bluuebunny/crossref_metadata_2025 huggingface dataset:
PATH-46. DETECTING MISDIAGNOSED ATYPICAL TERATOID/RHABDOID TUMOR (ATRT) BY DNA METHYLATION-BASED TUMOR CLASSIFICATION
Authors: Hsiao Meng-Chang , Holinka Lauren , Peracchio Michael , Kelly Kevin , Hesse Andrew , Lau Ching , Reddi Honey
Published: November 2019

Brain tumor diagnostics is achieved by combining morphology assessment and biomarker identification. However, the inter-observer variability of the histopathological diagnosis and lack of distinctive biomarkers makes these diagnoses particularly challenging. Recently, the potential for methylation-based characterization has been developed for brain tumors. To provide accurate and efficient brain tumor diagnostics, The Jackson Laboratory developed a DNA methylation array (Illumina Infinium HD Methylation EPIC), combining the “Classifier” established by the German Cancer Research Center (DKFZ), which can identify 82 distinct central nervous system tumors. Here we present a pediatric patient referred to us for medulloblastoma subtype classification by the methylation profile. Surprisingly, the array classified the tumor type as atypical teratoid/rhabdoid tumor (ATRT), subclass SHH. Also, the CNV profile indicated the SMARCB1/INI1 heterozygous deletion as part of the chromosome 22q deletion typically seen in ATRT, and absent was the isochromosome 17q commonly associated with medulloblastoma. Immunohistochemistry confirmed the loss of SMARCB1/INI1 expression leading to ATRT. Additionally, our NGS panel found a novel SMARCB1/INI1 frameshift variant c.1150delG (p.Ala384fs) in the last exon (exon 9). Although this variant is not expected to induce nonsense-mediated mRNA decay, it is located in the ATP-dependent nucleosome-remodeling complex domain Sfh1/SNF5 (IPR017393), which is associated with cell proliferation and differentiation. In addition, ClinVar reported several pathogenic/likely pathogenic variants in this domain, further supporting SMARCB1/INI1 c.1150delG which, together with the SMARCB1/INI1 deletion, may contribute to the loss of SMARCB1/INI1 expression, resulting in ATRT. We have identified the ATRT misclassification by the methylation profile and characterized a novel SMARCB1/INI1 variant c.1150delG most likely contributing to ATRT. We further propose that the DNA methylation profile will significantly improve the brain tumor diagnostics for cases with ambiguous, or contradictory histology and molecular profiles.
PATH-49. CLINICAL UTILITY OF PLASMA CELL-FREE DNA IN ADULT PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA – A PILOT PROSPECTIVE STUDY
Authors: Bagley Stephen , Nabavizadeh Seyed , Mays Jazmine , Till Jacob , Yee Stephanie , Ware Jeffrey , Guiry Samantha , Nasrallah MacLean , Levy Scott , Sarchiapone Whitney , Hussain Jasmin , Prior Timothy , Cucciara Andrew , Binder Zev , O’Rourke Donald , Brem Steven , Desai Arati , Carpenter Erica
Published: November 2019

BACKGROUND

Liquid biopsy has been not been widely utilized in patients with glioblastoma (GBM) compared to other solid tumors. However, the clinical utility of plasma cell-free DNA (cfDNA) in GBM has not been assessed prospectively or at the time of initial diagnosis.

METHODS

We conducted a prospective cohort study of patients with newly diagnosed GBM. Whole blood was collected in Streck® tubes at baseline prior to initial surgical resection and longitudinally during the course of adjuvant chemoradiotherapy. Plasma cfDNA concentration (ng/mL) was quantified by qPCR for a 115 bp amplicon of the human ALU repeat element, correlated with radiographic tumor burden by volumetry at multiple time points using Spearman rank correlation, and assessed for its impact on progression-free (PFS) and overall survival (OS) by Cox regression.

RESULTS

Prior to initial resection, GBM patients (N=42) had higher plasma cfDNA concentration compared to age-matched healthy controls (N=42) (mean 13.43 vs. 6.70 ng/mL, p< 0.001). Plasma cfDNA concentration was correlated with radiographic tumor burden on subjects’ first post-radiation MRI scan (r=0.77, p=0.003) and tended to rise prior to or concurrently with radiographic tumor progression. Pre-operative plasma cfDNA concentration above the mean (>13.4 ng/mL) was associated with inferior PFS (median 4.9 vs. 9.5 months, p=0.038) and OS (median 8.9 vs. 14.8 months, p=0.078). The impact on PFS persisted after adjusting for age, extent of resection, performance status, MGMT promoter methylation, and IDH1/2 mutational status (HR 2.48, 95% CI 1.1–6.1, p=0.046).

CONCLUSIONS

Plasma cfDNA may be an effective prognostic tool and noninvasive surrogate of tumor burden in newly diagnosed GBM. Tumor tissue samples from our cohort have been subjected to targeted next generation sequencing (NGS), and baseline plasma samples have been sent to Guardant Health for NGS. Plasma NGS results and concordance with matched tissue NGS will be included at time of presentation.
PATH-56. PYROSEQUENCING METHOD FOR RAPID DETECTION OF KIAA1549-BRAF FUSION GENES IN PEDIATRIC BRAIN TUMORS
Authors: Shimizu Yuzaburo , Adachi Satoshi , Suzuki Mario , Akiyama Osamu , Ogino Ikuko , Kondo Akihide
Published: November 2019

BACKGROUND

Fusion genes driving tumorigenesis have drawn the attention of oncologists and researchers. Recently, independent genomic researchers have identified a tandem duplication of BRAF at 7q34 that leads to several KIAA1549-BRAF gene exon fusions in the majority of pilocytic astrocytoma (PA). Because KIAA1549-BRAF fusion transcripts are usually absent in diffuse astrocytoma, these genetic alterations may have diagnostic value. Despite the importance of such molecular alterations, there are no comprehensive reproducible methods to detect these fusion genes.

METHODS

Samples of brain tumors were selected retrospectively from our institution. 22 pediatric brain tumors of five types, namely PA, oligodendroglioma (OD), anaplastic astrocytoma (AA), glioblastoma (GBM) and, ganglioglioma (GG), were evaluated to detect KIAA1549-BRAF fusion genes using a pyrosequencing-based method following RNA isolation, cDNA synthesis and real-time polymerase chain reaction. We designed the primers to detect the three most common fusion variants: KIAA1549 ex15-BRAF ex9, KIAA1549 ex16-BRAF ex9, and KIAA1549 ex16-BRAF ex11.

RESULTS

Our method successfully detected KIAA1549-BRAF fusion in 16 out of 22 samples, that is, eleven PA, two OD, one AA, one GBM, and one GG. The entire procedure from RNA extraction to obtaining mutation data was performed within 2 hours.

CONCLUSION

A comprehensive method for detecting fusion genes in pediatric brain tumors was evaluated. This method identified KIAA1549–BRAF fusion variants quickly compared to other methods. Our results will be useful for studies on intraoperative diagnosis and classification of tumors for improving surgical decisions.
PATH-59. HISTOPATHOLOGICAL INVESTIGATION OF THE 1p/19q-CODELETED GLIOMAS RESECTED FOLLOWING ALKYLATING AGENTS CHEMOTHERAPY
Authors: Kanazawa Tokunori , Ohara Kentaro , Yoshida Kazunari , Sasaki Hikaru
Published: November 2019

BACKGROUND

Little is known about histopathological changes after chemotherapy in lower-grade gliomas (LrGGs).

METHODS

We investigated 15 1p/19q-codeleted gliomas resected following tumor volume decrease after alkylating agents chemotherapy in comparison with their pre-chemotherapy specimens. Histopathological changes by chemotherapy were evaluated by hematoxilyn-eosin staining and immunohistochemistry for Ki-67/MIB-1, CD68 as pan macrophage/monocyte marker, CD163 as presumed marker of M2 polarity, and nestin and CD133 as markers of glioma stem cells (GSCs).

RESULTS

Histologically, there were several presumed chemotherapy-related changes in the post-chemotherapy specimens, with the most frequent findings being sparse glial background and abundant foamy cell infiltration. The Ki-67/MIB-1 indices significantly decreased, and CD68+ cells significantly increased after chemotherapy. The increasing rate of CD68+ cells in the post-/pre-chemotherapy specimens was prone to be associated with patients’ progression-free survival (PFS) and overall survival (OS), but not tumor response. The number of CD163+ cells and the ratio of nestin+ cells and CD133+ cells significantly increased after chemotherapy. The number of CD163+ cells, the ratio of nestin+ cells and CD133+ cells, and M2 (CD163+)/M1+M2 (CD68+) ratio in the post-chemotherapy specimens were negatively correlated with patients’ PFS and OS. There was no difference between chemotherapy regimens (temozolomide versus nitrosourea-based) in the number of CD163+ cells and the ratio of nestin+ and CD133+ cells.

CONCLUSIONS

GSCs in conjunction with M2 macrophages constitute the mechanism of resistance to and recurrence after alkylating agents chemotherapy in LrGGs.
PATH-65. MOLECULAR SIGNATURE OF FAT1 RELATED MOLECULES IN GLIOMAS IN THE CONTEXT OF THE WHO 2016 CLASSIFICATION
Authors: Chosdol Kunzang , Arora Manvi , Malik Nargis , Jha Prerana , Singh Jyotsna , Suri Ashish , Sinha Subrata , Suri Vaishali
Published: November 2019

Glioblastoma (GBM, WHO grade-IV) being the most malignant and aggressive form of glioma remains a major clinical challenge, with an overall 5-year survival rate of only 9.8%. Till recently, glioma diagnosis and grading were solely dependent on the phenotypic and histological features. However, with the advancement in the understanding of the molecular biology of glioma several molecules have been identified. The importance of these molecular/genotypic features of the tumor became evident by the inclusion of these molecular features by World Health Organization (WHO) in 2016 in glioma sub-grouping. Our lab is focused on studying the role of FAT1 gene (human ortholog of Drosophila tumor suppressor gene, fat) in glioma biology and aggressiveness. We observed FAT1 gene to have an oncogenic role in glioma where it has been found to upregulate migration/invasion, inflammatory microenvironment of the tumors, HIF1α expression/activity in the tumor-cells under severe hypoxia and in regulating EMT/stemness properties of GBM-cells under hypoxia. Here, we have characterized the molecular relationship between FAT1 related molecules and known- molecular markers of glioma with the hope of identifying glioma subgroup with a molecular signature of clinical significance by (i) analyzing the expression correlation of FAT1 and FAT1 regulated pro-inflammatroy molecules like COX2, IL1b and IL6 with the known- molecular markers of glioma like p53, IDH1, MGMT, EGFR, TERT in low-grade (grade-II) and high-grade (grade-III/IV) gliomas (n=50) by real-time PCR, sequencing, immunohistochemistry and in-silico analysis of TCGA-GBM-data (ii) Analyzed the regulatory role of FAT1 on the above known markers by siRNA mediated knockdown of FAT1 in in-vitro cell-culture system and (iii) further analyzed the identified molecular signature for their correlation with the patients prognosis/survival in the follow up patients. We observed a novel molecular signature with significant correlation with patients’ clinical outcome. Therapeutic targetting of FAT1 may benefit patients with high FAT1 expressing tumors.
NCOG-05. IMPACT OF ADDITIONAL RITUXIMAB TO STANDARD THERAPY ON COGNITIVE PERFORMANCES IN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA PATIENTS
Authors: van der Meulen Matthijs , Dirven Linda , Habets Esther , Bakunina Katerina , Taphoorn Martin , van den Bent Martin , Issa Samar , Doorduijn Jeanette K , Bromberg Jacoline E C
Published: November 2019

BACKGROUND

The goal of treatment of primary central nervous system lymphoma patients is to improve survival, without compromising neurocognitive functioning. The aim of this study was to analyze the effect of Rituximab and low-dose whole brain radiotherapy (WBRT) on cognition.

METHODS

199 patients from a phase III trial (HOVON 105/ ALLG NHL 24), randomized to standard chemotherapy (and 30Gy WBRT for patients < 61 years-old only) with or without Rituximab, were asked to participate in a short neuropsychological evaluation (NPE) before and during treatment, and up to 2 years of follow-up or until progression. A difference in z-score, corrected for sex, age and education, of ≥ 1 point was considered as clinically relevant. The primary outcome was a difference over time between the arms in multiple cognitive domains, assessed by linear mixed models (LMM). Changes in cognitive performances between baseline and 24 months after treatment were assessed for both arms in cross-sectional analyses. Effect of WBRT was analyzed in irradiated patients only.

RESULTS

105/199 patients completed at least one NPE; baseline characteristics were similar to the total trial population. Compliance was >60% at all evaluation points. No clinically relevant differences over time between the arms were seen in all domains in LMM analysis. Comparing changes from baseline to 24 months of follow-up, mean cognitive scores remained stable in both arms for attention, executive functioning (TMT B), and information processing speed. A clinically relevant improvement was seen in both arms for executive functioning (TMT A), memory and motor speed. In the irradiated patients (n=33) all scores remained stable after WBRT, up to 24 months of follow-up in all domains.

CONCLUSION

Cognitive performance remained stable or improved after treatment. Addition of Rituximab to standard treatment did not impact cognitive performance over time. After low-dose WBRT, cognition remained stable up to 2 years.
NIMG-05. THE T2-FLAIR MISMATCH SIGN IN IDH-MUTANT ASTROCYTOMAS - IS THERE AN ASSOCIATION WITH FET PET UPTAKE?
Authors: Galldiks Norbert , Werner Jan-Michael , Stoffels Gabriele , Kocher Martin , Tscherpel Caroline , Jain Rajan , Shah Nadim , Fink Gereon , Langen Karl-Josef , Lohmann Philipp
Published: November 2019

BACKGROUND

The purpose of this study was (i) to assess the reproducibility of the previously described T2-FLAIR mismatch sign as a highly specific MR imaging marker in non-enhancing IDH-mutant, 1p/19q non-codeleted lower-grade gliomas (LGG) of the WHO grades II or III, and (ii) its association with the uptake of the radiolabeled amino acid O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) in PET to further metabolically characterize that sign, which is currently poorly understood.

METHODS

Consecutive MRI and dynamic FET PET scans (n=134) from newly diagnosed and neuropathologically confirmed IDH-mutant LGG (n=65) and IDH-wildtype gliomas as control group (n=69) were evaluated by two independent raters to assess presence/absence of the T2-FLAIR mismatch sign as well as FET uptake. Interrater agreement was assessed using Cohen’s kappa (κ), as well as diagnostic performance (i.e., positive/negative predictive value; PPV, NPV) of the T2-FLAIR mismatch sign to identify IDH-mutant astrocytomas.

RESULTS

In the LGG group, 13 patients (20%) had a T2-FLAIR mismatch sign, which could be identified with a substantial interrater agreement (κ=0.75). In contrast, that sign was absent in IDH-wildtype gliomas. All 13 cases that were positive for the T2/FLAIR mismatch sign were IDH-mutant, 1p/19q non-codeleted tumors (PPV=100%, NPV=57%). Interestingly, compared to IDH-mutant gliomas without the T2-FLAIR mismatch sign, the sign was significantly (P=0.027; 10 of 13 patients) associated with a negative FET PET scan (i.e., 5 tumors with indifferent FET uptake comparable to the background activity, or FET uptake below background activity (photopenic defect) in 5 tumors).

CONCLUSIONS

With a robust interrater agreement, our findings are in line with previously reported findings regarding the T2-FLAIR mismatch sign. Additionally, the T2-FLAIR mismatch sign seems to be significantly related with a lack of increased FET uptake in PET, which may help to further characterize patients with that sign. Notwithstanding, the clinical relevance of this imaging constellation warrants further investigation.
NIMG-30. REPRODUCIBLE RADIOMIC MAPPING OF TUMOR CELL DENSITY BY MACHINE LEARNING AND DOMAIN ADAPTATION
Authors: Wang Lujia , Yoon Hyunsoo , Hawkins-Daarud Andrea , Singleton Kyle , Clark-Swanson Kamala , Bendok Bernard , Mrugala Maciej , Eschbacher Jenny , Smith Kris , Nakaji Peter , Gonzalez Ashlyn , Nespodzany Ashley , Baxter Leslie , Wu Teresa , Swanson Kristin , Hu Leland , Li Jing
Published: November 2019

BACKGROUND

An important challenge in radiomics research is reproducibility. Images are collected on different image scanners and protocols, which introduces significant variability even for the same type of image across institutions. In the present proof-of-concept study, we address the reproducibility issue by using domain adaptation – an algorithm that transforms the radiomic features of each new patient to align with the distribution of features formed by the patient samples in a training set.

METHOD

Our dataset included 18 patients in training with a total of 82 biopsy sample. The pathological tumor cell density was available for each sample. Radiomic (statistical + texture) features were extracted from the region of six image contrasts locally matched with each biopsy sample. A Gaussian Process (GP) classifier was built to predict tumor cell density using radiomic features. Another 6 patients were used to test the training model. These patients had a total of 31 biopsy samples. The images of each test patient were purposely normalized using a different approach, i.e., using the CSF instead of the whole brain as the reference. This was to mimic the practical scenario of image source discrepancy between different patients. Domain adaptation was applied to each test patient.

RESULTS

Among the 18 training patients, the leave-one-patient-out cross validation accuracy is 0.81 AUC, 0.78 sensitivity, and 0.83 specificity. When the trained model was applied to the 6 test patients (purposely normalized using a different approach than that of the training data), the accuracy dramatically reduced to 0.39 AUC, 0.08 sensitivity, and 0.61 specificity. After using domain adaption, the accuracy improved to 0.68 AUC, 0.62 sensitivity, and 0.72 specificity.

CONCLUSION

We provide candidate enabling tools to address reproducibility in radiomics models by using domain adaption algorithms to account for discrepancy of the images between different patients.
NIMG-32. CHALLENGES OF IMAGING INTERPRETATION TO PREDICT OLIGODENDROGLIOMA GRADE
Authors: Aboud Orwa , Gilbert Mark , Armstrong Terri , Vera Elizabeth , Wu Jing , Wall Kathleen , Theeler Brett , Siegel Christine , Reyes Jennifer , Leggiero Nicole , Crandon Sonja , Cordova Christine , Boris Lisa , Bryla Christine , Burton Eric , Antony Ramya , Quezado Martha , Shah Ritu , Penas-Prado Marta
Published: November 2019

BACKGROUND

A recent report examining 75 Oligodendrogliomas indicated that specific imaging features may help predict grading and guide target selection for biopsy when resection is not possible. This report attempted to validate these findings in a separate sample and evaluate interrater reliability.

METHODS

Two Neuro-Oncologists, blinded to radiology report and grading reviewed diagnostic pre-radiation MRI. Imaging features and reviewer interpretations were evaluated included contrast enhancement, necrosis, calcification, and restricted diffusion; examiner concordance is reported.

RESULTS

Sixty-two patients with diagnosis of Oligodendroglioma (50 WHO grade II, 12 WHO grade III); 54 were molecularly confirmed as IDH-mutant/1p19q co-deleted based on the NOB Natural History Study. Four patients (grade III) were excluded due to lack of imaging studies. Among 58 evaluable patients, their location was frontal (n=32), temporal (n=14), parietal (n=4), occipital (n=1), and multi-lobe (n=11). Extent of resection: gross total 9, subtotal 36, biopsy 17. Partial to extensive contrast enhancement was present in 18/58 patients (6 grade II, 33%; 12 grade III, 67%); Kappa interrater agreement k= 0.37 on grade II and k=0.50 on grade III; extensive enhancement was present in 4/58 (all grade III), k= 0.70. Necrosis noted in 7/58 patients (all grade III), k=0.61. Calcification noted in 7/17 patients reviewed (all grade III), k=1.0; restriction noted in only 2/39 patients reviewed (all grade III), k=1.0.

CONCLUSIONS

THE presence of extensive enhancement, necrosis, calcification and restricted diffusion were only present in grade III with substantial agreement between readers, but there was lower agreement for partial enhancement. Image reviewers commented on the variability of enhancement intensity in normal structures between scans, likely contributing to this poor concordance. Tumor areas with extensive enhancement and/or necrosis are associated with higher grade and can guide biopsy if resection is not feasible. Discrepancies in imaging interpretation may be ameliorated by implementing a standardized imaging protocol.
NIMG-33. TUMOR GROWTH AND MRI TRAJECTORIES IN GRADE II AND III GLIOMA
Authors: Luks Tracy , Li Yan , Alcaide-Leon Paula , Lafontaine Marisa , Jakary Angela , Chang Susan , Villanueva-Meyer Javier
Published: November 2019

INTRODUCTION

The purpose of this work was to investigate the trajectory of tumor growth and multiparametric MRI characteristics in grade II and III gliomas leading up to the onset of new contrast enhancement or the expansion of FLAIR signal abnormality.

METHODS

Fifty-one grade II and III glioma patients (39 grade II, 12 grade III) underwent serial MR imaging at standard of care timepoints. Multiparametric MR imaging was performed and maps of the apparent diffusion coefficient (ADC) and percentiles (10th, 50th, 90th) from histograms of normalized signal intensities were calculated. Regions of Interest (ROIs) were defined for the entire T2/FLAIR lesion, and when present, the contrast-enhancing (CE) lesion. Serial imaging parameters were acquired for each of these ROIs. Linear rates of change were calculated for CE volume, T2/FLAIR volume, normalized T2 FSE intensity within the FLAIR volume, normalized T2/FLAIR intensity within the FLAIR volume, and normalized median, 10th percentile and 90th% ADC values within the FLAIR volume.

RESULTS

Thirty-nine patients progressed while on study (7 by CE growth, 32 by T2/FLAIR growth), and 12 patients remained stable, according to RANO criteria. In progressed patients, T2/FLAIR volume and T2 FSE intensity increased over time to progression. The rate of T2/FLAIR volume growth was significantly greater in progressed than stable patients (mean = .42, -.07 mL/week, respectively). The rate of normalized T2/FLAIR signal intensity change was also significantly different in progressed than stable patients (mean = -.002, .0035 mL/week). There were no significant interactions with grade or molecular subgroup by WHO criteria. Additionally, 44% (17/39) of progressed patients by RANO criteria were characterized as having stable disease by radiologic assessment.

CONCLUSION

Tumor volumes remain the gold standard for response assessment in lower grade gliomas and there exists a need for standardized measurement as visual assessment for determination of tumor status is inconsistent.
NIMG-43. LONGITUDINAL TRACKING AND GROWTH RATE CHARACTERIZATION OF BRAIN METASTASES ON MAGNETIC RESONANCE IMAGING
Authors: Patel Jay , Beers Andrew , Chang Ken , Brown James , Hoebel Katharina , Rosen Bruce , Huang Raymond , Brastianos Priscilla , Gerstner Elizabeth , Kalpathy-Cramer Jayashree
Published: November 2019

PURPOSE

Measuring treatment response is vital for assessing efficacy of treatment regimen for patients with brain metastases (BM). Unfortunately, manual delineation of all lesions on MRI across time-points is prohibitively time-consuming, making it infeasible to track individual lesion growth/shrinkage rates as part of the clinical workflow. To overcome this challenge, we propose a deep learning approach to segment all BM, and furthermore, show that certain brain regions are more prone to high-growth rate lesions.

METHODS

163 longitudinal MRIs from 77 patients with MPRAGE-post contrast imaging protocol were prospectively obtained from Massachusetts General Hospital (MGH). An expert neuro-oncologist provided ground truth segmentations for all patients. A 3D U-Net architecture was trained to automatically segment BM; training was stopped when validation set Dice score plateaued to prevent overfitting. To enable lesion tracking, all time-points per patient were affinely registered to each other. Every lesion was subsequently classified based on its growth rate (responder: overall lesion shrinkage; inconclusive: 0% to 40% lesion growth; non-responder: more than 40% lesion growth). Characterization of global lesion growth rate patterns was accomplished by affinely registering all time-points to the MNI brain atlas. Segmented lesions were projected onto the atlas, which was qualitatively analyzed to identify spatial regions composed primarily of one class of lesion.

RESULTS

For automatic segmentation, we report a mean dice score of 0.778, 0.737, and 0.704 on training, validation, and testing sets respectively. Furthermore, we find that the largest BM with the highest average growth rate (non-responders) tend to be located in the posterior frontal/parietal lobes, while smaller, lower growth rate lesions (responders) tend to be localized in the frontal lobes. The posterior fossa was found to be heterogeneous in lesion size and growth rate.

CONCLUSION

We developed automatic metastatic lesion tracking over time-points and identified brain regions associated with differing growth rate lesions.
NIMG-66. LONG-TERM FOLLOW-UP OF NEUROFIBROMATOSIS TYPE 1 PATIENTS USING WHOLE-BODY MRI DEMONSTRATES DYNAMIC CHANGES IN INTERNAL NEUROFIBROMA SIZE
Authors: Ly Ina , Thalheimer Raquel , Cai Wenli , Bredella Miriam , Merker Vanessa , Plotkin Scott , Jordan Justin
Published: November 2019

BACKGROUND

Neurofibromas affect 40–50% of neurofibromatosis type 1 (NF1) patients and can cause significant morbidity and mortality. They grow more rapidly during childhood and adolescence but studies in adults are limited by their retrospective nature and follow-up time < 3 years. The long-term natural history of neurofibromas remains unknown. No guidelines exist on the need and frequency of surveillance imaging for patients. Whole-body MRI (WBMRI) can detect whole-body tumor burden, including internal neurofibromas.

METHODS

17 adult NF1 patients who underwent WBMRI between 2007–2010 (Scan 1) underwent repeat WBMRI between 2018–2019 (Scan 2). Internal neurofibromas were segmented on short tau inversion recovery (STIR) sequences and tumor volume was calculated using a computerized volumetry and three-dimensional segmentation software. Circumscribed tumors were defined as discrete; invasive tumors or those involving multiple nerves were defined as plexiform. Tumor growth and shrinkage were defined as volume change ≥ 20% over the entire study period.

RESULTS

Median patient age was 43 years during Scan 1 and 53 years during Scan 2. Median time between Scan 1 and 2 was 9 years. A total of 140 neurofibromas were assessed. 24% of tumors grew by a median 63% (6.8% per year). 54% of tumors spontaneously decreased in volume by a median 60% (7% per year) without treatment. On a per-patient basis, 18% of patients had overall tumor growth and 41% overall tumor shrinkage. 8 new tumors developed in 7 patients. 16 tumors resolved entirely without medical or surgical intervention. Growth behavior did not correlate with discrete or plexiform morphology.

CONCLUSION

A subset of internal neurofibromas in adult NF1 patients grow significantly over a long-term period, suggesting that continued monitoring of these patients may be warranted. Surprisingly, more than half of neurofibromas shrink spontaneously without intervention. Continued patient enrollment and correlation of imaging findings with functional outcomes are underway.
NCMP-06. THE INCIDENCE OF POST-IRRADIATION CAVERNOUS ANGIOMA AND CYSTIC MALACIA AFTER HIGH DOSE CRANIAL IRRADIATION IN PEDIATRIC AND ADULT MALIGNANT BRAIN TUMORS
Authors: Taniguchi Hiroki , Yamasaki Fumiyuki , Takano Motoki , Yonezawa Ushio , Sugiyama Kazuhiko , Kurisu Kaoru
Published: November 2019

PURPOSE

The purpose of this study is to investigate the incidence of cavernous angioma (CVA) and cystic malacia in long-term survivors of pediatric and adult malignant brain tumors treated by cranial irradiation.

MATERIALS AND METHODS

36 pediatric (age < 18, M:F=24:12, mainly consisted of embryonal tumors) and 43 adults (age ≥18,M:F=27:16, mainly consisted of gliomas) patients with malignant tumors receiving high dose cranial irradiation and at least three years disease free period were included in this study. Follow-up of adult patients ranged from 3.2–19.4 years (median 7.6 years), the local irradiation dose from 50 to 60Gy. Follow-up of pediatric patients ranged from 3.8–18.4 years (median 9.0 years), the local irradiation dose from 49.6 to 60.4Gy. All patients underwent follow-up magnetic resonance imaging studies at least once a year, and the diagnosis of post-treatment CVA and cystic malacia was based solely on MRI findings.

RESULTS

At the timing of preparing this abstract, 16 adult patients developed CVAs during the median course of 13 years, while 24 pediatric patients developed CVAs during the median course of 5.8 years, and the difference was significant (P=0.0298, log-rank test). While, there was no statistical difference between adult and pediatric patients for the development of Zabramski type 1 & 2 CVAs, or of cystic malacia (P=0.6254 and P=0.4652, respectively).

CONCLUSION

We attribute the high rate of post-RT CVAs in our long-term follow-up study of adult patients to the delivery of cranial irradiation for glioma patients. Our data imply the importance of long term follow-up not only for pediatric patients but also for adult patients after high dose cranial irradiation.
NCMP-10. OUTCOMES WITH ACYCLOVIR TREATMENT IN HERPES SIMPLEX ENCEPHALITIS AFTER SURGERY FOR SOLID CNS TUMORS: A CASE REPORT AND SYSTEMATIC REVIEW OF THE LITERATURE
Authors: Ambe Solomon , Yari Niloofar , Fonkem Ekokobe , Benardete Ethan , Chen Wencong
Published: November 2019

OBJECTIVE

To characterize the incidence, diagnostic and therapeutic trends and raise awareness of cases of Herpes Simplex Encephalitis occurring within 30 days after neurosurgery for CNS tumors.

METHOD

Literature search for cases meeting above criteria and meta-analysis of data.

RESULTS

18 cases were studied. The most common tumor was meningitis. Encephalopathy, fever and seizure were the most common presenting symptoms (94%, 83% and 50 % respectively). 50% of cases had HSV-1, 22% had HSV-2, while 28% were unspecified. A majority of the patients (78%) received in acyclovir, with a 79% survival rate with treatment. Mortality rate was 100% without acyclovir treatment. Median time of starting acyclovir was 17 days. Most patients received steroids (78%) but steroids was not associated with a specific outcome.

CONCLUSION

Herpes simplex Encephalitis should be suspected after neurosurgery for tumors in patients with fever, encephalopathy or seizures and should be promptly treated with iv acyclovir. A delay in recognition and failure to treat could result in severe morbidity and mortality. In our study steroid use was not associated with improved outcome but larger studies are needed.
PDTC-17. A RETROSPECTIVE STUDY OF RECOMBINANT HUMAN ENDOSTATIN COMBINED WITH CARBOPLATIN AND VINCRISTINE FOR PEDIATRIC LOW-GRADE GLIOMAS
Authors: Zhang Jun-Ping
Published: November 2019

OBJECTIVE

To analyze the response and toxicity of recombinant human endostatin (rh-ES) combined with carboplatin and vincristine (CV) chemotherapy regimen for pediatric low-grade gliomas (LGGs).

METHODS

Retrospectively reviewed the clinical data of the patients who were received rh-ES with CV chemotherapy regimen at Department of Neuro-Oncology, Sanbo Brain Hospital, Capital Medical University from October 2014 to October 2018. Carboplatin was administrated at a dose of 200~300 mg/m2 and the vincristine dose was 1.5 mg/m2 (maximum dose: 2 mg). Rh-ES was administrated 15 mg/d, daily for 14 days of each 28-day treatment cycle.

RESULTS

26 patients were enrolled. By the time of the last follow-up, 14 patients had completed the treatment and 6 were still in treatment. Of the 26 patients, 14 had partial response (PR), 12 had stable disease (SD), and the objective response rate (ORR) was 53.8%. Of the 14 patients who completed all the treatment, 10 achieved PR, 4 got SD, and the ORR was 71.4%. The median time interval to response was 3.3 months (range 2–12.6 months). The main adverse reactions were myelosuppression and allergy to carboplatin. Three patients were terminated in the consolidation phase due to adverse reactions.

CONCLUSIONS

The rh-ES combined with CV regimen is effective in the treatment of pediatric LGGs and had a rapid time interval to response, which is conducive to the rapid relief of brain stem or visual function damage.
PDTM-05. SONIC HEDGEHOG SIGNALING PRIMES CEREBELLAR GRANULE NEURON PROGENITORS AND MEDULLOBLASTOMA CELLS FOR APOPTOSIS BY INDUCING PRO-APOPTOTIC BIM
Authors: Cleveland Abigail , Veleta Katherine , Gershon Timothy
Published: November 2019

Medulloblastomas, unlike other malignant brain tumors, are typically sensitive to radiation therapy (xRT). However, although xRT allows medulloblastoma patients to survive, it can also confer significant long term cognitive sequelae. Understanding the mechanisms of radiation sensitivity in medulloblastoma may identify ways to increase this sensitivity through targeted therapy. Cerebellar granule neuron progenitors (CGNPs), the cells of origin for SHH-subgroup medulloblastoma, are also sensitive to xRT. We have shown that SHH signaling, which induces CGN proliferation and in excess can cause medulloblastoma, induces the pro-apoptotic protein BIM, resulting in increased radiation sensitivity. SHH-stimulated CGNPs show robust BIM expression, which is blocked by the SMO inhibitor vismodegib. CGNPs in BIM null mice show normal SHH-driven proliferation, but are markedly less sensitive to radiation. Protein studies show that BIM binds to the anti-apoptotic proteins BCL-xL and MCL-1, suggesting a mechanism for increasing the sensitivity to radiation by lowering the apoptotic threshold. On-going studies will determine whether BIM is required for radiation sensitivity in SHH-driven medulloblastoma. If validated, the BIM interactions with BCL-xL and MCL-1 may be novel mechanisms to be targeted to improve medulloblastoma therapy.
PDTM-13. A NOVEL DIFFUSE MIDLINE GLIOMA MODEL INITIATED IN OLIG2-EXPRESSING PROGENITORS OF THE NEONATAL BRAIN
Authors: Shimazu Yosuke , Somasundaram Agila , Brat Daniel , Becher Oren
Published: November 2019

Diffuse intrinsic pontine glioma (DIPG) is an incurable brain tumor that arises in the pons of children. Recent studies using single cell RNA-seq and enhancer analysis of DIPG tumor cells, together with analysis of the developing human pons, strongly suggest that an oligodendrocyte progenitor cell is the most likely cell-of-origin for DIPG. Here we describe a novel mouse model by expressing PDGF-B, with H3.3K27M or H3.3 wild-type in Olig2-expressing progenitors via injection into the 4th ventricle using Olig2-tva-cre;p53fl/fl mice. H3.3K27M tumors have high rate of Ki-67, Sox2, and Olig2 positivity and show a higher rate of leptomeningeal dissemination than H3.3 wild-type tumors (95.2％ vs 68.8%, p=0.0303) and mice harboring H3.3K27M tumors demonstrate a significantly shorter survival period than those harboring H3.3 wild-type tumors (31 days vs. 37 days, p=0.0473). While there is not any difference in survival between mice harboring PDGF-B; p53 wild-type; H3.3K27M tumors and those harboring PDGF-B; p53 wild-type; H3.3 wild-type tumors at the 6-month endpoint, we found that H3.3K27M tumors show a higher rate of high-grade glioma than H3.3 wild-type tumors (100% vs. 41.7%, p=0.0017). RNA-seq analysis identified 25 significantly differentially expressed genes with 23 upregulated and 2 downregulated genes in the PDGF-B; p53 null; H3.3K27M tumors compared with the H3.3 wild-type tumors. Phox2b, which is the most upregulated gene in the PDGF-B; p53 null; H3.3K27M tumors, was validated by qRT-PCR and expressed only in brainstem tumors and not expressed in tumors located in any other areas. IHC with Phox2b also revealed positivity in PDGF-B; p53 null; H3.3K27M tumors located only in the brainstem. Ongoing work includes validation of other significant differentially expressed genes as well as elucidation of their role in K27M-mediated gliomagenesis.
PDTM-17. MiR-126, miR-369-5p AND miR-487b DRIVE PEDIATRIC GLIOBLASTOMA INVASION VIA KCNA1
Authors: Huang Yulun , Qi Lin , Kogiso Mari , Du Yuchen , Braun Frank , Zhang Huiyuan , Huang Lei , Teo Wan-yee , Lindsay Holly , zhao Sibo , Baxter Patricia , Su Jack , Adekunle Adesina , yang Jianhua , Brabetz Sebastian , Kool Marcel , Pfister Stefan , Chintagumpala Murali , Parsons Williams , Perlaky Laszlo , Wang Zhong , Zhou You-Xin , Man Chris , Li Xiao-Nan
Published: November 2019

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

BACKGROUND

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

METHODS

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

RESULTS

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

CONCLUSIONS

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

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

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

INTRODUCTION

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

METHODS

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

RESULTS

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

CONCLUSIONS

The important factors to maintain QOL are reinstatement and preserving brain functions including language, motor, and working memory. This suggests that awake surgery aiming for preserving these functions is a benefit for postoperative QOL.