bluuebunny/crossref_metadata_2025_split huggingface dataset:
PDTM-32. RESOLVING MEDULLOBLASTOMA CELLULAR ARCHITECTURE BY SINGLE-CELL GENOMICS
Authors: Bihannic Laure , Hovestadt Volker , Smith Kyle , Filbin Mariella , Shaw McKenzie , Baumgartner Alicia , DeWitt John , Groves Andrew , Mayr Lisa , Weisman Hannah , Richman Alyssa , Shore Marni , Goumnerova Liliana , Rosencrance Celeste , Carter Robert , Phoenix Timothy , Hadley Jennifer , Tong Yiai , Houston Jim , Ashmun Richard , DeCuypere Michael , Sharma Tanvi , Ligon Keith , Pomeroy Scott , Rivera Miguel , Rozenblatt-Rosen Orit , Rusert Jessica , Wechsler-Reya Robert , Li Xiao-Nan , Peyrl Andreas , Gojo Johannes , Kirchhofer Dominik , Lötsch Daniela , Czech Thomas , Dorfer Christian , Haberler Christine , Geyeregger Rene , Halfmann Angela , Gawad Charles , Easton John , Pfister Stefan , Regev Aviv , Gajjar Amar , Orr Brent , Slavc Irene , Robinson Giles , Bernstein Bradley , Suvà Mario , Northcott Paul 
Published: November 2019

Abstract
Medulloblastoma is a malignant childhood cerebellar tumor comprised of distinct molecular subgroups. Whereas genomic characteristics of these subgroups are well defined, the extent to which cellular diversity underlies their divergent biology and clinical behaviour remains largely unexplored. We used single-cell transcriptomics to investigate intra- and inter-tumoral heterogeneity in twenty-five medulloblastomas spanning all molecular subgroups. WNT, SHH, and Group 3 tumors comprised subgroup-specific undifferentiated and differentiated neuronal-like malignant populations, whereas Group 4 tumors were exclusively comprised of differentiated neuronal-like neoplastic cells. SHH tumors closely resembled granule neurons of varying differentiation states that correlated with patient age. Group 3 and Group 4 tumors exhibited a developmental trajectory from primitive progenitor-like to more mature neuronal-like cells, whose relative proportions distinguished these subgroups. Cross-species transcriptomics defined distinct glutamatergic populations as putative cells-of-origin for SHH and Group 4 subtypes. Collectively, these data provide novel insights into the cellular and developmental states underlying subtype-specific medulloblastoma biology.
PDTM-39. CRACKING THE HISTONE CODE: REVEALING THERAPEUTIC EPIGENETIC TARGETS THROUGH HISTONE H3 TAIL ANALYSIS OF DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Li Daphne , Huang Tina , Camarillo Jeannie , Qi Jin , Weiss Hannah , Nazarian Javad , Thomas Paul , Saratsis Amanda 
Published: November 2019

Abstract

INTRODUCTION
Diffuse intrinsic pontine glioma (DIPG) is a highly morbid pediatric cancer. Up to 80% harbor a Histone H3K27M mutation, which alters wild type Histone H3 protein post-translational modifications (PTMs) and genomic enrichment patterns to impact chromatin structure and transcription regulation. We previously identified tumorigenic patterns of H3K27Ac/bromodomain co-enrichment in DIPG, and demonstrated pre-clinical efficacy of bromodomain inhibition (JQ1). Here, we employ a novel proteomics platform, developed at our institution, to further elucidate the impact of H3K7M mutation on glioma histone codes and response to bromodomain inhibition.

METHODS
Epiproteomic analysis was performed on pediatric glioma cell lines (H3K27 WT n=2, H3K27M n=2) to characterize 95 distinct Histone H3.3 and H3.1 N-terminal tail modification states. Cells were treated with JQ1 or DMSO, and collected at 0h, 24h, 48h. Histones were extracted from isolated nuclei, immunopurified, and analyzed by LC-MS/MS. Results were integrated with RNA-Seq and ChIP Seq results (H3K27M, H3K27Ac, H3K27me3, H3K4me1, H3K4me3) from the same DIPG cell lines. Pediatric glioma tissues (H3K27M WT n=3, H3K27M n= 9) were similarly analyzed to validate cell line results.

RESULTS
Cell PTM profiles cluster by H3 mutation status on unsupervised analysis. Relative H3 PTM abundance were compared across cell lines by tumor location, H3 mutation status, and in response to treatment. Significant differential genomic enrichment H3K27M and H3.3 WT proteins, H3K27Me3 and H3K27Ac were observed between mutant and wild type cell lines with epigenetic-targeted therapy, correlating with cell transcriptomes.

CONCLUSIONS
Histone H3 tail epiproteomic analysis reveals DIPG histone codes in situ, revealing the effects of bromodomain inhibition on the tumor epigenetic landscape and providing new insight to the mechanism of tumor formation and therapy response. Further investigation of the utility of these signatures as biomarkers for diagnosis and longitudinal monitoring of treatment response are therefore currently underway.
QOLP-13. IMPACT OF CANNABIS USE ON QUALITY OF LIFE IN PATIENTS WITH CENTRAL NERVOUS SYSTEM TUMORS
Authors: Rodriguez Almaraz Eduardo , Butowski Nicholas , Chang Susan , Ann Oberheim-Bush Nancy , Clarke Jennifer , Taylor Jennie , Buerki Robin , Berger Mitchel 
Published: November 2019

Abstract

BACKGROUND
Nearly 80,000 new cases of primary brain tumors are expected to be diagnosed this year, 32% of CNS tumors are malignant. Anecdotally, patients who report use of cannabis, frequently describe higher quality of life scores (QOL) in standardized instruments. However, the lack of available tools that allow systematic documentation of cannabis use results in a barrier to accurately assess efficacy, potential benefits and risks.

METHODS
We conducted a single center, observational study: patients with primary brain tumors answered a previously validated instrument to explore cannabis use. QOL was assessed using the instruments from the European Organisation for Research and Treatment of Cancer: QLQ-C30 and its complementary module BN-20 as well as the EuroQol instrument EQ-5D-5L. Eligible participants were identified as cannabis users or non-users, completing the instruments in a self-administered fashion.

RESULTS
To date, 51 patients who signed informed consent were enrolled and answered the questionnaires, mean age was 51 (SD 12.95) years, 34 were male, 30 were considered active cannabis users (66.6% males and 33.3% females). The mean global health score in the QLQ-C30 instrument was 68.4 (SD: 20.7) among cannabis users and 82.2 (SD: 17.5) among non-users. The mean difference in QOL scores between users and non-users was 13.8 (95%CI: 2.8, 24.8; p=0.01). In contrast the difference between cannabis users and non-users in QOL index in the EQ-5D-5L instrument was 0.13 (95% CI: 0.06, 0.2; p=0.001). Among cannabis users, patients perceive their symptoms as moderate before using cannabis and mild after using cannabis (p >0.001)

CONCLUSIONS
In our analysis, patients who use cannabis reported, on average, lower QOL scores. Potentially, sicker patients resort to cannabis to improve their symptoms and ultimately quality of life. The perception of patients is that cannabis usage improves overall quality of life. Findings provide support to perform prospective studies.
QOLP-14. CAREGIVER PERCEPTIONS OF END OF LIFE CARE IN PATIENTS WITH HIGH GRADE GLIOMA
Authors: Fortunato John , Schultz Lonni , Phillips Joel , Walbert Tobias 
Published: November 2019

Abstract

INTRODUCTION
Patients dying from high-grade gliomas (HGG) often suffer from a high symptom burden in the end-of-life (EoL) phase. Since patients with HGG typically do not follow up with providers in the EoL phase, information about quality of life and symptom management is sparse. Family caregivers are most informed about the patient’s symptoms and disease course. The aim of this study is to assess the quality of EoL care of HGG patients from the caregiver perspective.

METHODS
Caregivers participated in the Toolkit After-Death Bereaved Family Member Interview (TIME survey). This validated survey assesses EoL care by calculating “domain scores” (DS) in five different areas: 1) physical comfort and emotional support, 2) advance care planning, 3) focus on the individual, 4) attention to family, and 5) coordination of care. Caregivers also rated aspects of care using a 10 point Likert scale.

RESULTS
In a prospective study, 40 of 55 enrolled family caregivers completed the interview a median of 26 days after death. 68% of caregivers were female. DS indicate the quality of care. (0 = no opportunity to improve care, 1 = care was always sub-optimal). Caregivers perceived high satisfaction with information and decision-making (0.18), advance care planning (0.19), focus on the individual (0.16) and coordination of care (0.11). Attention to family (0.25) was not as well rated. Caregivers rated the overall care 8.90 ±1.36/10 on a 0–10 scale.

CONCLUSIONS
Caregivers reported a high overall satisfaction with EoL care provided, though attention to family could be improved. While previous research suggests the importance of good physician communication in allowing patients to die with dignity, more focus should be on the caregiver in the EoL phase to improve end of life care, caregiver burnout and bereavement.
QOLP-19. A NEW MODEL OF CARE FOR PATIENTS WITH CENTRAL NERVOUS SYSTEM CANCERS
Authors: Nevel Kathryn , Konig Franchesca , Elizabeth Davis Mary , Skakodub Anna , Sibilla Maryann , Harrison Mabel , Rawlins-Peters Gayle , Jean-Charles Dominique , Zankowsky Anastasia , Gilman Jody , Kelly Brian , Reiner Anne , Zavolas Stephanie , Goldman Hannah , Diamond Eli , Carver Alan , Ruppert Lisa , DeAngelis Lisa , Pentsova Elena 
Published: November 2019

Abstract
Patients (pts) with primary or metastatic central nervous system (CNS) cancers often have multiple physical, psychosocial, and spiritual needs. Neurological impairments can transform relationship dynamics with caregivers. These issues are difficult to address within a single outpatient oncology clinic. The Neurological Multidisciplinary Care Clinic (MdCC) at Memorial Sloan Kettering Cancer Center was a pilot study from 08/2017 to 04/2019 to foster a new model of care for complex pts with CNS cancers to identify and address their needs. The MdCC team: a neurologist, nurse, physiatrist (RM), physical therapist, social worker (SW), case manager (CM), dietitian (RD), and chaplain saw each pt/caregiver during a 3-hour visit. Since 11/2017 participants completed validated surveys on unmet needs, financial strain, and home equipment prior to their visit and satisfaction surveys afterward. Descriptive statistics were used to analyze results. Seventy-eight pts were seen: 39 were female, median age 59. Of these 78 pts, 65 had primary CNS cancers; predominantly glioblastoma (52%) and high-grade glioma (29%). Over 60% had never seen a SW, CM, RD, or physiatrist prior to MdCC. Seventy-six pts (97%) received symptom management recommendations. Prognosis/coping with cancer was discussed with 72 (92%) which increased signed health care proxy forms by 17% and DNR orders by 6% at time or within a month post MdCC. New/updated physical therapy was ordered for 48 pts (61%), orthotics for 8 (10%), and new equipment for 12 (15%). 25 pts (32%) continued following with physiatrists. Forty-eight pts completed a satisfaction survey; of these, 96% were highly satisfied, and would recommend MdCC to others. Pts’/caregivers’ unmet needs were effectively identified and addressed in this new model, The presence of these providers at time of MdCC allows for real time assessment of pts’/caregivers’, their support system, multidisciplinary team collaboration, planning, coordination of community services and implementation of a safe patient centered plan of care.
QOLP-30. CLINICAL PREDICTIVE MODEL FOR THE DEVELOPMENT OF VENOUS THROMBOEMBOLISM IN GLIOBLASTOMA
Authors: Yust-Katz Shlomit , Donthireddy Vijaya , Mandel Jacob , Abunafeesa Hussna , Patil Neha , Yadav Dhiraj , Jabbour-Aida Hiba , Wu Jimin , Yuan Ying , Tsavachidis Spiridon , Walbert Tobias , Bondy Melissa , Armstrong Terri 
Published: November 2019

Abstract

INTRODUCTION
The risk of venous thromboembolism (VTE) remains high for patients with glioblastoma (GBM) throughout the disease trajectory. Our previous work demonstrated the Khorana scale lacks specificity in this population. We therefore constructed, and attempted to validate a predictive model specific for the development of VTE during adjuvant chemotherapy in glioblastoma patients.

METHODS
A prior study of GBM patients treated at MD Anderson (MDACC) during the years 2005–2011 found from a multivariate analysis that male sex, BMI ≥ 35, KPS ≤ 80, and steroid therapy were significantly associated with the development of VTE. A predictive model from the MDACC cohort was created using these risk factors, and we attempted to validate the model in an independent cohort of GBM patients treated at Henry Ford from 2010–2015.

RESULTS
To develop the model 315 patients from the MDACC cohort were randomly divided into two parts: training (75% of data) used for model building, and validation (25% of data) used for model validation. Using the predictive model, the MDACC validation cohort found 80% sensitivity and 80% specificity. We then validated the model in the Henry Ford cohort of 190 GBM patients of which 50 developed a VTE. In the external validation set, the predictive model was found to have a sensitivity = 78% and specificity = 49.3% (Fisher test p-value = 0.0008).

CONCLUSIONS
Our predictive model for the development of VTE during adjuvant chemotherapy in GBM patients retained high sensitivity in an external data set, however high specificity was lost. While the specificity in our model was higher than in previous studies examining the Khorona scale in GBM patients, further refinement to improve the models reliability to correctly identify people who will not later develop a VTE may be helpful.
QOLP-31. ASSESSING THE IMPACT OF GLIOBLASTOMA ON WORK PRODUCTIVITY IN PATIENTS AND THEIR CAREGIVERS
Authors: Armstrong Terri , Puduvalli Vinay , Walbert Tobias , Peters Katherine , Loughan Ashlee , Ahluwalia Manmeet , Province Warren Paula , Cachia David , Taylor Jennie , O Blakeley Jaishri , Ganguli Arijit , Khandelwal Nikhil , Kamalakar Rajesh , Noe Les , Kumthekar Priya 
Published: November 2019

Abstract
Information is limited on the impact of glioblastoma (GBM) on patient employment and caregiver time commitments. This observational multisite study evaluated the impact of GBM on patients’ employment and on caregivers’ ability to work and perform daily activities. A total of 180 adults diagnosed with GBM and their caregivers were stratified across 4 groups representing specific stages in the disease course: Group 1=newly diagnosed; 2=postradiation; 3=stable disease; 4=recurrence. We assessed the impact of GBM on employment status and self-reported cognitive function in patients (EORTC QLQ-C30) and in caregivers (Work Productivity and Activity Impairment Questionnaire). Prior to diagnosis, 64% of all patients (74% < 65 years old) were employed, while only 22% (26% for those < 65 years old) were employed after diagnosis. Though not reaching significance, newly diagnosed patients and those with stable disease reported higher mean cognitive function scores (72.0 and 71.9) than other groups (61.1 and 61.3; P=0.227). At study enrollment, 56% of all caregivers were employed, while 41% had left their jobs to care for their patients. The impact on caregiver work productivity varied with a higher percentage of caregivers of newly diagnosed patients and those with recurrent disease missing work (45% and 24%, respectively) and experiencing work impairment (54% and 36%, respectively) than the other groups (P< 0.05). Forty-one percent of caregivers of newly diagnosed patients to 25% of patients with stable disease reported impairment of daily activities. GBM had a significant impact on patient and caregiver employment from the time of diagnosis. High cognitive burden among patients might have impacted their employment. Overall work and activity impairment for caregivers was evident in all groups with a notable impact at the time of first diagnosis and recurrence of disease. Future studies will explore the impact of these findings in a longitudinal cohort.
RDNA-12. THE FANCONI ANAEMIA (FA) PATHWAY AND GLIOBLASTOMA: A NEW FOUNDATION FOR DNA DAMAGE RESPONSE TARGETED COMBINATIONS
Authors: Rominiyi Ola , Myers Katie , Gomez-Roman Natividad , Lad Nikita , Dar Dawoud , Jellinek David , Chalmers Anthony , Carroll Thomas , Chen Beining , Al-Tamimi Yahia , Collis Spencer 
Published: November 2019

Abstract
Treatment resistance in glioblastoma is underpinned by highly interconnected DNA damage response (DDR) processes. The FA-pathway is a fundamental DDR process required for the resolution of replication fork impeding lesions, and we have previously shown that it is inactive in normal brain, but is re-activated in glioblastoma, providing a cancer-specific target for combination DDR therapies. Here, we find that elevated FA-pathway gene expression in gliomas is associated with poor survival (-17.1% 5-year OS, p< 0.0001, n=329–REMBRANT). Furthermore, patient-derived glioblastoma stem cell (GSC) populations, which drive therapeutic resistance, display high FA-pathway expression relative to paired bulk tumour cell populations (mean 2.3-fold higher across genes, p=0.0073). We further show that inhibition of a single DDR process (FA-pathway, PARP, ATR or ATM) increases the susceptibility of glioblastoma cell lines and patient-derived GSCs to current adjuvant therapy. Importantly, clinically approved PARP inhibitor (PARPi) monotherapy stimulates robust FANCD2 mono-ubiquitination, supporting a role of FA-pathway activation in response to current DDR-targeted therapy. In clinically-relevant 3D GSC models, simultaneous inhibition of the FA-pathway (FAPi) and PARP or ATR enhanced temozolomide sensitisation compared to a single DDR inhibitor (DDRi). Furthermore, combined FAPi+PARPi consistently conferred radiosensitisation whilst combined FAPi+ATRi led to a profoundly radiosensitising effect; e.g. sensitizer enhancement ratio (SER0.37) of 3.23 (3.03–3.49, 95% CI). Furthermore, comparison of α/β ratio enhancement suggests dual-DDRi strategies fundamentally alter the response of GSCs, whilst single cell gel electrophoresis & immunofluorescence studies suggest FA-pathway based DDRi combinations profoundly delay the resolution of IR-induced DNA strand breaks at 6 hours post-treatment, with increased persistent DNA double strand breaks at 24 hours. In conclusion, simultaneously targeting the FA-pathway and interconnected DDR processes represents an appealing therapeutic strategy. Additionally, constitutive lack of FA pathway function in some tumours, could serve as a novel predictive biomarker for patient response to PARPi and ATRi currently in clinical trials.
RDNA-14. RADIATION-INDUCED miR-4516 CONTRIBUTES TO RADIO-RESISTANCE AND PROMOTES AGGRESSIVE PHENOTYPE IN GLIOBLASTOMA
Authors: Sebastian Ebin , Cui Tiantian , Hlavin Bell Erica , McElroy Joseph , Johnson Benjamin , Manchanda Gulati Pooja , Geurts Marjolein , Paixao Becker Aline , Fleming Jessica , Jaharul Haque S , Robe Pierre , Chakravarti Arnab 
Published: November 2019

Abstract

BACKGROUND
Glioblastoma is the most aggressive brain tumor with poor prognosis despite the best available treatment. MicroRNAs (miRNAs) are emerging as promising, novel prognostic biomarkers and therapeutic targets in glioblastoma. In a previous study, we demonstrated that miR-4516 predicts poor prognosis and functions as an oncogene in glioblastoma. Aim of the current study is to examine the role miR-4516 in radiation resistance and identify downstream targets contributing to this phenotype

METHODS
Radiosensitization was evaluated by cell viability and clonogenic assays. Cell apoptosis was evaluated using flow cytometry and immunoblotting. Potential targets of miR-4516 were identified using bioinformatic analysis (Targetscan and miRDB) and confirmed by luciferase reporter assays. Results were validated using immunoblotting. miR-4516 expression in glioblastoma cell lines after radiation treatment was quantified by qRT-PCR.

RESULTS
Expression of miR-4516 was increased up to 15 fold following radiation treatment, peaking at around 15min-60 min in primary and established glioblastoma cell lines including GBM 08-387, GBM 30 and U87-MG. Furthermore, inhibition of miR-4516 sensitized GBM 08-387, GBM30 and U87-MG cells to radiation in comparison to control groups as determined by cell viability and clonogenic assays. Further, miR-4516 inhibition induced apoptosis in these cell lines following radiation treatment. While conducting mechanistic studies, we found that the tumor-promoting function of miR-4516 was, in part, mediated by inhibition of p21 and PTPN14, two direct targets of miR-4516

CONCLUSION
Our data suggest that radiation induces the expression of miR-4516 in glioblastoma cell lines. This miRNA plays a critical role in radio-resistance and promotes aggressive phenotypes in glioblastoma and therefore, functional analyses of its target pathways may uncover novel therapeutically vulnerable target(s) in glioblastoma. FUNDING: R01CA108633, R01CA169368, RC2CA148190, U10CA180850-01(NCI), Brain Tumor Funders Collaborative Grant, and OSU-CCC (all to AC). The Ton and Patricia Bohnenn Fund for Neuro_Oncology Research (to PR).
RTHP-03. FRAME-BASED AND MASKED STEREOTACTIC RADIOSURGERY: A PATIENT EXPERIENCE COMPARISON WITH THE GAMMA KNIFE ICON
Authors: Dawley Troy , Rana Zaker , Goenka Anuj , Schulder Michael 
Published: November 2019

Abstract

INTRODUCTION
Patients undergoing stereotactic radiosurgery (SRS) for intracranial pathology have two treatment options: frame-based (FB) versus masked (MB). There is sparse information on a patient’s experience between the two types and to what extent a patient’s diagnosis will predict their SRS experience.

METHODS
A retrospective analysis of patients who completed a questionnaire of their experience after SRS using the Gamma Knife Icon was completed.

RESULTS
Fifty-eight patients completed the questionnaire, 60% were FB and 40% MB. The average age was 63.3 + 15.3 years, 40% were male. Of the patients treated with a FB technique, 51% didn’t find SRS to be uncomfortable. Comparatively, 91% of MB patients didn’t find SRS to be uncomfortable. Patients who underwent FB treatment rated their pain of frame placement on a visual analog scale (VAS) 1–3, 24%, VAS 4–6, 46%, VAS 7–10, 30%. Eight patients answered that they didn’t tolerate the procedure as expected, most of which were treated using a FB method (87%). Compared to previous surgery or SRS, five patients found their experience of SRS wasn’t tolerable, while 93% of patients would consider repeat SRS. All patients treated felt adequately informed about the procedure. The patient experience of discomfort during SRS and their evaluation of pain during frame placement between patients treated for benign versus malignant lesions (discomfort: 59% vs. 22%, respectively and median VAS pain: 6 + 2.67, 4.5 + 1.99, respectively) determined a benign diagnosis had more discomfort during SRS compared to a malignant diagnosis. Pain during frame placement was similar for both diagnoses.

CONCLUSION
Patients experienced frame-based SRS as more uncomfortable than mask-based treatment. Benign pathologies appeared to have more discomfort compared to malignant pathologies. All patients of both techniques felt adequately informed about their procedure.