bluuebunny/crossref_metadata_2025_split huggingface dataset:
CSIG-18. NERVE/GLIAL ANTIGEN (NG)2 EXPRESSION IN GLIOBLASTOMA IS REGULATED BY miR-29b-3p
Authors: Schmitt Beate , Boewe Anne , Gu Yuan , Sippl Christoph , Urbschat Steffi , Oertel Joachim , Laschke Matthias , Menger Michael , Ampofo Emmanuel 
Published: November 2019

Abstract
Overexpression of NG2 in human glioblastoma cells is associated with an elevated drug resistance and thereby worsens clinical outcome. However, the regulatory mechanisms of NG2 expression are largely unknown. In this study, we identified miR-29b-3p as a posttranscriptional factor of NG2 expression. The basal mRNA levels of miR-29b-3p and NG2 were detected in the NG2-positive glioblastoma cell lines A1207 and U87 by qRT-PCR. The cells were transfected with miR-29b-3p-mimic or scrambled-miR (control) and the expression of NG2 was analyzed by qRT-PCR, flow cytometry and Western blot. Reporter gene analyses of the NG2 promotor region and 3’UTR were performed to study the effect of miR-29b-3p on NG2 expression. Finally, we analyzed the mRNA levels of NG2 and miR-29b-3p in samples from glioblastoma patients. We found that the two NG2-positive glioblastoma cell lines A1207 and U87 are positive for miR-29b-3p. Transfection with miR-29b-3p-mimic reduced NG2 mRNA levels in A1207 (29%±9.9; Mean±SD) and U87 (6%±2.8), resulting in a significantly decreased NG2 protein expression in A1207 (67%±6.4) and U87 (75%±4) when compared to controls. The analysis of the 3’UTR revealed that miR-29b-3p is a posttranscriptional regulator of NG2 expression. Moreover, miR-29b-3p affects the pretranscriptional NG2 expression by diminishing SP-1-dependent NG2 promotor activity. These results were confirmed by the analysis of glioblastoma patient-derived samples, demonstrating that a high NG2 expression is associated with low levels of miR-29b-3p. In conclusion, we identified miR-29b-3p as a crucial regulator of NG2 expression in glioblastoma. Hence, targeting NG2 expression by miR-29b-3p may provide a novel therapeutic strategy to overcome drug resistance in NG2-positive glioblastoma cells.
CSIG-25. MTAP LOSS COMPROMISES DNA DAMAGE RESPONSE IN GBM CELLS
Authors: Du Changzheng , Hansen Landon , Singh Simranjit , Roso Kristen , Greer Paula , He Yiping 
Published: November 2019

Abstract
Homozygous deletion of methylthioadenosine phosphorylase (MTAP) is one of the most frequent genetic alterations in glioblastomas (GBMs), occurring in about half of all patients. Here, we demonstrated that MTAP loss compromises the proteostasis of genomic stability guardian, H2AX, via disrupting a signaling cascade of PRMT5-RNF168-SMURF2. We showed that PRMT5 sustains the expression of RNF168, an E3 ubiquitin ligase essential for cellular response to DNA damage. Suppression of PRMT5 function, as occurring in MTAP-null GBM cells, attenuates the expression of RNF168, which consequently leads to degradation of H2AX protein by a HECT-type E3 ubiquitin ligase, SMURF2. We revealed that RNF168 and SMURF2, serving as a stabilizer and destabilizer of H2AX respectively, functionally oppose each other via their dynamic interactions with H2AX. In supporting the important role of this PRMT5-RNF168-SMURF2 signaling cascade in controlling H2AX homeostasis, MTAP-null GBM cells display a compromised DNA damage response, highlighted by higher levels of DNA damage spontaneously or in response to genotoxic agents. Collectively, these results identify a novel signaling cascade that is essential to the DNA damage response, reveal the profound impact of MTAP loss on GBM cells, and suggest novel therapeutic opportunities.
CSIG-27. PRC2-INDEPENDENT FUNCTION OF EZH2/HP1BP3 COMPLEX IN GLIOMA STEM CELLS
Authors: Zhang Junxia , Yu Tianfu , Liu Ning 
Published: November 2019

Abstract
Glioblastoma (GBM) displays cellular and genetical heterogeneity harboring a subpopulation of glioma stem cells (GSCs). Enhancer of zeste homolog 2 (EZH2), a histone lysine methyltransferase, is the core subunit of the polycomb repressor 2 (PRC2) complex, mediates gene transcriptional repression in both normal and tumor stem cells. An oncogenic role of EZH2 as a PRC2-dependent transcriptional silencer is well established; however, non-canonical functions of EZH2 are incompletely understood. Here we found a novel oncogenic mechanism for EZH2 in a PRC2-indenpend way in GSCs. Using HPLC-MS/MS and IP assay, EZH2 bound to HP1BP3 (heterochromatin protein 1 binding protein 3), a heterochromatin-related protein, with its pre-SET domain. Overexpression of H1P3B3 enhanced the proliferation, self-renewal and temozolomide (TMZ) resistance of GBM cells. Intriguingly, H1PBP3 was up-regulated in high grade gliomas with proneural (PN) subtypes and had a high predictive value on prognosis in patients with PN gliomas. Furthermore, EZH2 and HP1BP3 co-activated the expression of WNT7B by blocking the methylation of H3K9, thereby increasing TMZ resistance and tumorigenicity of glioblastoma cells. Interestingly, inhibition of WNT7B autocrine via LGK974, a specific porcupine inhibitor, effectively reversed the TMZ resistance of both GSCs and GBM glioma cells expressing HP1BP3. Hence, targeting the PRC2-independent function of EZH2 is an effective approach to enhance the efficacy of treating GBM.
CMET-03. MANAGEMENT OF MULTIPLE BRAIN METASTASES BY STAGED SRS FOCUSING ON UTMOST RISK LESIONS
Authors: Zhen Junjie , Li Shaoqun , Lai Mingyao , wen lei , cai linbo 
Published: November 2019

Abstract

BACKGROUND
Patients with multiple large brain metastases (LBMs) are subject to cause intracranial hypertension, which remains a clinical difficulty so far. The present study is to investigate whether staged stereotactic radiosurgery (SRS) is a feasible solution to improve clinical symptoms and life quality in palliative management.

METHODS
Patients with brain metastases treated between 1 January 2016 and 30 March 2019 were retrospectively studied. The patients inclusion criteria included were: 1) metastatic lesions ≥ 3; 2) tumor lesions with a supratentorial invasion ≥ 3 cm or a subtentorial invasion ≥ 2 cm; 3) with neurological impairment or with a high risk for intracranial hypertension. The first stage of SRS dose regimens for utmost risk supratentorial lesions were 20-24Gy within 2-fractions (fx); whereas 24Gy/3-fx for subtentorial lesions. For the 2nd stage, the rest metastatic lesions with relatively lower risk were treated with 16-18Gy/1-fx one week after that.

RESULTS
A total of 30 patients were enrolled included in this study. The neurological symptoms were significantly relieved following 1st stage of SRS, with a median period of 3 days (2–14 days). 13 out of 30 patients were randomly selected for MR imaging two weeks after SRS. It suggested that 84.6% (11/13) of the patients were observed with a clear reduction of tumor volume. The median reduced diameter was 0.38 (0.17–0.83) cm and a median volume reduction was 3.22 (0.01–9.08) mm3. According to RANO-BM, the objective remission rate of utmost risk lesions was 100%, whereas the less critical lesions was 95.16% (59/62). One patient (3.33%) was identified with acute adverse reaction (> grade 3).

CONCLUSIONS
Staged SRS with a priority for utmost risk lesions was indicated to be an effective approach for multiple large brain metastases. Further prospective study is highly warranted.
CMET-05. EVALUATING RADIATION NECROSIS IN PATIENTS WITH INTRACRANIAL METASTASES FROM MELANOMA
Authors: Edmonds Victoria , Thomson Holly , Sharma Akanksha , Butterfield Richard , Zhang Nan , Sio Terence , Vora Sujay , Daniels Thomas , Schild Steven , Ashman Jonathan , Patel Naresh , Zimmerman Richard , Mrugala Maciej , DeLeon Thomas , Bryce Alan , Porter Alyx 
Published: November 2019

Abstract

BACKGROUND
Radiation is an integral component of the multidisciplinary treatment of patients with intracranial metastasis (ICM) from melanoma. The risk of radiation necrosis (RN) post-treatment can range from 5–25%. We retrospectively evaluated pre- and post-radiation clinical and radiographical characteristics in patients with ICM from melanoma to identify potential risk factors for RN.

METHODS
After IRB approval, patients with ICM from melanoma who received radiation at our institution between 2013 and 2018 were retrospectively reviewed. We recorded demographics, intracranial metastasis (burden and location), systemic therapy, resection, stereotactic radiosurgery versus whole brain radiation, and outcomes. Brain MRI was evaluated using the Response Assessment in Neuro-Oncology criteria (RANO).

RESULTS
A total of 27 patients were included in the study. RN was diagnosed in 14 patients (52%) at one month to three years following radiation. Cerebellar location (n=7) was significantly associated with RN (p=0.0058). Metastasis-associated hemorrhage was present in 7 patients, 6 of which developed RN (43% vs 8%, p=0.08). Surgical resection prior to radiation was performed in 9 patients, 7 of which developed RN (50% vs 15%, p=0.1). RN appeared to be less often diagnosed when ICM were treated with higher doses of radiation (24 Gy vs 20 Gy, p=0.07). Systemic treatment was administered prior to radiation in 25 patients and we found no relationship with systemic therapy type and RN. Presumed RN was treated in 12 of 14 patients (86%). Steroids or surgical resection were the primary treatment modalities, with laser ablation used in 1 case. Following treatment, improvement was noted in 3 patients radiographically and in 1 of these clinically.

CONCLUSIONS
This series of patients with radiotherapy-treated brain metastases from melanoma reveals cerebellar involvement, hemorrhage, and prior surgical resection as potential risk factors for radiation necrosis. Neoadjuvant systemic treatment did not appear to be a risk factor in our review.
CMET-06. AN ANALYSIS OF RESPONSE ENDPOINTS FOR BRAIN METASTASIS PATIENTS TREATED WITH STEREOTACTIC RADIOSURGERY AND PD(L)-1 INHIBITORS
Authors: Kotecha Rupesh , Miller Jacob , Kim Joseph , Juloori Aditya , Chao Samuel , Murphy Erin , Peereboom David , Mohammadi Alireza , Barnett Gene , Vogelbaum Michael , Angelov Lilyana , Suh John , Ahluwalia Manmeet 
Published: November 2019

Abstract

PURPOSE
Recent trials have evaluated the role of anti-PD(L)-1 inhibitors alone in patients with newly diagnosed brain metastasis, resulting in a suggested paradigm shift. In the absence of randomized comparisons, an evaluation of outcomes for similar patients treated with radiotherapy are needed to provide baseline comparative data.

METHODS
This retrospective cohort study included patients diagnosed with brain metastasis from 2010–2017 at a single tertiary care institution who received SRS and at least one anti-PD(L)-1 inhibitor. Primary endpoints included the rate of best intracranial response (either a complete [CR] or partial response [PR]), rate of intracranial benefit (percentage of patients with stable disease [SD] for at least 6 months), and overall objective response rates.

RESULTS
150 patients met the eligibility criteria for this study and the median follow-up time was 10 months (Range: 1–130 months). Only a minority of patients from this cohort would have been eligible for comparative systemic therapy alone trials: 8 (CheckMate 204, CM), 8 (ABC), and 50 patients (Yale Institutional trial, YI). Best intracranial objective response rates for these trial eligible patients were 64% (CM), 64% (ABC), and 72% (YI), respectively. The 6-month rates of intracranial benefit across patients were 75% (CM), 75% (ABC), and 93% (YI), respectively. The rates of either a CR, PR, or SD across trial eligible patients were 100% (CM), 100% (ABC), and 94% (YI), respectively. More than 50% of patients experienced out-of-field progression in each of the patient subgroups.

CONCLUSIONS
Over a seven year period, very few patients treated with SRS and anti-PD(L)-1 inhibitor therapy in a busy academic practice would have been eligible for systemic therapy alone per trial eligibility criteria. In these highly favorable subgroups, patients experience high rates of objective response, best intracranial response, and intracranial benefit after SRS and anti-PD(L)-1 therapy, representing optimal brain metastasis management.
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

Abstract
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

Abstract

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

Abstract

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

Abstract

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

Abstract
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.