bluuebunny/crossref_metadata_2025_split huggingface dataset:
PDTM-17. MiR-126, miR-369-5p AND miR-487b DRIVE PEDIATRIC GLIOBLASTOMA INVASION VIA KCNA1
Authors: Huang Yulun , Qi Lin , Kogiso Mari , Du Yuchen , Braun Frank , Zhang Huiyuan , Huang Lei , Teo Wan-yee , Lindsay Holly , zhao Sibo , Baxter Patricia , Su Jack , Adekunle Adesina , yang Jianhua , Brabetz Sebastian , Kool Marcel , Pfister Stefan , Chintagumpala Murali , Parsons Williams , Perlaky Laszlo , Wang Zhong , Zhou You-Xin , Man Chris , Li Xiao-Nan 
Published: November 2019

Abstract
Diffuse invasion is one of the key features that make GBM particularly difficult to treat. We hypothesize that direct comparison of matched invasive (GBMINV) and tumor core GBM cells (GBMTC) would facilitate the discovery of drivers of pediatric GBM (pGBM) invasion. However, GBMINV cells are extremely difficult to obtain from normal brain tissues because aggressive surgical resection of normal tissue carries the risk of serious neurological deficits. Most past and current studies on GBM invasion were and are forced to utilize the resected primary tumor masses. To overcome this barrier, we utilized a panel of 6 pediatric patient tumor-derived orthotopic xenograft (PDOX) mouse models to isolate matching pairs of GBMTC cells and GBMINV cells and confirmed a significantly elevated invasive capacity in GBMINV cells both in vitro and in vivo. Global profiling of 768 human microRNA using a real-time PCR-based Taqman system identified 23 microRNAs were upregulated in the GBMINV cells in at least 4 of the 6 pGBM models as compared with the matching GBMTC cells. We subsequently showed that silencing the top three miRNAINV, miR-126, miR-369-5p, and miR-487b, suppressed tumor cell migration in vitro (both as neurospheres and monolayer cultures) without affecting cell proliferation, and blocked pGBM invasion in mouse brains. Integrated analysis of the mRNA profiling of the same set of GBMTC and GBMINV cells revealed the affected signaling pathways and identified KCNA1 as the sole common computational target gene of the three miRNAINV. Treatment of three pairs of GBMTC and GBMINV cells with two KCNA1 inhibitors, ADWX1 and Agitoxin 2, caused significant suppression of pGBM cell migration in vitro. In conclusion, this study revealed an intrinsically elevated invasive phenotype in GBMINV cells, identified miR-126, -369-5p, and -487b as novel drivers of pGBM invasion, and characterized KCNA1 as a potential therapeutic target for arresting pGBM invasion.
PDTM-30. UNDERSTANDING THE EFFECTS OF MOLECULAR SIZE ON VOLUME OF DISTRIBUTION IN CONVECTION-ENHANCED DELIVERY
Authors: Power Erica , Rechberger Julian , Zhang Liang , Daniels David 
Published: November 2019

Abstract

BACKGROUND
Diffuse midline gliomas harboring the H3K27M mutation, previously known as diffuse intrinsic pontine gliomas (DIPG), are rare and aggressive pediatric brain tumors. Over 100 clinical trials with different chemotherapeutics have failed to show any therapeutic benefit. One reason for failure is likely due to poor delivery of these agents to the brainstem. Convection-enhanced delivery (CED) is an emerging delivery technique used to directly inject the agent of interest into the brainstem under pressure. While there is evidence that this may be an effective delivery method, little work has been done to understand the optimal physical properties of these drugs. We sought characterize volume of distribution in the brain based on molecular size of the agent delivered via CED.

METHODS
Sprague- Dawley rats underwent a single injection of FITC-dextran (3,000 Da, 10,000 Da, 20,000 Da, 70,000 Da, 150,000 Da) via CED into the pons. Post-injection, animals were sacrificed and their brains harvested. Fluorescent microscopy imaging was used to calculate the volume of distribution of the FITC-dextran throughout the brain.

RESULTS
The volume of distribution (Vd) decreased exponentially according to a two-phase delay (r2= 0.94) as the molecular size of the FITC-dextran increased. The highest mean Vd (107.87mm3) was at a molecular weight of 3,000 Da, and lowest mean Vd (26.48 mm3) was at a molecular weight of 150,000 Da. ANOVA analysis was statistically significant (p= 0.0017).

CONCLUSIONS
As the molecular size of the FITC-dextran increased, the volume of distribution within the brain following a single injection via CED into the pons decreased. A better understanding of how drugs distribute by convection will allow us to optimize treatment regimens for DIPG tumors.
PDTM-36. WHOLE EXOME SEQUENCING (WES) OF DIPG PATIENTS FROM THE BIOMEDE TRIAL REVEALS NEW PROGNOSTIC SUBGROUPS WITH SPECIFIC ONCOGENIC PROGRAMMES
Authors: Debily Marie-Anne , Kergrohen Thomas , Varlet Pascale , Le Teuff Gwenael , Nysom Karsten , Blomgren Klas , Leblond Pierre , Bertozzi Anne-Isabelle , De Carli Emilie , Chappé Celine , Ghermaoui Samia , Barret Emilie , Picot Stephanie , Tauziède-Espariat Arnaud , Puget Stephanie , Castel David , Vassal Gilles , Grill Jacques 
Published: November 2019

Abstract
BACKGROUND & METHODS. The BIOlogical MEdicines for DIPG Eradication (BIOMEDE) trial is a randomized multi-arm multi-stage program (drop-the-loser adaptive design). The first trial was an open-label phase-II trial comparing three drugs (everolimus, dasatinib, erlotinib) combined with irradiation, allocated according to the presence of their specific targets. All patients underwent a biopsy at diagnosis to confirm the DIPG molecularly and establish the expression of pre-specified biomarkers. Patient samples were explored by WES with a sequencing depth average >100X for the tumor and >60X for the blood. RESULTS. Unsupervised clustering of copy-number-variations (CNV) identified 4 groups corresponding to a new stratification of DIPG: cluster 1 (n=42) with high CNV, cluster 2 (n=23) with chromosome 1q + chromosome 2 gains, cluster 3 (n=9) with low CNV and cluster 4 (n=21) with isolated 1q gain. Clusters 1 had higher hazard-ratio for death than the others (mean HR 1.959, range 1.054–3.643, p< 0.0001, adjusted Cox model). Extensive structural rearrangements/chromotrypsis were significantly more frequent in TP53-mutated samples. Indeed, when stratiftying patients in 4 groups based on type of histone H3 mutated at K27 and the presence of a TP53 pathway alteration the subgroup with TP53 altered pathway had a significantly higher hazard-ratio for death than the others (mean HR 3.450, p=0.0017, adjusted Cox model). Additional drug targets were identified, especially in the DNA repair machinery that could be exploited for new targeted therapies. CONCLUSION. WES at diagnosis was feasible in most patients and brings new prognostic and theranostic informations. This allows a better patients stratification and the development of personalized medicine in DIPG.
PDTM-45. MECHANISM OF NEURAL STEM CELL TRANSFORMATION BY C11ORF95-RELA TRANSLOCATIONS
Authors: Kupp Robert , Gilbertson Richard J 
Published: November 2019

Abstract
Highly recurrent chromosome translocations that produce oncogenic fusions are a prime example of practical therapeutic targets translating into clinical successes. We have previously described the genetic driver of supratentorial ependymomas as translocation fusions of the C11orf95 gene of unknown function and RELA, the canonical nuclear transducer of NF-κB signaling5. Subsequent studies have reinforced our original findings on the frequency (>70%) of these C11orf95-RELA (CR) fusions in human disease, as well as their transformative potential in murine models. However, the mechanisms by which CR fusions transform neural stem cells into ependymomas remain elusive. Using a multi-OMICS approach, we show that oncogenic C11orf95 fusions co-opt spatio-temporally regulated transcriptional activators in ependymoma. We henceforth demonstrate that supratentorial ependymomas, which have been previously described as a RELA fusion disease6, are truly a C11orf95 fusion disease, with C2H2-ZFs serving as a scaffold for transcriptional dysregulation. Our studies lay the architectural framework for a molecular roadmap into the heart of C11orf95 fusion ependymomas, elucidating the biochemical mechanisms which furnish the capacity of these fusions to operate as single gene oncogenes, and henceforth providing potential avenues for therapeutic intervention in ependymoma.
QOLP-02. PRESERVING FUNCTIONS OF LANGUAGE, MOTOR, AND WORKING MEMORY BY AWAKE MAPPING CONTRIBUTES TO MAINTAIN QUALITY OF LIFE IN GLIOMAS
Authors: Nakajima Riho , Kinoshita Masashi , Okita Hirokazu , Nakada Mitsutoshi 
Published: November 2019

Abstract

INTRODUCTION
Aims of awake surgery are considered as maximum resection and functional preservation for postoperative quality of life (QOL). However, any studies have not been focused on the fundamental hypothesis that preservation of brain functions contributes to patient’s QOL. In this study, we investigated postoperative QOL and its related factors to reveal contribution of awake surgery for maintaining QOL.

METHODS
A total of 63 patients who underwent awake surgery were studied. Several kinds of neuropsychological/neurological tests and SF-36 to assess QOL were performed at 6-month postoperatively. In SF-36, 3-component scores, including physical, mental, and role/social component were calculated and they were compared with healthy volunteers. Additionally, their background factors were collected from medical records. Then, influenced background and functional factors to QOL were analyzed using multiple regression analysis. Moreover, voxel-based lesion symptom (VLSM) analyses were performed to investigate relationship between resected regions and QOL.

RESULTS
Though physical and mental QOL scores were almost equivalent to healthy volunteers, role and social component score (RCS) were significantly declined (36.7, < .0001). Using multiple regression analysis, RCS significantly related to reinstatement among several background factors (p=0.0038). Until postoperative 6 months, 71.6% returned to professional work. Moreover, RCS correlated significantly with working memory, language, and motor function among several brain functions (p=0.019, 0.0028, 0.010, respectively). In the VLSM analysis, patients who resected following regions showed significantly low RCS; the left inferior frontal and superior to middle temporal gyri which relate to language; and right supplementary motor area and cingulate cortex which are involved in motor control or working memory.

CONCLUSIONS
The important factors to maintain QOL are reinstatement and preserving brain functions including language, motor, and working memory. This suggests that awake surgery aiming for preserving these functions is a benefit for postoperative QOL.
QOLP-03. MEASURING CHANGE IN HEALTH-RELATED QUALITY OF LIFE: THE ADDED VALUE OF ANALYSIS ON THE INDIVIDUAL PATIENT LEVEL IN GLIOMA PATIENTS IN CLINICAL DECISION MAKING
Authors: Coomans Marijke , Taphoorn Martin , Aaronson Neil , Baumert Brigitta , van den Bent Martin , Bottomley Andrew , Brandes Alba , Chinot Olivier , Coens Corneel , Gorlia Thierry , Herrlinger Ulrich , Keime-Guibert Florence , Malmström Annika , Martinelli Francesca , Stupp Roger , Talacchi Andrea , Weller Michael , Wick Wolfgang , Reijneveld Jaap 
Published: November 2019

Abstract
BACKGROUND: Health-related quality of life (HRQoL) is an important outcome in glioma research, reflecting the impact of disease and treatment on a patient’s functioning and wellbeing. Data on changes in HRQoL scores provide important information for clinical decision-making, but different analytical methods may lead to different interpretations of the impact of treatment on HRQoL. This study aimed to study whether different methods to evaluate change in HRQoL result in different interpretations. Methods: HRQoL and sociodemographical/clinical data from 15 randomized clinical trials were combined. Change in HRQoL scores was analyzed: (1)at the group level, comparing mean changes in scale/item scores between treatment arms over time, (2)at the patient level per scale/item by calculating the percentage of patients that deteriorated, improved or remained stable on a scale/item per scale/item, and (3)at the individual patient level combining all scales/items. Results: Data were available for 3727 patients. At the group scale/item level (method 1), only the item ‘hair loss’ showed a significant and clinically relevant change (i.e. ≥10 points) over time, whereas change scores on the other scales/items showed a statistically significant change only (all p< .001, range in change score:0.1–6.2). Analyses on the patient level per scale (method 2) indicated that, while a large proportion of patients had stable HRQoL over time (range:27–84%), many patients deteriorated (range:6–43%) or improved (range:8–32%) on a specific scale/item. At the individual patient level (method 3), the majority of patients (86%) showed both deterioration and improvement, while only 1% of the patients remained stable on all scales. Conclusion: Different analytical methods of changes in HRQoL result in distinct interpretations of treatment effects, all of which may be relevant for clinical decision-making. Additional information about the joint impact of treatment on all outcomes may help patients and physicians to make the best treatment decision.
QOLP-04. CALCULATING THE NET CLINICAL BENEFIT IN BRAIN TUMOR TRIALS BY COMBINING SURVIVAL AND HEALTH-RELATED QUALITY OF LIFE DATA USING TWO METHODS: QUALITY ADJUSTED SURVIVAL EFFECT SIZES AND JOINT MODELLING
Authors: Coomans Marijke , Dirven Linda , Bottomley Andrew , van den Bent Martin , Sloan Jeff , Stupp Roger , Weller Michael , Reijneveld Jaap , Taphoorn Martin , Aaronson Neil , Baumert Brigitta , Brandes Alba , Chinot Olivier , Coens Corneel , Gorlia Thierry , Herrlinger Ulrich , Keime-Guibert Florence , Malmström Annika , Martinelli Francesca , Talacchi Andrea , Wick Wolfgang 
Published: November 2019

Abstract

INTRODUCTION
The impact of treatment on both the quality and the quantity of life, i.e. the ‘net clinical benefit’, should be considered to facilitate shared decision making. Two methods that combine survival and health-related quality of life (HRQoL) data: Quality Adjusted Effect Sizes (QASES) and Joint Modelling (JM) were applied to gain insight in the net clinical benefit.

METHODS
The net clinical benefit in one RCT (EORTC 26951 comparing radiotherapy (RT) + PCV chemotherapy versus RT alone) was calculated as a proof of concept for other trials. With the QASES method, effect sizes for differences in survival and HRQoL between treatment arms were calculated. JM allows simultaneous modeling of a longitudinal outcome (HRQoL), and a time-to event outcome (survival). HRQoL scales/items that were selected for primary analysis in the main study were also selected for this analysis: fatigue, global health, social functioning, communication deficit, seizures, physical functioning, and nausea/vomiting.

RESULTS
288/386 patients completed baseline HRQoL forms and were included in the analysis. Overall survival (OS) was significantly longer with combined treatment (42.3 vs. 30.6 months). The percentage of patients who experienced a clinically relevant deterioration (≥10 points) in nausea/vomiting, fatigue, social functioning and global health up to one year after treatment compared to baseline was larger in the RT+PCV arm. QASES corresponded to a reduction in the median OS difference from 9.7 months up till 5.5 months, given equal weights to OS and HRQoL. JM analyses resulted in a theoretical loss of treatment effect in OS of 2–6% when adjusting for HRQoL.

CONCLUSION
Both methods showed that adjusting for the impact of treatment on a relevant HRQoL parameter reduced the survival benefit in the experimental treatment arm compared to standard treatment arm. Applying these methods may facilitate communicating the impact of treatment to patients in clinical practice.
QOLP-05. PREDICTING SURVIVAL WITH THE HEIDELBERG PROGNOSTIC MODEL AFTER SALVAGE STEREOTACTIC RADIOSURGERY OF PREVIOUSLY IRRADIATED PROGRESSIVE HIGH-GRADE GLIOMAS
Authors: Ampil Federico , Richards Troy , dela Cruz Nestor 
Published: November 2019

Abstract

BACKGROUND
The concept of repeat radiotherapy for previously irradiated, progressive high-grade gliomas (PHGG) is intuitively rational for a disease that has the potential to be a life-threatening illness and seriously affect the quality of remaining life. Recently, a simplified method of prognosis prediction (the Heidelberg prognostic model/HPM) was developed to evaluate survival after re-irradiation of PHGGs.

OBJECTIVE
This retrospective study aimed to assess whether salvage stereotactic radiosurgery (SSRS) is worthwhile in patients with PHGGs, and to determine which individuals are likely to benefit from retreatment using the HPM.

METHODS
Three hundred eighty-three people were diagnosed with intracranial glioma between 2000 and 2010 at our institution. From this population, 25 patients (7%) who had a history of prior irradiation and underwent SSRS for PHGGs formed the subjects of this clinical audit. In the HPM system, scores were assigned for clinicopathological features such as age, histology and interval duration between treatments. There were five and 20 patients with HPM determined low and high prognostic scores, respectively. The mean follow-up period was 9.9 months.

RESULTS
Overall median survival (MS) was 7 months, and the 6, 12- and 24-months crude survival rates (CSR) were 60%, 28% and 16%, respectively. The MS and CSRs for the low scoring patients were 20 months, 100%, 100% and 20%, respectively; for the 20 high-scoring individuals, the corresponding findings were 8 months, 75%, 35% and 10%, respectively. Among the evaluable 11 people, the quality of life was acceptable in approximately half of the cases. Local recurrence rate after SSRS was 12%. Adverse-related events were not observed.

CONCLUSION
A trend towards improved survival was observed in the HPM low-scoring patients. More documentation of favorable effects is required to support the useful role of SSRS as second line treatment of PHGGs.
QOLP-06. EXISTENTIAL DISTRESS: UNADDRESSED CONCERNS FOR ADULT NEURO-ONCOLOGY PATIENTS
Authors: Loughan Ashlee , Braun Sarah , Husain Mariya , Aslanzadeh Farah , Boutte Rachel , Lanoye Autumn 
Published: November 2019

Abstract

BACKGROUND
Primary brain tumor (PBT) patients may experience existential distress including fear of cancer recurrence and death anxiety; however, to date few have examined this issue. The objectives of this study were twofold: first, to systematically review PBT representation in the psycho-oncology literature on existential distress, and second, to preliminarily assess the prevalence and correlates of existential distress in a sample of PBT patients. PRIMARY OBJECTIVE METHODS/

RESULTS
Three databases (PsycINFO, PubMed, and CINAHL) were systematically searched to identify articles measuring fear of cancer recurrence, fear of dying, or death anxiety in oncology patients. Included studies were examined to determine the frequency of PBT patients and identify exclusion criteria relevant to neuro-oncology. For studies including PBT patients, a more thorough data extraction was undertaken. Systematic searching found 336 studies meeting inclusion criteria (N=133,027). Eight studies (0.16% of the participants) included PBT patients. Exclusion criteria such as cognitive impairment and specific treatment parameters may have prohibited PBT patient participation. Studies including PBT patients used mixed methods with limited demographic analyses; existential distress was correlated with heightened psychological distress and poor quality of life. SECONDARY OBJECTIVE METHODS/

RESULTS
A cross-sectional analysis of 81 PBT patients (20–86 years old) was conducted. Patients completed validated questionnaires of death anxiety, death distress, generalized anxiety, and depressive symptoms. Descriptive analyses, t-tests, chi-square, and Pearson correlations were conducted. Up to 79% of PBT patients endorsed death anxiety. These patients were significantly younger, more likely to be female, and have a low-grade brain tumor (p< 0.05). Significant correlations were found between death anxiety and distress and symptoms of anxiety and depression (p< 0.01).

CONCLUSIONS
PBT patients are underrepresented in existential psycho-oncology literature, despite preliminary findings suggesting prevalence of these concerns. Future investigations of existential distress in neuro-oncology is warranted to inform psychosocial screening and treatment for PBT patients.
QOLP-07. A PILOT STUDY TO ASSESS THE INTEGRATION OF A UNIQUE PROQOL TOOL AND EARLY PALLIATIVE CARE INTERVENTION IN THE CARE OF HIGH GRADE GLIOMA PATIENTS AND THEIR CAREGIVERS
Authors: Sharma Akanksha , Wolfe Eric , Barrera Celina , Williamson Samantha , Farfour Hannah , Mrugala Maciej , Edwin Mark , Sloan Jeff , Porter Alyx 
Published: November 2019

Abstract

BACKGROUND
Early involvement of palliative care (PC) in patients with metastatic cancer has been associated with improved quality of life (QOL). Patients with high grade glioma (pwHGG) and their caregivers have unique needs such that similar results are anticipated in this population but cannot be extrapolated. Recognizing that pwHGG often require a caregiver early in the course of disease, this patient population also experiences significant personal and caregiver distress that has been given limited attention and resources. AIM: To assess the feasibility of implementation of a novel patient reported outcomes (PRO) quality of life (QOL) tool administered by smart device in routine office visit (OV) and early integration of palliative care (PC) for pwHGG and their caregivers to improve QOL for both. DESIGN: Prospective, single-center cluster-randomized pilot conducted for 6 months during completion of adjuvant therapy for newly diagnosed high grade glioma. After informed consent was obtained, 15 pwHGG and their caregivers were randomized to: routine OV with basic QOL survey; OV with PROQOL; or PC consultation, in addition to OV with PROQOL.

RESULTS
Two elderly patients with declining performance status transitioned to hospice after initial visit, and one moved out of state prior to adjuvant visits. Thus far 5/15 patients/caregivers have successfully completed the pilot with the 6 remaining participants due to complete in November 2019.

DISCUSSION
The PROQOL appears to be easily integrated into OV without significant patient, caregiver, or provider burden. Providers confirmed utility in prioritizing symptoms and concerns. Thus far, it appears that patients (and caregivers) appeared to benefit from the PROQOL and PC support as evidenced by longitudinal improvement in QOL scores over the control group.

CONCLUSIONS
A unique PROQOL tool and early PC can be easily integrated into practice, and may improve the QOL of pwHGG and their caregivers.