bluuebunny/crossref_metadata_2025 huggingface dataset:
CMET-21. A PHASE IB STUDY OF PROTON CRANIOSPINAL IRRADIATION FOR THE TREATMENT OF SOLID TUMOR LEPTOMENINGEAL METASTASES
Authors: Jonathan Yang T , Wolden Suzanne , Yamada Josh , Mehallow Michelle , Skakodub Anna , Young Robert , Gavrilovic Igor , Lin Andrew , Santomasso Bianca , Grommes Christian , Piotrowski Anna , Schaff Lauren , Stone Jacqueline , Boire Adrienne , Pentsova Elena
Published: November 2019

Leptomeningeal metastases (LM) is associated with limited survival and treatment options for patients with solid tumor malignancies. While focal radiotherapy is effective for local palliation, it lacks durability due to cerebrospinal fluid (CSF) tumor cells reseeding. Craniospinal irradiation (CSI) in contrast treats the entire central nervous system (CNS) compartment thus potentially improves disease control. We performed a phase IB study of proton CSI using 30CGE in 10 fractions for treating solid tumor LM (NCT03520504). The primary end point is dose-liming toxicity (DLT) within 1 month of treatment. Clinical outcomes and CSF circulating tumor cells (CTCs) by CellSearch® were evaluated. Overall (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier estimates. Of the 24 patients enrolled, 4 were excluded from analysis: 3 did not complete treatment due to CNS or systemic disease progression (PD), and 1 completed treatment outside study window. The majority of patients had metastatic lung (55%) and breast (30%) malignancies. At this submission, the median follow-up was 2.8 months (0.5–9.4 months). No DLT was observed. Treatment-related grade 2+ toxicities were: fatigue (G2=43%), anorexia (G2=5%), anemia (G2=10%), thrombocytopenia (G3=5%, G2=10%), and leukopenia (G3=14%, G2=14%). Median survival is not reached with 17 patients (85%) alive with stable/improved LM including 2 with durable CNS control for >9 months, 1 patient alive with CNS and systemic PD at 3.7 months, 2 patients died at 3.6 and 5.1 months with CNS and systemic PD. At 3-month, OS and PFS were 100% and 90% (95% CI 100–72%), respectively. In the 13 patients with CSF CTCs evaluation, decreased quantifiable CTCs at 1-month after proton CSI correlated significantly with improved CNS PFS (log-rank p=0.014). These early findings suggest that proton CSI is a safe and potentially effective treatment for patients with solid tumor LM. CSF biomarkers assessment is needed to better elucidate predictors of response.
CMET-25. COMPARATIVE EFFICACY OF TREATMENT PARADIGMS FOR BRAIN METASTASES – A SYSTEMATIC REVIEW
Authors: Brar Karanbir , Ellenbogen Yosef , Deng Jiawen , Warsi Nebras , Mansouri Alireza
Published: November 2019

BACKGROUND

Brain metastases (BM) are prevalent in several primary cancers and are the most commonly diagnosed intracranial tumours in adults. The aim of this systematic review was to critically evaluate and compare existing management paradigms for BMs from all primary tumour sites.

METHODS

We searched MEDLINE, EMBASE, Web of Science, ClinicalTrials.gov, and CENTRAL for randomized controlled trials (RCTs) published until October 2018 and selected comparative RCTS with >50 patients. The primary outcomes of interest were overall survival (OS) and progression-free survival (PFS).

RESULTS

A screen of 3188 abstracts yielded 49 RCTs with 8122 patients. The median sample size was 103 (range 39–779). 17/49 RCTs included lung cancer patients, 3/49 breast cancer, 2/49 melanoma, and 27/49 all primary tumour sites. Most studies were phase II/III superiority, open-label, parallel trials. All included patients >18 years of age with at least 1 BM proven on CT/MRI. Most included patients with favorable performance status (KPS >70 or ECOG 0–2). Interventions compared included targeted therapies (e.g. EGFR inhibitors, 7/49), chemotherapeutic regimens (28/49), WBRT (43/49), SRS (12/49), and surgical resection (3/49). A statistically significant difference in OS was reported by 7 studies, and in PFS by 8 studies. Of these, 3 showed improved PFS or OS on addition of temozolomide to WBRT, and 2 showed improved PFS in EGFR-positive patients treated with EGFR inhibitors. The incidence of serious adverse events was not substantially different between treatment arms in most studies.

CONCLUSIONS

Though the majority of studies did not report a benefit to OS or PFS, temozolomide + WBRT showed a benefit in 3 studies, and improvement in PFS was seen in EGFR-positive patients treated with EGFRi. Given the varying treatment approaches in practice today, these data support the need for a meta-analysis to accurately characterize the efficacy of existing treatment options for specific patient populations.
CMET-34. IMPROVEMENT OF LEPTOMENINGEAL DISEASE FOLLOWING INFECTIOUS MENINGITIS
Authors: Metrus Nicholas , Kamiya Carolos , Weathers Shiao-Pei , Seligman Christa , O’Brien Barbara
Published: November 2019

INTRODUCTION

The incidence of leptomeningeal disease (LMD) is increasing, due to better imaging, earlier diagnosis and improved systemic disease control. However, many of the systemic therapies do not cross the blood brain barrier (BBB) and, despite treatment with radiation and/or intrathecal (IT) chemotherapy, median survival is approximately 4-6months in solid tumors complicated by LMD. Repeated IT injections increase the risk of CNS infection. Preclinical models have shown that infectious meningitis transiently modifies the BBB.

METHODS

Our series consisted of 6 LMD patients (5 breast cancer primary, 1 lung cancer primary) treated on IT chemotherapy at MD Anderson Cancer Center between 2013 and 2018, who subsequently developed infectious meningitis. Three patients had history of parenchymal metastases in addition to LMD and four had history of radiation to brain and/or spine. LMD was confirmed by cytology and/or imaging. All were treated with IT topotecan.

RESULTS

CSF cultures were positive for Proprionobacterium acnes in three patients, Pseudomonas aeruginosa in two, and Raoultella ornithinolytica in one, who died shortly thereafter. Antibiotic regimens were variable. Three patients went on to receive IT chemotherapy post-infection (two never discontinued IT chemotherapy throughout infection). Those that had IT chemotherapy post-infection cleared CSF and imaging findings of LMD or maintained stability of radiographic LMD burden until death. No patients died directly from LMD. One patient, who developed infection after Ommaya placement and was never initiated on IT chemotherapy, still cleared his CSF of malignant cells. Excluding the patient who died shortly after meningitis diagnosis, the average time from meningitis diagnosis to death was 8.8 months and the average median survival from LMD diagnosis to death was 14 months.

CONCLUSION

Our findings support further evaluating the safety and timing of IT chemotherapy with active infectious meningitis and the potential synergistic benefit of increased immunogenicity and chemotherapy in LMD.
CMET-41. OUTCOMES FOLLOWING STEREOTACTIC RADIOSURGERY (SRS) FOR LIMITED BRAIN METASTASES - AN AUSTRALIAN SINGLE INSTITUTIONAL EXPERIENCE
Authors: Shen Lilly , Loon Ong Wee , Farrugia Briana , Seeley Anna , Augusto Gonzalvo Carlos , Wada Morikatsu
Published: November 2019

INTRODUCTION

Despite increasing use of stereotactic radiosurgery (SRS) for management of brain metastases (BM), published Australian data is scarce. We aim to report on the outcomes following SRS for limited BM in a single Australian institution.

METHODS

This is a retrospective cohort of patients with limited BM treated with SRS between August 2015 and March 2019. A dose of 24Gy/3# were prescribed to intact lesion, and 21Gy/3# to surgical cavity post-surgical resection. All patients were followed with 3-monthly surveillance MRI brain. Primary outcomes were: local failure (LF: increased in size of SRS-treated BM lesion/ recurrence in surgical cavity), distant failure (DF: intracranial progression outside of the SRS-treated lesion/ cavity), and overall survival (OS). LF, DF and OS were estimated using the Kaplan-Meier method. Multivariate Cox regressions were used to evaluate factors associated with outcomes of interest, with death as competing-risk events for LF and DF.

RESULTS

76 courses of SRS were delivered in 65 patients (54 unresected BM lesions, and 22 surgical cavities). 43 (66%) patients were ECOG 0–1. 35 (54%) patients had solitary BM. 41 (63%) had symptomatic BM. Half of the patients had primary lung cancer. Median follow-up was 4.8 months (range:0.1–39 months). 10 LF were observed at a median of 3.5 month post-SRS, with 6- and 12-month LF cumulative incidence of 14% and 24% respectively. 30 DF were observed at a median of 3.3 months, with 6- and 12-month DF cumulative incidence of 38% and 63% respectively. The 12- and 24-month OS were 39% and 26% respectively. In multivariate analyses, better ECOG status, solitary BM lesion, resection of BM pre-SRS, and use of subsequent systemic therapy were independently associated with improved OS.

CONCLUSION

This is one of the few Australian series reporting on outcomes following SRS for limited BM, with comparable outcomes to published international series.
COMP-02. MINING-GUIDED MACHINE LEARNING ANALYSES SUPPORTS GRASPING THE LATEST TRENDS ON NEURO-ONCOLOGY
Authors: Hana Taijun , Tanaka Shota , Nejo Takahide , Kitagawa Yosuke , Takahashi Satoshi , Koike Tsukasa , Kushihara Yoshihiro , Yamazawa Erika , Nomura Masashi , Takayanagi Shunsaku , Saito Nobuhito
Published: November 2019

The systems that can objectively predict the future trends of a particular research field are always anticipated while conducting medical research. Such systems also provide a considerable aid to researchers while determining and acquiring appropriate research budgets. This study intended to establish a novel and versatile algorithm that can predict the latest trends in neuro-oncology. Seventy-nine neuro-oncological research fields were selected using computational sorting methods, such as text-mining analyses, along with 30 journals that represent the recent trends in the neuro-oncology field. Further, the annual impact (AI) for each year with respect to each journal and field (number of articles published in the journal × the impact factor of the journal) was calculated as a novel concept. Subsequently, the AI index (AII) for the year was defined as the sum of the AIs for the aforementioned 30 journals. With respect to the aforementioned neuro-oncological research fields, the AII trends from 2008 to 2017 were subjected to machine learning predicting analyses. The prediction accuracy of the latest trends in neuro-oncology was validated using actual data obtained from previous studies. In particular, the linear prediction model achieved a relatively good accuracy. The most notable and latest predicted fields in neuro-oncology included some interesting emerging fields, such as microenvironment and anti-mitosis, as well as the already renowned fields, such as immunology and epigenetics. Furthermore, we retrospectively attempted an analysis of the fields different from neuro-oncology. Interestingly, as of 2008, the future emergence of the CRISPR-Cas9 gene editing system has been predicted using this system. Overall, the presented algorithm displays potential to be an effective and versatile tool for the prediction of future trends in a particular medical field.
COMP-04. MODELING PRECISION ONCOLOGY FOR GLIOBLASTOMA THROUGH INTEGRATION OF DESCRIPTIVE, FUNCTIONAL, AND NETWORK-BASED GENOMICS
Authors: Hoellerbauer Pia , Kufeld Megan , Arora Sonali , Girard Emily , Olson James , Biery Matthew , Chambwe Nyasha , Paddison Patrick
Published: November 2019

Precision oncology is largely based on the notion that identification and targeting of oncogenic drivers will lead to improved clinical outcomes. However, the promise of precision oncology awaits to be fulfilled for many cancers, including Glioblastoma (GBM), where identification of oncogenic drivers has yet to improve survival rates. Here, we have attempted to systematically identify GBM vulnerabilities by performing genome-wide CRISRP-Cas9 lethality screens in patient-derived GBM stem-like cells (GSCs). In validation studies, we comprehensively retested GSC-specific hits in multiple GSC isolates, which were also genomically profiled (e.g. RNA-seq, exome-seq, CNV), and further integrated these data with CRISPR-Cas9 lethality screens from over 500 human cell lines from the Broad Institute’s CRISPR Avana dataset. As a result, we have begun making GBM dependency predictions and functional associations for top scoring hits, including: tumor developmental subtype; loss of functional redundancy with other genes/proteins; cancer-specific subnetworks of genes involved in mitochondrial protein turnover and membrane trafficking; and genes of unknown function essential for subset of GBMs. A few examples of these categories include the following scenarios. We find ADAR (Adenosine Deaminase RNA Specific) gene dependency is associated with the mesenchymal GBM subtype. The EFR3Agene, which has roles in maintaining active pools of phosphatidylinositol 4-kinase, appears required when the expression of its paralog EFR3Bis low or absent in tumor cells. The F-box protein-encoding gene FBXO42appears non-essential to most human cells lines and neural stem cells, but when knocked out in sensitive GSCs causes mitotic arrest, mitotic catastrophe, and cell death. While still a work in progress, we hope to use these results as a foundation for exploring and illuminating patient-specific molecular vulnerabilities for brain tumors. The results also underscore the need for integration of functional genetic approaches, where gene activities are inhibited, into precision oncology paradigms.
COMP-10. THE MUTATIONAL PROFILE OF GLIOBLASTOMA-DERIVED CELL-FREE DNA IN PLASMA REPRESENTS A DISTINCT SUBSET OF THE SOMATIC MUTATIONS PRESENT IN GLIOBLASTOMA SOLID TUMOR DNA
Authors: Underhill Hunter , Nix David , Davidson Christian , Hellwig Sabine , Fuertes Carrie , Colman Howard , Bronner Mary , Jensen Randy
Published: November 2019

Glioblastoma’s mutational landscape varies widely in the same tumor. Using conventional criteria to identify mutations from a focal tissue specimen (e.g., variant allele frequency > 5%) undersamples glioblastoma’s broad clonal diversity, which may limit detection of glioblastoma-derived circulating cell-free DNA in plasma (i.e., circulating tumor DNA; ctDNA). Here, we sought to enhance somatic variant identification in solid tumor DNA to improve detection and characterize glioblastoma-derived ctDNA. Tumor DNA and plasma cell-free DNA (collected < 24 hours prior to the surgical procedure) were isolated from eight glioblastoma patients. DNA was capture-enriched using a custom-designed, glioblastoma-targeted, next-generation sequencing panel (124 genes, 118 kb) followed by paired-end sequencing. Samples were prepared in duplicate with molecular barcodes to enable detection of very-low frequency variants. Somatic mutations in tumor DNA were identified using variable allele frequency thresholds and were considered positive in ctDNA if present in both duplicate samples. Using a lower allele frequency threshold to identify mutations in tumor DNA significantly increased detection of ctDNA (F(1.04,7.29)=14.81, P=0.006). At a solid tumor allele frequency threshold of ≥ 5%, only a single patient (12.5%) had tumor mutations detected in ctDNA. However, at a threshold ≥ 1%, all patients (100%) had at least one tumor mutation detected in ctDNA. Moreover, at a threshold ≥ 0.5%, 7 out of 8 patients (87.5%) had > 12 tumor mutations present in ctDNA. The increased detection of ctDNA enabled the subsequent discovery that somatic mutations in APC, KIT, MSH6, and NF1 were more likely to be present in ctDNA compared to somatic mutations in ATRX, LZTR1, SLC26A3, and TERT which were absent in ctDNA (χ 2=8.0, P=0.005). Thus, stronger sampling of glioblastoma’s genetic heterogeneity in tumor DNA improves detection of ctDNA allowing comparisons between mutational profiles that may lead to the identification of similarities and differences with key biologic and/or clinical implications.
DDIS-01. NEW DRUG DISCOVERY WITH DRUG RE-POSITIONING SYSTEM TOWARD GBM TREATMENT
Authors: Michiue Hiroyuki , Tsuboi Nobushige , Hayashi Keiichiro , Matsui Hideki , Kurozumi Kazuhiko
Published: November 2019

INTRODUCTION

Invasion of Glioblastoma (GBM) cells into normal brain is the major cause of poor prognosis and requires dynamic reorganization of the actin cytoskeleton, which includes lamellipodial protrusions, focal adhesions, and stress fibers at the leading edge of GBM cells. Therefore, we hypothesized that the inhibition of actin polymerization with existing medication could lead to clinical GBM treatment directly in short time. The Drug Repositioning system is also known as drug repurposing or drug reprofiling and understood as the process of redeveloping a compound for use in a different disease. In this time, we would show the new direction of drug development with drug repositioning.

MATERIALS AND METHODS

We adopted a drug repositioning system for screening with a pyrene-actin-based actin polymerization assay and identified fluvoxamine, a clinically used antidepressant. Fluvoxamine, selective serotonin reuptake inhibitor, was a potent inhibitor of actin polymerization and confirmed as drug penetration through the blood–brain barrier (BBB) and accumulation of whole brain including brain tumor with no drug toxicity.

RESULTS

Fluvoxamine inhibited serum-induced ruffle formation, cell migration, and invasion of human GBM and glioma stem cells in vitro by suppressing FAK signaling. Fluvoxamine showed no drug toxicity. Daily treatment of athymic mice bearing human glioma-initiating cells with fluvoxamine blocked tumor cell invasion and prolonged the survival with almost same doze of anti-depressant effect.

CONCLUSIONS

The SSRI group has big potential for clinical GBM treatment with low cost, short time and low side effect.
DDIS-06. ANTICANCER EFFECTS OF THE SMALL MOLECULE INHIBITOR SB747651A IN GLIOBLASTOMAS
Authors: Knudsen Arnon , Boldt Henning B , Kristensen Bjarne
Published: November 2019

INTRODUCTION

Most glioblastomas harbor several different genetic alterations in major cell signaling pathways, leading to tumor progression and treatment resistance. Single-targeted therapies against these alterations have thus far failed to show major clinical value. The aim of this study was to investigate the anticancer effects of SB747651A, a multi-target small molecule inhibitor, targeting the RAS-MAPK and AKT-PI3K kinases AKT, MSK1/2, RSK1/2 and p70S6K in glioblastomas.

METHODS

Three patient-derived glioblastoma cultures were grown as free-floating spheroids and treated with 5 or 10 µM SB747651A. Exposed cells were subject to assays investigating cell viability (propidium iodide), apoptosis (Caspase 3/7), spheroid formation capacity, chemo sensitivity (temozolomide), and migration. In vivo studies are currently ongoing.

RESULTS

Exposed cells showed increased cell death and apoptosis across all three cell cultures in a dose-dependent manner vs. controls (P=0.001). Combination treatment with SB747651A and temozolomide resulted in a significant dose-dependent synergistic effect on cell death in all cell cultures. The fraction of spheroid-initiating cells was significantly reduced in exposed cells (1 in 12 cells) compared to controls (1 in 5 cells; P=0.001), and the growth rate of treated tumor spheroids was reduced by up to 47% (P=0.001). Exposed spheroids showed reduced cell migration in 2 of 3 cell lines, with a maximum reduction of migration distance by 60.4% (P=0.001).

CONCLUSION

SB747651A treatment has shown promising in vitro results by targeting mechanisms with high relevance for the progression and treatment resistance of glioblastomas. Ongoing in vivo studies are aiming to validate these findings, and to uncover potential use of SB747651A in the clinical setting.
DDIS-21. IN VITRO MICRODIALYSIS RECOVERY OF TRAMETINIB
Authors: Romo Carlos , Anders Nicole , Scardina Morgan , Mukherjee Debraj , Grossman Stuart , O Blakeley Jaishri , Rudek-Renaut Michelle
Published: November 2019

BACKGROUND

Dysregulation of the mitogen-activated protein kinase and phosphoinositide 3-kinase (PI3K) pathways is common in several primary brain tumors and metastatic cancers affecting the central nervous system. Trametinib, and oral MEK1/2 inhibitor, has been effective in preclinical studies against a variety of cell lines and improves survival in select patients with gliomas. Unfortunately, limited and often short-lived benefits are frequently seen in patients. A potential explanation for this is insufficient blood brain barrier penetration at therapeutic concentrations. The primary objective of this study is to measure the in vitro relative recovery of trametinib using microdialysis to establish the feasibility of characterizing its intratumoral pharmacokinetics in vivo using this technique.

METHODS

In vitro recovery experiments were performed utilizing commercially available microdialysis instruments. Two perfusion rates (0.5–1µL/min), the use of iso- and hypertonic perfusates (artificial CSF and 10% bovine serum albumin in PBS), and the addition of dimethyl sulfoxide (DMSO) were evaluated using the extraction efficiency method. Liquid chromatography-tandem mass spectrometry was used to measure the concentrations of trametinib in stock solutions, dialysate samples, and controls over time.

RESULTS

Dialysate was initially collected from a solution spiked with 15ng/mL at a rate of 1µL/min for 60 minutes, the recovery was 0.3ng/mL (0.2%) in two samples and below the limit of quantification (< 0.2ng/mL) in three. Dialysate samples were then collected from a stock solution with 150ng/mL of trametinib, recovery ranged from 0.3–15.3ng/mL (0.2–10.2%) in nine detectable samples out of sixteen. Recovery was greater with the addition of DMSO to the perfusate and with the use of a hypertonic perfusate.

CONCLUSIONS

The poor relative recovery of trametinib using microdialysis suggests that this technique would be unreliable in in vivo studies. Trametinib has poor aqueous solubility, limiting the ability of characterizing its pharmacokinetic profile through microdialysis.
DDIS-24. DECREASE IN GLIOBLASTOMA GROWTH IN VITRO WITH TREATMENT OF NOVEL ANALOGS OF GLUCOSE TRANSPORTER INHIBITORS
Authors: GC Sajina , Libby Catherine , Zhang Sixue , Benavides Gloria , Scott Sarah , Li Yanjie , Tran Anh , Otamias Arphaxad , Darley-Usmar Victor , Napierala Marek , Pathak Vibha , Moukha-Chafiq Omar , Augelli-Szafran Corinne , Zhang Wei , Hjelmeland Anita
Published: November 2019

Despite available treatments including surgical resection, radiation and chemotherapy, glioblastoma (GBM) is incurable with rapid recurrence and low median survival rate of just fourteen months. Development of more effective treatments is difficult due to the highly heterogeneous nature of GBM. One aspect of that heterogeneity involves brain tumor initiating cells (BTICs) that have a stem cell-like ability to self-renew. BTICs can readily alter their metabolism and survive in low nutrient environments due in part to increased GLUT3 expression. We believe that the higher expression of GLUT3 in cancer cells compared to non-tumor cells makes it a therapeutic target, although the potential for toxicity must be considered. In recently accepted studies by Libby et al., we reported on two novel GLUT inhibitors identified by structure based virtual screening (SBVS) using a GLUT3 homology model. We are creating a structure-activity relationship profile and seek to increase the potency, selectivity and stability of the GLUT inhibitors. In this study we have tested a number of novel analogs and identified three that have maintained efficacy against BTICs in vitro. Importantly, these compounds display minimal toxicity against human astrocytes. The novel derivatives have increased stability compared to the lead compounds and are efficacious in the nanomolar range. In the future, we intend to utilize our anti-GLUT compounds alone and in combination with radio- and chemotherapy with the hope of clinical translation.
DDIS-28. A HIGH THROUGHPUT SCREENING PLATFORM TO IDENTIFY RADIOSENSITIZERS FOR DIPG
Authors: Clutter Matt , Romero Megan , Becher Oren
Published: November 2019

Diffuse intrinsic pontine glioma (DIPG) is an incurable brainstem tumor and the leading cause of death in children with brain cancer. Despite numerous clinical trials, no drugs have been found to prolong survival for DIPG patients, suggesting an urgent need to test therapeutics in preclinical models more predictive of clinical activity. To address this gap, we developed a genetically engineered mouse model incorporating the Histone H3.3 K27M mutation, p53 deletion, and PDGFR-α amplification, which co-occur in up to 40% of human DIPG. Here we report the results of a drug screen to identify radiosensitizers of DIPG cells isolated from our mouse model and cultured ex vivo as neurospheres. Although previous clinical trials combining radiotherapy with radiosensitizing agents failed to benefit DIPG patients, they incorporated general radiosensitizers. We hypothesize that searching for radiosynergy using 3-dimensional neurospheres derived from genetically defined primary cell DIPG models will enhance our ability to prioritize clinically relevant radiosensitizers. To identify candidates, we developed high throughput radiation and imaging protocols to quantify the number, size, and viability of neurospheres following treatment. We screened 1,280 FDA-approved drugs and 1,600 molecules with a history of clinical use. Two mechanistic classes of compounds were identified that sensitized DIPG neurospheres to radiotherapy, both targeting epigenetic factors. An HDAC1/3 inhibitor along with several different BET bromodomain inhibitors increased cell death 2–3 fold beyond the effect of radiation with minimal activity from the compounds alone. In addition to optimizing the dosing and timing of these compounds for animal studies, we are investigating whether radiosensitization occurs in H3.3 wildtype neurospheres. In the current molecular era of cancer, genetic features like the H3.3 K27M mutation could present an opportunity to develop therapeutics that preferentially radiosensitize diseased cells relative to normal cells. Such “precision radiosensitizers” would advance radiotherapy by enhancing tumor-specific toxicity while sparing bystander cells.
DDIS-30. EVALUATION OF THE SUSCEPTIBILITY OF NEURONS DERIVED FROM HUMAN INDUCED PLURIPOTENT STEM CELLS TO ANTICANCER DRUGS FOR CNS TUMORS
Authors: Kanemura Yonehiro , Fukusumi Hayato , Handa Yukako , Shofuda Tomoko
Published: November 2019

Various chemical substances, including pharmaceuticals, pose potential risks of inducing acute or delayed neurotoxicity in adults and causing developmental neurotoxicity in fetuses or children. To ensure the safety of chemical substances and drugs, neurotoxicity risk assessment is critical, and an appropriate evaluation platform for neurotoxicity is desired. At present, several anticancer reagents, including temozolomide, cisplatin, and etoposide, are used for treatment of high-grade astrocytic tumors or medulloblastomas. In comparison to lots of information about anti-tumor cells effects of these reagents, their neurotoxicity to normal neurons, especially human derived cells, have been poorly investigated because of the low accessibility of human central nervous system (CNS) tissues, the technical difficulties related to neuron isolation from adult human CNS tissues, and the higher ethical controversy surrounding the use of human CNS tissues and/or fetal cells compared to animal tissues or cells. In this study, to overcome these issues, we made human induced pluripotent stem cells derived neurons (hiPSC-neurons) for preparing alternative assay for in vitro test using primary human neuronal cells, and evaluated their susceptibility to six commonly used anticancer drugs (temozolomide, nimustine, cisplatin, etoposide, mercaptopurine, and methotrexate). Human iPSC-neurons were differentiated using 5-week monolayer culture from hiPSC-derived neural stem/progenitor cells (hiPSC-NSPCs) established by combination the dual SMAD inhibition method with neurosphere culture. In vitro cytotoxic effects of six drugs on hiPSC-neurons and their parental hiPSC-NSPCs were evaluated by ATP assay and immunocytostaining. The hiPSC-neurons were generally more resistant to the anticancer drugs than hiPSC-NSPCs, although a high dose of cisplatin decreased the levels of the neuronal marker protein ELAVL3/4 in the hiPSC-neurons after a 48-h drug treatment. These results suggest that our methodology is potentially applicable for efficient determination of the toxicity of any drug to hiPSC-neurons.
DDIS-31. A NOVEL BRAIN-PERMEANT CHEMOTHERAPEUTIC AGENT FOR THE TREATMENT OF BREAST CANCER LEPTOMENINGEAL METASTASIS
Authors: Deng Jiaojiao , Chernikova Sophia , Fischer Wolf-Nicolas , Koller Kerry , Jandeleit Bernd , Ringold Gordon , Hayden Gephart Melanie
Published: November 2019

Leptomeningeal metastasis (LM), a spread of cancer to the cerebrospinal fluid and meninges, is universally and rapidly fatal due to poor detection and no effective treatment. Breast cancers account for a majority of LMs from solid tumors, with triple-negative breast cancers (TNBCs) having the highest propensity to metastasize to LM. The treatment of LM is challenged by poor drug penetration into CNS and high neurotoxicity. Therefore, there is an urgent need for new modalities and targeted therapies able to overcome the limitations of current treatment options. Quadriga has discovered a novel, brain-permeant chemotherapeutic agent that is currently in development as a potential treatment for glioblastoma (GBM). Recently, we have demonstrated dose-dependent in vitro and in vivo anti-tumor activity with various breast cancer cell lines including the human TNBC cell line MDA-MB-231. To evaluate the in vivo antitumor activity of the compound on LM, we used the mouse model of LM based on the internal carotid injection of luciferase-expressing MDA-MB-231-BR3 cells. Once the bioluminescence signal intensity from the metastatic spread reached (0.2 - 0.5) x 106photons/sec, mice were dosed i.v. (8 mg/kg once a week for nine weeks) or i.p. (4 or 8 mg/kg twice a week for nine weeks). Tumor growth was monitored by bioluminescence. The compound was well tolerated and caused a significant delay in metastatic growth resulting in significant extension of survival. Tumors regressed completely in ~ 28 % of treated animals in the i.p. group. Given that current treatments for LM are palliative with only few studies reporting a survival benefit, Quadriga’s new agent could be effective as a therapeutic for both primary and metastatic brain tumors such as LM. REF: https://onlinelibrary.wiley.com/doi/full/10.1002/pro6.43
DDIS-34. HIGH-THROUGHPUT DRUG SCREENING OF FDA-APPROVED ANTINEOPLASTIC DRUGS FOR THE TREATMENT OF AGGRESSIVE MENINGIOMAS
Authors: Jungwirth Gerhard , Yu Tao , Liu Fang , Warta Rolf , Unterberg Andreas , Herold-Mende Christel
Published: November 2019

Currently, we are facing several challenges in the treatment of meningiomas: only subtotally removable tumors, high rate of recurrence in higher-grade meningiomas, malignancy, and lack of effective chemotherapeutic agents for aggressive or inoperable tumors. For these reasons, there is an urgent need for more successful treatments for aggressive meningiomas. Therefore, we used 147 FDA-approved antineoplastic drugs on two different meningioma cell lines, including the genetically modified cell line Ben-Men-1 (WHO°I) and the newly established anaplastic meningioma cell line NCH93 (WHO°III). The impact of the drugs on proliferation was assessed in a high-throughput 386-well format with CellTiter-Glo (Promega) and further validation was done by crystal-violet assay. Subsequent screening of 147 FDA-approved drugs resulted in the identification of potential 5 drugs, including Bortezomib, Carfilzomib, Omacetaxine, Paclitaxel, and Ponatinib. Dose-curve analysis revealed IC50 values of these drugs in the Ben-Men-1 and NCH93 cell lines as follows: Bortezomib 16.2 and 5.7 nM, Carfilzomib 4.8 and 2.6 nM, Omacetaxine and 5.0 and 8.9 nM, Paclitaxel 2.6 and 1.9 µM, and Ponatinib 278 and 206 nM. Inhibitor dosage of 10xIC50 values and higher lead to an average inhibition of Ben-Men-1 and NCH93 cells by up to 90% on day 2 (P< .001). The impact of the antineoplastic agents on the cell cycle was analyzed by flow cytometry. Percentages of sub-G1 phase were significantly elevated with increasing drug concentrations of all five tested compounds (P< .001). To assess the effects of the drugs on migration scratch assay was performed. Drug concentrations of 10xIC50 values resulted in an inhibition of migration in Ben-Men-1 cells for Bortezomib, Carfilzomib, and Omacetaxine by 49%, 30%, and 23%, respectively (P< .05). In conclusion, we identified 5 promising drugs for the treatment of aggressive meningiomas by applying a high-throughput drug screening of 147 FDA-approved antineoplastic drugs.
EPID-01. SEX DIFFERENCE IN EXPRESSION OF IRON-RELATED GENES AND SURVIVAL IN GLIOBLASTOMA PATIENTS
Authors: Lee Sang , Walter Vonn , Salzberg Anna , Nesterova Darya , Lathia Justin , Rubin Joshua , Berens Michael , Barnholtz-Sloan Jill , Connor James
Published: November 2019

Sex impacts the clinical outcome of glioblastoma (GBM) patients. Iron is a key metabolic driver in glioma biology impacting both the neoplastic cells directly and tumor progression through the immune system. We previously reported the expression of HFE (iron homeostatic) gene has a sexually dimorphic impact on survival in GBM patients. To further interrogate the relationship of iron and sexual dimorphism in GBMs, we expanded our analysis to include the ferrome (profile of genes and proteins involved in iron regulation). These genes were identified using IronChip and then interrogated for sexually dimorphic expression and survival in primary GBM patients using The Cancer Genome Atlas GBM database. Biological pathway analysis indicated that the Toll receptor signaling and immune system signaling pathways are most strongly correlated to sex difference and GBM patient survival. Toll like receptor 4 (TLR4) expression in the bottom quartile is associated with a modest survival benefit for female GBM patients compared to male, but in the top quartile of expression of this gene the survival for males is dramatically greater than that for females (18 months versus 3.6 months). Males expressing top quartile of Dual specificity phosphatases (DUSP1) also known as MKP1 survive 24.2 months whereas females survive 5.8 months. There is no sex effect of DUSP1 in the bottom quartile of expression. These data suggest that top quartile expression of TLR4/DUSP1 are both a benefit for males (extending their survival) and a detriment to females (shortening their survival). Both TLR4 and DUSP1 are richly expressed in macrophages. The data suggest that macrophage infiltration into the tumor could be particularly negatively impactful in females; a finding consistent with our previous reports for the HFE gene. In summary, iron related gene expression is linked to sexual dimorphism in survival and may provide insights on sex specific tumor biology.
EPID-02. HEIGHT AND THE RISK OF MENINGIOMA
Authors: Yust-Katz Shlomit , Amiel Alexandra , Abu Shkara Ramiz , Siegal Tali , Twig Gilad
Published: November 2019

BACKGROUND

Meningiomas are the most common primary central nervous system tumors. Risk factors for meningiomas including obesity, height, history of allergy/atopy or autoimmune diseases, have been previously assessed with conflicting results. We reviewed a large cohort of Israeli adolescents in order to assess potential risk factors for the development of meningiomas.

METHODS

This study analyzed a cohort of 2,035,915 Jewish men and women who underwent obligatory physical examination when aged 16 to 19 years, from 1967 to 2011. Meningioma incidence was identified by linkage to the national cancer registry. Cox proportional hazard models were used to estimate the hazard ratios for meningioma according to sex, body mass index (BMI), height, history of allergic and autoimmune disease.

RESULTS

Linkage of the adolescent military database with the Israeli cancer registry identified 480 cases (152 males and 328 females) of meningioma during a follow up of 40,304,078-person years. The median age at diagnosis of meningioma was 42.1 ± 9.4 (range 17.4–62.6). On univariate analysis, only female gender (p< 0.01) and height (p< 0.01) were associated with risk for meningioma in the total study population. When stratified by gender, height remained a significant risk factor only in men. Spline analysis in the men group showed the minimum risk at a height of 1.62 meters and a statistically significant increase in the risk for meningioma at heights taller than 1.85 meters. BMI, past medical history including asthma, diabetes, and atopic and autoimmune diseases, were not associated with meningioma risk.

CONCLUSION

in this large population study, we found that sex and taller height in adolescent males was associated with an increased risk of adult meningioma.
EPID-08. TYPES OF BRAIN CANCER IN THE CENTRAL TEXAS MILITARY POPULATION
Authors: Murillo Jennifer , Brahmaroutu Ankita , Chen Wencong , Benge Jared , Fonkem Ekokobe
Published: November 2019

Multiple studies have demonstrated a correlation with military service and brain tumors, both for primary tumors and meningiomas. However, there is little comprehensive research on tumor types in the US military population. We evaluated our local brain tumor bank to identify types and correlates of brain tumors in a military vs. civilian population in central Texas.

PURPOSE

The purpose of our research was to describe brain cancers in the military population when compared to nonmilitary population in our local database.

METHODS

Retrospective data was derived from our brain tumor bank at the Baylor Scott & White in central Texas. Tumors were classified based on final histologically confirmed diagnosis when possible. Demographics and correlates. We obtained military background by chart review of notes, occupation, insurance provider and relationship to insured in the electronic medical record.

RESULTS

Data from 53 veterans and 170 non-veterans were analyzed. The most common tumor type in Veterans was glioblastoma multiforme (20.75%) followed by metastatic lesions (18.87%), meningiomas (16.98%) and adenomas (13.21%). There was no statistically significant difference in distribution of tumor types between civilians and controls. Demographic analysis revealed an older age of diagnosis in Veterans than civilians for the top three most common tumor types with glioblastoma multiforme (67.64 vs 61.65) with a difference of 5.99 years; metastatic lesions (69.4 vs 61.22) with a difference of 8.18 years and meningiomas (63.88 vs 57.57) with a difference of 6.31 years. (military versus civilians average age, respectively).

CONCLUSION

The age of onset for the three most common types of tumors were older in the Veteran population than civilians by an average of 6.82 years. More research into the older age of diagnosis for the Veterans should be further explored. Our research did not find any correlation between military service and tumor types as previous studies have shown.
EPID-14. OCCURRENCE OF SYSTEMIC CANCER IN PATIENTS WITH OLIGODENDROGLIOMAS: POPULATION CHARACTERIZATION AND COMPLICATIONS
Authors: Horta Erika , Snyder James , Walbert Tobias
Published: November 2019

Following clinic observations of patients with the diagnosis of oligodendroglioma and a systemic cancer, a chart review was done to understand the possible complications that a systemic cancer might bring to the treatment of the patient. Inclusion criteria was histological diagnosis of diffuse or anaplastic oligodendroglioma and another non-skin systemic cancer. Exclusion criteria was the diagnosis of genetic syndrome that predispose tumorigenesis. A total of 12 patients and 13 cancers were identified. 1p19q co-delection information was available for all patients except for 2. The most common systemic cancers were breast (46%) and gynecological cancers (16%). Different from CBTRUS data, men were underrepresented, being 31% of the patients, but difference did not reach statistical significance (p =0.08). Regarding age, patients were older than expected (53 + 12 years old, p< 0.0001). Systemic cancer was diagnosed after the oligodendroglioma diagnosis in 54% of the cases. Age at the diagnosis of systemic cancer was 54 + 10 years old. All patients are alive, except for two. Thromboembolism was seen in 25% of the patients (p=0.2 when comparing with literature for oligodendroglioma), and occurred always after the oligodendroglioma diagnosis. Thrombocytopenia was not associated to prior chemotherapy. No deviation of glioma treatment was seen. This chart review of patients with Oligodendroglioma and a systemic cancer identifies that this population is older than expected and thromboembolism rates are similar to the literature. The overrepresentation of women in this cohort represents the profile of systemic cancer that accompanied oligodendrogliomas. It is unclear why breast and other gynecological cancers were the most common. Further studies, likely multicentric due to the rarity of this diagnosis, as further research in large repository data should be performed to confirm this finding.
EPID-16. COMPARATIVE ANALYSIS OF OVERALL SURVIVAL AND ADVERSE EVENTS BY ADJUVANT TREATMENT MODALITIES IN ELDERLY PATIENTS WITH GLIOBLASTOMA USING THE SEER-MEDICARE DATABASE
Authors: Zhu Ping , Du Xianglin , Zhu Jay-Jiguang
Published: November 2019

OBJECTIVES

Few studies have investigated the frequency of adverse event (AE) by adjuvant therapy modalities in elderly patients with glioblastoma (GBM) in “real-world” setting. We conducted a retrospective cohort analysis to compare survival differences and incidences of AE with different treatment modalities.

METHODS

A total of 3100 elderly GBM patients were derived from the Surveillance, Epidemiology and End Results (SEER)-Medicare dataset (2004–2013). Adjuvant therapy modalities were either chemoradiation (CRT) followed by maintenance chemotherapy with temozolomide or RT alone. Primary outcomes include overall survival (OS) and cumulative incidences of 6-month and 1-year AEs with adjuvant therapies. Kaplan-Meier method and Cox proportional hazards regression were applied for survival analysis. Fine-Gray competing risk models were performed to estimate the risk of incident AEs over time with death as the competing risk event.

RESULTS

Superior OS was observed among GBM patients treated with CRT compared to RT alone (median OS: 6.9 vs. 2.9 months, P< 0.001). In multivariable Cox proportional hazard model, the risk of death was decreased by 52% for patients in the CRT group over the RT alone group (P< 0.001). Based on the multivariable competing risk models, the receipt of CRT was associated with higher risk of incident 6-month AEs with nausea/vomiting [sub-hazard ratio (SHR): 1.82, P=0.003] and constipation (SHR: 1.47, P=0.022); and 1-year AEs with neutropenia (SHR: 1.63, P=0.002), anemia (SHR: 1.64, P< 0.002), DVT (SHR: 1.25, P=0.035), seizure/epilepsy (SHR: 1.47, P=0.001), nausea/vomiting (SHR: 2.08, P< 0.001), diarrhea (SHR: 1.70, P=0.034), gastroenteritis/colitis (SHR: 2.77, P=0.024), constipation (SHR: 1.62, P=0.001), and dehydration (SHR: 1.27, P=0.020).

CONCLUSION

Comparing to the RT alone group, elderly GBM patients received CRT had 4-month median OS benefit, but experienced significantly higher incidences of AEs.
EPID-17. ANALYSIS OF THE USE OF BEVACIZUMAB FOR THE TREATMENT OF GLIOBLASTOMA IN THE UNITED STATES
Authors: Garcia Catherine , Chitwood Holly , Harwood Christopher , Shelton Brent , Morgan Rachael , Vermuelen Lee , Villano John
Published: November 2019

INTRODUCTION

Bevacizumab is an antibody against vascular endothelial growth factor that has been well investigated for glioblastoma, however, has limited proven efficacy. The drug has, however, demonstrated survival benefit in non-small cell lung carcinoma, renal cell carcinoma and colorectal carcinoma. We provide an overview of its use in the United States for select cancers.

METHODS

We queried the IQVIA database for all cases of glioblastoma diagnosed between January 2014 and June 2018 to analyze the use of bevacizumab for glioblastoma, non-small cell lung carcinoma, and colorectal carcinoma in the United States, and was compared to the standard of care for each indication (temozolomide for glioblastoma, pemetrexed for non-small cell lung carcinoma, and oxaliplatin for colorectal carcinoma).

RESULTS

A total of 85,351 patients were treated for glioblastoma as captured by IQVIA. Bevacizumab was prescribed in 17,958 patients, with a projected median annual total of 3,718 patients. The use of bevacizumab for glioblastoma during the study period decreased from 2014 to 2018 (p< 0.0001). The use of temozolomide has remained stable since 2014 to 2018 (p=0.49). For non-small cell lung cancer, we saw a significant decrease in the use of both bevacizumab and pemetrexed (p< 0.0001), with bevacizumab being used in less than 2% of the cases since 2017. For colorectal carcinoma, the use of bevacizumab has overall decreased with a peak use in 2016 (p< 0.0001). The use of oxaliplatin has increased (p< 0.0001).

CONCLUSIONS

Our findings demonstrated a decreased use of bevacizumab in oncology for three indications, likely associated with a changing role due to the benefit of novel therapy such as immunotherapy. The use of bevacizumab has decreased in glioblastoma, that may be associated to the lack of overall survival benefits in randomized clinical trials.
EPID-21. THE NATIONAL SPECTRUM OF NEWLY-DIAGNOSED BRAIN TUMORS IN ADULT PATIENTS VARIES SIGNIFICANTLY BY PATIENT DEMOGRAPHICS
Authors: Torre Matthew , Ascha Mustafa , Harary Maya , Smith Timothy , Aizer Ayal , Ligon Keith , Reardon David , Barnholtz-Sloan Jill , Iorgulescu Bryan
Published: November 2019

INTRODUCTION

Herein we examine the epidemiology and outcomes of the entire spectrum of intracranial tumors in the contemporary era.

METHODS

Adult patients (≥20yo) presenting between 2010–2015 where the first evidence of cancer involves an intracranial tumor were queried from the National Cancer Database, which comprises >70% of cancers newly-diagnosed in the U.S. Tumor types were classified by WHO2016 ICD-O3, and stratified by patient characteristics.

RESULTS

361,841 adults without a history of cancer presented with intracranial tumors between 2010–2015. Across all ages, these were comprised of 1) brain metastases (BMs; 25%: 29% in males vs. 23% in females); 2) meningiomas (25%: 15% in males, but 34% in females) including atypical (n=4,565) and anaplastic (n=833); 3) diffuse infiltrative gliomas (21%: 26% in males vs. 17% in females), mostly GBMs (14%); followed by 4) sellar (14%), 5) cranial nerve (6%), and PCNSL (3%) tumors. The remaining types each comprised ≤2 % of brain tumors, including mesenchymal non-meningothelial tumors (2%), intracranial ependymal (0.8%), mixed neuronal-glial (0.7%), circumscribed “other astrocytomas” (0.6%, mostly pilocytic astrocytomas n=1,307 and PXAs n=272), CNS embryonal (0.3%), pineal (0.2%), GCTs (0.1%), and choroid plexus (0.1%) tumors. In the 91,686 patients presenting with a BM, the most common primaries were lung adenocarcinoma (39%), lung SmallCC (14%), lung SqCC (8%), breast (8% of females), melanoma (3%), kidney (3%), colorectal (2%), and esophageal (1%). The distributions of brain tumor types differed significantly by age, sex, race/ethnicity, and insurance status.

CONCLUSIONS

In adult patients where the first manifestation of cancer includes an intracranial tumor, the most common diagnosis is either metastatic disease (predominantly from NSCLC) in males or benign meningiomas in females; but varies substantially by age group. Notably, our results adjust the traditional teaching that half of all new brain masses are BMs, which in fact represent only ~25% of new intracranial masses.