bluuebunny/crossref_metadata_2025_split huggingface dataset:
MODL-01. Targeting replication stress in pediatric brain tumors
Authors: Krausert Sonja , Mack Norman , Schwalm Benjamin , Peterziel Heike , Oehme Ina , van Tilburg Cornelis M , Witt Olaf , Pfister Stefan M , Kool Marcel 
Published: June 2022

Abstract
Previously, we have found that Embryonal Tumors with Multilayered Rosettes (ETMR) tumor cells harboring high levels of R-loops, a potential marker for replication stress and genomic instability, are vulnerable to a combination of topoisomerase and PARP inhibitors. To follow up on this, we investigated whether other pediatric brain tumor types with high levels of R-loops, such as MYC-amplified Group 3 medulloblastoma (MB) and ZFTA-fusion positive ependymoma, are also sensitive to these inhibitors. First, we performed in vitro drug screens using HD-MB03, a Group 3 MB cell line, and the ETMR cell line BT183, and in both screens PARP inhibitors were identified as the most synergistic combination partners for the topoisomerase inhibitor Irinotecan, respectively the active metabolite SN-38. Normal Astrocytes were not sensitive to these combinations. Secondly, we performed in vivo studies using patient-derived xenograft (PDX) models injected subcutaneously or intracranially into NSG mice, and treated with the PARP inhibitor Pamiparib, Irinotecan or a combination of both. For a MYC-amplified Group 3 MB and a ZFTA-fusion positive Ependymoma model, both injected intracranially, treatment with Irinotecan or the combination led to a significant survival benefit and inhibition of tumor growth including transient tumor shrinkage, but addition of Pamiparib did not add any further benefit in vivo, even though intratumoral PARP was inhibited by at least 80%. In contrast, in the subcutaneously injected ETMR model, the combination treatment with Irinotecan and Pamiparib led to a synergistic effect and complete regression of the tumors. Further refinements of the treatment strategy as dose adaptations and the use of a pegylated version of SN-38 (PLX038A) did also not induce a synergistic effect of the drugs for the intracranial tumors. Additional in vivo studies to evaluate the differences in efficacy and whether these are tumor specific or due to incomplete brain penetrance of the drugs are ongoing.
MODL-05 Metronomic Intrathecal Delivery of CDK4/6 Inhibitors in Preclinical Models of Pediatric Brain Tumors
Authors: Guadix Sergio , Martin Brice , Laramee Madeline , Dahmane Nadia , Thomas Craig , Souweidane Mark 
Published: June 2022

Abstract
INTRODUCTION: CDK4/6 inhibitors have shown promise against central nervous system (CNS) tumors in vitro. This class of drugs relies on long-term exposure. Their use in early phase clinical studies in children with CNS tumors has defined dose limitations due to systemic toxicity. We have sought to circumvent these limitations in using CDK4/6 inhibitors for pediatric CNS tumors by first demonstrating enhanced efficiency with long-term administration and exploiting prolonged intrathecal delivery (IT). METHODS: Pediatric CNS tumor cell lines were used for cell viability assays: ATRT (BT-12, BT-16), CPC (CCHE-45), diffuse midline glioma (DIPG-XIII, HSJD-007), and medulloblastoma (DAOY); the assays were conducted at 24h, 72h, and 7d post-administration of CDK4/6 inhibitors (abemaciclib, palbociclib, ribociclib). Half maximal growth inhibitory concentrations (GI50) and areas under the curve (AUC) were compared for short-term (24h, 72h) and long-term (7d) dose-response curves. Toxicity with chronic IT administration was assessed using a neurobehavioral safety profile of 7-day continuous infusion of 2.5mM palbociclib (n = 5) into the mouse lateral ventricle compared with vehicle (n = 4). RESULTS: Our results demonstrate increased CDK4/6 inhibitor potency with longer administration. The greatest reductions in short-term to long-term GI50 were observed in ATRT, CPC, and DIPG across all inhibitors. The most pronounced time-dependent efficacy was observed with palbociclib for ATRT and abemaciclib for CPC and DIPG. AUCs significantly decreased (P &lt; 0.05) with increasing drug exposure time across all inhibitors. 7-day intraventricular palbociclib infusion was equivalent in safety to PBS at doses ranging from 1,000 to 10,000-fold the in vitro GI50. CONCLUSIONS: The efficiency of CDK4/6 inhibitors in pediatric CNS tumors is enhanced with prolonged exposure. Long-term IT administration can achieve high CNS doses without associated systemic toxicities. Translational efforts using a metronomic IT strategy are logical to explore for pediatric CNS tumors which have potential for a leptomeningeal disease pattern.
MODL-10. Tumor-brain-organoids as a model for pediatric brain tumors research
Authors: Riedel Nicole , De Faria Flavia W , Walter Carolin , Bruder Jan M , Kerl Kornelius 
Published: June 2022

Abstract
BACKGROUND: Embryonal brain neoplasms like atypical teratoid rhabdoid tumor (ATRT) or embryonal tumor with multilayered rosettes (ETMR) still have a very poor outcome despite intensive treatment including chemotherapy, irradiation and surgery. To date, precision oncology has identified clinically relevant innovative therapeutic targets only for a minor subpopulation of pediatric brain tumor patients, which may be due to current in vitro screens not recapitulating the cellular heterogeneity and cellular interactions in vivo. As cellular heterogeneity and cellular interactions majorly influence the response of tumor cells to treatment, we established an innovative 3D screening platform that combines human neural tissue surrounding primary tumor tissue. METHODS: We established a model of tumor-brain-organoids (TBO) by incorporating embryonal tumor cells (ATRT and ETMR tumor cells) into hiPSC-derived forebrain organoids. Using whole mount immunostaining (WMI), we evaluated cancer-phenotype, the neuronal and progenitor cell distribution in brain organoids, and we performed drug screening analysis. Furthermore, we used single-cell RNA-sequencing to characterize the cellular heterogeneity and the effect of tumor-organoid cell-cell communication on transcriptional programs. RESULTS: ATRT as well as ETMR tumor cells incorporated extensively into the organoid tissue. We observed remarkable differences in the invasiveness of ATRT-MYC cells into TBO in comparison with ATRT-SHH and ETMR cells via high content imaging. Moreover, tumor cells affected the gene expression of different cell types of the organoid by upregulating genes of important signaling/growth related pathways (e. g. MAP2K2, IGFBP2) and epigenetic regulators (like BRD7). Screening through a 300 compound FDA-approved drug library in these TBO, we identified potential innovative therapeutic approaches against these embryonal tumors. CONCLUSION: Tumor-brain-organoids can be used as a platform to study tumor biology, tumor interactions with its neural tissue microenvironment, as well as for high-throughput drug and toxicity screening in pediatric brain tumor precision oncology.
MODL-11. The tumor suppressor CREBBP and the oncogene MYCN cooperate to induce malignant brain tumors in mice
Authors: Melanie Schoof , Epplen Gefion Dorothea , Walter Carolin , Ballast Annika , Holdhof Dörthe , Göbel Carolin , Neyazi Sina , Albert Thomas , Kerl Kornelius , Schüller Ulrich 
Published: June 2022

Abstract
CREBBP (cAMP response element-binding protein binding protein) and MYCN (v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog), two essential proteins in central nervous system development that are described to be genetically altered in the same brain tumor entities, such as high grade glioma or medulloblastoma. Therefore, we hypothesized that alterations in both genes cooperate to induce brain tumor formation. In order to investigate molecular mechanisms and potential tumor formation, we established a novel mouse model combining a deletion of Crebbp with an overexpression of MYCN in neural stem cells (hGFAP-cre::CrebbpFl/Fl::lsl-MYCN). The animals developed highly aggressive forebrain tumors with 75 % penetrance already detectable in seven-day old mice, leading to tumor-related death within eight months. Although tumors mostly developed in the olfactory bulb region, we hypothesized that these tumors develop from subventricular stem cells that migrate into the olfactory bulb, where they settle and establish large solid tumors. In order to test this hypothesis, we analyzed neural stem cells (NSCs) derived from our mouse model. Compared to control cells, NSCs from transgenic mice have a significantly increased cell viability and proliferation in vitro and did not undergo full glial differentiation. In order to gain further insights into the cellular origin and biology of the tumors, we finally employed single cell RNA sequencing. Apart from a high intratumoral heterogeneity within the tumor cell population, data comparison with non-neoplastic CNS cell populations revealed a high similarity with transit-amplifying NSCs of the subventricular zone. Together, we were able to show the oncogenic potential of a combined loss of Crebbp and aberrant expression of MYCN in neural stem cells. This novel mouse model will be an important tool for understanding tumor-driving mechanisms and a valuable model for preclinical testing and will thereby help to improve patient care.
MODL-13. Patient-derived organoids for modeling pediatric brain tumors
Authors: Lago Chiara , Ballabio Claudio , Miele Evelina , Tiberi Luca 
Published: June 2022

Abstract
Central nervous system (CNS) tumors are the most common solid tumors in the pediatric population and the main cause of death among childhood cancers. They present common features related to the development and produce symptoms based on the age of the child, their location and rate of tumor growth. Tumors of embryonal origin, such as medulloblastoma or primitive neuroectodermal tumor, have a higher incidence in younger patients, whereas older ones tend to present tumors of glial origin. Most of CNS-embryonal tumors are highly malignant and consequently leading to poor prognoses. Despite the understanding of the underlying molecular landscape of these tumors that has helped in clinical advances to improve life expectancies of the patients, there is still an emerging need to minimize morbidity and manage the long-term therapy effects. Developing new models to better understand the heterogeneity of these tumors and to test personalized treatment strategies remains a clinical challenge. We are willing to answer to this medical need with Patient-Derived Organoids (PDOs) established through the direct in vitro culture of primary tumors and patient derived xenograft (PDX)-derived tumors. We developed a method for generating PDOs from a variety of pediatric brain cancers that recapitulates the cellular heterogeneity, histological features and mutational profiles of the corresponding parental tumors, also confirmed by the DNA methylation profile analysis, nowadays used for an accurate routine CNS tumors diagnosis. Through this new model, we confirmed the action of some clinically used drugs, obtaining a proof of concept of their possible application as a reliable tool for drug screening. Further applications derive from the enrichment of PDOs culture media for possible tumor-specific antigens that could be useful to define tumor markers identifiable with diagnostic tests or as candidates for new therapies.
MODL-16. Generation of immunocompetent syngeneic allograft mouse models for pediatric diffuse midline glioma
Authors: du Chatinier Aimée , Meel Michaël H , Das Arvid I , Metselaar Dennis S , Waranecki Piotr , Bugiani Marianna , Breur Marjolein , Simonds Erin F , Lu Edbert D , Weiss William A , Garcia Vallejo Juan J , Hoving Eelco W , Phoenix Timothy N , Hulleman Esther 
Published: June 2022

Abstract
Diffuse midline gliomas (DMG) are highly aggressive pediatric brain tumors with a grim prognosis. A lack of effective treatment options highlights the critical need to investigate new therapeutic strategies. This includes the use of immunotherapy, which has shown promise in other hard-to-treat tumors. To facilitate immunotherapeutic research in this field, and to complement the existing immunodeficient patient-derived DMG models, we developed three distinct immunocompetent mouse models representing different DMG subtypes, i.e., histone 3 wildtype and histone 3 K27M mutant DMG (H3.3K27M or H3.1K27M), that can be used for preclinical testing of new therapies. We first established primary tumor cell cultures from murine DMG tumors that were generated by brainstem-targeted intra-uterine electroporation (IUE). This method enabled the introduction of DMG-associated mutations within the intact developing brainstem, thereby generating DMG tumors in a spatially and temporally defined manner, while maintaining a genetically identical (isogenic) background. We then created allograft DMG mouse models by orthotopically implanting the established primary cell cultures into syngeneic (C57BL/6) mice. Herewith, we provide an allograft tool that is better suitable for large-scale therapeutic studies and more accessible to the scientific community. Importantly, we demonstrated that these allograft models recapitulate the histopathologic phenotype of human DMG, including their diffuse infiltrative growth and expression of DMG-associated antigens. Furthermore, CyTOF mass cytometry analysis indicated that these murine pontine tumors exhibit a tumor immune microenvironment (TIME) similar to human DMG, characterized by considerable myeloid cell infiltration and a paucity of T-lymphocytes and NK cells. As such, we provide a representative model to further delineate the immune landscape in DMG and to preclinically investigate novel (immuno)therapies. Currently, we are using these immunocompetent models to study the interaction between DMG cells and microglia, and we are investigating how we can modify the immune microenvironment to improve checkpoint inhibition in DMG.
MODL-27. An organotypic brain slice culture platform as a novel pre-clinical model for diffuse intrinsic pontine glioma and diffuse midline glioma
Authors: Mann Breanna , Zhang Xiaopei , Bell Noah , Adefolaju Adebimpe , Dasari Rajaneekar , Valdivia Alain , Buckley Andrew , Quinsey Carolyn , Hingtgen Shawn , Satterlee Andrew 
Published: June 2022

Abstract
High-grade pediatric brain tumors (PBTs) such as diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma (DMG) are devastating diseases with a median survival of just 11 months. Little progress has been made in identifying effective treatments due to the lack of effective pre-clinical models to accurately assess drug sensitivity. Historically, models of DIPG and DMG have been limited due to the low availability of surgical biopsies and small patient populations. Existing in vitro models are often unable to recapitulate growth and migration patterns seen in patients, while in vivo work is costly, time intensive, and many biopsies fail to establish in mice. We have developed an ex vivo organotypic brain slice culture (OBSC) platform to model DIPG and DMG. Through our partnership with the Ian’s Friends Foundation and Children’s Healthcare of Atlanta Biobank, we have seeded, grown, and treated several low-passage patient-derived PBT lines such as DIPG and DMG. Additionally, we can assess treatment response to a variety of agents used in clinical patient care. Viability assays revealed differences in the sensitivity of cell lines to individual agents, indicating that OBSCs have the potential to capture minute differences in efficacy between cell lines and drugs. When we assessed combination treatments, we found low doses of radiation with low doses of temozolomide were synergistic, but using higher doses of radiation was antagonistic, suggesting the OBSC platform has the potential to guide dosing strategies to maximize therapeutic synergy. Overall, these results suggest that OBSC PBT models have the potential to effectively model PBTs, including DIPG and DMG, to accelerate preclinical evaluation of therapeutics and guide drug development towards more effective treatment strategies.
RONC-01. A 10 year, single institution experience of re-irradiation for paediatric intracranial tumours
Authors: Durno Kimberley , Lim Pei , Gandhi Vanita , Shankar Ananth , Dahl Christine , Jorgensen Mette , Gaze Mark , Gains Jenny , Chang Yen-Ch'ing 
Published: June 2022

Abstract
INTRODUCTION: Re-irradiation has become integral in the management of relapsed and recurrent intracranial tumours in children. It is used as salvage therapy for a number of tumours including; diffuse intrinsic pontine glioma (DIPG), high grade glioma (HGG), ependymoma and medulloblastoma. We report the patient demographics, dose, outcomes and toxicity for patients treated with re-irradiation at our institute. METHODS: 33 patients with a diagnosis of DIPG (n=11, 33%), ependymoma (n=11, 33%), HGG (n=4, 12%) or medulloblastoma/sPNET (n=7, 21%), treated with intracranial re-irradiation since 2012 were analysed in this retrospective study. Statistical survival analysis was performed. RESULTS: The median follow-up was 19 months (range 0–216 months). The median age at re-irradiation was 10 years (2-20 years). The median time from first radiation to re-radiation was 34 months (range 3–113 months). Re-irradiation techniques included; photons (n=26), protons (n=2) and stereotactic radiotherapy (n=6). The median re-irradiation dose was 36.37Gy EQD2 (range 20-95.05Gy), given in dose per fraction between 1.8Gy–2Gy. The median overall survival (OS) and progression free survival (PFS) for the cohort was 15.68 months and 7 months respectively. For DIPG, the median OS and PFS were 6.12 months and 4 months respectively. At 2 years, the OS and PFS rates for the cohort were 34.37% and 32.45% respectively. For the non-DIPG cohort, the 2 year OS and PFS rates were 55.37% and 48.13% respectively. In the DIPG cohort, 88% (n=7) had a reported symptomatic benefit from re-irradiation. A stable or improved radiological response was reported in majority of patients (78%, n=18). No acute or late toxicities ≥ grade 3 were reported within the cohort, specifically, there were no reports of brainstem necrosis. CONCLUSION: Re-irradiation for paediatric intracranial tumours is safe and offers a benefit to patients. Further work is ongoing to evaluate cumulative brainstem doses and predictive variables.
RONC-06. Stereotactic radiosurgery and stereotactic radiotherapy for pediatric brain metastases or recurrences
Authors: McGovern Susan , Mackin Dennis , Li Jing , Paulino Arnold , Grosshans David , Weinberg Jeffrey , Sandberg David , Chintagumpala Murali , Gill Jonathan , Zaky Wafik , Briere Tina , McAleer Mary Frances 
Published: June 2022

Abstract
BACKGROUND/PURPOSE: Stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT) deliver highly conformal, ablative doses of radiation over 1–5 treatments, while minimizing dose to surrounding normal tissues. To document toxicities and outcomes of these treatments in children, our updated institutional experience with SRS or SRT for intracranial targets in pediatric patients was reviewed. METHODS: On an IRB approved study, institutional databases were reviewed to identify pediatric patients with intracranial lesions treated with SRS or SRT from October 2009 to July 2021. Medical records were retrospectively reviewed for patient and treatment characteristics. Outcomes were analyzed for symptomatic radionecrosis and CNS progression. RESULTS: Thirty SRS or SRT treatment courses in 26 patients age 3.2 to 17.8y (median, 15.6y) at the time of SRS or SRT were identified. Twenty-two patients had one treatment and four had two treatments. Sixteen patients had brain metastases from extracranial primary disease; 10 had recurrence of a primary CNS tumor. Fifteen patients had prior fractionated radiation to the brain. Nineteen treatments used Gamma Knife (GK) with Leksell frame, three used GK ICON with mask, and eight used linear accelerator with volumetric modulated arc therapy with thermoplastic mask. All patients (10 treatments in nine patients) treated since July 2016 received mask-based radiation. Twelve of 26 (46%) patients were treated with anesthesia. With 9.6-month median follow up (range, 0.1-96.2m), five patients had progression of treated lesions, eight had distant CNS failure, and one had both local and distant failure, for a crude local failure rate of 6/26 (23%) and a crude distant failure rate of 9/26 (35%). There were no skull fractures or other complications from Leksell frame placement. One patient developed symptomatic radionecrosis requiring surgery. CONCLUSION: SRS and SRT can be safely performed in pediatric patients with intracranial lesions. Mask-based immobilization provides an alternative to frame-based treatments.
RONC-08. Validation of Online Calculator for Estimating Severe Hearing Loss Risk Among Patients with Medulloblastoma After Receiving Photon Radiation and Cisplatin Chemotherapy
Authors: Abu-Arja Mohammad , Brown Austin , Lupo Philip , Chintagumpala Murali , Paulino Arnold 
Published: June 2022

Abstract
BACKGROUND: Children with medulloblastoma are at risk of hearing loss (HL) following cranial radiotherapy and platinum-based chemotherapy. Keilty et al. 2021. J Clin Oncol. (PMID: 34570616) recently published a computer-based HL risk calculator based on children with central nervous system tumors treated with photon radiotherapy. The objective of this study was to evaluate the performance of the risk calculator in an independent cohort of children with medulloblastoma treated with photon radiotherapy. METHODS: We identified children with medulloblastoma treated with cisplatin and photon radiotherapy at Texas Children’s Hospital between 1997-2007. Audiograms were graded using the International Society of Pediatric Oncology-Boston scale (SIOP-Boston). The risk calculator considered age at treatment, time since radiotherapy, cumulative cisplatin dose (mg/m2), and cochlea radiation dose (Gy). The calculated risk was compared between ears with and without clinical evidence of grades 3/4 HL using t-test. RESULTS: We identified 45 eligible patients (male: 31, female: 14) diagnosed at a median age of nine years (range: 3-18 years). The mean cochlea dose was 37.2 Gy (range: 25.2-54.9 Gy) and mean cumulative cisplatin dose was 352 mg/m2 (range: 55-860 mg/m2). Audiograms of 89 total ears were available with a median follow-up of 65 months post-diagnosis (range: 13-163 months). The median number of post-radiotherapy audiograms per patient was 6 (range: 2-15). A total of 22 ears (25%) belonging to 13 individual patients (29%) met the SIOP-Boston criteria for grades 3/4 HL. The mean of predicted probability of severe HL based on the calculator for ears with SIOP-Boston grades 3/4 was 24% (range: 10% - 48%) compared to 32% (range: 10%-70%) among ears with grades &lt; 3 HL. CONCLUSION: The published HL risk calculator did not clearly differentiate between patients with and without clinically significant HL in our cohort. Future multicenter studies are required to validate this tool and improve the prognostic potential.³