bluuebunny/crossref_metadata_2025_split huggingface dataset:
OTHR-17. FACILITATING THE POSTMORTEM DONATION OF WHOLE BRAIN AND SPINAL CORD IN PEDIATRIC PATIENTS WITH CENTRAL NERVOUS SYSTEM CANCERS
Authors: Kopsidas Caroline A , Morinigo Denise , Nourmohammadi Niku , Eze Augustine , Debasish Roy , Bornhorst Miriam , Yadavilli Sridevi , Packer Roger , Nazarian Javad 
Published: June 2024

Abstract

BACKGROUND
Postmortem tissue donation is often presented to families during end-of-life discussions. The sensitive nature requires every step to be handled with care, leading with empathy and delicately balancing scientific research and humanity. The Children’s National Hospital Postmortem Tissue Donation Workflow (The Workflow) provides a step-by-step guide for coordinating a successful donation. It outlines the order in which clinical research teams communicate with patient care teams, families and collaborators to make the donation possible. This program, established in 2010, aims to acquire more pediatric brain and spinal cord tumor specimens to further understand the disease biology.

OBJECTIVE
This paper aims to provide a template for coordinating a successful postmortem tissue donation. Ultimately, to broaden the network of tissue donation across all hospitals and institutions, thus furthering scientific research.

METHOD
In order to create The Workflow, Clinical Research Coordinators from Children’s National Hospital conducted numerous postmortem donations and noted the failures and successes of each case. This information was compiled into a stepwise workflow including email templates and checklists. It begins with contacting the care team, and the following hours to days are spent obtaining a pathologist for tissue procurement, and facilitating the shipment of samples. While these steps must be completed in a timely manner for sample integrity, we also prioritize the wishes of the family and act with compassion at the forefront.

RESULTS/DISCUSSION
Children’s National Hospital was designated as a Center of Excellence for postmortem coordination by the Swifty Foundation in 2018. Our team has since established and standardized a workflow for the donation process. The Children’s National Hospital Postmortem Workflow allows our research team to study brain tumors including DMGs, High and Low Grade Gliomas, and Medulloblastomas. The generosity of the families and hard work of each collaborator allows us to expand our knowledge of tumor biology.
OTHR-24. CLINICAL COURSE OF ISOLATED PITUITARY STALK THICKENING IN PEDIATRIC PATIENTS AND RISK FACTOR FOR NEOPLASTIC ETIOLOGY: A SINGLE INSTITUTIONAL EXPERIENCE
Authors: Miller Hannah K , Rajan Vikram P , Gorsi Hamza S 
Published: June 2024

Abstract

BACKGROUND
The incidence of pituitary stalk thickening (PST) has increased in recent years due to the increased utilization of diagnostic MRI of the brain. The etiology of PST includes germ cell tumors, Langerhans cell histiocytosis (LCH), and lymphocytic hypophysitis, among others. The clinical significance of PST, appropriate diagnostic workup, and clinical course for these patients is not well documented. We report our institutional experience with patients presenting with PST.

METHODS
After IRB approval, we reviewed lists of patients discussed in pediatric tumor boards from 2003-2023 to identify patients with PST. We excluded patients with other significant intracranial masses from our analysis. We followed the clinical course of these patients to collect applicable data.

RESULTS
A total of 20 patients were identified with PST, five patients were excluded due to additional MRI findings. The median age of diagnosis with PST was 14 years; 60% of cases were female. Seven patients had diabetes insipidus (DI), and five patients had other endocrinological abnormalities. Initial diagnostic workup included serum and CSF tumor markers (AFP, B-HCG), skeletal survey, CBC, and CMP. With this initial workup, no patients were diagnosed with neoplasm. All patients were followed with serial MRIs. Four patients (26.6%) displayed progression of PST, warranting biopsy. The median time from diagnosis to biopsy was seven months (range 4-26 months). Among four patients with biopsy, two had LCH, one had germinoma, and one inconclusive result. Among those diagnosed with neoplasm, 100% of them had DI. Three patients had complete resolution of PST during the follow-up period. Eight patients had stable PST during the median follow-up period of 19.5 months (Range 3-59 months).

CONCLUSIONS
Most isolated PST among pediatric patients remained stable during the follow-up period. The risk for neoplastic process was high among patients with increasing thickening of pituitary stalk and DI.
OTHR-25. ANAPLASTIC TRANSFORMATION OF DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMORS: TWO PEDIATRIC CASES
Authors: Aguilera Dolly , Janss Anna , Schniederjan Matthew , Goldman-Yassen Adam , Velazquez Jose , Mazewski Claire , Gray Rachel , MacDonald Tobey , Fangusaro Jason , Castellino Robert Craig 
Published: June 2024

Abstract

BACKGROUND
Diffuse Leptomeningeal Glioneuronal Tumors (DLGT) typically have a clinical course with slow progression; however, there have been cases of anaplastic transformation. We describe the clinical presentation, radiographic features, and molecular characteristics in 2 pediatric DLGT cases that underwent aggressive transformation.

METHODS
Patient 1: A 20 y/o male with DLGT with BRAF-KIAA1549 fusion and loss of 1p who was first diagnosed at 2.5 y/o. Over the course of 17 years, he was treated with numerous therapies due to multiple progressions, including temozolomide, carboplatin/vincristine, selumetinib, and vinblastine. At age 17, he developed significant growth of a posterior fossa mass with solid and cystic characteristics. Resection revealed new anaplastic pathologic features. Patient 2: He was diagnosed with DLGT at age 2 y/o. Imaging demonstrated intramedullary spinal nodules at T4 and T5 with abnormal thickening and enhancement over the cerebral leptomeningeal space. A biopsy revealed DLGT with a BRAF-KIAA1549 fusion, 1p loss and Ki67 5%. He received multiple therapies including carboplatin/vincristine, vinblastine, and selumetinib.

RESULTS
Patient 1: Molecular characterization revealed new ATRX mutation, and CDKN2A/B homozygous deletion. Over the following 2 years, he had multiple treatments, progressions, and surgeries. Final pathology revealed significant anaplasia with Ki67 90%, ATRX loss, and mutation of PPM1D and ARID1A. He rapidly declined. Patient 2: Approximately 2.5 years after diagnosis, he developed rapid progression in the 4th and lateral ventricles. Pathology confirmed recurrent DLGT, but with high-grade transformation, H3K27M (-), H3k27m3 loss, ATRX (+), Ki67 40%. He was treated with focal irradiation followed by temozolomide/CCNU.

CONCLUSION
In rare cases, DLGT can undergo anaplastic transformation. Once this occurs, it behaves clinically like a high-grade glioma. Understanding the molecular underpinnings and prognostic features that lead to this transformation are important for future study.
PALC-02. PALLIATIVE RADIOTHERAPY FOR HAEMOSTASIS IN CHILDREN WITH CEREBRAL METASTATIC HAEMORRHAGE
Authors: Coassin Elisa , Vitullo Angelo , Pilotto Chiara , Liguoro Ilaria , Toniutti Maristella , Tuniz Francesco , Vindigni Marco , Pegolo Enrico , Cogo Paola Elisa , Mascarin Maurizio 
Published: June 2024

Abstract

BACKGROUND
Among children, bleeding from brain metastases is rare. Bleeding could be caused by: cancer, treatments and chemotherapy/other drugs such as Bevacizumab, NSAIDs and anticoagulants. We report a case of brain RT after metastases bleeding.

METHODS
A 14-years-old boy with a negative previous medical history presented to the Emergency Department with seizures and loss of consciousness. Full-body CT scan revealed brain and renal haemorrhages and a right testicular lesion. Serum βhCG was 223,773 mIU/mL. Neurosurgical bleeding control and right orchiectomy were performed: the histopathology revealed a metastatic mixed non-seminomatous germ cell neoplasia of the testis. First-line chemotherapy (4 cycles of Cisplatin/Etoposide/Ifosfamide) and second-line treatments (Paclitaxel/Ifosfamide/Cisplatin and Gemcitabine/Paclitaxel/Oxaliplatin) were performed. Suddenly, he presented with left-sided hyposthenia and partial left hemibody seizure. CT scan revealed 2 haemorrhagic brain lesions, one in each hemisphere. Surgery was not feasible. We started anti-oedema and anti-epileptic therapy, and whole brain RT (WBRT, 36 Gy/12 fx, BEDα/β= 10 Gy= 46.8 Gy). After 5 days from the start, RT had a 7-day stop because of acute oedema and clinical deterioration. Fourth-line chemotherapy was administered with CarboPEB (1st of further 4 cycles), and then WBRT was restarted. At the end of WBRT a stereotactic RT boost to both the haemorrhagic lesions was delivered (20 Gy/10 fx, BEDα/β= 10 Gy= 24.0 Gy). As of today, eight months after the end of therapy, the patient is free from disease and βhCG is negative.

CONCLUSION
Palliative RT in children is a non-conventional indication, but potentially effective at providing rapid haemostasis, especially in selected cases (surgery not feasible/contraindicated, adult-type histologies, …) and it is ensuring a good tumor control and low-grade acute toxicities. Hypofractionation is suggested to balance patient comfort and treatment effectiveness, especially when life expectancy is short. The optimal RT schedule, dose and fractionations need to be further investigated.
PATH-11. FEASIBILITY OF BRAIN TUMOR CLASSIFICATION BY ENZYMATIC DNA METHYLATION SEQUENCING ANALYSIS OF CELL-FREE DNA OBTAINED FROM CEREBROSPINAL FLUID
Authors: Taylor Aaron Michael , Lombardi Jody T , Patel Areeba , Martin Jonathan , Bookland Markus J , Hersh David S , Cantor Evan , Song Xianyuan , Sahm Felix , Ng Patrick Kwok-Shing , Gell Joanna J , Lau Ching C 
Published: June 2024

Abstract

BACKGROUND
Array-based DNA methylation profiling is the gold standard for molecular classification of brain tumors. However, it relies on significant amount of input DNA extracted from surgical tissue, thus limiting its use for tumors where biopsy is challenging or limited in quantity. Cell-free tumor DNA (cfDNA) in cerebrospinal fluid (CSF) presents alternative opportunities for brain tumor diagnosis and disease monitoring following treatment. Novel enzymatic DNA methylation sequencing (EM-seq) methods may allow us to overcome input DNA limitations and accurately quantify methylation from cfDNA.

METHODS
We performed methylation sequencing using the NEBNext EM-seq kit on cfDNA from archival CSF samples collected from three brain tumor patients with confirmed histopathological diagnoses. Variable amounts of input cfDNA (0.1ng-10ng) were tested. We utilized the methylseq pipeline for data processing. For tumor classification, data was limited to CpG sites overlapping the MethylationEPIC array before analysis using MNP-Flex, a modified platform-agnostic version of the Heidelberg methylation classifier

RESULTS
Using the EM-seq method, genomic coverage for 10 and 1ng input DNA samples (average: 46x and 26x, respectively) was sufficient for generating global methylation profiles. Samples with 0.1ng input showed an average coverage of only 5.32x due to high levels of read duplication. However, methylation levels for CpG sites with at least 5x coverage were highly correlated across varying input DNA amounts, suggesting that lower input cfDNA could still be used for tumor classification based on relevant CpG sites.

CONCLUSIONS
Using the MNP-Flex classifier, which was originally trained with methylation array data from tumor tissue, we successfully predicted brain tumor types (both high-grade glioma and medulloblastoma) with cfDNA methylation data down to only 0.1ng of input cfDNA, matching diagnosis based on tissue methylation and histopathology in this pilot study. Further classification of additional tumor types using CSF cfDNA is required to confirm the clinical utility of this platform.
LMIC-15. OUTCOMES OF PEDIATRIC MEDULLOBLASTOMA IN LOW- AND MIDDLE-INCOME COUNTRIES: A REPORT OF 330 PATIENTS FROM 8 COUNTRIES
Authors: Diaz-Coronado Rosdali , Hernandez-Broncano Eddy , Negreiros-Chinchihuara Tatiana , Casavilca-Zambrano Sandro , Campos Danny A , Baticulon Ronny E , Alcasabas Ana Patricia A , Khu Kathleen , Hamid Ahmer , Zia Nida , Syed Yumna , Yousuf Bisma , Omran Nuha , Sharafeldin Hend A , Seddik Khaled , Fadel Shady , Pineda Estuardo , Polanco Ana , Foo Jen Chun , Rajagopal Revathi , Ganesan Dharmendra , Campo Regina Navarro-Martin del , Arredondo-Navarro Luis , Escamilla Gabriela , Ruvalcaba Rafael , García Beatriz , Amarillo Paloma , Villegas Cesar A , Job Godwin , Faughnan Lane , Devidas Meenakshi , Qaddoumi Ibrahim , Moreira Daniel C 
Published: June 2024

Abstract

BACKGROUND AND AIMS
Reports from low-and middle-income countries (LMICs) indicate lower survival in medulloblastoma (MB), though these studies are mainly from single institutions. This multi-institutional, retrospective study aimed to analyze the outcomes for MB in 9 centers in 8 LMICs.

METHODS
Patients &lt;18 years old with newly diagnosed MB, treated from January 2014 to December 2018 in Egypt, El Salvador, Malaysia, Mexico, Pakistan, Peru, Philippines, and Uruguay were included. Data on demographics, clinical presentation, treatment and biological characteristics were collected. Factors associated with patient outcomes were analyzed.

RESULTS
The study included 330 patients with a median age of 7.7 years. Of these, 49 patients (15%) were &lt;3 years old and 212 (64%) were male. Eighty-eight patients (26%) had experienced symptoms for &gt;3 months at diagnosis. Gross total resection was achieved in 153 (47%) patients. Sixty-three patients (19%) experienced post-operative infections. Eighty-four patients (24%) had metastatic disease at diagnosis. The histologic subtype was not specified in 98 cases (30%), and 25 patients (7%) had molecular subgroups identified. Radiotherapy was administered to 216 patients (64%). The median number of chemotherapy cycles was 8 (range 0-14). There were 64 patients (19%) who abandoned treatment, and 24 patients (7%) died due to treatment-related toxicity. The 5-year event-free survival (EFS) was 44±4%, while the 5-year overall survival was 58±4%. The 5-year EFS for patients &lt;3 years was 42±9%, while 44±4% for older patients (p=0.49). The 5-year EFS for patients with metastasis was 38±7%, while it was 46±4% for patients without metastasis (p=0.13).

CONCLUSIONS
This large, multinational cohort of MB in LMICs describes poor outcomes, which may be attributed to delays in care, high abandonment rate, surgical complications, treatment-related mortality and a low fraction of patients receiving radiotherapy. Interventions to build care capacity can be prioritized based on these data.
RADT-03. IDENTIFYING BRAIN STRUCTURES LINKED TO RADIATION-INDUCED ENDOCRINE AND COGNITIVE SEQUELAE: A MULTI-CENTRE VOXEL-BASED ANALYSIS
Authors: Davey Angela , Wilson Lydia J , Osorio Eliana Vasquez , Green Andrew , Vaughan Kate , Clayton Peter , Albutt Lesley , van Herk Marcel , Merchant Thomas E , McCabe Martin G , Aznar Marianne C 
Published: June 2024

Abstract

BACKGROUND
Radiotherapy (RT) is a common treatment for paediatric brain tumours. Despite advancements in techniques to mitigate RT-induced toxicity, almost two-thirds of patients develop long-lasting endocrine and cognitive sequalae. Image-based data mining (IBDM) is a voxel-based analysis tool that can identify dose-sensitive regions, supporting development of tailored radiation treatments for future patients that avoids these regions. We present the first IBDM study localising endocrine and cognitive effects in paediatric brain tumour patients.

METHODS
Imaging (MRI and CT) and clinical data were available for 261 children (146 medulloblastoma patients in centre A, 115 patients with mixed diagnoses in centre B). Outcomes were reported as Growth Hormone Deficiency (GHD, presence/absence, both centres) and processing speed (PS, continuous slope derived from a linear mixed-effects model, centre A). IBDM evaluated where dose was associated with outcome (p-value&lt;0.01). Mean dose to this region was included in multivariable analysis adjusting for age, risk status, hydrocephalus status/management, and chemotherapy.

RESULTS
GHD was associated with dose to a region overlapping the pituitary and brainstem. In centre A, multivariable analysis revealed a 13(2-27)% average increase in GHD odds per 1Gy increase in dose, with an inverse effect for age. Center B showed a 8(4-13)% average increase for every 1Gy, with no other predictors. For PS, a central frontal region from the medial frontal lobes to the hypothalamus was identified (139 patients in centre A). Every 1Gy increase led to a -0.08(-0.20 – 0.04) PS change, with age and hydrocephalus management as contributing factors.

CONCLUSION
We identified a region (encompassing the pituitary and brainstem) associated with increased risk of GHD, that was consistent in two independent cohort analyses. Furthermore, PS decline was linked to dose to a frontal region. Minimising dose to these regions for future patients could reduce the risk of cognitive and endocrine sequelae.
RADT-08. BASAL GANGLIA TOXICITY FOLLOWING PROTON THERAPY OF THE PINEAL REGION WITH BILATERAL ACTION-INDUCED MYOCLONUS
Authors: Soike Michael H , Warren Emily , Gonçalves Fabrício G , Cardenas Agustin , Littrell Mary E , Metrock Laura K , Alva Elizabeth , Thompson Marla , Gantz Emily , Rocque Brandon , Murdaugh Donna , Dhall Girish 
Published: June 2024

Abstract

INTRODUCTION
We sought to evaluate the toxicity profile for children receiving 54Gy to the pineal region with a significant dose delivered to posterior thalamus and basal ganglia.

METHODS
We performed a retrospective review of patients treated at a single institution with intensity modulated proton therapy (IMPT) receiving 54Gy to the pineal region. Multiple beam angles were utilized for planning. Patient characteristics and dosimetric data were correlated with late-toxicity and imaging.

RESULTS
From 2021-2023, six children were treated, and at a median follow-up of 13 months [9-26], all patients remain disease-free. Three patients had non-germinomatous germ cell tumors, 1 low-grade glioma, 1 atypical teratoid rhabdoid tumor (ATRT), and 1 embryonal tumor with multilayered rosettes. Age range was 2.4 to 16.8 years. All patients received chemotherapy prior to IMPT. Neuropsychological evaluation indicated range of intellectual functioning (mean = 98.3 [83-118]). One patient, a 4-year-old female with ATRT, developed T2 changes within the globus pallidus and thalamus on 3 month follow-up. At 5 months, she developed bilateral action-induced myoclonus with corresponding enhancing lesions in the globus pallidus bilaterally. Neuropsychological evaluation at 5 months post-treatment indicated memory impairments. She was treated with dexamethasone without improvement. Between 912 months post-treatment, tremors improved with physical therapy and imaging showed near complete resolution of enhancement within globus pallidus.

CONCLUSION
One of six children developed grade 3 toxicity manifesting as bilateral action-induced myoclonus with imaging changes in the globus pallidus bilaterally following IMPT and exhibited related neuropsychological deficits. While brainstem toxicity from IMPT is well documented, globus pallidus toxicity is not well characterized. Given the contiguous neuronal tracts with the brainstem, it is logical to apply similar treatment planning techniques, i.e. minimizing hotspots within the globus pallidus and thalamic “core” structures, and being cognizant of LET/RBE effects for treatment involving the pineal region in young children.
STEM-03. A NOVEL MOUSE MODEL OF CHOROID PLEXUS CARCINOMA UNRAVELS SEQUENTIAL DEDIFFERENTIATION OF HINDBRAIN CHOROID PLEXUS TISSUE AND REVEALS NEW THERAPEUTIC PROSPECTS
Authors: Peter Levke-Sophie , Altendorf Lea , Hack Karoline , Thaden Vanessa , Göbel Carolin , Krebs Christian F , Jauch-Speer Saskia-Larissa , Kordes Uwe R , Obrecht-Sturm Denise , Thomas Christian , Schüller Ulrich , Schoof Melanie 
Published: June 2024

Abstract

BACKGROUND
Choroid Plexus tumors constitute 10-20% of brain tumors in the first year of life. Among those, Choroid Plexus Carcinomas (CPC) pose a significant challenge due to their aggressiveness, resulting in poor survival rates and long-term adverse effects stemming from intense therapeutic approaches. Although loss of p53 and Sonic hedgehog signaling have been implicated in CPC development, a deeper biological understanding is needed to expand mechanistic insights and advance targeted therapies.

METHODS
We generated a novel mouse model with a simultaneous loss of TP53 and overexpression of MYCN and Gli2 in central nervous system precursors (hGFAP-cre::P53Fl/Fl::lsl-MYCN::lsl-Gli2). Resulting tumors were histologically characterized and compared to human CPC. Moreover, spatial transcriptomic data were generated for molecular characterization. Finally, mouse tumor-derived cell lines were employed for differentiation analysis and therapeutic testing.

RESULTS
Examinations at different developmental stages revealed brain tumors in the choroid plexus as well as smaller lesions in the subcallosal cortex with a penetrance of 80% within 18 days. We observed a gradual dedifferentiation of hindbrain CP tissue from day 5 onwards, indicating a continuous developmental sequence corresponding with expanding tumor growth. The mouse model recapitulates early tumor development, aggressive and metastatic growth along with histological features of human tumors. Spatial transcriptomic analysis highlighted chromosomal aberrations as well as other features known from human CPCs and emphasized the disturbance of ciliary pathways in tumor development. In vitro studies revealed rapidly growing tumor cells with stem cell-like differentiation potential and high sensitivity to targeted therapies.

CONCLUSION
Through in-depth analysis, including multiple data types, we show that our novel CPC mouse model closely resembles human tumors. Our tumors reveal a strict pattern of dedifferentiation implying similar mechanisms in humans. Additionally, primary mouse tumor cells in culture facilitate further in vitro analysis, and newly generated spatial transcriptomic data enables further insights into tumor biology.