bluuebunny/crossref_metadata_2025 huggingface dataset:
LINC-13. Subependymal giant cell astrocytoma in a child with tuberous sclerosis complex: a case report
Authors: Estetika Citra , Rahmartani Ludi Dhyani , Soebadi Amanda , Gunawan Kevin , Susanto Eka , Amal Muhammad Yanuar
Published: June 2022

INTRODUCTION: Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder causing the formation of hamartomas in many organs, including the brain. It is generally benign but can block the flow of cerebrospinal fluid that increases intracranial pressure and leads to severe neurologic and behavioural changes. Subependymal giant cell astrocytoma (SEGA) occurs in 10-15% of TSC patients. Routine brain surveillance is important to look for SEGA in all TSC patients. CASE: We report a girl who was previously diagnosed with TSC at the age of two. She had hypomelanotic macules, facial angiofibroma, and a shagreen patch. Her first brain magnetic resonance imaging (MRI) was normal. She had routine consultation until she complained of recurrent headaches, walking instability, and seizures six years later. Her brain MRI showed a solid heterogenous intraventricular mass suggestive SEGA, with multiple subcortical hyperintense lesions (subcortical tubers), and hydrocephalus. She underwent emergency ventriculoperitoneal shunt (VP shunt) and tumor removal surgery. The histopathology examination matches SEGA, World health organization (WHO) grade I. It consists of polygonal to spindle cells with abundant eosinophilic cytoplasm. There are also large to multinucleated cells. After surgery, she had significant clinical improvement, and the seizure was controlled with valproic acid. CONCLUSION: It is essential to do brain evaluation using brain scan or MRI every 1-3 years as surveillance recommendation in all TSC patients. Early detection dramatically increases the chance of giving early treatment or surgery to lower complications and provide better outcomes.

Keywords: Subependymal giant cell astrocytoma, tuberous sclerosis complex, surveillance, early diagnosis
LINC-20. Impact of the COVID-19 pandemic on 30-day mortality and unplanned reoperation rates for pediatric central nervous system tumors
Authors: Jovett Sanchez Diana , Gaspi Sally Andrea , Talan Ceri Jane , Alcasabas Ana Patricia , Baticulon Ronnie
Published: June 2022

INTRODUCTION: Unplanned reoperations and mortality within 30 days are important indicators when evaluating the quality of care provided by surgical systems. We reviewed these outcomes among children with primary central nervous system (CNS) tumors treated during the COVID-19 pandemic. METHODS: This is a retrospective study of all pediatric patients who underwent neurosurgery for primary CNS tumors at the Philippine General Hospital, the national university hospital, from January 1, 2020 until December 31, 2021. Their clinical presentation, perioperative course, and outcomes were analyzed. During this time, our hospital concurrently served as a COVID-19 referral center, thus, the workforce was restructured, and resources were reallocated to care for COVID-19 patients. RESULTS: A total of 92 pediatric patients with CNS tumors underwent 140 neurosurgical operations during the study period. Two-thirds of the patients were males, and mean age was 9.3 ± 5.0 years (range: 3 months to 18 years). Average preoperative length of stay was 3.9 ± 2.6 days. Tumor resection was performed in 73 patients (79%). Most common histologic diagnoses were medulloblastoma (20%) and low-grade glioma including pilocytic astrocytoma (20%). Overall, the 30-day mortality and unplanned reoperation rates were 12% and 22%, respectively. Eight patients died from brain herniation and/or tumor progression. Reasons for unplanned reoperations were postoperative hydrocephalus (20%), infection (9%), hematoma (7%), and tumor residual (3%). DISCUSSION: Worldwide, the COVID-19 pandemic has altered hospital protocols and shifted resources considerably. The observed high rates of death and reoperation are likely due to delays in seeking care leading to worse neurologic status at presentation, delays in performing essential surgery within the hospital, and shortage of health workers providing specialist care. It is important to periodically assess perioperative outcomes to improve the quality of surgical care given to children with CNS tumors, who remain a vulnerable population during the COVID-19 pandemic.
LINC-22. Primary central nervous system (CNS) germ cell tumors (GCT) in Central America and the Caribbean region: an AHOPCA 20-year experience
Authors: Veronica Giron Ana , Calderon Patricia , Pineda Estuardo , Montero Margarita , Lizardo Yamel , Bartels Ute , Osorio Diana S
Published: June 2022

BACKGROUND: Primary CNS GCT are rare neoplasms in pediatrics. Treatment depends on histological subtype and extent of disease. Overall survival (OS) is above 85% in high-income countries (HIC). OBJECTIVE: To describe the experience in treating CNS GCT in 4 of 8 countries, members of AHOPCA (Asociación de Hemato-Oncología Pediátrica de Centro América) and 5-year OS. DESIGN/METHODS: We conducted a retrospective chart review of patients treated for CNS GCT. Epidemiological, clinical characteristics, histology, treatment modalities and outcome were analyzed. RESULTS: From 2001 to 2021, 45 patients were included. Guatemala: 22, Nicaragua: 15, Dominican Republic: 3 and El Salvador: 5. Thirty (66.6%) were male, mean age at diagnosis was 8.6 years (range 12 months to 17 years). Presenting symptoms were headaches/vomiting (n=26, 57.7 %), visual disturbances (n=15, 33.3%), diabetes insipidus (n=7, 15.5%). Two patients (NGGCT) presented with precocious puberty. Upfront surgery was done in 33 cases (73.33%); 21 (63.6%) germinomas, 9 (27.2%) NGGCT and 3 (9%) CNS GCT. Eight patients were diagnosed and treated based on CSF tumor marker elevation; four germinomas (BHCG 11.32-29.41mUI/mL) and four NGGCT (BHCG 84.43-201.97mUI/mL or positive AFP>10 ng/mL). Tumor locations included suprasellar (n=15, 33.3%), pineal (n=14, 31.1%), thalamus/basal ganglia (n=5, 11%), other (n=6, 13.3%); and one bifocal. Four (8.8%) had metastatic disease, 6 with positive CSF, staging data was incomplete in 25 patients (55.5%). Patients were treated with varied chemotherapy and radiotherapy modalities. Nine patients had incomplete data regarding treatment. Five-year OS was 65% (61.5% for germinoma and 56% for NGGCT). Two patients with histologically confirmed germinoma relapsed. CONCLUSIONS: Germinoma was the most common histology and there was a male predominance. More than half patients had incomplete staging data and treatment was variable. OS is lower compared to HIC. Standardized treatment protocols will aid in adequate staging, treatment planning, prevent complications and improve survival.
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

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

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 < 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

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

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

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

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

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

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

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

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 < 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
RONC-09. The comparison of dosimetric parameters for predicting radiation-induced cataract in pediatric patients
Authors: Leangcharoensap Siriphan , Thephamongkhol Kullathorn , Treechairusame Teeradon , Suntornpong Nan , Rongthong Warissara
Published: June 2022

OBJECTIVE: The lens dose constraint for pediatric patients was still unknown due to conflicting data of dosimetric parameter. The aim of this study was to compare predictive ability for radiation-induced cataract between the maximum point dose of lens (Lens Dmax) ≥7 Gy, lens mean dose (Lens Dmean) ≥7 Gy, Lens Dmax ≥10 Gy, and Lens Dmean ≥10 Gy. METHOD: Patients 3-18 years received cranial irradiation or radiation therapy at head and neck area with three-dimentional conformal radiation therapy (3DCRT), intensity modulated radiation therapy (IMRT), or volumetric modulated arc therapy (VMAT) between 2010 and 2019 at our institute were included. Patients who have no eye exam before radiation or within 6 months of radiation (baseline) and/or have no follow-up eye examination after complete radiation >6 months (follow-up) were excluded. Receiver operating characteristic (ROC) curves were used to identify the dosimetric parameter of potential predictors and to access their predictability. Univariate and multivariate analyses were performed using cox regression analysis to identify correlation between potential factors and cataract. RESULTS: Sixty-three patients (122 eyes) were analyzed. Cataracts were detected in 14 eyes (11.5%). The median follow-up time was 4 years (range 0.5-10 years). The median time to develop cataract was 2.5 years (range 0.3-7 years). Three (21.4%) patients developed cataract grade ≥3. Lens Dmean ≥10 Gy had highest predictive ability for predicting radiation-induced cataract in pediatric patients. The area under the ROC curve (AUC) were 0.591 for Dmax ≥ 7 Gy, 0.597 for Dmean ≥ 7 Gy, 0.642 for Dmax ≥ 10 Gy, and 0.698 for Dmean ≥ 10 Gy. Univariate analysis showed significant effect of age, diagnosis, and Lens Dmean on cataract formation. On multivariate analysis, cataract remained significantly predicted by diagnosis and Lens Dmean. CONCLUSION: Lens Dmean ≥10 Gy had highest predictive ability for predicting radiation-induced cataract in pediatric patients.
RONC-14. Olfactory Perception During Proton Radiation and Differences in Frequency of Olfactory Perceptions Based on Proton Craniospinal Irradiation Technique for Pediatric Brain Tumor Patients.
Authors: Ioakeim-Ioannidou Myrsini , Erfani Parsa , Urell Tobias , Daartz Juliane , Berv Julia , Leahy Shannon , Fullerton Barbara , Bolton Rachel , Yock Torunn , Tarbell Nancy , Yeap Beow , MacDonald Shannon
Published: June 2022

BACKGROUND: Unusual olfactory perception has been reported during brain radiation treatments but is infrequent and does not typically interfere with the ability to deliver treatment or cause notable distress. Methods: We performed a retrospective review of 127 pediatric patients treated with proton radiation therapy (PRT) for primary brain tumors in a single institution between 2016-2021. Patients received PRT to the brain as part of craniospinal irradiation (CSI) followed by a boost to the brain. Proton CSI was delivered with 3D-CRT protons (n=53) or pencil beam scanning technique (PBS) (n=74). Within the PBS group, treatment delivery to the CSI utilized a single PA field (n=24) or two posterior oblique fields (n=50). We collected data on abnormal olfactory sensations, nausea/vomiting, and the use of medical intervention for those symptoms. Results: Our cohort included 80 males and 47 females. The median age of patients was 10 years old (range, 3 – 21). Seventy-one patients received concurrent chemotherapy. Prior to PRT, 31 patients were nauseous. During the radiation course, 104 patients developed worsening nausea while 63 patients reported emesis. Four patients vomited while receiving radiation. Seventeen patients reported olfactory perceptions during CSI. We found a higher rate of olfactory perception in patients treated with PBS (n=16, 22%) than 3D-CRT (n=1, 2%) (p=0.001) and, within the PBS group, patients treated with a single PA field (n=11, 46%) than two oblique fields (n=5, 10%) (p=0.002). Seventy-eight patients required intervention including addition of anti-emetic or anti-anxiety medication. Two patients required sedation due to the malodorous smell during CSI. We did not find any significant difference in nausea/vomiting based on treatment technique. Conclusions: PBS and PBS technique influence olfactory perceptions but not the occurrence of the rate of nausea/vomiting. Further studies should be performed to validate these findings and determine techniques to minimize unpleasant olfactory perceptions.
RONC-15. FEASIBILITY AND EFFECTIVENESS OF REIRRADIATION IN CHILDREN AND ADOLESCENTS WITH RELAPSED OR RESISTANT BRAIN TUMORS
Authors: Campello Anna , Mussano Anna , Vallero Stefano , Bertin Daniele , Peretta Paola , Morana Giovanni , Sciortino Paola , Ricci Federica , Bertero Luca , Fagioli Franca
Published: June 2022

Few reports exist about reirradiation (RT2) for recurrent brain tumors in pediatric patients.A monocentric retrospective analysis of 22 patients with reirradiated CNS neoplasms was conducted with the objective to describe clinical outcomes and toxicities associated with RT2. Median age at diagnosis and RT2 was 8.5 years and 11.5 years respectively. Primary diagnoses included ependymoma (n=7, 32%), medulloblastoma (n=5, 23%), DIPG (n=4, 18%), glioblastoma (N=2, 9%), and others (N=4, 18%). The median interval between the first radiotherapy and RT2 was 16.5 months. Two patients underwent in-field RT2 for a secondary tumor. RT2 was administered with a curative intent in 13 patients, with a palliative-only treatment in the remaining 9. Sixteen patients received brain RT2 and 3 patients spine RT2, with a median cumulative dose of 19.9 Gy and 30 Gy respectively. Three patients received combined RT2. Volumetric Modulated Arc Therapy(VMAT) was the most frequent technique used (60%). Eight patients showed neurological symptoms before RT2, 6 had clinical benefit with RT2. Among patients who were asymptomatic before RT2, 5 later showed progressive neurological symptoms (at least partly attributable to RT2). Radionecrosis was radiologically detected in 6 patients, but accompanied by symptoms only in 3. Median event-free survival (EFS) and overall survival(OS) after RT2 was 4.7 and 8.7 months respectively, similarly to previous results. One-year EFS and OS was 13% and 36% respectively. As previously reported, OS appeared to be longer for patients with >12 months elapsed time between first irradiation and RT2 (1-year OS=45% versus 0%, p=0.07). In our cohort RT2 appeared feasible and provided short-term disease control with tolerable short-term toxicity, while providing relief in most symptomatic patients. Larger prospective studies are needed to understand which subsets of patients may benefit from either curative or palliative reirradiation, to provide respectively a longer survival and a significantly improved symptom control.
RONC-17. Feasibility of proton therapy with and without simultaneous chemotherapy in CNS malignancies of children and adolescents
Authors: Schuermann Eicke , Tippelt Stephan , Zeller Julia , Geismar Dirk , Jazmati Danny , Peters Sarah , Timmermann Beate , Mikasch Ruth , Fleischhack Gudrun
Published: June 2022

BACKGROUND: Proton therapy (PT) is a valuable alternative to photon radiotherapy in treatment of CNS tumors in children and adolescents. The aim of this study was to investigate the feasibility of recent treatment strategies with a particular focus on the acute toxicity of a simultaneous radiotherapy and chemotherapy (sRCT). PATIENTS AND METHODS: We investigated 199 patients (116 male, 83 female, median age 7.4 years) who received in total 200 cycles of PT (60.5% at new diagnosis, 39.5% at relapse) from September 2013 to February 2017. Entities included ependymomas (34%), medulloblastomas (16%), low grade gliomas (13%), ATRTs (12%), craniopharyngiomas (9%), germ cell tumors (6%), and other entities (10%). SRCT was administered in 52 (26%) treatment cycles. The target tumor was predominantly localized infratentorial (53%), supratentorial (23.5%) and supra-/intrasellar (18%). 38 patients received additional CSI and 8 patients a boost to metastases. Data were collected retrospectively based on patient records. Toxicity was documented according to CTCAE version 4.03. RESULTS: Severe adverse events (SAE ≥ grade 3) occurred in 33.5% of all patients, in particular in form of hematotoxicity (64.1%) and infections (26.8%). In-patient treatment for unexpected SAEs was necessary in 33 patients (16.5%). In the group treated with sRCT 15 out of 52 (28.8%) patients couldn’t receive the recommended dose or time schedule of planned chemotherapy due to SAEs. Comparing the SAE frequency in both groups, the children who have been treated with sRCT had a significantly higher risk of SAEs than the patients who have received proton therapy only (63.5% vs. 23.0%, p=0.001). CONCLUSIONS: PT and concomitant chemotherapy are feasible, but require an interdisciplinary team with continuous out-/inpatient management of patients, as the risk of toxicity is significantly increased. Risk-adapted adjustment of simultaneous chemotherapy is necessary to reduce relevant interruptions of radiotherapy.

Funded by the German Childhood Cancer Foundation
SWK-02. Palliative sedation in pediatric patients suffering from brain tumors: choosing the best drugs to improve end of life
Authors: Podda Marta , Schiavello Elisabetta , Clerici Carlo Alfredo , Biassoni Veronica , Simonetti Fabio , Massimino Maura
Published: June 2022

INTRODUCTION: For terminally-ill children with brain tumors care focuses on quality of life, and patient management fundamentally affects grieving families. We describe our experience of palliative sedation (PS) for children with refractory symptoms caused by solid tumors, focusing on BT (brain tumor). METHODS: Retrospective data on all children treated for cancer who died between 1/2016-12/2020 in our Institution were collected. RESULTS: Of the 29 patients eligible for the study, M/F 17/12, the median duration of disease was 12.5 months(range 3-51) and the median age at death was 8.5 years(range 1-22). Fifteen had BT (5 DIPG, 2 Ependymoma, 8 high-grade-glioma). The reasons for starting PS in BT were: seizures(5), central respiratory failure(6), locked-in-syndrome(1), decerebration(1). Midazolam was combined in 16 cases with other drugs (neuroleptics, alpha-2 agonists, antihistamines) to achieve adequate sedation. Ten/15 with BT received antiepileptic therapy, apart midazolam. BT patients received oral benzodiazepins before PS less frequently than those with other cancers (p = 0.0033). Throughout the period of PS and on the day of death, patients with BT were given lower doses of midazolam and morphine. Mean dose of midazolam was 0.027 mg/kg/h (range 0.0069-0.06) for patients with BT, 0.055 mg/kg/h (range 0.01-0.38) for the others, while the mean morphine doses were 0.048 mg/kg/h (range 0-0.08) and 0.09 mg/kg/h (range 0.013-0.13), respectively. CONCLUSIONS: BT patients require less intensive analgesic-sedative therapies because their already impaired state of consciousness. Optimizing pharmacological treatments demands a medical team that knows how drugs (even developed for other indications) work. Emotional-relational aspects are important too, any action to lower a patient’s consciousness should be explained to the family. Guidelines on PS in pediatrics could help, providing they acknowledge that any child’s death is always a unique case.
SWK-05. Clinical social work in pediatric neuro-oncology – A research project on the social dimension using social diagnostics
Authors: Krottendorfer Kerstin , Rosenmayr Verena , Weiler-Wichtl Liesa Josephine , Pletschko Thomas , Peyrl Andreas , Leiss Ulrike
Published: June 2022

PURPOSE: A neuro-oncological disease of a child represents a high psychosocial burden for the whole family (Wiener, Kazek et al. 2015). A biopsychosocial and family-oriented approach for the treatment of children and their families focusing on medical, psychological and social care is significant in the course of the disease. Studies show that existential problems or lack of social support are risk factors. Therefore, this research investigates the impact of a pediatric neuro-oncological disease on the social dimension using a standardized social assessment. RESEARCH DESIGN: The project is based on a retrospective cross-sectional study (04/2015-12/2021) including consecutive patients with high- or low-grade gliomas at the Medical University of Vienna - Department of Pediatrics (n= 160). By using a specialized and standardized social diagnostic tool (DISAPO) starting at the onset of disease, the clinical social worker surveys the social situation (social network, work situation, financial and housing situation, legal status, insurance status, etc.) with the parents. Based on the assessed social situation the clinical social work interventions (CSWI) are recorded throughout the child′s treatment. The results are statistically evaluated including medical data. RESULTS: The results of the DISAPO show that in the course of the disease all families need CSWI in one or more areas of the social dimension: disease-related interventions: 100%, work intervention: 80,6% (n=129), living situation: 43,8% (n=70), social support: 39,4% (n=63), socioeconomic interventions: 19,4% (n=31), residence law aspects: 18,8% (n=30). CONCLUSION: These results emphasize that in case of a pediatric neuro-oncological disease the social dimension is always affected and comprehensive CSWI are highly needed. For a holistic care of the patients and their families a biopsychosocial standard-of-care including all professions is indispensable. In addition, a standardized approach for assessment and intervention showed that needs could be assessed more adequately and interventions more targeted.
SWK-09. Baseline Survey of Hematology/Oncology/Cellular Therapy Staff/Faculty Perceptions of Palliative Care
Authors: Hemenway Molly , Raybin Jennifer , Waters Melissa
Published: June 2022

Recent literature has shown that pediatric oncology patients and families prefer early integration of palliative care, yet the perception persists by staff and providers that palliative care has a negative connotation. We examined the baseline views of staff at our tertiary care center, prior to expansion of a formal palliative care service. We will describe baseline survey results in a diverse group of hematology/oncology/cellular therapy staff/faculty. This quality improvement project was conceived by the unit-based palliative care committee to compare baseline and follow-up survey results. We report the baseline results of a convenience sample of providers with varied roles. A validated survey for staff perception of palliative care found in the literature was utilized. After institutional qualitative review board approval, the survey was emailed to members of the inpatient and outpatient units. Demographic data collected included gender, level of education, role, patient population, length of career globally and locally. Perception of palliative care was evaluated by asking questions regarding 1) overlap with disease focused care, 2) risks/benefits of palliative care, and 3) timing of palliative care consults. Results were tabulated and graphed for dissemination to the unit-based palliative care committee. A follow-up survey is planned after integration of the developing formal palliative care service. Longitudinal comparison with statistical analysis will be completed at that time. Although most participants disagreed that palliative care is not consistent with curative care and that early palliative care does not induce parental anxiety, yet is perceived by the lay public as end-of-life care. Strong agreement was demonstrated with items regarding integration of palliative care early in the disease trajectory to decrease suffering. Participants also predominantly agreed that education for patients/families and staff/faculty would ameliorate misconceptions about palliative care. Future evaluation after increased palliative care penetration will provide comparison data.
TBIO-03. Angiogenesis in Pituitary Adenoma
Authors: Yoshida Daizo , Nomura Ryutaro , Teramoto Akira
Published: June 2022

The role of angiogenesis in pituitary tumor development used to be questioned, since pituitary tumors have been usually found to be less vascularized than the normal pituitary tissue. Nevertheless, a significantly higher degree of vasculature has been shown in invasive or macropituitary prolactinomas when compared to nonin- vasive and microprolactinomas. We should know VEGF was found firstly in pituitary anterior lobe, then tumor angiogenesis must occur. Meanwhile the vascular arrange- ment raised by VEGF is irregular, that sometimes lead to pituitary apoplexy. In this chapter, hypoxia inducible factors (HIF), transcription factors regulating expression of several genes related to oxygen homeostasis are in response to hypoxic stress. We focus on tumor angiogenesis regulated by the signaling cascade in tumor angiogenesis in pituitary tumor.