bluuebunny/crossref_metadata_2025 huggingface dataset:
PATH-27. MUTATION DETECTION USING PLASMA CELL-FREE DNA IN CHILDREN WITH CENTRAL NERVOUS SYSTEM TUMORS
Authors: Mangum Ross , Reuther Jacquelyn , Baksi Koel Sen , Zabriskie Ryan C , Gandhi Ilavarasi , Recinos Alva , Potter Samara L , Lin Frank Y , Chintagumpala Murali , Muzny Donna M , Fisher Kevin , Plon Sharon E , Roy Angshumoy , Parsons D Williams
Published: December 2020

BACKGROUND

The role of plasma cell-free DNA (cfDNA) as a cancer biomarker for tracking treatment response and detecting early relapse has been well described for solid tumors outside the central nervous system (CNS). However, the presence of a blood-brain barrier complicates the application of plasma cfDNA analysis for patients with CNS malignancies.

METHODS

cfDNA was extracted from plasma of pediatric patients with CNS tumors utilizing a QIAmp® MinElute® kit and quantitated with Qubit 2.0 Fluorometer. Extensive genomic testing, including targeted DNA and RNA solid tumor panels, exome and transcriptome sequencing, as well as copy number array, was performed on matched tumor samples as part of the Texas KidsCanSeq study. An Archer® Reveal ctDNA28 NGS kit was then used for assaying the sensitivity of detecting tumor-specific mutations in the plasma of these patients.

RESULTS

A median of 10.7ng cfDNA/mL plasma (Interquartile range: 6.4 – 15.3) was extracted from 78 patients at time of study enrollment. Longitudinal samples from 24 patients exhibited a median yield of 7.7ng cfDNA/mL plasma (IQR: 5.9 – 9.1). An initial cohort of 6 patients was identified with 7 somatic variants covered by the Archer® Reveal kit. Four of seven mutations identified in matched tumor specimens were detected in patient plasma at variant allele frequencies ranging from 0.2–1%.

CONCLUSIONS

While challenging, detection of cfDNA in the plasma of pediatric patients with CNS tumors is possible and is being explored in a larger patient cohort along with pilot studies investigating cerebrospinal fluid as an additional source for tumor-specific cfDNA.
PATH-29. HIGH FREQUENCY OF CLINICALLY-RELEVANT TUMOR VARIANTS DETECTED BY MOLECULAR TESTING OF HIGH-RISK PEDIATRIC CNS TUMORS – PRELIMINARY FINDINGS FROM THE TEXAS KidsCanSeq STUDY
Authors: Lin Frank Y , Mangum Ross , Reuther Jacquelyn , Potter Samara L , López-Terrada Dolores H , Adesina Adekunle M , Mohila Carrie A , Aldave Guillermo , Chintagumpala Murali M , Muzny Donna M , Bernini Juan Carlos , Gill Jonathan , Griffin Timothy , Tomlinson Gail , Vallance Kelly , Fisher Kevin E , Roy Angshumoy , Plon Sharon E , Parsons D Williams
Published: December 2020

BACKGROUND

DNA and RNA-based tumor sequencing tests have the potential to guide the clinical management of children with CNS tumors. However, data describing the utility of these tests are limited.

METHODS

Children with high-risk or recurrent CNS tumors are included in the diverse cohort of patients enrolling in the KidsCanSeq study from six Texas sites. DNA and RNA from FFPE tumor is subjected to targeted sequencing using a 124-gene mutation panel and an 81-gene fusion panel. Tumor capture transcriptome sequencing, exome sequencing, and copy number array (as well as germline panel and exome testing) are also performed. Tumor variants are classified using AMP/ASCO/CAP consensus guidelines.

RESULTS

A total of 74 children with high-risk/recurrent CNS tumors enrolled as of 1/28/20. Targeted tumor DNA and RNA panel testing was completed for 57 patients with varied diagnoses. At least one tumor variant with strong or potential clinical significance was identified in 43 of 57 (75%) tumors, with therapeutic significance in 20 of 57 (35%) tumors. The 38 therapeutically-relevant variants most frequently affected MAPK signaling (BRAF x9, EGFR x3, FGFR2, FGFR3, KRAS, NF1, NTRK2) and the AKT/mTOR pathway (PIK3CA x3, PTEN x2, mTOR, TSC1, PIK3R1). Most had not been detected by prior targeted diagnostic testing (27/38, 71%).

CONCLUSION

Integrated DNA and RNA-based panel testing identified variants with potential to impact clinical decision-making in a majority of children with high-risk/recurrent CNS tumors. The comparative yield of panel testing vs. exome/transcriptome/array will be evaluated in the KidsCanSeq study cohort.
QOL-05. TUMOR LOCATION IS LESS LIKELY INFLUENCE ON COGNITIVE DYSFUNCTION IN CHILDREN
Authors: Nakajima Riho , Kinoshita Masashi , Tanaka Shingo , Nakada Mitsutoshi
Published: December 2020

INTRODUCTION

Though several factors are known to influence on long-term cognitive function in children with brain tumor, the impact of tumor localization to specific cognitive function was not well known. Here we investigated the influence of local brain resection by surgery on postoperative cognitive outcome in school-aged children.

METHODS

Participants were seven pediatric patients who underwent craniotomy for tumor resection in our hospital (mean age, 13.9 years). Their diagnosis were WHO grade 1 or 2 glioma (n=6) and hemangioma (n=1). Tumor were mainly located in following regions; frontal, n=2; parietal, n=2; temporal, n=3 (These lesions included hippocampus or were located very close to it). Temporal assessments for cognitive function of several functional domains were performed according to tumor location until post-op 1 year. Based on MRI, we estimated cognitive dysfunctions and compared them to observational symptoms.

RESULTS

Preoperative cognitive function was normal in all patients. Cognitive dysfunctions estimated from resected area were as follows (cumulative total number); memory or working memory disorder, n=4; visuospatial cognitive disorder, n=3; disorder of processing speed, n=2; facial or topographical agnosia, n=2; Gerstman syndrome, n=1. Just after surgery, cognitive function was declined in two functional domains of two patients, which were only 16.7% of estimated deficit from resected region. They recovered completely until 3 months postoperatively, and returned to school without any deficits.

CONCLUSIONS

In pediatric lower-grade tumor, focal cognitive symptom was unlikely to be induced by local resection.
QOL-07. CORTICAL VOLUME AND THICKNESS IN ADULT SURVIVORS OF CHILDHOOD POSTERIOR FOSSA TUMORS
Authors: Sleurs Charlotte , Lemiere Jurgen , Blommaert Jeroen , Deprez Sabine , Van Beek Karen , Uyttebroeck Anne , Jacobs Sandra
Published: December 2020

PURPOSE

A brain tumor treatment including cranial radiotherapy has previously been associated with long-term neurocognitive sequelae. Since underlying neurological mechanisms remain inconclusive, we investigated cortical features in childhood posterior fossa tumor survivors.

METHODS

T1-weighted MRI (MPRAGE, resolution=.98x.98x1.2mm) was acquired to investigate the cortical structure in adult survivors of childhood infratentorial tumors (n=19, 15males) (16.4–34.8 years old, >2years after treatment). These scans were compared to age- and gender- matched controls. Supratentorial cortical volume and thickness were investigated using voxel-based morphometry (VBM) and surface-based morphometry (SBM), respectively. We compared patients and controls, irradiated (n=13) versus non-irradiated patients, and investigated the age at radiotherapy (peak level: p<.001).

RESULTS

Lower GM volumes were encountered in multiple brain areas of patients compared to controls, with the largest clusters in the right and left occipital fusiform gyri. Irradiated patients showed lower GM volumes then non-irradiated patients in the superior and middle frontal gyri, the right supramarginal gyrus and precuneus. Age at radiotherapy was associated with GM volume in the inferior frontal gyrus. SBM yielded larger cortical thickness in patients in the left precuneus, inferior temporal and fusiform gyrus. The opposite effect was only marginally significant, in the left temporal lingual gyrus. Age at radiotherapy was not associated with cortical thickness, but radiotherapy was associated with lower thickness of the left pars opercularis.

CONCLUSION

Widespread differences in cortical volumes and thickness were observed in posterior fossa tumor survivors. Both radiotherapy and age at radiotherapy could be suggested as risk factors for long-term cortical development.
QOL-09. WHOLE-BRAIN WHITE MATTER NETWORK CONNECTIVITY IS DISRUPTED BY PEDIATRIC BRAIN TUMOR TREATMENT
Authors: Oyefiade Adeoye , Beera Kiran , Moxon-Emre Iska , Skocic Jovanka , Bartels Ute , Laughlin Suzanne , Ramaswamy Vijay , Mabbott Donald
Published: December 2020

INTRODUCTION

Treatments for pediatric brain tumors (PBT) are neurotoxic and lead to long-term deficits that are driven by the perturbation of underlying white matter (WM). It is unclear if and how treatment may impair WM connectivity across the entire brain.

METHODS

Magnetic resonance images from 41 PBT survivors (mean age: 13.19 years, 53% M) and 41 typically developing (TD) children (mean age: 13.32 years, 51% M) were analyzed. Image reconstruction, segmentation, and node parcellation were completed in FreeSurfer. DTI maps and probabilistic streamline generation were completed in MRtrix3. Connectivity matrices were based on the number of streamlines connecting two nodes and the mean DTI (FA) index across streamlines. We used graph theoretical analyses to define structural differences between groups, and random forest (RF) analyses to identify hubs that reliably classify PBT and TD children.

RESULTS

For survivors treated with radiation, betweeness centrality was greater in the left insular (p < 0.000) but smaller in the right pallidum (p < 0.05). For survivors treated without radiation (surgery-only), betweeness centrality was smaller in the right interparietal sulcus (p < 0.05). RF analyses showed that differences in WM connectivity from the right pallidum to other parts of the brain reliably classified PBT survivors from TD children (classification accuracy = 77%).

CONCLUSIONS

The left insular, right pallidum, and right inter-parietal sulcus are structurally perturbed hubs in PBT survivors. WM connectivity from the right pallidum is vulnerable to the long-term effects of treatment for PBT.
QOL-33. THE PROMOTE STUDY: DEVELOPMENT AND TESTING OF KLIK-UK, AN ONLINE PLATFORM, TO ENHANCE OUTPATIENT COMMUNICATION ABOUT HEALTH-RELATED QUALITY OF LIFE (HRQOL) AT THREE UK CHILDREN’S BRAIN TUMOUR TREATMENT CENTRES (CBTTCs)
Authors: Bull Kim , Stubley Shelly , Kouzoupi Natalia , Darlington Anne-Sophie , Grootenhuis Martha , Hargrave Darren , Liossi Christina , Morris Christopher , Walker David , Kennedy Colin
Published: December 2020

BACKGROUND

The HRQoL of survivors of childhood brain tumour is significantly reduced into adulthood but is not systematically assessed. In the UK, referral for appropriate support is often reactive rather than proactive. We developed KLIK, the online Dutch platform, for use to enable the systematic assessment of HRQoL in the UK NHS using patient-reported outcomes measures (PROMs) which could be fed back to clinicians during outpatient review appointments.

METHODS

PARTICIPANTS: Children aged 5–17.9 years, receiving outpatient care >6 monthly for a brain tumour diagnosed within preceding 5 years and their parents and clinicians. SETTING: Three UK CBTTCs – UHS, Southampton; GOSH, London; and QMC, Nottingham. PROCEDURE: KLIK-UK was developed throughout the study and barriers and opportunities for its use logged. A. Development phase: relevant PROMs were identified through systematic literature review1 and families’ views regarding choice of PROMs, communication needs within consultations, and KLIK-UK were obtained by interview. B: Feasibility phase: KLIK-UK was tested in outpatient review appointments followed by interviews with the family and clinician.

RESULTS

57 families and 10 clinicians participated. The PedsQL-Core module was preferred by families. Communication needs and barriers were identified. All clinicians reported that they could see the potential value of using KLIK-UK but views differed as to whether they could use it within their current timetable. Analysis of interviews from the feasibility phase will be reported.

CONCLUSION

KLIK-UK is ready for use in the UK but will need to be adapted according to local resources, needs, and preferences. 1Bull et al. 2019 https://doi.org/10.1093/nop/npz064
QOL-38. USE OF COMPUTERIZED NEUROPSYCHOLOGICAL MEASURES TO ASSESS COGNITIVE MORBIDITY IN SURVIVORS OF CHILDHOOD BRAIN TUMORS
Authors: Dickson Duncan , Channell Jessica , Mettetal Ashley , Chick Elizabeth , Wilkening Greta , Liu Arthur , Hankinson Todd , Foreman Nicholas , Hutaff-Lee Christa
Published: December 2020

Treatment of central nervous system (CNS) tumors in pediatric populations is associated with significant cognitive morbidity. Documentation of neuropsychological deficits is vital to treatment and educational planning. We investigated the feasibility and utility of a computerized neuropsychological measure (NIH Toolbox Cognitive Battery) in differentiating individuals who received tumor treatment from healthy controls. Participants included pediatric CNS tumor survivors (N = 85; Mean Age = 13.47; SD = 4.76) at least 1-year post-completion of treatment and healthy sibling controls (N = 20; Mean Age = 10.2; SD = 3.21) who completed the NIH Toolbox. Ninety-eight percent of the participants enrolled completed the computerized tasks. The overall logistical regression model, with NIH Toolbox tests as predictors, was statistically significant [χ2 (7, N = 105) = 26.176; p < .001] and improved correct group classification from 81% to 82.9%. Picture Sequencing (β = -0.059; Wald = 6.942; p = .008) and Flanker (β = -0.083; Wald = 7.473; p = .006) were both statistically significant and negatively predictive of membership in the treatment group. For each 1 unit increase in standard score on measures of working memory and inhibition, odds of membership in the treatment group decreased by 6.2% and 8.7%, respectively. Consistent with the literature, worse performance on computerized measures of cognitive functioning mediated by executive functioning was correlated with a history of brain tumor treatment. Further investigation will focus on comparing computerized neuropsychological tools to traditional comprehensive neuropsychological evaluations and clarifying the trajectory of these deficits across recovery.
QOL-48. INTERDISCIPLINARY SPIRITUAL CARE TRAINING IN PEDIATRIC NEURO-ONCOLOGY
Authors: Lion Alex , Maiko Saneta , Szilagyi Csaba , Slaven James , Puchalski Christina
Published: December 2020

INTRODUCTION

Pediatric neuro-oncology requires attention to not only cancer biology and therapeutics, but also to the suffering of the patient. In addressing patient suffering, consensus guidelines direct attention to the spiritual distress and resources of patients and families. A lack of training has been a key barrier to integrating this aspect of health into patient care.

METHODS

A neuro-oncologist and a chaplain participated in a train the trainer for the Interprofessional Spiritual Care Education Curriculum (ISPEC) through the George Washington University’s Institute for Spirituality and Health. After the train the trainer, the online curriculum was offered to interdepartmental team members, combined with in-person discussion groups, which met weekly for six sessions. A survey was given before and after the training, and Likert scores were analyzed using the Wilcoxon rank-sum non-parametric test. OUTCOMES: 17 interdisciplinary members participated in the training. These members included neuro-oncologists, neuro-surgeons, rehabilitation physicians, nurse practitioners, nurses, physical therapists, music therapists, a child life specialist, a school liaison, and a patient experience specialist. The training resulted in multiple improvements, including increased ability to identify spiritual issues (p=.0278) and increased ability to respond to these issues (p=.0056).

CONCLUSION

ISPEC addressed a key barrier to providing generalist spiritual care to patients with pediatric brain tumors. Diverse disciplines were represented during the training. With implementation of interdisciplinary spiritual care, outcomes that may be measured in the future include improved quality of life, patient satisfaction, and the resilience of both patients and team members.
QOL-55. INTEGRATED MULTI-SCALE MODEL FOR PEDIATRIC BRAIN TUMOR SURVIVAL PREDICTION
Authors: Qiu Yeping Lina , Sabran Amaury , Zheng Hong , Gevaert Olivier
Published: December 2020

Brain tumors are the most common solid tumors affecting children, and its prognosis has been a great challenge for physicians and researchers. With the advances in high-throughput sequencing technology and digital pathology, more quantitative data is now becoming available and more information may potentially be discovered in whole slide images (WSIs) and molecular tumor characteristics to determine survival and treatment. Imaging and genomic data, though very different in nature, both may contain different aspects of disease characteristics that are important for survival prediction. Hence our work aims to build a framework to integrate two data modules, whole-slide histopathology image data, and RNA sequencing data, for a unified model to improve pediatric brain tumor survival outcome prediction. The imaging data and genomic data are both of high dimensions and on different scales. We use two independent modules, each of which consists of a deep neural network, to extract lower dimensional features from imaging and genomic data respectively. We concatenate the extracted features and use a third neural network to train a Cox regression model using the merged feature as input. Each module is first pre-trained with TCGA adult brain tumor data, and subsequently fine-tuned with pediatric brain tumor data. The entire pipeline is tested on the holdout pediatric brain tumor dataset. Preliminary results suggest that the integrated framework achieves improved prediction performance than using each single data module alone. The concordance index (C-index) of integrated model is 0.68, compared to 0.62 with imaging data only, and 0.66 with genomic data only.
QOL-57. SOUTHERN CALIFORNIA KAISER PERMANENTE PEDIATRIC NEURO-ONCOLOGY PROGRAM DEVELOPMENT
Authors: Tran Hung
Published: December 2020

KEY MESSAGE

Standardization of care for subspecialty patients require centralization and support across multi-disciplinary groups within the Kaiser Permanente medical group, which is a large health maintenance organization (HMO) in the United States.

BACKGROUND

Prior to the development of a Pediatric Neuro-Oncology program, Southern California Kaiser Permanente pediatric neuro-oncology patients were routinely referred to respective regional academic centers for consultation. The process was not standard across the region, resulting in additional costs and differences in treatment recommendations, potentially affecting outcomes.

METHODS

A Pediatric Neuro-Oncology program was established, July 2017, based at the Kaiser Permanente Los Angeles Medical Center (LAMC), consisting of pediatric neuro-oncology, pediatric neurosurgery, pediatric neuro-radiology, pediatric radiation oncology, and pediatric neuro-oncology case management.

RESULTS

A Pediatric Neuro-Oncology tumor board was established to meet on a bi-monthly basis. Pediatric neuro-oncology patients across the Southern California now have their magnetic resonance imaging (MRI) reviewed by the same pediatric neuro radiologists. Neuropathology is standardized and sent to Children’s Hospital Los Angeles and reviewed at the molecular neuropathology tumor board attended by the pediatric neuro-oncologist. Cases discussions regarding the patients include the regional pediatric neurosurgeons, the pediatric radiation oncologists, and the pediatric neuro-oncologist, and treatment plans are recommended and recorded by the case manager.

CONCLUSIONS

Centralization of care has allowed for more consistent and standard care across the Southern California Region, but requires support from multi-disciplinary groups.
QOL-58. ASSESSING FATIGUE EXPERIENCED BY PEDIATRIC PATIENTS WITH INTRACRANIAL NEOPLASMS
Authors: Eccles Eamon , Han Yan , Liu Hao , Holmes Jordan , Coven Scott
Published: December 2020

BACKGROUND

Indiana University possessed one of the earliest clinical proton facilities in the United States. The purpose of this study was to assess fatigue and nausea/vomiting in children with central nervous system (CNS) tumors undergoing radiation therapy as part of their treatment regimen, and to understand what factors influence fatigue. DESIGN: The study was approved by the institutional review board at Indiana University and consent and/or assent from eligible participants was obtained prior to enrollment. The validated Fatigue Scale is scored on a 5-point Likert scale. Surveys were completed 1) prior to radiation therapy, 2) week three of radiation therapy, and 3) week six of radiation therapy. A score of 41 or higher for the Fatigue Scale-Parent (< 7 years), 12 or higher for the Fatigue Scale-Child (8–12 years), and 17 or higher for the Fatigue Scale-Adolescent (13–18 years), indicates significant cancer-related fatigue.

RESULTS

The study aimed to recruit a total of 50 patients during the eligible period; however, data on 31 individual participants were available for analysis. 25 patients underwent proton radiation therapy, while 6 patients underwent conventional photon therapy. The mean age of children was 8.8 years. Of the 31 patients, 22 recorded scores indicating significant cancer-related fatigue at some point during radiation therapy.

CONCLUSIONS

Cancer related fatigue continues to be a challenge, with limited understanding of factors that might predict clinically relevant fatigue This work demonstrates the feasibility of conducting symptom research for children undergoing radiation therapy; further research is needed to characterize predictors of fatigue.
RARE-11. QUANTITATIVE MR IMAGING FEATURES ASSOCIATED WITH UNIQUE TRANSCRIPTIONAL CHARACTERISTICS IN PEDIATRIC ADAMANTINOMATOUS CRANIOPHARYNGIOMA: A POTENTIAL GUIDE FOR THERAPY
Authors: Mirsky David , Prince Eric , Staulcup Susan , Hengartner Astrid , Vijmasi Trinka , Johnston James , Massimi Luca , Anderson Richard , Souweidane Mark , Naftel Robert , Limbrick David , Grant Gerald , Niazi Toba , Dudley Roy , Kilburn Lindsay , Jackson Eric , Jallo George , Ginn Kevin , Smith Amy , Chern Joshua , Lee Amy , Drapeau Annie , Krieger Mark , Handler Michael , Hankinson Todd
Published: December 2020

METHODS

Through the Advancing Treatment for Pediatric Craniopharyngioma (ATPC) consortium we accumulated preoperative MRIs and tumor RNA for 50 unique ACP patients. MRIs were assessed quantitatively for 28 different features and analyzed using Multiple Factor Analysis (MFA) and optimal clustering was determined via maximization of Bayesian Information Criterion (BIC). Following bulk RNAseq, differential expression and pathway enrichment were performed using standard methodologies (i.e., DESeq2 and GSEA).

RESULTS

MRI features were well represented in the first 3 dimensions of MFA (variance explained=67.32%); specifically tumor/cyst size, ventricular size, and cyst fluid diffusivity. Using this three-way axis, we identified 3 patient subgroups. Transcriptional differences between these subgroups indicated one group was enriched for DNA damage response and MYC related pathways, one group enriched for SHH, and one group enriched for WNT/β-catenin and EMT-related pathways.

CONCLUSION

This preliminary work suggests that there may be unique gene expression variants within ACP, which may be identified preoperatively using easily quantifiable MRI parameters. These radiogenomic signatures could provide prognostic information and/or guidance in the selection of antitumor therapies for children with ACP.
RARE-37. NOONAN SYNDROME AND GLIONEURONAL TUMORS: A CENTRAL NERVOUS SYSTEM CANCER PREDISPOSITION ASSOCIATION?
Authors: Shatara Margaret , Varga Elizabeth A , Boué Daniel R , Martin Lisa , Rusin Jerome A , Rodriguez Diana P , Jones Jeremy , McAllister Aaron , Leonard Jeffrey R , Pindrik Jonathan , Schieffer Kathleen M , Leraas Kristen M , Lichtenberg Tara M , Mardis Elaine R , Cottrell Catherine E , Osorio Diana S , AbdelBaki Mohamed S , Finlay Jonathan L
Published: December 2020

BACKGROUND

Noonan syndrome (NS) is associated with germline Ras signaling pathway mutations, RAS overactivation and increased tumorigenesis risk. Rosette-forming glioneuronal tumors (RFGT) are rare indolent tumors. We report the molecular profiling of two patients with NS and RFGT. PATIENT 1: A 22-year-old male with NS was diagnosed with RFGT after partial tumor resection followed by focal irradiation. He was enrolled on a comprehensive genomic profiling study involving paired tumor-normal whole exome sequencing and RNA sequencing of the disease-involved tissue, revealing a germline PTPN11 alteration (p.Gly60Ala) consistent with NS, and a somatic deletion (p.Ile442_Thr454del) in PIK3R1 and a somatic variant (p.Lys656Glu) in FGFR1 with concomitant increased expression of PIK3R1 and FGFR1 by RNA-sequencing. The patient remains without tumor progression now nine months since irradiation. PATIENT 2: A 19-year-old male with persistent headaches, underwent a brain MRI demonstrated multiple abnormal signals in the pineal region and midbrain. He had a stereotactic biopsy revealing RFGT. He was enrolled on the genomic study revealing a germline PTPN11 alteration (p.Asn308Asp) resulting in a new diagnosis of NS. Several family members were subsequently identified with clinical features of NS, including his mother and two siblings, enabling appropriate counseling. Two somatic variants were found in trans in PIK3R1 (p.Thr454_Phe456del and p.Glu451_Asn453delinsAsp), and a somatic variant (p.Val695Met) in FGFR1, with resultant overexpression of PIK3R1. The patient is monitored with surveillance imaging.

CONCLUSION

We report the molecular profiling of two patients with NS and RFGT; strongly suggesting their connection to RASopathies through the overactivation of the MAPK and PI3K/AKT/mTOR signaling pathways.
RARE-49. CHOROID PLEXUS ADENOMA WITHOUT ASSOCIATED HYDROCEPHALUS PRESENTING AS PRECOCIOUS PUBERTY
Authors: Utley Kaylyn , Dedekian Michael , Wilson James , Chaleff Stanley
Published: December 2020

Precocious puberty (PP) is a rare presentation of intracranial pathology unrelated to the pituitary. PP in this setting is considered a paraneoplastic phenomenon, achieved through synthesis of sex-hormones by the tumor itself or via alterations in the release of gonadotrophins from the pituitary. The latter has been described with masses adjacent to the pituitary or with those which cause hydrocephalus. We describe a case of a choroid plexus papilloma (CPP) without hydrocephalus presenting as precocious puberty. An 18 month-old female presented with 4-months of weight loss, bilateral galactorrhea and constipation. Her weight decreased from the 15th to below the 1st percentile. CBC, celiac and thyroid studies were normal. Prolactin was at the upper limit of normal (25.8;ref 3.3–26.3). Breast ultrasound demonstrated symmetric breast tissue development. She was referred to pediatric gastroenterology for constipation and failure to thrive. Caloric supplementation, bowel regimen and barium enema were recommended. One week later, she was admitted with dehydration, painful constipation and further weight loss in the setting of an acute febrile illness. MRI revealed a normal pituitary and an intraventricular mass without hydrocephalus. She underwent gross total resection of the mass, later determined to be a choroid plexus papilloma. The patient’s galactorrhea resolved abruptly following resection. Because of her galactorrhea, our patient underwent neuroimaging revealing an incidental mass without associated hydrocephalus. To our knowledge, precocious puberty and hyperprolactinemia have not been described in neoplasms distant from the pituitary. Thus, these lesions should be recognized as a potential etiology of precocious puberty and hyperprolactinemia.
RARE-51. MOLECULAR INSIGHTS INTO MALIGNANT PROGRESSION OF CHOROID PLEXUS PAPILLOMA (CPP)
Authors: Yankelevich Maxim , Finlay Jonathan L , Gorsi Hamza , Kupsky William , Boue Daniel R , Koschmann Carl J , Kumar Chandan , Mody Rajen
Published: December 2020

Malignant transformation of CPP is rare and the mechanisms remain elusive. We report a case of progression of papilloma into carcinoma where we performed molecular sequencing of both samples. A boy was found to have a brain mass soon after birth. The gross total resection (GTR) was diagnostic of CPP. Six years later he developed a recurrent mass that demonstrated progression to a choroid plexus carcinoma (CPC). The patient received chemotherapy according to a “HeadStartII” protocol. He is 2.5 years off therapy and disease-free. A sequencing study consisting of 1700 genes and tumor transcriptome was done. The analysis of both samples revealed a germline variant of TP53(R248W) with LOH and an allele frequency of 39% in the germline sample, suggesting a mosaicism. Analysis of both samples identified extensive aneuploidy and similar pattern of gains in chromosomes 7/8/12/20/21/X. Copy number aberrations newly acquired in the carcinoma included copy gain of chromosomes 5q/12/15q/20, and copy loss of chromosomes 5q/13/22. The papilloma was found to harbor 3 somatic mutations with 4% to 21% allelic fractions, all lost in the carcinoma. These mutations were of unknown significance and with too low allelic fractions to be responsible for the transformation. More pertinently, chromosomal aneuploidy was significant with additional losses in the carcinoma. This resulted in the losses of two critical tumor suppressor genes, RB and BRCA2, playing a possible role in the observed transformation. The “HeadStart” experience suggested that the prognosis of TP53 mutant CPC may be improved in the absence of radiation therapy.
RARE-53. PINEAL PARENCHYMAL TUMOR OF INTERMEDIATE DIFFERENTIATION (PPTID) AND DICER1 SYNDROME: A CASE REPORT
Authors: Toll Stephanie , Gupte Avanti , Sood Sandeep , Kupsky William , Altinok Deniz , Miller Steven , Bhambhani Kanta
Published: December 2020

BACKGROUND

DICER1 syndrome is a rare inherited tumor predisposition syndrome linked to an increased risk of several malignancies. Affected individuals most commonly develop pleuropulmonary blastoma (PPB) and ovarian sex cord-stromal tumors. Brain tumors in these patients are rare, however; the increased frequency of pineoblastoma in this population has been established. Traditionally, pineal parenchymal tumors of intermediate differentiation (PPTIDs) have not been associated with DICER1 syndrome, with research suggesting alternative mutations driving tumorigenesis. These tumors are pathologically and clinically diverse, with long-term surveillance based on therapeutic interventions. Here we describe a case of a germline DICER1 mutation in a patient with a PPTID, suggesting that this mutation is not limited to pineoblastoma as previously reported. CASE: We describe a 19 year-old female with a WHO grade III PPTID treated with multimodal therapy including surgery, craniospinal irradiation (CSI) and chemotherapy. She was noted to have a thyroid mass at diagnosis and was subsequently diagnosed with a benign thyroid nodule, followed most recently by a cataract with pathology concerning for medulloepithelioma of the ciliary body. Due to the known association between medulloepithelioma and DICER1 syndrome, targeted germline sequencing was obtained and confirmed a pathogenic heterozygous mutation.

CONCLUSION

To our knowledge this is the first report of a PPTID in a patient with DICER1 syndrome. This association highlights the clinical implications of molecular evaluation in pediatric brain tumors, for both immediate therapeutic decisions and long-term surveillance.
RARE-54. MOLECULAR ANALYSIS OF ROSETTE-FORMING GLIONEURONAL TUMOR AT MIDBRAIN; REPORT OF TWO CASES
Authors: Handa Hajime
Published: December 2020

Rosette-forming glioneuronal tumor (RGNT) is a tumor that primarily arises at posterior fossa. We experienced two rare cases of RGNT located at midbrain and investigated their molecular features. Case 1 is a 23-year-old female, and Case 2 is an 18-year-old male. Both cases were surgically removed by the occipital transtentorial approach. Histological analysis demonstrated a biphasic pattern of neurocytic and glial components. The former consisted of neurocytic rosettes and perivascular pseudorosettes, and the latter was GFAP positive, corresponding to the diagnosis of RGNT. Both cases have an excellent clinical course without receiving chemotherapy or radiation therapy. Small residual tumors of both cases shrunk and maintained for 27 and 12 months, respectively. Case 1 underwent DNA methylation array and a subsequent DNA methylation-based classifier, indicating that the case matched RGNT with a 0.99 calibrated score. Also, we identified FGFR1 K656 mutation. Pyrosequence analysis of other genes such as IDH1 R132, IDH2 R172, BRAF T599, BRAF V600, H3F3A K27, H3F3A G34, HIST1H3B K27, TERT C228, FGFR1 N546 had no mutations. RT-PCR of KIAA1549-BRAF fusion was not detected. DNA methylation status of Case 2 is under investigation. Pyorosequence analysis identified TERT C228 mutation but did not identify other mutations such as FGFR1 N546 and K656. Midbrain RGNT corresponds to the histological and molecular features of RGNT. RGNT needs to be differentially diagnosed in the case of a midbrain tumor.
RARE-59. CARDIAC REMODELING IN PATIENTS WITH CHILDHOOD-ONSET CRANIOPHARYNGIOMA – RESULTS OF HIT-ENDO AND KRANIOPHARYNGEOM 2000/2007
Authors: Sowithayasakul Panjarat , Buschmann Leona Katharin , Boekhoff Svenja , Müller Hermann L
Published: December 2020

BACKGROUND

Hypothalamic obesity caused by childhood–onset craniopharyngioma results in long–term cardiovascular morbidity. Knowledge about clinical markers and risk factors is rare.

PATIENTS AND METHODS

A cross–sectional study on transthoracic echocardiographic parameters was performed to determine the associations with clinical and anthropometric parameters in 36 patients with childhood-onset adamantinomatous craniopharyngioma.

RESULTS

Body mass index (BMI) correlated with the thickness of interventricular septum in diastole (IVSd) (r=0.604, p<0.001) and left ventricular diastolic posterior wall in diastole (LVPWd) (r=0.460, p=0.011). Due to wide range of disease duration, 17 pediatric and 19 adult patients were analyzed separately. In the adult subgroup (age at study ≥18 years), BMI correlated with IVSd (r=0.707, p=0.003), LVPWd (r=0.592, p=0.020) and left ventricular internal diameter in diastole (LVIDd) (r=0.571, p=0.026). In the pediatric subgroup (age at study <18 years), no correlation between cardiac parameters and BMI was observed. Only LVIDd correlated with disease duration (r=0.645, p<0.001). All cardiac functions were within the normal range, indicating no association with severe functional impairments.

CONCLUSIONS

Cardiac remodeling in patients with childhood-onset craniopharyngioma correlates with the degree of hypothalamic obesity and disease duration. However, echocardiography has limited sensitivity in craniopharyngioma patients with obesity, so cardiac magnetic resonance imaging (MRI) should be considered as an alternative diagnostic approach for patients with craniopharyngioma and hypothalamic obesity.
RONC-02. MEASURING THE EFFECT OF CLINICALLY-RELEVANT RADIOTHERAPY PROTOCOLS ON THE JUVENILE MOUSE BRAIN
Authors: Buck Jessica , Somers Kale , Whitehouse Jacqueline , Howlett Meegan , Hii Hilary , Strowger Brooke , Ebert Martin , Mehnert Andrew , Gottardo Nick , Endersby Raelene
Published: December 2020

Treatment for medulloblastoma involves craniospinal irradiation which is associated with devastating late effects. Clinical trials that simply reduce radiotherapy dosage have resulted in inferior survival rates, whereas new chemo/radiotherapy combinations that improve survival have been identified using preclinical models. However, the potential late effects of novel treatments are currently understudied and the assessment of radiation-induced late effects in mice remains challenging. Here, we aimed to measure the effect of multifractionated radiotherapy on the juvenile mouse brain as a baseline measure for future studies. NOD/Rag1-/- mice received either 8Gy whole-brain radiotherapy (WBRT) using an X-RAD SmART preclinical platform, 18Gy fractionated WBRT (9x2Gy doses), single, or multiple sham treatments beginning at postnatal day (P)16. Mice were aged to adulthood (>P63), then high resolution anatomical brain scans were obtained on a Bruker 9.4T MRI to measure the effects of WBRT on whole brain and specific regional area volumes. A single 8Gy dose (n=10) markedly reduced brain volume by 8.5% compared to single-sham controls (n=11, p<0.0001), whereas fractionated 18Gy treatment (n=7) did not cause significant differences in brain volume compared to multi-sham controls (n=4, p>0.99). Current analyses are focused on measuring treatment effects on specific areas of the brain, as well as other anatomical differences using a range of MRI techniques. These results will serve as a valuable tool to measure potential treatment-associated effects caused by novel chemo/radiotherapy combinations on the developing brain. This will enable future studies to assess the potential safety of novel treatment to inform clinical decision making.
RONC-05. PRESERVING VISION IN OPTIC PATHWAY GLIOMA AMONG PATIENTS WITHOUT NEUROFIBROMATOSIS TYPE 1
Authors: Hanania Alexander , Paulino Arnold , Ludmir Ethan , Shah Veeral , McGovern Susan , Grosshans David , Okcu Fatih , Baxter Patricia , Su Jack , Chintagumpala Murali
Published: December 2020

PURPOSE

Sporadic optic pathway/hypothalamic gliomas (OP/HGs) represent a unique entity within pediatric low-grade glioma. Despite favorable survival, the location makes treatment difficult and local progression debilitating. We conducted longitudinal assessment of visual acuity (VA) among patients treated in the modern era with chemotherapy (CT) or early radiotherapy (RT).

METHODS

Clinical characteristics were abstracted for patients treated over a 15-year period (2000–2015) at a single institution. Comprehensive ophthalmologic data taken at three to six-month intervals was examined with age-appropriate VA metrics converted to LogMAR scale. Kaplan-Meir “blindness-free survival” (BFS) curves were calculated as time to bilateral functional blindness (i.e. LogMAR ≥ 0.8 in both eyes), stratified by treatment and compared using log-rank test.

RESULTS

Thirty-six patients with median follow-up of 7.6 years (range: 2–17) were identified. Median age at diagnosis was 2.5 years (IQR: <1–5). Early RT was administered as initial therapy (n=6) or first-line salvage (n=5) in a total of eleven patients (31%) at a mean age of 12 years (range: 6–17). Twenty-five patients (69%) were maintained primarily on CT with a mean age at initiation of 2.4 years (range <1–8). Of these, five patients received RT after ≥2 systemic therapy regimens. In terms of visual preservation, five/eight-year BFS rates were 84%/59% and 100%/100%, for CT and early RT, respectively (p=0.046).

CONCLUSIONS

In a contemporary cohort, early RT, defined as initial or 1st line salvage therapy for OP/HGs manifested in superior VA. Children undergoing CT are at highest risk of functional blindness following five years of treatment.
RONC-20. RECURRENT HIGH-GRADE ASTROBLASTOMA TREATED WITH STEREOTACTIC RADIOTHERAPY
Authors: Nishimoto Shota , Kawanishi Yu , Fujita Shohei , Yawata Toshio , Ueba Tetsuya
Published: December 2020

INTRODUCTION

Astroblastoma is a rare, mostly supratentorial glial tumor, occurring predominantly in children and young adults. However, treatment strategies have not yet been established for this rare disease.

CASE PRESENTATION

A 6-year-old male presented with headache and nausea. CT and MR imaging revealed a left frontal mass lesion with slight edema and macrocalcifications. Gross tumor resection was performed. Histological examination found neoplastic cells with astroblastic characteristics, and a striking perivascular array of pseudorosettes. The final diagnosis was high-grade astroblastoma. MR imaging 13 months after surgery suggested local recurrence and enlargement was found 3 months later. Stereotactic radiotherapy (SRT) was performed. MR imaging after SRT showed enhanced cyst formation around the tumor bed, suggesting tumor recurrence. However, 11C-methionine PET revealed radiation necrosis. The last follow-up MR imaging 15 months after SRT showed no further recurrence.

CONCLUSION

Astroblastoma is rare, so no optimal management is known. SRT may be effective to treat recurrent astroblastomas. 11C-methionine PET/CT is useful for the differentiation from radiation necrosis.
RONC-21. IDENTIFICATION OF EPIGENETIC DRUGS AS RADIOSENSITIZERS IN PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Metselaar Dennis , ter Huizen Giovanna , Meel Michaël Hananja , Goulding Joshua , Waranecki Piotr , Carcaboso Angel Montero , Kaspers Gertjan , Hulleman Esther
Published: December 2020

Pediatric high-grade gliomas (pHGG) are malignant brain tumors with a high mortality rate. Radiotherapy (RT) is one of the cornerstones of current pHGG treatment, while the efficacy of chemotherapeutics remains inferior. The use of chemotherapeutics that specifically sensitize tumor cells to irradiation are poorly understood, but may help to increase the effect of RT in pHGG treatment. Since recent studies revealed pHGG to be epigenetically dysregulated, we tested 148 epigenetic drugs on eight primary pHGG models in the presence and absence of RT, to assess their radiosensitizing potential. Based on synergy scores, we found 22 compounds that resulted in enhanced cytotoxicity in the presence of RT. The effect of these compounds on pHGG was further investigated by tracking spheroid growth microscopically for 30 days, identifying four molecules that stopped spheroid-expansion solely in combination with RT (p=<0.001, multilevel regression). Parallel cell-viability assays reported identical results. Furthermore, tumor migration in 3D matrigel growth assays, using non-toxic doses of the four identified compounds, revealed that two compounds (the selective HDAC-inhibitors; chidamide and entinostat) stop the infiltrative growth characteristics of pHGG cells, exclusively in combination with RT. RNA-Seq data showed that entinostat and chidamide inhibit DNA-repair pathways like the Fanconi anemia cascade and homologous recombination. Since we anticipate that entinostat- or chidamide-induced radiosensitization can be enhanced by blocking kinase-driven escape mechanisms, we are currently conducting a kinome-wide CRISPR/Cas9 knockout screen in three primary pHGG models to develop combinational therapies. These results highlight entinostat and chidamide as potential radiosensitizers in pHGG treatment.
RONC-23. NOVEL APPROACH TO REDUCE ACUTE ESOPHAGEAL TOXICITY IN CRANIO-SPINAL IRRADIATION USING INTENSITY MODULATED PROTON THERAPY
Authors: Nakra Vineet , Chilukuri Srinivas , Gaikwad Utpal , MP Noufal , Patro Kartikeshwar , T Rajesh , Shamurailatpam Dayananda , Sunder Sham , Burela Nagarjuna , T Rishan , Tonse Raees , K Muthiah , Jalali Rakesh , A Manikandan , Krishnan Ganapathy
Published: December 2020

INTRODUCTION

We present our experience of a novel approach using intensity modulated proton therapy(IMPT) for cranio-spinal irradiation(CSI) leading to reduced acute esophageal toxicity and reduced treatment interruptions. MATERIAL AND

METHODS

Seven children younger than 12 years old treated consecutively with CSI using IMPT were included in this study. Three among 7 children received concurrent chemotherapy(CCT). Entire vertebral body(VB) was part of target volume in all patients. The IMPT plan was generated using 3 fields with single field optimisation technique. Last 5 patients were treated using dose gradient(DG) (98-93%) deliberately created in anterior most 3-5mm of VB. Initial 2 patients were treated with intention of covering entire VB with 98% isodose. Monte Carlo algorithm was used for dose calculations and optimisation, and robustness assessed for 3mm setup and 3.5% range uncertainty.

RESULTS

The CSI dose ranged from 21.6GyE to 35GyE. In patients without DG, maximum and mean dose to esophagus(36.67GyE vs. 25.45GyE, 31.53GyE vs. 20.41GyE), midline mucosa(28.95GyE vs. 25.31GyE, 21.8GyE vs. 14.61GyE) and bowel bag(32.9GyE vs. 24.27GyE, 3.59GyE vs. 3.21GyE) were higher compared to patients with DG. Both patients where DG was not created, developed grade 2 esophageal toxicities requiring supportive care and treatment interruptions(4 and 2days). All 5 patients with DG did not develop significant esophageal toxicity and had no interruptions.

CONCLUSION

Creating a dose gradient over anterior VB using IMPT reduces dose to esophagus and midline mucosa leading to lower acute esophageal toxicity which potentially avoids treatment interruptions during CSI.
SURG-06. AWAKE CRANIOTOMY FOR BRAIN TUMOR IN PEDIATRIC PATIENTS
Authors: Almeida Carlos , Antoniazzi Alessandra Levy , Mançano Bruna Minniti , Matsushita Marcus , Bacci Rachel Eggers , Basso Danielli , Lourenço Lucas Dias
Published: December 2020

BACKGROUND

The challenge of surgery in neurooncology is to achieve the maximum extent of resection while preserving eloquent functions. Intra-operative cortical mapping during resection of a brain tumor allows direct stimulation in eloquent areas with a reduction in postoperative deficits. This procedure has been performed in adults and children down to the age of 11 years. There are only two cases reported on the literature of an 8-year-old and 9-year-old child submitted to an awake craniotomy for brain tumor resection. Pediatric patients are prone to more risks than adults because they become easily agitated after pain sensation. Extensive preparation for the procedure is essential for pediatric patients in order to avoid a lack of cooperation. CASE PRESENTATION: Two patients, with 9-year-old presented with seizures due to a tumor in the left temporoparietal region. In order to identify language and motor–controlling areas during resection, we proposed an awake craniotomy. Because of their ages, they were prepared by a multidisciplinary team. The children’s cooperation during the mapping procedure and tumor resection were exceptional. Postoperative cranial MRI confirmed partial resection of the lesion, whose remnant was located in the left motor area. No seizures occurred during the postoperative period, and both were discharged without a neurological disability on the fifth day after the surgery. Histology revealed a dysembryoplastic neuroepithelial tumor (WHO grade I).

CONCLUSION

Brain mapping during resection of a tumor in an awake pediatric patient is feasible and can be safely performed even in patients under 11-year-old.