bluuebunny/crossref_metadata_2025 huggingface dataset:
OTHR-10. Pilocytic astrocytoma with respect to treatment
Authors: Hwee Tang Phua , Nisa Sameema
Published: June 2022

AIM: To describe the sizes of pilocytic astrocytoma with respect to treatment Methodology Pediatric pilocytic astrocytomas cases from 2001 to 2021 were retrospectively reviewed in this Institutional Review Board approved study. Imaging reports, location of tumour, maximum dimension of tumour at diagnosis, treatment given (operation/chemotherapy/ radiotherapy), degree of tumor excision were captured. RESULTS: Imaging was available in 33 with 23 centered in the posterior fossa (1 extending into thalamus), 4 in suprasellar region, 2 in cerebral hemisphere, 2 in thalamus, 1 in pineal thalamic region and 1 in cervicomedullary spine, Tumor dimension at presentation was 5.40 cm ± 2.34 cm. Tumor size at presentation did not show significant correlation with age. 30 patients underwent operation with tumours completely excised in 15 and partially excised in 14 and no postoperative information for 1. Three patients, where tumour involved the thalamus, did not have operation and were given radiotherapy, average size of tumour being 3.47 + 1.15 cm. compared to the 5.59 + 2.34 size of tumours that underwent operation (p=0.06). Completely excised tumours measured 6.29 ± 2.04 cm at presentation while incompletely excised ones measured 4.76 ± 2.53 cm, not significantly different (p=0.09). Unoperated tumours are statistically smaller than those completely excised (p=0.02). One of the completetly excised tumours was located in the parietal cerebral hemisphere with the rest of the 15 in the posterior fossa. Seven of the incompletely excised tumours were located in the posterior fossa with 4 in suprasellar region, 1 in thalamus, 1 in spine and 1 in cerebral hemisphere. 3 patients with uncompletely excised tumours (1 cerebral, 1 post fossa, 1 spine) had post-operative radiation while 2 suprasellar tumours were given post-operative chemotherapy. CONCLUSION: Completely excised tumours are mainly located in posterior fossa. Tumours not operated on are located in thalamus and significantly smaller than tumours which are completely excised.
OTHR-12. Incidentalomas; should benign, indeterminate MRI findings be discussed at the paediatric neuro-oncology MDT
Authors: Large Alexandra , Picton Sue
Published: June 2022

BACKGROUND: In 2020, 503 patients were discussed at the weekly neuro-oncology MDT meeting, at a UK tertiary paediatric hospital. This was a 50% increase from 2016. Anecdotally, an increased number of non-tumours were being discussed. OBJECTIVES: To determine whether Paediatric Neuro-oncology MDT is consistent with follow up of benign, incidental findings on MRI scan and whether these lesions become significant.METHODS: MDT discussion notes reviewed for all incidental and benign MRI head findings between 05/09/18 and 02/09/20.RESULTS: 59 MRI head lesions, that were deemed to be both incidental and benign were discussed at the MDT. 44% of referrals were from the local hospital; this may be due to availability of the MDT or complexity of the patient cohort. Findings discussed included pineal cysts (24), arachnoid cysts (3), epidermoid cysts (1), pituitary lesions (4) and other indeterminate lesions or signal change (27). The majority of children received serial MRI imaging after MDT. There were large inconsistencies in the follow-up interval recommended, even within similar pathologies. For example, pineal cysts follow up ranged from no repeat imaging to multiple repeat scans with 6 and 12 month intervals. ‘Complex’ cysts were more likely to receive follow up but there is little consensus between radiologists about criteria for a ‘complex cyst’. None of the lesions reviewed changed significantly over time. Perhaps most strikingly, only 2/27 of the ‘indeterminate lesions’ have been discharged from the MDT. CONCLUSIONS: As clinical reasoning is seldom recorded in reports or MDT discussion notes the reasons for different surveillance recommendations is difficult to ascertain retrospectively. However, as MRI scans become more readily available incidental and being findings will increase, potentially putting great pressure on an already stretched service. Serial MRI imaging also creates unnecessary anxiety for both the child and their family.
OTHR-16. Nutritional screening of U.S. pediatric central nervous system tumor survivors
Authors: Soja Jacqueline , Wilson Rebekah , Yunker Alexandra , Aziz-Bose Rahela , Gordon Erin , Dieli-Conwright Christina , Cooney Tabitha
Published: June 2022

INTRODUCTION: Adult survivors of pediatric central nervous system (CNS) tumors are at the highest risk for morbidity and late mortality among all childhood cancers – owed in part to chronic health condition burden, which intersects with environmental and lifestyle factors. Their weight epidemiology has not been previously characterized. METHODS: An institutional, cross-sectional study was carried out amongst young adults ages 18-39 years, previously treated for pediatric CNS tumors and seen in our specialty survivorship clinic from January 2016 to December 2021. Sociodemographic, clinical, and treatment information was extracted from medical records and summarized by descriptive statistics. Anthropometric information extracted from clinical visit records was used to calculate body mass index (BMI) and weight status category according to CDC guidelines. RESULTS: We identified 200 survivors, 47% male and 53% female. Median age was 26 years (range 18-39); patients were median 16.5 years (range 1.5-34.2) from initial diagnosis. Most common primary diagnoses were low grade-glioma (51.0%) and embryonal tumor (20.5%.) One hundred and five (52.5%) survivors had received prior cranial radiation; 81 (40.5%) had an endocrinologic disorder at time of visit. Amongst the entire cohort, 39% were healthy weight, 5% were underweight, 27% overweight, 21% obese, and 8% severely obese. CONCLUSION: The majority of young adult survivors seen in our clinic were not healthy weight by BMI definition. The distribution of BMI groups appears comparable to contemporary studies of the general young adult U.S. population. For those with decreased muscle mass, a previously recognized issue in pediatric CNS tumor survivors, BMI may underestimate body fat. By abstract presentation, univariable analyses will be performed using the Fisher’s exact test or Wilcoxon rank sum test to assess for undernutrition and overnutrition risk factors. Our refined understanding of the nutritional epidemiology in this population will allow for more strategic diet and exercise interventions.
OTHR-17. Guidance for providing families with autopsy research results
Authors: Meyer Ashley , Beck Mary , Cluster Andrew , Ogle Andrea , Rubin Joshua
Published: June 2022

BACKGROUND: The Legacy Program is a project where research autopsies are performed on the brain of Neuro-Oncology patients. There continues to be growing consensus that investigators should offer their study participants results once the research project has concluded. Several organizations like the Children’s Oncology Group have established Return of Results programs however, returning research results from autopsy samples is not a common practice. Families have voiced the importance of autopsy donation and want results from that donation. To them, this donation creates a legacy for their loved one and provides hope that their contribution to research will impact the life of future patients. As researchers, this project provides a novel platform where patients and their families can directly influence new research endeavors. OBJECTIVES: We organized a retreat to disseminate research findings to the families of patients who have donated tissue. In addition to the family members, the entire research team and clinical staff were invited. Our primary aims were to evaluate participant satisfaction and obtain feedback that would be utilized for future program planning. METHODS: At the end of the retreat a de-identified, open-ended questionnaire was handed out. Six were returned and evaluated. RESULTS: All participants were in favor of the format and content that was presented and requested an invitation to future retreats. Participant feedback included how to become more involved with the Legacy Program and the request for the creation of a social media group where families could continue to connect and provide support to each other CONCLUSIONS: Our study confirmed the importance of returning autopsy results. The retreat provided needed support to the participating families. During the retreat, researchers were able to hear direct feedback from their findings and the families voiced their goals for future research. This information was invaluable and helped shape our program.
OTHR-19. Disordered cell migration in the cerebral cortex caused by Lin28A overexpression and Wnt pathway activation in neural precursor cells
Authors: Navolic Jelena , Middelkamp Maximilian , Sumislawski Piotr , Ruck Lisa , Krisp Christoph , Dottermusch Matthias , Schlüter Hartmut , Neumann Julia E
Published: June 2022

LIN28A overexpression and mutations of the Wnt pathway gene CTNNB1 have been described in rare malignant brain tumors of early childhood. In order to investigate the interplay of the oncogenic proteins Lin28A and Ctnnb1 during embryonal brain development, we overexpressed these components in neural progenitor cells in vivo. The sole overexpression of either Lin28A, stabilized Ctnnb1 (Ctnnb1Δex3) or the combination of both in hGFAP-positive forebrain precursor cells did not lead to brain tumor formation but resulted in distinct phenotypes in the cerebral cortex during embryonal development. The hGFAP-cre::IsI-Lin28A (GL) mouse model showed transiently increased proliferation in the cerebral ventricular zone and proper isocortical layering. hGFAP-cre::Ctnnb1Δex3fl/+ (GB) and hGFAP-cre::Ctnnb1Δex3fl/+::IsI-Lin28A (GBL) mice developed a hydrocephalus and showed disturbed cortical layering. GB mice displayed cerebral hypoplasia with a thinned cortex, while the GBL cortices showed variable thickness. Immunostainings with the pial marker Laminin and dendritic marker Map2c revealed a porous pia mater and aggregations of neurons above the pial border in the GBL model at embryonal day 14 (E14.5). At later embryonal stage (E18.5), the GBL model showed also large blood vessels located in deeper cortical layers. Proteome analyses of GB and GBL cortices revealed decreased abundance of the Lissencephaly associated component Reelin-receptor Lrp8 compared to hGFAP-cre control mice. Additionally, we found 92 proteins, which were altered specifically in the GBL mouse model. These results indicate that the co-expression of Lin28A and Ctnnb1Δex3 in neural precursor cells does not lead to brain tumor formation but results in neuronal migration disturbances with ectopic neurons in the subarachnoid area. Whereas the GB phenotype is reminiscent of human lissencephaly type I, GBL brain morphology showed similarities to neuronal overmigration observed in the migration disorder of human Cobblestone (Type II) Lissencephaly.
OTHR-22. Malignant mesothelioma (MM) as second cancer in childhood brain tumor survivors: the first child with neurofibromatosis type 2 and concurrent MM
Authors: Crocco Marco , Verrico Antonio , De Marco Patrizia , Ognibene Marzia , Capra Valeria , Romano Ferruccio , Moreiro Cristina , Bennicelli Elisa , Salfi Nunzio , Barra Salvina , Rizzo Francesca , Rossi Andrea , Milanaccio Claudia , Garrè Maria Luisa , Piccolo Gianluca
Published: June 2022

We report two cases of malignant mesothelioma (MM) in childhood brain tumor survivors. A 40-year-old man, who was treated at the age of ten with chemotherapy and craniospinal radiotherapy (up to 54.5 Gy) for a pineal secreting non-germinomatous germ cell tumor, had persistent fever, fatigue, and weight loss. A total body CT scan revealed several pulmonary and abdominal wall nodularities. The histological examination on a biopsy diagnosed a biphasic MM. The karyotype and array-CGH of peripheral blood were normal; a FISH of tumor cells showed a breakage of locus EWSR1 (22q12.2). In this case, environmental exposure was identified (asbestos in public water tanks). His MM followed an aggressive course and resulted in death after three months. A twelve-year-old boy affected by severe neurofibromatosis type 2 (NF2) already treated with several neurosurgical exeresis and chemotherapy lines (hydroxycarbamide, bevacizumab, sirolimus), developed multiple abdominal lesions, associated with pleural effusion and weight loss. The CT scan showed the thickening of the left pleura and multiple peritoneal nodules. The cytological examination on thoracentesis diagnosed an epithelioid MM. The karyotype on paracentesis-obtained cells revealed monosomy of chromosomes 14 and 22, loss of Y, and trisomy of 6, 10, 11, 16, and 20. NGS is currently ongoing to exclude germline or somatic second hits. Importantly, no exposure to asbestos was found. Less than 2% of MMs occur below 45 years of age; it is a rare secondary tumor in cancer survivors and environmental or genetic contributing causes are often detectable on a careful investigation. Variants in NF2 are considered to be the second most common after those in BAP1. To our knowledge, this is the first child with NF2 and concurrent MM reported to date. Compared to the expected prognosis, his MM has followed a mild course, and one year after diagnosis he is still alive.
OTHR-26. A pilot study of clinical minimal residual disease detection in pediatric embryonal brain tumors
Authors: Cole Bonnie , Lockwood Christina , Paulson Vera , Lee Amy , Hauptman Jason , Goldstein Hannah , Vitanza Nicholas , Crotty Erin , Leary Sarah
Published: June 2022

Cell-free DNA (cfDNA) presents an opportunity for measurement of minimal residual disease (MRD) in pediatric central nervous system (CNS) tumors. In this pilot study, we sought to evaluate the clinical use of low-pass whole genome sequencing (LP-WGS) of cfDNA in cerebrospinal fluid (CSF) of patients with embryonal neoplasms. 31 CSF samples were collected from 16 patients with molecularly characterized medulloblastoma (12), embryonal tumor with multilayer rosettes (2), and CNS embryonal tumors, NEC (2). Samples were collected at various treatment time points. Processing included centrifugation and freezing prior to cfDNA extraction, repair, adapter ligation, amplification, purification, and sequencing on an internally-developed and clinically-validated LP-WGS assay utilizing custom-developed bioinformatics and molecular pathologist review. 29 of 31 samples (94%) had adequate cfDNA in CSF for LP-WGS analysis. Copy number variants (CNVs) compatible with tumor were detected in 23 of 29 (79%) samples, including isodicentric chromosome 17, monosomy 6, MYCN amplification, and regional amplification of chromosome 19. In all cases with detectable cfDNA alterations in CSF, CNV were compatible with the molecular findings in tumor tissue. Two CSF samples had additional chromosomal alterations detected at the time of tumor progression that were not identified in the original tumors. All 9 lumbar puncture samples (100%) collected at initial staging had CSF cfDNA alterations indicative of MRD while corresponding cytologic evaluations of the same samples were positive in only 1 of 9 (11%). No MRD was detected in the single sample evaluated at the end of therapy time point. These findings suggest that LP-WGS of cfDNA in CSF represents a sensitive and clinically useful test for detection of MRD in patients with embryonal tumors of the CNS independent from CSF cytology. Future prospective studies are warranted to determine whether LP-WGS analysis of cfDNA in CSF can predict tumor recurrence and early treatment resistance in our patients.
OTHR-32. The Pediatric Targeted Therapy 2.0 registry: robust molecular diagnostics for precision oncology
Authors: Ecker Jonas , Selt Florian , Sturm Dominik , Sill Martin , Korshunov Andrey , Capper David , Hirsch Steffen , Dikow Nicola , Sutter Christian , Müller Carina , Sigaud Romain , von Deimling Andreas , Pajtler Kristian W , van Tilburg Cornelis M , Jones David T W , Sahm Felix , Pfister Stefan M , Witt Olaf , Milde Till
Published: June 2022

BACKGROUND: The Pediatric Targeted Therapy (PTT) 2.0 program was established to enable precision oncology for relapsed pediatric oncology patients by performing a set of molecular analyses on tumor samples to improve diagnostic accuracy and to detect actionable alterations. METHODS: International pediatric oncology patients with relapse or progression after standard of care treatment independent of histological diagnosis were included. Required material was an FFPE sample from any disease episode available to perform a DNA methylation array, customized targeted gene panel sequencing (130 genes), RNA Sanger sequencing in selected cases, and a pathway-specific immunohistochemistry (IHC) panel. For sequencing a blood sample was used as paired constitutional DNA, allowing for detection of potential cancer predisposition syndromes. All molecular results were discussed in an interdisciplinary tumor board and reported back to the submitting centers. The clinical impact of reported findings was assessed by a serial questionnaire-based two year follow-up. RESULTS: n=266 patients were registered, the molecular workup was successfully performed for n=263 (99%) patients. The most frequent diagnostic category was central nervous system tumors (n=172/263, 65%). Integrated molecular diagnostics suggested a refined or changed diagnosis in n=95/172 (55%) brain tumors. Actionable targets were detected in n=106/172 (61%) cases. In n=11/155 (7.1%) of brain tumor patients pathogenic or likely pathogenic constitutional DNA variants with clinical relevance were identified, n=5 (45%) of which were previously unknown. Clinical follow-up of revealed that n=11/131 (12%) of brain tumor patients received mechanism-of-action based treatment matched to the molecular findings in PTT2.0. CONCLUSIONS: Molecular diagnostics adds robust and clinically relevant information on diagnosis, actionable alterations, and cancer predisposition syndromes in CNS and other pediatric tumors even when tissue from the current disease episode is limited.
OTHR-35. Health-Related Quality of Life and Social Determinants of Health within Children with Brain and Spinal Cord Tumors
Authors: Knight Kelsey , Balsara Karl , Coven Scott
Published: June 2022

Social determinants of health (SDOH) have a significant impact on health, well-being, and quality of life (QOL). Validated tools to assess these disparities have been developed but not utilized prospectively in children with central nervous system tumors (CNS). OBJECTIVE: To establish a baseline assessment of health-related quality of life and associated social determinants of health in children with CNS tumors in Indiana. METHOD: We implemented the Pediatric Quality of Life Inventory™ (PedsQL™) for patients (ages 0-21 years) diagnosed with a CNS tumor evaluated in the neuro-oncology clinic from July 2019-January 2022. A higher score is associated with better quality of life. Patient's address was utilized to obtain Area Deprivation Index (ADI) and Child Opportunity Index (COI). ADI allows for rankings of neighborhoods by socioeconomic disadvantage at state or national level (1-10: 1 is least disadvantaged). COI measures the quality of resources in a patients’ community, with five categories ranging from very low- to very high-opportunity. RESULTS: We assessed 107 patients and their parents. The ADI decile within Indiana ranged 1 to 10 (median 5, mean 5.3); national percentile ranged 7 to 100 (median 71, mean 67.3). Overall COI mean was 3, with sub-scores for education - 2.9, health/environment - 2.6, and social/economic - 3.1. The PedsQL™ was completed by 96 parents and 91 patients. Physical mean was 67.4 and 71.2, psychosocial mean 67.8, 68.9, and total mean 67.7, 69.8, respectively. Simple linear regressions demonstrated a correlation between increasing disparity and decreasing quality of life across all dimensions. CONCLUSION: This is one of the first studies to associate a decrease in pediatric quality of life with disparities of social determinants of health. These data demonstrate the need for expanded prospective evaluation to track social determinants of health that may impact on the quality of life in children diagnosed with CNS tumors.
OTHR-36. Management of Central Diabetes Insipidus (CDI) with Low-Dose Vasopressin Infusion in Patients with Non-Germinomatous Germ Cell Tumors (NGGCT) Requiring Hyperhydration during Chemotherapy
Authors: Fitzgerald Caroline , Matson Kathryn
Published: June 2022

Primary intracranial germ cell tumors (GCT) represent 3-5% of central nervous system tumors with non-germinomatous germ cell tumors (NGGCTs) comprising approximately one-third. Located in the pineal and suprasellar regions, the tumors can cause central diabetes insipidus (CDI). Induction chemotherapy for NGGCT includes ifosfamide. Due to the risk of hemorrhagic cystitis associated with ifosfamide, 3000 mL/m2/day of intravenous fluids is administered. Oral desmopressin (DDAVP), the mainstay of treatment for CDI, has a long duration of action, variable intensity and can lead to hyponatremia and water intoxication due to the retention of large quantities of free water. Therefore, DDAVP is held during hyperhydration resulting in significant diuresis leading to patient discomfort and increased risk for wide electrolyte fluctuations. The volume of dextrose-containing IV fluids also places patients at risk for hyperglycemia and other metabolic disturbances. Patients with NGGCTs and CDI at our institution are admitted to the ICU for ifosfamide cycles due to the need for close monitoring and prompt interventions. ICU admission can delay therapy and potentially places patients in a setting where staff are unfamiliar with chemotherapy administration, increasing the risk of safety-related events. From a cost, resource, and patient care perspective, these admissions are suboptimal. This prompted a search for evidence to maintain patients safely out of the ICU. A literature search provided case studies citing the use of low-dose IV vasopressin. In collaboration with our endocrine and pharmacy colleagues we created a protocol to treat patients with CDI receiving chemotherapy with hyperhydration with a low-dose, easily titratable intravenous vasopressin infusion, to keep urine mildly diluted to allow enough diuresis to decrease injury while preventing excessive fluid losses and wide variations in electrolytes.
OTHR-40. DICER 1- a rare , but important tumor driver in malignant progressive brain tumors
Authors: Fried Iris , Rosiman Laila , Fisher Yael
Published: June 2022

BACKGROUND: DICER mutation is a known tumor driver involved in pleuropulmonary blastoma ,renal tumors, masses in the thyroid and ovary and multiple other manifestations. Brain tumors are considered to be a rare manifestation of germline DICER mutation. Currently, brain imaging is not included in the standard follow up of patients with DICER germline mutation, and data re the prevalence of somatic DICER mutations in brain tumors is limited. AIMs: evaluation of prevalence of DICER mutations in a large cohort of rare/relapsed brain tumors. METHODS: over the last year all patients with tumors lacking curative standard therapy in Israel were sent for next generation sequencing,. Molecular evaluation was done using either panel based evaluation (ONCOMINE/Foundation) or whole exome and whole transcriptome (INFORM consortium). Epidemiological data as well as clinical outcome were provided by the treating physician. RESULTS: Between April 2021 and January 2022 one hundred twenty nine samples were sent for molecular analysis, 58 of them were brain tumors. Six patients had DICER associated malignant tumors , 33% of them were brain tumors . One patient with pinealoblastoma was diagnosed with a highly metastatic disease associated with a very grave prognosis. CONCLUSION: brain tumors are an important group among malignant DICER associated tumors. Surveillance may lead to early detection which may be associated with a better outcome.
OTHR-43. Composition of cell-free miRNA in cerebrospinal fluid and plasma as a monitoring tool for pediatric brain tumors
Authors: Anne Coyle , Hollawell Madison , Rathi Komal , Beck Christopher , Choudhari Namrata , Smith Tiffany , Peter Madsen , Storm Phillip , Resnick Adam , Foster Jessica , Koptyra Mateusz
Published: June 2022

Current clinical management of pediatric brain tumor patients involves non-invasive imaging studies to monitor therapeutic response and tumor progression. However, results are often inconclusive and unable to capture biological changes that presage progression on imaging. Non-invasive diagnostics, also termed liquid biopsy, have emerged for detection of cell-free cancer material but there are no such standard, clinically defined biomarkers or methods for pediatric brain tumors. Circulating miRNA presents an attractive biomarker platform given its stability in bio-fluids, selective expression in tumors and release from tumor cells into the extracellular environment. Technology development has permitted high throughput analysis of material obtained from biofluids including plasma and cerebrospinal fluid (CSF). We performed miRNA profiling across a cohort of 54 pediatric brain tumors from different histologies (low grade glioma, ependymoma, germinoma, medulloblastoma, atypical teratoid rhabdoid tumor and high-grade glioma) using CSF (33) and plasma (53) with HTG EdgeSeq platform. CSF and plasma specimens clustered independently of each other providing separate biomarker platforms. Consensus clustering performed on CSF specimens revealed clusters correlated with disease severity (tumor grade). We identified miRNA targets closely correlated with tumor grade (p<0.001), tumor dissemination or metastases (p<0.001) and survival (p=0.001). Similarly in plasma, through consensus clustering we identified cohorts with correlation to tumor grade. While distinct from those identified in CSF, specific plasma miRNA also correlated with clinical (tumor grade; p<0.001, dissemination or metastasis; p=0.002) and demographic (gender; p=0.001) features. Independently, histology-specific miRNA signature was also identified for low grade glioma, medulloblastoma and germinoma in plasma and CSF. The results present differential expression of cell-free miRNAs in plasma and CSF as biomarkers associated with diverse clinical diagnostic and prognostic measures. Further utilization of this approach provides unique platforms (plasma and/or CSF) to inform liquid biopsy-based management in the clinical setting.
OTHR-44. Building narrative competence on the neuro-oncology team: a narrative medicine approach to fostering unity and resilience for work with pediatric brain tumor families
Authors: Riley Kathy
Published: June 2022

Narrative medicine relies on recognizing, taking in, reflecting on and responding to the stories of suffering in others. Drawing on the practice of the close reading of literature and reflection through writing, healthcare professionals gain fresh insights into their own stories and in turn connect in meaningful ways to stories of illness in their patients (Charon, 2001). The lived experience of pediatric neuro-oncology teams seesaws between hard-fought victories and stories of pain, loss, and even death. For patients who survive, many face life-long challenges that impact long-term quality of life. Learning to be an eyewitness of both beauty and pain in literature and art and writing about that witness helps teams reflect on the stories that shape them and their patients as they process the unthinkable in their work. This type of narrative competence requires what Sayantani DasGuspta refers to as narrative humility (Das Gupta, 2008). Narrative humility recognizes that stories of illness are ambiguous, contain contradictions, and belong wholly to the patient, and encourage providers to explore the role their own narrative brings to the clinician-patient relationship (Das Gupta, 2008). This narrative competence enables team members to find new ways to navigate their practice and foster team unity. Connecting to their own narrative allows them to connect to the narratives of others. They learn to be uncomfortable, to feel pain or joy, and to find power in being physically present with someone who is healed, feels marginalized, or is wounded. By listening closely to the stories of illness and loss in others and reflecting on their own stories through narrative medicine techniques, they learn to engage with the stories that define both their patients and their team dynamics. This theoretical and practical presentation explores the principles of narrative medicine and applies them to the particular experience of neuro-oncology teams.
PATH-04. Array-based global DNA Methylation profiling of mouse brain tumors allows comparison to human tumors
Authors: Schoof Melanie , Spohn Michael , Dorostkar Mario , Neyazi Sina , Bockmayr Michael , Swartling Fredrik , Kawauchi Daisuke , Gilbertson Richard , Taylor Jessica , Pei Yanxin , Glass Rainer , Cheng Jiying , Galarza Natalia Moreno , Hench Juergen , Herms Jochen , Jurmeister Philipp , Schweizer Leonille , Capper David , Harter Patrick , Thomas Christian , Hasselblatt Martin , Blattner-Johnson Mirjam , Jones David , Frank Stephan , Kerl Kornelius , Schüller Ulrich
Published: June 2022

The classification of human brain tumors by global DNA methylation profiling has become an essential part of modern integrated neuropathological diagnostics. It has proven to reliably identify known and novel brain tumor (sub-)types that are biologically and clinically distinct. Therefore, this technique has critically improved diagnostic accuracy and risk stratification of brain tumor patients. Although indispensable for the understanding of tumor biology and for preclinical drug trials, the comparison of genetically engineered mouse models to human brain tumors is still difficult. The assessment of tumor morphology only provides an approximate picture, and transcriptomic data from human brain tumors are sparse and suffer from platform-related technical incomparability. Here, we show array-based DNA methylation profiling of well-established murine brain tumors, such as Wnt and Shh medulloblastoma, YAP and RELA ependymoma, ETMR, and AT/RT. Similar to human brain tumors, unbiased clustering methods revealed distinct methylation profiles and mean methylation levels for mouse brain tumors types. Analyses were possible for fresh-frozen as well as for paraffin-embedded tissue, and copy number alterations could be inferred from methylation profiles. Most importantly, first results suggest that inter-species comparisons allow the classification of brain tumors from known or novel mouse models based on the constantly growing spectrum of human brain tumor types and subtypes with hundreds of thousands of available datasets. As an example, upon DNA methylation profiling, cerebellar tumors arising in Math1-cre::SmoM2Fl/+ mice display the highest similarity to human SHH medulloblastoma when compared to multiple human brain tumor entities including WNT and Non-WNT/Non-SHH medulloblastoma. These results suggest that global DNA methylation profiling may add another very important level of information to the characterization of genetically engineered mouse models.
PATH-05 Challenge and clinical relevance of a non-matching classifier output in genome-wide DNA methylation analysis for CNS neoplasms in pediatric and adolescent patients
Authors: Drexler Richard , Eckhardt Alicia , Bode Helena , Lamszus Katrin , Westphal Manfred , Schüller Ulrich , Mohme Malte
Published: June 2022

OBJECTIVE: The molecular classification of CNS tumors has revolutionized our understanding of the biological heterogeneity and diversity of tumor subtypes. DNA methylation-based classification allows to discriminate subtypes. Although DNA methylation-based classification can diagnose tumors with high specificity, there are tumors which cannot be classified. We aimed to gain further insight into these challenging cases. METHODS: Overall, 21 patients with a CNS tumor that was non-classifiable (confidence score <0.3), or had a low confidence score (<0.9) using the DNA methylation-based classifier version 11b4, were included. Tumors were re-classified using version (v12.3), and clinical data were analyzed. RESULTS: A total of 21 pediatric and adolescent brain tumors with a calibrated score below 0.9 in the classifier output were identified. Of these, 11 patients (52.4 %) were assigned to the “no matching methylation class” with a score below 0.3. IDH-wild type glioblastoma (23.8 %), ETMR (14.3 %), and DMG (14.3 %) were the most common histological diagnoses. Surgical and clinicopathological features as well as DNA input and tumor purity did not influence the confidence score. Cases with non-classifiable tumors had a significantly longer time until a decision for adjuvant therapy (p<0.01). Application of the latest classifier version v12.3 led to a re-classification of 9 (42.9 %) cases, of which 5 cases (55.6 %) had an improved calibrated score. CONCLUSION: Our study presents unclassifiable cases and the possible clinical impact when waiting for the accurate diagnosis in these challenging cases. Even though DNA methylation profiling significantly contributes to advanced CNS tumor diagnostics, clinicians should be aware of a prolonged interval to treatment initiation, especially for highly malignant brain tumors. Therefore, we would recommend to schedule adjuvant treatment as early as possible, if surgical and histological results are suspicious for this disease.
PATH-10. Nanopore sequencing reveals novel ALK fusion with interposed element in a neonate with hemispheric glioma
Authors: Liu Anthony P Y , Chan Chris T L , Ma Edmond S K , Ho Wilson W S , Ku Dennis T L , Shing Matthew M K , Kan Amanda N C , Chan Godfrey C F , Ng Ho-Keung
Published: June 2022

Here we describe the clinical course and unique molecular findings in a female neonate with infantile hemispheric glioma (IHG). The patient presented at the age of 17 days with macrocephaly and suboptimal weight gain. MRI brain revealed an 8.5cm mass over the right frontal region with significant mass effect and entrapment of ventricles. Urgent ventriculoperitoneal shunt insertion and biopsy of the highly vascular lesion was performed. Pathology was compatible with glioblastoma multiforme. Methylation profiling classified the sample as inflammatory tumor tissue (MNP v11b4), while panel RNA-sequencing revealed a fusion event between HMBOX1 and ALK which has not been described in primary CNS tumors. Long-read sequencing with the Nanopore system further revealed complex genomic rearrangement involving an interposed genomic fragment from a third chromosome with validation by Sanger sequencing. Based on an integrated diagnosis of IHG, the patient went on to receive neoadjuvant chemotherapy per the CNS-14 protocol (cyclophosphamide, carboplatin, etoposide) with significant tumor shrinkage. Near total removal of the lesion was achieved after 4 cycles of chemotherapy and adjuvant treatment with 4 additional cycles was given. The patient tolerated therapy well other than self-limiting transaminitis. At the end of treatment, the patient enjoyed intact neurology and satisfactory developmental progress. Our case report illustrates the value a multi-pronged approach to characterizing rare pediatric CNS tumors. The precise delineation of breakpoints in fusion-driven tumors might be of value in the design of cfDNA-based assays. (APYL and CTLC contributed equally to the submission)
PATH-13. Methylation analysis in the diagnosis of pediatric CNS tumors; a single center experience
Authors: Filippidou Maria , Binenbaum Ilona , Glentis Stavros , Roka Kleoniki , Vlachou Antonia , Avgerinou Georgia , Stefanaki Kalliopi , Selt Florian , Milde Till , Sahm Felix , Witt Olaf , Jones David T , Pfister Stefan M , Kattamis Antonis
Published: June 2022

BACKGROUND: Tumors of Central Nervous System (CNS) comprise major cause of cancer-related morbidity and mortality during childhood. Recent advances in genome and epigenome research allow for molecular classification of CNS tumors, treatment stratification and therapeutic target identification. In many countries, including Greece, this integrated diagnosis is not possible, yet, in a routine setting due to financial and infrastructural reasons. DESIGN/METHODS: We analyzed the results from the methylation profiling performed on tumor samples from newly diagnosed and selected retrospective patients followed in our unit. Analyses were performed through the PTT2.0 and MNP2.0 Studies, as part of a collaboration project between ACCC (Athens Cancer Comprehensive Center) and DKFZ (German Cancer Research Center). RESULTS: Methylation arrays from 50 patients (mean age: 8years, range: 0-17years) have been analyzed. High calibrated score (>0.9) was achieved in 38 patients (76%) and in 33 (86%) of these, the histological diagnosis matched the methylation class. The remaining 5 cases, diagnosed by the local pathologist as ganglioneuroma, primitive neuroectodermal tumor, anaplastic astrocytoma, pineoblastoma and oligodendroglioma, were classified according to the methylation profiling as dermatofibrosarcoma protuberans, medulloblastoma group 3, high-grade glioma H3.3G34mutant, high-grade neuroepithelial tumor with BCOR alteration and glioneuronal tumor, respectively. Only four cases had no match in the classifier, while seven cases received low score (0.5-0.8). In 6 out of the 7 cases with low score, the diagnosis was confirmed with the use either of the copy-number profile inferred from the methylation array or by additional testing for gene fusions and mutations. In 25 medulloblastomas, methylation profiling provided molecular classification, according to the 2021 WHO Classification. CONCLUSIONS: Our experience on the first 50 cases suggests that methylation array needs to be considered as an integral part of the diagnostic process of pediatric patients with CNS tumors and highlights the importance of international collaboration programs in pediatric neuro-oncology.
PATH-16. Noninvasive diagnosis of gliomas through CSF cfDNA sequencing in pediatric and adolescent and young adult (AYA) patients
Authors: Hill Katherine , Miller Alexandra M , Li Bryan Kincheon , Bouvier Nancy , Li Shanita , Alano Tina , Doe-Tetteh Seyram , Huereca Claudia , DiNapoli Sara , Lee Alex , Szalontay Luca , Riviere-Cazaux Cecile , Burns Terry C , Haque Sofia , Bale Tejus , Benhamida Jamal , Dogan Snjezana , Vanderbilt Chad , Ross Dara , Chang Jason , Donzelli Maria , Dunkel Ira J , Sait Sameer Farouk , Khakoo Yasmin , Gilheeney Stephen , Souweidane Mark , Greenfield Jeffrey , Berger Michael , Benayed Ryma , Arcila Maria E , Ladanyi Marc , Mellinghoff Ingo , Karajannis Matthias
Published: June 2022

PURPOSE: A subset of pediatric, adolescent and young adult (AYA) gliomas are located in the brainstem, eloquent locations, or present with diffuse/leptomeningeal disease, and are associated with high risk and low yield of biopsy. At the same time, accurate molecular diagnosis is necessary to direct optimal therapy. In such cases, analysis of cell free DNA (cfDNA) form cerebral spinal fluid (CSF) may represent a diagnostic alternative to biopsy. METHODS: We investigated the utility of CSF cfDNA sequencing through a stepwise approach, using clinically validated, targeted molecular assays. Testing was performed using a broad hybrid capture next generation sequencing assay (MSK-IMPACT) and subsequent targeted digital droplet PCR in a subset of cases. RESULTS: We analyzed 17 CSF samples from 17 pediatric (n=6) and AYA (n=11) glioma patients with primary or recurrent disease. Thirteen had tumors located within the brainstem, and four had leptomeningeal involvement. Somatic alterations were detected in 12/17 samples (71%). In 3/4 patients with leptomeningeal involvement, cfDNA testing revealed a BRAF fusion consistent with the diagnosis of diffuse leptomeningeal glioneuronal tumor (DLGNT). Among the 13 patients with brainstem involvement, four had somatic H3 K27M mutations, three had IDH mutations, and one had TP53 and ATRX mutations; five patients had no detectable mutations. CONCLUSION: In our analysis, we found that established glioma hotspot mutations were able to be detected within the CSF. We propose that in patients for whom tissue biopsy is high risk, not feasible, or tissue was nondiagnostic, CSF cfDNA sequencing has a substantial diagnostic yield and should be considered as a valuable novel diagnostic tool. Ongoing research is aiming to further increase the sensitivity of cfDNA testing, especially in patients with very low levels of CSF cfDNA.
LINC-02. Gamma Knife Radiosurgery as an efficacious treatment for Pediatric Central Nervous System Tumors: A Retrospective Study of 61 Neoplasms
Authors: Pahwa Bhavya , Agrawal Deepak
Published: June 2022

PURPOSE: Brain tumors have an incidence of 1.15 to 5.14 cases per 100,000 children and are associated with significant morbidity and mortality. Radiosurgery has become a promising approach to manage these pediatric CNS tumors. The aim of the present study was to analyse the efficacy of radiosurgery in the treatment of a variety of pediatric tumors of CNS METHODS: This retrospective study was conducted from 1997-2012 at a single Neurosurgery centre. All paediatric patients (≤ 18 years of age) with CNS tumours who were treated with gamma knife radiosurgery (GKRS) and had a minimum follow up of 6 months were included in the study. Patients with lesions other than tumours were excluded. Clinical, radiological and GKRS planning data was collected and analysed in all patients. RESULTS: A total of 76 children with brain tumors had GKRS during the study period. Of these, 40 children (with 61 neoplasms) had follow up available and were included in the study. The mean age was 16 years (6-18 years). 17 patients received primary GKRS, 20 patients received secondary and 3 patients received both. The median tumor volume was 3.3cm3 (0.14 - 38.9 cm3). The mean dose was 12.56 Gy at 50% isodose line. The majority of the tumors were Meningioma (n=20) followed by Acoustic Schwannoma (n=17). The mean treatment time was 67.04 minutes. 33 tumors responded favourably to GKRS, 24 showed a stable size, 3 had no response while 1 progressed requiring surgery. CONCLUSION: GKRS has the potential to become an indispensable tool in the management of pediatric brain neoplasms
LINC-06. Prevalence and outcomes of Autoimmune encephalitis in a tertiary hospital in Baguio City, Philippines
Authors: Sagay Jaidi
Published: June 2022

INTRODUCTION: Autoimmune Encephalitis is a debilitating neurological disorder that develops as a rapidly progressive encephalopathy, occurring usually less than 6 weeks, caused by brain inflammation. There are limited data on the autoimmune cases in the locality. This study aims to determine the prevalence and outcomes of patients with Autoimmune encephalitis cases admitted in a tertiary hospital in Baguio City, Philippines. METHODOLOGY: This is a descriptive retrospective cross-sectional study that reviewed health records of patients managed as autoimmune encephalitis in a tertiary hospital from January 2015 to December 2020. Descriptive Statistics using frequencies and percentages were employed in the study. RESULTS: A total of 21 patients were included in the study, majority of which were adolescent patients, with male predominance and are residing in rural areas. The most common clinical manifestation presented were fever, behavioral changes, generalized motor seizures, orofacial and limb dyskinesias. EEG revealed abnormal results in 14 patients (66.67%). Majority of patients had normal CSF analysis, while 2 (38.1%) revealed elevated CSF protein levels. Eight patients (38.1%) tested positive for anti-NMDAR titers. Most patients had normal ultrasound and cranial CT Scan (47.62%). The length of stay was more than 2 weeks and majority (80.95%) of patients were discharged improved. CONCLUSION: The prevalence of autoimmune encephalitis is 5/10,000 pediatric population in a span of 6 years which was noted to be increasing over time. The demographic and clinical profile maybe used as predictors of outcome of autoimmune encephalitis, hence, it can help in the management of the said disease.
LINC-09. Coexisting glioneuronal tumor and adrenal ganglioneuroma
Authors: Shahbandi Ataollah , Atashpanjeh Saeid , Azari-Yam Aileen , Nejat Farideh , Habibi Zohreh
Published: June 2022

BACKGROUND: While both glial/glioneuronal neoplasia and ganglioneuroma have been reported as components of multiple primary neoplasms, no patient has been diagnosed with multiple primary neoplasms of cerebral glial/glioneuronal tumors with oligodendroglioma-like features and adrenal ganglioneuroma up to now. CASE: A previously healthy five-year-old girl was admitted with a two-week history of headaches and vomiting. Brain Magnetic resonance imaging (MRI) showed a massive heterogenous multi-cystic enhancing lesion in the right temporoparietal area with substantial vasogenic edema. The patient underwent craniotomy and tumor gross total resection. The intra-operative histomorphological assessment of the tumor was well-matched with a glial tumor. The patient developed systolic hypertension during postoperative care in the Intensive Care Unit. Subsequent abdominal CT scan unveiled a calcified mass of the left adrenal gland origin. Blood and urine catecholamine tests, vanillylmandelic acid (VMA), were within the normal range. The surgical excision specimen exhibited a clear cell neoplasm with diffuse infiltrative growth. A distinguishing combination of oligodendroglioma-like perinuclear haloes, clear cell appearance and vascular proliferation rendered the diffuse Glioneuronal tumor with Oligodendroglioma-like features. With the combination of oligodendroglial-like appearance, negative 1p/19q codeletion, Wild IDH, no BRAF mutation, weak GFAP, and positive synaptophysin altogether, the tumor was compatible with the novel diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC). The patient underwent laparotomy and tumor resection subsequently. Morphologic histopathological examinations of the adrenal mass were in line with ganglioneuroma. After discharge, no pathological uptake was identified with iodine-131 meta-iodobenzylguanidine scan (MIBG scan). No tumor residue was apparent on postoperative brain MRI. The patient received no adjuvant therapy for brain and adrenal tumors and underwent close surveillance for both tumors. No clinical or radiologic recurrence was recognized after six months of follow-up. CONCLUSIONS: Concurrent glioneuronal tumor and ganglioneuroma can be managed safely when diagnosed timely, leading to favorable outcomes.