bluuebunny/crossref_metadata_2025 huggingface dataset:
NIMG-39. REVEALING THE TUMOR-IMMUNE LANDSCAPE THROUGH SPATIALLY-RESOLVED RADIOMICS: CASE STUDIES
Authors: Hawkins-Daarud Andrea , Yoon Hyunsoo , Monie Dileep , Singleton Kyle , Ranjbar Sara , Tran Nhan , Badie Behnam , Rockne Russell , Brown Christine E , Hu Leland , Bruce Jeff , Canoll Peter D , Li Jing , Swanson Kristin
Published: November 2019

BACKGROUND

Conventional magnetic resonance imaging (MR) guides patient care in GBM. However, there is mounting awareness that MR enhancement is non-specific reflecting either tumor progression or non-tumoral inflammatory changes. Histological evaluation of GBM is held as the gold standard for disease assessment. However, the invasiveness of this methodology and the sample sparsity limit its usefulness. Methods to infer histological underpinnings of MRI are needed to improve clinical care.

METHODS

A transfer learning mixed effects model based on T1Gd and FLAIR MR voxel based image features trained and cross-validated to predict FPKM values of CD68, CASP3, CD8A and IL13RA2. Training data included RNAseq from 38 image-localized biopsies from 15 newly-diagnosed GBM patients. These models were then applied to two independent patients, chosen based on therapy and the quality of image registration, at three different time points, just prior to receiving IL13RA2 targeted CAR-T therapy for rGBM, after 2 cycles and after 4 cycles, resulting in a voxel-based prediction of the relative expression levels of these genes.

RESULTS

Cross-validation of the proposed machine learning models demonstrated a Pearson Correlation coefficient between predicted and observed FPKM values of 0.89 (CD68), 0.92 (CASP3), 0.93 (CD8A), and 0.88 (IL13RA2). When the models were applied to the two CAR-T patients, CD68-modeled expression levels were seen to increase throughout therapy for one patient, while remaining stable for the other. Survival from first CAR-T infusion was, respectively, 412 and 83 days suggesting that the increased CD68 was indicative of therapeutic effectivity. Further, the spatial activity predictions were consistent with expected therapeutic action as the correlation coefficient between CASP3 and the product of IL13R2 and CD8A expression was 0.81, suggesting the T-cells targeting IL13RA2 were inducing cell death.

CONCLUSIONS

Preliminary results with our model highlights the potential of spatially resolved radiomic maps to provide insight into regional therapeutic effectivity.
NIMG-42. RECURRENT TUMOR AND TREATMENT-INDUCED EFFECTS HAVE DIFFERENT MR SIGNATURES IN CONTRAST ENHANCING AND NON-ENHANCING LESIONS OF HIGH-GRADE GLIOMAS
Authors: Cluceru Julia , Nelson Sarah , Molinaro Annette , Alcaide-Leon Paula , Olson Marram , Berger Mitchel , Chang Susan , Phillips Joanna , Nair Devika , Wen Qiuting , Villanueva-Meyer Javier , Chunduru Pranathi , Cha Soonmee , Lupo Janine
Published: November 2019

INTRODUCTION

It is estimated that 25 to 35% of patients experience treatment-induced effects that can mimic recurrent high-grade gliomas. This diagnostic challenge is complicated by the coexistence of treatment-related changes and recurrent tumor within the same lesion which limits the accuracy of classification based on summary metrics of multi-parametric MRI. This study aimed to determine whether different MR features were relevant for distinguishing pathological features of recurrent tumor from the effects of treatment in the contrast enhancing and non-enhancing lesions of recurrent high-grade gliomas.

METHODS

Leveraging our unique dataset of image-guided tissue samples that directly maps pathology to MR characteristics, we analyzed 291 tissue samples (222 recurrent tumor; 69 treatment effect) with known coordinates on imaging from 139 patients that underwent preoperative 3T MRI and surgery for a suspected high-grade recurrent tumor. 8 MR parameter values from perfusion-weighted, diffusion-weighted, and MR spectroscopic imaging at each tissue sample location were tested for association with histopathological outcome using univariate and multivariate generalized estimating equation models for enhancing and non-enhancing tissue samples. Individual cutoff values were determined and evaluated using ROC-Curve analysis with 5-fold cross-validation.

RESULTS

In tissue samples obtained from contrast-enhancing lesions, elevated relative cerebral blood volume (rCBV) was significantly associated with the presence of recurrent tumor (p< 0.03), while increases in normalized choline (nCho) and choline-to-NAA index (CNI) were significantly associated with the presence of recurrent tumor in non-enhancing tissue samples (p< 0.008). Cutoff values of 1.6(rCBV), 2.7(CNI), and 2.1(nCho) had the highest performance.

CONCLUSION

Our results confirm the utility of rCBV in distinguishing the effects of treatment from recurrent tumor within the contrast enhancing lesion. We report a novel finding that metabolic parameters can differentiate recurrent tumor from treatment-related changes in the non-enhancing lesion of high-grade gliomas. These results will help improve future management of patients with suspected recurrence.
NIMG-46. IMPACT OF FET PET ON MULTIDISCIPLINARY NEUROONCOLOGICAL TUMOR BOARD DECISIONS IN PATIENTS WITH BRAIN TUMORS
Authors: Ceccon Garry , Werner Jan-Michael , Ruge Maximilian , Hampl Jürgen , Grau Stefan , Goldbrunner Roland , Celik Eren , Reinhardt Christian , Kabbasch Christoph , Borggrefe Jan , Bauer Elena , Wollring Michael , Rosen Jurij , Tscherpel Caroline , Fink Gereon , Langen Karl-Josef , Galldiks Norbert
Published: November 2019

BACKGROUND

Following neurooncological treatment of brain tumors, neurooncologists are frequently confronted with equivocal MRI findings (e.g., treatment-related changes, nonmeasurable (speckled) contrast-enhancing lesions, increase of T2/FLAIR signal alterations, pseudoresponse). Especially in Europe, amino acid PET is increasingly being integrated into multidisciplinary neurooncological tumor boards (MNTB) to overcome these diagnostic uncertainties as well as to improve patient management. We here evaluated the correctness of MNTB decisions, in which amino acid PET findings were taken into account.

METHODS

In a single university center, we retrospectively evaluated 114 MNTB decisions concerning 99 patients with malignant glioma (n=81) (glioblastoma, n=54; anaplastic glioma, n=26; gliosarcoma, n=1) or brain metastases (n=18) secondary to NSCLC, melanoma, breast cancer, or colorectral cancer, presenting with equivocal MRI findings following neurooncological treatment. All patients underwent amino acid PET imaging using O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) as an adjunct for decision-making. Additionally, the patients’ clinical status, pretreatment, and multimodal MRI findings were considered for decision-making. Presence of neoplastic tissue in PET was considered if the mean FET uptake as assessed by tumor-to-brain ratios was >2. The decisions’ diagnostic performance was evaluated by 2x2 contingency tables using the neuropathological results or clinicoradiological follow-up.

RESULTS

In the majority of MNTB decisions (n=102; 89%), FET PET results were integrated into the decision-making with considerable impact on the clinical management. In particular, 85% of MNTB decisions (n=87) prompted a treatment change (i.e., resection, radiotherapy, chemotherapy, or combinations thereof, as well as palliative therapy), or, in the case of suspected treatment-related changes, the continuation of the initial treatment regimen (15%; n=15). The MNTB decisions were validated using neuropathological data in 38% (n=39) or clinicoradiological information in 62% (n=63) and yielded a diagnostic accuracy of 88% (sensitivity, 89%; specificity, 75%; P=0.008).

CONCLUSIONS

Our results suggest that the integration of FET PET derived information significantly aids MNTB decisions.
NIMG-47. VOLUMETRIC ANALYSIS OF PHASE 2 AND 3 TRIALS IN RECURRENT GLIOBLASTOMA TREATED WITH VB-111 WITH OR WITHOUT BEVACIZUMAB OR BEVACIZUMAB MONOTHERAPY
Authors: Ellingson Benjamin , Raymond Catalina , Yao Jingwen , Goldman Jodi , Schlossman Jacob , Tran Caleb , Brenner Andrew , Butowski Nicholas , Wen Patrick , Rachmilewitz Minei Tamar , Cohen Yael , Harats Dror , Cloughesy Timothy
Published: November 2019

VB-111 is a non-replicating adenovirus carrying a pro-apoptotic transgene for TNFR1/Fas under the control of a modified murine promoter to pre-proendothelin 1. The transgene is expressed only in angiogenic endothelial cells, and therefore VB-111 results in targeted apoptosis of neovascular vessels. The current study characterizes the quantitative radiographic results and impact on OS in phase 2 and 3 trials of recurrent glioblastoma (GBM) patients treated with VB-111 with or without bevacizumab (BV) or BV monotherapy. MRI data from a phase 2 (NCT01260506) and randomized, double arm, controlled phase 3 (GLOBE; NCT02511405) trial of VB-111 in recurrent GBM were used in current study: Arm A) VB-111 monotherapy until progression followed by combination VB-111 and bevacizumab (BV) (“Primed Combination”; Phase 2; N=24); Arm B) VB-111 in combination with BV (“Unprimed Combination”; Phase 3; N=124); Arm C) BV monotherapy (“Control”; Phase 3; N=120). Contrast enhanced T1-weighted digital subtraction was used to quantify tumor volume at all time points. Baseline tumor volume was prognostic for OS in all treatment groups when controlling for therapy and age (Cox, P< 0.001, HR=1.02). In patients with smaller tumors (< 25mL), the “primed combination” cohort (Arm A) from the phase 2 trial had a significant OS advantage compared to both upfront combination of VB-111 and BV (Arm B; P=0.0094, HR=0.53; median OS = 7 vs. 15mo) as well as BV alone (Arm C; P=0.025, HR=0.58; median OS=8.5 vs. 15mo). Patients with a radiographic response (>65% reduction) had a significant survival difference from non-responders when controlling for age, baseline tumor volume, and treatment arm (P=0.0014, HR=0.58). Responders to VB-111 monotherapy or combination therapy after priming with VB-111 exhibited characteristic, expansive areas of necrosis in areas of initial disease.
NIMG-52. UNCERTAINTY QUANTIFICATION IN RADIOMICS
Authors: Wang Lujia , Yoon Hyunsoo , Hawkins-Daarud Andrea , Singleton Kyle , Clark-Swanson Kamala , Smith Kris , Nakaji Peter , Eschbacher Jenny , Baxter Leslie , Gonzalez Ashlyn , Nespodzany Ashley , Bendok Bernard , Patra Devi , De Leon Gustavo , Zimmerman Richard , Porter Alyx , Krishna Chandan , Salomao Marcela , Hoxworth Joseph , Zhou Yuxiang , Mrugala Maciej , Tran Nhan , Wu Teresa , Swanson Kristin , Li Jing , Hu Leland
Published: November 2019

INTRODUCTION

The quantification of intratumoral heterogeneity – through radiomics-based approaches - can help resolve the regionally distinct genetic drug targets that may co-exist within a single Glioblastoma (GBM) tumor. While this offers potential diagnostic value under the paradigm of individualized oncology, clinical decision-making must also consider the degree of uncertainty associated with each model. In this study, we evaluate the performance of a novel machine-learning (ML) algorithm, called Gaussian Process (GP) modeling, that can quantify the impact of multiple sources of uncertainty in ML model development and prediction accuracy, including variabilities in the copy number measurement, radiomics features, training sample characteristics, and training sample size.

METHOD

We collected 95 image-localized biopsies from 25 primary GBM patients. We coregistered stereotactic locations with preoperative multi-parametric MRI features (conventional MRI, DSC perfusion, Diffusion Tensor Imaging) to generate spatially matched pairs of MRI and copy number variants (CNV) for for each biopsy. We developed a Gaussian Process (GP) model to predict CNV for Epidermal Growth Factor Receptor (EGFR) based on MRI radiomic features in each patient. We used leave-one-patient-out cross validation to quantify prediction accuracy and model uncertainty. Spatial prediction and uncertainty (p-value) maps were overlaid to help visualize regional genetic variation of EGFR and uncertainty of the radiomic predictions. RESULT: The initial GP radiomics model for EGFR amplification (CNV > 3.5) produced a sensitivity of 0.8 and specificity of 0.8. Samples/regions associated with high uncertainty (p-value >0.05) correlated with either 1) extrapolation of radiomic features from the training set-defined feature space or 2) insufficient training samples in the feature space.

CONCLUSION

We present a ML-based model that quantifies spatial genetic heterogeneity in GBM, while also estimating model uncertainties that result from multi-source data variabilities. This approach lays the groundwork for prospective clinical integration of modeling-based diagnostic approaches in the paradigm of individualized medicine.
NIMG-53. 3D BRAIN TUMOR MODELING FACILITATES NEURO-ONCOLOGY CLINIC VISIT AND IMPROVES PATIENT HEALTH LITERACY AND VISIT SATISFACTION
Authors: Landau Zoe , Flora Sarah , Tosha Gatson Na
Published: November 2019

Explanation of brain tumor imaging (BTI) complexities to patients is a challenge in neuro-oncology. With limited tools, neuro-oncologist attempt to demonstrate tumor volumes and anatomy, estimate surgical risks, and treatment responses. Arming clinicians with alternative BTI might help alleviate the stress of initial patient consults and follow-up surveillance visits. These interactions are critical to the physician-patient relationship, patient compliance, and satisfaction. Currently, 2D-MRI review is standard, often leaving the patient with a less-than-complete understanding of their tumor. Historically, 3D-Brain-Tumor-Modeling (3DBTM) has been used for neurosurgical simulation and planning. Here, we evaluated the use 3DBTM alongside routine MRI impact on patient health literacy and satisfaction. Our institution introduced 3DBTM as a best practice approach. Images were presented as 3D video or tangible 3D color renditions, or 2D MRI. We collected patient pre-visit and post-visit surveys to assess patient’s understanding of tumor features, opportunity to review images, and patient level of satisfaction. Data from 277 pre-visit and 159 post-visit surveys was collected from the Geisinger Neuro-Oncology Clinic over a six-month period. Post-visit survey categories included reviews of: 3DBTM (n=54), 2D-MRI (n=51), and no imaging (n=55). Patients without CNS tumors were excluded (n=101). Pre-visit surveys showed 30% (n=82) of patients had little-to-no prior understanding of their tumor location and size, and 53% (n=147) of patients believed that a 3DBTM would improve their understanding. Post-visit analysis demonstrated that only 21% (n= 29) of patients reported not seeing any imaging during the visit. Nearly 85% (n=46) of patients who had reviewed a 3DBTM noted improved tumor understanding. Of the patients who solely viewed 2D-MRI, 68% (n=35) reported improved understanding of their tumor but would like more advanced imaging teaching. In total, 84% of patients noted overall satisfaction with the clinic visit. These results support the use of 3DBTM in patient education and facilitating clinical interviews.
NIMG-64. IMPACT OF TUMOR LOCATION ON IMAGE-DERIVED VOLUME, PROLIFERATION RATE AND GROWTH VELOCITY IN GLIOBLASTOMA PATIENTS
Authors: Lorence Julia , Swanson Kristin , Rickertsen Cassandra , Ranjbar Sara , Johnston Sandra , Singleton Kyle , Porter Alyx , Bendok Bernard , Mitchell Ross , Rubin Joshua , Hu Leland , White Haylye , Whitmire Paula , Mrugala Maciej
Published: November 2019

INTRODUCTION

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults with a median overall survival (OS) of 15months. Despite advancements in treatments, prognosis is dismal and the prognostic significance of tumor location is not entirely understood. METHODOLOGY: In our study, we investigated sex-specific volumetric, tumor growth kinetics, and outcome differences among GBMs in various brain locations. Primary GBM patients with pretreatment magnetic resonance imaging (MRI) data (N=289, 173 males, 116 females) were selected from our brain tumor repository. Tumor abnormality was segmented on T1-weighted post-gadolinium contrast agent (T1Gd) MRIs. We utilized the Harvard-Oxford brain atlases to determine the location of GBMs.

RESULTS

Overall, our study found smaller tumors in the left hemisphere. This may be expected as left-hemispheric GBM symptoms could present earlier, leading to earlier diagnosis and treatment. However, when the cohort was split by sex, we found this observation significant for females only in the parietal lobe (p < 0.0001). Further, female GBMs demonstrated smaller necrotic volume in the left hemisphere (p = 0.030). Sex-specific differences in incidence were noted in the temporal and occipital lobes (2M:1F). Comparing tumor growth kinetics in different brain locations and hemispheres, females had significantly lower tumor proliferation rates in the left hemisphere (p = 0.009) and lower tumor proliferation rates in the left frontal lobe (p = 0.031). Controlling for treatment, patients with frontal lobe tumors had significantly longer OS compared to those with GBMs in the temporal lobe (p = 0.046, 312 days). Differences in growth velocities were noted between frontal and parietal lobe with frontal GBMs having lower velocities in comparison to parietal lobe GBMs.

CONCLUSION

Together, our results demonstrate that tumor growth and proliferation rates may vary based on location and sex. Additional research is needed to further explore the clinical significance of tumor location.
NIMG-69. RAPID INTRAOPERATIVE DIAGNOSIS OF GLIOMA RECURRENCE USING STIMULATED RAMAN HISTOLOGY AND DEEP NEURAL NETWORKS
Authors: Hollon Todd , Urias Esteban , Adapa Arjun , Jairath Neil , Save Akshay , Canoll Peter D , Lee Honglak , Freudiger Christian , Orringer Daniel
Published: November 2019

Accurate intraoperative diagnosis of recurrence versus treatment effect (TE) is essential for determining the management of suspected recurrent gliomas. Cytologic and histoarchitectural changes related to chemoradiation overlap with common findings in recurrent tumors (e.g. atypia, abnormal vasculature, necrosis). Moreover, H&E tissue processing artifact complicates interpretation. Stimulated Raman histology (SRH) uses the intrinsic biochemical properties of fresh, unprocessed surgical specimens to provide rapid label-free digital histologic images. Here, we report an automated technique using deep convolutional neural networks (ConvNet) that differentiates recurrent glioma and TE in fresh surgical specimens imaged using SRH with equivalent accuracy and 10x faster (tissue-to-diagnosis, 2 minutes) than conventional methods. Our ConvNet, based on Google’s Inception-ResNet-v2 architecture, was first trained on 3.6 million SRH images from 441 patients with the most common brain tumor subtypes. To optimize the network for classifying glioma recurrence, we used cross-validation (CV) on 35 patients (24 recurrent, 9 TE) for model hyperparameter tuning and to identify an optimal probability threshold to classify recurrence. To perform rigorous model validation, we used a 50 patient external testing set to evaluate overall model accuracy. Over 5 iterations of CV, the mean held-out classification accuracy was 94.8% (range, 91.4 - 97.1%). Using ROC analysis, we found that a probability of recurrence greater than 25% was the optimal threshold to render a recurrence diagnosis for whole-slide SRH images. Using our external testing set, we achieved a classification accuracy of 96% (total 48/50; 30/30 recurrences, 18/20 TE). Moreover, our method effectively identifies regions of glioma recurrence in whole slide SRH at no additional computational cost. Our study demonstrates the feasibility of applying deep learning for intraoperative diagnosis of recurrent gliomas in SRH imaged tissues. In the future, ConvNets may ultimately be used to guide decision-making in the surgical care of recurrent gliomas, independent of conventional neuropathology resources.
NIMG-75. RADIOMIC FEATURES LOCALIZED TO STEREOTACTIC BIOPSY LOCATIONS CAN CAPTURE EGFR PRESENCE IN GLIOBLASTOMA
Authors: Ismail Marwa , Correa Ramon , Bera Kaustav , Saeed Bamashmos Anas , Statsevych Volodymyr , Prasanna Prateek , Beig Niha , Madabhushi Anant , Ahluwalia Manmeet , Tiwari Pallavi
Published: November 2019

PURPOSE

Epidermal growth factor receptor amplification (EGFRamp), occurs in >60% of Glioblastoma (GBM) patients, and can predict response to alkylating chemotherapy. However, due to high genetic instability in GBM, a significant caveat to sampling EGFRamp during biopsy, is that reliable identification of its presence is dependent on the site of the biopsy, and may vary throughout the tumor. Previous studies have employed radiomics (computerized feature extraction) from the entire tumor to characterize EGFRamp presence. Our work is based on the rationale that radiomics measurements from stereotactic biopsy locations on Gd-T1w MRI, may allow to build accurate training models for predicting EGFRamp compared to using radiomic features from the entire tumor.

METHODS

MRI scans from 78 GBM subjects (33 EGFRamp, 45 non-amp) were obtained, of which 54 subjects were used for training while 24 were used for testing. Stereotactic biopsy locations were mapped by co-registering CT-images with MRIs (confirmed by two radiologists). For each biopsy region (1-cm diameter sphere), gradient entropy features and gender information were used to train a discriminant analysis classifier, on a voxel-wise manner. Our training model also included per-voxel spatial probabilities that were obtained by building atlases to quantify frequency of occurrence of EGFRamp and non-amp cases. All of these features were then used within the test set to predict EGFR status.

RESULTS

The model achieved a training accuracy of 81.4%, correctly classifying 17/23-amp, 27/31 non-amp cases. Accuracy on test set was 79.2% (7/10 amp, 12/14 non-amp cases correctly classified). Extracting features from the entire tumor achieved a training accuracy of 74% (17/23-amp, 23/31 non-amp cases correctly classified), and a testing accuracy of 70.8% (6/10 amp, 11/14 non-amp cases correctly classified).

CONCLUSION

Radiomic features, trained using features from only the stereotactic biopsy locations, may be more reliable in training models to predict EGFR mutation in GBM.
NIMG-77. RESPONSE ASSESSMENT USING MULTIPARAMETRIC MRI DURING CHEMORADIATION PREDICTS OVERALL SURVIVAL IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Kim Michelle , Aryal Madhava , Parmar Hemant , Li Pin , Schipper Matthew , Wahl Daniel , Lawrence Theodore , Cao Yue
Published: November 2019

INTRODUCTION

Identifying both aggressive hypercellular (HCV) and hyperperfused (hCBV) regions of glioblastoma (GBM) prior to radiation (RT) using multiparametric MRI (mpMRI) predicts PFS and recurrence better than either technique alone, and is under investigation in a phase II trial as a novel target for dose-intensified RT. We hypothesized that early response in combined HCV/hCBV could be assessed using mpMRI and predict OS better than baseline assessment.

METHODS

Forty-three patients with newly diagnosed GBM underwent prospective high b-value (b=3000 s/mm2) DW-MRI and DCE-MRI pre-RT and 3 weeks into RT. Twenty patients were treated on a dose-escalation trial specifically targeting HCV/hCBV identified by mpMRI. An automated threshold method was used to generate HCV (mean contralateral normal brain+2SD) and hCBV (contralateral normal frontal grey matter+1SD). Survival was calculated using Kaplan-Meier method and compared using log-rank test. Age, gender, performance status, RT dose, extent of surgery, MGMT methylation, and imaging characteristic were tested in Cox proportional hazards models for survival.

RESULTS

Most patients had gross total (47%) or subtotal resection (37%), and 25% were MGMT methylated. Significant volumetric reduction during RT was observed in the Gd-enhanced volume (4.4 cc reduction, 95%CI 1.1–7.7, 17%), as well as HCV (1.8 cc reduction, 95%CI 0.2–3.4, 19%) and hCBV (1.1 cc reduction, 95%CI -0.4–2.6, 10%). No difference was observed between MGMT subgroups, but patients treated on protocol specifically targeting the mpMRI volume had significant reduction in combined HCV/hCBV (-4.4 cc, 95%CI -6.6,-2.3) vs non-protocol patients (-0.3 cc, 95%CI -2.6,2.0, p=0.006). A reduction in combined HCV/hCBV was associated with superior OS (AHR 0.60, 95%CI 0.40–0.89, p=0.01), while baseline imaging (all p< 0.90) and change in Gd-enhanced volume (p=0.61) were not.

CONCLUSIONS

Significant early response in HCV/hCBV during treatment is observed when targeted with dose-intensified RT, and is associated with improved OS with potential for adaptive strategies in future trials.
NCMP-02. MYASTHENIA GRAVIS INDUCED BY AVELUMAB
Authors: Yuen Carlen , Fleming Gini , Soliven Betty , Myers Michael , Rezania Kourosh
Published: November 2019

Monoclonal antibodies targeting PD- 1 (nivolumab and pembrolizumab) and PD-L1 (avelumab, atezolizumab, and durvalumab) are FDA approved for the treatment of metastatic cancers. Immune-related adverse events (irAEs) are autoimmune diseases which occur following treatment with PD-1 and PD-L1 inhibitors. Neurological irAEs following PD-L1 blockade are rarely reported, and mainly consist of Myasthenia Gravis (MG) and myositis. MG induced by avelumab has not been previously reported. We present a 74-year-old female with stage IV ovarian adenocarcinoma who entered a clinical trial involving avelumab and entinostat after disease progression following extensive resection, chemotherapy with doxorubicin, then docetaxol and cisplatin. She developed progressive generalized weakness and fatigue two months after entering the trial, leading to respiratory weakness and hypoventilation, and resulting in intubation and mechanical ventilation. Exam showed head-drop, diplopia, and proximal > distal upper and lower limb weakness. Antibodies to acetylcholine receptors, muscle specific tyrosine kinase, and voltage-gated calcium channels (P/Q and N type) were negative, and serum creatine kinase was normal. Repetitive nerve stimulation showed significant decrement in the left spinal accessory nerve motor response with recording at trapezius. She was diagnosed with seronegative MG and was treated with IVIG, 2 grams/kg divided over 4 days, prednisone 60 mg daily, and pyridostigmine, which resulted in successful extubation, followed by gradual resolution of MG symptoms over a period of 3 months. At approximately 2 year follow-up, she remains on maintenance IVIG at 0.5 grams/kg every 3 weeks, as she develops proximal lower limb and neck extension weakness at the end of each IVIG cycle. We conclude that MG is a potentially life threatening but treatable irAE associated with avelumab. Our case also adds to the accumulating literature of the role of PD-1 signaling in the pathogenesis of autoimmune diseases of the muscles and neuromuscular junctions.
NCMP-04. OPSOCLONUS-MYOCLONUS SYNDROME ASSOCIATED WITH CONTACTIN-ASSOCIATED PROTEIN-LIKE 2 AUTOANTIBODY IN THE SETTING OF NON-SMALL CELL LUNG CARCINOMA
Authors: Rosenow Christian , Dawit Sara , Henry Katharine , Farrugia Luca , Sharma Akanksha , Grill Marie
Published: November 2019

INTRODUCTION

Opsoclonus–myoclonus syndrome (OMS) is a rare neurological disorder characterized by spontaneous multidirectional saccadic eye movements, myoclonus, and ataxia. It is suspected to be an autoimmune mediated process precipitated by a paraneoplastic or infectious trigger. Among the pediatric population, OMS is often associated with neuroblastoma and anti-Hu antibody. Paraneoplastic syndromes in adults manifesting as OMS are most commonly described in breast, gynecological and small cell lung cancer with associated anti-neuronal antibodies (ANNA-2; anti-Ri). We describe the first case of OMS associated with lung adenocarcinoma and Contactin-associated protein-like 2 (Caspr2) antibody. CASE REPORT: A 46-year-old-woman with history of limited small cell lung cancer (SCLC) status-post chemotherapy with cisplatin and etoposide and prophylactic whole brain radiation, presented with new onset gait instability, nausea, vomiting, vertigo, and opsoclonus. Two months prior to her presentation, a chest computed topography (CT) revealed no evidence of recurrent disease. Brain MRI revealed T2 hyperintensities in the white matter and central pons presumably related to chronic small vessel ischemic changes, unchanged from prior imaging. CSF studies revealed normal cell count, glucose, and protein. Gram stain, culture and meningoencephalitis panel were negative. Her paraneoplastic panel revealed a positive Caspr2 antibody. A repeat CT chest for cancer surveillance revealed a new lung mass. Immunotherapy treatment included plasmapheresis, corticosteroids, and intravenous immunoglobulin therapy. She underwent a biopsy of the new pulmonary lesion and the pathology was consistent with non-small cell lung carcinoma. Her symptoms slowly improved after treatment. Unfortunately, her disease progressed on repeat PET scan despite surgical resection of the lung mass. She ultimately elected for hospice.

CONCLUSION

We report a novel antibody, Caspr2, occurring in association with paraneoplastic OMS. While SCLC is the most common neoplasm associated with OMS among adults, non-small cell lung carcinoma should be considered. Prompt immunotherapy and neoplasm treatment may result in improvement.
NCMP-05. THE INCIDENCE AND IMPACT OF POST-OPERATIVE STROKE IN SURGERY FOR LGG
Authors: Berger Asaf , Tzarfati Garry , Costa Mathias , Serafimova Marga , Korn Akiva , Alfassi Tali , Aviram Daniel , Kashinian Alon , Ram Zvi , Grossman Rachel
Published: November 2019

BACKGROUND

Postoperative neurological deficits may outweigh the benefit conferred by maximal resection of gliomas. We evaluated the incidence of ischemic events in patients undergoing surgery for low-grade gliomas (LGG) and the long-term neurological and cognitive sequelae.

METHODS

Between 2013–2017, 168 patients underwent surgical resection or biopsy for LGG at our center. A full dataset, including pre- and postoperative magnetic resonance imaging (MRI) and long-term clinical evaluation findings, was available for 82 patients (study group). Ischemic complications, overall and progression-free survival, and functional and neurocognitive outcomes were evaluated.

RESULTS

The immediate postoperative MRI revealed an acute ischemic stroke adjacent to the tumor resection cavity in 19 patients (23%), 13 of whom developed new neurological deficits due to the ischemic event. Infarcts were more common in patients with recurrent tumors, especially those involving the Sylvian fissure (p< 0.05). Surgery for insular gliomas had the strongest association with postoperative infarcts. Survival of patients w/wo a postoperative infarct was the same. The median Karnofsky-Performance Status was lower for the infarct group vs. the non-infarct group at 3 months post-surgery (p=0.016), with a gradual significant improvement for the former over one year (p=0.04). Immediately after surgery, 27% of the patients without infarcts and 58% of those with infarcts experienced a new motor deficit (p=0.037), decreasing to 16% (p=0.028) and 37% (p=0.001), respectively, at one year. Neurocognitive analysis findings before and 3 months after surgery were unchanged, but patients with an infarct had a significant decrease in naming (p=0.04). Confusion during awake craniotomy was a strong predictor of an ischemic stroke.

CONCLUSIONS

Intraoperative strokes are more prevalent among patients who undergo recurrent surgeries, especially in the insula. Although they do not affect survival, these strokes negatively impact the patients’ activity and performance status, especially during the first 3 postoperative months, with gradual functional improvement over one year.
NCMP-09. NEUROLYMPHOMATOSIS, A RARE INDEX MANIFESTATION OF CD5/CD10 NEGATIVE MATURE B CELL LYMPHOMA PRESENTING AS SUBACUTE SENSORIMOTOR LAMBOSACRAL POLYRADICULONEUROPATHY
Authors: Hrachova Maya , Xiao-Tang Kong , Zhao Xiaohui
Published: November 2019

INTRODUCTION

Neurolymphomatosis (NL) is a rare entity characterized by direct invasion of neoplastic cells into endoneurium of cranial or peripheral nerves, nerve roots or plexuses. It is most commonly seen with non-Hodgkin’s lymphoma with occurrence rate of 0.2%. Here we report a case of subacute length-dependent sensorimotor lumbosacral polyradiculoneuropathy secondary to NL as the first manifestation of CD5−/CD10− mature B-cell lymphoma. CASE REPORT: A 54-year old man with diabetes mellitus type 2, hypertension and psoriasis presented with subacute onset of progressive lower extremity weakness with pertinent examination findings of bilateral mildly asymmetrical distal greater than proximal lower extremities weakness, length depended hypoesthesia, fasciculations and decreased reflexes. EMG/NCS study showed active and chronic denervation changes concerning for multilevel lumbosacral polyradiculopathy. Routine blood investigations produced normal findings. CSF examination showed nucleated cells at 125 cells/HPF with lymphocyte predominance, protein at 538 mg/dL, and glucose 18 mg/dL. Flow cytometry identified mature CD5-/CD10- B cell lymphocytes. MRI spine identified marked enhancement, thickening, nodularity of cauda equine nerve roots and focus of myelopathy at the left posterior conus. Based on the clinical and radiographic findings a diagnosis of neurolymphomatosis was made and her underwent workup for systemic lymphoma.

DISCUSSION

Our case demonstrates the importance of comprehensive evaluation of sensorimotor polyradiculoneuropathy as rare entities such as neurolymphomatosis could mimic common etiologies.
NCMP-15. BEVACIZUMAB FOR THE TREATMENT OF CEREBRAL RADIATION NECROSIS: A RETROSPECTIVE COHORT STUDY
Authors: Luitse A , Dankbaar Jan , De Vos Filip , Fonville Susanne , Robe Pierre , Seute Tatjana , Verhoeff Joost , Snijders Tom
Published: November 2019

BACKGROUND

Cerebral radiation necrosis (RN) is a critical complication of radiotherapy for brain tumors. Treatment with corticosteroids provides suboptimal symptom relief, and may have considerable side effects. Small-scale studies support the use of bevacizumab, but systematic data from clinical practice on its efficacy and toxicity remain scarce.

METHODS

In this retrospective cohort study, we included consecutive patients with symptomatic RN that underwent treatment with bevacizumab in our academic neuro-oncology clinic. RN was diagnosed based on imaging, histology or both. The primary outcomes were reported neurological improvement during follow-up, the duration of response, the reported improvement on MRI, and radiological outcome according to RANO criteria. Other outcomes included reduction of dexamethasone dose and the occurrence of adverse events.

RESULTS

Of the 37 included patients (39 RN-episodes), the majority had a glioblastoma (n = 22) or other diffuse glioma (8), followed by brain metastases (4) or other (3). Clinical response was reported in 17 RN-episodes (43.6%) and lasted for a median of 13 weeks (IQR 6–32 weeks). Radiological improvement during follow-up was reported in 29 RN-episodes (80.6%). RANO-defined radiological responses included 1 complete response (3.4%), 7 partial responses (24.1%), 1 minor response (3.4%) and 17 stable disease (58.6%). In total, 36 adverse events occurred, most commonly venous thrombo-embolism, hypertension and dyspnea, with 8 grade III-IV complications and 2 deaths (grade V) which were possibly related to bevacizumab. Of 32 patients on dexamethasone, 9 (28.1%) had completely stopped its use at treatment cessation.

CONCLUSION

This observational study confirms that patients with cerebral RN can benefit both clinically and radiologically from bevacizumab treatment in a real-life clinical setting, although our results are more modest than previous literature suggests. The high prevalence of – sometimes severe – adverse events should be weighed against the possible clinical benefit when counselling patients about this treatment option.
PDCT-01. BIOLOGICAL MEDICINE FOR DIFFUSE INTRINSIC PONTINE GLIOMAS ERADICATION (BIOMEDE): RESULTS OF THE THREE-ARM BIOMARKER-DRIVEN RANDOMIZED TRIAL IN THE FIRST 230 PATIENTS FROM EUROPE AND AUSTRALIA
Authors: Grill Jacques , Le Teuff Gwenael , Nysom Karsten , Blomgren Klas , Hargrave Darren , McCowage Geoff , Bautista Francisco , van Vuurden Dannis , Dangouloff-Ros Volodia , Puget Stephanie , Varlet Pascale , Debily Marie-Anne , Vassal Gilles , Le Deley Marie-Cécile
Published: November 2019

BACKGROUND

Diffuse intrinsic pontine glioma (DIPG) is one of the most devastating brain neoplasms. Despite 50 years of clinical trials, no improvement of survival has been observed and most children die within 2 years of diagnosis. Only radiotherapy transiently controls disease progression. METHODS/AIMS: BIOMEDE was conceived as a randomized multi-arm multi-stage program (drop-the-loser adaptive design). It started with an open-label phase-II trial comparing three drugs (everolimus, dasatinib, erlotinib) combined with irradiation, allocated according to the presence of their specific targets) with a planned sample size of 250 patients. A stereotactic biopsy was performed at diagnosis to centrally confirm the diagnosis of DIPG (presence of histone H3K27M mutation or loss of K27 trimethylation) and assess biomarkers/targets (PTEN-loss, EGFR-overexpression). Targeted therapies were started concomitantly with radiotherapy and were continued until disease progression. The main objective of the study was to compare the efficacy of randomized groups in terms of overall survival (OS).

RESULTS

At the 3rd interim analysis, based on 193 randomized patients among the 230 study patients, the IDMC concluded that the study was unlikely to meet its primary objective even if 250 patients were randomized. The median OS from the time of randomization was 10.9, 9.5 and 9 months for everolimus, dasatinib and erlotinib, respectively, which is comparable to historical controls. The median number of courses administered was 7, 5.5 and 6 respectively. Treatment was discontinued due to toxicity in 2%, 13%, and 15%, respectively. No biopsy-related death was reported and diagnostic yield was excellent, with only 5 non-informative biopsies.

CONCLUSION

BIOMEDE shows the feasibility of biologically-driven treatment in DIPG on a large international scale. Based on the better toxicity profile and the slightly better efficacy, although not statistically significant, the steering committee proposed that everolimus should be used as the control arm for the next step, BIOMEDE 2.0.
PDCT-07. EARLY RESULTS OF THE EMULATE THERAPEUTICS HÆLO™ SYSTEM IN PEDIATRIC BRAIN TUMORS
Authors: Chang Andrew , Gardner Sharon , Jaboin Jerry , Leary Sarah , Loret De Mola Rebecca , McClay Edward , Morgan Murray Donna , Nazemi Kellie , Pai Panandiker Atmaram , Salacz Michael , Stapleton Stacie , Kesari Santosh , Prados Michael
Published: November 2019

BACKGROUND

The EMulate Therapeutics Hælo system is an investigational non-sterile, non-invasive, non-thermal, non-ionizing, portable, home-use medical device that uses a specific, localized ultra-low radio frequency energy (ulRFE®) cognate for the treatment of pediatric brain tumors.

METHODS

Sixteen patients with brain tumors consisting of diffuse midline glioma/diffuse intrinsic pontine glioma (DMG/DIPG, n=14), recurrent medulloblastoma (n=1), or anaplastic astrocytoma (n=1) – were treated with the Hælo under FDA’s single-patient compassionate use pathway, as protocol deviations in a glioblastoma trial, or under TGA’s Special Access Scheme. Baseline information and on-treatment safety and exposure data were collected.

RESULTS

Patients ranged in age from 4 to 28 years (median = 8 years) and were diagnosed 91 – 1399 days (median = 397 days) prior to treatment with the Hælo system. Patients were treated for 2 – 52 weeks (median = 15 weeks), with 4 patients still alive (all with a diagnosis of DMG/DIPG), and 3 still on treatment (ranging 18 – 52 weeks). Two out of the 16 patients reported mild-moderate adverse events - one patient reported nausea, fatigue, and excessive sleepiness, and one patient reported vomiting. No device-related serious adverse events were reported. Other adverse events reported were generally associated with progressive disease. Unsolicited, anecdotal reports from some parents/caregivers noted improvements in mobility, speech, and visual acuity while on treatment.

CONCLUSIONS

The Hælo system appears to be safe and feasible for the treatment of pediatric brain tumors. Given that therapy is delivered non-invasively and no device-related serious adverse events were reported, further prospective study of the investigational device is warranted.
PDTM-02. TARGETING THE RB PATHWAY IN MEDULLOBLASTOMA
Authors: Jonchere Barbara , Stripay Jennifer , Pribnow Allison , Zindy Frederique , Min Jaeki , Freeman Burgess , Shelat Anang , Rankovic Zoran , Roussel Martine
Published: November 2019

Medulloblastoma (MB), the most common malignant pediatric brain tumor, is classified into four major molecularly and histopathologically distinct subgroups, among which MYC-driven Group 3 MBs confer a poor prognosis. The Cyclin D/CDK4/CDK6/RB pathway is frequently deregulated in MB leading to uncontrolled cell proliferation, but tumors express an intact RB protein (Northcott et al., Nature, 2017). Therefore, CDK4/6 inhibitor drugs offer a possible therapeutic approach to treat MBs. Because single agent therapy ultimately leads to drug resistance, we initiated in vitro combination drug screens to identify drug classes potentiating CDK4/6 inhibitors. We used Group 3 MB patient-derived orthotopic xenografts (PDOXs), a human cell line (HDMB03), and freshly dissociated tumor cells propagated only in the mouse brain. The drug screen included 90 compounds comprising targeted and cytotoxic drugs that are FDA approved or under active clinical investigation. Using a bioluminescence-based assay that measures ATP consumption (CellTiter-Glo) to evaluate the number of viable cells, these 90 compounds were screened in combination with a fixed concentration of ribociclib, one of the three FDA approved CDK4/6 inhibitors. The primary screen, carried out in HDMB03 cells, revealed several drugs with additive or synergistic potential when combined with ribociclib, including BET inhibitors, MEK inhibitors, PI3K/mTOR inhibitors and gemcitabine. We are currently evaluating the combination of brain penetrant compounds in Group 3 MB PDOXs. The identification of potent drug combinations should provide new therapeutic options for the treatment of Group 3 MB, one of the most difficult to treat.
PDTM-03. CHICKEN EMBRYO CHORIOALLANTOIC MEMBRANE (CAM) ASSAY AS A XENOGRAFT MODEL FOR TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMAS
Authors: Power Erica , Zhang Liang , Lucien-Matteoni Fabrice , Daniels David
Published: November 2019

BACKGROUND

Diffuse intrinsic pontine gliomas (DIPG), known today as diffuse midline gliomas with the H3K27M mutation, are inoperable and aggressive brain tumors found predominantly in children. Despite extensive research no treatment or cure has been elucidated. Studies in 2012 showed that the majority of DIPG tumors have the H3K27M mutation, but the development of novel therapeutics has been hindered by lack of good laboratory models. Although patient derived cell lines with the H3K27M mutation have increased, the development of good murine xenografts are lagging, requiring extensive time and money. Previous studies have shown that the chicken embryo Chorioallantoic Membrane (CAM) model is an affordable and time-efficient method of studying tumor biology and response to treatment. We sought to develop this in H3K27M tumors to bridge the gap between in vitro—in vivo studies.

METHODS

Three patient-derived H3K27M cell lines were cultured and implanted on the chick embryo CAM on day 9 post-fertilization. Tumors underwent multiple drug treatment with 0.5uM or 2.0uM Alisertib (days 11, 13, 15) or a single targeted radiation treatment at 2 Grey (day 13). Tumor volume was assessed via ultrasound on day 16. The tumor specimens were harvested and analyzed by immunohistochemistry.

RESULTS

Patient-derived DIPG cells implanted on the CAM maintain their molecular characteristics and form tumors on the surface of the CAM as evidenced by H&E and H3K27M status. Statistically significant differences in volume were found in three H3K27M DIPG lines in Alisertib treated tumors compared to the control (p< 0.001, p< 0.001, p= 0.005). Statistically significant differences in tumor volume were found when treating two DIPG lines with targeted radiation therapy compared to controls (p= 0.01, p= 0.02).

CONCLUSIONS

These results validated the CAM assay as a reliable xenograft model for studying DIPG tumor biology and determining efficacy of drug and radiation treatment.
PDTM-09. Yap1 FUNCTION IN SEX-BIASED MEDULLOBLASTOMA FORMATION AND ANTI-TUMOR IMMUNITY
Authors: Abdelfattah Nourhan , Natarajan Sivaraman , Chen Yaohui , Chow Kin-Hoe , Chen Shu-hsia , Olson James , Baskin David , Yun Kyuson
Published: November 2019

Immunotherapies offer remarkable potential to provide robust therapeutic benefit. Patients suffering from medulloblastoma (MB), the most frequent pediatric brain malignancy, can especially benefit from this approach, minimizing the devastating side effects of aggressive radiation and chemotherapies that disrupt normal brain development. However, regulators of the immune landscape remain poorly understood and no effective immunotherapies exist yet for MB. Here, we describe a sex-dependent Yap1 function in fSmoM2;GFAPcre SHH-MB (SG) mouse model. We show that Yap1 is both a cell-autonomous regulator of MB stem-cells and a non-cell-autonomous regulator of immune infiltrates in SHH-MB. Yap1 deletion in SG mice results in increased neuronal differentiation, significantly extended survival, and enhanced infiltration of peripheral blood immune cells (including cytotoxic T-cells, neutrophils, and macrophages). Additionally, this rescue phenotype is observed in a sex-biased manner: 65% of Yap1f/f;fSmoM2;GFAPcre males are rescued in contrast to 35% of females. These observations implicate Yap1 as a mediator of sex-biased brain-tumor formation, either through direct modulation of MB cells and/or through indirectly mediating the MB immune landscape. We are currently testing the role of sex-specific differences in the developing mouse brain to elucidate context-dependent function of Yap1 in MB genesis and maintenance.