bluuebunny/crossref_metadata_2025_split huggingface dataset:
ETMR-03. REPORT OF 9 CASES OF EMBRYONAL TUMORS OF THE CENTRAL NERVOUS SYSTEM WITH MULTILAYERED ROSETTES (ETMR)
Authors: Ai Ruyu , Li Juan , Lai Mingyao , Cai Linbo 
Published: June 2024

Abstract

OBJECTIVE
Embryonal Tumors of the Central Nervous System with Multilayered Rosettes (ETMR) are rare, and there’s no standard treatment protocol. This article reports on the current treatment status and prognosis of ETMR in our hospital.

METHODS
We retrospectively collected patients with ETMR who received treatment in the Oncology Department of Guangdong sanjiu Brain Hospital from January 2017 to January 2021, analyzed their clinical data.

RESULTS
Among 31 cases of central nervous system embryonic tumors (excluding medulloblastoma and ATRT), 9 (29.03%) were ETMR. The median age at diagnosis was 3 years old (1-15), and the male to female ratio was 4:5. Among them, 5 cases were accompanied by C19MC gene variation. Tumor location:6 was in supratentorial, 1 in the pineal region, 1 in the pons, 1 in the cerebellopontine. Eight patients underwent surgical resection at the first diagnosis, with 6 cases of total resection, 1 case of partial resection, and 1 case of biopsy. One case was misdiagnosed as a germinoma in the pineal region at the initial. After recurrence, surgical resection was performed to confirm the pathology as ETMR. One case was misdiagnosed as glioblastoma during the first surgery. The initial treatment for 4 patients after surgery was radiotherapy combined with concurrent chemotherapy. Recurrence patterns: 2 cases were intracranial dissemination, 2 cases were local recurrence, 1 was spinal cord dissemination. One patient did not receive treatment after surgery and tumor recurrence 3 months later. Survival analysis: The median survival time was 20 months. The 1-year progression-free survival rate (PFS) and overall survival rate (OS) were 22% and 61%, and the 2-year overall survival rate (OS) was 31%.

CONCLUSION
ETMR has a low incidence and poor prognosis. It is easy to misdiagnose and NGS is necessary to assist diagnosis when needed. More effective treatment methods need to be explored.
ETMR-05. DEVELOPMENT OF NOVEL PRECLINICAL MODELS AND THERAPEUTIC STRATEGIES FOR ETMR
Authors: Cocito Carolina , Arias-Stella Esteban Uceda , Padilla Christopher C , Zhang Xiaohu , McKnight Crystal , Itkin Zina , Klumpp-Thomas Carleen , Holland David , Beck Erin , Cruzeiro Gustavo Alencastro Veiga , Chi Susan N , Pisapia David J , Filbin Mariella G , Souweidane Mark M , Dahmane Nadia , Thomas Craig J , Greenfield Jeffrey P 
Published: June 2024

Abstract

BACKGROUND
Embryonal Tumor with Multilayered Rosettes (ETMR) is a very rare, aggressive pediatric brain tumor with a dismal 5-year overall survival rate. Few genetic aberrations in miRNA clusters and processing machinery have been detected in ETMRs with 90% of ETMR patients having the C19MC amplification. ETMRs show unique histopathological features which, together with the detection of C19MC or DICER alterations, are necessary for diagnosis. The cellular and molecular mechanisms underlying ETMR development are poorly understood, and targeted therapeutics have not been developed due to scarcity of preclinical models. To expand knowledge of ETMR biology and accelerate the design of novel and therapies, it is thus essential to develop preclinical models.

METHODS
We have generated two novel patient-derived ETMR cell lines from resected patient derived tumor samples (CTBP-03A and CBTP-139) and created three patient-derived xenograft (PDX) models (CTBP-03A, CBTP-139 and CBTP-38). We have used these unique patient-derived cell lines to identify mechanisms driving ETMR development and progression. To identify novel therapeutic targets, we conducted high-throughput drug screening (HTDS) utilizing 2480 approved and investigational drugs, against the CBTP-03A and CBTP-139 lines.

RESULTS
Among the candidate drugs showing an inhibitory effect on both lines, compounds were selected based on their activity, CNS penetration ability, mechanism of action, and bioavailability, if known. The top selected hits were screened in an all-versus-all format, totaling 1953 combinations. The rapidity of action and efficacy of the top choice compounds used as single agent or in double and triple combination was assessed by caspase glow and cell titer glow assays. This initial combination screen identified DNA replication stress, retinoid receptor agonist and FGF signaling as potential combinatorial targets. Data are currently being validated in vivo.

CONCLUSIONS
This is the first combinatorial HTDS on two novel patient-derived cell lines which highlighted potential drug combination strategies for the treatment of ETMR.
ETMR-09. HEALTH-RELATED QUALITY OF LIFE OF CHILDREN, ADOLESCENTS AND ADULTS AFTER DIAGNOSIS OF CHILDHOOD-ONSET MENINGIOMA
Authors: Wagener Katharina , Beckhaus Julia , Friedrich Carsten , Müller Hermann L 
Published: June 2024

Abstract

BACKGROUND
Meningiomas are rare intracranial tumors in childhood. Childhood-onset meningiomas differ from their adult counterparts in terms of frequency, molecular features and clinical presentation. There is limited data on health-related quality of life (HRQoL) of pediatric meningioma patients. The aim of this study was to analyze the HRQoL of pediatric or adult patients after completion of treatment for childhood-onset meningioma. Further, the influence of disease-specific characteristics on HRQoL, fatigue or functional capacity was analyzed.

METHODS
In this cross-sectional study, the HRQoL of 8 pediatric and 27 adult meningioma patients from the clinical trials HIT-ENDO, KRANIOPHARYNGEOM 2000/2007 and KRANIOPHARYNGEOM Registry 2019 was assessed. The validated questionnaires EQ-5D-Y, EQ-5D-3L, PedsQL Generic Core Scale, EORTC QLQ-C30 and QLQ-BN20 were used. Patients’ fatigue and functional capacity were scored using the EORTC QLQ-C30, the PedsQL Multidimensional Fatigue Scale and the FMH questionnaire. Exploratory data analysis was performed using univariate, bivariate and multivariate analyses (α=0.05).

RESULTS
The HRQoL was assessed in median 10 (IQR: 5-17) years after diagnosis. The mean HRQoL value was 86 (IQR: 79-92) for pediatric and 75 (IQR: 67-92) for adult patients using the PedsQL Generic Core Scale or EORTC QLQ-C30 questionnaire, respectively. Most limitations were reported in emotional function and fatigue. The median functional capacity of patients was at the 90th (IQR: 65-90) percentile. HRQoL was lower in adults with neurofibromatosis type 2 or at older age (p=0.009) and higher HRQoL after progressive disease. Age at diagnosis, WHO grade, residual tumor, use of radiotherapy, tumor location, tumor entity (meningioma vs. craniopharyngioma), degree of disability, or time since diagnosis did not affect HRQoL in adults.

CONCLUSION
The median HRQoL of childhood-onset meningioma patients indicates that it is comparable to the healthy normal population. Nevertheless, HRQoL is a construct that can be influenced in many ways. Further research on HRQoL is warranted.
ETMR-26. MIR-34/449 FAMILY PLAYS A CRUCIAL ROLE IN CHOROID PLEXUS MULTICILIATION AND TUMORIGENESIS
Authors: Guru Navjot , Zaman Ahnaf , Umer Maheen , Zahran Mariam , Siluveru Anjali , Faltings Lukas , Virga James , Attia Andrew , Cao Ping , Zhao Haotian 
Published: June 2024

Abstract

BACKGROUND
Choroid plexus (CP), an epithelial structure within the brain ventricles, produces cerebrospinal fluid and serves barrier functions in the brain. Primary CP neoplasms are rare intracranial tumors that predominantly occurs in childhood. Recent studies revealed multiciliated cells in the CP in humans and mice. In contrast, benign CP papilloma, and malignant CP carcinoma (CPC) in humans are characterized by solitary cilia, and disturbances to multiciliation program directed by transcription factor GMNC. Additionally, most CPC in humans carry mutations in TP53 tumor suppressor. Consistently, Trp53-deficient CPC in mice display singular cilia consequent to defects in GMNC multiciliation program. Thus, the impairment of multiciliation enables tumor cell proliferation. MicroRNAs (miRNAs) are non-coding small RNAs with gene regulatory functions. Specifically, the mir-34/449 family comprises of six miRNAs collaborate to influence multiciliation in diverse tissues but role of mir-34/449 family in the brain is poorly understood. Knowledge of multiciliation program regulation may provide crucial insights into tumor suppression mechanisms in CPC.

METHODS
To investigate the role of mir-34/449 family in the CP, human CP organoid and mir-34/449 mutant animals were used. RNAscope, In situ hybridization as well as immunofluorescence staining was utilized to identify gene expression in tissues.

RESULTS
Preliminary studies revealed GMNC program activity and multiciliated cells in CP organoid derived from human induced pluripotent stem cells. Disruption of the mir-34/449 family led to supernumerary cilia and ectopic multiciliation program activity in the CP. Importantly, Trp53-deficient CPC exhibited distinct expression of the mir-34/449 family. Further, sequencing studies revealed an overlap of differentially expressed miRNAs in CP tumors in humans and mice, with an enrichment of the mir-34/449 family.

CONCLUSIONS
Together, these findings indicate that the mir-34/449 family regulates multiciliation in the CP, whereas the study of its interactions with the multiciliation program holds the key to understanding multiciliation as a tumor suppression pathway in CPC.
ETMR-27. ANTI-ANGIOGENIC METRONOMIC THERAPY OF RARE TUMOURS OF THE CENTRAL NERVOUS SYSTEM
Authors: Schned Hannah , Haberler Christine , Peyrl Andreas , Azizi Amedeo , Mayr Lisa , Aistleitner Barbara , von Hoff Katja , Kool Marcel , Kjaersgaard Mimi , Trkova Katerina , Andre Nicolas , Lippolis Maria Aliotti , Hedrich Cora , Köller Clara , Stepien Natalia , Slavc Irene , Gojo Johannes 
Published: June 2024

Abstract

BACKGROUND
Improvement of molecular diagnostics has led to significant changes in the categorization of paediatric brain tumours, unveiling novel tumour entities in the latest 2021 WHO classification of central nervous system (CNS) tumours (5th edition), particularly within the group of rare tumours of the CNS (encompassing rare embryonal and sarcomatous tumours (REST) and gliomas). However, treatment recommendations are currently based on small patient cohorts lacking standardized protocols, with even more limited options for progressive or relapsed disease.

METHODS
Patients from specialized European oncologic centres diagnosed or reclassified as REST receiving anti-angiogenic therapy after relapse (Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial - MEMMAT) will be analysed.

RESULTS
So far, 14 patients from Austria, Czech Republic, Denmark and France were identified, with molecularly reclassified 4 CNS tumours with BCOR/BCORL1 alteration (CNS BCOR/BCORL1), 4 CNS astroblastomas, MN1-altered (ABM_MN1), 3 embryonal tumours with multi-layered rosettes (ETMR) and 1 DICER1-mutated intracranial sarcoma (CNS DICER1) as well as 2 primitive neuroectodermal tumours (PNETs, reclassification ongoing). Initial histological classifications ranged from ependymoma group 3, ETMR, malignant peripheral nerve sheath tumour (MPNST) to EGFR-positive glioblastoma. In 2 cases categorization was unclear with either anaplastic ependymoma, plexus carcinoma or ETMR. 10 patients received standard MEMMAT protocol (biweekly intravenous Bevacizumab with oral drugs: Celebrex, Thalidomide, Fenofibrate, Cyclophosphamide/Etoposide alternating and intrathecal Etoposide and Cytarabine). In 4 cases therapy was modified with an individualized metronomic treatment regimen.

CONCLUSION
Therapy at initial diagnosis, duration of relapse-treatment, clinical as well as radiological response, overall survival, progression-free survival and molecular hallmarks will be presented.
ETMR-31. A UNIQUE CASE OF CNS DIFFUSE, NON-SYSTEMIC ALK+ HISTIOCYTOSIS IN A PEDIATRIC PATIENT
Authors: DeMarsh Samantha J , Orr Brent , Willard Nicholas , Dahl Nathan 
Published: June 2024

Abstract

BACKGROUND
Histiocytic disorders are a group of rare diseases with accumulation of of macrophages, monocytes, or dendritic cells in various parts of the body. ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 that is very rarely described in pediatrics.

METHODS
A 20 month old male presented to an adult hospital after a prolonged period of headaches, vomiting, and loss of developmental milestones. Imaging demonstrated severe hydrocephalus and extensive thickened leptomeningeal enhacement with mass effect. He underwent VP shunt placement and revision, a T7-T10 laminectomy, and tumor debulking. Extensive molecular testing, including DNA and RNA analysis by NGS was performed and a CLTC::ALK fusion was identified, along with Tier III DNA variants, yielding a diagnosis consistent with ALK-Positive Histiocytosis, with diffusivity in the CNS system. Full evaluation demonstrated no involvement of the peripheral nervous system or other systemic involvement. He initially demonstrated signs of neuro-irritation, altered tone, and lower extremity clonus.

RESULTS
After review of very little literature published on similar patients, although none with a clinical picture matching his, he was started on a treatment course of high dose dexamethasone, vinblastine, and lorlatinib targeting the ALK+, likely driver, mutation of his disease. On evaluation scans two months into treatment, he showed no change in his disease burden. He was transitioned to clofarabine cycles with daily lorlatinib for continued targetted therapy. After six total cycles, he demonstrated a high partial to complete remission (allowing for evidence of scarred tissue) and tremendous neurologic and developmental milestone gains.

CONCLUSIONS
This case demonstrates a unique presentation in which there is little described in the literature in way of clinical features or treatment standards, and further none exactly similar to this patient. After undergoing extensive evaluation and therapy modication, he responded remarkably well and continues to have optimal quality of life.
EPEN-23. TARGETING TRISOMY MDM4 INDUCES CELL DEATH IN 1Q+ PFA EPENDYMOMA THROUGH REACTIVATION OF THE P53 PATHWAY
Authors: Calzadilla Annaliese J , Griesinger Andrea M , Donson Andrew M , Grimaldo Enrique , Madhavan Krishna , Alimova Irina , Pierce Angela M , Brunt Breauna , Vibhakar Rajeev , Foreman Nicholas K 
Published: June 2024

Abstract

BACKGROUND
Gain of chromosome 1q (1q+), gives a grave prognosis in pediatric posterior fossa group A ependymoma (PFA). The prevalence of 1q+ in newly diagnosed PFA stands at 25%, escalating to 50% upon recurrence. Conventional therapeutic modalities, such as complete resection and radiation, exhibit minimal efficacy in cases of 1q+ PFA, and the incorporation of additional chemotherapy in clinical trials has failed to yield substantial improvements. In this investigation, we delineate the trisomy-induced overexpression of the MDM4 gene on chromosome 1q as a driver of malignant progression in 1q+ PFA and a viable therapeutic target via idasanutlin, an MDM4 pathway inhibitor.

METHODS
We are using genetic and pharmaceutical inhibition of the MDM4/MDM2 pathway high-risk PFA 1q+ in vitro and in vivo models to test the efficacy of idasanutlin in a preclinical setting. Treatment effects are measured utilizing growth assays as well as genomic and transcriptomic analysis.

RESULTS
Our investigation reveals that two 1q+ in vitro models demonstrate a dose dependent sensitivity to idasanutlin compared to normal brain tissue. Upon exposure to idasnutlin, they also have an increase in p21 expression, a critical marker demonstrating reactivation of the p53 pathway, evidenced at both the gene expression and protein levels. Moreover, we found radiation synergistically enhances the efficacy of idasanutlin. Currently, we are evaluating our in vitro results with combination radiation and idasanutlin treatment in our 1q+ PFA preclinical in vivo models.

CONCLUSIONS
In summary, our study advocates for the exploration of small molecule inhibitors, with a primary focus on the promising idasanutlin compound, as a therapeutic avenue for addressing the challenge posed by ultra-high-risk 1q+ PFA. The compelling preclinical evidence presented herein lays the groundwork for advancing our understanding of the molecular intricacies underlying this malignancy, paving the way for novel and targeted treatment strategies.
EPEN-28. NOVEL TARGET IDENTIFICATION IN RECURRENT POSTERIOR FOSSA EPENDYMOMA GROUP A
Authors: Przelicki David , Rasnitsyn Alex , Richman Cory , MacLeod Graham , Diaz Jacob Torrejon , Angers Stephane , Ayrault Olivier , Michealraj Kulandaimanuvel A , Taylor Michael D 
Published: June 2024

Abstract

BACKGROUND
Posterior fossa ependymoma group A (PF-EPN-A) are an aggressive subgroup of ependymal tumors which occur predominantly in infants and possess a poor prognosis. Treatment is limited to surgical resection and adjuvant radiation with no approved chemotherapies or targeted therapies available. Despite treatment efforts, nearly half of all PF-EPN-A cases will experience tumor recurrence within a decade of initial diagnosis. Our current understanding of relapse is limited to clinical risk stratification based on subtotal resection of the primary tumor, male sex and specific chromosomal copy number aberrations. In an effort to overcome the shortcomings of current literature on PF-EPN-A recurrence, we present a concerted effort to investigate the biology of both recurrent human tissue specimens and patient-derived cell models to identify novel drivers of recurrence.

METHODS
Utilizing a multi-omics approach, we have conducted transcriptomic (bulk RNA-Seq), proteomic and phosphoproteomic (LC-MS/MS) analyses in order to identify molecular pathways that are enriched in recurrent disease as compared to primaries. We have also performed genome-wide CRISPR essentiality screens to further pinpoint essential genes and pathways with therapeutic potential.

RESULTS
Through the comparison of primary and recurrent PF-EPN-A samples, we have identified both previously implicated and novel genes and pathways in recurrent disease. Our multi-omic analyses identified the upregulation of genes involved in DNA repair, DNA damage response and cell cycle pathways in recurrent PF-EPN-A.

CONCLUSIONS
Our combined approach has enabled the identification of novel targets with therapeutic potential in the treatment of recurrent PF-EPN-A. The identified targets will be validated using a combination of drug screening and knockdown approaches in vitro. Top candidates will be further validated in vivo with established recurrent xenograft mouse models. PF-EPN-A is an aggressive disease with limited treatment options and the identification of novel targets with potential therapeutic utility will allow us to better treat this patient population.
METB-02. GENETIC COUNSELLING IN SOTOS AND NS1-RELATED OVERGROWTH SYNDROMES PREDISPOSING TO BRAIN TUMORS
Authors: Abdelmoula Nouha Bouayed , Abdelmoula Balkiss 
Published: June 2024

Abstract

BACKGROUND
Sotos and many other overgrowth syndromes are among the rare tumor predisposition syndromes that might be under-recognized in pediatric neuro-oncology practice. NSD1 gene (5q35), belonging to the histone lysine methyltransferases family, is involved in the majority of Sotos patients who exhibited haploinsufficiency and loss-of-function variants of the gene, but also in other overgrowth entities such as Beckwith-Wiedemann syndrome. Somatic mutations in this gene are likewise responsible of numerous cancers, particularly brain tumors. Here, we aim to assess the neurologic cancer risks and provide genetic counseling for appropriate clinical follow-up in Sotos syndrome.

METHODS
From our genetic counseling database at the medical University of Sfax (Tunisia), we selected among patients presented for genetic management of overgrowth syndromes, those with Sotos syndrome.

RESULTS
Only two Tunisian consanguineous pedigrees were enrolled in this study. Two boys were diagnosed with typical Sotos syndrome based on the three major clinical manifestations: specific facial dysmorphism, mental retardation and excessive growth including advanced bone age and macrocephaly. Chromosomes 5 in both pedigrees did not show structural abnormalities. During genetic counselling, parents were informed about the molecular testing options and the advantage of the exome sequencing. Furthermore, they were informed about the rate of cancer predisposition (3%) and the gains of neurologic and neuro-oncologic management, particularly regarding the intellectual disability and the increased risk of developing neural crest tumors, astrocytoma, glioma/glioblastoma and neuroblastoma cancer, during childhood.

CONCLUSIONS
Neurological pediatric malignancies are described in patients with Sotos syndrome, but the genotype-phenotype correlation is still unclear. It is suggested that NDS1 disruptions in Sotos patients trigger specific patterns of DNA methylation alterations leading to the development of cancer. Accurate molecular exploration is needed in the heterogeneous Sotos condition in order to improve the management according to the implicated gene and to benefit in the future from targeted therapies.