bluuebunny/crossref_metadata_2025_split huggingface dataset:
LGG-03. LONG-TERM FOLLOW UP OF TARGETED THERAPY IN PEDIATRIC LOW-GRADE GLIOMAS: THE DANA-FARBER/BOSTON CHILDREN’S EXPERIENCE
Authors: Tsai Jessica , Vogelzang Jayne , Sousa Cecilia , Yeo Kee Kiat , Ligon Keith , Bandopadhayay Pratiti , Cooney Tabitha 
Published: June 2021

Abstract

Background
Pediatric low grade gliomas (pLGGs) are the most common central nervous system (CNS) tumor in children and characterized by alterations in the MAPK pathway. Standard of care is not well defined, and treatment has evolved over the last decade to include molecular targeted therapies. The impact of targeted agents on the natural history of pLGGs remains unknown. We present a retrospective review of patients receiving targeted agents integrated with molecular profiling.

Methods
We performed an IRB-approved, retrospective chart review of pLGGs treated with off-label use of dabrafenib, vemurafenib, everolimus, and trametinib at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center from 2010 to 2020.

Results
Forty-nine patients were identified (dabrafenib n=9, everolimus n=27, trametinib n=10, and vemurafenib n=3). All patients receiving BRAF inhibitors harbored BRAF V600E mutation. Targeted agent was used as first-line therapy for 25% of patients, while for 31% of patients, targeted agent was second-line therapy. The median time from diagnosis to targeted therapy initiation was 4.76 years (0.10 – 23.77), median duration of targeted therapy was 0.79 years (0.01 – 4.87), median time to subsequent therapy post first-line targeted therapy was 0.2 years (0.01 – 3.33), and overall median follow-up for the entire cohort was 3.09 years (0.36 – 11.87). The 1-year, 3-year, and 5-year EFS from targeted therapy initiation was 58.0%, 32.2%, and 26.9%, respectively. Survival analyses by molecular subgroup and agent were performed. Reasons for cessation of targeted therapy included toxicities, progression, and/or planned end of therapy.

Conclusions
Further efforts are ongoing to perform volumetric analysis of growth rates before, during, and after treatment. While targeted molecular therapies show great promise, it will be critical to understand how these agents alter the natural history of pLGGs, particularly in the context of genomic profiling.
LGG-07. IS BRAF ALTERATION OR A HISTOLOGIC ‘QUALIFIER’ A PREDICTOR OF OUTCOME IN PEDIATRIC PILOCYTIC ASTROCYTOMA?
Authors: Cler Samuel J , Skidmore Alexander , Yahanda Alexander T , Mian Ali , Mackey Kimberly , Dahiya Sonika , Strahle Jennifer 
Published: June 2021

Abstract

Introduction
Pediatric pilocytic astrocytomas (PA) are the most common pediatric central nervous system tumor. Surgical resection is the primary treatment for PA with five-year survival rates up to 95%. Despite a favorable prognosis, our understanding about the prognostic value of histopathological findings, such as histopathologic qualifier* or BRAF alterations is evolving.

Methods
Patients treated for a WHO grade 1 PA at Washington University in St. Louis/St. Louis Children’s Hospital were analyzed for clinical details, including pathology diagnosis (*histopathologic qualifier refers to designations in the diagnosis such as “WHO Grade I pilocytic astrocytoma with increased proliferative index”). BRAF alterations include gene fusions and point mutations.

Results
224 patients were analyzed (51% female, mean age 9.6 years). Tumors were located in the cerebellum/fourth ventricle (50%), optic pathway/hypothalamus (15%), brainstem (12%), and cerebral cortex (11%). BRAF alterations were identified in 55/77 patients (71.4%) and additional histopathologic qualifiers were present in 27/220 patients (12.3%). 196 patients (87.5%) underwent surgical treatment and 22 (9.8%) had biopsy alone. 45 patients (22%) displayed tumor progression or recurrence after resection. The presence of a histopathologic ‘qualifier’ in the topline or BRAF alteration was not associated with tumor progression or recurrence (p=0.36, p=0.77). Ki-67 proliferative indices were not predictive of progression or recurrence (p=0.94), including when controlling for extent of resection and adjuvant therapy. BRAF alterations, specifically KIAA1549 fusions, were associated with cerebellar/fourth ventricular tumor location (p&lt;0.001) and younger patient age (p=0.03). Extent of resection was the only predictor of outcome identified in this study; patients with gross total resection had significantly lower rates of progression and recurrence (p&lt;0.0001).

Conclusion
BRAF alterations and histopathologic qualifiers were not associated with tumor progression or recurrence in pediatric PA, although BRAF fusions were more common in tumors located in the cerebellum/fourth ventricle and in younger patients.
LGG-13. PILOCYTIC ASTROCYTOMAS WITH NOVEL BRAF FUSIONS DEMONSTRATE MAPK PATHWAY ACTIVATION
Authors: Chatwin Hannah , Lind Katherine , DeSisto John , Sanford Bridget , Gilani Ahmed , Green Adam 
Published: June 2021

Abstract

Background
Pilocytic astrocytomas (PAs) are the most common pediatric low-grade glioma subtype. Oftentimes, PAs demonstrate somatic genetic alterations, the most common being the BRAF-KIAA1549 fusion, which results in constitutive activation of the MAPK pathway. Better understanding of the effects of other RAF fusions is necessary to determine the potential utility of MAPK-targeting therapies.

Methods
Three patients presented to Children’s Hospital Colorado and were ultimately diagnosed with PAs harboring previously unreported gene fusions identified as FYCO-RAF1, CCTTNNBP2-BRAF, and SLC44A1-BRAF. Utilizing immunohistochemistry, we stained novel samples and controls for ERK and pERK (phosphorylated ERK) to assess the activation of the MAPK pathway. PAs with known BRAF-KIAA1549 fusions (4 samples) and normal brain tissue (5 samples) were used as positive and negative controls, respectively. We additionally performed RNA sequencing to better understand expression changes associated with these fusions, utilizing Metascape and GSEA (Gene Set Enrichment Analysis) for analysis.

Results
Immunohistochemistry of negative control samples demonstrated less p-ERK than ERK (ratios of 0.6–0.9, mean 0.8). All samples with novel fusions demonstrated statistically significantly higher p-ERK expression compared to negative controls (ratios of 1.3–1.7, mean 1.4). These experimental samples also all fell within the p-ERK to ERK expression range of the positive control samples, which demonstrated the widest range of expression (ratios of 1.1–4.5, mean 2.2). Our molecular analysis further confirmed these results, with GSEA demonstrating positively upregulated MAPK and ERK pathways in 2 positive controls and 1 novel fusion sample. Metascape analysis emphasized overall similar gene expression between these samples, demonstrating many shared genes and functional pathways.

Conclusions
We identified 3 previously unreported RAF fusions in PA that demonstrate activation of the MAPK pathway, although not as extensively as seen in some positive control samples with BRAF-KIAA1549 fusions. MEK inhibition may be a useful therapeutic strategy in these tumors if targeted therapy is indicated.
TMOD-06. LOSS OF DICER COOPERATES WITH TUMOR SUPPRESSORS TO INITIATE METASTATIC MEDULLOBLASTOMA
Authors: Alcantara Llaguno Sheila , Nazarenko Inga , Chen Yuntao , Sun Daochun , Rocca Gaspare La , Pedraza Alicia , Gudenas Brian , Saulnier Olivier , Burns Dennis , Bale Tejus , Northcott Paul , Taylor Michael , Ventura Andrea , Parada Luis 
Published: June 2021

Abstract
To determine the role of microRNA regulation in brain tumor development, we incorporated a conditional allele of the microRNA processing enzyme Dicer to a previously characterized glioma mouse model based on inactivation of the tumor suppressors Nf1, Trp53, and Pten using the Nestin-creERT2 transgene. Loss of Dicer and tumor suppressors at adult ages led to glioma development; however, mutant mice tamoxifen induced at early postnatal ages developed medulloblastoma instead of glioma. The switch in tumor spectrum occurred with 100% penetrance and tumors were histologically indistinguishable from human medulloblastoma (MB). The minimum genetic mutations required for MB formation were Dicer and Trp53. Nf1 was dispensable, while additional loss of Pten produced more invasive tumors and leptomeningeal metastases. The time window for initiation of tumorigenesis was until the 2nd postnatal week, coinciding with the disappearance of the external granule layer (EGL), where cerebellar granule neuron precursors (CGNPs) undergo proliferation. Analysis of pre-symptomatic mutant mice showed proliferative defects and retained cells in the EGL, suggesting that the tumors may arise from CGNPs. However, targeting a subset of CGNPs using Math1-creERT2 did not lead to MB development, suggesting that an earlier EGL precursor may be required for tumorigenesis. Analysis of tumor transcriptome and MB subtype-specific genes and markers show that Dicer tumors most resemble extremely high risk p53-mutated SHH MB. Small RNA and mRNA sequencing analyses showed downregulation of microRNAs and dysregulation of its targets such as N-Myc. These studies demonstrate a role for microRNAs in MB development and show a fully penetrant genetic mouse model of highly metastatic MB.
OMIC-08. COMPOUND HETEROZYGOSITY OF POLE AND PMS2 LEADS TO CMMRD-LIKE PHENOTYPE- “POLYNCH” SYNDROME
Authors: Michaeli Orli , Ladany Hagay , Maruvka Yosef E , Erez Ayelet , Shachar Shay Ben , Izraeli Shai , Goldberg Yael , Toledano Helen 
Published: June 2021

Abstract
Mono-allelic germline pathogenic variants (PV) in one of the mismatch repair (MMR) system genes cause Lynch syndrome, associated mainly with colon and endometrial cancer in adults. Germline PVs in DNA polymerase epsilon (POLE) are associated with a dominantly inherited syndrome which confers risk for polyposis and colon cancer. Brain tumors have been described as part of Lynch syndrome and POLE associated syndrome, mostly in adults. Constitutional mismatch repair deficiency (CMMRd) is caused by bi-allelic mutations in the MMR genes, associated with multiple café au lait macules (CAMs) and high incidence of pediatric cancer, including brain tumors. Both MMRD and POLE associated tumors have high tumor mutation burden (TMB), however, microsatellite status is usually unstable in MMR tumors, and stable in POLE. Germline POLE and CMMRd tumors have different mutational signatures, as is signature of MMR tumors with secondary somatic POLE. We describe a 4.5 y/o male who presented with a grossly metastatic SHH-activated, TP53-wildtype desmoplastic medulloblastoma. Physical examination was noted for CAMs. Family history was positive for a heterozygous POLE variant with variable clinical manifestations. Immunohistochemistry of the tumor showed loss of nuclear expression of the MMR gene PMS2, specifically in tumor cells. Analysis showed exceptionally high TMB (up to 276 Mut/Mb) and both the MMR and the POLE signatures. Germline analysis detected the familial POLE variant as well as a de novo heterozygous PMS2 PV. The phenotype of the patient together with the tumor’s features, led us to classify this case as a CMMRd-like. The patient had a partial response to intensive chemotherapy and is currently on immunotherapy without radiation. Collectively, our data suggest that heterozygous simultaneous germline mutations in MMR and polymerase genes can lead to novel “POLYNCH syndrome” that manifests with an ultra-hypermutant aggressive tumor and requires appropriate treatment and surveillance.
OMIC-14. OPENPBTA: AN OPEN PEDIATRIC BRAIN TUMOR ATLAS
Authors: Shapiro Joshua , Savonen Candace , Bethell Chante , Gaonkar Krutika , Zhu Yuankun , Brown Miguel , Duong Nhat , Rathi Komal , Noureen Nighat , Zhang Bo , Ennis Brian , Spielman Stephanie , Farrow Bailey , Van Kuren Nicolas , Koganti Tejaswi , Kannan Shrivats , Raman Pichai , Miller Daniel , Jain Payal , Guo Yiran , Huang Xiaoyan , Kraya Adam , Heath Allison , Koptyra Mateusz , Wong Jessica , Mason Jennifer , Robbins Shannon , Santi Mariarita , Viaene Angela , Waanders Angela , Hanson Derek , Scolaro Laura , Xie Hongbo , Zheng Siyuan , Kline Cassie , Lilly Jena , Storm Philip , Resnick Adam , Rokita Jo Lynne , Greene Casey , Taroni Jaclyn 
Published: June 2021

Abstract
Pediatric brain tumors comprise a heterogeneous molecular and histological landscape that challenges most current precision-medicine approaches. While recent large-scale efforts to molecularly characterize distinct histological entities have dramatically advanced the field’s capacity to classify and further define molecular subtypes, developing therapeutic and less toxic molecularly-defined clinical approaches remains a challenge. To define new approaches to meet these challenges and advance scalable, shared biospecimen- and data-resources for pediatric brain tumors, the Children’s Brain Tumor Network and Pacific Pediatric Neuro-Oncology Consortium, in partnership with the Alex’s Lemonade Stand Foundation Childhood Cancer Data Lab, launched OpenPBTA, a global open science Pediatric Brain Tumor Atlas initiative to comprehensively define the molecular landscape of pediatric brain tumors. The initiative contains multi-modal analyses of research- and clinical-trial based DNA and RNA sequences from nearly 1,000 subjects (with 1,256 tumors) along with their longitudinal clinical data. The OpenPBTA’s open science framework for analysis tests the capacity of crowd-sourced collaborative architectures to advance more rapid, iterative and integrated discovery of the underlying mechanisms of disease across pediatric brain and spinal cord tumors. Since the launch of the project, OpenPBTA has collaboratively created reproducible workflows for integrated consensus SNV, CNV, and fusion calling, enabled RNA-Seq-based classification of medulloblastoma subtypes, and more than 25 additional DNA- and RNA-based analyses. The open-science platform and associated datasets and processed results provide a continuously updated, global view of the integrated cross-disease molecular landscape of pediatric brain tumors. Such biospecimen- and clinically-linked scalable data resources provide unprecedented collaborative opportunities for precision-based, personalized therapeutic discovery and drug development with the upcoming further integration of proteomic sample data (N &gt;300) and drug response datasets, additionally diversifying the multimodal discovery potential of crowd-sourced approaches for accelerated impact for children with brain tumors.
RARE-18. NF1-MUTATED TUMORS EXHIBIT INCREASED SENSITIVITY TO AUTOPHAGY INHIBITION ALONE AND IN COMBINATION WITH MEK INHIBITION
Authors: Baird-Daniel Eliza , Zahedi Shadi , Morin Andrew , Desmarais Michelle , Williams Kyle , Williams Rory , Vibhakar Rajeev , Foreman Nicholas , Mulcahy-Levy Jean 
Published: June 2021

Abstract

Background
Autophagy inhibition is a potential treatment for central nervous system (CNS) tumors. Autophagy, a heavily regulated process by which cellular waste is transferred to lysosomes for degradation and processing, is an integral part of tumor cell survival under stressful conditions including nutrient deprivation and chemotherapy. While the efficacy of autophagy inhibition has been demonstrated in CNS tumors with BRAFV600e mutations, it has yet to be explored in other CNS tumor types with MAPK pathway dysregulation including NF1-mutated tumors. Many tumors associated with the NF1 phenotype can be difficult to treat surgically thus development of further pharmacologic interventions is necessary.

Methods
A CRISPR/Cas9 mediated NF1 KO was derived from human immortalized Schwann cells and utilized as a tumor model. Autophagy inhibition was achieved pharmacologically by chloroquine (CQ) and genetically via shRNAi of ATG5 and ATG7. Trametinib was used for MEK inhibition. Cell growth and viability were determined by Incucyte, Cell Titer-Glo luminescent assay, and colony-formation assays. Protein expression was measured by western blot.

Results
We demonstrate increased autophagic activity in NF1 KO cell as compared to control lines both at baseline and in response to cellular stress. Furthermore, we describe that NF1 KO cells exhibit increased sensitivity to CQ alone, CQ in combination with trametinib, and shRNAi-mediated autophagy inhibition in combination with trametinib.

Conclusion
Here, we describe increased autophagic dependence of NF1 mutated tumors and demonstrate increased tumor sensitivity to autophagy inhibition both alone and in combination with MEK inhibition. These findings indicate that autophagy inhibition via CQ may be an effective adjunctive treatment for NF1 mutated tumors and suggests that diverse CNS tumor types with MAPK pathway dysregulation are susceptible to autophagy inhibition. Clinical investigation of combined MEK and autophagy inhibition has the potential to improve outcomes for NF1 patients with CNS tumors.
RARE-21. A RARE CASE OF PEDIATRIC SPINDLE CELL ONCOCYTOMA WITH EML4-ALK FUSION
Authors: Michaiel George , Hawes Debra , Guzman Samuel , Margol Ashley , Biegel Jaclyn , Ji Jianling 
Published: June 2021

Abstract
A 12 year-old male presented with a 2-month history of intermittent headaches, nausea, and vomiting. Magnetic resonance imaging (MRI) of the brain revealed a 2.2 x 3.5 x 2.6 cm lobulated, sellar/suprasellar mass, mildly T1/T2 hyperintense, with mild homogeneous enhancement and diffusion restriction. He underwent transsphenoidal and right craniotomies for gross total resection of the mass. Pathology demonstrated a hypercellular neoplasm with spindled to ovoid tumor cells arranged in fascicles and tight whirls, consistent with a spindle cell oncocytoma. OncoKids, a DNA- and RNA-based next generation sequencing panel, demonstrated an in-frame EML4 exon 2-ALK exon 19 fusion with a total of 179,872 supporting reads. The EML4-ALK fusion gene is predicted to encode a chimeric tyrosine kinase that facilitates multimerization and autophosphorylation of ALK, and activates its downstream targets, such as RAS/ERK, PI3K/AKT, and JAK/STAT pathways. This fusion is found in approximately 5% of patients with non-small cell lung cancer, a subset of inflammatory myofibroblastic tumors, as well as single cases of pulmonary atypical carcinoid, cholangiocarcinoma, and high-grade glioma. However, it has not been previously described in oncocytoma. Chromosomal microarray analysis demonstrated two interstitial non-contiguous deletions in 2p, and an interstitial deletion in 18q that does not include any known cancer-related genes. The deleted segment in 2p23.3p23.2 includes DNMT3A, which mediates DNA methylation and functions in modification of gene expression. DNMT3A mutations are frequent in hematological malignancies, however their role in oncocytoma is currently unknown. The proximal breakpoint of the deletion in 2p23.3p23.2 is in close proximity to but does not reside within ALK. Spindle cell oncocytoma is rarely reported in the pediatric population, with only one case described in the literature. This is the first case report of an oncocytoma with an EML4-ALK fusion. Additional studies are warranted to confirm its functional effect.
EPCT-01. A NOVEL PEPTIDE VACCINE DIRECTED TO CMV PP65 FOR TREATMENT OF RECURRENT MALIGNANT GLIOMA AND MEDULLOBLASTOMA IN CHILDREN AND YOUNG ADULTS: PRELIMINARY RESULTS OF A PHASE I TRIAL
Authors: Thompson Eric , Landi Daniel , Archer Gerald , Lipp Eric , Walter Ashley , Archambault Bridget , Balajonda Bea , Flahiff Charlene , Jaggers Denise , Herndon James , Buckley Evan , Schroeder Kristin , Randazzo Dina , Desjardins Annick , Johnson Margaret , Peters Katherine , Khasraw Mustafa , Malinzak Michael , Michell Duane , Ashley David , Sampson John 
Published: June 2021

Abstract

Introduction
The cytomegalovirus (CMV) antigen, pp65, is ubiquitously expressed in malignant glioma and medulloblastoma but not in healthy brain. The objective of this Phase I trial (NCT03299309) was to assess the safety and feasibility of a novel pp65 peptide vaccine (PEP-CMV) in children and young adults with recurrent medulloblastoma and malignant glioma.

Methods
Vaccines contain a synthetic long peptide (SLP) of 26 amino acids encoding multiple potential class I, class II, and antibody epitopes of CMV pp65 across several haplotypes. This SLP is administered as an emulsion in Montanide ISA 51. Patients receive a single course of temozolomide to induce lymphopenia, tetanus/diphtheria toxoid site preconditioning, then vaccines administered intradermally every two weeks for 3 doses, then monthly.

Results
To date, 22 patients have been enrolled. Diagnoses include medulloblastoma (n=2), glioblastoma (n=12), anaplastic oligodendroglioma (n=2), anaplastic astrocytoma (n=3), and malignant glioma NOS (n=3). Mean number of prior treatment regimens is 4.9 (range 1–12). Mean age is 22yo (range 6–35) and 45% of patients are male. The median KPS is 80. The median number of vaccines given at time of analysis is 3.3 (range 1–12). There have been no ≥ 3 Grade toxicities related to the vaccine. One patient developed nausea, vomiting, palpitations, and tachycardia after vaccination and had elevated inflammatory cytokines consistent with cytokine release syndrome. Median PFS is 2.5 months (95% CI: 1.7,4.5) and median OS is 6.5 months (95% CI 3.3, 7.9). Immune response to pp65 as determined by ELISpot was found in 75% of patients. On MRI 6 of the 11 evaluable patients have had at least stable disease with three of those having a partial response.

Conclusions
Preliminary results demonstrate that PEP-CMV is well-tolerated and elicits an immune response in heavily pretreated, multiply recurrent patients. A multi-institutional Phase II trial is scheduled to open fall 2021.
EPCT-16. LENALIDOMIDE ACTIVITY IN PILOCYTIC ASTROCYTOMA AND OPTIC PATHWAY GLIOMAS: REPORT ON CHILDREN’S ONCOLOGY GROUP ACNS1022
Authors: Warren Katherine , Vezina Gilbert , Springer Linda , Buxton Allen , Peer Cody , Figg W Douglas , Fouladi Maryam , Gajjar Amar , Krailo Mark , Bowers Daniel 
Published: June 2021

Abstract

Children with low-grade glioma have excellent survival rates but often suffer from the morbidity of treatment, particularly from cytotoxic chemotherapies. Targeted agents appear to have some activity but the long-term effects of inhibiting normal developmental pathways are unknown. Lenalidomide is an oral immunomodulatory agent with additional properties including anti-angiogenesis. Phase I studies indicated greater tolerability of this agent compared to adults, and a potential dose-response effect. We performed a Phase 2 trial of lenalidomide in children with pilocytic astrocytoma and optic pathway gliomas who failed initial therapy. The primary objective was to determine the objective response rate of children randomized to Regimen A low-dose (20 mg/m2 /dose) or Regimen B high-dose (115 mg/m2 /dose) lenalidomide, each administering lenalidomide daily x 21 days of each 28-day course. Secondary objectives included estimation of event-free survival (EFS) in this population and correlation of plasma lenalidomide concentration with toxicity and outcome.

Results
74 eligible patients were enrolled (n=37 to each arm). The pre-defined activity level of interest was achieved for both arms. Objective responses were observed in both arms, with 4 partial responses in each. A total of n=18 patients completed 26 courses of therapy (Arm A, n=12, Arm B, n=6) The median number of courses on each arm was 14 (range 2–26) for Arm A and 11 for Arm B (range 1- 26). Of the 74 eligible patients who received study drug, 30 required a dose reduction for toxicity (Arm A, n=6, Arm B, n=24) and 16 discontinued treatment on protocol due to toxicity (Arm A, n=2, Arm B, n=14).

Conclusion
Lenalidomide demonstrates a sufficient level of activity in children with low-grade glioma to warrant further exploration in Phase 3 studies. Low-dose (20 mg/m2) lenalidomide appears to have better tolerability.