bluuebunny/crossref_metadata_2025_split huggingface dataset:
ATRT-05. Infants and newborns with atypical teratoid/rhabdoid tumors (ATRT) and extracranial malignant rhabdoid tumors: a unique and challenging population
Authors: Nemes Karolina , Johann Pascal D , Steinbügl Mona , Gruhle Miriam , Bens Susanne , Kachanov Denis , Teleshova Margarita , Peter Hauser , Simon Thorsten , Tippelt Stephan , Eberl Wolfgang , Chada Martin , Lopez Vicente Santa-Maria , Grigull Lorenz , Hernáiz-Driever Pablo , Eyrich Matthias , Pears Jane , Milde Till , Reinhard Harald , Leipold Alfred , de Wetering Marianne v , João Gil-da-Costa Maria , Ebetsberger-Dachs Georg , Kerl Kornelius , Lemmer Andreas , Boztug Heidrun , Furtwängler Rhoikos , Kordes Uwe , Siebert Reiner , Vokuhl Christian , Hasselblatt Martin , Bison Brigitte , Kröncke Thomas , Melchior Patrick , Timmermann Beate , Gerss Joachim , Frühwald Michael C 
Published: June 2022

Abstract
INTRODUCTION: Malignant rhabdoid tumors (MRT) predominantly affect infants. Patients below six months represent a particularly challenging group: intensity of therapy is limited by toxicity to developing organs. Information on prognostic factors, toxicity and long term outcome is sparse. METHODS: Clinical, genetic, and treatment data of 100 patients (less than 6 months at diagnosis) from 13 European countries were analyzed (2005-2020). Tumors and matching blood samples were examined for SMARCB1 mutations using FISH, MLPA and Sanger sequencing. DNA-methylation subgroups (ATRT-TYR, ATRT-SHH, and ATRT-MYC) were determined using DNA methylation arrays. RESULTS: A total of 45 patients presented with ATRT, 29 with extracranial, extrarenal (eMRT) and 9 with renal rhabdoid tumors (RTK). Seventeen patients demonstrated synchronous tumors (SYN). Distant metastases at diagnosis (M+) were present in 27% (26/97). A germline mutation (GLM) was detected in 55% (47/86). Methylation subgroup status was available in 50% (31/62) of ATRT or SYN (SHH=13, TYR=13, MYC=4, SHH+TYR=1). The 5-year overall- (OS) and event free survival (EFS) rates were 23.5±4.6% and 19±4.1%, respectively. Male sex (11±5% vs. 35.8±7.4%), M+ (6.1±5.4% vs. 36.2±7.4%), presence of SYN (7.1±6.9% vs. 26.6±5.3%) and -GLM (7.7±4.2% vs. 45.7±8.6%) were significant prognosticators of 5-year OS, in univariate analysis. Molecular subgroup and survival analyses confirmed the previously described survival advantage of ATRT-TYR. In an adjusted multivariate model clinical factors that influence prognosis were: male sex [HR: 2.1 (1.2 – 3.6)], M+ [3.3 (1.8 – 6)], GLM [HR: 2 (1.1 – 3.6)] and maintenance therapy [HR: 0.3 (0.1 – 0.8)]. CONCLUSION: In this large cohort of homogenously treated infants with MRT, significant predictors of outcome were sex, M+, GLM and maintenance therapy. We confirm the need to stratify which patient group benefits from multimodal treatment, and which patients need novel therapeutic strategies. Biomarker-driven tailored trials may be a key option.
ATRT-06. Atypical Teratoid Rhabdoid Tumors (ATRT): results from a Single Institution in Brazil - São Paulo University
Authors: Barreto Juliana Silveira , Gomez Karen Nirit Melo , Dutra Alvaro Pimenta , De Azambuja Alessandra Milani Prandini , Cristofani Lilian Maria , Sanders Felipe Hada , Petito Carlo , Baraldi Helena Espindola , Weltman Eduardo , Ferraciolli Suely Fazio , Frassetto Fernando Pereira , Lucato Leandro Tavares , Rosemberg Sérgio , Filho Vicente Odone 
Published: June 2022

Abstract
OBJECTIVES: Atypical teratoid/rhabdoid tumor (AT/RT) is a rare, highly malignant tumor of the central nervous system with poor prognosis. Nowadays, multimodal management, including surgery, chemotherapy (CMT), radiation therapy (RT) and Bone Marrow Transplantation (BMT). The aim of this study was to assess the experience and survival in a center of reference of treatment in childhood cancer in Brazil. PATIENTS AND METHODS: Medical records of AT/RT patients who underwent surgery from 2008 to 2020 at a center of childhood cancer treatment (ITACI) in São Paulo University were retrospectively reviewed and statistically analyzed. RESULTS: Eight patients (2 males and 6 females) were presented with AT/RTs. Median age during presentation was 22 months (range, 0 - 6 years). Seven patients (88%) were &lt; 18 months and one patient were &gt;18 months. Tumor location was supratentorial in four patients, infratentorial in 2 patients. Kidney disease as the primary diagnosis in 2 patients (25%). Surgical treatment was performed in 4 patients. Seven children underwent total CMT and 3 children were treated with RT. Only 3 patients underwent Autologous Bone Marrow Transplantation (ABMT). The chemotherapy management protocol of the patients was variable: 2 patients received the EU-RHAB protocol, 2 patients received the HEAD START III protocol, 3 patients received chemotherapy in the ICE regimen (Ifosfamide + Carboplatin + Etoposide) and 1 patient received chemotherapy in the CDDP+CTX+VCR (Cyclophosphamide + Cisplatin + Vincristine) regimen. All patients had episodes of neutropenic fever when they received chemotherapy, requiring hospitalization and use of an antibiotic treatment. Among the 8 patients analyzed, all died. CONCLUSIONS: Despite progress in treatment, AT/RT of the CNS disease or primary kidney disease associated with a lack of standardization in a regimen contributes to the dismal prognosis. There is a high mortality in patients with AT/RT, similar to that found in the literature.
ATRT-15. Primordial germ cells identified as one potential cell of origin of MYC rhabdoid tumors
Authors: Graf Monika , Interlandi Marta , Moreno Natalia , Roy Rajanya , Holdhof Dörthe , Göbel Carolin , Melcher Viktoria , Mertins Julius , Albert Thomas K , Kastrati Dennis , Alfert Amelie , Holsten Till , de Faria Flavia , Meisterernst Michael , Rossig Claudia , Warmuth-Metz Monika , Nowak Johannes , Hörste Gerd Meyer zu , Mayère Chloe , Nef Serge , Johann Pascal , Frühwald Michael C , Dugas Martin , Schüller Ulrich , Kerl Kornelius 
Published: June 2022

Abstract
Rhabdoid tumors (RT) are embryonal neoplasms occurring most frequently in the central nervous system where they are termed atypical teratoid rhabdoid tumor (ATRT). A common hallmark of RT is homozygous loss of the BAF complex subunit SMARCB1. RT patients have a poor prognosis with an overall survival time of 17 months and &gt;60% of patients suffer from relapses. The lack of an optimal treatment strategy could be attributed to the heterogeneity within and between different subgroups of ATRT. Despite the recent advancements in characterizing RT at a molecular level, the cellular origin of RT remains elusive. Thus, this study focused on the identification of the cellular origin of MYC-RT and underlying epigenetic deregulations which account for the cellular heterogeneity in these tumors. We showed that Smarcb1 abrogation in Sox2-positive progenitor cells at E6.5 give rise to RT of the MYC and SHH subgroup in genetically engineered mouse models (GEMM). To uncover distinct cells of origin (COO) for the SHH and MYC subgroups, unbiased computational approaches were used to compare single-cell transcriptomes of GEMMs with single-cell reference maps of murine early embryogenesis. While SHH tumors arise from mid/hindbrain progenitor cells, primordial germ cells (PGCs) emerge as COO of both intracranial and extracranial MYC tumors. PGCs as COO of MYC-RT were validated in vivo by using PGC-specific Smarcb1 knockout mouse model. We further characterized a deregulated transcriptome in MYC-RT compared to PGCs, which is sustained by a subset of epigenetically driven tumor cells. Deregulated expression of genes driving methylation/demethylation processes in MYC tumors and regression of these tumors upon treatment with decitabine in vitro and in vivo, indicates that DNA methylation plays a key role in cellular transformation and development of MYC-RT.
RARE-08. Profiling of recurrent adamantinomatous cranionpharyngioma confirms the activation of the MAPK pathway and identifies copy number aberrations in relapsed tumours
Authors: Apps John , Pickles Jessica , Stone Thomas , Chalker Jane , Ogunbiyi Olumide , Schwalbe Edward , Brandner Sebastian , Otto Georg , Castellano Sergi , Jacques Thomas , Deutschbein Timo , Martinez-Barbera Juan Pedro 
Published: June 2022

Abstract
Craniopharyngiomas are rare challenging tumours, with around 25% of cases recurring despite surgery and/or radiotherapy. Whilst transcriptomic and proteomic profiling of adamantinomatous craniopharyngioma (ACP) have revealed activation of the MAPK pathway and IL-6 mediated inflammation, relatively little is known about the biological processes involved in tumour recurrence. To address this, we have analysed a cohort of primary and relapsed ACP tumour accessed from tissue banks, local pathology departments and international collaborators. Serial samples of recurrent ACP (n=11), recurrent papillary craniopharyngioma (PCP) (n=4) and 3 non-recurrent ACP were analysed using β-catenin, pERK1/2 immunostaining, DNA methylation array and RNA sequencing. Differential expression and methylation analyses confirmed differences between ACP and PCP, with over representation of WNT pathway genes in ACP and the MAPK pathway genes in PCP. All of the primary and all except for one of the relapsed ACP tumours showed a pERK1/2 expression. Differences in the immune environment were also identified between ACP and PCP, with higher levels of some inflammatory mediators and CD14+ cell signatures in PCP compared with ACP. Whilst differential methylation and expression analysis revealed relatively stable methylomes and transcriptomes between serial samples of cases, segmental chromosomal alterations were identified in recurrence samples from five ACP cases (5/11,45%). One relapsed case showed histological and molecular signs of malignant transformation, including high ki67 and deletion of TP53. Surprisingly, this malignant tumour showed nuclear beta-catenin in all neoplastic epithelial cells and absence of pERK1/2 staining, despite the primary tumour showing the typical beta-catenin and pERK1/2 expression patterns. These results suggest that the molecular landscape of craniopharyngioma remains stable between recurrences in most cases, but, there is evidence of molecular evolution in a subset of cases. Activation of the MAPK pathway in the vast majority of ACP tumours supports the clinical evaluation of MAPK pathway inhibitors in ACP patients.
RARE-18. Pediatric craniopharyngioma; single center experience in 246 cases with different management modalities
Authors: El Beltagy Mohamed , Enayet Abdelrahman , Sameh Rana 
Published: June 2022

Abstract
PURPOSE: To report our experience with different craniopharyngioma management strategies done for 246 patients in a single institution during a period of 14 years. METHODS: The medical records of all children with the diagnosis of craniopharyngioma treated at Children's Cancer Hospital Egypt (CCHE-57357) during the period from July 2007 to December 2021 were retrospectively reviewed. RESULTS : our registry included 246 pediatric craniopharyngiomawith median age of 7.4 years old. The main strategies of management after initial surgery were follow up, radiotherapy or administration of intracystic interferone post ommaya insertion. The number of cases in each group were 92, 147,and three respectively. Three patients were not operated upon because of heavily calcified lesions, two of them received radiotherapy while the third was kept under follow up. Overall gross or near total total excision was achieved in 31.2 % , subtotal resection was the case in 42.1% while Ommaya insertion and biopsy was done in 21.1 % of cases. Total number of patients received radiotherapy initially or on progression was 195 patients( 78.9%). The five-year overall survival was 88% (95% CI 82.9 – 93.1) while 5- year progression free survival (PFS) was 49.2% (95% CI 41.2—57.2). The five-year PFS rates for patients in the follow up group versus radiotherapy group were 25.2% and 68.7% respectively (P&lt; 0.0001). Beta catenin was positive in 76.4% of cases that were available for testing (123/161). CONCLUSION: management of craniopharyngioma should be individualized with the main objective is the quality of life. Conservative surgery which entails gross total safe resection whenever possible or lesser extent of resection followed by radiotherapy is the main strategy followed in our institution.
RARE-22 Characterizing the landscape of structural variants in adamantinomatous craniopharyngioma
Authors: Jomaa Danny , Khadka Prasidda , Novikov Dana , Condurat Alexandra L , Tsai Jessica W , Dubois Frank , Zhang Shu , Zhou Kevin , Gold Rose , Sousa Cecilia , Vogelzang Jayne , Prince Eric , Lu Sophie , Slivova Veronika , Otto Georg W , Hereza Sergi Castellano , Ashley David , Cohen-Gadol Aaron A , Thompson Eric , Beroukhim Rameen , Apps John , Martinez-Barbera Juan Pedro , Hankinson Todd , Bandopadhayay Pratiti 
Published: June 2022

Abstract
INTRODUCTION: Adamantinomatous craniopharyngiomas (ACPs) are rare brain tumors that primarily occur in children and impact long-term morbidity and mortality. The canonical driver mutation for ACP growth occurs in CTNNB1 and leads to constitutive activation of the Wnt/β-catenin signaling pathway. In this study, we outline the genomic, transcriptomic, and structural variant (SV) landscape in a cohort of 41 ACP samples. METHODS: We performed whole-genome sequencing (WGS) and RNA-sequencing of 41 ACP samples. Matched normal samples were also characterized by WGS. Mutect2 was used to detect single nucleotide variants (SNVs) and indels, and copy number data was generated using the GATK pipeline. SvABA was used to perform SV analysis and to identify significantly recurrent breakpoints and juxtapositions. DESeq2 was used to perform differential gene expression analysis based on clinical and molecular annotation data. RESULTS: 29/41 (70%) of the ACP samples harbored missense mutations in exon 3 of CTNNB1, all of which have previously been reported in ACP tumors. SV analysis identified a median of 11.5 events per tumor. Overall, 9.7% of events were interchromosomal. Of the remainder, the majority (78.6%) were deletions. No SVs occurred within CTNNB1. A positive correlation (r = 0.533) was observed between the frequency of SVs and SNVs within samples. Analysis of significantly recurring breakpoints (SRBs) did not identify recurrent breakpoint events. Differential gene expression analysis comparing samples with and without CTNNB1 variants identified 2,143 differentially expressed genes with q-value &lt; 0.05. CONCLUSION: This study identifies activating mutations in exon 3 of CTNNB1 in a large cohort of ACP samples. We also integrate SV and transcriptomic data to comprehensively investigate ACP tumor genomes and identify putative novel tumorigenic mechanisms that advance our understanding of ACP biology.
RARE-29. Transcriptome characterization of pediatric adamantinomatous craniopharyngioma at the cellular level
Authors: Prince Eric , Trudeau Tammy , Chatain Oscar , Staulcup Susan , Martinez-Barbera Juan Pedro , Goerg Carsten , Hankinson Todd 
Published: June 2022

Abstract
BACKGROUND: Adamantinomatous Craniopharyngioma (ACP) is a neurologically devastating brain tumor that affects children and adults. It is histologically heterogeneous with epithelial populations that are characterized by the nuclear accumulation of mutated β-catenin, and activated Wnt signaling. Current models suggest that ACP growth is driven through paracine mechanisms characterized by the senescence-associated secretory phenotype (SASP). However, detailed pathogenic mechanisms remain unknown. Improved definition of the various cellular phenotypes that compose ACP will inform and advance our understanding of this disease. METHODS: Single cell RNA-sequencing (scRNA-seq) and multiplex ELISA were performed on pediatric ACP tissue and cyst fluid, respectively. Reference scRNA-seq data was obtained from PanglaoDB. Preprocessing and standard analyses were conducted using Seurat software. Cellular phenotypes were annotated using the Human Primary Cell atlas. Differential expression and functional enrichment analyses were utilized to identify Wnt-signaling activation and epithelial subpopulations. Paracrine signaling was inferred via CellChatDB. SASP Atlas was utilized to query marker gene lists. Pseudotemporal ordering was performed using monocle3. RESULTS: ACP tissue is heterogenous and contains multiple distinct immune signatures. ACP tissue contains 2 unique epithelial subpopulations, which demonstrate canonical Wnt-signaling and SASP, respectively. Pseudotemporal ordering suggests the initial oncogenic event to be of epidermal character, with subsequent aggressive behavior from a separate epithelial cell population. CONCLUSIONS: Based on gene expression, cell populations that correspond to the histologically identifiable epithelial whorls and palisading epithelium can be identified. These subpopulations display unique functional signatures. Simultaneous and synergistic therapeutic targeting of these separate epithelial populations may lead to improved patient care.
DIPG-04. Feasibility and early results of phase 2 open label randomized study of radiotherapy(RT), concomitant nimotuzumab and vinorelbine and re-irradiation at relapse, versus multiple elective radiotherapy courses with concomitant vinorelbine and nimotuzumab for newly diagnosed childhood and adolescence Diffuse intrinsic Pontine Glioma (DIPG)
Authors: Massimino Maura , Biassoni veronica , Mastronuzzi Angela , Schiavello Elisabetta , Barretta Francesco , Quaglietta Lucia , Milanaccio Claudia , Pecori Emilia , Cacchione Antonella , Boschetti Luna , Ruscio Valentina Di , Chiesa Silvia , Scimone Giuseppe , Barra Salvina , De Martino Lucia , Ramaglia Antonia , Picariello Stefania , Verrico Antonio , Alessandro Ombretta , Vennarini Sabina , Podda Marta , Gattuso Giovanna , Cinalli Giuseppe , Antonelli Manila , Modena Piergiorgio , De Cecco Loris , Buttarelli Francesca R , Gandola Lorenza 
Published: June 2022

Abstract
BACKGROUND: The purposes of this trial were to evaluate the feasibility, response, PFS/OS of a randomized study comparing two different RT schedules for DIPG while administering the same systemic treatment. METHODS: Patients: 2-21 years-old with a not-pretreated radiologically verified DIPG (MRI blindly reviewed at diagnosis and every 12 weeks thereafter) and symptoms duration below 6 months. Biopsy was required if suggested by atypical imaging. Vinorelbine 20 mg/m2+nimotuzumab 150 mg/m2 were administered weekly for 12 weeks; thereafter every other week until tumor progression or for up to 2 years. Standard(ST) arm included focal RT at total dose of 54Gy (1.8Gy/day); for local progression re-irradiation was proposed at 19.8Gy, in case of dissemination craniospinal irradiation(CSI) at 36Gy was adopted. Experimental(SP) arm included three elective courses of RT at defined timepoints at 36Gy, 19.8Gy and 19.8Gy with possible reirradiation for relapse at 9 Gy. Incidences of local(L) and distant(D) progression were assessed in a competing risk setting. RESULTS: Aggregated preliminary results are given for 4 Italian centers. 54 pts were screened and 51 included, 27 in ST, 28 males, median age 7 years (range 3-17). Median time of observation was 17.9 months. Twelve patients needed a shunt, 10 during treatment; 20 were biopsied, in 18 cases according local protocols. 19/20 tumors had H3.3 K27 mutation. 41 relapsed, 28 locally, 13 with a component of dissemination. 36 died, one for tracheotomy bleeding. SP irradiation was feasible and never produced significant radionecrosis. Median EFS/OS were 7.3/12.9 months, respectively; EFS/OS at 1 year were 19.0%/57.3%, not differing between patients with local vs. disseminated relapses. Patients submitted to biopsies had more dissemination (P=0.04) and less local progression (P=0.077). CONCLUSIONS: Treatment was feasible and OS confirmed previous results obtained in a single center. Randomization results will be later reported.
DIPG-19. FOXR2 is an oncogenic driver across pediatric and adult cancers
Authors: Tsai Jessica W , Cejas Paloma , Wang Dayle K , Patel Smruti , Wu David W , Arounleut Phonepasong , Wei Xin , Zhou Ningxuan , Syamala Sudeepa , Dubois Frank P B , Crane Alexander , Pelton Kristine , Vogelzang Jayne , Sousa Cecilia , Baguette Audrey , Chen Xiaolong , Condurat Alexandra L , Dixon-Clarke Sarah E , Zhou Kevin N , Lu Sophie D , Gonzalez Elizabeth M , Chacon Madison S , Digiacomo Jeromy J , Kumbhani Rushil , Novikov Dana , Hunter J'Ya , Tsoli Maria , Ziegler David S , Dirksen Uta , Jager Natalie , Balasubramanian Gnana Prakash , Kramm Christof M , Nathrath Michaela , Bielack Stefan , Baker Suzanne J , Zhang Jinghui , McFarland James M , Getz Gad , Aguet Francois , Jabado Nada , Witt Olaf , Pfister Stefan M , Ligon Keith L , Kleinman Claudia L , Long Henry , Jones David T W , Bandopadhayay Pratiti , Phoenix Timothy N 
Published: June 2022

Abstract
BACKGROUND: Understanding how aberrant transcription factors (TFs) hijack normal development to induce oncogenesis is a critical question in oncology. Forkhead box (FOX) proteins are a superfamily of transcriptional regulators characterized by a forkhead DNA-binding domain. Within this family, Forkhead Box R2 (FOXR2) has been identified as a candidate structural variant (SV) driver in a subset of pediatric cancers including CNS embryonal tumors and peripheral neuroblastoma. While FOXR2 has been shown to stabilize MYC isoforms, the mechanistic details through which it enhances tumor formation, other non-SV mechanisms of activating aberrant expression, and the true extent of its role as an oncogene across all cancers have not been systematically evaluated. METHODS: We applied an integrative approach using transcriptomics, epigenetics, in vitro cancer models, and in vivo mouse models to systematically evaluate the mechanisms by which FOXR2 is activated across human cancers. RESULTS: We performed a pan-cancer analysis of FOXR2 activation across over 10,000 adult and pediatric cancer samples, and surprisingly found FOXR2 to be aberrantly upregulated in 70% of all cancer types (including diffuse midline gliomas), and 8% of all individual tumors. FOXR2 expression occurred predominantly in the absence of rearrangement/fusions, single nucleotide variants, or copy number aberrations at the DNA level. Transcriptomic and epigenomic analyses show the vast majority of tumors (78%) aberrantly express FOXR2 through a previously undescribed epigenetic mechanism via hypomethylation of a novel promoter. Using both in vitro and in vivo models, we demonstrate that FOXR2 expression is both sufficient and necessary for transformation across multiple lineages, including DMGs. CONCLUSION: Taken together, this study demonstrates that FOXR2 is a novel and potent oncogene across pediatric and adult cancers, and highlights a new epigenetic mechanism by which its expression is activated.