bluuebunny/crossref_metadata_2025_split huggingface dataset:
LMIC-22. TOWARD A COMPREHENSIVE PEDIATRIC BRAIN TUMOR REGISTRY: ESTABLISHING FUNDAMENTAL VALUE IN INDONESIA TERTIARY HOSPITAL
Authors: Rahmartani Ludi Dhyani , Budiarso Michael Nathaniel , Ilmana Ganda , Muhaimin Riski , Susanto Eka , Amal Mohamad Yanuar ,   Handoko., Nuryadi Endang , Rafli Achmad , Gunawan Kevin 
Published: June 2024

Abstract

BACKGROUND
Systematic documentation and research on pediatric brain tumor (PBT) have been underreported in Indonesia. Precise and readily available epidemiological data hold significant value in enhancing the PBT service of any center, each with its own distinctive characteristics. We aim to evaluate our PBT registry and service after Cipto Mangunkusumo National General Hospital utilized the St. Jude (SJ) Cares Registry program.

METHODS
A retrospective observational longitudinal study, carried out at Cipto Mangunkusumo National General Hospital, utilizing primary registry data encompassing patients’ profiles, diagnoses, and follow-up issues from January 2022 to December 2023, was performed. An evaluative review was then carried out to delineate our center’s unique problems and solutions to improve the overall PBT health services.

RESULTS
A total of 103 patients participated, dominated by females (55.3%), with a median age of 8 (IQR 4-12). The most identified diagnoses were gliomas (48.6%), germ cells (16.5%), and medulloblastomas (8.7%), with high-grade gliomas contributing to the most death (48.4%). The main symptoms contributing to the most extended diagnosis delay (from onset to diagnosis) were puberty issues, motoric paresis, vertigo, macrocephaly, proptosis, disequilibrium, and headache. Some critical findings from this registry evaluation were the mapping of patients’ key clinical symptoms and most diagnoses to be anticipated, factors related to diagnosis delay, and the numerous ineffective yet revisable health service systems that led to incomplete patient data and loss of follow-up. These led to our team’s effort to implement more effective multidiscipline communication (through regular synchronous and asynchronous meetings), orbit the pediatrician to become the St. Jude virtual fellow and recruit more trained data registry specialists.

CONCLUSION
In conclusion, as each center has unique problems in its own PBT health services, it is essential to have accurate registry data to be the fundamental value and starting point for comprehensively delineating and improving PBT service.
LMIC-23. PEDIATRIC CRANIOPHARYNGIOMA SURVIVAL OUTCOMES IN THE US-MEXICO BORDER: RESULTS FROM A CROSS-BORDER NEURO-ONCOLOGY PROGRAM
Authors: Crawford John R , Tenorio Alexander , Brandel Michael G , Produturi Gautam R , Gomez Rebeca Rivera , Roberts William , Gonda David , Levy Michael L , Aristizabal Paula 
Published: June 2024

Abstract

BACKGROUND
Management of pediatric craniopharyngioma requires complex, multidisciplinary care. Data on outcomes in low- and middle-income countries (LMIC) are lacking. To improve survival for children with brain tumors in the US-Mexico border, we established the Cross-Border Neuro-Oncology Program (CBNP) and facilitated access to high-complexity neuro-oncology for Mexican children.

METHODS
We retrospectively assessed clinical and surgical characteristics and progression-free survival (PFS) and overall survival (OS) in US and Mexican children who received neurosurgical intervention for craniopharyngiomas at Rady Children’s Hospital, San Diego (RCHSD) between January 2010 and December 2022. Patients either received follow-up care at RCHSD (RCHSD cohort) or returned to Hospital General, Tijuana (HGT), Mexico (HGT cohort) to continue care.

RESULTS
Thirty-five children with craniopharyngioma were included; 30 patients (mean age 8.7 years, 60% male) in the RCHSD cohort and five (mean age 14 years, 20% male) in the HGT cohort. The HGT cohort had longer symptom duration at presentation compared to the RCHSD cohort (24 weeks vs. 4 weeks, p=0.011). Pituitary dysfunction at diagnosis was observed in 20 (57%) patients, with growth hormone deficiency (n=17, 47%) being most common. Gross total resection was achieved in 32 (94%) patients. Seven (23%) patients in the RCHSD cohort received adjuvant therapies, compared to none in the HGT cohort (p = 0.6). Endocrine treatment compliance was lower in the HGT cohort vs..RCHSD cohort (50% vs. 100%, p=0.012). OS was significantly lower in the HGT cohort compared to the RCHSD cohort (67.3 months vs. N/A __ months, p&lt; 0.001), whereas PFS was not different between cohorts.

CONCLUSION
Despite providing access to complex neurosurgical care through the CBNP for Mexican children with craniopharyngioma, we demonstrated lower survival. To address this inequity, delayed presentation and post-operative endocrine management will be addressed through infrastructure enhancements, engaging a pediatric endocrinologist at HGT, and providing training in early-detection and management of complications.
LMIC-27. MEK INHIBITORS IN PEDIATRIC LOW-GRADE GLIOMAS (PLGG)- EARLY EXPERIENCE IN A RESOURCE LIMITED SETTING
Authors: Chinnaswamy Girish , Gollamudi Venkata Rama Mohan , Choudhari Amit , Prasad Maya , Dasgupta Archya , Chatterji Abhishek , Shah Aekta , Sahu Arpita , Bhattacharya Kajari , Singh Vikas , Sahay Ayushi , Shetty Prakash , Moiyadi Aliashgar , Gupta Tejpal , Sridhar Epari 
Published: June 2024

Abstract

BACKGROUND
Pediatric Low-Grade Gliomas (PLGG), encompass a heterogenous set of tumours, with upregulation of RAS/MAPK pathway, making them amenable to therapeutic targeting. MEK inhibitors are emerging as a promising alternative to conventional chemotherapy strategies which have modest efficacy with significant toxicity/hospitalisation and hence long periods of stay away from home (& school). Recently, we transitioned to use of MEK inhibitors, where feasible, in children with PLGG.

METHODOLOGY
Retrospective analysis of children(&lt;15 years) with newly diagnosed, recurrent/progressive PLGG who received Trametinib at Tata Memorial Hospital, India between September’2021-October’2023. Diagnosis of PLGG was by histopathology/radiology. Molecular testing was performed by qualitative real-time PCR for BRAFV600E and KIAA1549:BRAF fusion. Decision to start MEK inhibitors was taken at the Neuro-oncology MDT meeting. Financial support for therapy was provided through the childhood cancer foundation (ImPaCCT) and other agencies.

RESULTS
Twenty four children were treated with Trametinib, of which 22 were evaluable for response (&gt;3 months therapy). Median age at start of Trametinib was 6.4 years(2.3–14.5years). Histopathological confirmation of PLGG was done in 19 patients and 5 had a clinico-radiological diagnosis. 13/18(72%) had KIAA1549:BRAF fusion, and 5 were BRAF-Wild type. While 12/22 children received Trametinib as salvage therapy, 10 children received it upfront. 2 received Trametinib due to chemotherapy intolerance. At a median therapy duration of 18 months(3-28 months), 17/22(77%) showed stable disease and 3/22 showed response(2 Partial and 1 minor) as per RANO criteria. Two patients had disease progression [BRAF status included unavailable (n=1), wild-type (n=1)]. Toxicities noted were skin rash(n=8), paronychia(n=3), oral ulcers(n=2) & thrombocytopenia(n=1). Dose reduction due to toxicity was done in one child. School attendance increased and frequency of hospital visits significantly decreased in this cohort.

CONCLUSIONS
Early experience with Trametinib as an effective/well tolerated alternative to chemotherapy in PLGG is encouraging. Long-term treatment related toxicities and disease control after Trametinib withdrawal are yet unanswered questions.
MODL-08. PATIENT-DERIVED ORGANOIDS RECAPITULATE THE MOLECULAR LANDSCAPE OF PEDIATRIC BRAIN TUMORS
Authors: Ferreira Bárbara , Peixoto Joana , Ferro Anabela , Pinheiro Jorge , Silva Roberto , Pereira Josué , Oliveira Joana , Da Paula Arnaud Cruz , Soares Paula , Nunes Susana , Fernandes Ana Paula , da Costa Maria João Gil , Lima Jorge 
Published: June 2024

Abstract

BACKGROUND
Pediatric brain tumors (PBT) are the leading cause of non-accidental death in pediatric age. These tumors are rare and lack adequate experimental models capable of accurately capturing their complex molecular landscape.

METHODS AND RESULTS
Our team has established specific protocols for the generation and expansion of ex-vivo patient-derived organoids (PDO) from fresh surgical material of a variety of PBT, within a clinically relevant timeframe. These include pilocytic astrocytomas, a pleomorphic xanthoastrocytoma, a rosette-forming glioneuronal tumor, a supratentorial ependymoma, diffuse high-grade gliomas, a medulloblastoma, an atypical teratoid rhabdoid tumor, and a meningioma. The PDO cultures were set within 7-15 days, with organoids reaching 200-800 μm in diameter. Immunofluorescence analysis using confocal high-content microscopy imaging revealed that PDO kept the protein markers typically found in the corresponding primary tumors. Likewise, at a genomic level, PDO recapitulated the molecular landscape of corresponding primary tumors, as denoted by the maintenance of NF1, PIK3CA, and FGFR1mutations (rosette-forming glioneuronal tumor), KIAA1549::BRAF fusions (pilocytic astrocytomas), ZFTA::RELA fusion(supratentorial ependymoma) or gene amplifications, such as KRAS, CDK4, MDM2, GLI1, PTPN11 and PI3KCA. Additionally, PDO exhibited minimal genetic drift after over one month in culture. In three PBT cases from a medulloblastoma, an atypical teratoid rhabdoid tumor, and a meningioma, where no molecular alterations were detected using a comprehensive NGS panel, we are running DNA methylation arrays and copy number variations.

CONCLUSIONS
Our results underscore the potential of PDO as a robust ex-vivo experimental model. The generated PDO cultures can be rapidly established and retain key molecular features of corresponding primary tumors. This preclinical model presents versatile applications, serving as a valuable molecular tool for precision medicine approaches in PBT patients, the study of PBT biology, and the acceleration of drug development processes within the context of PBT.
MODL-10. COMPUTATIONAL DRUG SENSITIVITY PREDICTS TAILORED THERAPY FOR MEDULLOBLASTOMA SUBGROUPS
Authors: Jermakowicz Anna M , Ruiz Luz , Suter Robert , Ayad Nagi 
Published: June 2024

Abstract

BACKGROUND
Medulloblastoma is the most common malignant pediatric brain tumor. Tumors are typically characterized as SHH α- δ, WNT α-β, Group 3α- γ, or Group 4 α- γ. Current standard-of-care includes surgery, radiation, and chemotherapy; however, treatment response and prognosis vary widely between subgroups. Despite extensive characterization of medulloblastoma tumors into four molecular subgroups, few subgroup specific therapies have advanced to the clinic and a universal approach is unlikely to be effective due to the considerable intertumor heterogeneity of medulloblastoma. Hence, there is an urgent demand for innovative therapeutic strategies.

METHODS
To address heterogeneity between patients, we have developed a novel platform called DrugSeq, which predicts drug sensitivities in patients and is able to stratify drug response based on subgroup. We first calculated disease signatures for each patient by normalizing patient gene expression to median gene expression across the Cavalli dataset. Using previously developed transcriptional consensus signatures (TCSs), which contain genes that are consistently dysregulated following drug treatment, we then calculated the discordance between each patient disease signature and drug TCS. In doing so, we were able to identify drugs to target specific molecular subtypes based on Cavalli molecular classifications.

RESULTS
As a proof of concept we identified vismodegib and curcumin as selective for SHH-MB. Furthermore, we correlated predicted drug response with target protein expression. For example, we found that predicted sensitivity to vismodegib correlates closely with GLI1 protein expression.

CONCLUSIONS
Collectively, we show that DrugSeq may identify novel therapies and facilitate patient stratification in clinical trials, leading to more successful targeted medulloblastoma therapies.
MODL-16. CRANIOSPINAL RADIOTHERAPY IN COMBINATION WITH DNA-DAMAGE RESPONSE INHIBITORS IN PATIENT-DERIVED ORTHOTOPIC XENOGRAFT MODELS OF MEDULLOBLASTOMA
Authors: Hii Hilary , Howlett Meegan , Buck Jessica , Dholaria Hetal , Kuchibhotla Mani , Palanisamy Ranjith , Larder Sally , Whitehouse Jacqueline P , Carline Brooke , Ebert Martin A , Gottardo Nicholas G , Endersby Raelene 
Published: June 2024

Abstract

BACKGROUND
Despite treatment intensification, survival for high-risk subgroups of medulloblastoma (MB) such as MYC-amplified Group 3 (Gr3-II) and p53-mutant SHH (SHH-3p53mut) have remained dismal with overall survival around 40% and 20% respectively. Our previous studies have shown that the DNA-damage response inhibitors (DDRis) prexasertib and ceralasertib enhance the effects of CSI using medulloblastoma cell line-derived orthotopic mouse models. However, patient-derived orthotopic xenografts (PDOXs) are considered superior models for preclinical testing compared to immortalised cell lines. Here, we developed a CSI protocol for multiple PDOX models of high-risk medulloblastoma and tested the optimal protocol with concurrent DDRis.

METHOD
For our CSI optimisation studies, MED211FH (Gr3-II) or MED813FH (SHH-3p53mut) tumour-bearing mice were monitored for clinical symptoms of tumour before commencing treatment. Multiple, fractionated CSI dosing schedules using a 5-days-on, 2-days-off treatment cycle were trialled based on our lab’s previously established CSI protocols before a schedule of 10 x 0.5 Gy fractions (5.0 Gy total) proved optimal. This schedule was then used in both PDOX models plus an additional SHH-3p53mut model (MED314mCLFH), either alone or in combination with concurrent prexasertib or ceralasertib.

RESULTS
MED211FH and MED813FH mice treated with 5.0 Gy CSI alone resulted in significantly improved median survival compared to control mice (p&lt;0.0001 and p&lt;0.005 respectively) While 5.0 Gy CSI plus concurrent prexasertib or ceralasertib showed significantly improved survival when compared to CSI alone for each model used. MED211FH: p&lt;0.01 and p&lt;0.001 respectively, MED813FH: p&lt;0.05 and p&lt;0.01 respectively and MED314mCLFH: p&lt;0.05 for both DDRi combination groups.

CONCLUSION
Remarkably, concurrent use of prexasertib or ceralasertib with CSI significantly improved survival in fatal Gr3-II and SHH-3p53mut models. With these results, we provide robust preclinical evidence for radiosensitising use of DDRi in paediatric high-risk MB and recommend swift clinical translation.
RADT-01. TUMOR VOLUME INCREASE AND NEED FOR RADIOTHERAPY PLAN ADAPTATION IN PEDIATRIC HIGH-GRADE GLIOMA AND DIFFUSE MIDLINE GLIOMA DURING A SIX-WEEK COURSE OF RADIOTHERAPY
Authors: Hoeben Bianca A W , Peters Max , Seravalli Enrica , Willemsen-Bosman Mirjam , van Ommen Fasco , van der Lugt Jasper , Nievelstein Rutger A J , Mueller Sabine , Hulleman Esther , Hoving Eelco W , Janssens Geert O 
Published: June 2024

Abstract

BACKGROUND
Pediatric High-Grade Glioma/ diffuse midline glioma (pHGG/DMG) growth during a six-week course of radiotherapy may precipitate geographical miss of target volumes and early disease progression. In a patient cohort, we retrospectively evaluated the evolution of tumor volumes during radiotherapy, the clinical need for plan adaptation, and potential correlation with local disease progression.

METHODS
Twenty-four pHGG/DMG patients (12M/12F, ages 4-20 years) with gross tumor volume (GTV) after debulking (n=7) or biopsy (n=17) received 30 fractions of Volumetric Modulated Arc Therapy within an adaptive radiotherapy-protocol. The GTV was defined by combined T1+FLAIR MRI sequence abnormalities. A 1-cm margin was applied for Clinical Target Volume (CTV). MRI-based target volume re-evaluation was performed at fraction 10 and 20, defining GTV increase &gt;1mL as growth. The clinical need for plan adaptation was based on tumor volume changes. GTV increase and need for plan adaptation were evaluated against local progression-free survival (LPFS).

RESULTS
Median time between baseline MRI and radiotherapy start was 10 days (range 3-29). From baseline, GTV growth was observed in 7/24 patients at fraction 10, and in an additional 7/24 patients at fraction 20 (cumulative 14/24), corresponding to a mean volume increase of 21%/3.7mL (range [-7%/-2.7mL] to [+185%/24.4mL]) and 40%/8.7mL (range [-18%/-8.1mL] to [+329%/115.1mL]) after 10 and 20 fractions, respectively. At fraction 10 and 20, respectively 6 and 6 plans needed adaptation in a total of 11 patients. Baseline tumor volumes between patients with/without plan adaptation were equivalent. Median LPFS was 8.3 months (95%CI 8.0-12.7). No significant difference in LPFS was observed between patients with versus without GTV increase or plan adaptation.

CONCLUSIONS
Between MRI at baseline and at fractions 10 and 20, this adaptive radiotherapy protocol using 1-cm CTV margins demonstrated pHGG/DMG tumor volume increase with a clinical need for plan adaptations in 11/24 patients.
RADT-02. PROTON THERAPY IN PEDIATRIC ONCOLOGY IN SLOVAKIA: A COMPREHENSIVE ANALYSIS
Authors: Bublakova Estera , Hederova Stanislava , Kolenova Alexandra , Makohusova Miroslava 
Published: June 2024

Abstract

INTRODUCTION
Radiotherapy has been a cornerstone in pediatric oncology for decades. Recognizing the potential to mitigate side effects, proton therapy (PT) has gained prominence, becoming part of treatment in pediatric oncology in Slovakia since 2014.

METHODOLOGY
This retrospective analysis investigates a cohort of patients with CNS tumors treated at the National Institute of Children’s Diseases in Bratislava, who underwent PT at the Proton Center in Prague between 2014 and 2022.

RESULTS
Among 47 patients, embryonal tumors constituted the largest group (40%), followed by germ cell tumors (21%), ependymal tumors (19%), less common CNS tumors (10%), and glial tumors (8%). Acute complications included skin toxicity (38%), CNS toxicity (23%), GIT toxicity (14%), and blood count changes (8%). Notably, 22 patients experienced no acute toxicity. Late reactions, predominantly endocrine dysfunction (65%), featured central hypothyroidism (45%), ACTH deficiency (22%), GH deficiency (16%), and gonadotropin deficiency (10%). Ocular complications affected 55%, while tensive cephalea and post-radiation necrosis-related epileptic seizures were observed in limited cases. Disease recurrence was absent in 89% of patients, with 10% exiting due to disease progression.

CONCLUSION
This pioneering analysis highlights the unique experiences of Slovak pediatric patients undergoing PT at the Proton Center in Prague. The study emphasizes the dual impact of PT, enhancing survival rates while reducing adverse effects, thereby significantly contributing to a better quality of life for pediatric cancer patients.
RADT-06. ENCOURAGING OUTCOMES AFTER CRANIO-SPINAL IRRADIATION (CSI) WITH MODERN IMAGE GUIDED INTENSITY MODULATED PROTON THERAPY (IMPT) (IMPT-CSI) IN CHILDREN AND YOUNG ADULTS (AYA)- AN INSTITUTION EXPERIENCE
Authors: AS UDAY KRISHNA , KC Ganapathy , Das Anindita , S Preethi , Wakde Manoj , S Dayananda , C Srinivas , Jalali Rakesh 
Published: June 2024

Abstract

BACKGROUND
Outcomes of IMPT-CSI in children and adolescent-young adults (AYA) treated at our institute over a period of 5 years was analyzed

MATERIALS AND METHODS
92 children/AYA were treated by IMPT-CSI. PTV definition of the spine for skeletally immature patients was modified to only the vertebral body without isotropic margins. All plans were multifield optimized for 5 mm robustness (cranio-caudal) & 2.5% range uncertainty. The treatment set-up was confirmed by both orthogonal radiograph and CBCT. Toxicity was graded as per RTOG criteria.

RESULTS
Median CSI dose of 35GyE in 21 fractions was given to cohort with 74% males, median age of 7 years (2-39 years), consisting of Medulloblastoma (58%), other Embryonal tumours (20%), recurrent Ependymoma (10%), GCT (10%) and others (2%) with 18% being reirradiation and under sedation in 25%. Concurrent chemotherapy was given in 40%. The median V98% for clinical target volumes and V95% for PTVs of the brain, spine and craniospinal were &gt;97%. Isodose 95% covered the cribriform plate completely and optic nerves keeping Dmax to the lens &lt;3.9 GyRBE, critical OARs (mean of the cohort- Cochlea Dmax 28GyE, midline mucosa 23.2GyE, Esophagus 23.2GyE and gonads (testes and ovaries- 0GyE and 0.4GyE). The online set-up verification showed translational and rotational deviation within 2 mm and 0.5 in 94% and 97% of the cases. Radiation dermatitis was Grade 2-40%; Gr3-10%. Neutropenia was Grade 3 in 30%; few needed G-CSF. Less than 10% developed &gt;grade 3 significant weight loss/ anorexia/ mucositis. At median F/U 20 months (6–60m), 12 patients have progressed with PFS of 78% & OS of 87%, best in GCT and worst in Ependymoma (recurrent), 100% vs. 55% (p&lt;0.014)

CONCLUSION
Outcomes of IMPT-CSI in children and young adults, showed very encouraging dosimetry, toxicity profile and long-term survival.
RADT-07. CLINICAL RESULTS, ACUTE AND EARLY LATE TOXICITY AFTER PROTON RADIOTHERAPY FOR PEDIATRIC MEDULLOBLASTOMA, RETROSPECTIVE ANALYSIS
Authors: Ondrova Barbora , Sumerauer David , Zapotocky Michal , Hederova Stanislava , Jadrijevic-Cvrlje Filip , Pavelka Zdenek , Vlahova Irena , Andrlik Michal , Vondracek Vladimir , Landova Lucie 
Published: June 2024

Abstract
Craniospinal irradiation with boost to primary tumor site (and metastatic sites) is current radiotherapy standard for most patients diagnosed with medulloblastoma (MB). This treatment is effective, but survivors frequently develop long-term toxicity affecting the quality of life. Proton radiotherapy has the same efficacy compared to conventional photon-based techiques, but might achieve lower risk of toxicity. We retrospectivelly analyzed our cohort of patients irradiated for MB in our institution, using IMPT (intensity modulated proton therapy). Between May 2013 and December 2023 eighty patients (50 male, 30 female, median age at radiotherapy 8 years/range 3-17/) with primary or recurrent MB (not previously irradiated) were treated and included into analysis. 36 patients were treated for high-risk MB (mostly metastatic), 44 pts for SR disease. Neoadjuvant, concurrent and adjuvant systemic treatment was applied according to the protocol selected by the pediatric oncologist. All but one patients completed their treatment, acute toxicity including hematological was mild and lead to treatment interruption in seven cases. With a median of follow-up 39,6 months (range 3-119) 62 pts were in complete remission, 3 pts alive with disease, 14 died from disease progression and one died from complication (intracranial hemorrhage). We were able to identify two secondary malignancies potentially associated with IMPT (thyroid cancer, radiation induced high-grade glioma). Most common endocrinopathy observed in our patients was hypothyroidism and growth-hormon decifit. Due to lack of data, we were not able to analyze cognitive functions and quality of life. There was one case of severe brainstem necrosis with persistent neurological deficit, treated with corticosteroids and bevacizumab. Proton radiotherapy using IMPT for craniospinal irradiation in MB is feasible, treatment outcomes and toxicity are encouraging, although a longer follow-up is needed.