bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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

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<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

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)>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 >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

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

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<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

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

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 >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

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.
IMMU-19. HDAC INHIBITORS SENSITIZE MYC-AMPLIFIED MEDULLOBLASTOMA TO IMMUNOTHERAPY BY ACTIVATING THE NF-kB PATHWAYS
Authors: Marquardt Viktoria , Theruvath Johanna , Pauck David , Picard Daniel , Reifenberger Guido , Borkhardt Arndt , Cheshier Samuel , Kurz Thomas , Remke Marc , Mitra Siddhartha
Published: December 2020

Medulloblastoma is the most common malignant brain tumor in childhood and comprises four distinct molecular subgroups with further layers of intertumoral heterogeneity. Amplification of the oncogene MYC drives tumorigenesis and constitutes a hallmark feature underlying Group 3 biology. Employing our in-house drug screening pipeline, we evaluated a library of epigenetic inhibitors (n=78) in various brain tumor cell lines followed by a secondary HDACi library (n=20) screen, we identified the clinically established, class I selective HDACi CI-994 as the compound with the most preferential antitumoral effect in MYC-driven medulloblastoma. We confirmed that the inhibitor response was in part MYC-dependent as our lentiviral-based MYC-overexpression model showed higher sensitivity towards CI-994 treatment as compared to the isogenic control with low endogenous MYC expression. CI-994 showed significant antitumoral effects at the primary site and at the metastatic compartment in two orthotopic mouse models of MYC-driven medulloblastoma. RNA sequencing profiling of tumor cells treated with CI-994 at IC50 revealed an up-regulation of multiple innate inflammatory pathways like NFκB, TLR4, Interferon-gamma, and TGFbeta. Flow cytometry analysis revealed an increased surface expression of MHC-I. We combined CI-994 with an anti-body against the innate checkpoint CD47 which acts as a “don’t eat me” signal previously shown by us to have significant anti-tumor activity against MYC-driven MB. Combining CI-994 with anti-CD47 shows a significant increase in macrophage-mediated phagocytosis of tumor cells and a significant increase in the survival of tumor-bearing mice.
LGG-18. EVEROLIMUS TREATMENT IN PEDIATRIC PATIENTS AFFECTED BY LOW-GRADE GLIOMAS (pLGG) NON-TSC, BRAF v600-WT
Authors: Cacchione Antonella , Miele Evelina , Lodi Maria Chiara , Carai Andrea , Colafati Giovanna Stefania , Camassei Francesca Diomedi , Locatelli Franco , Mastronuzzi Angela
Published: December 2020

BACKGROUND

MAPK pathway is the hallmark of pediatric low grade gliomas (pLGGs); hyperactivation of mTOR (mammalian target of rapamycin) might be a suitable biomarker for therapeutic response. We investigated the feasibility of Everolimus, mTOR inhibitor, in patients affected by pLGGs.

METHODS

Patients 1 to 18 years old, diagnosed with pLGG, with a positive tumor biopsy for mTOR/phospho-mTOR and radiological and / or clinical disease progression, treated at Bambino Gesù Children’s Hospital in Rome were evaluated. Tumor DNA methylation analysis was performed in 10 cases. Exclusion criteria included: Tuberous Sclerosis patients, Sub Ependymal Giant Astrocytoma. Everolimus was administered orally at a dose of 2.5 mg or 5 mg daily based on body weight. Patients were evaluated with brain MRI every 4, 8 and 12 months after treatment start and every six months thereafter.

RESULTS

16 patients were enrolled from September 2014 and 2019. The median age was 7.5 years old. All patients had at least one adverse event. Events rated as severe (grade 3/4) were reported in 6 patients. Stomatitis was the most frequent adverse event. One patient discontinued treatment due to grade 4 toxicity (ulcerative stomatitis and fatigue). The median duration of treatment was 21 months (4–57 months). Brain MRI evaluations have showed disease stability in 11 patients, partial response in 2 patients and disease progression in 3 patients.

CONCLUSIONS

Everolimus has proven to be well tolerated and effective treatment in terms of disease stability in patients with pLGGs. It’s also an excellent example of chemo-free personalized approach.
LGG-32. CLINICAL OUTCOME OF PEDIATRIC GLIOMAS IN SINGLE INSTITUTION
Authors: Uchida Hiroyuki , Higa Nayuta , Yonezawa Hajime , Oyoshi Tatsuki , Yoshimoto Koji
Published: December 2020

Gliomas in children are rarer than in adult, then treatment strategies might vary from facility to facility. We report clinical features and outcome of pediatric glioma in our institution. Twenty-nine patients diagnosed with glioma, exclude ependymoma, 14 boys and 15 girls, among 98 pediatric brain tumor patients treated at Kagoshima University Hospital since 2006 were reviewed histopathology, extent of resection, adjuvant therapy and outcome, etc. Mean age at surgery was 10.4 (S.D. 5.6) years. Median follow-up period was 19.1 months. Histopathological diagnosis comprised 8 pilocytic astrocytoma, 3 ganglioglioma, 2 subependymal giant cell astrocytoma, 5 WHO grade Ⅱ astrocytoma, 8 glioblastoma, and desmoplastic infantile astrocytoma, anaplastic astrocytoma and astroblastoma were one case each. Tumor resection was performed in 24 cases, and 5 cases underwent biopsy. Chemotherapy was performed in 15 cases and irradiation was performed in 9 cases. Out of 5 WHO grade Ⅱ astrocytoma cases, 2 cases underwent biopsy following chemotherapy, 1 case underwent biopsy only and other 1 case underwent total resection. The four cases show long survival ranged from 71 to 136 months without irradiation. All of eight glioblastoma cases show poor prognosis ranged from 8.6 to 26.7 months regardless of chemo-radiotherapy. In management for pediatric brain tumor patients, irradiation is often laid over until recurrence. In WHO grade Ⅱ astrocytoma, the treatment strategy might be reasonable using appropriate chemotherapy even though biopsy cases.
LGG-47. SYSTEMIC THERAPY OF ROSETTE-FORMING GLIONEURONAL TUMOR OF THE FOURTH VENTRICLE INAN ADOLESCENT
Authors: McNall-Knapp Rene , Gross Naina , Zaky Wafik , Cornwell Benjamin , Gavula Theresa , Bavle Abhishek
Published: December 2020

An 11 y.o. female presented to a GI specialist with complaints of morning vomiting and periumbilical abdominal pain for several months. Had progressing symptoms with GI work-up for ~1 year. She developed diplopia and worsening headaches. Imaging revealed a T2/FLAIR hyperintense mass in the 4th ventricle with heterogeneous enhancement and obstructive hydrocephalus. Three T2 bright, non-enhancing, subcentimeter masses identified in the right cerebellum. Due to poor differentiation between tumor and normal tissue at brainstem, only partial resection (PR) was feasible. Pathology initially called pilocytic astrocytoma (PA). All symptoms resolved after PR. Slow progression in the tumor and “satellite” lesions noted over two years. Second opinion and molecular typing reclassified the tumor as rosette-forming glioneuronal tumor (RFGNT) with a mutation in PIK3CA. Therapy started with vinblastine and carboplatin with stable disease x 7 months, discontinued due to allergic reaction to carboplatin. Initiated therapy with everolimus, an mTOR inhibitor. The tumor’s characteristics on imaging changed with initial growth and increase in peripheral enhancement in one satellite and the primary tumor. Nevertheless, we persevered. When comparing pre-treatment MRI to most recent 7 months later, there has been an overall decrease in volume of expansile heterogenous tumor along the margins of the fourth ventricle. The degree of peripheral enhancement associated with the mass has increased. RFGNT is a rare tumor included in WHO classification since 2007. Ellezam et al identified recurrent PIK3CA mutations. To our knowledge, this is the only report of treatment targeting the mutation. We report a radiographic response despite initial growth.
LGG-50. INTEGRATED MOLECULAR AND CLINICAL ANALYSIS OF 1,000 PEDIATRIC LOW-GRADE GLIOMAS UNCOVERS NOVEL SUBGROUPS FOR CLINICAL RISK STRATIFICATION
Authors: Tabori Uri , Ryall Scott , Zapotocky Michal , Bennett Julie , Nobre Liana , Ellison David , Santi Mariarita , Karajannis Matthias , Hawkins Cynthia
Published: December 2020

Pediatric low-grade gliomas (pLGG) are primarily driven by genetic alterations in the RAS/MAPK pathway, most commonly involving BRAF of NF1. Despite their molecular convergence, pLGG often show unexplained variability in their clinical outcome. To address this, we molecularly characterized a cohort of >1,000 clinically annotated pLGG. 84% of cases harbored a detectable driver mutation. The remaining 16% of patients nonetheless showed RAS/MAPK pathway up-regulation at the RNA level. The clinical presentation and outcome of pLGG appeared highly variable and linked to the alteration type: re-arrangement or SNV. Re-arrangement-driven tumors were diagnosed at a younger age (6.6 versus 10.9 years, p<0.0001), enriched for WHO grade I histology (88% versus 66%, p<0.0001), infrequently progressed (27% versus 46%, p<0.0001), and rarely resulted in death (3 versus 13%, p<0.0001) as compared to SNV-driven tumors. These included the rarest molecular drivers of pLGG, for which we now have the clinicopathologic features of including MYB, MYBL1, FGFR2 fusions, FGFR1-TACC1, FGFR1 SNVs, IDH1 p.R132H, and H3.3 p.K27M. Utilizing this information, we suggest novel risk categories of pLGG that effectively predicted patient outcome. Low-risk tumors progressed infrequently and rarely succumbed to their disease (10-year PFS of 71% and OS of 98%). Intermediate-risk pLGG had a 10-year PFS and OS of 35% and 90%, respectively. High risk pLGG almost invariably progressed (10-year PFS of 0%) and these patients often succumbed to their disease (10-year OS of 41%). These data highlight the biological and clinical differences between pLGG subtypes and offers molecular based risk stratification to these cancers.
LGG-51. BRAF ALTERATIONS IN PEDIATRIC LOW-GRADE GLIOMAS: RESULTS FROM A BRAZILIAN COHORT
Authors: Restine Felipe , Sakamoto Luis Henrique , Real Juliana Monte , Pereira Gregorio , Fernandes Jennifer Marx , Aguiar Simone dos Santos , Epelman Sidnei
Published: December 2020

BACKGROUND

Pediatric low grade gliomas (PLGG) are the most common central nervous system neoplasms in children. These are driven almost exclusively by alterations in the RAS/MAPK pathway. Specifically, alterations in the BRAF gene have emerged as an important target for therapy. This study aimed to identify the frequency of BRAF alterations in a Brazilian cohort of PLGGs.

RESULTS

Forty-one patients diagnosed between 2001 and 2017 had enough FFPE tissue available for analysis. Real-time PCR test (n=35) was used to assess for BRAFV600E mutations, while BRAF fusions were detected by break-apart fluorescence in situ hybridization (n=30). The histologic distribution was as follows: 73% pilocytic astrocytoma, 12% ganglioglioma, 3% diffuse astrocytoma, 5% pleomorphic xanthoastrocytomas (PXA) and 7% NOS (n = 41). BRAF fusions were present in 21 patients (51%): 17 pilocytic astrocytomas, 2 xanthoastrocytoma, 1 pilomyxoid astrocytoma and 1 diffuse astrocytoma. BRAFV600E was detected in 4 cases (10%): 2 pilocytic astrocytomas, 1 ganglioglioma and 1 PXA. As expected, BRAF translocations were more frequent in pilocytic astrocytomas (p<0.001). From 22 patients treated in our institution, 59% were male with a mean age of 9.7 years, 50% occurred in the posterior fossa and 77% treated by surgery only. One patient relapsed and died from disease (BRAF V600E positive) (follow-up median=44.7 months). These are the first results using a CLIA method showing the frequency of BRAF abnormalities in a Brazilian population. Although preliminary, BRAF alterations are present in 61% of the cases emphasizing the importance of incorporating this analysis in the current work-up guidelines.
LGG-53. PNOC001 (NCT01734512): A PHASE II STUDY OF EVEROLIMUS FOR RECURRENT OR PROGRESSIVE PEDIATRIC LOW-GRADE GLIOMAS (pLGG)
Authors: Mueller Sabine , Aboian Mariam , Nazemi Kellie , Gauvain Karen , Yoon Janet , Minturn Jane , Leary Sarah , AbdelBaki Mohamed S , Goldman Stewart , Elster Jennifer , Resnick Adam , Molinaro Annette M , Phillips Joanna , Prados Michael , Haas-Kogan Daphne
Published: December 2020

OBJECTIVE

To estimate the 6-month Progression Free Survival (PFS6) associated with everolimus for progressive/recurrent pLGGs and to determine if activated PI3K/Akt/mTOR pathway as measured by positive phosphorylated-ribosomal protein S6 (p-RPS6) status was associated with response. METHOD: Patients 3–21 years of age with recurrent or progressive pLGG were enrolled. Everolimus was administered orally at 5 mg/m2 daily. Tissue availability for molecular analysis was mandatory. Immunohistochemistry (IHC) for p-RPS6 was performed centrally. An adaptive Simon two-stage design was employed based on p-RPS6 status. Based on results of the first stage, enrollment in the second stage was either limited to pathway activated patients or open to all subjects.

RESULTS

From December 2012 to July 2019 a total of 65 subjects enrolled [median age 9 years (range 3–19); 43% female]. As of December 15, 2019 median number of treatment cycle is 8 (range 1–24); 7 patients remain on treatment. Toxicity profile is similar to published reports with rash and elevated lipid profiles as most common adverse events. PFS6 for the entire cohort is 63%; PFS6 is 64% for the activated and 61% for the non-activated patients. Central imaging review (n=52) revealed 1 partial response, 1 complete response, 33 stable disease, and 17 progressive disease at the end of study treatment. Initial molecular analysis identified BRAF alterations in 35/65 patients.

CONCLUSION

Everolimus is well tolerated and active in a subset of pLGGs. Ongoing analyses will assess predictive biomarkers of response and will be reported at the meeting.
LINC-02. IMPLEMENTATION OF AN INTEGRATED NEURO-ONCOLOGY SERVICE: CLINICIANS’ PERSPECTIVE ON CONDUCT OF NEURO-ONCOLOGY MULTIDISCIPLINARY TEAM MEETING FROM A SINGLE-INSTITUTION IN MALAYSIA
Authors: Foo Jen Chun , Vida Jawin , Hany Ariffin , Loh Pei Yuin , Sutharsan Sockalingam , Dharmendra Ganesan , Chandran Thambinayagam Hari , Revathi Rajagopal
Published: December 2020

INTRODUCTION

Multidisciplinary Team (MDT) meetings are essential in the management of complex cancer cases. There are limited data regarding clinicians’ perception on conduct of neuro-oncology MDT meetings and its impact on clinical management. In University Malaya Medical Centre (UMMC), weekly neuro-oncology MDT meeting was established since 2013 to discuss adult and paediatric complex central nervous system tumour cases.

OBJECTIVE

To determine clinicians’ perception and level of satisfaction of neuro-oncology MDT meeting.

METHODOLOGY

Web-based questionnaire was distributed via e-mail to all neuro-oncology MDT clinicians at UMMC in April 2019.

RESULT

Eighteen out of 20 clinicians responded to the survey. Respondents were: neurosurgeons (n=5), adult oncologists (n=4), paediatric oncologists (n=3), radiologists (n=2), radiation oncologists (n=2) and pathologists (n=2). Majority of clinicians (65%) agreed at current weekly MDT meeting with maximum length of one hour duration and 75% of them suggested to discuss 5 to 10 cases during each meeting. Almost all of them (94.4%) preferred e-mail as method of communication to disseminate information before and after the meetings. MDT members expected 100% attendance from neurosurgeons. Fourteen (70%) clinicians agreed that patients/ parents/ carers do not receive copy of MDT meeting plans and only seven (35%) clinicians document MDT meeting plans in patients’ medical record. Overall, all clinicians felt that MDT meeting improved decision-making process, enhanced continuity of coordinated care and promoted good communication among team members.

CONCLUSION

The structure and logistics of neuro-oncology MDT meeting in UMMC are generally agreed upon. However, documentation of post-meeting plan and notification to patients need uniformity.
LINC-12. COMBINED ADULT AND PAEDIATRIC NEURO-ONCOLOGY LONG-TERM SURVIVOR CLINIC EXPERIENCE FROM A TERTIARY CANCER CENTRE IN A LOW-MIDDLE-INCOME COUNTRY
Authors: Krishnatry Rahul , Prasad Maya , Chinnaswamy Girish , Chaterjee Abhisheik , Goda Jayant , Sridhar Epari , Moiyadi Aliasgar , Shetty Prakash , Saha Arushi , Singh Vikas , Golambade Nayana , Gupta Tejpal
Published: December 2020

NeuroOncology survivor clinics (NOS) is uncommon in low-middle-income countries. We started combined (paediatric and adult) NOS clinic in our tertiary a cancer centre (Jan-2017) and review here the demographic, clinical-pathological and treatment spectrum for our paediatric (0-18years) and adult (>18years) survivors (>5years since their initial diagnosis) till date. Of total 312 patients registered, 198 (63.5%) were adults while 114 (36.5%) were paediatric at-diagnosis with median age (IQR) at presentation: 34 (23–41) and 9(6 – 13) years respectively. In both groups, only 33% were females. The median (IQR) time since diagnosis was 9 (9–14) and 8 (6–12) years respectively with 60% of paediatric turning into adult survivors. The commonest paediatric tumours were glioma (52, 45.6%), embryonal (34, 29.8%), and ependymoma (12, 10.5%) versus gliomas (114, 57.6%) and benign tumours (42, 21.2%) in adults. The low-grade-glioma comprised 90.4% of all pediatric gliomas and intermediate-grade (90%) in adults. The primary treatment consisted of radiotherapy and chemotherapy in 95% and 43% versus 99% and 36% in adults versus paediatric patients respectively. Temozolomide and multi-drug combinations were the commonest chemotherapy used in adults and paediatrics respectively. Relapse and retreatments were seen in 16.6 and 14% of adults and paediatric patients. There were two deaths each in each group since registration (median 12 months). Although the baseline diagnosis/treatment characteristics are different, survivors of both group had a similar number of retreatments and deaths. Combined survivor clinics may present an interesting and unique opportunity to learn and provide challenging service in this part of the world.
LINC-16. MEDULLOBLASTOMA IN A BOY WITH RUBINSTEIN-TAYBI SYNDROME: A CASE REPORT
Authors: del Campo Regina M Navarro-Martin , Soto-Mancilla Juan Luis , Arredondo-Navarro Luis A , Orozco-Alvarado Ana L , Sanchez-Zubieta Fernando A
Published: December 2020

BACKGROUND

Rubinstein–Taybi syndrome (RTS) is characterized by multiple congenital anomalies and associated with mutations in CREBBP (70%) and EP300 (5–10%). Previous reports have suggested an increased incidence of benign and possibly also malignant tumors, but the correlation remains unclear. Here we present a case of a patient with RTS and medulloblastoma. CLINICAL CASE: A 5-year-old male presented with increased intracranial pressure. An MRI revealed a 4.2 x 4.7 cm mass in the midline of cerebellum arising from the floor of 4th ventricle. The patient underwent a complete resection and pathology revealed medulloblastoma, classic histology. Staging established no disseminated disease. At diagnosis, a peculiar phenotype consisting in mild mental retardation, microcephaly, down-slanting palpebral fissures, broad nasal bridge, highly arched palate, mild micrognathia, screwdriver incisors and wide thumbs and toes was noted. Clinical genetics evaluation was consistent with RTS. Karyotype was performed and normal. Further genetics testing was not done. Treatment consisted in 8 cycles of chemotherapy and craniospinal radiation (2300 cGy to spine, 5500 cGy Total). At the end of treatment, there was no evidence of disease. He was under surveillance for 33 months free of disease, but relapsed with a supratentorial meningeal disease that ultimately resulted in death.

CONCLUSION

This report highlights the fact that pediatric medulloblastoma can be associated to RTS, in this case associated to classical histology and recurrent disease.
LINC-19. CURRENT SITUATION OF PEDIATRIC TUMORS OF CENTRAL NERVOUS SYSTEM IN CHINA - THE FIRST CNOG NATIONAL WIDE REPORT
Authors: Ma Jie ,   CNOG (Children’s Neuro-Oncology Group) in China
Published: December 2020

Tumors of Central Nervous System (CNS) are most seen solid tumor in childhood. Accounting approximate 25–30% of pediatric neoplasms, treatments on these tumors are complicated as they occur in different age ranges, have various types according to classification system and contain different characteristic molecular profiles. There are huge gaps of medical services for children with CNS tumors in different regions in China, which is blamed to limited medical resources and lack of epidemiology data for Chinese population. After the establishment of CNOG (Children’s Neuro-Oncology Group) in China in 2017, national wide registry (CNOG-MC001) was conducted to collect data on the basic information about pediatric tumors of CNS. Results of 4059 cases from 37 centers providing medical services for pediatric CNS tumors in 25 provinces from 6 greater administrative areas in China showed distinct tumor ratio, compared to worldwide data by WHO classification. The mean of age was 8.01 ± 4.73, with a male vs. female ratio as 1.48 to 1. Embryonal tumor, astrocytic & oligodendroglial tumors, and other astrocytic tumors were three most common tumor types in CNS of children. The lost follow-up rate was surprisingly high as 53.07%. In all, this is the first national wide registry for pediatric CNS tumor in China and the results attracted public and government’s attentions for further epidemic investigations.
LINC-23. PRE-OPERATIVE AND POST-OPERATIVE INTERVENTIONS REDUCE RATES OF VENTRICULITIS IN PEDIATRIC BRAIN TUMOR PATIENTS: A PILOT STUDY
Authors: San Laura Melissa Stephanie Diamante - , Pedro Marciel , Alcasabas Ana Patricia , Lukban Marissa , Khu Kathleen , Legaspi Gerardo , Qaddoumi Ibrahim , Moreira Daniel
Published: December 2020

BACKGROUND

The Philippine General Hospital, a public national referral center, sees 60–80 pediatric brain tumor cases per year. Historically, the rate of post-operative ventriculitis has been high, resulting in treatment delays and poor outcomes. Starting in July 2019, as a means to decrease infections, patients were provided standardized bathing and wound care kits and caregivers were trained to follow a bathing and wound care protocol.

METHODS

This quality improvement study included patients younger than 18 years who underwent craniotomy at PGH were enrolled. The type of surgery, length of surgery, existence of post-operative CNS infection, length of stay and total cost of care was collected. The outcome of these interventions are analyzed 6 months after implementation.

RESULTS

Thirty-two 32 patients were included, with mean age of 7 years (1–16). The surgeries performed were: tumor resection (n=20), ventriculo-peritoneal shunt insertion (VPS) (n=3), endoscopic third ventriculostomy (n=3), resection with tube ventriculostomy (n=3), Ommaya reservoir placement (n=2), and resection with shunt (n=1). Median surgery time was 4 hours (1–10). Three patients (9.4%) developed ventriculitis. No surgical site infections occurred. Compared to historical controls, a lower rate of infections was noted (9.4% vs. 15.5%, runchart analysis). Patients without post-operative infections had a shorter length of stay (median 14 vs 48 days, p<0.05) and a lower cost of care (median $1098 vs. $2425 USD, p<0.05).

CONCLUSION

Implementation of simple hygiene interventions effectively lowered post-operative CNS infections and hospital costs in a public hospital setting. Incorporation of these into standard clinical practices is urgently needed.
LINC-26. ORAL VINORELBINE IN PROGRESSIVE UNRESECTABLE LOW-GRADE GLIOMA
Authors: Cappellano Andréa M , Oliveira Milena R S , Cavalheiro Sergio , Dastoli Patricia , Almeida Daniela B , Silva Frederico A , Alves Maria Teresa S , Silva Nasjla S
Published: December 2020

BACKGROUND

The management of progressive unresectable low-grade glioma (PULGG) remains controversial. Some series suggests that chemotherapy may delay or even avoid radiotherapy and/or surgery in a group of patients. Within this context, we performed at IOP/GRAACC/UNIFESP an institutional protocol with IV vinorelbine, a semi-synthetic vinca alkaloid that showed activity against PULGG. The objective of this study was to evaluate the response as long as the tolerability of oral vinorelbine in PULGG.

PATIENTS AND METHODS

From April 2013 to Aug 2017, 17 patients with recurrent (n=5) and newly-diagnosed (n=12) optic-pathway glioma (OPG) were treated with oral vinorelbine in a dose of 90 mg/m² days 0, 8 and 22 for 18 cycles. Response criteria used a combination of magnetic resonance imaging, physical and visual evaluation.

RESULTS

Mean age 8.6 years (4.8–17.9y). Three children with neurofibromatosis type 1. Eleven patients had neurosurgical intervention revealing grade I (n=8) and grade II astrocytoma (n=3). Twelve patients were assessable after 8 cycles of vinorelbine with 2 objective response (OR), 8 stable disease (SD) and 2 progressive disease (PD), one died after surgery and 1 alive in different protocol. After 18 cycles, eight patients were assessable to date for response with 1 OR, 7 SD. The most important toxicity was gastrointestinal observed in 12 patients- six of them switched to IV vinorelbine (3OR, 3SD). None of the patients showed neurotoxicity.

CONCLUSION

These results suggest that oral vinorelbine, as the IV formulation, may show some activity in OPG. However, gastrointestinal toxicity should be considered.
LINC-38. 500 CONSECUTIVE SURGICAL CASES FROM THE PEDIATRIC ONCOLOGY NEUROSURGERY GROUP: UNDERSTANDING THE PERSPECTIVE OF A TERTIARY CENTER IN BRAZIL
Authors: Sanders Felipe Hada , Matushita Hamilton , Teixeira Manoel Jacobsen
Published: December 2020

With this presentation we aim to present cases submitted to surgery by the same group of surgeons since 2010, presenting the physical structure, medical assistance, scientific production and the challenges that we need to overcome in the second decade of the twenty-first century, in a developing country.
MBCL-04. 5 – AZACYTIDINE IN TREATMENT OF CHILDREN WITH DE NOVO AND RELAPSED METASTATIC MEDULLOBLASTOMA: RESULTS OF INTERCENTER PILOT STUDY
Authors: Levashov Andrey , Khochenkov Dmitry , Stroganova Anna , Ryzhova Marina , Gorelyshev Sergey , Kadirov Shavkat , Zagidullina Svetlana , Babelyan Stepan , Subbotina Natalya , Mentkevich Georgy , Sidelnikov Dmitry , Daylidite Vidmante , Grigorenko Vasily
Published: December 2020

The aim of this study was to estimate treatment toxicity and event-free survival (EFS) according to therapeutic program, MYC/MYC-N gene amplification and MGMT/DNMT (1, 3a, 3b) proteins expression in tumor cells. From 2016 to 2018 twenty four patients were included in trial. Children underwent adjuvant therapy: craniospinal radiation (CSI) or local radiation therapy (RT) to the relapsed site up to 23.4Gy with 5-azacytidine, 2 cycles methotrexate/5-azacytidine/cisplatin/etoposide, 3 cycles 5-azacytidine/temozolomide - for relapsed group (arm A, n = 5); for patients with de novo medulloblastoma: arm B, n = 11 – vincristine/cyclophosphamide/cisplatin/etoposide (OPEC) - based induction, CSI 36Gy + local RT to the tumor bed up to 54Gy with 5-azacytidine, 1 cycle OPEC and 2 cycles thiophosphamide/carboplatin with auto stem cell transplantation (auto-SCT); arm C, n = 8 – cyclophosphamide/cisplatin - based induction, CSI 23.4 Gy followed by 2 cycles 5-azacytidine/thiophosphamide/carboplatin with auto-SCT, local RT with 5-azacytidine. The combination of 5-azacytidine with local RT or temozolomide was safety and tolerability. Arm C was discontinued due to severe gastrointestinal grade 3/4 toxicity, hemorrhagic syndrome after combination of 5-azacytidine with thiophosphamide/carboplatin. EFS was 0% in arm A, 53.0 ± 15.5%, 50.0 ± 17.7% in arms B and C, a median follow-up 8.8 ± 1.1 months (arm A), 18.8 ± 2.5 months (arm B), 25.0 ± 4.4 months (arm C). Addition of 5-azacytidine to RT or chemotherapy did not improve EFS of patients with MYC/MYC-N gene amplification positive tumor. There was not determined any prognostic significance of MGMT/DNMT (1, 3a, 3b) proteins expression in this cohort.
MBCL-07. NON-METASTATIC MEDULLOBLASTOMA OF EARLY CHILDHOOD: RESULTS FROM THE PROSPECTIVE CLINICAL TRIAL HIT-2000 AND AN EXTENDED VALIDATION COHORT
Authors: Mynarek Martin , von Hoff Katja , Pietsch Torsten , Ottensmeier Holger , Warmuth-Metz Monika , Bison Brigitte , Pfister Stefan , Korshunov Andrey , Sharma Tanvi , Jaeger Natalie , Ryzhova Marina , Zheludkova Olga , Golanov Andrey , Rushing Elisabeth Jane , Hasselblatt Martin , Koch Arend , Schüller Ulrich , von Deimling Andreas , Sahm Felix , Sill Martin , Riemenschneider Markus J , Dohmen Hildegard , Monoranu Camelia-Maria , Sommer Clemens , Staszewski Ori , Mawrin Christian , Schittenhelm Jens , Brück Wolfgang , Filipski Katharina , Hartmann Christian , Meinhardt Matthias , Pietschmann Klaus , Haberler Christine , Slavc Irene , Gerber Nicolas U , Grotzer Michael , Benesch Martin , Schlegel Paul-Gerhardt , Deinlein Frank , von Bueren André O , Friedrich Carsten , Obrecht Denise , Fleischhack Gudrun , Kwiecien Robert , Faldum Andreas , Kortmann Rolf-Dieter , Kool Marcel , Rutkowski Stefan
Published: December 2020

OBJECTIVE

To avoid craniospinal irradiation (CSI) in children younger than four years with non-metastatic medulloblastoma by chemotherapy, intraventricular methotrexate and risk-adapted local radiotherapy.

PATIENTS AND METHODS

Eighty-seven patients received systemic chemotherapy and intraventricular methotrexate. Until 2006, CSI was reserved for non-response or progression. After 2006, local radiotherapy was introduced for non-responders or classic (CMB), anaplastic or large-cell medulloblastoma (LCA). Infantile SHH-activated medulloblastomas (SHH_INF) were subdivided by DNA-methylation profiling. Survival in SHH_INF subtypes were also assessed in a validation cohort (n=71).

RESULTS

Patients with desmoplastic medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN) (n=42) had 93% 5-year PFS, 100% 5-year OS and 93% 5-year CSI-free survival. Patients with CMB/LCA (n=45) had 37% 5y-PFS, 62% 5y-OS and 39% 5y-CSI-free survival. Local radiotherapy did not improve survival in CMB/LCA patients. All DMB/MBEN assessed by DNA methylation profiling belonged to the SHH_INF subgroup. Group 3 patients (5y-PFS 36% [n=14]) relapsed more frequently than SHH_INF (5y-PFS 93% [n=28]) or Group 4 patients (5y-PFS 83% [n=6], p<0.001). SHH_INF split into iSHH-I and iSHH-II subtypes in HIT-2000-BIS4 and the validation cohort, without prognostic impact (5y-PFS: iSHH-I 73% vs. iSHH-II 83%, p=0.25, n=99). Mean IQ was 90 (radiotherapy-free survivors) vs. 74 (patients that received CSI) [p=0.012].

CONCLUSION

Systemic chemotherapy and intraventricular methotrexate led to favorable survival in both iSHH-subtypes of SHH-activated DMB/MBEN with acceptable neurotoxicity. Survival in non-WNT/non-SHH CMB/LCA patients was not improved by local radiotherapy. Survival was more favorable in patients with Group 4 than in patients with Group 3 medulloblastoma.