bluuebunny/crossref_metadata_2025_split huggingface dataset:
NIMG-60. IDH MUTANT GLIOMAS WITH 1p/19q CO-DELETION ARE LESS ACIDIC THAN NON-CO-DELETED GLIOMAS AS MEASURED WITH PH-WEIGHTED AMINE CEST-MRI AND AMINO ACID PET
Authors: Yao Jingwen , Nathanson David , Yong William H , Salamon Noriko , Lai Albert , Leia Nghiemphu P , Prins Robert , Pope Whitney , Czernin Johannes , Everson Richard , Liau Linda , Cloughesy Timothy , Ellingson Benjamin 
Published: November 2019

Abstract
1p/19q co-deleted gliomas are known to have slower growth rates and are more sensitive to chemotherapy and radiotherapy. This may be partially explained by the lower tumor acidosis compared to non-co-deleted gliomas, as extracellular acidosis is one of the driving forces toward tumor invasion and resistance to treatments. Amine CEST-EPI is a fast chemical exchange saturation transfer (CEST) imaging technique sensitive to decreased extracellular pH, transverse relaxation rate, and amino acid concentration. In the current study, we demonstrated that 1p/19q co-deleted gliomas are less acidic than non-co-deleted gliomas, using a combination of pH-sensitive amineCEST-EPI, T2 relaxometry, and 18F-FDOPA (18[F] fluorodopa) amino acid PET. 70 histologically-confirmed glioma patients (World Health Organization WHO grade II, N=35; grade III, N=35) received amine CEST-EPI scans. Among them, 16 patients received 18F-FDOPA PET scan and 45 patients received T2 relaxometry quantification. Mann-Whitney u-test is performed to evaluate the differences. Median MTRasym at 3ppm (magnetization transfer ratio asymmetry at amine proton resonance frequency) within T2 hyperintense lesions was significantly lower in 1p/19q co-deleted gliomas compared to non-co-deleted ones (co-deleted 1.19±0.31%; non-co-deleted 1.66±0.45%; p< 0.0001). The significantly lower MTRasym persists when comparing within grade II (p=0.003), grade III (p=0.031), IDH1 mutated gliomas (p=0.002), and gliomas exhibiting classical oligodendroglial histology (p=0.0007). The ROC analysis shows that the prediction of 1p/19q status using MTRasym has area under the curve (AUC) of 0.80 (sensitivity 75.6%. specificity 72.7%). Median FDOPA and T2 in T2-hyperintense lesions were not different between 1p/19q co-deleted and non-co-deleted tumors (FDOPA p=0.84; T2 p=0.63). Results suggest 1p/19q co-deleted gliomas have notably lower acidity compared with non-co-deleted gliomas, as indicated by lower MTRasym and no differences in amino acid concentration or transverse relaxation rate. Further, data indicate the 1p/19q co-deleted gliomas may have distinct metabolic characteristics and tumor microenvironment that can be measured using pH-sensitive amineCEST-MRI at 3T.
NCMP-03. AN UNUSUAL CASE OF NEUROBLASTOMA ASSOCIATED OMS: HIGH RISK DISEASE REQUIRING IMMUNOTHERAPY
Authors: Stiefel Jessica , Khakoo Yasmin , Basu Ellen , Meyer Rina , Kaur Gurcharanjeet 
Published: November 2019

Abstract

INTRODUCTION
Opsoclonus-myoclonus-ataxia syndrome (OMS) is a rare paraneoplastic syndrome (PNS) typically associated with low-risk pediatric neuroblastoma (NB). Overall survival is excellent but patients are at risk for long-term neurologic sequelae. As with many PNS, the etiology of NB-associated OMS is thought to be immune mediated and patients are managed with immunosuppressive therapy. The use of other immunotherapy such as checkpoint inhibitors for advanced stage cancers has been associated with sporadic reports of the development of PNS. We report a case of a child with NB-associated OMS who received anti-GD2 antibody immunotherapy for advanced relapsed NB without exacerbation of OMS. While the mechanism of action of anti-GD2 is unique, this case demonstrates that further study is required to understand which patients are at risk for PNS development/flare during therapy for advanced stage cancers. CASE: Our patient presented at 16 months of age with acute onset of tremors, irritability and ataxia and was diagnosed with OMS; at that time, evaluation revealed intermediate risk stage 4 neuroblastoma which was treated with 4 cycles of chemotherapy with complete response. His OMS was managed initially with high dose dexamethasone, followed by monthly IVIG, ACTH and rituximab with improvement in neurologic symptoms. The patient developed NB relapse (stage 4) 18 months after completion of initial chemotherapy and received chemotherapy and anti-GD2 antibody immunotherapy. Through this second course of therapy he continued to wean his immunosuppressive anti-OMS therapy without flare of his neurologic symptoms.

DISCUSSION
We present an unusual case of a child with NB-associated OMS whose OMS symptoms did not flare despite the use of immunotherapy to treat relapsed stage 4 disease.

CONCLUSION
While immunosuppression is used to treat OMS and other paraneoplastic syndromes, the use of immunotherapy to treat the underlying malignancy may be tolerated. Further study is needed.
NCMP-11. THE CANCER AND COGNITION CLINIC AT WAKE FOREST BAPTIST HOSPITAL: SATISFYING AN UNMET NEED
Authors: Cummings Tiffany , Giles Abigail , Liberatore Mary , Laxton Adrian , Carter Annette , Tatter Stephen , Chan Michael , Lesser Glenn , Strowd Roy , Cramer Christina 
Published: November 2019

Abstract
Preservation of cognitive functioning is a top priority for brain tumor patients but is often not addressed in a systematic manner. To address this unmet need, we established a virtual neurocognitive clinic within our brain tumor center. The aim was to incorporate standardized neuropsychological examinations into routine care. To make neuropsychological testing achievable for patients with primary brain tumors, we developed a one-hour battery to measure core cognitive functions. We established a process where patients are offered cognitive testing at initial consult by neuro-oncology or radiation oncology. To reduce the burden of an extra appointment, patients are seen by neuropsychology in the Cancer Center (as opposed to the main hospital). Appointments are coordinated on the same day as other essential visits. Results are reviewed in multidisciplinary tumor boards. When possible, patients are seen for serial cognitive assessments at 3, 6 and 12 months after RT treatment. Providers in neuro-oncology, neurosurgery, and radiation oncology were encouraged to refer survivors to neuropsychology. After the clinic launch in 2017, 143 brain tumor patients were referred to neuropsychology. Prior to the clinic launch, 22 referrals were made over a comparable timeframe. Cognitive deficits were identified in most patients. After testing, patients received education on the brain-function relationship pertaining to their deficits. The patients’ referring provider received a full report containing recommendations for interventions based on testing outcomes 11 of the 38 patients who underwent pre-treatment assessments underwent testing 6 months post-RT. With the recent addition of a dedicated clinical coordinator, the rate of successful post-treatment cognitive evaluation is increasing. The cognitive, emotional, behavioral, and psychosocial impact of a brain tumor can be difficult to categorize and treat without formal evaluation. Integrating neuropsychological examination into routine care has resulted in a massive increase in the number of brain tumor patients getting a neuropsychologic assessment.
NCMP-18. POST-OPERATIVE NEUROLOGICAL DEFICIT /VASOSPASM AFTER CRANIOPHARYNGIOMA SURGERY: EVALUATION OF CAUSATIVE FACTORS AND PREVENTION
Authors: Bisht Mukesh , Phalak Manoj 
Published: November 2019

Abstract

INTRODUCTION
Referring to a rare post-operative complication associated with craniopharyngioma surgery, Vasospasm. A number of possible causative factors have been postulated, like tumour encasing vessel, handling of vessels during surgery, but none have been able to explain delayed complication. Thus, we have evaluated series of patients operated in a single centre, to look for the possible aetiology

METHODS
Patient’s data have been collected retrospectively in the past 4 year, from a single centre, and cases that developed post-operative neurological deficit/vasospasm, proven clinically and/or radiology were included. Of 116 patients operated 6 were found to have clinical deterioration, and were confirmed using transcranial Doppler and/or radiologically demonstrable vasospasm. Each case was analysed retrospectively, and relevant variables were studied.

RESULTS
Patients developed neurological deficit/vasospasm ranging from Post-operative day 2 to second week after surgery. 1 expired, 2 improved over time, and 3 had persisting deficits. On evaluation, fluid balance showed changes, with serum Sodium levels. However, change of status from high volume status to low volume status was seen in almost all.

CONCLUSIONS
Development of post-operative neurological deficit/vasospasm is usually a cumulative result of some intraoperative insult like vessel handling, which could be a predisposing factor, and various post-operative factors like change In volume status, serum electrolytes levels, hormone status levels. Most important of all is to have an early and low threshold level to diagnose it, as early detection and action may a significant and possibly preventable morbidity or mortality
PDCT-10. FEASIBILITY OF LEUKAPHERESIS FOR HARVESTING MONOCYTES AND GENERATING AUTOLOGOUS DENDRITIC CELL VACCINES IN CHILDREN WITH MALIGNANT BRAIN TUMORS
Authors: Landi Daniel , Archer Gary , Driscoll Timothy , Herndon James , Sampson John , Ashley David 
Published: November 2019

Abstract

BACKGROUND
Recurrent medulloblastoma and malignant glioma are virtually incurable. In children, these tumors are often disseminated or occur in deep midline structures that preclude surgery and are not amenable to highly inflammatory treatments. Active immunization is an attractive immunotherapeutic approach. We are conducting a phase I trial evaluating autologous CMV pp65 RNA-pulsed dendritic cell (DC) vaccines in children with recurrent malignant glioma or medulloblastoma. A primary objective is establishing the feasibility of using leukapheresis to harvest sufficient monocytes in order to generate at least 3 autologous DC vaccines.

METHODS
For children unable to receive two 16-guage IVs, a temporary pheresis catheter is placed in the jugular vein under anesthesia. Leukapheresis is performed with the goal of processing 3 total blood volumes. Circulating monocytes are collected and cultured for 7 days in media supplemented with GM-CSF and IL-4, then matured into dendritic cells and loaded with antigen. The target dose for a single vaccine is 2 x 107 dendritic cells.

RESULTS
To date, five patients (ages 9, 13, 16, 17, 30) have undergone leukapheresis. All patients tolerated leukapheresis without complications, with run times between 3 to 6 hours depending on achievable pheresis flow rate. Patients generated 2, 3, 7, 8, 8, and 8 vaccines. The medulloblastoma patient who generated 2 vaccines underwent a second leukapheresis that generated 8 vaccines. In this patient, although the initial leukapheresis collected a high number of monocytes, the conversion rate to mature DCs was low. Thusfar, there has not been a strong correlation between the number of monocytes collected and the eventual number of mature dendritic cells.

CONCLUSIONS
Leukapheresis is tolerable for younger children and appears to be a viable strategy for harvesting sufficient monocytes for creating DC vaccines. Conversion rates between harvested monocytes and the final number of mature dendritic cells vary.
PDCT-13. ENTRECTINIB IN CHILDREN AND ADOLESCENTS WITH RECURRENT OR REFRACTORY SOLID TUMORS INCLUDING PRIMARY CNS TUMORS
Authors: Robinson Giles , Desai Ami , Gauvain Karen , Basu Ellen , Dorris Kathleen , Maese Luke , Sabnis Amit , Foster Jennifer , Shusterman Suzanne , Yoon Janet , Weiss Brian , Abdelbaki Mohamed , Farid-Kapadia Mufiza , Meneses-Lorente Georgina , Cardenas Alison , Hutchinson Katherine , Bergthold Guillaume , Chow Maneval Edna , Fox Elizabeth , Gajjar Amar 
Published: November 2019

Abstract
The phase 1/2 STARTRK-NG trial is evaluating entrectinib, a CNS-penetrant oral inhibitor of TRK, ROS1 and ALK tyrosine kinases, in children with solid tumors, including primary CNS tumors. Eligible patients are ≤22y with recurrent/refractory solid tumors. The recommended dose was determined in all-comers, and then expansion cohorts of CNS and solid tumors with NTRK1/2/3, ROS1 or ALK gene fusions, and neuroblastomas (NBL) regardless of mutation spectrum, were enrolled. Investigator-assessed response was classified as complete (CR) or partial response (PR), stable (SD) or progressive disease using RANO (CNS), RECIST (solid tumors), or Curie score (NBL). By the clinical data cut-off, 01 April 2019, 32 patients were enrolled. As of 31 Oct 2018 (enrollment data cut-off), 29 patients were enrolled and included in the evaluable population. Median age was 7y (range 4.9m to 20y). Entrectinib was well tolerated; phase 1 dose-limiting toxicities were: elevated creatinine, dysgeusia, fatigue, and pulmonary edema. The recommended dose was 550mg/m2 daily; all responses occurred at doses ≥400mg/m2. In 6 patients with high-grade CNS tumors, all gene-fusion-positive, ORR was 100% (Investigator-assessed responses): 2 CR (ETV6-NTRK3, EML1-NTRK2); 4 PR (TPR-NTRK1, KANK1-NTRK2, EEF1G-ROS1, GOPC-ROS1). In extracranial solid tumors 6/8 had a fusion; of these, 2 achieved a confirmed CR (DCTN1-ALK, ETV6-NTRK3), and 4 achieved PR (ETV6-NTRK3, EML4-NTRK3, TFG1-ROS1, KIF5B-ALK). Central imaging review is being performed and will be provided. Duration of therapy ranged from 0.2 to 22.2 months for all 32 patients. In responding patients, time to response ranged from 1 to 8.3 months. In children with refractory CNS tumors harboring NTRK1/2/3 or ROS1 fusions, entrectinib produced striking, rapid, and durable responses. No responses were seen in tumors lacking target gene fusions. These results support the continued evaluation of entrectinib in solid tumors with target gene fusions, especially high-grade CNS neoplasms.
PDTM-19. MYC AND FAK/SRC COMBINATION TREATMENT OF FOXR2-HIGH BRAIN TUMORS
Authors: Beckmann Pauline , Krebs Ryan , Larson Jon , Largaespada David 
Published: November 2019

Abstract
Brain tumors are the leading cause of cancer-related deaths in children. To identify novel therapeutic targets in two types of pediatric brain tumors, medulloblastoma (MB) and central nervous system primitive neuroectodermal tumors (CNS-PNETs), we performed a Sleeping Beauty transposon mutagenesis screen in mice. In doing this, we identified FOXR2 (Forkhead box R2) as a candidate oncogene in MB. FOXR2 is expressed at high levels in a subset of human MB and increased FOXR2 expression drives MB formation in mice. FOXR2 has been implicated as an oncogene in several cancers of neural original, including CNS-PNET, adult and pediatric high-grade glioma, and malignant peripheral nerve sheath tumors. We have also found that FOXR2 is upregulated in non-MYCN amplified high-risk neuroblastoma. Therefore, we propose that FOXR2 represents a strong candidate for targeted therapy across multiple brain tumor entities. We have uncovered a dual role of FOXR2 in stabilization of CMYC protein and activation of the FAK/SRC signaling pathway. We are working to further define the mechanism of FOXR2-mediated MYC stabilization and FAK/SRC activation. We plan to treat FOXR2-high tumors with combinations of drugs effective against tumors with high MYC, FAK, or SRC in clinical development. Inhibitors or combinations of that score well in vitro will be used to treat mice with orthotopically injected FOXR2-high tumor cells (MB, neuroblastoma, and glioma). In addition, we are working to construct mouse models of FOXR2-driven neural tumors for use in drug testing. We hypothesize that FOXR2-high tumors will be sensitive to MYC and FAK/SRC inhibitor combination therapy, establishing FOXR2 as a molecular marker for treatment success of MYC and FAK/SRC inhibitors in patients.
PDTM-20. THE HISTONE MUTATION H3.3-G34R ENCOUNTERED IN PEDIATRIC HIGH GRADE GLIOMA MODIFIES THE TUMOR IMMUNE MICROENVIRONMENT RENDERING IT MORE PERMISSIVE FOR IMMUNE MEDIATED THERAPIES
Authors: B Garcia-Fabiani Maria , Kadiyala Padma , Haase Santiago , Alghamri Mahmoud , Comba Andrea , Nunez Felipe , Whalen Matthew , Lowenstein Pedro , Castro Maria 
Published: November 2019

Abstract
Pediatric high grade gliomas (pHGGs) have a median survival (MS) of 9–15 months and are the most common malignant brain tumors in children. No significant improvement in the MS of these patients has been registered in decades. Thus, a representative in vivo model to study these tumors is critical. Recurrent mutations in genes encoding histones H3.3 and H3.1 have been described, which are distinctive of pHGGs. To stablish a mouse model for pHGG harboring the mutation H3.3-G34R, which co-occurs with inactivating mutations in ATRX and TP53, we used the Sleeping Beauty transposase system (H3.3-G34R group). The MS of mice harboring H3.3-G34R mutation was significantly longer than the MS of the WT-H3.3 control group (p< 0.0001). We performed RNA-Sequencing of these tumors which yielded 233 differentially expressed genes between these two groups (p< 0.05). Gene set enrichment analysis of the upregulated genes in H3.3-G34R group showed significant GOs related to immune response activation and response to IFNγ. Thus, we next studied the tumor microenvironment (TME) to determine the distinctive immune cell populations, at the phenotypic and functional level. We observed that the H3.3-G34R TME exhibited less frequency of Gr-1+/CD11b+ cells (myeloid-derived suppressor cells: MDSC). MDSC are immature myeloid cells that impair T cell functions and the adaptive immune response. Moreover, the H3.3-G34R TME had increased numbers of total macrophages (p< 0.05), a higher proportion of M1 anti-tumor macrophages, and higher levels of CD8+ T cells (p< 0.01). Also, the H3.3-G34R renders glioma cells more sensitive to IFNγ regulation as it induced a higher pSTAT1/STAT1 ratio in H3.3-G34R cells. These results shed light on the interaction between the immune system and the H3.3-G34R glioma cells and how this could be harnessed to develop immune mediated therapies specific for pHGG harboring the H3.3-G34R mutation.
PDTM-34. RADIOSENSITIZATION BY BRD4 INHIBITION IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Sasaki Takahiro , Katagi Hiroaki , Unruh Dusten , Goldman Stewart , Zou Lihua , Shilatifard Ali , Hashizume Rintaro 
Published: November 2019

Abstract
Diffuse intrinsic pontine glioma (DIPG), the most frequent brainstem tumor in pediatrics, is one of the devastating childhood cancers, and virtually all patients die within two years after diagnosis. Since these tumors occur in the brainstem which is vital area, there are no surgical options for providing relief to patients, and conventional chemotherapy as well as radiation therapy provides palliative relief at best. DIPG shows increased H3 K27 acetylation (H3K27ac), which binds to BET bromodomain protein 4 (BRD4) and they are strongly associated with active transcription. Here we tested the hypothesis that BRD4 inhibition by JQ1 enhances radiation-induced DNA damage, making it a potential radiosensitizer in the treatment of DIPG. We evaluated the effects of JQ1 on genes expression using RNA sequence. Radiation-induced DNA double-strand break (DSB) repair was analyzed by immunocytochemistry and western blotting of DSB markers γH2AX and 53BP1, and DSB repair markers pRad50 and Rad51. Clonogenic survival assay was used to determine the effect of JQ1 on radiation response of DIPG cells. In vivo response to radiation monotherapy and combination therapy of RT and JQ1 were evaluated in patient-derived DIPG xenografts. JQ1 significantly reduced the expression of DNA DSB repair genes in DIPG cells. JQ1 sustained high levels of γH2AX and 53BP1 and reduced the levels of pRad50 and Rad51 in irradiated DIPG cells. JQ1 reduced clonogenic survival and enhanced radiation effect in DIPG cells. In vivo studies revealed increased survival of animals treated with combination therapy of RT and JQ1 in compared to either monotherapy. Together, these results highlight JQ1 as a potential radiosensitizer and provide a rationale for developing combination therapy with radiation in the treatment of DIPG.
PDTM-38. HISTONE H3.3 SER31 PHOSPHORYLATION REGULATES CHROMOSOME SEGREGATION AND CELL CYCLE CHECKPOINT CONTROL AND IS IMPAIRED IN PEDIATRIC GLIOMAS
Authors: Day Charles , Langfald Alyssa , Fadness Sela , Zykova Tatyana , Sepaniac Leslie , Stumpff Jason , Dong Zigang , Vaughan Kevin , Robinson James , Hinchcliffe Edward 
Published: November 2019

Abstract
Diffuse intrinsic pontine glioma (DIPG) carries a signature mutation in histone H3.3 (K27M) that induces epigenetic reprogramming via suppressed Lys27 triple methylation (K27me3). H3.3 has a Ser at position 31, which is adjacent to the K27M DIPG mutation. H3.3 Ser31 is phosphorylated beginning in prophase. This phosphorylation is restricted to pericentromeric heterochromatin and becomes dephosphorylated in anaphase. Surprisingly, chromosome missegregation triggers Ser31 hyperphosphorylation on the lagging chromosome, and masking phosphoS31 prevents p53 accumulation; part of the G1 checkpoint response to aneuploidy. Whether the K27M mutation influences Ser31 phosphorylation, chromosome segregation or G1 checkpoint control is unknown. We show that K27M DIPG cells have reduced pericentromeric phosphoS31 and increased chromosome instability (CIN) compared to normal, diploid human cells. CRISPR-editing of K27M to M27K restored phosphoS31 to WT levels and dramatically decreased the rate of CIN. We also demonstrate that Chk1 is the H3.3 Ser31 kinase. S31A abolishes Ser31 phosphorylation by Chk1, while K27M reduces it by ~60% in vitro. Chk1 knockdown abolishes phosphoS31 in normal, diploid mitotic cells, and induces CIN. In normal, diploid cells, expression of S31A or K27M mutations increased chromosome missegregation, whereas cells expressing a phosphomimetic double mutant (K27M/S31E) divide normally. WT cells arrest following chromosome missegregation. Yet, normal cells expressing H3.3 K27M or S31A do not arrest - despite having wild-type p53. Finally, using RCAS/TVA, we expressed H3F3AS31A in the brains of BRAFV600E mice, and ~50% developed tumors, suggesting that loss of phosphoS31 alone is oncogenic. Importantly, H3.3 S31A-expressing cells are WT for K27me3. Our results demonstrate that expressing H3.3 K27M reduces the population of H3.3 that is phosphorylatable at Ser31, leading to chromosome missegregation and preventing G1 arrest – thus creating proliferating CIN cells. We propose that a single amino acid substitution drives oncogenesis of DIPG, at least impart, by triggering the evolution of complex karyotypes.