bluuebunny/crossref_metadata_2025_split huggingface dataset:
GCT-73. EXPRESSION PROFILING OF INTRACRANIAL GERM CELL TUMORS REVEALS UPREGULATION OF RAS THROUGH mRNA-microRNA SIGNALING PATHWAY
Authors: Taylor Aaron M , Shen Jianhe , Ren Lingzhao , Terashima Keita , Huang Lei , Snyder Elizabeth M , Adesina Adekunle , Su Jack , Nishikawa Ryo , Nakamura Hideo , Ng Ho-Keung , Wong Stephen T C , Braun Robert E , Man Tsz-Kwong , Lau Ching C 
Published: December 2020

Abstract
Intracranial germ cell tumors (IGCTs) account for 3% of CNS tumors in children in the U.S. and 11% in Japan and East Asian countries. IGCTs are separated into two distinct subtypes based on histology: germinomas and non-germinomatous germ cell tumors (NGGCTs). The deep central location of IGCTs makes surgical resection and therefore molecular subtype classification difficult, and previous gene expression studies are limited. We performed mRNA expression profiling (Human Genome U133 Plus 2.0) and microRNA expression profiling (ABI TaqMan) with 36 and 49 IGCTs, respectively. Sample stratification using non-negative matrix factorization clustering of gene expression revealed two distinct subgroups that delineated germinomas from NGGCTs. Employing stepwise model building in each data set separately, we were able to separate these groups using only mRNA probes for the LIN28B and L1TD1 genes, and two microRNA, microRNA-26a and microRNA-373. MicroRNA26a suppresses the LIN28B gene and is down-regulated in germinoma. LIN28B directly binds and suppresses the let-7 microRNA family, which suppress the KRAS oncogene, previously found to be mutated in ~19% of IGCTs. L1TD1 is required for human stem cell renewal and directly interacts with LIN28B for its RNA binding function. LIN28B and L1TD1 are both known to be upregulated in other systemic germ cell tumors, but this has not yet been documented in IGCTs. In conclusion, these results show that intracranial germinomas have similar gene expression compared to systemic seminoma, and suggest a mechanism by which activation of LIN28B and L1TD1 downregulates the let-7 microRNA and subsequently upregulates KRAS.
HGG-38. A COMPARATIVE PROTEOMIC-ANALYSIS OF THE CELL MEMBRANE FRACTIONS OF HISTONE 3 MUTATED BRAIN TUMOURS TO IDENTIFY NOVEL THERAPEUTICS
Authors: Pickering James , Rahman Ruman , Grundy Richard , Layfield Robert , Haque Farhana 
Published: December 2020

Abstract
Improvements in the treatments for childhood and adolescent brain tumours, High-Grade Glioma (pHGG) and Diffuse Intrinsic Pontine Glioblastoma (DIPG), have not advanced much and they continue to carry a very poor prognosis. These brain tumours are now defined by mutations affecting histone 3 proteins, indeed 80% of DIPGs harbour histone H3.1 and H3.3 K27M somatic mutations whilst 30% of pHGGs exhibit H3.3 G34R or G34V mutations. We hypothesized that the histone 3 mutant tumours will have distinct mutation specific surfactome. We therefore analysed the cell surface proteomics of pHGG and DIPG, in order to identify novel targets for therapy. We have at first isolated the cell membrane fractions from a range of patient cells carrying different histone 3 mutations (G34R, G34V, K27M), relative to wild type histone 3. A comparative quantitative mass-spectrometry analyses of these cell surface membrane fractions is then performed to identify specific targetable factors, which can be then be used for tumour specific precision-therapy. Results of these experiments will be presented.
HGG-48. ROS1 INHIBITOR ENTRECTINIB USE IN RELAPSE/REFRACTORY INFANTILE GLIOBLASTOMA WITH POSITIVE ROS1 FUSION - A CASE REPORT WITH PROMISING RESPONSE
Authors: Ku Dennis Tak-Loi , Shing Matthew Ming-Kong , Chan Godfrey Chi-Fung , Fu Eric , Yau Ping-Wa , Luk Chung-Wing , Cheng King-Fai , Ho Wilson Wai-Shing , Ng Ho-Keung , Po Yin-Chung , Ling Alvin Siu-Cheung 
Published: December 2020

Abstract

INTRODUCTION
Infantile glioblastoma is rare with poor prognosis. Recent molecular study for infantile hemispheric high grade glioma found its association with ALK/ROS1/NTRK/MET pathway. This suggested the potential use of targeted therapy for refractory / relapse patients. CASE: A newborn presented with apnea, CT brain showed intracranial haemorrhage. MRI then showed a left parietal tumour with bleeding and mass effect. Craniotomy achieved subtotal resection. Chemotherapy VCR/CPM alternating with CDDP/VP-16 was given for one year. Patient was stable with static residual tumour during chemotherapy. However patient developed status epilepticus two weeks after off treatment. MRI showed significant tumour progression which required 2nd & 3rd debulking surgery. Molecular assay by nanostring panel showed BRAF-KIAA1549 fusion. MEK inhibitor Trametinib was tried for 3 months and stopped as disease progression. Further molecular assay by RNASeq showed presence of ROS1 fusion (ZCCHC8-ROS1) while absent of BRAF fusion. Patient underwent 4th debulking surgery as impending herniation while waiting for the targeted therapy. It was complicated with right hemiplegia and facial nerve palsy postoperatively. Finally, ROS1 inhibitor Entrectinib was started 2 weeks later. It was well tolerated without significant adverse reaction. Patient made dramatic neurological recovery including improved facial nerve palsy, able to walk unaided and self feed. MRI brain 1 and 3 months after Entrectinib showed interval reduction in residual tumour. Patient is currently progression-free for 6 months.

CONCLUSION
Early molecular study for infantile glioblastoma is useful to guide novel therapy. Molecular result may varies between different panels or change over time, to be interpreted with caution.
HGG-52. SUSTAINED RESPONSE TO CRIZOTINIB MONOTHERAPY IN AN INFANT WITH GOPC-ROS1 FUSED CONGENITAL HEMISPHERIC GLIOMA
Authors: Lulla Rishi , Svokos Konstantina , Pelton Kristine , Anthony Douglas , Touat Mehdi , Ligon Keith L 
Published: December 2020

Abstract
Recent studies identified the presence of ALK/ROS/NTRK/MET alterations in a subset of infantile hemispheric gliomas. We report a case of GOPC-ROS1 fused congenital hemispheric glioma with a sustained response to crizotinib. An infant born at 28 weeks gestation was diagnosed with a large hemispheric mass at 2 weeks of life. The tumor was partially resected at 7 weeks of life. Histological evaluation confirmed a neoplasm with a spindle cell growth pattern, hypercellularity, nuclear pleomorphism, endothelial proliferation and necrosis consistent with glioblastoma. Fresh tissue was submitted for targeted panel sequencing (Oncopanel) which identified the presence of a GOPC-ROS1 fusion (exon 36:intron 4). This was confirmed by copy number analysis which showed a focal intragenic deletion with a breakpoint in ROS1 on 6q22. Given the lack of preclinical native models for ROS1 and other congenital kinase-driven gliomas, live cells were utilized to attempt to establish a patient derived cell line (organoid/neurosphere model) and intracranial patient derived xenograft model, the results of which are pending and will be reported. The GOPC-ROS1 rearrangement was structurally predicted to respond to kinase inhibitors with activity against ROS1 and crizotinib was started at 280 mg/m2/dose twice daily at 6 months of life with progressive tumor noted on imaging. Three months after initiating therapy, a 56% reduction in the tumor size and subsequent imaging revealed additional response. Our report is the first to demonstrate clinical response to crizotinib in a GPOC-ROS1 fused congenital glioblastoma and describe the development of a renewable resources for future analysis.
IMG-05. INITIAL RADIOGRAPHIC ASSESSMENT OF DWI AND ADC VALUES IN CHILDREN AND YOUNG ADULTS TREATED WITH DAY101 (TAK-580) FOR RECURRENT LOW-GRADE GLIOMAS (LGG) HARBORING MAPK ALTERATIONS
Authors: Krzykwa Emily , Korn Ronald L , Blackman Samuel C , Wright Karen D 
Published: December 2020

Abstract

BACKGROUND
Apparent diffusion coefficient (ADC) is a quantitative measure reflecting observed net movement of water calculated from a diffusion-weighted image (DWI), correlating with tumor cellularity. The higher cellularity of high-grade gliomas results in diffusion restriction and reduced ADC values, whereas the lower cellularity of low-grade gliomas (LGGs) gives higher ADC values. Here we examine changes in ADC values in patients with LGGs treated with the type 2 RAF inhibitor DAY101 (formerly TAK580).

METHODS
Historical, baseline, and on-treatment brain MRIs for 9 patients enrolled on a phase 1 study of DAY101 in children and young adults with radiographically recurrent or progressive LGG harboring MAPK pathway alterations were obtained, de-identified and independently evaluated for ADC changes. Time points included baseline, first follow-up, and best response. Data processing of ADC estimates was performed using pmod molecular image software package. ADC changes were displayed as a histogram with mean values. Results were based upon a single read paradigm.

RESULTS
There was a clear shift to lower ADC values for the solid component of tumors, reflecting changes in cellularity and tissue organization, while necrosis correlated with a shift toward higher ADC values. DWI reveals reduced ADCs in responding tumors, with the percent change in ADC from baseline correlating with deeper RANO responses.

CONCLUSION
DWI analysis reveals reductions in ADC values that correlates with treatment response and a shift toward more normal cellularity in tumors treated with DAY101. Changes in ADC may represent a novel imaging biomarker, reflecting biological response to DAY101 treatment.
IMG-13. MRI-BASED RADIOMICS PROGNOSTIC MARKERS OF POSTERIOR FOSSA EPENDYMOMA
Authors: Tam Lydia , Yecies Derek , Han Michelle , Toescu Sebastien , Wright Jason , Mankad Kshitij , Ho Chang , Lober Robert , Cheshier Samuel , Vitanza Nick , Fisher Paul , Hargrave Darren , Jacques Tom , Aquilina Kristian , Grant Gerald , Taylor Michael , Mattonen Sarah , Ramaswamy Vijay , Yeom Kristen 
Published: December 2020

Abstract

PURPOSE
Posterior fossa ependymomas (PFE) are common pediatric brain tumors often assessed with MRI before surgery. Advanced radiomic analysis show promise in stratifying risk and outcome in other pediatric brain tumors. Here, we extracted high-dimensional MRI features to identify prognostic, image-based, radiomics markers of PFE and compared its performance to clinical variables.

METHODS
93 children from five centers (median age=3.3yrs; 59 males; mean PFS=50mos) were included. Tumor volumes were manually contoured on T1-post contrast and T2-weighted MRI for PyRadiomics feature extraction. Features include first-order statistics, size, shape, and texture metrics calculated on the original, log-sigma, and wavelet transformed images. Progression free survival (PFS) served as outcome. 10-fold cross-validation of a LASSO Cox regression was used to predict PFS. Model performance was analyzed and concordance metric (C) was determined using clinical variable (age at diagnosis and sex) only, radiomics only, and radiomics plus clinical variable.

RESULTS
Six radiomic features were selected (all T1): 1 first-order kurtosis (log-sigma) and 5 texture features (3 wavelet, 2 original). This model demonstrated significantly higher performance than a clinical model alone (C: 0.69 vs 0.58, p&lt;0.001). Adding clinical features to the radiomic features didn’t improve prediction (p=0.67). For patients with molecular subtyping (n=48), adding this feature to the clinical plus radiomics models significantly improved performance over clinical features alone (C = 0.79 vs. 0.66, p=0.02). Further validation and model refinement with additional datasets are ongoing.

CONCLUSION
Our pilot study shows potential role for MRI-based radiomics and machine learning for PFE risk stratification and as radiographic biomarkers.
IMG-19. RADIOMICS AND SUPERVISED DEEP LEARNING TO PREDICT MOLECULAR SUBGROUPS IN MEDULLOBLASTOMA BASED ON WHOLE TUMOR VOLUME LABELING: A SINGLE CENTER MULTIPARAMETRIC MR ANALYSIS
Authors: Voicu Ioan Paul , Chiacchiaretta Piero , Caulo Massimo , Miele Evelina , Carboni Alessia , Carai Andrea , Diomedi-Camassei Francesca , Rossi Sabrina , Cacchione Antonella , Del Baldo Giada , Ferretti Elisabetta , Mastronuzzi Angela , Tomà Paolo , Colafati Giovanna Stefania 
Published: December 2020

Abstract

PURPOSE
Medulloblastoma (MB) is a complex pathology. Four molecular subgroups have been unveiled (Wingless-WNT, Sonic Hedgehog-SHH, Group 3-G3 and Group 4-G4), characterized by significant differences in patient clinical outcome. We investigated the utility of a radiomic analysis to predict molecular subgroups in patients with MB.

MATERIALS AND METHODS
We retrospectively evaluated 42 patients with histological diagnosis of MB, known molecular subgroup, and diagnostic MRI scan performed in our Institution on a 3 Tesla magnet. For each patient, FLAIR, ADC, T2 and contrast-enhanced MPRAGE sequences were analysed. Solid tumor volumes were segmented semiautomatically. 107 features were extracted for each sequence (Pyradiomics, Python). Features were tested for stability against labelling variations, selecting those presenting Intraclass Correlation Coefficient (ICC)&gt;0.9 across all labelling variations and all sequences. Among the remaining features, relevant features were selected with an all-relevant wrapper algorithm (Boruta, R). Remaining features were used to predict MB subgroup with a Random Forest algorithm(R). The most relevant features were ranked based on Gini index (R).

RESULTS
83/107 features presented ICC &gt;0.9 for all sequences. Boruta selected 10 features. Classification analysis yielded an out-of-bag (OOB) error rate of 0.6%, (99.4% accuracy). The most relevant features for classification were “simple” first-order features such as volume, major axis or shape.

CONCLUSION
This radiomic study yielded robust features, which showed high accuracy in predicting the molecular MB subgroups. Random forest algorithms are ideal for multiclass classification (eg. MB subgroups) and are intrinsically suited against overfitting. The most relevant for molecular classification were first-order features.
IMMU-05. B7-H3-SPECIFIC CAR T CELLS HAVE POTENT ANTI-TUMOR ACTIVITY IN THE GL261 IMMUNE-COMPETENT MURINE BRAIN TUMOR MODEL
Authors: Haydar Dalia , Yi Zhongzhen , DeRenzo Chris , Gottschalk Stephen , Krenciute Giedre 
Published: December 2020

Abstract

BACKGROUND
We and others have identified B7-H3 (CD276) as a promising target for CAR-based immunotherapies for pediatric brain tumors. So far, B7-H3-CAR T cells have only been studied in xenograft models for brain tumors, which do not recapitulate the immunosuppressive tumor microenvironment (TME). To overcome this obstacle, we decided to adapt the immune-competent GL261 murine glioma model which mimics human disease and host immune barriers.

METHODS
To evaluate the safety and efficacy of antigen-specific CAR T cells, murine B7-H3-CAR T cells were generated using retroviral particles encoding 2nd generation B7-H3-specific CD28.z CAR. Expansion, persistence, and anti-tumor activity were evaluated in vitro and in vivo. Components of the brain TME were then evaluated using flow cytometry and immunostaining.

RESULTS
B7-H3-CAR T cells only killed B7-H3+ tumor cells, secreted significant levels of IFNγ and IL-2 in an antigen-dependent manner and expanded an average of 33-fold in repeat stimulation assay with B7-H3+ tumor cells in contrast to control CAR T cells. In vivo, intratumoral injection of B7-H3-CAR T cells into orthotopic GL261 glioma induced complete regression in 60% of treated mice. Preliminary studies show numerous infiltration of suppressive tumor-associated macrophages within the tumor and its periphery.

CONCLUSIONS
In summary, we successfully generated murine B7-H3-CAR T cells and have demonstrated that these cells have potent anti-tumor activity in the immune-competent GL261 glioma model. However, it is likely that the tumor-associated macrophages are mediating immunosuppressive effects on B7-H3-CAR T cells. Therefore, studies focusing on TME/CAR T cell interactions are in progress.
IMMU-11. LOCOREGIONAL DELIVERY OF TRANSIENT GD2 CAR T CELLS FOR SAFE AND EFFECTIVE TREATMENT OF DIPG
Authors: Foster Jessica , Griffin Crystal , Stern Allison , Brimley Cameron , Smith Tiffany , Storm Phillip , Resnick Adam 
Published: December 2020

Abstract
Diffuse intrinsic pontine glioma (DIPG) is a universally fatal pediatric brain tumor with a median survival of one year. Recently Mount et al (Nat Med 2018) discovered the disialoganglioside GD2 is present at high levels on the surface of DIPG and can be targeted using GD2-directed CAR T cells. However, permanently expressed CAR T cells created by lentiviral transduction resulted in a significant number of deaths from tumor swelling with uncontrolled T cell proliferation. We hypothesized that using mRNA to create transient GD2-directed CAR T cells delivered locally with repeated dosing would result in a safer yet equally effective way to treat DIPG using CAR T cell therapy. In vitro studies using mRNA GD2-directed CAR T cells resulted in robust tumor cytotoxicity and T cell degranulation across a panel of six DIPG cell lines. Using an orthotopic murine model of SU-DIPGXIIIP*, an extremely aggressive model, we delivered of a single dose of two million mRNA GD2-directed CAR T cells locoregionally to the pons via stereotactic injection. The mRNA GD2-directed CAR T cells resulted in no toxic deaths of the mice. In addition, a single dose of mRNA CAR T cells targeting GD2 prolonged survival of the mice by a median of six days (p&lt;0.05). Ongoing studies using an indwelling catheter for repeated dosing of mRNA CAR T cells are currently underway and results expected at the time of presentation. This work will form of the basis of an mRNA CAR T cell trial targeting GD2 for patients with DIPG.
IMMU-12. PHASE I/II TRIAL OF IMMUNOTHERAPY WITH FUSIONS OF DENDRITIC CELLS AND TUMOR CELLS FOR RELAPSED OR REFRACTORY BRAIN TUMORS IN CHILDREN AND YOUNG ADULTS
Authors: Yamaoka Masayoshi , Akasaki Yasuharu , Takei Jun , Akiyama Masaharu , Tasaki Tetsunori , Ohashi Toya , Ida Hiroyuki , Yanagisawa Takaaki 
Published: December 2020

Abstract

BACKGROUND/OBJECTIVES
Relapsed or refractory brain tumors in childhood continue to have a dismal prognosis in spite of intensive multidisciplinary treatment. Cancer immunotherapy is newly developed to be expected as next promising treatment for highly aggressive pediatric cancer. This trial was designed to evaluate the safety and effectiveness of an immunotherapy with fusions of dendritic cells (DCs) and tumor cells in patients with malignant brain tumors.

METHODS
Patients with histopathologically confirmed malignant and recurrent/refractory brain tumor were eligible for this immunotherapy trial. Autologous cultured tumor cells obtained from surgical specimens were fused with autologous DCs using polyethylene glycol. The fusion cells (FC) were inoculated intradermally in the cervical region and repeated 3–10 times in each 28–84 days cycle. Treatment-related toxicity, progression-free survival (PFS), and overall survival (OS) were evaluated.

RESULTS
Six patients were enrolled, three with high grade glioma and three with ependymoma. Median age at first course of immunotherapy was 10 years (range 8–25 years) and median follow-up time from the first course of immunotherapy was 13.5 months (range 3–33 months). All patients with immunotherapy were well tolerated to this treatment with no adverse events except local erythema in injected site. Median progression free survival and overall survival were 18 months and 18.5 months, respectively.

CONCLUSIONS
FC immunotherapy with autologous DCs and tumor cells for brain tumor in children and young adults were extremely well tolerated and showed encouraging responses in this series. Further phase II study of FC immunotherapy is planned to improve survival and reduce treatment related morbidity.
IMMU-14. IMMUNE CHECKPOINT INHIBITOR THERAPY FOR TREATMENT OF SYNCHRONOUS CANCERS IN PAEDIATRIC PATIENTS WITH CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY
Authors: Henderson Jacob , Morgenstern Daniel , Edwards Melissa , Sudhaman Sumedha , Kram David , Osborn Michael , Cho Yoon-Jae , Tabori Uri 
Published: December 2020

Abstract
Constitutional mismatch repair deficiency (CMMRD) is an autosomal recessive condition in which affected patients carry biallelic germline mutations in the MMR genes. This highly penetrant syndrome results in nearly universal development of malignant neoplasms at a young age, most commonly pediatric brain tumors. Importantly, in addition to brain tumors, patients frequently develop multiple metachronous or even synchronous tumors making it impossible to treat these cancers with current chemotherapeutic approaches due to the complexity of different chemoradiation regimens required, resulting in excess toxicity and lack of efficacy. We first, assessed the metachronous (defined here as serial tumors diagnosed &gt;1 year apart or after completion of definitive treatment for the initial tumor) or synchronous cancers (defined here as tumors diagnosed within a year of each other or during the definitive treatment for the initial tumor) in all patients within the consortium. Strikingly, 47% developed synchronous and/or metachronous cancers leading to patient demise. Molecular analysis revealed that all synchronous tumors (n=26) harbored a hypermutational burden accompanied by high genomic microsatellite instability and the relevant signatures. We therefore treated two patients with glioblastomas who had synchronous solid tumors with checkpoint inhibitors. In both patients, objective tumor response was associated with clinical benefit and prolonged survival. Biomarker analysis revealed increased tumor mutational burden, microsatellite instability and immune cell infiltration. These cases highlight the role of universal, mechanism based and tumor-agnostic approach to treat patients with brain tumors with additional synchronous cancers in the setting of cancer predisposition.
IMMU-15. PROTEOGENOMIC DISCOVERY OF NOVEL TUMOR PEPTIDES AS NEOANTIGENS FOR PERSONALIZED T CELL IMMUNOTHERAPY IN MEDULLOBLASTOMA
Authors: Rivero-Hinojosa Samuel , Grant Melanie , Panigrahi Aswini , Zhang Huizhen , Caisova Veronika , Bollard Catherine , Rood Brian 
Published: December 2020

Abstract
T cell immunotherapies are promising new tools to combat high-risk subgroups of medulloblastoma without increasing the late effects burden. The ideal target antigen of an effective antitumor T-cell response is abundantly expressed by tumor cells but not by normal tissues, in order to limit off-target effects. Tumors translate a host of highly novel transcripts that are the result of aberrations in tumor DNA and the unmasking of alternative or novel exons. We developed a novel proteogenomic approach to identify tumor-restricted peptides and used them to select and expand T cells capable of mounting a tumor-specific cytotoxic immune response. Using RNA-seq and WGS data, we created personalized custom searchable databases containing predicted novel proteins from somatic mutations, novel junctions and fusion transcripts from 56 medulloblastoma tumors. By searching these databases with raw mass spectrometry data from paired medulloblastoma tumors, we identified tens of neoantigen peptides arising from the translation of tumor-specific transcripts; novel isoforms being the predominant source. We tested these peptides for their ability to select and expand autologous polyclonal populations of T cells and tested the immunogenicity of each individual peptide. Flow cytometry revealed populations of CD4+ and CD8+ cells with an activation profile marked by IFN-γ and TNF-α. Immunosuppressive marker profiles were also characterized. Using cytotoxicity assays, we demonstrated that tumor specific T cells can eliminate neoantigen bearing tumor cells. Thus, proteogenomics can identify immunogenic tumor specific peptides that can be used to create a personalized, targeted T cell therapy for children with high risk medulloblastoma.