bluuebunny/crossref_metadata_2025 huggingface dataset:
LMIC-02. FREQUENCY OF NTRK FUSIONS IN PEDIATRIC LOW GRADE GLIOMAS. DATA FROM A SINGLE CENTER IN MONTERREY, MEXICO
Authors: Leal-Cavazos Carlos A , Arenas-Ruiz Jose A , Vidal-Gutierrez Oscar
Published: June 2024

BACKGROUND

Neurotrophic tyrosine receptor kinases (NTRK 1-3)fusions have been identified in a range of pediatric cancer. Among children with cancer NTRK fusions can be detected in less than 1% of cases. Low grade gliomas (LGG) are the most pediatric brain tumors and the frequency of NTRK fusions reported is between 0.4 -4.3%. NTRK2 fusions are the most commonly reported in pediatric brain tumors.

METHOD

We describe the characteristics of patients analysed. Due to limited access to Next Generation Sequencing (NGS) only patients with recurrent, progressive, metastatic or midline location LGG were tested during 2021-2022. Positivity to Pan-Trk immunohistochemistry was needed to proceed to confirmation with NGS. 10 patients with LGG were included. Median age of patients at baseline was 4.7 (range,1-12) years. 10/10 showed positivity to Pan-Trk stain and NTRK fusions were detected in 6/10 patients, 3/6 had NTRK1 fusions, 2/6 NTRK2 fusion and 1 with NTRK3 fusion.. All 4 patients without NTRK fusions are off therapy (more than 1 year survellaince) and 2/4 were treated with surgery only. All patients with NTRK fusions are still on treatment due to progressive disease, 4/6 patients have required 2 or more surgeries and 5/6 patients have needed 2 or more chemotherapy regimens.

CONCLUSION

This small cohort of patients represents a highly selected population with LGG and the frequency of NTRK fusions resulted significantly higher than expected (6 out of 10 patients tested). This finding could reflect a clinical or prognostic significance, it will be important to analyze a larger cohort of patients that share these same clinical characteristics to determine its real value as a prognostic marker in these heavily treated patients. There is well known molecular alterations that predict outcome in patients with LGG. NTRK targeted therapy already exists with proven efficacy although access may limits its use.
LMIC-04. BUILDING PEDIATRIC NEURO-ONCOLOGY CAPACITY IN LMICS THROUGH MULTIDISCIPLINARY EDUCATION AND COLLABORATION
Authors: Moreira Daniel , Andujar Allyson , Qaddoumi Ibrahim
Published: June 2024

BACKGROUND

The St. Jude Global Academy Neuro-Oncology Training Seminar (NOTS) is a course in pediatric neuro-oncology (PNO) designed for physicians from low-income and middle-income countries. The curriculum was systematically designed and includes 9 weeks of online learning and a 5-day in-person workshop. The NOTS has been run 3 times: 2019, 2022, and 2023. We sought to evaluate the outcomes of these courses.

METHODS

After the initial course where institutions were invited, applying institutions were selected based on the size of the neuro-oncology program, multidisciplinary representation, and perceived impact of the course. Data on course participants have been prospectively collected. A survey evaluating course impact was completed by graduates.

RESULTS

For 2022, 51 institutions from 29 countries applied and 15 were selected. In 2023, 60 institutions from 31 countries applied and 18 were selected. Overall, 41 institutions from 29 countries have participated in NOTS. Furthermore, 191 individuals, including 68 pediatric oncologists, 37 neurosurgeons, 22 radiation oncologists, 19 radiologists, 18 pathologists, and 27 other specialists have participated. Survey responses (n=39) describe that 47% did not have multidisciplinary tumor boards (MDTB) before NOTS. 55% of those institutions now have MDTB, all claiming to be influenced by their participation in NOTS. 89% of participants claim that multidisciplinary communication improved after the course. The participants of NOTS have continued to be engaged beyond the course through the creation of the Global Alliance in Pediatric Neuro-Oncology (GAPNO). GAPNO workstreams have included monthly cases discussions, a multisite retrospective review of medulloblastoma outcomes collecting >300 patients in 8 countries, and the design of a comprehensive tool to evaluate PNO services.

CONCLUSIONS

A multidisciplinary course focused on pediatric CNS tumors care for resource-limited settings can help expand international engagement in PNO. Furthermore, through multidisciplinary collaboration, the PNO community can be galvanized to expand activities in capacity building.
LMIC-07. OUTCOMES OF NEUROFIBROMATOSIS TYPE 1-ASSOCIATED OPTIC PATHWAY GLIOMAS AT A SINGLE TERTIARY PEDIATRIC ONCOLOGY CENTER IN EGYPT: BORG EL ARAB UNIVERSITY HOSPITAL (BAUH) EXPERIENCE
Authors: Omran Nuha , Bahaie Nourelhoda S , Fadel Shady
Published: June 2024

BACKGROUND

Neurofibromatosis type 1 (NF-1) is a multisystem disease inherited in an autosomal dominant fashion. About 15% of the pediatric cases have associated brain tumors, among which the optic pathway gliomas (OPG) remain the most common. Due to their location, OPG can cause visual impairment, and endocrinal dysfunction, hence requiring therapeutic interventions, more commonly in sporadic non-NF-1 cases.

METHODS

NF-1 children with associated OPG followed at a single tertiary pediatric oncology center since its establishment from 2018 to 2023 were retrospectively evaluated.

RESULTS

Forty patients were identified either as firstly diagnosed NF-1 cases in our center or referred to us for follow up. Twenty-three of them who had associated OPG (mean age at diagnosis 83.7 months) were included in our study. The commonest clinical presentation was the bilateral initial visual affection occurring in 13 patients. Six had hormonal imbalance and four presented with seizures. Biopsy was taken only in 30%, with histopathology being mainly pilocytic astrocytoma. In terms of treatment, 10 cases received only one line of chemotherapy, six patients were kept on follow up, and the rest received more than one line of therapy. Overall survival (OS) was 100% throughout the study period, and progression-free survival was 64.1% at 1.5 years, and 46.8% at 5 years. Visual assessment at the end of treatment was stable in 71%, better in 22%, and worse in 7% of cases. Same pattern was observed in MRI assessment post therapy showing 57% stable disease, 39% regression, and 4% progression.

CONCLUSIONS

Survival of children with OPG is different in every center of the world as decisions regarding their management being challenging. Therefore, NF-1 multidisciplinary clinics are important to be established, with a high emphasis on early detection and referral of patients, standardization of symptoms grading and indications to start treatment.
LMIC-08. NEUROSURGERY UTILIZATION RATE FOR PEDIATRIC LOW-GRADE GLIOMA: A SIMULATION-BASED ANALYSIS
Authors: Boop Scott , Bhakta Nickhill , Bolous Nancy S , Moreira Daniel
Published: June 2024

BACKGROUND

The outcomes of pediatric low-grade glioma (pLGG) are markedly influenced by accessibility to neurosurgical services. Even when clinically recommended, neurosurgical interventions might not be feasible when there is scarcity in qualified medical professionals and preparedness of medical facilities, which is the case in many low- and middle-income countries (LMICs). To aid cancer control planning efforts and guide policy makers and clinicians to prioritize allocation of resources, accurate neurosurgical utilization rate (NUR) estimations are crucial. This study developed a model to estimate the NUR, to facilitate the approximation of neurosurgery needs for pLGG.

METHODS

A decision tree model was developed to assess the NUR in HICs and LMICs. Patients were classified into five groups based on the anatomic site of the tumor. For each type of cancer, patients had three surgical options, gross total resection, subtotal resection, and biopsy. Anatomic distribution and likelihood to perform surgical resection were retrieved from the literature for both HICs and LMICs.

RESULTS

Findings showed discrepancy in the anatomic distribution of pLGG in HICs and LMICs. Proportion of patients with cerebral hemisphere, cerebellum, OPHG/diencephalon, brainstem, and spine tumors and their likelihood to undergo surgical intervention were 34% | 28%, 32% | 27%, 17% | 4%, 12% | 3% and 5% | 4% in HICs, and 26% | 22%, 39% | 32%, 26% | 5%, 6% | 2% and 3% | 2% in LMICs, respectively. Overall, NUR in pLGG patients was 66% in HICs and 63% in LMICs.

CONCLUSION

Despite the limited resources in LMICs, the overall proportion of patients recommended to undergo a surgical intervention is comparable to HICs. For this need to be met, long-term planning need to take place at the policymaking level. It is possible to estimate the NUR for all pediatric CNS tumors following the same approach to more comprehensively estimate the neurosurgical needs of this patient population globally.
LMIC-09. CRADLE TO CRAYON: THE IMPACT OF COLLABORATION ON PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS IN GHANA
Authors: Schandorf Ernestina N B , Quarcoopome Mary-Ann Dadzie , Gbadamosi Hafisatu , Renner Lorna A , Bouffet Eric , Bankah Patrick E
Published: June 2024

BACKGROUND

A multidisciplinary team (MDT) approach is essential for quality care, especially in paediatric oncology. In developing countries like Ghana, paediatric neuro-oncology is a relatively young subspecialty and requires a multidisciplinary team approach. The St Jude Global Academy Neuro-Oncology Training Seminar in 2022 saw a significant milestone in this MDT journey. Four MDT members benefited from the training, with a profound impact. This study aims to study the effect of neuro-oncology training on the number of CNS cases reviewed at MDT meetings.

METHODS

A retrospective review of case announcements made on the Pediatric Oncology MDT WhatsApp group page were collated spanning the period August 1, 2022, to July 31, 2023. Tumour distribution of cases discussed at MDT was compared 4 months pre- and 4- and 8-months post-St Jude Global Academy Neuro-Oncology Training Seminar (NOTS) completion in November 2022. A T-test was used to calculate for statistical significance of the difference in the number of cases discussed over the period.

RESULTS

A total of 208 cases were discussed after 52 MDT Zoom meetings. The number of cases discussed at MDT increased from 40 recorded in the first four months (August -November 2022) to 89 cases in the last four months (April- July 2023). There was a significant increase in the number of CNS cases discussed by 3.9% (p=0.012) at 4 months and 6.6% (p=0.023) at 8 months after NOTS. The complexity of CNS tumours discussed also increased.

CONCLUSIONS

The St Jude Global NOTS positively influenced the number of CNS cases discussed at MDT. Multidisciplinary team discussions allow for collations of ideas from all specialists with a patient-centred approach which is particularly invaluable to the care of neuro-oncology patients. Further studies on the effect on time of plan implementation, and client satisfaction will be beneficial to evaluate the effectiveness of our MDTs.
LMIC-14. MAPPING THE REFERRAL PATH - HURDLES IN PEDIATRIC BRAIN TUMOR DIAGNOSIS: A PERSPECTIVE FROM TERTIARY CANCER CARE CENTRE IN A LOW MIDDLE-INCOME COUNTRY
Authors: K Vasudeva Bhat , V Archana M , Vellu Umesh , Bharadwaj Vishnu , V Vinay M , T Harish Varma , Rahiman Emine A , M Swathi P , Qaddoumi Ibrahim , Salman Zeena , Dhall Girish , Menon Girish
Published: June 2024

BACKGROUND

Delayed referral remains leads to worse outcomes for children with cancer in low- and middle-income countries (LMIC), especially for patients with brain tumors. Delay in treatment could be due to the ignorance from the families to seek health care advice or lack of awareness of primary care physician.

METHODS

A retrospective study was conducted to delineate the referral path of children with brain tumors who presented to our institution. Patients <18 years with brain tumors registered from June 2022-December 2023 were included. Patients with relapsed disease, second opinion, or partially treated in an outside institute prior to referral were excluded. Data were captured using a proforma after obtaining permission from Institutional ethics committee.

RESULTS

Thirty-one children were enrolled with a median age of 5 years (range: 0-17) with M: F ratio of 1.58:1. The most common diagnosis in this cohort was medulloblastoma in 13(42%) followed by high grade glioma in 7(22%) and low-grade glioma in 4 patients (13%). Twenty-four (77%) belonged to low socio-economic strata defined by Modified Kuppuswamy classification, of which 22 (71%) were hailing from rural area with median distance from cancer center being 121 miles (range: 4.34 -242). Median of 3 (range: 1-6) consultations were sought prior to being referred to us and about 11 (35%) had visited alternative system of medicine before consulting us. Mean delay from symptom onset to diagnosis was 52 days (range: 2-530) with healthcare seeking delay of 5.4 days (Range: 0-30) and health system delay of 46 days (range: 1-500). The factors influencing delay included rural background (p=0.04) and lower socioeconomic strata (p=0.03).

CONCLUSIONS

Health system delay was a major cause of delayed referral in our study. By improving awareness of the primary care physicians about symptomatology of pediatric brain tumors, the referral pathway can be expedited thereby improving the outcomes of these children.
LMIC-17. DIAGNOSTIC DELAY IN CHILDREN WITH CNS TUMORS IN A TERTIARY HOSPITAL IN MEXICO
Authors: de la Peña-Hernández Beth Sainz , Arreguín-González Farina , Valdéz-Orduño Ricardo , Almazán-García Blanca , Sandoval-de Jesús San Juanita , Baños-Rodríguez Eduardo , López-Azcárraga Alejandra , García-Ramos Jeannie , Sebastian-Barajas Ruben , Ochoa-Madrigal Georgina , Moreira Daniel , Benito-Reséndiz Alma
Published: June 2024

BACKGROUND

Delays in diagnosis of central nervous system (CNS) tumors have been associated with increased morbidity and mortality. We aimed to describe the time intervals for diagnosis and explore factors related to diagnostic delays in a tertiary public hospital in a middle-income country.

METHODS

A retrospective study was carried out, collecting data from patients diagnosed with brain tumors between 2000 and 2021 at the National Medical Center “20 de Noviembre” in Mexico City. The data were analyzed using descriptive statistics.

RESULTS

Data were collected from 163 patients with a median age of 8 years (range 0-18 years). 81 (49.7%) patients were diagnosed with gliomas, 47 (28.8%) with embryonal tumors, 20 (12.3%) with ependymomas, 10 (6.1%) with germ cell tumors of the central nervous system, 3 (1.8%) with choroid plexus carcinoma, and 2 (1.2%) with other diagnoses. The median time of symptom start and first visit with a physician was 20 days (rage 1 to 180 days). The median time in which the patients arrived at the tertiary hospital after the first visit to a physician was 184 days (range 1 to 2520). The population served by the institution, included the 32 states, with 153 patients (93.9%) coming from an urban location, with easy access to medical services. 145 (89%) of the 163 patients had parents with a medium socio-economic level (urban housing, all basic services, at least one of the parents with higher education.) Of the patients studied, 75 (46%) died, 18 (11%) abandoned treatment, 65 (39.9%) survived and 5 (3.1%) were lost to follow-up.

CONCLUSION

An important delay was found in the start of treatment from the moment patients begin symptoms. The identified delays warrant local and national strategies that allow prompt referrals.
LMIC-18. RESOURCES FOR THE PRACTICE OF PEDIATRIC NEURO-ONCOLOGYIN MEXICO: A CROSS-SECTIONAL EVALUATION
Authors: Arce-Cabrera Daniela , Escamilla-Asiain Gabriela , Nájera-Castillo Melisa , Campo Regina Navarro-Martín del , Ortiz-Azpilcueta Mariana , Pantoja-Guillén Francisco , González Farina Arreguín , Zapata-Sosa Imelda , Lugo-Juárez Jocelyn , Santillán-Cortés Daniel , La Madrid Andrés Morales- , Moreira Daniel , Benito-Reséndiz Alma
Published: June 2024

BACKGROUND

The evaluation of existing resources and services is key to identify gaps and prioritize interventions to expand care capacity for children with central nervous system (CNS) tumors. We sought to evaluate the resources for pediatrc neuro-oncology (PNO) in Mexico.

METHODS

A cross-sectional online survey with 35 items was designed to assess PNO resources and services. The survey was distributed to the members of the Mexican Association of Pediatric Oncology and Hematology (AMOHP).

RESULTS

Overall, responses from 33 institutions were obtained. Responding institutions covered 9 healths systems in Mexico, including private and public institutions. Most of the participating centers have at least 2 pediatric oncologists, so in up to 42% of cases, the approach to children with brain tumors is initiated by a pediatric oncologist. Only half of the responding centers have complete chemotherapy treatments. Only 18% of the centers had access to targeted therapy. The majority (88%) of institutions had a blood bank, but 4 of the participating centers did not have a PICU. All centers have a pathologist but only perform basic immunohistochemistry techniques and have an average diagnostic timeframe of 2 weeks. Surgical treatment is usually available 8 to 14 days after the patient is admitted in 45% of centers. Some centers have radiotherapy available at the facility, others must be sent to other hospitals, but most (42%) can start radiotherapy within the first week after treatment is requested. Infectious processes are a common cause of death in children with brain tumors and only the centers have a half-integrated palliative care team.

CONCLUSIONS

This is the first situational overview of the resources available in Mexico, showing disparities in resource capacity and lack of a specific and efficient diagnosis that allow early initiation of treatmen. These data will allow for the prioritization of interventions.
LMIC-20. REAL-WORLD EXPERIENCE IN DEALING WITH CHILDREN WITH SUSPECTED CENTRAL NERVOUS SYSTEM (CNS) TUMORS AT THE CHILDREN’S HOSPITAL LAHORE (UCHS), PAKISTAN
Authors: Ain Rahat Ul , Rehman Laeeq Ur , Qaiser Rabia Aqeel , Hussain Mahwish , Goraya Amber , Zaman Samina , Ahmad Alia , Riaz Shazia , Faizan Mahwish , Salman Zeena , Qaddoumi Ibrahim , Mushtaq Naureen , Bouffet Eric
Published: June 2024

BACKGROUND

CNS tumors are the leading cause of cancer-related deaths in children in HICs, but data from LMICs are scarce. The objectives of this study were to document the trajectory of children with CNS tumors at a tertiary-care hospital in Pakistan.

METHODS

This prospective, analytic, cohort study recorded all new cases of suspected CNS tumors (birth to 16 years) presented from 2023/01/01 to 2023/12/31 at UCHS, Lahore.

RESULTS

A total of 145 cases were included. Median age at presentation was 7.0 years (1.5 months–15 years); male-to-female ratio was 1.4:1. Median time to presentation was 2 months (0.1 – 96 months); delay of >6 months was observed in 30.5% cases due to delayed presentation to medical facility (74%) and healthcare delay (26%). Headaches and vomiting (56%), focal neurological deficit (23%), and seizures (15%) were the most common presenting complaints. Consanguinity (46%), and family history of cancers (19%) were frequent; café au lait macules were observed in 9.7%. 50% tumors were infratentorial, 46% supratentorial and 4% spinal. Tumor excision was done in 45%, VP-shunts in 42%, and upfront chemotherapy in 2%. Only 60% had a final diagnosis. Tissue diagnosis in 39% cases showed Medulloblastoma (18 patients, 32%), Pilocytic Astrocytoma (27%), and High-grade glioma (16%) as the commonest diagnoses, while 21% had a radiological diagnosis based on CT/MRI features: DIPG/DMG (12%), Craniopharyngioma (7.6%), and Optic Pathway Glioma (1.4%). Of 18 medulloblastoma patients, only 7 received postoperative radiotherapy. Seventy (48%) patients expired (including 38 before surgery), 27% are on follow-up and 25% are LAMA/LTFU/defaulted treatment. One-year survival was 36% with median survival of 4 months (0.07-96 months).

CONCLUSION

Less than half of the patients with CNS tumors undergo active treatment, a large proportion leave treatment/follow-up and have poor overall survival. Considerable cases with cancer predisposition syndromes were suspected.
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

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

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< 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

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(<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 (>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

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

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

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<0.0001 and p<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<0.01 and p<0.001 respectively, MED813FH: p<0.05 and p<0.01 respectively and MED314mCLFH: p<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

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 >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

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

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 >97%. Isodose 95% covered the cribriform plate completely and optic nerves keeping Dmax to the lens <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 >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<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

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.
RADT-11. PROTON BEAM THERAPY (PBT) FOR CENTRAL NERVOUS SYSTEM (CNS) TUMOURS IN CHILDREN: A CANADIAN PEDIATRIC BRAIN TUMOUR CONSORTIUM STUDY
Authors: Wong Kendrew S K , Patel Samir , Lafay-Cousin Lucie , Logie Natalie , D’Alessandro Paul , Magimairajan Vanan , Cacciotti Chantel , Perreault Sebastien , Alves Melanie , Galopin Marie , Poirier Éloise , Skamene Sonia , Bergeron-Gravel Samuel , Lagacé Simon , Charpentier Anne-Marie , Erker Craig , Crooks Bruce , Rutledge Rob , Sandhu Ash , Brooks Beth , Lo Andrea C , Tsang Derek S , Cheng Sylvia
Published: June 2024

BACKGROUND

Radiotherapy is important for treating pediatric CNS tumours. The main modalities include photon therapy and PBT. PBT offers potential advantages over photon therapy in children since its precise dose control can limit long-term side effects. However, Canadian patients needing PBT are referred to the United States (US) because PBT is unavailable in Canada. We aimed to describe PBT use and outcomes over time for Canadian pediatric patients with CNS tumours.

METHODS

Patient demographics, treatment characteristics, and outcomes were extracted from medical records of patients from 10/13 Canadian provinces/territories. Patients diagnosed with a CNS tumour at ≤20 years old between 2001-2021 who received curative-intent PBT were included. PBT plans were compared using Fisher’s exact or Kruskal-Wallis rank sum tests. Overall survival (OS) was estimated using the Kaplan-Meier method.

RESULTS

Of 195 patients (59.0% male) included in the study, majority were from Alberta (28.7%), Quebec (26.7%), British Columbia (22.6%), and Ontario (20.5%). Median age at diagnosis was 8.0 years. Most tumours (77.9%) were non-metastatic. Medulloblastoma was the most common diagnosis (30.8%). Provinces/territories referred patients to proton centres in the same geographical regions, except Alberta (74.5% referred to Florida). Referral numbers have increased ~180%/year since 2011. Median time from diagnosis to PBT was 126 days [11-5236] for all patients, and 36 days [21-1313] for medulloblastoma. Radiation doses, irradiation site, therapy duration, and time to treatment were not different (p≥0.2) across all PBT facilities for medulloblastoma. 5-year OS were 86.8% and 73.0% for the PBT study population and the Cancer in Young People-Canada reference population, respectively, in those aged <15 years.

CONCLUSIONS

Given the unavailability of PBT in Canada, pediatric CNS tumour patients were referred to US PBT facilities close in proximity. Further studies are needed to better understand provincial referral patterns and barriers to equitable PBT access across Canada.