bluuebunny/crossref_metadata_2025_split huggingface dataset:
ATRT-02. Neuropsychological function in infant atypical teratoid/rhabdoid tumor versus low-grade glioma survivors reflects tumor malignancy and multimodal treatment
Authors: Traunwieser Thomas , Loos Elena , Nemes Karolina , Kandels Daniela , Neumayer Petra , Neumann-Holbeck Anne , Lüttich Peggy , Baust Katja , Faulstich-Ritter Kristin , John Rainer , Kreisch Andrea , Manteufel Eva , Nest Alexandra , Prüfe Jenny , Schubert Lisa , Siebrands Joy , Stamm Walther , Timmermann Beate , Gerss Joachim , Gnekow Astrid K , Frühwald Michael C 
Published: June 2022

Abstract
BACKGROUND: Therapy of infants with brain tumors predisposes these patients to increased risks for cognitive sequelae, especially following radiotherapy. Neuropsychological outcome gains importance for those 40-60% of patients with an atypical teratoid/rhabdoid tumor (ATRT) who survive beyond 2 years. Still, reports on cognitive late-effects in children with ATRT are scarce compared to other pediatric brain tumor groups. We analyzed neuropsychological outcome for long-term ATRT-survivors registered in EU-RHAB and infant low-grade glioma (LGG) survivors from the SIOP-LGG 2004-study and LGG-registry. PATIENTS+METHODS: Age at diagnosis of both cohorts was 0-36 months. ATRT-patients (n=13) treated with up to 54Gy radiotherapy (median age 22 months (±7.1)) were evaluated with the “ATRT-Neuropsychology” tool based on SIOPE-BTG QoS-Group recommendations at median 6.8 years (±2.8) after diagnosis. LGG-patients (n=15) treated without radiotherapy (4/15 with chemotherapy) were analyzed with the German “Neuropsychological-Basic-Diagnostic” tool 5.2 years (±0.6) post-diagnosis. RESULTS: The ATRT- vs. LGG-cohorts were comparable for median age at diagnosis, sex-ratio and tumor-localization, though they differed slightly in median age at assessment (9.5/7.2 years (±2.5/1.1)). Results of age-appropriate tests showed increased impairments for ATRT-patients in fluid intelligence (FI) (p=.006, d=1.214) and in visual-spatial processing (VSP) (p&lt;.001, d=2.233) compared to LGG-patients. The median for neuropsychological test results of ATRT-patients spanned from considerably below the normal to the lower normal range (median=65-90), while results of LGG-patients were mostly in the lower normal range (median=83-103). Results for psychomotor speed abilities (PMS) were distinctly below the norm for both patient groups (p=.002-.007). CONCLUSION: Infant ATRT- and LGG-patients develop significant impairments in PMS abilities following multimodal treatment. Long-term survivors of ATRT suffer from additional FI and VSP deficits. Our data suggest that high malignancy requiring multimodal treatment determines the inferior cognitive outcome for the ATRT-cohort. Long-term neuropsychological monitoring (and treatment options) should be implemented as standard of care in ATRT- and LGG-trials.
ATRT-08. SMARCB1- and SMARCA4-deficient malignant brain tumors with complex copy number alterations andTP53 mutations may represent the first clinical manifestation of Li-Fraumeni syndrome
Authors: Hasselblatt Martin , Thomas Christian , Federico Aniello , Nemes Karolina , Johann Pascal D , Bison Brigitte , Bens Susanne , Kordes Uwe , Redlich Antje , Lessel Lienhard , Pajtler Kristian W , Mawrin Christian , Schüller Ulrich , Nolte Kay , Kramm Christof M , Hinz Felix , Sahm Felix , Giannini Caterina , Penkert Judith , Kratz Christian P , Pfister Stefan M , Siebert Reiner , Paulus Werner , Kool Marcel , Frühwald Michael C 
Published: June 2022

Abstract
Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant central nervous system tumor predominantly affecting infants. Mutations of SMARCB1 or (rarely) SMARCA4 causing loss of nuclear SMARCB1 or SMARCA4 protein expression are characteristic features, but further recurrent genetic alterations are lacking. Most AT/RTs occur de novo, but secondary AT/RTs arising in other central nervous system tumors have been reported. Malignant gliomas, IDH-wildtype, arising in patients with Li-Fraumeni syndrome typically show somatic mutations of TP53 as well as complex copy number alterations, but little is known about loss of SMARCB1 or SMARCA4 protein expression in this context. Here we report two children, in whom malignant supratentorial brain tumors with SMARCB1-deficiency, complex copy number alterations and somatic TP53 mutations lead to the discovery of pathogenic/likely pathogenic TP53 variants in the germ line. Screening of the molecularneuropathology.org data set for cases with similar genetic and epigenetic alterations yielded another case with SMARCA4-deficiency in a young adult with Li-Fraumeni syndrome. In conclusion, SMARCB1- or SMARCA4-deficient malignant brain tumors with complex copy number alterations and somatic TP53 mutations in children and young adults may represent the first clinical manifestation of Li-Fraumeni syndrome and should prompt genetic counseling and investigation for TP53 germline status.
ATRT-10. Single-cell transcriptional profiling of ATRTs reveals heterogeneous signatures of tumor and non-malignant cell populations
Authors: Blanco-Carmona Enrique , Büllesbach Annette , Federico Aniello , Liu Ilon , Young Matthew D , Kildisuite Gerda , Behjati Sam , Vibhakar Rajeev , Donson Andrew , Foreman Nicholas , Hovestadt Volker , Shaw McKenzie , Chi Susan , Frühwald Michael , Drost Jarno , Korshunov Andrey , Hasselblatt Martin , Pfister Stefan M , Jäger Natalie , Johann Pascal , Filbin Mariella , Kool Marcel 
Published: June 2022

Abstract
Atypical Teratoid/Rhabdoid Tumors (ATRTs) are known for exhibiting high inter-tumor heterogeneity, even though they are almost all characterized by a common loss of SMARCB1 (or rarely SMARCA4). Three subgroups have been identified at bulk methylome and transcriptome level: ATRT-TYR, ATRT-SHH, and ATRT-MYC. To better understand the biology underlying each subgroup and potentially unveil their (different) cell(s) of origin, we performed single-cell transcriptomic analyses in 22 ATRTs using fresh frozen samples and both 10X and Smartseq technology. All data, grouped by technology, underwent quality control and normalization, regressing out the biases introduced by each sample. Tumor microenvironment (TME) and tumor bulk (TB) clusters were characterized by a combination of copy number variant analyses, enrichment in literature lists of marker genes for specific cell populations, and in-depth analysis of differentially enriched (DE) genes. Non-negative Matrix Factorization (NMF) was applied to TB to reveal major transcriptional profiles, which were grouped into meta-signatures. A total of 71 gene lists were retrieved from NMF (TB) and DE analyses (TME + TB), that gathered into 11 signature groups by Jaccard similarity, with one extra group accounting for unique signatures. Three groups targeted TME, accounting for either microglia, fibroblasts and endothelial cells, or OPCs, oligodendrocytes, astrocytes and neurons. These signatures are enriched in specific clusters across technologies. The remaining eight groups divide into two types, either enriched in clusters predominantly formed by cells of one or two ATRT subgroups or signatures enriched for a particular phenotype, such as cilial, cycling, axonogenesis or EM transition. While the first type is enriched across clusters in a gradient fashion, the second shows enrichment for selected clusters across technologies. Further analyses on the integrated dataset and additional samples are ongoing to validate and refine these 11 signature groups in ATRTs to see how this may lead to new treatment approaches.
ATRT-13. An integrative analysis of the ATRT proteome unravels novel drug targets and refines molecular subgrouping
Authors: Johann Pascal , Müller Torsten , Kalxdorf Mathias , Hasselblatt Martin , Frühwald Michael C , Pfister Stefan M , Krijgsveld Jeroen , Kool Marcel 
Published: June 2022

Abstract
INTRODUCTION: Atypical teratoid/rhabdoid tumors (ATRT) represent frequent brain tumors in infants. In recent years, large-scale landscaping efforts on the epigenome and transcriptome of these tumors have unravelled a high degree of heterogeneity and three major molecular subgroups, termed ATRT-TYR, ATRT-SHH,ATRT-MYC, have been identified. The ATRT-proteome, in turn, still represents a largely unchartered territory. METHODS: We have performed a peptide-based screening approach to characterize the proteome of 40 ATRTs and six ATRT cell-lines. All of these samples had matching methylation data available and 28 also corresponding gene expression data. RESULTS: Unsupervised clustering recapitulated the previously described ATRT groups, revealing also a clear split of the SHH-subgroup in a supratentorial (SHH_1) and an infratentorial subgroup (SHH_2). Overall, we identified 7265 proteins, of which 1320 were differentially expressed between the groups, with an enrichment of spliceosome associated terms in SHH_1 and integrins/cell adhesions molecules in SHH_2. ATRT-MYC displayed an overrepresentation of immune cell markers and the TYR subgroup an enrichment of PI3K- as well as mTOR-signaling. Particularly, genes that have previously been described as signature genes for the ATRT-groups such as FABP7 in ATRT-SHH and OTX2 and MITF in ATRT-TYR were among the highly correlating genes that were both expressed in the proteome and the gene expression datasets. On top of this, our analysis revealed highly differentially expressed drug targets such as the tyrosine-kinase MARCKS (overexpressed in ATRT-TYR) not previously identified in ATRT transcriptome data, which warrant investigation by in vitro drug tests. CONCLUSION: Our data reveal the importance of previously described regulatory hubs in the ATRT subgroups, but additionally highlight novel drug targets that merit further exploration. Currently, drug treatment experiments in ATRT cell lines are ongoing to validate these proteins as drug targets, ultimately aiming to establish new therapeutic strategies in this deadly disease.
ATRT-20. Novel prognostic molecular signatures for improved risk-classification of Atypical Teratoid Rhabdoid Tumours
Authors: Keeling Claire , Grabovska Yura , O'Hare Patricia , Crosier Stephen , Pickles Jessica C , Finetti Martina A , Fairchild Amy R , Anderson John , Hargrave Darren , Brennan Bernadette , Jacques Thomas S , Clifford Steven C , Bailey Simon , Williamson Daniel 
Published: June 2022

Abstract
Malignant Rhabdoid Tumours (MRT) are aggressive paediatric malignancies seen in the central nervous system (Atypical Teratoid Rhabdoid Tumours (ATRT)), and kidney and other soft tissues (Extra-cranial Rhabdoid Tumours (ECRT)). With current therapies often proving ineffective and a lack of clear prognostic associations with consensus subgroups, we explored the possibility of using prognostic molecular signatures to further identify the biological characteristics of high risk ATRT patients. By employing a cross-validated feature selection method the methylation profiles of 121 MRT patients were analysed with clinical data to obtain meta-CpG signatures associated with prognosis for ATRT, ECRT and MRT. The relationship between these meta-CpG signatures and the consensus subgroups were further explored, along with the correlation of meta-CpGs with gene expression to establish biological significance. By selecting CpGs for their ability to predict survival this method obtained three novel prognostic methylation signatures which predict MRT outcome (ATRT-5, ECRT-14 and MRT-42). These signatures are independent of molecular subgroup and each signature was significantly associated with overall survival (OS) and event free survival (EFS) in their respective cohorts (p&lt;0.001). Both ATRT-5 and MRT-42 maintained their significant association with OS in an independent ATRT cohort (n=64) and each meta-CPG signature is prognostically independent of other major clinical risk factors (e.g. receipt of radiotherapy and presence of metastases). Biologically, individuals with high-risk methylation signatures showed a gene expression profile suggestive of higher proliferative rates and tumours with low-risk scores in ATRT-5 and MRT-42 had an upregulated inflammatory response and increased immune infiltration. Combining these meta-CpGs with other significant clinical risk-factors produced high performing multivariate Cox-models enabling us to propose new stratification models for ATRT and MRT patients. These subgroup-independent prognostic signatures represent a distinct biology in ATRT and, if validated in prospective studies, could progress the use and efficacy of precision-based medicine in this therapeutically challenging disease.
ATRT-21. Contribution of germline mosaic alterations of SMARCB1 in rhabdoid tumor predisposition syndrome
Authors: Masliah-Planchon Julien , Maillot Laetitia , Rybak Noémie , Simaga Fatoumata , Hamza Abderaouf , Villars Marion Gauthier , Delattre Olivier , Bourdeaut Franck 
Published: June 2022

Abstract
Rhabdoid tumors are rare and aggressive tumors that usually arise in very young children. They are characterized by a bi-allelic inactivation of the SMARCB1 gene. Although the majority of alterations of SMARCB1 are acquired in tumors, a heterozygous germline alteration is seen in one third of patients and defines the rhabdoid tumors predisposition syndrome. Penetrance is almost complete and the vast majority of germline alterations of SMARCB1 are acquired de novo but rare familial cases with a healthy carrier have also been described. Since the advent of more sensitive molecular analysis technologies such as next-generation sequencing (NGS), the number of mosaicisms of genes involved in genetic diseases discovered from blood samples has increased considerably. The aim of our study was to explore the mosaicisms of SMARCB1 in the blood 1/ of children with rhabdoid tumors with at least one alteration of SMARCB1 previously identified in the tumor but not found in the blood with old-fashioned low-sensitivity technologies and 2/ in parents of children with heterozygous germline alteration of SMARCB1. We analyzed a custom NGS panel which covers the SMARCB1 gene with an average depth of 1.500X on blood samples of 111 children with rhabdoid tumors and 32 parents collected at the Institut Curie since 1999. The mosaicism rate found in index cases was 11.7% (13/111) and 3.1% (1/32) in parents. The variant allele frequency vary from 0.8% to 12.9%. Our results also indicate to be cautious about the possible confounding effect of circulating tumor DNA. This hitherto underestimated SMARCB1 mosaicism rate should motivate an optimization of the genetic counseling as well as the oncological monitoring of these children and thus have a significant medical impact given the catastrophic prognosis of rhabdoid tumors.
RARE-03. Vision-related quality of life in patients with childhood-onset craniopharyngioma – results of KRANIOPHARYNGEOM 2000 / 2007
Authors: Sowithayasakul Panjarat , Boekhoff Svenja , Friedrich Carsten , Müller Hermann L 
Published: June 2022

Abstract
BACKGROUND: Quality of life (QoL) has become a critical component of therapeutic outcomes in the survivors of childhood-onset adamantinomatous craniopharyngioma (CP) patients. Visual deficiency adversely affects daily functioning and QoL. This study aimed to report the vision-related QoL and associated factors in CP patients. PATIENTS AND METHODS: 120 CP patients recruited between 2001 and 2019 in KRANIOPHARYNGEOM 2000/2007 were included in this study. Mean age at CP diagnosis was 10 years (range: 1.3-16.8 years); age at study was 18 years (range: 6-33 years). The primary outcome measures were QoL assessed by PEDQOL, functional capacity measured by Fertigkeitenskala Münster-Heidelberg ability scale and risk factors associated with decreased QoL during 3 years follow-up in CP patients with and without visual impairment (VI). RESULTS: The most common presenting symptoms were headache (42%), VI (20%), and growth retardation (12%). After diagnosis, VI defined as visual acuity less than 20/40, was found in 87 (70%) patients. Ophthalmologic examination and PEDQOL score were evaluated at three months, one year, and 3 years after CP diagnosis. A difference in the parental assessment of CP patient social functioning within the family was found between patients with and without VI in the first year (48 vs. 39, p=0.017) and third year (43 vs. 37, p=0.011). For the PEDQOL domain autonomy, a difference in self- (51 vs. 45, p=0.029) and parental (47 vs. 42, p=0.048) assessment was observed 3 years after diagnosis. In terms of risk factors, tumor volume more than 21 mm3, incomplete tumor resection and optic atrophy at initial presentation were associated with VI during follow-up. CONCLUSIONS: VI has an impact on QoL after CP. Accordingly, early detection of VI, together with the assessment of the patient’s QoL and the provision of adequate support during follow-up plays an important role in minimizing adverse late effects after CP.
RARE-06. Expanding the clinical and molecular spectrum of pituitary blastoma
Authors: Pak-Yin Liu Anthony , Li Kay Ka-Wai , Chow Chit , Chan Shing , Leung Alex Wing-Kwan , Shing Matthew Ming-Kong , To Ka-Fai , Chan Danny Tat-Ming , Chan Godfrey Chi-Fung , Ng Ho-Keung 
Published: June 2022

Abstract
Pituitary blastomas (PitB) are rare DICER1-associated tumors that occur exclusively in children &lt; 2 years of age. They are locally aggressive tumors that are driven by a combination of germline and somatic alterations involving DICER1. Here, we report two patients with pituitary neoplasms that expand the clinical and molecular spectrum of PitB. Patient 1 presented at 10 months with diabetes insipidus and was initially diagnosed with pituitary ependymoblastoma. She received debulking, chemotherapy and focal radiation with complete response achieved, but unfortunately died at the age of 8 years due to cerebral edema. Patient 2 was a survivor of infant leukemia who was treated with chemotherapy and then further chemotherapy with cranial irradiation at relapse. The patient was then diagnosed at the age of 8 years with pituitary CNS-PNET, which was treated with craniospinal irradiation and chemotherapy, and had remained in remission for 6 years. Review of histology in both cases indicates presence of neuroendocrine lobules, primitive cells, and Rathke pouch-like glandular structures, with high Ki67, ACTH and PRAME positivity compatible with PitB. Next-generation sequencing revealed presence of two DICER1 mutations (germline frameshifting and somatic missense) in Patient 1, and one somatic missense DICER1 mutation plus loss of heterozygosity in Patient 2 (no germline alteration). Surprisingly, C19MC amplification was also detected in Patient 1. Methylation profiling confirms clustering among our samples and PitB references, but not ETMR references. MicroRNA array revealed decrease in mature microRNA expression and preferential down-regulation of 5p/3p species in tumor compared to control pituitary tissue. In all, PitBs may present with clinical and molecular characteristics not conforming with the classical descriptions. It might be prudent to consider sequencing for DICER1 alteration in pediatric pituitary tumors to facilitate diagnosis of this increasingly heterogeneous rare entity.
RARE-10. Neurocutaneous melanocytosis-associated hydrocephalus: the MSK experience from 2001-2022
Authors: Rodriguez Scarlett , Sener Ugur , Elmore Kevin , Haque Sofia , Suser Stephanie , Greenfield Jeffrey , Donzelli Maria , DePass Courtnee , Pugh John , Porter Joanne , Meeker Nathan , Wells Elizabeth , Marghoob Ashfaq , Khakoo Yasmin 
Published: June 2022

Abstract
OBJECTIVE: We hypothesize that patients with neurocutaneous melanocytosis-associated melanoma and ventriculoperitoneal shunts are at risk of developing intraperitoneal spread of melanoma. BACKGROUND: Neurocutaneous melanocytosis, a rare condition characterized by excessive proliferation and deposition of melanocytes in the leptomeninges and brain parenchyma, typically occurs in children with large congenital melanocytic nevi and multiple smaller congenital nevi. These patients are at heightened risk for developing NRAS+ melanomas in the central nervous system, which in turn may lead to symptomatic hydrocephalus requiring cerebrospinal fluid diversion for symptom relief. METHODS: Retrospective single-institution study of patients with histologically or radiographically confirmed NCM evaluated at Memorial Sloan Kettering Cancer Center (MSKCC) from 2001-2022. RESULTS: Of the 47 patients with a diagnosis of NCM, 44 patients had symptomatic neurological complications. Eleven patients developed hydrocephalus, 10 had CNS melanoma, and required ventriculoperitoneal shunt placement. Nine of the 10 patients ultimately died of their disease. Three patients were diagnosed with intraperitoneal melanoma, though data are unavailable for the remaining eight. CONCLUSIONS: All (n=11) patients with NCM-associated CNS melanoma required VP shunts for symptomatic relief. Ten of these patients died within 4.3 years of VP shunt placement, with a range of 1 month to 13.5 years prior to succumbing to their disease. While the intraperitoneal pathology remains unknown for 7 of the cases, 3 had confirmed intraperitoneal melanoma, suggesting that VP shunts provided the conduit to CNS melanoma seeding of the peritoneum. Obtaining baseline abdominal imaging studies prior to VP shunt placement may be helpful in the follow-up of these patients.
RARE-11. 60 years single centre experience of craniopharyngioma management
Authors: Rodrigues Beryl , Adamski Jenny , English Martin , Curry Helen , Solanki Guirish , Peet Andrew , Apps John 
Published: June 2022

Abstract
Adamantinomatous craniopharyngiomas are challenging intracranial tumours associated with significant morbidity. Management includes surgery and radiotherapy, with a shift towards more conservative surgery in recent years, aimed at preserving hypothalamic function. The West Midlands Regional Children’s Tumour Registry collects detailed clinical, pathological and follow up information on patients treated within the region from 1957. 52 cases (26 male, 26 female) of craniopharyngioma treated at Birmingham Children’s Hospital 1957-2018, were identified, with further clinical details obtained from patient records, where available. Visual symptoms were the commonest presenting feature (63%), followed by headache (48%), vomiting (31%), neurological symptoms (31%) and features of endocrine disorders (21%) with a median symptom duration of 6 months (range &lt;1-24). Initial management was with gross total resection (GTR) in 14 patients, subtotal resection in 22 patients and subtotal resection with adjuvant radiotherapy in seven patients. Two patients received radiotherapy without resection, and five patients underwent cystic drainage procedures alone. Two patients initially underwent shunt insertion alone, but received radiotherapy at progression. 30 (58%) patients underwent relapse/progression, with a median time to progression of 1.2 years (range 0.2-6.3). 15 had further surgery. Radiotherapy was used in 14/15 patients who had not previously received radiotherapy, with the other undergoing a GTR. To date 10 patients have died, nine from tumour related reasons and one from pulmonary embolism. Where data was available at follow up, all patients had at least one endocrinopathy, with 38/45 patients having diabetes insipidus. Hypothalamic obesity was identified in 14/36 (39%) patients with sufficient records, with this more common in those undergoing GTR (7/9 (78%)) compared to other surgical procedures (7/27)(26%)(p&lt;0.05). Three patients have developed neurovascular complications and three fatty liver disease. This experience is consistent with the literature and supports the increasing usage of hypothalamic sparing surgical management.