fatal. There are four groups of MBs (WNT, SHH, Group III, and Group Ⅳ) and they are characterized by specific mutations, copy number alterations, transcriptomic profiles, and clinical outcomes. Recent advances in noncoding RNA genome could contribute to sub-classification of medulloblastoma. The focus of this study is to identify novel long noncoding RNAs (lncRNAs) as molecular markers and potential therapeutic targets within each subgroup of MBs, in particular within the Group III. We analyzed publicly available 723 microarrays and 123 RNA-seq datasets using machine-learning statistical algorithms (random-forest and Lasso) to identify a group of putative lncRNA signatures that may be able to differentiate medulloblastoma subgroups accurately. Among those, lncHLX2-7 was highly upregulated in Group III MBs compared to other groups. RNA-FISH analysis revealed that lncHLX2-7 is highly expressed primarily in Group III MB as compared to other groups and normal brain (cerebellum). Furthermore, depletion of lncHLX2-7 significantly reduced 20- 30% of cell growth together with the induction of apoptosis in MED211 and D425-MED Group III MB cell lines (n=3, p< 0.01, t-test). We present here supporting evidence that lncHLX2-7 is a novel molecular marker and potential therapeutic target for Group III MBs in children.
GENE-13. GENOMIC AND RADIOMIC LANDSCAPE OF IDH WILDTYPE-TERT PROMOTER MUTATION IN LOWER-GRADE GLIOMAS
Authors: Liu Shuai , Zhang Chuanbao , Qiu Xiaoguang
Published: November 2019

BACKGROUND

Recently, a rare subset of lower grade glioma (LoG), characterized by wild-type isocitrate dehydrogenase (IDH) and mutated TERT promoter (IDHWT-TERTpMut), has been highlighted for its dismal clinical behavior and classified as world health organization (WHO) grade IV.

METHODS

We examined this distinct tumor subset through genome-wide analysis of 745 gliomas and radiomic analysis of 129 LoGs.

RESULTS

We found that the prognosis and genetic lineage of IDHWT-TERTpMut LoGs were similar to those of glioblastoma. Importantly, a signature of 7 radiomic features from magnetic resonance imaging data differentiated IDHWT-TERTpMut LoGs from other LoGs. In addition, we found the radiomic related genes involved in many tumorigenic processes.

CONCLUSIONS

Overall, our findings suggest that the biological characteristics of IDHWT-TERTpMut LoGs and the radiomic signature could help in the non-invasive diagnosis of this tumor subtype.
GENE-23. GENOME-WIDE DNA METHYLATION PROFILES DISTINGUISH SILENT FROM NON-SILENT ACTH ADENOMAS
Authors: Ricklefs Franz , Fita Krys , Rotermund Roman , Westphal Manfred , Schüller Ulrich , Flitsch Joerg
Published: November 2019

BACKGROUND Corticotroph adenomas are immunopositive for adrenocorticotrophic hormone (ACTH) associated with elevated blood ACTH levels leading to Cushing disease (CD). Yet silent ACTH adenomas (SCA) immunostain for ACTH but do not cause hypercortisolism. SCA have consistently been shown to have a more aggressive postoperative course, then nonfunctioning and ACTH adenomas. Here we show that genome-wide methylation profiles can be used to distinguish ACTH adenomas from SCA. METHODS16 SCA patients and 19 CD patients that underwent transsphenoidal resection were included. Tumor size was measured by MRI. Tumor histology was proven by immunstain for ACTH and routine histopathology. Sanger sequencing was performed to analyse mutational burden within the ACTH locus (n=3). Genome-wide DNA methylation profiling was performed using a 850k Illumina EPIC array and classified by the DKFZ brain tumor classifier as well as PCA analysis using R (n=17). RESULTS Mean age was 55,4 and 46,2 for SCA and CD patients, respectively. Patients with SCA had significantly larger tumors (SCA: 12,56±3,07ccm; CD: 1,9±1,2ccm p< 0.01). Both SCA and CD tumors showed strong expression of ACTH as proven by immunohistochemistry. Sanger sequencing revealed no mutations within the ACTH gene locus in SCA. Both, SCA and CD tumors classified as ACTH adenomas by genome-wide methylation profiling. Further PCA of DNA methylation profiles allowed subtype tumor classification into SCA and CD adenomas. CONCLUSION SCA show a strong expression of ACTH without causing hypercortisolism. The reason for this is not yet known. Our data suggest that SCA do not harbor specific mutations within the ACTH gene locus. However genome wide methylation profiles allows subgrouping of SCA and CD adenomas.
GENE-25. GWAS BY MOLECULAR SUBTYPE IDENTIFIED NOVEL RISK LOCI FOR ADULT DIFFUSE GLIOMA
Authors: Eckel-Passow Jeanette , Decker Paul , Kosel Matthew , Kollmeyer Thomas , Molinaro Annette , Rice Terri , Drucker Kristen , Hansen Helen , McCoy Lucie , Bracci Paige , Wiemels Joseph , Wiencke John , Lachance Daniel , Wrensch Margaret , Jenkins Robert
Published: November 2019

Genome-wide association studies (GWAS) have revealed that 25 regions in 24 genes are associated with adult diffuse glioma development. These regions were identified by performing GWAS of glioma overall and GWAS by pathology (GBM and nonGBM). Subsequently, these regions have been evaluated for associations with specific molecular subtypes. The 2016 WHO Classification of Tumors of the Central Nervous System utilizes two somatic alterations to molecularly-classify adult diffuse glioma: IDH mutation and 1p/19q codeletion. TERT promoter mutation has also been shown to be associated with age at diagnosis and patient outcome. We hypothesized that germline variants may increase susceptibility to, or interact with, these somatic alterations to accelerate the development of specific molecular subtypes of glioma. To test our hypothesis, we performed a GWAS by glioma molecular subtype – as defined by presence or absence of IDH and TERT somatic mutation and 1p/19q codeletion – utilizing a two-stage design and subsequent meta analysis that included 3001 total glioma cases and 2697 total controls. Data were imputed using the Michigan Server and logistic regression was used, adjusting for age and sex. The Cancer Genome Atlas (TCGA) data were used to perform an expression quantitative trait loci (eQTL) analysis on candidate germline variants. Variants in 2q37 and 7p22 were associated with IDH-mutated glioma (meta analysis p< 5x10-8). The eQTL analyses demonstrated significant associations between 2q37 variants and expression of nearby genes as well as associations between 7p22 variants and nearby genes (p< 0.0001). In conclusion, we identified and validated novel germline variants in two genes that are associated with etiology of IDH-mutated adult diffuse glioma.
GENE-26. HOST GENETIC VARIATIONS IN MACROPHAGE MIGRATION INHIBITOR FACTOR CONFER WORSE PROGNOSIS IN GLIOBLASTOMA
Authors: Otvos Balint , Grabowski Matthew , Alban Tyler , Golubovsky Joshua , Neumann Chase , Rabjlenovic Anja , Bayik Defne , Lauko Adam , Bucala Richard , Vogelbaum Michael , Lathia Justin
Published: November 2019

Genetic and systemic prognostic factors have been identified in glioblastoma (GBM) that correlate with survival, but patient-specific genomic risk factors that impact prognosis or response to immunotherapies have not been elucidated. GBM promotes an immune suppressive microenvironment via many mechanisms including the production of macrophage migration inhibitory factor (MIF) by GBM cancer stem cells, which activates myeloid derived suppressor cells (MDSCs). Increased circulating and intracranial MDSCs as well as intratumoral MIF expression in GBM patients portend a worse overall prognosis. Endogenous MIF expression is dependent on two genetic microsatellite loci: single nucleotide polymorphisms (SNPs) and CATT repeats within the promoter. To determine whether these genetic variations were linked to GBM development and/or prognosis, we assessed peripheral nucleated blood from 520 GBM patients for the MIF SNPs and CATT repeats. MIF microsatellite frequencies were similar between the normal population and GBM patients indicating loci variability was not a risk factor for GBM development. However, newly diagnosed IDH wild-type GBM patients with a minor allele SNP who received standard of care therapy had a 3.1 month shorter progression free survival (PFS), and a 4.3 month shorter overall survival (OS) when compared to patients with two major allele SNPs. This association was seen also with the CATT-repeat analyses. Furthermore, in a multivariate analysis for PFS that included age, sex, Karnofsky performance status, MGMT methylation status, 1p/19q co-deletion, and SNP status as covariates, only age and SNP status were independently associated with shorter PFS. Taken together, patients with variant MIF microsatellite loci experienced shorter PFS and decreased OS compared to those with the most common loci. These results are currently being validated in a separate 1700 patient cohort with the intent of understanding how MIF expression influences myeloid populations within the GBM microenvironment and then developing novel peripheral GBM screening markers for aggressiveness.
GENE-27. MENINGIOMA RECURRENCE: ROLE OF M1/M2 TUMOUR-ASSOCIATED MACROPHAGE INFILTRATION
Authors: Proctor Dustin , Huang Jordan , Lama Sanju , Albakr Abdulrahman , Van Marle Guido , Sutherland Garnette
Published: November 2019

BACKGROUND

Meningioma, a most common brain tumour, has a high rate of recurrence. Tumour-associated macrophages (TAMs) are the most abundant immune cell type in meningioma. TAMs display functional phenotypic diversity and may establish either an inflammatory and anti-tumoural or an immunosuppressive and pro-tumoural microenvironment. TAM subtypes present in meningioma and potential contribution to growth and recurrence is unknown.

METHODS

Fluorescence immunohistochemistry was used to evaluate the distribution and quantify M1 and M2 TAM populations in 30 meningioma tissues. Association between quantified M1 and M2 cells and M1/M2 ratio to tumour characteristics including WHO grade, tumour recurrence, size, location, peri-tumoural edema and patient demographics such as age and sex was examined.

RESULTS

TAM cells accounted for ~17% of all cells in tumour tissues. Importantly, greater than 80% of infiltrating TAMs were discovered to be of a polarized pro-tumoural M2 phenotype which positively associated with tumour size. TAM subtype profiles differed significantly between non-recurrent (n=18) and recurrent meningioma (n=12) (P=0.044). Specifically, the M1/M2 cell ratio was decreased by ~250% in recurrent tumours.

CONCLUSION

This study is the first to confirm existence of pro-tumoural M2 TAMs in the meningioma microenvironment and a potential role in tumour growth and recurrence.