bluuebunny/crossref_metadata_2025_split huggingface dataset:
LINC-10. The Adequate Treatment of Children and Adolescents with Primary Central Nervous System Germ Cell Tumors (CNS GCT) in a Developing Country
Authors: Cappellano Andréa M , Dassi Natalia , Mançano Bruna , Epelman Sidnei , Almeida Daniela B , Cavalheiro Sergio , Dastoli Patricia A , Seixas Maria Teresa , Nicácio Jardel M , Costa Marcos D , Silva Frederico A , Aguiar Simone S , Almeida Jr Carlos R , Teixeira Gustavo R , Silva Nasjla S , Finlay Jonathan L 
Published: June 2022

Abstract
INTRODUCTION: Primary central nervous system germ cell tumors (CNS GCT) are a heterogeneous group of malignancies that can be divided into germinomas and non-germinomatous GCT (NGGCT), accounting for 2-3% of brain tumors in children/adolescents in the Western hemisphere. The study aim is to report the ability to adequately treat Brazilian patients with CNSGCT through a consortium protocol, reporting their treatment, response and survival. Methods: Since 2013, 58 patients with histologic and/or tumor marker (TM) diagnosis of germinoma with/without HCGβ levels ≤200mIU/ml (n=43), five of them between 100-200mIU/ml, received carboplatin/ etoposide (4 cycles) and NGGCT (n=15), received carboplatin/etoposide/cyclophosphamide (6 cycles), all followed by 18Gy ventricular field irradiation and primary site(s) boost. Autologous hematopoietic cell transplant (AuHCT) was undertaken for NGGCT slow responders. Results: Mean age 13.2 years, 42 males. Diagnosis was made by TM (n=19), surgery (n=25) and both (n=12). Two bifocal cases with negative TM and inconclusive biopsy were treated as germinoma. Primary tumor location was pineal (n=30), suprasellar (n=16), bifocal (n=11) and basal ganglia/thalamus (n=1). Eighteen had ventricular/spinal spread. Second-look surgery occurred in seven patients. For the germinoma group, 36 achieved complete responses (CR) after chemotherapy, seven showed residual teratoma/scar. For the NGGCT after 4/6 cycles, six patients showed CR, two failure/progression and seven partial responses (five with negative TM). Two with positive TM underwent AuHCT. Radiotherapy was utilized as described, except in three patients. Four NGGCT patients died (two disease progression, two other causes with no disease). Toxicity was mostly grade 3/4 neutropenia/thrombocytopenia during chemotherapy. At a median follow-up of 40 months, event-free and overall survival was 100% for germinoma and 64.5% NGGCT. Conclusion: The proposed treatment was feasible to be performed in a developing country, with suitable survival even with VFI dose reduction to 18Gy.
LINC-14. A single center retrospective analysis of pediatric pineoblastoma in Beijing
Authors: Li Miao , Du Shuxu , Sun Yanling , Wang Shumei , Wu Wanshui , Sun Liming 
Published: June 2022

Abstract
OBJECTIVE: To explore the clinical characteristics and outcome in children with pineoblastoma in Beijing. METHODS: Clinical data of 18 pediatric patients with newly diagnosed pineoblastoma admitted to Beijing Shijitan Hospital between January 2014 and November 2021 were retrospectively analyzed. The diagnoses were confirmed by pathology. RESULTS: Male/female ratio=8:1. The median age at diagnosis was 4.7 (range, 0.2-12.6) years, with 2 cases in infancy, and 13 cases ≥ 3 years. The symptoms at diagnosis included headache (31%), vomiting (29%), convulsions (9%), strabismus (9%), nausea (6%), etc. Four patients experienced metastasis at diagnosis. Ki-67 index was under 30% in 5 cases, 30-80% and ≥80% in 10 and 2 cases, respectively. All were treated with surgery, and 12 children underwent gross total resection (GTR). Seventeen cases were administered both radiotherapy and chemotherapy, with one case only radiotherapy followed by surgery. Median follow-up time was 54 months. Nine patients developed a recurrence and 2 patients died at last follow-up. The 1-year/3-year progression-free survival (PFS) and overall survival (OS) were (77.8±10.5/11.1±10.5)%, and (100/90.9±8.7) %, respectively. The 3-year OS of boys (93.8%) was higher than that of girls (50.0%); and also higher in cases with GTR (91.7%) than STR (83.3%). However, the differences were not significant in the above two groups. The children with Ki-67 index ≥80% had worse 3-year OS than those&lt;80% (χ2=8.000, P=0.005). The median PFS of children treated under the order of craniospinal irradiation followed by chemotherapy was better than that of the inverse order (29m vs 13m, χ2=6.528, P=0.011).CONCLUSION: Pineoblastoma is rare and often fatal, but with better OS in our center, although the PFS is dismal. Boys, GTR resections, and Ki-67 index &lt;80% tends to have better OS, and the order of irradiation followed by chemotherapy tends to have better PFS.
Keywords: pineoblastoma; therapy; survival
LINC-15. Sustaining multidisciplinary care of children with central nervous system tumors during the COVID-19 pandemic
Authors: Richelle Ong Faustine , Baticulon Ronnie , Alcasabas Ana Patricia 
Published: June 2022

Abstract
INTRODUCTION: A multidisciplinary team (MDT) approach is essential for quality cancer care. Since 2019, we have conducted regular MDT meetings to discuss pediatric patients with central nervous system (CNS) tumors at the Philippine General Hospital. Because of COVID-19, an abrupt transition from in-person to virtual meetings became necessary. METHODS: We reviewed the proceedings of MDT meetings for pediatric CNS tumors from March 2020–December 2021. We identified the strategies and adaptations of our pediatric neuro-oncology group, and outlined recommendations for other institutions in low- and middle-income countries. RESULTS: Our pediatric neuro-oncology group conducted 18 virtual MDT meetings during the study period. Meetings were scheduled every last Tuesday of the month, with pediatric oncologists, neurologists, neurosurgeons, radiation oncologists, radiologists, and neuropathologists regularly attending. We invited other specialists as needed. In total, we had 135 case discussions for 79 unique patients, or about 8 patients per meeting. These included both inpatients (74%) and outpatients (26%). Ten patients received prior treatment elsewhere. At the time of the meeting, 86% were postoperative, 8% were preoperative, and 6% did not require surgery. Most (60%) had malignant CNS tumors and 15% had disseminated/leptomeningeal disease. Histopathologic diagnosis was obtained for 62 patients (79%). Concerns addressed were: formulating a treatment plan (88%), surveillance strategy (10%), and diagnostic workup (5%). DISCUSSION: Several factors contributed to the ease of online transition: (1) motivated care providers including a patient navigator, (2) fixed schedule, (3) institutional Zoom account for securing data privacy, and (4) availability of picture archiving and communication system (PACS) for neuroimaging. Challenges included: (1) delays due to internet connectivity, (2) Zoom fatigue and online distractions, and (3) risk for miscommunication or misunderstanding. Commitment of the entire neuro-oncology team is essential to ensure the delivery of best possible care for pediatric patients with CNS tumors.
LINC-18. Challenges in the neurosurgical care of pediatric patients with central nervous system tumors during the COVID-19 pandemic
Authors: Paul Golidtum Jared , Custodio John Emmanuel , Estanislao Jochrys , Alcazaren Jose Carlos , Seng Kenny , Navarro Joseph Erroll , Baticulon Ronnie 
Published: June 2022

Abstract
INTRODUCTION: Central nervous system (CNS) tumors account for 20 - 30% of all childhood cancers. The Philippines is a lower-middle income country, wherein brain centers are located mostly in urban areas. We aimed to identify challenges that pediatric patients with CNS tumors encountered during the COVID-19 pandemic, which aggravated delays in their diagnosis and treatment. METHODS: This is a retrospective review of all pediatric patients who underwent neurosurgery for CNS tumors at the Jose R. Reyes Memorial Medical Center, a tertiary referral center, from January 2020 until December 2021. We summarized patients’ demographic data, clinical course, and perioperative outcomes. RESULTS: A total of 38 pediatric patients underwent neuro-oncologic surgery in our center during the study period. There were 18 males and 20 females, with a mean age of 7.5 ± 4.9 years. Tumor was biopsied and/or resected in 35 cases (92%). The most common histologic diagnoses were medulloblastoma (n=8, 21%) and high-grade glioma/glioblastoma (n=5, 13%). Median preoperative length of stay and total length of stay were 10 (IQR: 17) and 28 (IQR 33.75), respectively. There was a high perioperative mortality rate in 2020 (71%), but this decreased to 20% in 2021. Six patients (16%) developed COVID-19 infection during the perioperative period. There were nine patients (24%) who had documented tumor progression because of delays in adjuvant therapy. DISCUSSION: Aside from geographic barriers and catastrophic health expenditure, the major challenges that disrupted the care of pediatric patients with CNS tumors in our center during the COVID-19 pandemic were delays in neuroimaging for diagnosis, unavailability of operating room slots, deficiency in critical care beds, and workforce shortage due to COVID-19 infection among health workers. Health care systems must adapt to the changes brought about by the pandemic, so that children with CNS tumors are not neglected.
LINC-24. Survival and genetic evaluation of patients diagnosed with choroid plexus tumor treated at a Brazilian institution
Authors: Oliveira Milena , Silva Nasjla , Cappellano Andrea , Rodrigues Jessica , Almeida Daniela , Cavalheiro Sergio , Dastoli Patricia , Silva Frederico , Seixas Maria Teresa , Lima Fernanda 
Published: June 2022

Abstract
INTRODUCTION: Choroid plexus tumors (CPT) are rare intraventricular neoplasms of epithelial origin. They usually occur in the 2nd year of life, corresponding to 0.4-0.6% of intracranial tumors in this age group. They are classified, according to WHO 2021: choroid plexus carcinoma (CPC), atypical choroid plexus papilloma (ACPP) and choroid plexus papilloma (CPP). Li-Fraumeni syndrome (LFS) is present in 50% of patients with CPC. In Brazil, the TP53p.R337H mutation affects 0.3% of the population in the South/Southeast. OBJECTIVE: Evaluate the genetic assessment and overall-survival (OS) of patients with CPT treated at IOP/GRAACC/UNIFESP. PATIENTS/METHODS: Between 1995-2021, 48 patients were diagnosed with CPT in our institution, 27 CPC, 18 CPP and 3 ACPP. From 2012-2021 patients were referred for genetic evaluation, 16 of which had CPC (2 had previously CPP). Family history for neoplasms was present in 87.5%, 37.5% compatible with Li-Fraumeni Syndrome (LFS) of which 50% with positive mutations. The molecular investigation of TP53 gene in patients with CPC was performed and positive in 62,5%:R337H(6 patients), R110C*, R158H*, H179R*, R196* (*1 patient each). For those with R337H, p53 protein immunohistochemistry resulted in 90-100% positivity. Treatment strategies consisted of surgery with gross total resection being achieve in all ACPP, 94,4% CPP and 55,5% CPC. Chemotherapy was performed in only 1 case of ACPP and all CPC with a variety of schemas, including high dose of chemotherapy and autologous bone marrow transplant for slow responders or recurrent disease. The three- and five-years OS for CPC was 72.5% and 61.7%, respectively. For CPP and ACPP 5y OS was 100%. CONCLUSION: The present study is in agreement with the literature showing an excellent survival for CPP and ACPP but an inferior outcome for patients with CPC and TP53 mutation despite being assisted by a well-prepared multidisciplinary team with an adequate treatment.
MODL-06. Targeting c-MET in combination with radiation is effective in MET-fusion driven high-grade glioma
Authors: Zuckermann Marc , He Chen , Andrews Jared , Sloan-Henry Roketa , Bianski Brandon , Xie Jia , Wang Yingzhe , Twarog Nathaniel , Onar-Thomas Arzu , Ernst Kati , Yang Lei , Li Yong , Dalton James , Li Xiaoyu , Chepyala Divyabharathi , Zhu Xiaoyan , Zhang Junyuan , Xu Ke , Hover Laura , McKinnon Peter J , Pfister Stefan M , Rankovic Zoran , Freeman Burgess B , Shelat Anang A , Chiang Jason , Jones David T W , Tinkle Christopher L , Baker Suzanne J 
Published: June 2022

Abstract
Oncogenic fusion events involving c-MET have been observed in up to 12% of pediatric high-grade glioma (pHGG). MET inhibitors have displayed potent initial responses in MET rearranged tumors but acquired resistance to single agent modalities invariably occurs. To identify new treatment options against these tumors, we established two novel orthotopic mouse models including an immunocompetent, murine allograft and an intracranial patient-derived xenograft (PDX), both harboring distinct MET fusions. We analyzed the pharmacokinetic and pharmacodynamic profiles of two MET inhibitors, crizotinib and capmatinib, and examined their efficacy against tumor cell cultures derived from the aforementioned models. Capmatinib outperformed crizotinib in terms of specificity, potency and brain availability, resulting in a highly differential cellular response compared to crizotinib treatment. We evaluated the efficacy of both compounds in combination with radiotherapy (RT) and found that radiation further potentiated the inhibitory effect of capmatinib on tumor cell growth. We then utilized both models to assess the combinatorial effect of capmatinib and radiation on intracranial tumors in vivo and found that the combination therapy significantly increased overall survival in both cohorts. In the PDX model, the combination, relative to either intervention alone, induced a remarkable decrease of tumor burden, which persisted throughout the observation period in all treated animals. RNA-sequencing of capmatinib-treated tumors and tumor cell cultures revealed impaired expression of DNA repair genes. Further, we showed that capmatinib enhanced radiation-induced DNA damage, as demonstrated by increased γ-H2AX foci in treated cells, providing mechanistic insight for the cooperative effects of the combined treatment. Our results validate capmatinib as an effective inhibitor of MET in pHGG and demonstrate the outstanding efficacy of capmatinib and radiation against MET-driven pHGG in two complementary preclinical models, informing future clinical trials.
MODL-07. DNA methylation-based biobank of murine models for pediatric tumors
Authors: Zheng Tuyu , Sill Martin , Imle Roland , Shiraishi Ryo , Wang Wanchen , Morcavallo Alaide , Chesler Louis , Kawauchi Daisuke , Ayrault Olivier , Pavlo Lutsik , Pfister Stefan M , Kutscher Lena M , Banito Ana , Jones David W , Pajtler Kristian W , Zuckermann Marc 
Published: June 2022

Abstract
Recent advances in molecular profiling methods led to the identification of multiple new molecularly defined tumor types and subtypes, distinguished by distinct molecular markers and characteristic DNA methylation signatures. While the analysis of human methylome using microarrays has become an affordable and a routine in many labs, this technology until recently was not available for murine samples. In the past years, we have successfully generated a variety of mouse models for childhood tumors (e.g brain tumors and sarcomas) using different techniques, most of which faithfully reflect the human tumor counterparts at the histological level. With the recently released Infinium Mouse Methylation BeadChip, we now set out to use our models to generate the first DNA methylation database for murine pediatric tumors. We profiled more than 70 mouse models of pediatric tumors including gliomas, medulloblastomas, ependymomas and sarcomas, as well as 40 normal brain and muscle control tissues. We are currently performing a cross-species comparative analysis of established mouse models and the human counterparts. This will assess, how faithfully each models reflect the human situation and examine the effects of multiple passages of allografting. We will also analyze purified immune cell populations and use the derived methylation signatures to assess the model-specific immune microenvironment. Furthermore, we will investigate the methylomes of multiple putative cells-of-origin, which is hardly possible in the human context due to the lack of purified material. We will correlate these to murine tumor samples and thereby provide novel insights into tumor origins. In summary, our study will generate a validated biobank of murine models for pediatric cancers and provide a valuable resource for future developmental studies and preclinical trials.
MODL-12.Ex vivo model identifies druggable vulnerabilities in medulloblastoma
Authors: Gries Alexandre , Romanino Davide , Kumar Karthiga Santhana , Guerreiro Stücklin Ana S , Grotzer Michael A , Baumgartner Martin 
Published: June 2022

Abstract
Medulloblastoma (MB) is the most common malignant brain tumour in children and long-term sequelae in survivors caused by the harsh, non-targeted treatments is common. Current screening protocols for the detection of novel druggable vulnerabilities rely on 2D and 3D cell culture systems using established or primary tumour cells. However, these assays do neither provide the cellular, chemical and biophysical context of the tissue, nor reveal drug effects on the invasive behavior of the tumour cells. To overcome these limitations, we have established ex vivo Organotypic Cerebellum Slice Co-culture (OCSC) models for SHH and group 3 MB tumours, which provide spatio-temporal insights in the growth and dissemination behaviour of the tumour cells. OCSCs represent an excellent translational model for patient sample profiling, drug testing, and microenvironmental or explorative target identification studies in a physiologically relevant tissue context. We found that the AURKB inhibitor Barasertib (AZD-1152), which was ineffective to reduce ONS-76 cell invasion in vitro, effectively reduced tumour volume and proliferation of these SHH tumour cells in the tissue context. The AURKB inhibitor thus displays higher efficacy ex vivo, indicating an impact of the microenvironment on its functional activity. We further validated tumour suppressive activity of AURKB inhibition with Barasertib at low nanomolar concentration or with siRNA-mediated depletion of AURKB in Grp3 MB tumour cells and in primary tumour cells ex vivo, thereby confirming the therapeutic potential of AURKB inhibition against MB progression. We furthermore found that the combination of AURKB inhibition with irradiation or with the SRC inhibitor Dasatinib, lead to a near complete eradication of the tumour cells. Thus, OCSCs are a clinically relevant model where tumour material can be efficiently tested for drug sensitivities, which allowed us to identify AURKB inhibition as an effective treatment against tissue invasive MB.
MODL-18. Enhancing anti-CD47 mAb efficacy with radiotherapy for Group 3 paediatric medulloblastoma in preclinical models
Authors: Abbas Zahra , Buck Jessica , Ancliffe Mathew , Arias Clara Andradas , Howlett Meegan , Hii Hilary , Johns Terrance , Mitra Siddhartha , Gottardo Nicholas , Endersby Raelene 
Published: June 2022

Abstract
Medulloblastoma is the most common paediatric brain cancer. Standard treatment approaches, including craniospinal irradiation (CSI), can result in severe lifelong side effects and have not changed for decades resulting in a stagnation of survival outcomes for children with aggressive medulloblastoma. Despite successes in other cancers, no immunotherapies have been approved for use in paediatric medulloblastoma. Unlike other solid tumours, medulloblastomas are myeloid dominant, and immunotherapies must be rationally designed with the tumour microenvironment in mind. Anti-CD47 antibody therapy activates macrophages against cancer cells by blocking anti-phagocytic signalling mediated by CD47-SIRPa ligation and has shown preclinical efficacy in brain cancer models. We have developed preclinical CSI protocols that mimic clinical treatment response using a small animal radiotherapy platform. We show that CSI depletes adaptive immune cells in the brain, increasing the proportional abundance of myeloid cells, suggesting an opportunity to combine radiation with myeloid-targeted immunotherapy. We show that anti-CD47 therapy is ineffective as a single agent against a patient-derived xenograft model of Group 3 medulloblastoma (SJ_MB002), and that while the CSI protocol causes temporary tumour regression, the combination of anti-CD47 with CSI results in marked and persistent tumour regression. To enhance our preclinical evaluation of CSI and anti-CD47, we have developed new mouse models that more accurately reflect the developing microenvironment of children and show that immune populations in paediatric brain are distinct from adult mouse brain. Future work will elucidate the mechanisms by which radiotherapy alters the medulloblastoma microenvironment to enhance the anti-tumour activity of myeloid immune cells in the brain. By evaluating this novel combination of immunotherapy with standard medulloblastoma treatments, in age-appropriate models, our research should facilitate the rational selection and rapid translation of optimised treatment combinations for future medulloblastoma clinical trials.
MODL-22. Establishment of a novel system to specifically trace and ablate quiescent/slow cycling cells in high-grade glioma
Authors: Antonica Francesco , Santomaso Lucia , Pernici Davide , Petrucci Linda , Aiello Giuseppe , Cutarelli Alessandro , Conti Luciano , Romanel Alessandro , Miele Evelina , Tebaldi Toma , Tiberi Luca 
Published: June 2022

Abstract
Pediatric and adult high-grade gliomas are the most common malignant brain tumors, with poor prognosis due to recurrence and tumor infiltration after surgical removal and chemotherapy. Quiescent/slow cycling stem cells have been proposed to be one of the main players of tumor relapse but their involvement in in the infiltration remain unclear. Despite they have been described in mouse models or after transcriptional profiling of human tumor samples, their direct visualization, targeting and ablation remains a challenge. Here, we identified a population of malignant cells expressing Prominin-1 in a non-proliferating state in pediatric high-grade glioma patients. We next used a fluorescent cell cycle sensor to visualize quiescence tumor cells in mouse brain cancer and human cancer organoids. In particular, we characterized them within the tumor revealing the invasiveness capacity of slow cycling tumor cells. Furthermore, we generated a new system to specifically trace and ablate such cells. Indeed, lineage tracing experiments allowed to trace quiescent Prom1 progeny in the tumors after temozolomide treatment. In addition, the selective ablation of quiescent Prom1+ cells in mouse brain cancer reduced tumor infiltration and improved survival. Furthermore, time-lapse experiments showed that slow cycling cells are also able to infiltrate co-cultured human brain cancer organoids. Finally, using our new cancer organoid- and GBM spheroids-based models we identified a drug acting on quiescent cells leading to a reduction in cell invasion. Overall, our data show that quiescence/slow cycling cells are key driver of tumor invasiveness, the major malignant feature of high-grade brain cancer.