bluuebunny/crossref_metadata_2025 huggingface dataset:
NIMG-20. EVALUATION OF HEAD SEGMENTATION QUALITY FOR TREATMENT PLANNING OF TUMOR TREATING FIELDS IN BRAIN TUMORS
Authors: R Shamir Reuben , Bomzon Ze’ev
Published: November 2019

Tumor treating fields (TTFields) is an FDA approved therapy for the treatment of glioblastoma multiform (GBM), malignant pleural mesothelioma (MPM), and currently being investigated for additional tumor types. TTFields are delivered to the tumor through the placement of transducer arrays (TAs) placed on the patient’s shaved scalp. The positions of the TAs are associated with treatment outcomes via simulations of the electric fields. Therefore, we are currently developing a method for recommending optimal placement of TAs. A key step to achieve this goal is to correctly segment the head into tissues of similar electrical properties. Visual inspection of segmentation quality is invaluable but time-consuming. Automatic quality assessment can assist in automatic refinement of the segmentation parameters, suggest flaw points to the user and indicate if the segmented method is of sufficient accuracy for TTFields simulation. As a first step in this direction, we identified a set of features that are relevant to atlas-based segmentation and show that these are significantly correlated (p < 0.05) with a similarity measure between gold-standard and automatically computed segmentations. Furthermore, we incorporated these features in a decision tree regressor to predict the similarity of the gold-standard and computed segmentations of 20 TTFields patients using a leave-one-out approach. The predicted similarity measures were highly correlated with the actual ones (average absolute difference 3% (SD = 3%); r = 0.92, p < 0.001). We conclude that automatic quality estimation of segmentations is feasible by incorporating segmentation-relevant features with statistical and machine learning methods, such as decision tree regressor.
NIMG-22. DEVELOPMENT AND VALIDATION OF A RADIOMIC MODEL FOR RWDD3 EXPRESSION PREDICTION IN PATIENTS WITH ACROMEGALY
Authors: Fan Yanghua , Wang Renzhi , Feng Ming
Published: November 2019

BACKGROUND

The expression of RWDD3 is closely related to the prognosis of acromegaly. Therefore, this study aimed to investigate a radiomics method based on MRI to noninvasively evaluate RWDD3 expression in acromegaly.

MATERIAL AND METHODS

132 patients with acromegaly were enrolled and divided into primary (n=88) and validation cohorts (n=44) according. The expression of RWDD3 was determined by immunohistochemistry. Radiomic features were extracted from the MR images and determined using the ‘Elastic Net’ feature selection algorithm. A radiomic signature was built using a support vector machine. Subsequently, multivariable logistic regression analysis was used to select the most informative clinical features, and a radiomic model, incorporating the radiomic signature and selected clinical features, was constructed and used as the final predictive model. The performance of this radiomic model was validated using receiver operating characteristics analysis, and its calibration, discriminating ability, and clinical usefulness were assessed.

RESULTS

The radiomic signature, which was constructed with radiomic features selected using the primary cohort, showed a favorable discriminatory ability in the validation cohort. The radiomic model incorporating the radiomic signature and three selected clinical features showed good discrimination abilities and calibration, with an area under the curve (AUC) of 0.89 for the primary cohort and 0.84 for the validation cohort. The radiomic model better estimated the treatment responses of patients with acromegaly than did the clinical features. Decision curve analysis showed the radiomic model was clinically useful.

CONCLUSION

This radiomic model could aid neurosurgeons in the prediction of RWDD3 expression in patients with acromegaly, and could contribute to predicting of patient prognoses.
NIMG-26. EVALUATING THE DAYS GAINED RESPONSE METRIC IN CLINICAL TRIALS USING BEVACIZUMAB PLUS ADDITIONAL AGENTS FOR RECURRENT GLIOBLASTOMA
Authors: Singleton Kyle , Johnston Sandra , Rickertsen Cassandra , Keith Anderson S , De Leon Gustavo , Whitmire Scott , Clark-Swanson Kamala , Bendok Bernard , Mrugala Maciej , Porter Alyx , Galanis Evanthia , Swanson Kristin
Published: November 2019

Determining effective therapies for patients with recurrent glioblastoma remains difficult especially in small early phase clinical trials. Currently utilized estimators of treatment response rely on two-dimensional measurements of tumor progression (e.g. RANO, RECIST, MacDonald) that have often fallen short in reliably connecting patients who respond with positive survival outcomes. This has prompted consideration of advanced imaging and volumetric measurements by the RANO working group and others. Our proposed approach, Days Gained (DG), uses volumetric measurements to calculate a personalized response metric based on change in tumor growth characteristics pre/post-treatment. DG has shown promise for connecting imageable treatment response with clinically meaningful (statistically significant) survival benefit when applied in upfront and recurrent therapy settings, even in the context of coincident bevacizumab treatment. In this study, we seek to consider a new cohort of patients receiving bevacizumab in combination with other novel therapies to distinguish any subpopulation of patients with meaningful response. In this work, we identified a subset of 16 patients from bevacizumab clinical trials with data available for DG analysis requiring serial imaging (T1Gd and FLAIR) prior to and after the first cycle of therapy. Each trial evaluated bevacizumab alone versus bevacizumab plus either dasatinib or TRC105 in recurrent disease. Discrimination of time to progression (TTP) was evaluated at DG thresholds identified from our prior analysis of patients treated with bevacizumab. Using previously identified DG thresholds for clinically significant treatment benefit, in our cohort, DG measured by serial FLAIR imaging was significant in predicting longer TTP (120 DG, p=0.014), but T1Gd DG scores did not attain significance (p=0.630). Given the limited insights in connecting response metrics to accurately predicted outcomes, these data further support the use of DG as a burgeoning marker of treatment response (or lack of response) that may be useful for more routine integration into clinical trials.
NIMG-38. RECOGNIZING DISSEMINATED NECROTIZING LEUKOENCEPHALOPATHY IN LEPTOMENINGEAL CARCINOMATOSIS PATIENTS TREATED WITH INTRATHECAL METHOTREXATE VIA OMMAYA RESERVOIR AFTER WHOLE BRAIN IRRADIATION
Authors: Conger Andrew , Scheeler Thomas , Leese Erika , Mongelluzzo Gino , Tosha Gatson Na
Published: November 2019

BACKGROUND

Disseminated necrotizing leukoencephalopathy (DNL) is a rare complication of intrathecal (IT) methotrexate administration with a previously reported incidence of 2.8%1 in patients undergoing treatment for central nervous system leukemia or lymphoma. The purpose of this study is to estimate the incidence of DNL in a series of patients undergoing treatment for leptomeningeal carcinomatosis (LMC) and to better characterize the radiographic findings associated with DNL.

METHODS

A retrospective review of a prospectively gathered database of 36 LMC patients was conducted. Patients were treated with whole brain radiation and a standardized regimen of twice-weekly IT methotrexate in the context of an established IT chemotherapy clinic. Data regarding the patients’ primary cancer pathology, time from initiation of IT methotrexate to onset of DNL, and radiographic characteristics of DNL were collected.

RESULTS

Six of 36 patients (16.7%) developed DNL. Mean time from initiation of IT treatment to development of DNL was 6.7 months. Primary pathologies of the DNL patients were breast (3), melanoma (1), GI (1), and pancreatic neuroendocrine (1). Radiologic presentation included areas of T2 hyperintensity, T1 hypointensity with contrast-enhancement, and restricted diffusion, all consistent with acute demyelination. These radiographic changes predominantly involved the catheter tract, periventricular and deep white matter, and grey-white interface. Interpretation of the magnetic resonance imaging by radiologists was highly inaccurate with the findings interpreted as catheter infection, progression of metastatic disease, stroke, or “possible treatment effect”, but never correctly identified as DNL.

CONCLUSION

DNL is a rare complication of intrathecal chemotherapy but may have a higher incidence in patients undergoing aggressive management of LMC than in those being treated for central nervous system lymphoma or leukemia. Although the imaging in DNL often exhibits characteristic findings, the rarity of this pathology leads to frequent misinterpretation, potentially complicating management of LMC.
NIMG-41. RAPID AND ACCURATE CREATION OF PATIENT-SPECIFIC COMPUTATIONAL MODELS FOR GBM PATIENTS RECEIVING OPTUNE THERAPY WITH CONVENTIONAL IMAGING (T1w/PD)
Authors: Wenger Cornelia , Sara Hershkovich Hadas , Tempel-Brami Catherine , Giladi Moshe , Bomzon Ze’ev
Published: November 2019

BACKGROUND

For understanding the electric field distributions in glioblastoma (GBM) patients receiving OptuneTM therapy computational head models are employed. Accurate and fast model creation is of high importance to patient-specific treatment planning for improving efficacy, i.e., for maximizing intensity delivered to the tumor which depends on the tissues’ electric properties (EPs). Traditional model creation relies on time-consuming tissue segmentation and troublesome binary categorization of distinct tumor areas for assigning homogenous EPs. Here, we present a feasibility study of a new approach for fast model creation that uses individually created, heterogeneous EP maps from conventional MRIs.

METHODS

In a previous animal study we adapted water-content based electrical properties tomography (wEPT) for creating electrical conductivity (σ) maps at 200 kHz, the operating frequency of OptuneTM therapy. This adapted wEPT approach uses a T1w and a PD image to map the tissues’ water-content (WC) with a simple function. Subsequently the σ map is calculated as a function of WC based on Maxwell’s mixture theory. Three patients of the EF-14 trial were selected for calculating WC and σ maps. One patient was chosen to create a computational head model for simulating OptuneTM treatment.

RESULTS

The wEPT-estimated values of WC and σ in the healthy brain are accurate, homogenous and consistent among patients. Contrary, wEPT-estimates of WC and σ in tumor tissues are very heterogeneous and variable between patients. The patient-specific model with wEPT reveals more detailed current pathways during OptuneTM therapy.

CONCLUSIONS

The results emphasize the need for individual head model creation, since binary segmentation masks with pre-defined σ values are not recommended for the heterogeneous and variable tumor. The presented approach holds great promise for rapid creation of patient-specific computational models because only conventional MRIs are needed. However, this method needs to be validated and further established with analyzing more patients.
NIMG-49. THE ACCURACY EVALUATION OF ARCUATE FASCICULUS OF DIFFUSION TENSOR TRACTOGRAPHY BY FUSION OF REAL SPACE AND VIRTUAL SPACE
Authors: Koike Tsukasa , Kin Taichi , Takeda Yasuhiro , Uchikawa Hiroki , Shiode Taketo , Takayanagi Shunsaku , Tanaka Shota , Saito Nobuhito
Published: November 2019

PURPOSE

Diffusion tensor-based tractography (DTT) is a method to estimate the direction of white matter fibers, but it is difficult to verify the relationship with brain function spatially with high accuracy. We developed a registration method to fuse the real space (brain surface photograph) and preoperative fused 3D image (virtual space) using the landmark method and thin plate spline method. In our previous study, this method was able to achieve highly accurate alignment registration error 0.7±0.1mm (mean±SE) even after brain shift due to craniotomy. In this study, we proposed a method to examine spatial errors of DTT and direct cortical stimulation (DCS) and verify its accuracy.

METHODS

We included 7 gliomas performed awake surgery. We created the fused three – dimensional image before surgery and acquired the brain surface photograph immediately after craniotomy, then we aligned them using the proposed method. Sites that showed speech arrest by DCS were plotted on the fused image. A circle with a radius of 15 mm centered on the same site was taken as the range over which the current spreads. The surface area of each of the circles was calculated to make it true if there was arcuate fasciculus drawn with DTT in the circle, and false if it did not exist. By using this method, the accuracy of the DTT was verified. RESULT: In 7 cases, speech arrest was shown at 21 DCS plots. The probability of the presence of DTT within the current spread of DCS was 64.4%.

CONCLUSION

The proposed method indicates that DTT does not necessarily match the DCS results by verification using real space and virtual space. We present some illustrative cases.
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

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

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

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

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

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

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

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

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

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

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.
QOLP-08. UNDERSTANDING THE EXPERIENCE OF YOUNG ADULTS (YAS) DIAGNOSED WITH AN EPENDYMOMA FROM THE ADULT EPENDYMOMA OUTCOMES PROJECT AND RARE CNS OUTCOMES AND RISK STUDY
Authors: Acquaye Alvina , Wall Kathleen , Gilbert Mark , Armstrong Terri
Published: November 2019

Research in young adult (YA) patients is novel, particularly in central nervous system tumors like ependymomas. Stagnant survival outcomes in YAs are concerning compared to improvements within pediatric and older adults. Additionally, uncertainty of the impact of treatment on psychosocial and behavioral outcomes during an essential developmental stage warrants attention. The purpose of this report is to explore ependymoma YA outcomes data to inform care. Adult ependymoma (n=191) patients participating in a web-based outcomes study completed clinical data and validated questionnaires (EQ-5D, MDASI-BT). YAs 18–39 (n= 58) were compared to older adults (OAs) >40 (n=133). Participants were predominantly female (68%), with tumor location in brain (29%) or spine (71%). The majority of YAs (67%) reported seeing a physician within 6 months from symptom onset, whereas OAs were more likely to delay for 7 months or longer. Headaches (brain tumor 70%) and numbness (spine tumor73%) were common presenting symptoms for both age groups. 76% of YAs were working before diagnosis, however 27% stopped work, 18% reduced hours, 7% switched jobs and 2% lost their job after diagnosis. At time of participation, most participants were not on active treatment (61%), but both YA and OA frequently endorsed use of pain medication (37%). Tumor recurrence was more common in YAs (30%) compared to OAs (19%). Common moderate to severe symptoms in YAs included distress (27%) and fatigue/sadness (18%) with brain tumors compared to fatigue (56%) and distress/disturbed sleep/drowsiness (36%) with spine tumors. Over a third of YAs reported some impact on general health (usual activities, pain/discomfort, and anxiety/depression). Despite stable disease, YAs with ependymoma experienced mood and lifestyle challenges and reported significant symptoms and use of pain medication. Further exploration is needed on the impact of cancer-related effects on YAs to gain insight on appropriate management and care.
QOLP-09. IMPACT OF GLIOBLASTOMA (GBM) PATIENTS’ CLINICAL AND TREATMENT CHARACTERISTICS ON CAREGIVER BURDEN AND QUALITY OF LIFE (QOL)
Authors: Au Trang , Willis Connor , Peters Katherine , Colman Howard , Cohen Adam , Leia Nghiemphu P , Taylor Jennie , Reblin Maija , Ryan Ormond D , Willmarth Nicole , Menon Jyothi , Ma Junjie , Singh Prianka , Marshall Alexander , Watanabe Alexandre , Korytowsky Beata , Stenehjem David , Brixner Diana
Published: November 2019

BACKGROUND

GBM is an aggressive cancer with poor prognosis. We explored impact of disease on caregivers by characterizing caregiver burden and QOL associated with patient characteristics.

METHODS

Primary caregivers of living adult GBM patients with cognitive dysfunction completed a GBM-specific caregiver burden survey and the validated Caregiver Quality of Life Index–Cancer Scale (CQOLC). Patient data were abstracted from medical records (7/2018-4/2019). Patient characteristics were compared between highest and lowest tertile of CQOLC scores (range 0–140); higher scores suggest better QOL.

RESULTS

There were 140 patient-caregiver dyads enrolled in the study. Mean patient age was 57 years (range 24–63); majority white males (62.9%), unifocal lesion (90%) and normal activity level at diagnosis. Forty-percent had methylated MGMT promoter status. Caregivers were mostly white (61.4%), college-educated female spouses of similar age; 87.8% were caregiving for >6 months. Median CQOLC score was 82 (tertiles: < 76 and >92). More caregivers in the lowest vs highest CQOLC tertile reported ‘not employed due to caregiving’ (52.4% vs 12%, P< 0.01), ‘changes in patients’ personality’ (73.3% vs 42.6%, P< 0.01), ‘patient memory problems’ (93.5% vs 77.1%, P=0.02), and caring for patient with recurrence treated with ‘chemotherapy other than temozolomide’ ([TMZ], 27.7% vs 8.3%, P=0.01). There was > 10% difference in proportion of caregivers in the lowest vs highest CQOLC tertile for the following patient characteristics: largest lesion in right temporal lobe at baseline and partial resection at initial treatment. Conversely, there was > 10% difference in the highest vs lowest CQOLC tertile for Karnofsky score (> 80), largest lesion in right frontal lobe at baseline, surgical clean margins, TMZ for initial treatment, and surgery for recurrence.

CONCLUSION

Unemployment, patient personality/memory changes, and chemotherapy other than TMZ use had significant impact on caregiver burden/QoL. This may help identify caregivers to receive support and intervention.
QOLP-15. LONGITUDINAL PERCEPTION OF PROGNOSIS OF PATIENTS WITH HIGH GRADE GLIOMA COMPARED TO THEIR CAREGIVERS AND CLINICIANS
Authors: Sharma Akanksha , Wolfe Eric , Barrera Celina , Williamson Samantha , Farfour Hannah , Mrugala Maciej , Edwin Mark , Sloan Jeff , Porter Alyx
Published: November 2019

BACKGROUND

Treatment options and prognosis are limited for patients with high grade glioma (pwHGG), underscoring the importance of patient and caregiver understanding to prioritize goals of care and quality of life (QOL). Although addressed by multiple providers, patients and caregivers may experience discordance in understanding the prognosis. This may be related to patient/caregiver perception, cognitive decline as a result of the tumor and/or treatment, or failure by the clinician to clearly articulate this information under emotional circumstances. AIMS: To evaluate the longitudinal perception of prognosis of patients compared to their caregivers and their providers during the adjuvant treatment of newly diagnosed HGG.

METHODS

After IRB approval, 16 pwHGG, their caregivers and their providers reported an overall survival estimate at each monthly visit during adjuvant treatment, as part of a larger survey. Options included “weeks,” “weeks to several months,” “several months to years,” “indefinite number of years”, or “I do not wish to answer.”

RESULTS

Seven of the sixteen patient/caregiver clusters have completed the appropriate duration of the study with the remaining completing in November. The perception of the patient differs from the caregiver at almost each visit. Regardless of the counseling provided by provider, the perception of both tends to change at each visit and can vary from dismal to overtly optimistic. There does not appear to be discrepancy between the neuro-oncology and palliative care provider’s perception of prognosis.

CONCLUSION

Newly diagnosed pwHGG and caregivers vary in their perception of prognosis, deviating not only from each other but also differing at each visit throughout the course of their illness. The providers’ perception appeared to remain consistent but often varied from that of the patient and caregiver. Providers need to be aware that prognostic understanding appears to fluctuate throughout the course of illness and cannot be clarified via a single discussion.
QOLP-39. UNRAVELING THE TRUE COST OF CARE THROUGH ANALYSIS OF THE SOCIOECONOMIC IMPACT OF GLIOMA SURVIVORSHIP
Authors: Haider Sameah , Asmaro Karam , Kalkanis Steven , Lee Ian , Bazydlo Michael , Nerenz Sam , Salloum Ramzi , Snyder James , Walbert Tobias
Published: November 2019

BACKGROUND

There is a paucity of data describing the socioeconomic impact and long-term implications of glioma survivorship. Objective: To characterize the socioeconomic impact of glioma survivorship using the standardized Medical Expenditure Panel Survey – Household Component (MEPS-HC).

METHODS

89 of 107 eligible adult glioma survivors that were post-treatment with stable disease were enrolled. The MEPS-HC was utilized to assess the socioeconomic hardship referable to the patient’s tumor. Comparisons between groups were evaluated using a Fisher’s exact test.

RESULTS

89 patients responded to the survey (response rate = 85%, female =52%). Median follow-up from diagnosis was 6.0 years (4.3, 9.2). Pathology at diagnosis was high-grade (40%) and low-grade (60. The majority of glioma survivors were insured (91%), employed (79%), and reported annual household incomes slightly above national average. Nearly a quarter incurred debt because of their tumor (24%), 53% required extended unpaid time off, and 46% retired or were no longer working. While 85% had a Karnofsky Performance Score of > 90, the majority of respondents reported lost productivity and decreased ability to perform cognitive and physical tasks (69%). Financial burden and workforce morbidity were insensitive to tumor location, laterality, and annual household income. Patients with a gross-total resection (GTR) at initial surgery were less likely to report ongoing limitations in daily activities (45% v. 83%, p=0.004).

CONCLUSIONS

Despite the skewed population of high-functioning glioma survivors, financial burden and workforce morbidity was ubiquitous across all tumor subtypes, treatment paradigms, and income levels. Those with GTR were less likely to report ongoing limitations. There was a trend towards greater financial burden among those with frontal and temporal lesions.
RDNA-04. CIRCADIAN RHYTHMS AND RADIATION CHRONOTHERAPY IN GLIOBLASTOMA CELL LINES AND CENTRAL NERVOUS SYSTEM CELL CONTROLS
Authors: Shuboni-Mulligan Dorela , Dahut Madeline , Young Demarrius , Gilbert Mark , Armstrong Terri
Published: November 2019

BACKGROUND

Chronotherapy is the optimally timed administration of treatment based on the circadian clock. In non-CNS cancers, circadian rhythms (CR) drive the expression of mechanisms responsible for radiation sensitivity and associated toxicity. Our previous work has shown that cranial irradiation in GBM patients produces a high incidence of hypersomnolence and susceptibility is linked to circadian clock gene polymorphisms. This study determined if CR can be demonstrated using in vitro GBM and CNS cells and then if sensitivity to radiation is circadian time and tissue dependent.

METHODS

Rat GBM, fibroblasts, and suprachiasmatic nucleus (SCN) cells were used and compared to human U251 GBM cells. Cells were synchronized using the serum shook method; protein levels for PER2 expression over 24 hr in 4 hr intervals were quantified to confirm CR. Colony formation and 3D invasion assays after radiation (0-8Gy or 8Gy, respectively) 8 and 20 hrs after synchronization were evaluated.

RESULTS

All cell types demonstrated CR by PER2 expression (trough ~8hr post (CT8); peak ~20hrs post (CT20)). In rat, GBM (LD50 = 4Gy) and SCN cells (LD50 =5 Gy) showed lower sensitivity than fibroblasts (LD50= 2 Gy). Human U251 GBM cells had similar radiation sensitivity to rat GBM. Time-of-day effects were dependent on tissue type with both rat and human GBM cell lines more affected by radiation at CT20, with less invasion (CT20:-35488.5±2622.1 vs CT8:-23160.5±3273.4µm) and survival in the colony assay (F(1,71)=4.105,p< 0.05). Conversely, SCN cells which drive sleep-wake, showed the converse with greater effect at the 8hr compared with 20hr (F(1, 35)=19.93,p< 0.001).

CONCLUSIONS

These data suggest that timing of radiation could be optimized to improve detrimental effects on healthy tissue, while still providing effective intra-tumor doses. In future studies, we will interrogate the mechanisms driving time-of-day effects in cells and test radiation chronotherapy in our radiation-induced hypersomnolence mouse model.