bluuebunny/crossref_metadata_2025 huggingface dataset:
NIMG-23. BRAIN TUMOR REPORTING AND DATA SYSTEM (BT-RADS) AND QUANTITATIVE TOOLS TO GUIDE ITS IMPLEMENTATION
Authors: Weinberg Brent , Ramesh Karthik , Gurbani Saumya , Schreibmann Eduard , Kleinberg Lawrence , Shu Hui-Kuo , Shim Hyunsuk
Published: November 2019

Glioblastoma is the most aggressive primary adult brain tumor, with median survival of 15 months despite surgery and chemoradiation. MRI is used to guide treatment decisions, but imaging interpretation is challenging because of subtle findings with overlap between treatment effect and disease progression. The most frequently used quantitative brain tumor assessment metric is the Response Assessment in Neuro-Oncology (RANO), but this scoring system requires manual delineation 2-D metrics which can be subjective and is not directly tied to patient management decisions. The Brain Tumor Reporting and Data System (BT-RADS) is a novel, management-based reporting system developed by the Emory brain tumor team to improve quantitation and reduce bias in imaging assessment. BT-RADS scoring incorporates quantitative volumetric changes in contrast-enhanced T1-weighted (CE-T1w) and fluid attenuation inversion recovery (FLAIR) MRI, patient medications, clinical outcome, and treatment dates, and has been aligned closely with management decisions. To improve repeatability and reliability of scoring, we have begun to develop a cloud platform to help physicians utilizing BT-RADS. Longitudinal MRI data from each patient are automatically co-registered using rigid registration and aligned using trilinear interpolation, enabling voxel-to-voxel comparisons across multiple scans. The platform implements a semi-automated algorithm to segment tumor volumes using curvature flow, thresholding, and morphological filtering which expedites clinical review, as physicians simply edit and confirm segmentation accuracy rather than manual segmenting and measuring 2D images. Additionally, radiation dose maps can be overlaid on clinical images to determine what may be treatment effect and in-field vs. out-of-field recurrence. A secure web interface allows easy use by the entire treatment team, e.g. in a “tumor board” setting. Future plans include incorporating clinical and genomic data and fully automating tumor segmentation. The goal of this work is to provide more quantitative and objective follow-up metrics that can guide clinical decision making in glioblastoma patients.
NIMG-51. THE CENTRALLY RESTRICTED DIFFUSION SIGN FOR DIFFERENTIATION BETWEEN TREATMENT-RELATED LESIONS AND TUMOR PROGRESSION IN GLIOMA PATIENTS: A VALIDATION STUDY
Authors: Alcaide-Leon Paula , Cluceru Julia , Luks Tracy , Lupo Janine , Villanueva-Meyer Javier
Published: November 2019

BACKGROUND

The aim of the study was to compare the diagnostic accuracy of different diffusion patterns for differentiation between treatment-related lesions and true tumor progression in patients with suspected glioma recurrence.

METHODS

A retrospective analysis of a prospective cohort was conducted. The images of 240 consecutive patients who underwent surgery for suspected glioma recurrence were reviewed for potential inclusion. Exclusion criteria were lack of a ring-enhancing lesion and presence of susceptibility artifact. Final diagnosis was established upon review of histopathology reports. Lesions showing treatment-related changes and less than 25% of viable tumor were considered treatment-related lesions. More than 25% of viable tumor was considered recurrent tumor. A neuroradiologist, blinded to the diagnosis, evaluated the diffusion patterns on preoperative MRI. ROC curve analysis was performed.

RESULTS

One hundred and ten patients were included (26 with treatment-related lesions and 84 with tumor progression). Of 110, 35 showed no reduced diffusion. Fifty patients had reduced diffusion in the solid lesion component (84%, recurrent tumor and 16%, treatment-related lesions). Twenty-five patients showed reduced diffusion within the central necrosis (48%, recurrent tumor and 52%, treatment-related lesions). Most cases with reduced diffusion in the central necrotic region showed mixed pathology with concurrent treatment effect and viable tumor. The AUC for the combined diffusion pattern (reduced diffusion in the solid lesion component vs in the necrotic region) was 0.68 (95%CI=0.55–0.81). The AUC for the traditional diffusion approach (reduced diffusion in the solid lesion component vs no reduced diffusion) was 0.59 (95%CI=0.49–070). No significant differences were found in AUC (p=0.3).

CONCLUSION

Although the existence of centrally reduced diffusion seems to be associated with the presence of treatment effect, it does not significantly increase the diagnostic accuracy of the traditional diffusion evaluation approach. This is most likely related to the high incidence of concurrent recurrent tumor and treatment effect.
NIMG-56. A MULTIMODAL 7 TELSA MRI INVESTIGATION OF LONG-TERM EFFECTS OF RADIOTHERAPY ON THE ADOLESCENT BRAIN & COGNITION
Authors: Morrison Melanie , Avadiappan Sivakami , Yuan Justin , Stoller Schuyler , Jakary Angela , Mueller Sabine , Molinaro Annette , Banerjee Anu , Hess Christopher , Braunstein Steve , Lupo Janine
Published: November 2019

INTRODUCTION

Radiation therapy (RT) remains an integral role in the treatment of adolescent brain tumors, despite evidence of its long-term effects including cognitive impairment, vascular injury and reduced white matter integrity. While prior studies have related vascular injury to cognitive decline and associated more severe cognitive impairment with a whole-brain versus a focal RT approach, the relationship between underlying imaging, clinical, and treatment parameters has yet to be explored in this population. In this study we used multimodal 7 Tesla MR imaging to probe RT-induced changes in the brain and identified risk factors for clinical outcome.

METHODS

Twenty-three patients (age 6–25 years) with non-supratentorial tumors treated with RT as children and 4 nonirradiated control patients (ages 13–16 years) were scanned on a 7T MRI system; eight patients underwent serial imaging 0.9–3.7 years following the first scan. Simultaneous MR-veniography and angiography, and 90-direction, dual-shell multi-band diffusion MRI were used to assess the relationships among cerebral microbleed (CMB) development, changes in arterial radii, and whole-brain white matter connectivity. A computerized cognitive battery (Cogstate) evaluated multiple domains of cognitive function. Multiple univariate and multivariate regression models with multiple comparison corrections identified risk factors.

RESULTS

Cognitive status measured via executive function and working memory tasks revealed the strongest associations with type of RT and imaging parameters. Specific risk factors for worse outcome included whole-brain RT, RT at a younger age, and time since RT. On imaging this corresponded to increased CMB burden, decreased arterial volume, and reduced global structural connectivity; intrasubject serial imaging followed these trends.

CONCLUSION

7T-MRI was highly sensitive to CMBs with cumulative incidence rates greatly exceeding prior 3T studies in this population. This work demonstrates the value of multimodal 7T-MRI in providing metrics that reflect cognitive deficits arising from RT and identifying patients who would benefit the most from cognitive rehabilitation.
NIMG-57. SERIAL HYPERPOLARIZED 13C PYRUVATE AND 1H METABOLIC IMAGING IN RECURRENT HIGH-GRADE GLIOMA
Authors: Villanueva-Meyer Javier , Autry Adam , Gordon Jeremy , Chen Hsin-Yu , Lafontaine Marisa , Chang Susan , Xu Duan , Larson Peder , Vigneron Daniel , Li Yan
Published: November 2019

INTRODUCTION

Hyperpolarized (HP) 13C MRI is a novel metabolic imaging that allows for real time in vivo probing of pathway-specific metabolic processes relevant to gliomas. The first human brain application reports were published recently. In this study, we characterized longitudinal dynamic and static brain metabolism changes from serial HP 13C and 1H metabolic imaging in a patient with multiply recurrent glioma.

METHODS

Eight dynamic HP 13C imaging, 1H MRI and MRSI examinations were acquired over a period of 15 months in a patient with multiply recurrent glioma that underwent malignant transformation. The patient was imaged after initial tumor debulking, after chemoradiotherapy, at first recurrence, after re-irradiation and anti-angiogentic therapy, and at second recurrence. Ratios of pyruvate-to-lactate and pyruvate-to-bicarbonate were calculated from HP 13C imaging and choline-to-NAA index (CNI) was derived from 1H MRSI. RESULTS/

DISCUSSION

Successful therapies are usually associated with a drop in pyruvate-to-lactate conversion, mediated by different mechanisms from various treatments. We identified three key findings over repeat HP 13C MRIs: 1) a marked response to therapy with a reduction in pyruvate-to-lactate conversion corresponding to associated imaging response to therapy at the primary site of disease. Following chemoradiotherapy, the volume of T2 hyperintensity decreased from 28.21cc to 15.29 cc, and the volume of metabolic abnormality (CNI >3) decreased from 27.84 cc to 10.36 cc. 2) increasing pyruvate-to-lactate conversion in a region of recurrence before morphologic signal abnormality, and 3) a reduction in pyruvate-to-lactate conversion in a recurrent lesion following anti-angiogenic therapy.

CONCLUSION

Here we show that one can reliably image glioma patients using HP 13C MRI alongside standard of care morphologic and physiologic MRI including diffusion, perfusion, and 1H MRSI. Serial HP 13C MRI can be performed in the neuro-oncologic clinical setting and pyruvate-to-lactate metabolism may be useful to monitor treatment response.
NIMG-59. ADVERSE EFFECTS OF IMAGE TILING FOR AUTOMATIC DEEP LEARNING GLIOMA SEGMENTATION IN MRI
Authors: Anthony Reina G , Thakur Siddhesh , Panchumarthy Ravi , Bakas Spyridon
Published: November 2019

BACKGROUND

Application of deep learning to neuro-oncology has shown promising clinically relevant results for tumor classification, localization, and segmentation. Hardware limitations, typically memory size of graphics cards, prevent magnetic resonance imaging (MRI) volumes from being processed as a whole, and hence they are divided into smaller, overlapping tiles. Deep learning algorithms (e.g., U-Net) can then be trained and applied for predictions on such tiles, followed by their combination/stitching as the final prediction for the whole volume. We investigate the hypothesis that image tiling options, such as tile placing, size, overlap, and stitching, introduce variations with adverse effects on predictions, both in terms of inconsistency and accuracy.

METHODS

We utilized the publicly available BraTS 2018 dataset of 285 baseline pre-operative MRI glioma scans, with corresponding expert tumor boundary annotations. We implemented a 3D U-Net to predict boundaries of the whole tumor extent, by virtue of the abnormal hyper-intense signal of T2-FLAIR scans.

RESULTS

Simply flipping the tile horizontally, or translating it by one voxel, produces different predictions. Use of small tiles (64x64x64 voxels) yields substantially more false positive predictions than when using larger tile size (i.e., 128x128x128 voxels). Overlapping tiles produce conflicting predictions, leading to ambiguous interpretations upon their stitching. In areas of overlapping tiles, rounding followed by averaging the overlapping predictions produce superior results to the inverse sequence. All these are particularly noticeable in the margins of the abnormal signal and in areas of large contrast variation.

CONCLUSIONS

Although tiling is a workaround for hardware limitations, it introduces variations detrimental to accuracy. Tiling of neuro-oncology scans for computational analysis using deep learning leads to non-generalizable, non-reproducible results, thereby affecting the performance and potential clinical translatability of such algorithms. Careful considerations and standardization recommendations should be established and appropriately documented for performing such analyses, in order to avoid misinterpretation of results.
NIMG-61. USING MACHINE LEARNING TO BUILD RADIOMICS MODELS THAT DISTINGUISH REGIONS OF GLIOBLASTOMA RECURRENCE VS TUMOR PROGRESSION ON MRI
Authors: Yoon Hyunsoo , Hawkins-Daarud Andrea , Save Akshay , Singleton Kyle , Clark-Swanson Kamala , Wang Lujia , Bendok Bernard , Mrugala Maciej , Wu Teresa , Bruce Jeffrey , Hu Leland , Li Jing , Canoll Peter D , Swanson Kristin
Published: November 2019

Recurrent glioblastoma is challenging to distinguish from so called “treatment effect” on routine clinical imaging. Further, within tumor heterogeneity reveals that some regions can be histologically dominated by tumor progression whilst others can be dominated by secondary effects of treatment response. Apparent tumor progression on MRI can be very difficult to manage clinically as it is unclear the degree to which the imaging changes are actually tumor progression vs response to treatment (including inflammatory response and necrosis). In this analysis, we study a unique cohort of patients for whom image localized-biopsies reveal heterogeneity in response vs progression. Our dataset included 70 biopsy samples from 32 patients with GBM each histolopatholgically characterized for tumor abundance vs immune infiltrate. Six multiparametric MRI contrasts were available, including T1, T1gd, T2, FLAIR, SWI, and ADC. Images were co-registered. Radiomic (statistical + texture) features were extracted from the region of six image contrasts locally matched with each biopsy sample. Machine learning models were built to predict each biomarker using radiomic features. Leave-one-out cross validation was used to evaluate the prediction accuracy. Radiomic features were found to be informative to the prediction of biomarkers. ANOVA tests show significant improvement of using radiomic features compared with the null model. The prediction accuracy was higher when considering the biomarkers on a binary scale using the median as the cutoff than on a numerical scale. Spatially-informed radiomics models for tumor progression vs treatment effect are possible and can play an instrumental role in navigating confounding imaging changed common during treatment progression.
NIMG-62. ATYPICAL IMAGING CHARACTERISTICS OF PRIMARY CNS LYMPHOMA AT INITIAL PRESENTATION LEADS TO FREQUENT MISDIAGNOSIS AND DELAYS IN DIAGNOSIS
Authors: Barbaro Marissa , Pan Peter , Thakur Kiran , Welch Mary
Published: November 2019

BACKGROUND

Primary CNS lymphoma (PCNSL) has protean appearances on magnetic resonance imaging (MRI) that may lead to delays in diagnosis.

METHODS

We retrospectively reviewed histologically-confirmed PCNSL at Columbia University Irving Medical Center (CUIMC, 2010–2019), and characterize imaging features on pre-treatment MRI scans.

RESULTS

64 patients were analyzed. 61 of 64 (95%) presented with enhancement. 35 of 64 (55%) were multiply enhancing, and 26 of 64 (41%) were singly enhancing (of which 2 were dural-based). 3 of 64 (5%) were non-enhancing. 42 of 59 (71%) had diffusion restriction. 36 of 49 (73%) lacked susceptibility. 40 of 64 (63%) were periventricular. 28 of 64 (43%) had callosal involvement. In 14 of 54 (26%), lymphoma was either not included in the differential or specifically noted less likely in radiographic report – this radiographically misdiagnosed group was significantly more likely to be either non-enhancing or non-periventricular (p=0.026). Furthermore, radiographic misdiagnosis was associated with an increased risk of a more than 14-day delay from the initial MRI to the initial invasive study, either lumbar puncture or brain biopsy (p=0.04). Presentation with a single enhancing lesion, on the other hand, was associated with significantly faster time to diagnosis – median 4.6 days (IQR 3) vs 21.6 days (IQR 4.5) from initial MRI (p=0.04).

CONCLUSION

In PCNSL, imaging characteristics influence outcomes. While a classic single enhancing lesion is associated with rapid diagnosis, non-enhancing and non-periventricular disease are the most likely to be misdiagnosed and require a heightened index of suspicion to avoid delays to diagnosis.
NIMG-68. FEDERATED LEARNING IN NEURO-ONCOLOGY FOR MULTI-INSTITUTIONAL COLLABORATIONS WITHOUT SHARING PATIENT DATA
Authors: Sheller Micah , Edwards Brandon , Anthony Reina G , Martin Jason , Bakas Spyridon
Published: November 2019

BACKGROUND

Training deep learning algorithms requires large amounts of data, which is a significant challenge in the medical domain, and particularly in neuro-oncology, where ample data can only be found in multi-institutional collaborations. The current paradigm for multi-institutional collaborations is based on pooled datasets that has always faced privacy, legal, technical, and data-ownership concerns. In this study we evaluate the hypothesis that federated learning can provide a method to overcome these concerns and facilitate a shift in the paradigm of multi-institutional collaborations without sharing patient data. We attempt to investigate this hypothesis in a feasibility study of automatically delineating the glioblastoma extent in T2-FLAIR scans.

METHODS

We identified a retrospective cohort of 165 glioblastoma patients with available clinically acquired pre-operative multi-parametric structural MRI (mpMRI) scans (i.e., T1, T1Gd, T2, T2-FLAIR), with corresponding expert tumor boundary annotations, from 10 independent institutions. We implemented a 3D deep learning algorithm (3D-UNet) to predict the boundaries of the whole tumor extent, by virtue of the abnormal hyper-intense signal of T2-FLAIR scans. We compare the performance of this 3D-UNet model resulting from federated learning with the performance of the same 3D-UNet model generated by sharing data to a single location where centralized/traditional training occurs.

RESULTS

Our quantitative results on federated learning (Dice:85.2%) across individual contributions from the 10 institutions demonstrate final model quality reaching 99% of the model quality achieved by sharing data (Dice:86.2%).

CONCLUSIONS

Translation and adoption of federated learning in a clinical configuration for multi-institutional collaborations is expected to have a catalytic impact towards precision and personalized medicine. The performance of computer-aided analytics and assistive diagnostics is expected to see a precipitous rise, as new models are trained on datasets of unprecedented size through such data-private collaborations.
NIMG-71. DETECTION OF CYSTIC GLIOBLASTOMA FROM MAGNETIC RESONANCE IMAGING USING DEEP LEARNING TECHNIQUES
Authors: Ranjbar Sara , Curtin Lee , Whitmire Paula , Hu Leland , Swanson Kristin
Published: November 2019

Glioblastoma (GBM) is the most aggressive primary brain tumor with an average survival of 15 months with standard of care treatment. GBM patients typically present with necrosis surrounded by enhancement on T1-weighted post gadolinium magnetic resonance imaging (T1gd MRI), however some patients present with a significant cystic component. Cysts are caused by different underlying biological mechanisms to necrosis and are important to identify for future clinical investigations. These cystic components can be manually identified through MRI but this process can be time consuming for large patient cohorts. Over the last two decades, our lab has collected serial MRI data of brain tumor patients. With over 70,000 images now in the database and that number increasing daily, it is clear that we have a unique resource for clinical investigation and a need to automate this process. To this end, the aim of this work was to develop and assess the performance of a convolution neural network (CNN) model for automatic detection of cystic GBMs. In this retrospective IRB-approved work, we collected pretreatment MRIs of a patient cohort consisting of 85 patients with a significant cystic component at presentation along with 400 non-cystic GBM, both identified manually through MRI. Image slices with a view of the cystic component were used as positive samples for training. Data were randomly split into training, validation, and test sets using a 70:15:15 ratio. The proportion of positive to negative cases was comparable between sets. Prior to training, we used image augmentation techniques to compensate for the class imbalance in our data. Our results showed that deep learning networks can automatically detect cystic GBMs on MRIs with high accuracy and thus illustrates the potential use of this technique in clinically relevant settings.
NCMP-12. DISSECTING THE ANTI-TUMOR IMMUNE RESPONSE IN GLIOBLASTOMA
Authors: Chen Dan
Published: November 2019

Glioblastoma multiforme (GBM) is the deadliest form of brain cancer, for which there is currently no effective therapy. In clinical trials with GBM patients, immunotherapy led to an increase in the number of immune cells infiltrating the tumor, yet surprisingly not to a clinical benefit. These trials reveal the need to study how the immune system is impacted by GBM and which immune cells are the key players in the anti-tumor response. Using a GBM mouse model to guide our studies, we have found anti-CTLA4 treatment improved survival, but the efficacy of anti-CTLA4 was lost in mice that were depleted of CD4+ T cells but no other immune cells, indicating ‘helper’ CD4+ T cells were essential for anti-tumor immunity and long-term survival in GBM. Thus, it is imperative to explore the types of CD4+ T cells in these tumors helping to controlling GBM and response to anti-CTLA4. We also find some specific myeloid population is disappeared after CD4 depletion. We need to understand how the function of CD4 T cells impacts other immune cells in the context of GBM. Furthermore, the future goal of this work is to extend to characterize the immune compartment of clinical GBM, which will provide important implications for how to effectively improve current immunotherapy to overcome GBM.
NCMP-13. BRAIN MRI FINDINGS IN PATIENTS TREATED WITH CHIMERIC ANTIGEN RECEPTOR T-CELLS (CAR-T) DURING SEVERE NEUROTOXICITY
Authors: Mokhtari Sepideh , Arrington John , Asquith Justin , Bachmeier Christina , Locke Frederick , Lazaryan Aleksandr
Published: November 2019

INTRODUCTION

Severe neurotoxicity occurs in ~30% of Diffuse Large B Cell Lymphoma (DLBCL) patients treated with CAR-T cell therapy. Brain MRI is used to assess and manage patients during neurotoxicity. Brain MRI can help understand which brain locations are affected during neurotoxicity. However, in majority of patients brain MRI is normal. It is unclear if the MRI findings are time dependent. Here we review our institutional experience with MRI findings.

METHOD

We reviewed MRI brain of 38 patients who received CAR-T at Moffitt Cancer Center from October, 2017 to March, 2019.

RESULTS

We identified 8 patients (21%) who had abnormal MRI findings. Five (63%) of these patients showed increased T2 FLAIR changes in bilateral mesial temporal lobes consistent with limbic encephalitis. One patient showed restricted diffusion and abnormal T2 FLAIR and T2 weighted images within the splenium of the corpus callosum plus increased T2 FLAIR changes in bilateral mesial temporal lobe, which resolved with follow up MRI in a month. One patient showed increased FLAIR signal intensity in left lateral cerebellum and cerebellar vermis. Two patients showed multiple new tiny areas of acute ischemic changes post CAR-T. One patient had several small and subtle areas of increased FLAIR signal intensity in bilateral frontal and parietal cortex on day 5 post CAR-T and multiple tiny areas of acute ischemia on day 10 post CAR-T. The median time to performing brain MRI was 8 days (range: 5–14).

CONCLUSIONS

MRI can show T2 FLAIR changes consistent with limbic encephalitis mostly in temporal lobes but also in frontal, parietal lobes, and cerebellum. The MRI changes can happen anytime from day 5 to day 14 post CAR-T infusion. We need larger, controlled studies to have better understanding of MRI findings and whether they are time dependent in relation to when CAR-T was given.
PDCT-05. FINAL RESULTS OF THE VINILO OPEN-LABEL PHASE II RANDOMIZED TRIAL FOR PEDIATRIC LOW-GRADE GLIOMAS (pLGG) COMPARING THE COMBINATION VINBLASTINE-NILOTINIB WITH VINBLASTINE ALONE
Authors: Grill Jacques , Brard Caroline , Picton Sue , Cruz Ofelia , Schouten-vanMetteren A Y N , Marie Sehested Astrid , Gerber Nicolas , Entz-Werle Natacha , Le Deley Marie-Cécile , Dangouloff-Ros Volodia , Varlet Pascale
Published: November 2019

Chemotherapy is the mainstay of non-surgical treatment in pLGG but many patients progress again after the end of the first treatment. Apart from the standard carboplatin-vincristine, new regimens with less toxicity are therefore desirable. Single agent vinblastine is an established regimen. PDGFRA TKI inhibitors have shown efficacy in refractory pLGG as well. The VINILO phase I showed the feasibility of the combination of vinblastine with nilotinib at the expense of a 50% decrease of the dose of vinblastine. The phase II trial therefore compared vinblastine 6 mg/m2 weekly (standard arm) to vinblastine 3mg/m2 weekly plus nilotinib 230mg/m2/day. The primary endpoint was the PFS, analysed on the intention-to-treat population. The target sample size was 120 patients. Accrual was stopped after recruitment of 109 patients (53 and 56 in the vinblastine-arm and the vinblastine+nilotinib arm, respectively) between July 2016 and April 2019. Fifty-four patients had an optic pathway glioma and 45 had NF1 (these patients were allowed to enter the trial as initial therapy). Half of the patients were treated after more than one line of therapy. The planned interim analysis showed that the vinblastine+nilotinib arm was associated with a worse PFS as compared to the standard arm (HR=2.37; 95%CI, 1.26–4.46; p=0.007; with 2-year PFS of 28% versus 49%). Overall, 156 biological adverse events (AE) of grade ≥ 3 have been reported after randomization (94 in vinblastine alone arm, 62 in vinblastine+nilotinib arm) and 84 non-biological adverse events of grade ≥ 3 (50 in vinblastine alone arm, 34 in vinblastine+nilotinib arm). We conclude that the combination of vinblastine plus nilotinib was less effective than vinblastine alone, possibly because of a lower dose intensity of vinblastine in the experimental arm. Vinblastine can serve as a backbone for combinations but lowering its dose may jeopardize the efficacy.
PDCT-08. SUPERIOR OUTCOME FOR BRAF V600E PEDIATRIC GLIOMAS TREATED WITH TARGETED BRAF INHIBITION
Authors: Nobre Liana , Zapotocky Michal , Ramaswamy Vijay , Ryall Scott , Bennett Julie , Balaguer Guill Julia , Baroni Lorena , Bartels Ute , Bornhorst Miriam , Boue` Daniel , Chintagumpala Murali , Cruz Ofelia , Dahiya Sonika , Dirks Peter , Dunkel Ira , Eisenstat David , Finch Elizabeth , Finlay Jonathan , Frappaz Didier , Luisa Garre Maria , Gauvain Karen , Grete Bechensteen Anne , Hansford Jordan , Hauser Peter , Huang Annie , Karajannis Matthias , Kaur Gurcharanjeet , Larouche Valerie , Lassaletta Alvaro , Leary Sarah , Lin Frank , McKeown Tara , Milde Til , Morales La Madrid Andres , Morse Helena , Mushtaq Naureen , Osorio Diana , Packer Roger , Pavelka Zdenek , Salgado Duarte , Sabel Magnus , Solano Palma , Su Jack , Sumerauer David , Toledano Helen , van Tilburg Cornelis , Wilson Bev , Bouffet Eric , Hawkins Cynthia , Tabori Uri
Published: November 2019

BACKGROUND

Children with pediatric low grade glioma’s (PLGG) harboring BRAF V600E mutation have poor outcome due to relative resistance to chemo-radiation and higher risk of malignant transformation. However, the role of targeted BRAF inhibition in these tumors is poorly defined.

METHODS

We assembled an international cohort of children with BRAF V600E mutant gliomas treated with BRAF inhibition, from 29 centers participating in the PLGG taskforce, and collected response, survival and molecular parameters.

RESULTS

Sixty-seven patients were treated with BRAFi (56 PLGG and 11 high grade gliomas) for a median time of 17.4 months (6 – 61 months), with 13 PLGG treated upfront. Objective responses was observed in 80% of PLGG patients compared to 28% with conventional chemotherapy (p< 0.001). Rapid responses were observed in most PLGG patients (median of 4 months), sustained in 86% of tumors up to 5 years while on therapy. In contrast, only 36% of PHGG responded to BRAFi with all but one tumor progressing within 18 months. Seventeen patients with PLGG discontinued BRAFi and 76.5% (13/17) progressed rapidly after discontinuation (median time 2.3 months). However, upon re-challenge with BRAFi therapy, 90% achieved an objective response. Poor prognostic factors to conventional therapies such as concomitant homozygous deletion of CDKN2A or H3K27M mutation were not associated with lack of response to BRAFi. Overall these responses translated to 2-year progression-free survival of 0.636 (95%CI 0.505–0.802) and 0.43 (95% CI 0.32–0.57) for BRAFi and chemotherapy treated BRAF V600E PLGG respectively (p=0.003).

CONCLUSION

The use of BRAFi results in objective, robust and durable responses in BRAF V600E PLGG and is associated with favorable survival. Larger prospective studies will be required to determine appropriate regiments, and long-term functional outcomes with BRAFi therapy in childhood gliomas.
PDCT-12. CLINICAL EFFICACY OF ONC201 IN THALAMIC H3 K27M-MUTANT GLIOMA
Authors: Rahman Kawakibi Abed , Gardner Sharon , Chi Andrew , Kurz Sylvia , Wen Patrick , Arrillaga-Romany Isabel , Batchelor Tracy , Butowski Nicholas , Sumrall Ashley , Shonka Nicole , Harrison Rebecca , DeGroot John , Mehta Minesh , Odia Yazmin , Hall Matthew , Daghistani Doured , Cloughesy Timothy , Ellingson Benjamin , Umemura Yoshie , Schwartz Jonathan , Yadav Vivekanand , Cartaxo Rodrigo , Miklja Zachary , Bruzek Amy , Siada Ruby , Mullan Brendan , Stallard Stefanie , Muruganand Ashwath , Wierzbicki Kyle , Paul Alyssa , Wolfe Ian , Kumar-Sinha Chandan , Marini Bernard , Leonard Marcia , Garton Hugh , Mody Rajen , Robertson Patricia , Merdinger Krystal , Tarapore Rohinton , Oster Wolfgang , Allen Joshua , Koschmann Carl
Published: November 2019

ONC201, the first bitopic DRD2 antagonist for clinical oncology, has shown efficacy in H3 K27M-mutant glioma. We performed an integrated preclinical and clinical analysis of ONC201 in thalamic H3 K27M-mutant glioma. ONC201 was effective in mouse intra-uterine electroporation (IUE)-generated H3 K27M-mutant gliomas, with an in vitro IC50 of 500 nM and 50% prolongation of median survival in vivo (p=0.02, n=14). Elevated DRD2 expression was found in the thalamus of non-malignant brain tissue, leading to the hypothesis that thalamic tumors may be a particularly ONC201-sensitive sub-group. We analyzed thalamic H3 K27M-mutant glioma patients treated with ONC201 as of the 05/22/2019 cutoff date, which included patients who had recurrent disease prior to initiating ONC201 (n=20; 15–73 years old) and post-radiation non-recurrent patients (n=11; 5–19 years old). As of 5/22/2019, 10 of 20 recurrent patients and 9 of 11 non-recurrent patients remain on-treatment. Median PFS has not been reached for either cohort: median follow-up of 2.2 months (range: 0.6–37.9) for recurrent patients and 10.6 months (range: 4.3–20.5) from diagnosis for non-recurrent patients. Best response so far by RANO includes 1 CR, 2 PR, 7 SD, 9 PD, 1 NE for recurrent patients and 1 PR, 7 SD, 3 PD for non-recurrent patients. Additionally, 3 recurrent (-66%, -47%, -34%) and 2 non-recurrent (-40%, -10%) patients experienced regressions but are not yet confirmed PRs. For recurrent patients, median onset of response is 3.5 months (range: 2.2–3.8) and median duration of response has not been reached with a median follow-up of 12.5 months (range: 8.1–32.8). Preliminary analyses demonstrated a strong correlation of cell-free tumor DNA in plasma and CSF with MRI response. In summary, ONC201 demonstrates promising clinical efficacy in thalamic H3 K27M-mutant glioma patients, regardless of age. Micro-environmental DRD2 expression may enhance the overall ONC201 response and extend its therapeutic utility beyond H3 K27M-mutant glioma.
PDTM-06. DISULFIRAM-COPPER PROLONGS SURVIVAL AND REDUCES STEM-CELLNESS IN PEDIATRIC GROUP 3 MEDULLOBLASTOMA THROUGH NUCLEAR SEQUESTRATION OF NPL4
Authors: Serra Riccardo , Zhao Tianna , Casaos Joshua , Leviton Gorelick Noah , Mangraviti Antonella , Olivi Alessandro , Brem Henry , Jackson Eric , Tyler Betty
Published: November 2019

Medulloblastoma (MB), an aggressive pediatric brain malignancy, is commonly classified into four subtypes. Although survival has improved remarkably, Group 3 and Shh-driven tumors still experience high rates of recurrent and metastatic disease. Disulfiram (DSF), a safe and inexpensive drug, has shown an antitumor effect when administered with copper (Cu++) against other brain malignancies, and its repurposing to MB could benefit current standards of treatment. ONS76 (Shh-driven Tp53 wild-type), UW228 (Shh-driven Tp53-mutated), D425med and D341med (Group 3) lines were treated with DSF-Cu++and tested with viability, proliferation and clonogenic assays. Flow cytometry (FACS) with AnnexinV-PI, Ki67, PI/RNAse for necrosis and cell cycle, and CD133 and Aldefluor for cell-stemness were carried out. MB lines were tested with western blotting (WB) and immunofluorescence (IF) for NPL4(Nuclear protein localization protein 4 homolog), AIF (apoptosis-inducing factor), cleaved-PARP(Poly-ADP-ribose-polymerase), H2AX and other molecular targets. In vivo safety (n=8) and efficacy studies (n=16) were carried out on Nu/Nu athymic mice implanted intracranially (IC) with D425med cells, along with Hematoxylin/Eosin and immunohistochemistry analyses on brain samples. DSF-Cu++showed remarkable cytotoxic and anti-proliferative activity against all MB lines. In particular, NPL4, a protein involved in the ubiquitin signaling, appears to be the primary DSF target, as previously shown in other malignancies. Apoptosis quickly follows the Heat-Shock Response, as confirmed by FACS, WB and IF, and cell-stemness is decreased significantly by nanomolar doses of DSF-Cu++(p=0.002). Oral administration of DSF-Cu++was proven safe at doses of 100 mg/kg and significantly prolonged survival in IC xenografts (median 28.5 days; p=0.02) compared to controls (median 24 days). DSF, a compound used in the treatment of chronic alcoholism, has recently shown a remarkable effect in a number of malignancies when co-administered with Cu++. We provide proof of its potential as a chemotherapeutic for pediatric MB, and describe its molecular mechanism of action.
PDTM-08. SINGLE-CELL GENOMICS REVEALS TUMOR-INITIATING PROGENITORS AND ONCOGENIC CASCADES DURING TUMORIGENESIS AND RELAPSE IN MEDULLOBLASTOMA
Authors: Zhang Liguo , He Xuelian , Liu Xuezhao , Berry Kalen , Lu Richard
Published: November 2019

Progenitor heterogeneity and identities underlying tumor initiation and relapse in medulloblastomas, the most common malignant pediatric brain tumor, remain elusive. Here, by utilizing single-cell analysis at different stages of tumorigenesis, we demonstrated a developmental hierarchy of diverse progenitor pools in sonic hedgehog (SHH)-medulloblastomas. Unexpectedly, we identified Olig2-expressing progenitors as transit-amplifying cells at the onset of tumorigenesis. Although Olig2+ cells become quiescent stem-like progenitors in full-blown tumors, they are highly enriched in therapy-resistant and recurrent medulloblastomas. High-level OLIG2 expression is associated with poor outcome in human SHH-medulloblastomas. Depletion of mitotic Olig2+ progenitors or Olig2-ablation impeded tumorigenesis. Transcriptome and chromatin-occupancy profiling revealed that Olig2 modulates the chromatin landscape and activates oncogenic networks including HIPPO-Yap/Taz and Aurora-A/MycN pathways. Co-targeting these oncogenic pathways induced tumor growth arrest. Together, our results raise the unanticipated possibility that glial lineage-associated Olig2-expressing progenitors are tumor-initiating cells during medulloblastoma tumorigenesis and relapse, suggesting Olig2-driven oncogenic networks as potential therapeutic targets.
PDTM-14. INTERACTIONS BETWEEN IMMUNE MICROENVIRONMENT, STEM CELLS, AND CELL PROLIFERATION IN PEDIATRIC EMBRYONAL CENTRAL NERVOUS SYSTEM [CNS] TUMORS
Authors: Schafernak Kristian , Utagawa Emma , Mehta Shwetal , Di Modica Tiffany , Mufson Elliott , Perez Sylvia
Published: November 2019

Mounting evidence suggests the brain’s own immune cells, microglia, and perivascular macrophages play important roles in immune surveillance/inflammation, but also support proliferation/growth of gliomas, possibly through interactions with tumor stem cells. Immune cells are increasingly regarded as potential targets for cancer therapy, however, the immune microenvironment has not been well-studied in pediatric embryonal CNS tumors. In a series of 13 medulloblastomas, 7 PNETs and 6 ATRTs, we quantified the number of cells immunopositive for macrophage/microglia Ionizing calcium binding adaptor molecule 1 [Iba1], CD68 (expressed on both “M1” antitumor/proinflammatory macrophages and “M2” protumor/anti-inflammatory macrophages), CD163 (“M2” macrophages), CD3 (T-cell marker), CD4 (helper T cell), CD8 (cytotoxic T cell) and CD20 (B-cell marker) and correlated these findings with the stem-cell marker nestin and the Ki67/MIB1 proliferation index. Significant results were as follows: Across groups, CD68 showed a strong Spearman rank-order correlation with both CD163 (r=0.610, p=0.0007) and nestin (r=0.577, p=0.0017), while CD3 correlated strongly with CD8 (r=0.601, p=0.004), CD4 (r=0.526, p=0.005) and CD20 (r=0.499, p=0.008). Between groups, the number of CD163-positive cells was significantly higher in PNETs compared to medulloblastomas (p=0.035). Within the medulloblastoma group, CD68 showed a significant relationship with nestin (r=0.595, p=0.0387) and Ki67 (r=0.606, p=0.0333), and there was a robust correlation between CD4 and CD8 values (r=0.846, p=0.0000002). Within PNETs, there was a strong negative correlation between CD163 and nestin (r=-0.883, p=0.0000002), while CD68 correlated with CD4 (r=0.803, p=0.006). Within ATRTs, nestin and Ki67 were strongly correlated (r=1.000, p=0.0028) as were CD68 and CD163 (r=0.943, p=0.017). These data suggest a role for blocking embryonal CNS tumor-associated macrophages by inhibiting the CSF1R pathway (perhaps in conjunction with CD8-positive T cells which could antagonize the immunosuppressive function of tumor-associated macrophages) or reprogramming them from an M2 to an M1 phenotype (particularly in PNETs, which had the highest number of CD163-positive cells).
PDTM-18. COMBINED SUPPRESSION OF THE mTOR AND MAPK PATHWAYS INHIBITS GROWTH, DECREASES VASCULARITY AND INDUCES APOPTOSIS OR SENESCENCE IN PEDIATRIC LOW GRADE GLIOMA
Authors: Arnold Antje , Harris Lauren , Yuan Ming , Rodriguez Fausto , Eberhart Charles , Raabe Eric
Published: November 2019

Pediatric low-grade glioma (pLGG) is the most common brain tumor in children. We and others have identified constitutive activation of the mTOR and MEK-pathway in pLGG. This led us to investigate TAK228, a mTORC1/2-inhibitor, and the FDA approved MEK-inhibitor, trametinib, in mono- and combination therapy in pLGG. We examined antitumor activity in four patient-derived pLGG cell models treated with TAK228, trametinib, and combination: JHH_NF1_PA1(NF1mut), BT40(BRAFV600E), Res186(PTEN-/-) and Res259(CDKN2A-/-). Treatment with TAK228 or trametinib reduced cell proliferation in a dose and time dependent manner (MTS-assay). The combination treatment exerted a synergistic effect at 5-20nM in JHH_NF1_PA1, Res186, and Res259 cells (Chou-Talay method). The combination of TAK228 and trametinib increased apoptosis by up to 127% (p< 0.001 by 1-way ANOVA) in Res186 and Res259 cells as measured by cleaved caspase 3 immunocytochemistry. Trametinib and combination treatment induces senescence in JHH_NF1_PA1 cell line verified through increase in p27 protein expression (Western Blot) and positive b-galactosidase staining. Mono-treatment with TAK228 or vehicle showed no signs of senescence. We tested trametinib and TAK228 against the mutant BT40BRAFV600E patient-derived cell line in immunodeficient mice. The combination treatment showed greater antitumor activity than that of either mono-treatment in vivo. BT40 tumor growth was significantly decreased in combination compared to vehicle or either agent alone (p< 0.01). Combination treatment strikingly reduced the vascularization in the tumor tissue after combination treatment analyzed by CD31 and CD34 protein expression (Western Blot), compared to vehicle and mono-treatment. Our study provides evidence that pLGG-derived cell lines in vitro and in vivo are sensitive to mTORC1/2 kinase inhibition and MEK inhibition. Combination treatment with TAK228 and trametinib had a significant anti-tumor activity in vivo shown in survival rate, decreased tumor size, and reduced vascularity. These results provide the first strong rationale for combination therapy with TAK228 and trametinib for clinical consideration in pLGG.
PDTM-23. DELTA-24-RGD ONCOLYTIC ADENOVIRUS MEDIATES ANTI-TUMOR EFFECT IN LOCALIZED AND DISSEMINATED AT/RT MURINE MODELS
Authors: Garcia-Moure Marc , González Huarriz Marisol , Laspidea Virginia , Marrodán Lucía , Gomez-Manzano Candelaria , Fueyo Juan , Patiño-García Ana , Alonso Marta M
Published: November 2019

Atypical teratoid/rhabdoid tumors (AT/RTs) are rare pediatric brain tumors affecting mainly infants and young children. However, AT/RTs encompass almost 10% of death caused by pediatric brain tumors, and the 2-year overall survival for these children remains below 20%. For this reason, AT/RT ranks among the deadliest pediatric brain tumors. Therefore, it is clear we need to find out new therapeutic options for these children. Delta-24-RGD oncolytic adenovirus has already demonstrated its efficacy in Phase I/II clinical trials in adult patients affected by high grade gliomas with no evidence of severe side effects. Of interest for pediatric brain tumors, the safety of Delta-24-RGD is has been demonstrated in an ongoing Phase I clinical trial for the treatment of DIPGs (NCT03178032). For these reasons, we propose to evaluate the anti-tumor effect of Delta-24-RGD in preclinical models of AT/RT. In vitro, the virus was able to infect and replicate in three different cell culture models of AT/RT, inducing a dose-dependent cytotoxic effect that results in IC50 values below 1 PFU/cell. In vivo, intratumor administration of the virus in mice bearing orthotopic localized AT/RT (supratentorial and infratentorial) extended significantly the survival the animals, leading to up to 20% of long-term survivors. We have also generated models of disseminated disease through intraventricular injection of the tumor cells, thus mimicking the lesions found in patients. AT/RT cell lines were transduced with a luc-expressing lentivirus in order to facilitate the follow up of these tumors. In disseminated AT/RT models, light emission reveals reduction of tumor growth in Delta-24-RGD treated animals in comparison to those mock treated, thus obtaining an increased overall survival. In conclusion, these results demonstrate that Delta-24-RGD could be a feasible therapeutic choice for patients affected by AT/RT.
PDTM-28. AN OTX2-PAX3 SIGNALLING AXIS REGULATES GROUP 3 MEDULLOBLASTOMA CELL FATE
Authors: Zagozewski Jamie , Shahriary Ghazaleh , Morrison Ludivine , Stromecki Margaret , Fresnoza Agnes , Palidwor Gareth , Porter Christopher , Forget Antoine , Ayrault Olivier , Hawkins Cynthia , Chan Jennifer , Saulnier Olivier , Vladoiu Maria , Taylor Michael , Ramaswamy Vijay , Werbowetski-Ogilvie Tamra
Published: November 2019

The majority of Group 3 medulloblastomas (MB) exhibit amplification or increased expression of OTX2. OTX2 is primarily known as an oncogenic driver of tumor growth and cell cycle progression in Group 3 MB; however, its role as a repressor of differentiation is poorly characterized. Therefore, we utilized extensive patient data and mapped Group 3 MB chromatin dynamics in stem cell-enriched cultures to evaluate the divergent role of OTX2 in cell fate decisions in Group 3 MB pathogenesis. Several PAX genes were identified as novel OTX2 targets in Group 3 MB. Examination of patient data revealed that PAX3 and PAX6 expression is significantly reduced in Group 3 MB patients and is associated with significantly reduced survival. Functional evaluation of PAX3 and PAX6 expression showed that PAX3 expression significantly reduced self-renewal capacity of Group 3 MB tumorspheres in vitro and significantly prolonged survival and reduced tumor size in orthotopic xenograft models in vivo. RNA-sequencing of PAX3 and PAX6 gain of function (GOF) tumorspheres revealed mTORC1 signalling was specifically downregulated in PAX3 GOF, indicating this pathway may be critical for the survival and self-renewal differences observed between PAX3/PAX6 GOF models. Treatment of Group 3 MB with mTOR inhibitors reduced self-renewal in vitro and significantly prolonged survival and reduced tumor size in vivo. To further evaluate the role for this signalling axis in the Group 3 MB neural lineage hierarchy, we carried out scRNA-sequencing in tumorspheres from 4 Group 3 MB cell lines. Interestingly, a broad range of OTX2 expression was observed across single cell clusters, suggesting distinct OTX2 regulatory hierarchies are present in Group 3 MB. Collectively, our work demonstrates the multifaceted role of OTX2 as a regulator of cell fate decisions in Group 3 MB and identifies a novel role for mTORC1 signalling in Group 3 MB self-renewal and differentiation.
PDTM-44. ROLE OF ONC-206 IN REGULATING MEDULLOBLASTOMA TUMOR PROGRESSION
Authors: Malhotra Anshu , Liu Jingbo , MacDonald Tobey
Published: November 2019

Medulloblastoma (MB) is the most common malignant brain tumor in children. Of the four different sub-groups, the Sonic Hedgehog (SHH) subgroup accounts for about 30% of human MBs. The current standard of care (resection, cranio-spinal irradiation, and chemotherapy) for MB is typically ineffective for SHH MB in non-infants and those with metastatic disease. Survivors are frequently beset with long-term side effects including cognitive deficiencies and a severely impaired quality of life. Taken together, there is a critical need for novel targeted therapies for SHH MB. Recently, promising preclinical and clinical results have been obtained in a variety of cancers treated with a small molecule antagonist, ONC-201, which acts against DRD2, a G-protein coupled receptor that is widely expressed in MBs and regulates pro-survival pathways in tumors. In the present study we report the activity of ONC-201 and another DRD2 antagonist, ONC-206, which binds DRD2 with increased affinity. We tested three different MB cell lines with varied levels of DRD2 expression against these drugs, and consistently observed increased cell death at lower doses of ONC-206 compared to ONC-201. Following literature reports about the mechanism of action of ONC-201, we also evaluated the role of ClpP gene in MB cell lines. ClpP is a mitochondrial protease that has been shown to directly bind ONC 201. We observed a decrease in the expression of this gene after treatment of MB cell lines with ONC-206. Current studies are focusing on exploring the mechanism by which ONC-206 affects MB growth and metastasis. Dissecting this mechanism will be pivotal in predicting the role of this small molecule as a pre-clinical therapeutic for MB treatment.