bluuebunny/crossref_metadata_2025_split huggingface dataset:
DDEL-07. A Phase I study examining the feasibility of intermittent convection-enhanced delivery (CED) of MTX110 for the treatment of children with newly diagnosed diffuse midline gliomas (DMGs)
Authors: Zacharoulis Stergios , Szalontay Luca , CreveCoeur Travis , Neira Justin , Higgins Dominique , Englander Zachary , Spinazzi Eleonora , Sethi Chankrit , Canoll Peter , Garvin James , Zylber Rebecca , Damment Steve , Zamoryakhin Dmitry , Maddocks Alexis , Feldstein Neil , Bruce Jeffrey 
Published: June 2022

Abstract
Histone deacetylase inhibitors have been found preclinically to be among the most active agents against DMGs, however, they are clinically ineffective with systemic delivery due to blood brain barrier limitations and toxicity. Using a repurposed device (implantable subcutaneous pump connected with a catheter directly implanted into the pons/thalamus) we are performing a phase I, standard 3 + 3 dose escalation study to investigate the safety and feasibility of repeated infusions of MTX110 (Midatech Pharma), a water-soluble formulation of panobinostat, via CED. Eligible patents are between 3 and 18 years of age with newly diagnosed DMG following radiation therapy, without hemorrhage or cyst in the tumor, and having intact organ function. Following tumor biopsy and device implantation, patients receive two 48-hour-infusion pulses 7 days apart of MTX110 (30, 60, or 90 mM). The infusion pump is prefilled with MTX110 (and gadolinium for co-infusion to serve as a surrogate for drug distribution) and administered using the wireless N’Vision clinical programmer at a rate of 0.2 mL/hr. Seven patients (30 mM group, n=3 and 60 mM group, n=4) have been treated with the MTX110 infusate. All but one patient had adequate tumor coverage as measured by co-infused gadolinium on MRI. One patient suffered a severe adverse event related to the infusion and tumor anatomy. Four patients had Grade 2 transient neurological deficits related to biopsy (n=1) and the infusion (n=3). In a follow up period of 12-22 months from diagnosis, progression free survival ranges from 8 to 20 months. With one objective response, 3 patients remain alive (2 without progression, both at 12 months, and 1 with progressive disease, at 22 months post diagnosis). Three patients are expected to be treated at 90 mM level. Using MTX110, we demonstrated the safety and feasibility of repeated drug infusion by CED in DMG patients.
EPCT-07. Updated report on the pilot study of using MRI-guided laser heat ablation to induce disruption of the peritumoral blood brain barrier to enhance deliver and efficacy of treatment of pediatric brain tumors
Authors: Shatara Margaret , Gauvain Karen , Cantor Evan , Meyer Ashley , Ogle Andrea , McHugh Michele , Beck Mary , Green Tammy , King Allison , Cluster Andrew , Brossier Nicole , Shimony Joshua S , Abdelbaki Mohamed S , Tran David D , Campian Jian , Leuthardt Eric C , Rubin Joshua , Limbrick David 
Published: June 2022

Abstract
BACKGROUND: MRI-guided laser interstitial thermal therapy (LITT) is a minimally invasive, cytoreductive surgery useful for managing unresectable brain tumors. LITT disrupts the blood brain barrier (BBB) and facilitates chemotherapy delivery. We report the toxicity and outcome for pediatric brain tumors treated on a pilot trial of LITT and chemotherapy. The primary objectives were to quantify peritumoral BBB disruption following LITT and evaluate toxicity and efficacy. METHODS: The trial had two arms, A: patients with newly diagnosed gliomas underwent LITT followed by standard of care management, and B: patients with relapsed malignant brain tumors received 6 weeks of weekly doxorubicin post-LITT followed by maintenance etoposide. RESULTS: Between 2015 – 2018, six patients were enrolled: five on arm A (four with low-grade gliomas, one with high-grade glioma), one on Arm B with progressive anaplastic astrocytoma. All patients tolerated the procedure well; four experienced a transient hemiparesis post-LITT. The Arm B patient progressed and died of disease 2 months and 22 months post-LITT, respectively. The HGG patient received standard therapy and remains without disease progression 44 months post-LITT. One patient with LGG required additional treatment for disease progression 14 months post-LITT. Two patients with LGGs did not require additional therapy, now 51 and 41 months post-LITT. One patient was alive 24 weeks post-LITT and subsequently lost to follow-up. Peritumoral BBB disruption was analyzed in two ways: serum abundance of brain-derived proteins and MRI Dynamic contrast enhancement (DCE). Neuron-specific enolase were measurable in the serum of all patients, using ELISA up to 84 days post-LITT. DCE 2 weeks post-LITT demonstrated increased enhancement and FLAIR signal, consistent with BBB disruption and vasogenic edema. This effect was evident up to 4 months post-procedure. CONCLUSION: LITT is safe in children with brain tumors and can be combined with chemotherapy. DCE and serum brain-derived proteins can measure BBB disruption.
EPEN-10. Elucidating the biological difference between pediatric supratentorial ependymomas using genetically engineered brain tumor organoids.
Authors: Roosen Mieke , Stathi Phylicia , Bunt Jens , Kool Marcel 
Published: June 2022

Abstract
Ependymomas (EPN) are neuroepithelial tumors of the central nervous system occurring both in adults and children. DNA methylation profiling has identified ten distinct molecular groups. In the supratentorial (ST) compartment, ZFTA-fusion positive and YAP1-fusion positive ST-EPN represent the two main groups in pediatric patients that are histologically very similar but have a completely different clinical behavior. While most ST-EPN-YAP1 patients survive, only 50% of ZFTA positive patients survive longer than 5 years. Improving survival of ZFTA positive patients requires better understanding of the tumor biology. Despite having different oncogenic fusions, it is unclear whether the cellular origin and tumor biology is related or not and why they respond differently to treatment. The development of human stem cell-derived brain organoids provides a novel opportunity to model these ST-EPN in vitro. These organoids mimic embryonal brain development, during which the cells-of-origin of ST-EPN as well as their micro-environment are present. To induce the development of ST-EPN in vitro, we genetically manipulated cerebral organoids to overexpress the group-specific oncogenic fusion proteins. Electroporating constructs expressing the different fusion proteins into organoids early in brain development (day 11), induced ectopic growth after approximately 30 days. Based on immunohistochemistry, we observed a different phenotype using either the ZFTA or YAP1 fusion constructs, as well as (over)expression of group-specific markers in the organoids. Preliminary transcriptomic analyses suggest that these genetically modified brain organoids represent models with features of human ST-EPN tumors. Ongoing single-cell RNA-sequencing and epigenomic analyses during normal organoid and tumor development will further reveal how well these models represent human primary tumors, how they develop in time, and possibly whether they originate from similar cells or different cells within these organoids. Hence, these models will uniquely contribute to the molecular and biological understanding of ependymomas and can be used to identify new targeted therapies.
EPEN-17. Recurrent infratentorial ependymomas in children: a meta-analysis on molecular-based outcomes
Authors: Montgomery Eric , Thirunavu Vineeth , Shlobin Nathan , Lam Sandi , DeCuypere Michael 
Published: June 2022

Abstract
The overall prognosis of infratentorial ependymoma differs based on molecular signature, however the impact of recurrence on prognosis remains poorly defined in the pediatric population. PubMed, Scopus, Embase, and Ovid were searched for publications on recurrent infratentorial ependymomas in patients under 25 years of age. Exclusion criteria were case series of less than 5 patients and studies that did not provide individualized patient data. Our search yielded 472 unique articles, of which 17 were included in the analysis. There was a total of 460 recurrent ependymomas reported, with 52.8% WHO grade II tumors and 47.2% grade III. The overall mortality for recurrent infratentorial ependymoma was 49.1% (226/460). The pooled median survival was 32.39 months after recurrence (95% CI: 23.45-41.33). Gross total resection was achieved in 237 (53.1%) patients at initial presentation. Raw mean survival post-recurrence was 32.9 months (SD: 11.2 months) for those who received GTR for their primary tumor versus 23.7 months (SD: 10.8 months) for those who received subtotal resection (STR) (p &lt; 0.001). There was no difference in survival between those that received GTR (49.3 months, 95% CI: 32.3-66.3) versus STR (41.4 months, 95% CI: 11.6-71.2) of their recurrent tumor (p=0.610). In the studies that provided molecular classification, there were 169 PFA tumors (83.3%) and 34 PFB (16.6%), with 28 that demonstrated 1q gain. PFA-A tumors demonstrated worse post-progression survival (24.7 months, 95% CI: 15.3-34.0) compared to PF-B (48.0 months, 95% CI: 32.8-63.2) (p=0.0073). The average post-recurrence survival for tumors with 1q gain was 5.93 months (SD: 9.15). The overall mortality rate for recurrent infrantentorial ependymomas was found to be 49.8%, with a pooled median survival of 32.39 months. Almost 90% of recurrent infratentorial ependymomas were of the PFA molecular subtype, and those tumors that demonstrated 1q gain had a worse survival than those that did not.
EPEN-19. Impact of molecular classification on prognosis in children and adolescents with spinal ependymoma: Results from the HIT-MED database
Authors: Engertsberger Lara , Benesch Martin , Mynarek Martin , Tonn Svenja , Stickan-Verfürth Martina , Funk Angela , Pajtler Kristian W , Timmermann Beate , Kortmann Rolf-Dieter , Pietsch Torsten , Bison Brigitte , Warmuth-Metz Monika , Rutkowski Stefan , Schüller Ulrich 
Published: June 2022

Abstract
PURPOSE: Ependymomas of the spinal cord are rare among children, and individual risks of disease progression are difficult to predict. This study aims at evaluating the prognostic impact of DNA methylation-based classification in children with spinal ependymoma. METHODS: Eighty-two patients with spinal ependymoma &lt;22 years registered in the HIT-MED database between 1992 and 2021 were included. Clinical, radiological, and histopathological data were collected retrospectively. DNA methylation profiles of 46 tumors were classified according to the Heidelberg Brain Tumor Classifier. RESULTS: Spinal myxopapillary ependymoma (SP-MPE, n=27) was the most common methylation group followed by spinal ependymoma (SP-EPN, n=15). Two cases belonged to MYCN-amplified subgroup, one had no match, and one was re-classified as anaplastic pilocytic astrocytoma (the latter excluded from final analysis). WHO grade I and III ependymomas (according to the WHO 2016 classification) classified predominantly as SP-MPE, whereas grade II ependymomas clustered into SP-MPE and SP-EPN. 6/15 patients with SP-EPN (40%) suffered from Neurofibromatosis type 2. Among patients with SP-MPE, 23 underwent gross-total and four a subtotal resection (GTR/STR). Relapses of SP-MPE were more common following STR (5-year progression-free survival (5y-PFS) [STR] 25.0% [95% confidence interval: 0.0-68.4], [GTR] 75.0% [53.4-96.6], p=0.003). In the SP-EPN group, 2/8 patients relapsed after STR (5y-PFS 64.3% [22,3-100]) and 0/7 after GTR (n.s.). WHO I° ependymoma had significantly inferior PFS than II° and III° ependymoma (5y-PFS [I°] 39.0% [5.8-62.2], [II°] 82.4% [67.8-97.0], [III°] 50.5% [18.9-82.1], p=0.009). However, PFS did not significantly differ between SP-MPE and SP-EPN (5y-PFS 65.9% [44.9-86.9], 76.9% [46.3-100], respectively). CONCLUSION: Spinal ependymomas of WHO grade I go along with relatively poor PFS in our cohort, while DNA methylation profiling does not segregate patients into distinct risk groups. Still, larger cohorts and further investigations of methylation class heterogeneity in pediatric spinal ependymomas are needed to complete the basis for future clinical decision-making.
EPEN-22. Molecularly aggressive ependymomas treated with Image guided pencil beam proton therapy: consecutive patient Indian experience
Authors: Sudarsan Rishan Thimma , Chilukuri Srinivas , Noufal M P , Adhithyan R , Uppuluri Ramya , Panda Pankaj Kumar , Patil Sushma , Sharma Dayananda , Roopesh Kumar V R , Jalali Rakesh 
Published: June 2022

Abstract
AIM: To assess the toxicities and early clinical outcomes in patients of primary and recurrent ependymomas treated with image guided pencil beam scanning proton beam therapy (PBS-PBT). MATERIALS AND METHODS: Between January 2019- December 2021, we analyzed consecutive patients of ependymomas treated with image guided PBS-PBT. They were also analyzed molecularly, and all recurrent/re-irradiated patients were considered for craniospinal irradiation (CSI). Acute toxicities were assessed based on NCI CTC v5.0, local control and radiological response by 3-monthly MRI post therapy. RESULTS: Seventeen consecutive patients with ependymoma (13 Grade III and 4 Grade II) (median age-9 years) were analyzed. 9 patients were primary, 7 were treated at first recurrence and 1 at second recurrence. Majority had posterior fossa (PF) tumors (12) followed by supratentorial (ST) (3) and spine (2). Among PF ependymomas, 10 had global loss of H3K27me3, whereas amongst ST, 1 had YAP1 fusion, 1 had L1CAM positivity and other, negative L1CAM and p65/RELA on immunohistochemistry. Gross/near-total resection was achieved in 87% patients. Primary ependymomas were treated with focal radiotherapy; and among recurrent cases, 7 received CSI followed by primary site boost to a total median dose of 55CGE (50.2-55.8CGE). Grade 2 dermatitis, grade 2 and 3 hematological toxicities (CSI) were noted in 3,2 and 2 patients respectively. Grade 2 fatigue noted in 53% of all and 71% receiving CSI. With a median follow-up of 10 months (2-24 months), local control (LC) and disease-free survival (DFS) was 87.5% (primary-100%, recurrent-75%) and overall survival (OS) was 94% (primary-100%, recurrent-88%). CONCLUSION: Our experience of treating patients of ependymoma with complete resection followed by PBS-PBT including CSI is encouraging with low acute toxicities. Recurrent/molecularly aggressive cases may be considered for CSI.
Keywords: PT, proton beam therapy, ependymomas, primary and recurrent
GCT-12. SIOP CNS GCT II: High Risk (HR) CNS Non-germinomatous Germ Cell Tumours (NGGCT) treated with Dose intensified PEI – final results
Authors: Calaminus Gabriele , Frappaz Didier , Ajithkumar Thankamma , Müller Jans-Enno , Zimmermann Martin , Conter Cecile Faure , Timmermann Beate , Alapetite Claire , Murray Matthew , Garre Maria Luisa , Dieckmann Karin , Peyrl Andreas , Gerber Nicolas U , Kortmann Rolf-Dieter , Nicholson James 
Published: June 2022

Abstract
Based on results of SIOP CNS GCT 96, patients enrolled in SIOP CNS GCT II with AFP higher or 1000 ng/ml (serum and/or CSF) and/or age less than 6 years with NGGCTs at diagnosis received two standard cycles of PEI and two higher dose PEI courses followed by radiotherapy according to dissemination (54 Gy local RT or 30 Gy CSI/24 Gy tumour boost). Between 2/2012 and 7/2018, 112 patients with CNS NGGCT were registered, of whom 23 were identified as HR patients; 18/23 had an AFP higher or 1000 ng/ml and were older than 6 years. Five children were &lt; 6 years and showed YST elements in histology. of whom 3 received chemotherapy alone due to age. Primary site was pineal in 15/23, suprasellar in 5/23, bifocal in 3/23 patients; 3/23 patients were metastatic at diagnosis and 9/23 patients relapsed. Three years EFS was 0.60±0.10 with a median observation time of 3.96 years. Two recurrences were local, 4 distant (metastatic) and 3 combined, local and distant. HR CNS NGGCTs appeared to benefit from dose intensified PEI, compared with those treated in SIOP CNS GCT 96 with standard dose PEI. These results support the further exploration of this chemotherapy regimen in future clinical trials in such patient groups, including the consideration of delivering three dose intensified courses after one standard chemotherapy course, as is the practice in some groups treating very high risk extracranial GCTs.
GCT-15. Multi-institutional analysis and literature review of central nervous system germ cell tumors in patients with Down syndrome
Authors: Harris Micah K , Stanek Joseph R , Graham Richard T , Cappellano Andréa M , Margol Ashley S , Michaiel George , Crawford John R , Liu Kevin X , MacDonald Shannon M , Abdelbaki Mohamed S 
Published: June 2022

Abstract
BACKGROUND: A standard-of-care has not been established for the management of patients with Down syndrome (DS) who develop primary central nervous system (CNS) germ cell tumors (GCTs) – the most common CNS neoplasm in DS – despite being more susceptible to treatment-related adverse events. METHODS: Data from large academic institutions were collected and a comprehensive review of the medical literature was conducted. RESULTS: Ten patients from six institutions (five USA, one Brazil) were reviewed. Additionally, thirty-one patients were identified in the literature from 1975-2021. Of the 41 total patients, mean age was ten years (range, birth to 35 years); males were predominant (61%). Basal ganglia were the most common tumor location (n=12; 29%), followed by posterior fossa (n=7; 17%). Sixteen patients had non-germinomatous germ cell tumors (NGGCTs) (39%), 14 had pure germinomas (34%), and eight had teratomas (20%); histology was unreported for two (5%). Nine patients (22%) experienced disease relapse, of which four died from tumor progression (one germinoma versus three teratoma). Fifteen patients (37%) experienced treatment-related complications - seven died (four germinoma versus three NGGCT). Of the germinoma patients, two died from chemotherapy-related sepsis, one from post-surgery cardiopulmonary failure, and one from Moyamoya following radiation-therapy (RT) only. Of the NGGCT patients, one died from chemotherapy-related sepsis, one from post-surgical infection, and one from pneumonia following surgery/chemotherapy/RT. Three-year overall survival (OS) was 66% for all histological types - 62% germinoma, 79% for NGGCT, and 53% for teratoma. Three-year OS for patients who received RT or chemotherapy was 71% and 75% respectively. Twenty-seven patients remain alive at latest follow-up (mean follow-up from diagnosis: 46.8 months). CONCLUSIONS: Patients with DS treated for CNS GCTs are at an increased risk of treatment-related adverse events. A different therapeutic approach may need to be considered for this patient population to mitigate treatment-related complications and long-term neurocognitive sequelae.
HGG-01. A novel genetically engineered H3.3G34R model reveals cooperation with ATRX loss in upregulation of PRC2 target genes and promotion of the NOTCH pathway
Authors: Abdallah Aalaa , Cardona Herminio , Gadd Samantha , Brat Daniel , Picketts David , Becher Oren , Li Xiao-Nan 
Published: June 2022

Abstract
BACKGROUND: Pediatric high-grade gliomas (pHGGs) are an aggressive CNS tumor which are often characterized by mutations in H3F3A, the gene that encodes Histone H3.3 (H3.3). A substitution of the Glycine at position 34 of H3.3 with either Arginine or Valine (H3.3G34R/V), was recently described in a large cohort of pHGG samples and has been characterized as occurring in anywhere between 5-20% of pHGGs. Attempts to study the mechanisms of H3.3G34R have proven difficult due to the developmental nature of the disease and the requirement of co-occurring mutations for model development. METHODS: We utilized the RCAS system to develop a genetically engineered mouse model (GEMM) that incorporates PDGF-A activation, TP53 loss and the H3.3G34R mutation both in the context of ATRX loss and ATRX presence in nestin expressing progenitors. RESULTS: We show that in H3.3G34R expressing mice, ATRX loss significantly increased tumor latency from 90 days to 143 days (p &lt; 0.01, Log rank test) and decreased tumor incidence from 81% to 57% (p &lt; 0.01, Fisher’s exact test). By contrast, H3.3G34R did not significantly impact tumor latency in either our ATRX loss (163 days to 143 days, p = 0.178, Log-rank test) or our ATRX expressing (95 days to 90 days, p = 0.415, Log-rank test) models. Transcriptomic analysis revealed that ATRX loss in the context of H3.3G34R upregulates the PRC2 associated genes Hoxa2, Hoxa3, Hoxa5, and Hoxa7 (p &lt; 0.05, unpaired t-test). GSEA analysis and RT-qPCR data suggest that ATRX loss works synergistically with H3.3G34R to promote NOTCH pathway activation through upregulation of the NOTCH ligand Dll3 (p &lt; 0.01, unpaired t-test). CONCLUSIONS: Our study proposes a model in which ATRX loss is the major contributor to transcriptomic changes in the majority of H3.3G34R pHGGs. Broadly, our work highlights the importance of studying mechanisms of co-occurring genetic events separately and in combination.
HGG-05. Systematic review of diffuse hemispheric glioma, H3 G34-mutant and clinical factors influencing outcomes
Authors: Crowell Cameron , Mata-Mbemba Daddy , Bennett Julie , Matheson Kara , Mackley Michael , Erker Craig 
Published: June 2022

Abstract
BACKGROUND: A comprehensive description of clinical features and factors impacting prognosis for patients with diffuse hemispheric glioma, H3 G34-mutant (DHG H3G34) is not easily accessible. Understanding survival data and prognostic features is paramount for clinical advancements and ensuring patients/families are fully informed. METHODS: To summarize clinical, basic histomolecular, and treatment variables and their impacts on survival of DHG H3G34, a systematic review was undertaken. PubMed, Embase, and Google Scholar were searched for English articles published between January 1, 2012, and June 30, 2021. Eligible studies included patient(s) of any age diagnosed with an H3 G34-mutant brain tumour with at least one measure of survival or progression. A protocol was prospectively registered in PROSPERO (CRD42021267764) and PRISMA guidelines were followed. RESULTS: 27 studies met criteria for inclusion (13 pediatric-focused, 3 adult-focused, and 11 all ages). 135 unique patients with DHG H3G34 were included (118 G34R, 8 G34V, and 9 determined via methylation alone). Median age at diagnosis was 15.8 years (IQR=13.3-22.0). At presentation, 90% had localized disease. Co-occurring alterations included ATRX mutation 93%, TP53 mutation 88%, PDGFRA mutation 46%, PDGFRA amplification 13%, and MGMT promoter methylation in 70%. 89% of patients reported progressive disease with a median time-to-progression of 10.0 months. At last follow-up, 71% had died. Median time from progression to death was 5.0 months (IQR=3.0-12.0). Median overall survival was 17.3 months (95% CI 13.5-21.1) with a 1-, 2-, 3-, 5-year survival of 75, 39, 24, and 12%, respectively. Factors found to influence survival duration were presence of MGMT promoter methylation (HR=0.48, 95% CI 0.25-0.90) and less than near-total resection upfront (HR=3.59, 95% CI 2.07-6.22). CONCLUSION: This review highlights the poor prognosis, available survival measures, important prognostic features of DHG G34, and serves as a baseline for future clinical trials, though further study to identify prognostic biomarkers is needed.